CN1242000A

CN1242000A - Farnesyl transferase inhibitors

Info

Publication number: CN1242000A
Application number: CN 97180944
Authority: CN
Inventors: J－D·博扎特; A·科姆康; N·德利; P·梅列特; F·索尼格－汤普森; J－P·马丁; M·卡佩特; M·切夫
Original assignee: Rhone Poulenc Rorer SA
Current assignee: Aventis Pharma SA
Priority date: 1996-12-30
Filing date: 1997-12-23
Publication date: 2000-01-19

Abstract

The invention relates to novel products of general formula , their preparation and compositions containing themPharmaceutical compositions containing them and their use in the manufacture of medicaments. In the general formula, Ar represents a substituted or condensed phenyl group or a polycyclic or heterocyclic aryl group, and R represents a general formula- (CH)₂)_m－X₁－(CH₂)_n-Z group, wherein X₁O, S, m =0,1, n =0,1,2, CH₂May be substituted, Z represents carboxyl, COOR₆,(R₆Alkyl group), CON (R)₇)(R₈)(R₇= hydrogen or alkyl), and R₈= hydrogen, hydroxy, arylsulfonyl, heterocyclyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkyl, amino, PO (OR)₉)₂(R₉= hydrogen or alkyl), -NH-CO-T (T = hydrogen or optionally substituted alkyl) or (II); R₁And R₂= hydrogen or halogen or alkyl, optionally substituted alkoxy, alkylthio, alkoxycarbonyl, or R in ortho position₁And R₂Constituting an optionally substituted heterocyclic compound containing 1 or 2 heteroatoms, R₃And R₄= hydrogen or halogen or alkyl, alkylene, alkoxy, alkylthio, carboxyl or alkoxycarbonyl, R₅= hydrogen, alkyl, alkylthio, X = O or S or-NH-, -CO-, methylene, vinyldiyl, alk-1, 1-diyl or cycloalkane-1, 1-diyl, and Y = O or S, the products of the general formula being in the form of the racemic or optically active isomers and also salts. The products of general formula are farnesase inhibitors which have remarkable antitumour and antileukemic properties.

Description

Farnesyl transferase inhibitors

The present invention relates to new benzo hexahydroisoindoline derivative, their preparation, the pharmaceutical composition that contains them and the application in the preparation medicine thereof.

Farnesyl transferase protein is a kind of enzyme, and the farnesyl group that it can the catalysis farnesyl pyrophosphate transfers to numerous protein, particularly expresses on the proteinic tetrapeptide array CAAX of the p21Ras terminal cysteine residue of oncogene ras.

People know that oncogene ras (H-, N-or K-ras) rises and does keying action in cell signal effect passage and fission process.Often the cancer with the people is relevant for oncogene ras sudden change or its overexpression: in many human cancers, p21Ras protein (people such as Kohl, science (Science), 260 of sudden change particularly in 50% above colorectal carcinoma and 90% pancreas cancer, have been found, 1834-1837,1993).

To the inhibition of farnesyl transferase, thereby the inhibition that the p21Ras protein method turns usefulness into has been blocked the sudden change protein induced cell proliferation of p21Ras and normal cell has been transformed into the ability of cancer cells.In addition, the inhibitor that has proved farnesyl transferase to the ras that do not express sudden change only scale reach ras, but the tumor cell line with oncogene sudden change or overexpression cancer protein also is active, wherein the signal effect passage of cancer protein utilizes proteinic farnesylation, as normal ras (people such as Nagasu, cancer research (Cancer Research) 55,5310-5314,1995; People such as Sepp-Lorenzino, cancer research 55,5302-5309,1995).

The inhibitor of farnesyl transferase is an inhibition of cell proliferation, is antitumor therefore and the leukemia agent.

Find that now theme also of the present invention just, following general formula (I) product innovation have farnesyl transferase very in surprise, unexpectedly and suppress active, demonstrating is significant antitumor and leukemia medicament.

Specifically,, find that the biological activity of The compounds of this invention is very good according to the present invention, and this beat all fully be owing to have the replacement of special groups (below represent) with Ar on 9 on benzo hexahydroisoindoline skeleton.

Particularly, to be much higher than up to now utilization structure close but do not have the activity of the compound of these substituent A r for the activity that has of corresponding compounds.

The present invention relates to the new compound of general formula I:

In the formula:

-Ar representative:

-by the one or more identical or different atoms or the phenyl of group replacement; described atom or group are selected from halogen atom and contain the alkyl such as the methyl of 1-4 carbon atom; the alkenyl that contains 2-4 carbon atom; hydroxyl; sulfydryl; alkylthio; alkyl sulphonyl or alkyl sulphinyl; amino; alkylamino; or dialkyl amido; formyl radical; alkyl-carbonyl; carboxyl; alkoxy carbonyl; formamyl; alkyl-carbamoyl or dialkyl amido formyl radical; cyano group or trifluoromethyl; the alkoxyl group such as the methoxyl group that contain 1-4 carbon atom; its moieties is randomly by perhalogenation; as trifluoromethoxy, or

-with contain one or more heteroatomss, have the phenyl of the heterocycle condensation of 4-7 chain link, wherein heteroatoms is selected from oxygen, nitrogen and sulphur, so the bicyclic system that forms can be selected from 2 especially, 3-dihydro-1,4-benzo two oxa-s English-6-base or 2,3-Dihydrobenzofuranes-5-base or 2,3-dihydrobenzopyrans-6-base or

Many cyclic groups of-aromatics or non-aromatics, as 1-or 2-naphthyl or 5-(2, the 3-indanyl), or 1,2,3,4-naphthane-6-base,

-contain the aromatics or the non-aromatic heterocycle of the one or more heteroatomic 5-12 of having chain links; wherein heteroatoms is selected from oxygen; nitrogen and sulphur atom; and heterocyclic radical is connected with condensed ring by C-C; described group can be replaced by one or more identical or different atoms or group if necessary; these atoms or group are selected from halogen atom and alkyl; the alkenyl that contains 2-4 carbon atom; hydroxyl; contain 1-4 carbon atom alkoxy; sulfydryl; alkylthio; alkyl sulphonyl or alkyl sulphinyl; amino; alkylamino or dialkyl amido; formyl radical; alkyl-carbonyl; carboxyl; alkoxy carbonyl; formamyl; alkyl-carbamoyl or dialkyl amido formyl radical; cyano group or trifluoromethyl

Preferably, Ar represents 2,3-dihydro-1, and 4-benzo two oxa-s English-6-base or 2,3-Dihydrobenzofuranes-5-base, or at 4 substituted phenyl, preferably by the phenyl of methyl, trifluoromethyl or methoxyl group replacement; Particularly 2,3-dihydro-1,4-benzo two oxa-s English-6-base; Highly beneficial ground, the Ar representative 4 by methyl substituted phenyl,

Wherein the alkyl of all these groups all contains 1-4 carbon atom,

-R represents the base of following general formula:

-(CH ₂) _m-X ₁-(CH ₂) _n-Z

In the formula:

-X ₁Represent singly-bound or oxygen or sulphur atom,

The integer that-m representative equals 0 or 1,

The integer that-n representative equals 0,1 or 2,

-one or more methylene radical can be replaced by carboxyl, alkoxy carbonyl, formamyl, alkyl-carbamoyl, dialkyl amido formyl radical, amino, alkylamino, dialkyl amido, and the alkyl of all these groups contains 1-4 carbon atom,

-Z representative:

-carboxyl,

-COOR ₆Group, wherein R ₆Representative contains the straight or branched alkyl of 1-3 carbon atom, as methyl, or

-Shi CON (R ₇) (R ₈) group, in the formula

-R ₇Represent hydrogen atom or contain the straight or branched alkyl of 1-6 carbon atom,

-R ₈Representative:

-hydrogen atom,

-hydroxyl,

-aryl sulfonyl, as phenyl sulfonyl, the aryl sulfonyl that is replaced by one or more identical or different atoms or group randomly, wherein atom or group are selected from halogen atom and alkyl, alkoxyl group, and the alkyl of all these groups contains 1-4 carbon atom,

-contain the heterocycle of the one or more heteroatomic 5-7 of having chain links, wherein heteroatoms is selected from nitrogen, oxygen or sulphur atom, and described heterocycle can connect by heteroatoms,

-randomly by the amino of one or two identical or different group replacement, described group is selected from:

-contain the alkyl of 1-4 carbon atom,

-aryl, as phenyl, the aryl that is replaced by one or more identical or different groups randomly, described group is selected from alkyl, alkoxyl group, and the alkyl of all these groups contains 1-4 carbon atom,

-contain one or more heterocyclic radicals that are selected from the heteroatoms of nitrogen, oxygen or sulphur atom and have the 5-7 chain link,

-aryl carbonyl as benzoyl, is randomly replaced by one or more identical or different groups, and this group is selected from alkyl, alkoxyl group, and the alkyl of all these groups contains 1-4 carbon atom,

-straight or branched the alkoxyl group that contains 1-6 carbon atom that randomly replaced by phenyl,

-contain the straight or branched alkyl of 1-6 carbon atom; as methyl; randomly replaced: amino by following groups; alkylamino; dialkyl amido; hydroxyl; the alkoxyl group that contains 1-4 carbon atom; sulfydryl; alkylthio; alkoxy carbonyl; carboxyl; cyano group; optional replace have a 5-12 chain link contain or do not contain one or more heteroatomic monocycles or polyaromatic; described heteroatoms is selected from oxygen; nitrogen and sulphur atom; described aryl can be 2-or 3-or 4-pyridyl especially; preferred 3-pyridyl or 4-pyridyl; or N-pyridine oxide; maybe can also be randomly by one or more halogen atoms or by one or more hydroxyls; the phenyl that amino or trifluoromethyl replace; or by one or more alkyl or alkenyl; alkoxyl group; alkylthio; alkylamino; alkyl-carbonyl or C2-C4 alkoxy carbonyl; formamyl; moieties is alkyl-carbamoyl or the dialkyl amido formyl radical of C1-C8; the phenyl of formyl radical or 1-naphthyl or 2-naphthyl substituted

Preferably, the R representation carboxy, or-the COOMe group or-CON (R ₇) (R ₈) group, wherein R ₇When representing hydrogen atom, R ₈The methyl that representative is replaced by the 3-pyridyl;

Highly beneficial ground, the R representation carboxy;

Special free burial ground for the destitute intentionally, R representative-CON (R ₇) (R ₈) group, wherein R ₇When representing hydrogen atom, R ₈The methyl that representative is replaced by the 3-pyridyl;

-Z representative:

-PO (OR ₉) ₂Group, wherein R ₉Represent hydrogen atom or contain the straight or branched alkyl of 1-6 carbon atom, or

-NH-CO-T group, the T straight or branched alkyl that contains 1-6 carbon atom representing hydrogen atom or randomly replaced wherein by amino, carboxyl, alkoxy carbonyl, hydroxyl, alkoxyl group, sulfydryl or alkylthio, or

Its gegenion is a negatively charged ion, as the trifluoromethanesulfonic acid radical ion,

All these that propose in the Z definition have in the group of alkyl, and alkyl contains 1-4 carbon atom.

-R ₁And R ₂Identical or different, they represent hydrogen atom, halogen atom or alkyl, alkoxyl group, as methoxyl group, each group is randomly replaced by dialkyl amido, wherein each moieties contains 1-4 carbon atom or constitutes the saturated heterocyclic of 5 or 6 chain links with nitrogen-atoms, or represent alkylthio, alkoxy carbonyl, or

R ₁And R ₂Be the ortho position each other, they constitute contains 1 or 2 heteroatomic saturated or unsaturated heterocycle, and its heteroatoms is selected from nitrogen and oxygen, and randomly replaced or replaced by alkyl or alkoxyl group by halogen atom,

Preferably, symbol R ₁And R ₂In one represent hydrogen atom, and the another one representation methoxy more advantageously is to be positioned at phenyl ring adjacent methoxyl group,

At R ₁And R ₂All these that propose in the definition have in the group of alkyl, and alkyl contains 1-4 carbon atom.

-R ₃And R ₄Identical or different; they represent hydrogen atom, halogen atom or alkyl, hydroxyl, alkoxyl group, alkyl carbonyl oxy, sulfydryl, alkylthio, alkyl sulphonyl or alkyl sulphinyl, amino, alkylamino or dialkyl amido, alkoxycarbonyl amino, carboxyl, alkoxy carbonyl, formamyl, alkyl-carbamoyl or dialkyl amido formyl radical, formyl radical, alkyl-carbonyl, cyano group or trifluoromethyl

Preferably, or R ₃And R ₄Each all represents hydrogen atom, or R ₃And R ₄In one represent hydrogen atom, and R ₃And R ₄In the another one representation methoxy, more advantageously be 5 at benzo hexahydroisoindoline nuclear;

Highly beneficial ground, R ₃And R ₄Each all represents hydrogen atom;

At R ₃And R ₄All that propose in the definition have in the group of alkyl, and alkyl contains 1-4 carbon atom.

-R ₅Represent hydrogen atom or alkyl, alkylthio, at R ₅In the definition, alkyl contains 1-4 carbon atom;

Preferably, R ₅Represent hydrogen atom or methyl;

Highly beneficial ground, R ₅Represent hydrogen atom;

-X represention oxygen atom or sulphur atom or-NH-,-CO-, methylene radical, alkene-1,1-two bases, as ethene two bases or contain the cycloalkanes-1 of 3-6 carbon atom, 1-two bases,

Preferably, X represents methylene radical or ethene two bases,

Particularly advantageously, X represents ethene two bases,

With

-Y represention oxygen atom or sulphur atom,

Preferably, the Y represention oxygen atom,

General formula (I) product is the salt of racemic form or their optically active isomer and general formula (I) product.

In front in definition and the following definition,

-" alkyl that contains 1-8 carbon atom ", or the group of " C1-C8 alkyl " or part be defined as methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group and corresponding iso isomer,

-" contain the alkyl of 1-6 carbon atom ", or the group of " C1-C6 alkyl " or part be defined as methyl, ethyl, propyl group, butyl, amyl group, hexyl and corresponding iso, sec, tert isomer,

-" alkyl that contains 1-4 carbon atom ", or the group of " C1-C4 alkyl " or part be defined as methyl, ethyl, propyl group, butyl and corresponding iso, sec, tert isomer,

-" alkenyl that contains 2-4 carbon atom " be defined as vinyl, allyl group, propylene-2-base, butene-1-Ji or-the 2-base or-3-base and corresponding iso isomer,

-" alkoxyl group that contains 1-4 carbon atom " is defined as methoxyl group, oxyethyl group, propoxy-, butoxy and corresponding iso, sec, tert isomer,

-" C2-C4 alkoxy carbonyl " is defined as methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl and corresponding iso, sec, tert isomer,

Preferably, compound of the present invention has general formula (I), in the formula:

Ar represents 2,3-dihydro-1, and 4-benzo two oxa-s English-6-base or 2,3-dihydro-1,4-cumarone-5-base, or preferably by methyl, trifluoromethyl, the methoxyl group phenyl 4 replacements,

The R representation carboxy, or-the COOMe group, or-CON (R ₇) (R ₈) group, wherein R ₇Represent hydrogen atom, R ₈The methyl that representative is replaced by the 3-pyridyl,

Symbol R ₁Or R ₂In one represent hydrogen atom, another one symbology methoxyl group, more advantageously, the representative at phenyl ring adjacent methoxyl group,

Or symbol R ₃Or R ₄In each all represent hydrogen atom, or symbol R ₃Or R ₄In one represent hydrogen atom, symbol R ₃Or R ₄Middle another one representation methoxy more advantageously, is represented the methoxyl group on 5 on benzo hexahydroisoindoline ring,

R ₅Represent hydrogen atom or methyl,

X represents methylene radical or ethene two bases,

The Y represention oxygen atom;

General formula (I) compound is racemic form or their optically active isomer and their salt.

According to the present invention, general formula (I) compound preferably is the dextrorotatory isomer form.

Owing to propose the technique effect of compound here, i.e. biological activity, may with as the substituent special properties of previously defined Ar relevant, so compound of the present invention particularly wherein R, R ₁, R ₂, R ₃, R ₄, R ₅, X and the defined general formula of Y such as front (I) compound, it is characterized in that the Ar representative:

-by the one or more identical or different atoms or the phenyl of group replacement; described atom or group are selected from halogen atom and contain the alkyl such as the methyl of 1-4 carbon atom; the alkenyl that contains 2-4 carbon atom; hydroxyl; sulfydryl; alkylthio; alkyl sulphonyl or alkyl sulphinyl; amino; alkylamino or dialkyl amido; formyl radical; alkyl-carbonyl; carboxyl; alkoxy carbonyl; formamyl; alkyl-carbamoyl or dialkyl amido formyl radical; cyano group or trifluoromethyl; contain 1-4 carbon atom alkoxy; as methoxyl group; its moieties is randomly by perhalogenation; as trifluoromethoxy, or

-contain the phenyl of the heterocycle condensation of the one or more heteroatomic 4-7 of having chain links, described heteroatoms is selected from oxygen, nitrogen and sulphur atom, so the bicyclic system that generates can be selected from 2 especially, 3-dihydro-1,4-benzo two oxa-s English-6-base or 2,3-Dihydrobenzofuranes-5-base or 2,3-dihydrobenzopyrans-6-base or

-aromatics or the many cyclic groups of non-aromatics, as 1-or 2-naphthyl, or 5-(2, the 3-indanyl) or 1,2,3,4-naphthane-6-base,

-contain one or more oxygen that are selected from; the heteroatomic aromatics or the non-aromatic heterocycle of nitrogen and sulphur with 5-12 chain link; this group is connected with condensed ring by C-C; described group if necessary can be replaced by one or more identical or different atoms or group; described atom or group are selected from halogen atom and alkyl; the alkenyl that contains 2-4 carbon atom; hydroxyl; the alkoxyl group that contains 1-4 carbon atom; sulfydryl; alkylthio; alkyl sulphonyl or alkyl sulphinyl; amino; alkylamino or dialkyl amido; formyl radical; alkyl-carbonyl; carboxyl; alkoxy carbonyl; formamyl; alkyl-carbamoyl or dialkyl amido formyl radical; cyano group or trifluoromethyl

Preferably, Ar represents 2,3-dihydro-1, and 4-benzo two oxa-s English-6-base or 2,3-Dihydrobenzofuranes-5-base, or preferably by methyl, trifluoromethyl or the methoxyl group phenyl 4 replacements; More preferably 2,3-dihydro-1,4-benzo two oxa-s English-6-base; Highly beneficial ground, Ar represents by the phenyl of methyl 4 replacements.

Following compound of Formula I has very special meaning,

In the formula:

-Ar representative

-by the one or more identical or different atoms or the phenyl of group replacement; described atom or group are selected from halogen atom and alkyl, contain the alkenyl of 2-4 carbon atom, hydroxyl, the alkoxyl group that contains 1-4 carbon atom, sulfydryl, alkylthio, alkyl sulphonyl or alkyl sulphinyl, amino, alkylamino or dialkyl amido, formyl radical, alkyl-carbonyl, carboxyl, alkoxy carbonyl, formamyl, alkyl-carbamoyl or dialkyl amido formyl radical, cyano group or trifluoromethyl, or

-polyaromatic, as 1-or 2-naphthyl or 5-(2, the 3-indanyl), or

-contain one or more oxygen that are selected from; the heteroatomic aromatic heterocyclic radical of nitrogen and sulphur atom with 5-12 chain link; it is connected with condensed ring by C-C; described group if necessary can be replaced by one or more identical or different atoms or group; described atom or group are selected from halogen atom and alkyl; the alkenyl that contains 2-4 carbon atom; hydroxyl; the alkoxyl group that contains 1-4 carbon atom; sulfydryl; alkylthio; alkyl sulphonyl or alkyl sulphinyl; amino; alkylamino or dialkyl amido; formyl radical; alkyl-carbonyl; carboxyl; alkoxy carbonyl; formamyl; alkyl-carbamoyl or dialkyl amido formyl radical; cyano group or trifluoromethyl

The alkyl of all these groups contains 1-4 carbon atom,

-R represents the group of following general formula:

-(CH ₂) _m-X ₁-(CH ₂) _n-Z

In the formula:

-X ₁Represent singly-bound or oxygen or sulphur atom,

The integer that-m representative equals 0 or 1,

The integer that-n representative equals 0,1 or 2,

-methylene radical can be replaced by carboxyl, carbalkoxy, formamyl, alkyl-carbamoyl, dialkyl amido formyl radical, amino, alkylamino, dialkyl amido, and the alkyl of all these groups contains 1-4 carbon atom,

-Z representative:

-carboxyl,

-COOR ₆Group, wherein R ₆Representative contains the straight or branched alkyl of 1-3 carbon atom, or

-Shi CON (R ₇) (R ₈) group, in the formula

-R ₈Representative:

-hydrogen atom,

-hydroxyl,

-amino, alkylamino or dialkyl amido, its alkyl contains 1-4 carbon atom,

-contain the straight or branched alkoxyl group that is randomly replaced of 1-6 carbon atom by phenyl,

-contain the straight or branched alkyl of 1-6 carbon atom; preferred methylene radical; randomly replaced: amino by following group; alkylamino; dialkyl amido; hydroxyl; the alkoxyl group that contains 1-4 carbon atom; sulfydryl; alkylthio; alkoxy carbonyl; carboxyl; cyano group; the substituted in case of necessity 5-12 of having chain link contain or do not contain one or more heteroatomic lists-or polyaromatic; described heteroatoms is selected from oxygen; nitrogen and sulphur atom; this aryl can be by one or more halogen atoms or by hydroxyl; the phenyl that amino or trifluoromethyl replace; or by alkyl or alkenyl; alkoxyl group; alkylthio; alkylamino; alkyl-carbonyl or C2-C4 alkoxy carbonyl; formamyl; C1-C8 alkyl-carbamoyl or two C1-C8 alkyl-carbamoyls; the phenyl that formyl radical or naphthalene-1-base or naphthalene-the 2-base replaces

-Z representative:

Propose in all groups with alkyl when definition Z, alkyl has 1-4 carbon atom.

-R ₁And R ₂Identical or different, they represent hydrogen atom, halogen atom or alkyl, the randomly alkoxyl group that is replaced by dialkyl amido (wherein each moieties contains the 1-4 carbon atom or constitutes the saturated heterocyclic of 5 or 6 chain links with nitrogen-atoms), alkylthio, alkoxy carbonyl, or

R ₁And R ₂Be the ortho position each other, they constitute contains 1 or 2 saturated or unsaturated heterocycle that is selected from nitrogen and oxygen heteroatom, and this heterocycle is randomly replaced by halogen atom or replaced by alkyl or alkoxyl group,

All these are at R ₁And R ₂In the group with alkyl that proposes in the definition, alkyl contains 1-4 carbon atom.

-R ₃And R ₄Identical or different; they represent halogen atom or alkyl, hydroxyl, alkoxyl group, alkyl carbonyl oxy, sulfydryl, alkylthio, alkyl sulphonyl or alkyl sulphinyl, amino, alkylamino or dialkyl amido, alkyl carbonyl oxy amino, carboxyl, alkoxy carbonyl, formamyl, alkyl-carbamoyl or dialkyl amido formyl radical, formyl radical, alkyl-carbonyl, cyano group or trifluoromethyl

At R ₃And R ₄All that propose in the definition have in the group of alkyl, and alkyl contains the 1-4 carbon atom.

-R ₅Represent hydrogen atom

-X represention oxygen atom or sulphur atom or-NH-,-CO-, methylene radical, alkene-1,1-two bases as ethene two are basic or contain the cycloalkanes-1 of 3-6 carbon atom, 1-two bases,

-Y represention oxygen atom or sulphur atom,

General formula (I) product is racemic form or their optically active isomer.

As preferred compound of the present invention, more specifically enumerate the compound of Formula I that R wherein represents following chemical formula:

-(CH ₂) _m-X ₁-(CH ₂) _n-CONH-CH ₂-Ar′

Wherein m, n, X ₁Define as the front, and Ar ' preferably represents the phenyl that is randomly replaced by one or more groups, described group is selected from the alkoxyl group that contains 1-4 carbon atom, trifluoromethyl, 1-or 2-naphthyl, 2-or 3-furyl or 2-or 3-thienyl or 2-or 3-pyrryl or 2-or 3-indyl or 2-or 3-or 4-quinolyl or 1-or 3-or 4-isoquinolyl, 2-or 3-benzofuryl, 2-or 3-benzothienyl, 2-or 4-or 5-pyrimidyl, 2-or 3-pyrazinyl, 2-or 4-quinazoline, the 1-phthalazinyl, 2-or 3-or 4-(1, the 5-phthalazinyl), 2-or 4-imidazolyl, 2-or 4-thiazolyl or 2-or 3-or 4-pyridyl, 2, the 3-indanyl, chromanyl or sulfo-chromanyl.

As the limiting examples of claimed compound, can more specifically enumerate following compound:

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-(2-p-methoxy-phenyl) acryl-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(4-methylthio group phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-fluorophenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(3-p-methoxy-phenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-xylyl)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-xylyl)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 3a-N-benzylamino formyl radical-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole,

(3aRS, 4SR, 9SR, 9aRS)-and 3a-formamyl-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid benzyl ester,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid,

Above-claimed cpd is racemic form and their optically active isomer.

According to the present invention, can also enumerate being selected from following any general formula (I) compound:

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-(2-p-methoxy-phenyl) acryl-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-fluorophenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(3-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(3-p-methoxy-phenyl)-2-[(2-p-methoxy-phenyl) ethanoyl-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 3a-N-benzylamino formyl radical-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole,

(3aRS, 4SR, 9SR, 9aRS)-and 3a-formamyl-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(4-pyridylmethyl)-methane amide,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid methyl esters,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N ', N '-dimethyl methyl hydrazides,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-phenyl formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N ', N '-pentamethylene formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(p-methoxy-phenyl) acryl]-9-(4-tolyl)-3a-phenyl sulfonyl amino carbonyl-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(N-oxo-3-pyridyl) methyl-methane amide,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-(4-p-methoxy-phenyl) formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-methyl-N '-phenyl formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-(2-tolyl) formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-9-(2,3-dihydro-1; 4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-[N-(3-pyridylmethyl) methane amide

(3aRS, 4SR, 9SR, 9aRS)-9-(2,3-dihydro-1; 4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(2-thienyl methyl) methane amide

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(3,4, the 5-trimethylphenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-trifluoromethyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-trifluoromethyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-trifluoromethyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(4-pyridylmethyl)-methane amide,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-trifluoromethyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-benzoyl-formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-trifluoromethyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-phenyl-formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-naphthyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-naphthyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(5-methyl-2-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(5-methyl-2-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(4-bromo phenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(4-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-dichlorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-chloro-phenyl-)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(4-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-methoxyl group-3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-indyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-isopropyl phenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-isopropyl phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-ethylphenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-ethylphenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(2,3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(2,3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(2,3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(4-chloro-3-fluorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(4-chloro-3-fluorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(1,3-benzo two divinylene oxides-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-phenyl formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1R-benzo [f] isoindole-3a-hydroxamic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a--N '-(3-pyridyl) formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a--N-(3-thienyl methyl) methane amide,

(RS) and (SR)-2-{ (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-carbonylamino } phenylacetic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-Trifluoromethoxyphen-l)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-fluorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-fluorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-fluorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-N, N-dimethylaminophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-N, N-dimethylaminophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-aminophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(4-N, N-dimethylaminophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(4-cyano-phenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(3-cyano-phenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(3-hydroxyl-4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-4-methyl-9-(4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

Above-claimed cpd is racemic form or their optically active isomer and their salt.

Above with hereinafter, term " optically active isomer " or optical activity formal definition are the pure form of described optically active isomer or the mixture of optical isomers of " enrichment " randomly, promptly mainly contain described optically active isomer or described form.

More preferably, according to the present invention, can also enumerate being selected from following any general formula (I) compound:

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide,

(3aRS, 4SR, 9SR, 9aRS)-9-(2,3-dihydro-1; 4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-trifluoromethyl-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(2,3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl)-2-acryl]-4-methyl-9-(4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

Be racemic form or their optically active isomer and their salt.

As any particularly advantageous optically active isomer of general formula of the present invention (I) compound, can enumerate being selected from following compound:

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a--N-(3-pyridylmethyl)-methane amide dextrorotation enantiomorph,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a--N-(3-pyridylmethyl)-methane amide levo-enantiomer,

(3aRS, 4SR, 9SR, 9aRS)-9-(2,3-dihydro-1; 4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a--N-(3-pyridylmethyl)-methane amide dextrorotation enantiomorph

(3aRS, 4SR, 9SR, 9aRS)-9-(2,3-dihydro-1; 4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a--N-(3-pyridylmethyl)-methane amide levo-enantiomer

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-trifluoromethyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl)-2-acryl]-4-methyl-9-(4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph

Or their salt.

Can enumerate especially:

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph

Or its salt.

The applicant proposes to can be used for preparing the various operation scheme and the reaction intermediate of general formula (I) compound below without limitation.Certainly, using for reference these schemes and/or intermediate and formulating the similar approach that obtains these same compounds all is that those skilled in the art can reach.

According to the present invention, claimed new general formula (I) product, in the formula:

-Y represents oxygen or sulphur atom,

-X representative-CO-group, methylene radical, alkene-1,1-two is basic as ethene two bases, or contains the cycloalkanes-1 of 3-6 carbon atom, 1-two bases,

Can be by methyl esters or derivative such as the carboxylic acid halides or the acid anhydrides of the acid of following general formula (II), this acid,

In the formula :-R ₁, R ₂As the general formula I definition, and X such as front define, and-Y represents oxygen or sulphur atom, obtain with the reaction of following general formula (III) product,

In the formula:

-Ar, R, R ₃, R ₄And R ₅As the general formula I definition,

-G ₁Represent hydrogen atom (to work as G ₁When representing benzyl or benzyloxycarbonyl, in the presence of catalyzer, adopt hydrogenolysis, or work as G as palladium/carbon and so on ₁When representing uncle-butoxy carbonyl, ethylene oxy carbonyl or benzyloxycarbonyl, in acidic medium, adopt hydrolysis, by G wherein ₁Representative obtains this product as general formula (III) product of the amino-functional blocking group of benzyl, benzyloxycarbonyl, uncle-butoxy carbonyl or ethylene oxy carbonyl and so on).

Below, G ₁The definition of representing benzyl just as an illustration property provide; adopting the scheme as other amino-functional blocking groups of benzyl, benzyloxycarbonyl, uncle-butoxy carbonyl or ethylene oxy carbonyl and so on, all is apparent for those skilled in the art.

Usually, in organic solvents such as halogenated aliphatic hydrocarbon as methylene dichloride and so on, as 1-ethyl-3-[3-(dimethylamino) propyl group] carbodiimide hydrochloride, 1, the condensing agent of 3-dicyclohexyl carbodiimide or phosphofluoric acid benzotriazole-1-base oxygen three (dimethylamino) phosphine and so on exists down, randomly the activator as hydroxybenzotriazole and so on exists down, operate to the reaction mixture refluxed temperature at 0 ℃, allow general formula (II) product and general formula (III) product that are sour form react.

Usually, in organic solvents such as halogenated aliphatic hydrocarbon, to the reaction mixture refluxed temperature, operate, allow general formula (II) product and general formula (III) product that are methyl ester form react at 0 ℃ as diox or picture methylene dichloride and so on.

Usually, in the organic solvents such as halogenated aliphatic hydrocarbon of like methylene dichloride and so on, in the presence of alkali (tert-aliphatic amine), to the reaction mixture refluxed temperature, operate, allow general formula (II) product and general formula (III) product that are the carboxylic acid halides form react at 0 ℃.

Usually, in the organic solvents such as halogenated aliphatic hydrocarbon of like methylene dichloride and so on, in the presence of alkali (tert-aliphatic amine, pyridine or 4-dimethylaminopyridine),, allow general formula (II) product and general formula (III) product that are anhydride form react temperature 0-50 ℃ of operation down.

In addition, after II and III reaction, randomly can followingly carry out:

When R representative or contain-COOR ₆Or-PO (OR ₉) ₂, and R ₆And R ₉When representing alkyl,

-resulting product carries out saponification reaction obtaining the representative of R wherein or to contain general formula (I) product of carboxyl, or

-transform resulting product by nucleophilic reagent, to obtain wherein R representative or to contain-PO ₃H ₂General formula (I) product.

Usually, by mineral alkali as sodium hydroxide or salt of wormwood or yellow soda ash and so on, in the organic solvent of the ether of the alcohol of like methyl alcohol or ethanol and so on or like diox and so on, 20 ℃ to the solvent refluxing temperature, allow wherein R representative or contain general formula-COOR ₆The general formula of ester (I) product is saponified into wherein R representative or contains general formula (I) product of carboxyl.

Usually, in the presence of trialkyl halo silicomethane (trimethylammonium chloro silicomethane, trimethylammonium bromo silicomethane), in solvent as tetracol phenixin or acetonitrile and so on, under temperature 0-50 ℃, by effect as the nucleophilic reagent of trialkylsilkl (trimethyl silyl) halogenide (iodide) or sodium or lithium halogenide (sodium iodide) and so on, or by with alkali metal halide (sodium iodide) heating, then hydrolysis is with its R representative or contain general formula-PO (OR ₉) ₂The general formula of group (I) product changes into its R representative or contains PO ₃H ₂General formula (I) product.

The invention still further relates to following general formula (III) product:

In the formula:

-Ar, R, R ₃, R ₄And R ₅Define according to general formula I

-G ₁Represent hydrogen atom or as the amido protecting group of benzyl and so on.

According to the present invention, new general formula (I) product:

In the formula:

-Y represents oxygen or sulphur atom,

-X represention oxygen atom

Can be by the haloformate or the halo thiocarboxylic of following general formula (IV), obtain with the product reaction of general formula (III),

In the formula:

-Y represents oxygen or sulphur atom,

-R ₁, R ₂Define as the front,

-Hal represents halogen atom.

Usually, as the organic medium of diox-water mixture and so on or contain in the aqueous organic media, in the presence of mineral alkali (sodium hydroxide) or organic bases (triethylamine), under temperature 0-50 ℃, allow general formula (IV) halogenide and general formula (III) product react.

In the mode same, when R representative or contain-COOR with the front ₆Or-PO (OR ₉) ₂The time, can make resulting product carry out saponification, obtaining its R representative or to contain general formula (I) product of carboxyl, or resulting product is changed into its R representative or contains PO by nucleophilic reagent ₃H ₂The general formula of group (I) product.

According to the present invention, new general formula (I) product:

In the formula:

-Y represents oxygen or sulphur atom,

-X represents the NH base

Can be by the isocyanic ester or the lsothiocyanates of following logical formula V, with as the reaction of previously defined general formula (III) product obtain,

In the formula:

-Y represents oxygen or sulphur atom,

-R ₁And R ₂Define as general formula (I).

Usually, in inert organic solvents, in the presence of activator, under temperature 0-50 ℃, allow logical formula V product and general formula (III) product react as 4-dimethylamino-pyridine or 4-pyrrolidyl-pyridine and so on as tetrahydrofuran (THF) or toluene and so on.

After V and the II reaction, when the R representative or contain-COOR ₆Or-PO (OR ₉) ₂The time, R wherein ₆Or R ₉Represent alkyl, randomly then carry out the saponification reaction of resultant product, obtaining its R representative or to contain general formula (I) product of carboxyl, or then transform resulting product, represent or contain PO to obtain its R by nucleophilic reagent ₃H ₂The general formula of group (I) product.Under above-mentioned condition ,-COOR ₆Or-PO (OR ₉) ₂Optional respectively carboxyl and the PO of changing into ₃H ₂Group.

According to the present invention, new general formula (I) product, wherein:

-R represents the base of following general formula

-(CH ₂) _m-X ₁-(CH ₂) _n-Z

X wherein ₁, m and n such as front define,

Z representative-COOR ₆Base, and R ₆Representative contains the straight or branched alkyl of 1-3 carbon atom,

Can obtain through esterification by general formula (I) product of its Z representation carboxy.

Usually, in organic solvent as dimethyl formamide and so on, temperature 0-50 ℃ of down operation, in acidic medium by R ₆As the defined general formula R in front ₆-OH alcohol, or in alkaline medium (alkaline carbonate or alkaline earth metal carbonate are as cesium carbonate), represent the general formula R of halogen atom (iodine) by its Hal ₆-Hal alkyl halide carries out saponification reaction.

According to the present invention, new general formula (I) product, wherein:

R represents the group of following general formula

-(CH ₂) _m-X ₁-(CH ₂) _n-Z

X wherein ₁, m and n such as front define,

Z representative-CON (R ₇) (R ₈) group,

Wherein:

R ₇Represent hydrogen atom or contain the straight or branched alkyl of 1-6 carbon atom,

R ₈Represent hydrogen atom or contain the straight or branched alkyl that is randomly replaced of 1-6 carbon atom: amino by following groups, the alkylamino that contains 1-4 carbon atom, its each moieties contains the dialkyl amido of 1-4 carbon atom, the alkoxyl group that contains 1-4 carbon atom, the alkylthio that contains 1-4 carbon atom, its moieties contains the alkoxy carbonyl of 1-4 carbon atom, carboxyl, cyano group, the phenyl that is replaced by one or more identical or different groups randomly, described group is selected from alkoxyl group or the trifluoromethyl that contains 1-4 carbon atom, 1-or 2-naphthyl, 2-or 3-furyl, 2-or 3-thienyl, 4-or 5-imidazolyl or 4-or 5-thiazolyl, 2-or 3-or 4-pyridyl, or 2,3-indanyl or chromanyl

Or

R ₈Representation hydroxy, amino, the straight or branched alkoxyl group, the moieties that are randomly replaced that contain 1-6 carbon atom by phenyl contain 1-4 carbon atom alkylamino or dialkyl amido,

Or preferably wherein:

R ₈Representative

-hydrogen atom

-hydroxyl

-aryl sulfonyl as phenyl sulfonyl, is randomly replaced by one or more identical or different atoms or group, and described atom or group are selected from halogen atom and alkyl, alkoxyl group, and these alkyl all contain 1-4 carbon atom,

-containing the heterocycle of the one or more heteroatomic 5-7 of having chain links, described heteroatoms is selected from nitrogen, oxygen or sulphur atom, and described heterocycle connects by heteroatoms,

-randomly by the amino of one or two identical or different group replacement, described group is selected from following base:

-contain the alkyl of 1-4 carbon atom,

-aryl as phenyl, is randomly replaced by one or two identical or different group, and described group is selected from alkyl, alkoxyl group, and these alkyl all contain 1-4 carbon atom,

-containing the heterocycle of the one or more heteroatomic 5-7 of having chain links, described heteroatoms is selected from nitrogen, oxygen or sulphur atom,

-aryl carbonyl as benzoyl, is randomly replaced by one or more identical or different groups, and described group is selected from alkyl, alkoxyl group, and these alkyl all contain 1-4 carbon atom,

-randomly contained 1-6 carbon atom straight chain or branched alkoxy by what phenyl replaced,

--contain 1-6 carbon atom straight chain or branched-chain alkyl; as methyl; randomly replaced: amino by following groups; alkylamino; dialkyl amido; hydroxyl; the alkoxyl group that contains 1-4 carbon atom; sulfydryl; alkylthio; alkoxy carbonyl; carboxyl; cyano group; the optional monocycle or the polyaromatic that contain or do not contain the one or more heteroatomic 5-12 of having chain links that replaces; its heteroatoms is selected from oxygen; nitrogen and sulphur atom; described aryl can be 2-or 3-or 4-pyridyl especially; preferred 3-pyridyl or 4-pyridyl; or N-pyridine oxide; maybe can also be randomly by one or more halogen atoms or by one or more hydroxyls; the phenyl that amino or trifluoromethyl replace; or by one or more alkyl or alkenyl; alkoxyl group; alkylthio; alkylamino; C2-C4 alkyl-carbonyl or alkoxy carbonyl; formamyl; its moieties is alkyl-carbamoyl or the dialkyl amido formyl radical of C1-C8; the phenyl of formyl radical or 1-naphthyl or 2-naphthyl substituted

R preferably ₇Represent hydrogen atom, R ₈The methyl that representative is replaced by the 3-pyridyl,

Described compound can pass through the product of following general formula:

HN(R ₇)(R ₈)

R in the formula ₇, R ₈As above-mentioned definition

Obtain with general formula (I) the product reaction of its Z representation carboxy.

Particularly advantageously be:

-or at first allow and react in the solution of general formula (I) compound in methylene dichloride of oxalyl chloride and its R representation carboxy, to generate the intermediate product acyl chlorides, then randomly in the presence of alkali, allow general formula HN (R as triethylamine and so on ₇) (R ₈) compound reacts,

-or, at organic solvent as alcohol (ethanol) and so on, or in the halogen-containing solvent as methylene dichloride and so on, as N, N '-carbonyl dimidazoles, 1,1-dicyclohexyl carbodiimide, 1-ethyl-3-[-(dimethylamino) propyl group] condensing agent of carbodiimide hydrochloride, phosphofluoric acid benzo-triazol-1-yl oxygen three (dimethylamino) phosphine and so on exists down, under temperature 0-50 ℃, allows general formula HN (R ₇) (R ₈) general formula (I) compound of compound and its R representation carboxy directly reacts.

As symbol R ₇And R ₈In at least one when being replaced by amino, particularly advantageous is at general formula HN (R ₇) (R ₈) before amine and the suitable sour condensation; use and protect its amino as the blocking group of uncle-butoxy carbonyl, benzyloxycarbonyl or benzyl and so on; then for example when blocking group is benzyl or benzyloxycarbonyl; as in the presence of the catalyzer of sedimentary palladium and so on the carbon; replace blocking group by hydrogenolysis with hydrogen atom by hydrogen; or when blocking group is uncle-butoxy carbonyl or benzyloxycarbonyl, in acidic medium, replace blocking group with hydrogen atom by hydrolysis.

As symbol R ₇And R ₈In at least one during by carboxyl substituted, particularly advantageous is at general formula HN (R ₇) (R ₈) before amine and the suitable sour condensation; the blocking group of the alkyl that uses as randomly replaced by phenyl such as benzyl and so on is protected its carboxyl; then for example as in the presence of the catalyzer of sedimentary palladium and so on the carbon; replace blocking group by hydrogenolysis with hydrogen atom by hydrogen; or under above-mentioned condition, replace blocking group with hydrogen atom by saponification reaction.

As R in general formula (I) product ₇Represent hydrogen atom or contain the alkyl of 1-6 carbon atom, and R ₈During alkoxyl group that representative is replaced by phenyl, the alkoxyl group that can be replaced by phenyl with the hydroxyl displacement as follows:

-or as in the presence of the catalyzer of sedimentary palladium and so on the carbon, pass through hydrogenolysis,

-or when the alkyl that is replaced by phenyl is benzyl, in organic solvent as Nitromethane 99Min. and so on, temperature be-20 ℃ to room temperature, in the presence of phenylmethylether, use aluminum chloride to handle,

This displacement can access its R ₇Represent hydrogen atom or contain the alkyl of 1-4 carbon atom, and R ₈The general formula of representation hydroxy (I) product.

According to the present invention, new general formula (I) product, wherein:

-R represents following general formula:

-NHCO-T

The alkyl (1-6 carbon atom) that T represents hydrogen atom or randomly replaced by amino, carboxyl, alkoxy carbonyl, hydroxyl, alkoxyl group, sulfydryl or alkylthio in the formula,

Can be by the acid of following general formula

T-CO-OH

In the formula T as defined above,

Obtain with following general formula VI product reaction:

In the formula:

Ar, R ₁, R ₂, R ₃, R ₄, R ₅, X and Y such as general formula (I) definition.

Usually, in the organic solvent of the halogenated aliphatic hydrocarbon of like methylene dichloride and so on, as 1-ethyl-3-[3-(dimethylamino) propyl group] carbodiimide hydrochloride, 1, the condensing agent of 1-dicyclohexyl carbodiimide or phosphofluoric acid benzotriazole-1-base oxygen three (dimethylamino) phosphine and so on exists down, randomly the activator as hydroxybenzotriazole and so on exists down, under 0-50 ℃ of temperature, operate, allow the general formula T-CO-OH acid that is sour form react with general formula (VI) product.

Usually, in the organic solvent of the halogenated aliphatic hydrocarbon of like methylene dichloride and so on, in the presence of alkali (tert-aliphatic amine), under 0-50 ℃ of temperature, operate, allow its T not react with general formula (VI) product for the general formula T-CO-OH acid that is the carboxylic acid halides form of hydrogen atom.

Usually, in the organic solvent of the halogenated aliphatic hydrocarbon of like methylene dichloride and so on, in the presence of alkali (tert-aliphatic amine, pyridine or 4-dimethylaminopyridine), under 0-50 ℃ of temperature, operate, allow the general formula T-CO-OH acid that is anhydride form react with general formula (VI) product.

After T-CO-OH compound and compound VI reaction, can randomly follow under these conditions, with carboxyl or amino ester functional group or amine functional group of replacing the protection that has respectively by T.

When T is replaced by amino; particularly advantageously be; before general formula T-CO-OH acid and suitable amine condensation; use as the blocking group protection of benzyloxycarbonyl or uncle-butoxy carbonyl and so on amino; then for example in the presence of the catalyzer of sedimentary palladium and so on the carbon; replace blocking group by hydrogenolysis by hydrogen atom by hydrogen, or in acidic medium, replace blocking group by hydrogen atom by hydrolysis.

As T during by carboxyl substituted; particularly advantageously be; before general formula T-CO-OH acid and suitable amine condensation; use blocking group protection carboxyl as methyl, ethyl or benzyl and so on; then for example in the presence of the catalyzer of sedimentary palladium and so on the carbon; replace blocking group by hydrogenolysis by hydrogen atom by hydrogen, or replace blocking group by saponification by hydrogen atom under these conditions.

According to the present invention, new general formula (I) product, wherein R represents the group of following general formula:

Can obtain by the derivative and the reaction of following general formula product of excess pyridine and strong acid or this acid:

Ar, R in the formula ₁, R ₂, R ₃, R ₄, R ₅, X and Y such as general formula (I) definition.

Preferably, strong acid is trifluoromethanesulfonic acid, randomly has trifluoromethanesulfanhydride anhydride.

According to the present invention, on behalf of new general formula (I) product of sulphur atom, its Y can be obtained through sulfuration by general formula (I) product of its Y represention oxygen atom.

Usually, in organic solvent,, under common condition, carry out sulfuration by thiophosphoric anhydride temperature 0-50 ℃ of operation down as tetrahydrofuran (THF) and so on.

According to the present invention, its R ₁Or R ₂In general formula (I) product of representing alkyl carbonyl oxy, can be under common enzymatic synthesis condition, use derivative such as the carboxylic acid halides or the acid anhydrides of aliphatic acid or this acid, make wherein R ₁Or R ₂In general formula (VI) the product acidylate of a representation hydroxy obtain.

About above-mentioned intermediate product, we also propose to be used to prepare their operation scheme and compound below.

Usually, its R representation carboxy or general formula COOR ₆The general formula of group (III) product can obtain by trifluoromethanesulfonic acid and the reaction of following general formula (VIII) product:

In the formula:

-Ar, R ₃, R ₄And R ₅Define as the front,

-G ₁Represent benzyl,

-R ₆Representative contains the alkyl of 1-3 carbon atom,

Then adopt following method to replace G with hydrogen atom ₁Group:

-or, under these conditions by hydrogenolysis, then according to circumstances with uncle-butoxy carbonyl displacement hydrogen atom, in organic solvent, pass through uncle-butoxy carbonyl acid anhydrides effect, or replace hydrogen atom with benzyloxycarbonyl, in organic solvent by the effect of benzyloxycarbonyl muriate

-or, in organic solvent as methylene dichloride and so on, at 0 ℃ to the temperature of room temperature, by as carbonochloridic acid vinyl acetate or chloro ethyl formate or carbonochloridic acid-2-chloroethene ester or carbonochloridic acid 2,2, the effect of the carbonochloridic acid alkyl ester of 2-trichloro ethyl ester and so on, then choose wantonly at alcohol as methyl alcohol or ethanol and so on, or in the organic solvent as the ether of tetrahydrofuran (THF) Huo diox and so on, generally by the 1-6M aqueous hydrochloric acid, the carbamate that generates in the middle of the acidolysis.

Usually, randomly in the presence of the catalytic amount trifluoromethanesulfanhydride anhydride, perhaps randomly adding with addition manner in succession under the condition of catalytic amount trifluoromethanesulfanhydride anhydride, in organic solvent as methylene dichloride and so on, 0 ℃ to the reflux temperature few minutes of operation by several days, under excessive (3-15 molar equivalent) strong acid effect, general formula (VIII) product can be generated the product of general formula (III) through the intramolecular cyelization of Friedel-Crafts type as trifluoromethanesulfonic acid and so on.Can also be in solvent as methylene dichloride or Nitromethane 99Min. or oil of mirbane and so on, by lewis acidic effect, carry out the intramolecular cyelization of Friedel-Crafts type as aluminum chloride or titanium tetrachloride or boron trifluoride (randomly being complex form) and so on ether.

After this reaction, randomly then allow resultant product carry out saponification, randomly then according to circumstances replace benzyl with hydrogen atom.

Normally, under condition commonly used, by general formula Ar-Mg-X organic-magnesium derivative, wherein Ar such as front define, and X represents halogen atom, or general formula Ar-Li organolithium derivative, wherein Ar such as front define, and general formula (IX) the product reaction with following can obtain general formula (III) product:

R in the formula ₃, R ₄, R ₅, R ₆And G ₁Define as the front.

Usually, in organic solvent as ether or tetrahydrofuran (THF) and so on, 0 ℃ of temperature to few minutes of operation to 24 between the reaction mixture refluxed temperature hour, will be randomly in the presence of anhydrous cerium chloride (III), (tetrahedron communication (TetrahedronLett.) under the condition that Imamoto describes, 1985, the 4763rd page) aryl magnesium that routine obtains, react with general formula (IX) ketone derivatives.But, find in toluene, randomly with the mixture of ether or tetrahydrofuran (THF) in operation be particularly advantageous.

Usually, in the organic solvent as ether or tetrahydrofuran (THF) and so on, to-20 ℃ of following few minutes of operation to 4 hour, the lithium aryl that allows routine obtain reacts with general formula (IX) ketone derivatives in temperature-78 ℃.But, find in toluene, randomly with the mixture of ether or tetrahydrofuran (THF) in operation be particularly advantageous.

Advantageously, providing a kind of is within the scope of the present invention set out by general formula (IX) compound, by generating intermediate product stable and that have general formula (XV) characteristic, can access the preparation method of general formula (III) compound, and intermediate product is characterised in that at 7 and has aryl year ethene functional group.

More properly, compound of formula III:

R in the formula ₃, R ₄, R ₅, Ar and R in the general formula I definition, and G1 represents benzyl, can be obtained by generating following general formula (XV) intermediate product by following general formula (IX) compound:

R in the formula ₃, R ₄, R ₅, R ₆And G ₁Define as the front,

R in the formula ₃, R ₄, R ₅, R ₆, Ar and G ₁Define as the front.

Operation scheme relates to following sequential step:

-or general formula (IX) ketone derivatives and hydrazine obtain hydrazone 7 condensations, then obtain with the iodine effect (according to Barton reaction (Chemical Society's magazine (J.Chem.Soc.) 1962, the 470th page) vinyl iodide derivative; Palladium and general formula Ar-B (OH) then ₂The coupled reaction of aryl boric acid, i.e. Suzuki reaction (tetrahedron communication, 1979 the 3437th page), perhaps randomly with the trimer acid anhydride reactant of aryl boric acid, wherein Ar such as front define, or with general formula Ar-SnMe ₃The reaction of d aryl stannane, be Stille reaction (Angew.Chem.Int.Ed.Engl., 1986, the 508th page), wherein Ar such as front define, and obtain the aryl ethylene intermediate product of this general formula (XV), by Friedel-Crafts type intramolecular condensation, this intermediate product transforms and obtains desired general formula (III) product

-or the ketone derivatives of general formula (IX) and trifluoromethanesulfonic acid anhydride reactant obtain the triflate (organic synthesis (Org.Synth.) nineteen ninety, the 116th page) at 7 enols; Palladium and general formula Ar-B (OH) then ₂The coupled reaction of aryl boric acid, i.e. Suzuki reaction (tetrahedron communication, 1979 the 3437th page), wherein Ar such as front define, perhaps with general formula Ar-SnMe ₃The reaction of d aryl stannane, be Stille reaction (Angew.Chem.Int.Ed.Engl., 1986, the 508th page), wherein Ar such as front define, obtain the aryl ethylene intermediate product of this general formula (XV), by Friedel-Crafts type intramolecular condensation, this intermediate product transforms and obtains desired general formula (III) product.

Usually, with the excessive hydrazine hydrate of 3-20 molar equivalent, the backflow several minutes was handled general formula (IX) ketone derivatives to several hours in as the solvent of ethanol and so on.The hydrazone that so obtains, in the presence of aliphatic tertiary amine as triethylamine and so on, about 20 ℃ in temperature, stirred several hours with excess iodine, obtain the vinyl iodide derivative.

Usually general formula (IX) ketone derivatives stands following processing:

-or, according to Stang (synthetic, 1980, the 283rd page), in solvent as methylene dichloride and so on, under temperature near room temperature, as 2, the organic bases of 6-two-tert-butyl-4-picoline and so on exists down, adopts three fluorosulfonic anhydride processing several hours,

-or, as methylene dichloride or 1, in the organic solvent of 2-glycol dimethyl ether and so on; in the presence of alkali, adopt two (trifyl) amide-treated, as according to Mac Murry (tetrahedron communication as lithium diisopropylamine and so on; nineteen eighty-three; the 979th page) adopt N, two (trifyl) aniline of N-are handled, or according to Comins (tetrahedron communication; 1992; the 979th page) employing 2-[N, two (trifyl) amino of N-] the pyridine processing

Obtain the enol triflate.

Usually, by organic solvent, preferably toluene and methanol mixture, and alkaline moisture solution are preferably in the biphasic system that the 2N sodium carbonate solution constitutes, palladium (O) derivative at catalytic amount, preferred tetrakis triphenylphosphine palladium exists down, stirs the enol triflate that makes the vinyl iodide derivative or obtain previously several hours under near the temperature that refluxes, that obtain with routine and carry out coupling with the aryl boric acid of trimerization acid anhydrides isolated in form, obtain general formula (XV) aryl ethylene compound.

Usually, in by polar non-proton organic solvent, preferably in dimethyl formamide or N-methyl-pyrrolidone, palladium (O) derivative at catalytic amount, preferably tetrakis triphenylphosphine palladium exists down, stirs the enol triflate that makes the vinyl iodide derivative or obtain previously several hours at 50-100 ℃, the aryl stannane that obtains with routine carries out coupling, obtains general formula (XV) aryl ethylene compound.

Usually, under the condition of the intramolecular condensation of the general formula of Miao Shuing (VIII) product, general formula (XV) compound is generated general formula (III) product through Friedel-Crafts type intramolecular condensation in front.

Advantageously, also provide second kind of preparation method within the scope of the present invention, this method is by general formula (IX) compound, by generating optional separable general formula (XV) intermediate product, obtains general formula (III) compound.When Ar base representative contraposition or-contraposition or-when a right-position is powered the phenyl ring that subbase group replaces, or represent nature to be rich in the heterocyclic radical of electronics or when being powered the heterocyclic radical that subbase group suitably replaces, this second method is particularly advantageous, this second method is in organic solvent, in the presence of excessive strong acid as three fluosulfonic acid and so on, or randomly in the presence of excessive Lewis acid as aluminum chloride and so on, by intermolecular, the mode of intramolecularly Friedel-Crafts type annulation then, aromatic hydrocarbon or heterocyclic hydrocarbon Ar-H and general formula (IX) compound directly react.

Operating method is that in the organic solvent as methylene dichloride and so on, under the temperature near room temperature, general formula (IX) product and excessive trifluoromethanesulfonic acid (5-20 molar equivalent) carried out condensation reaction several hours to several days.According to molar equivalent number and trifluoromethanesulfonic acid concentration and the Ar base and the substituent character of being with thereof, this reaction or can directly obtain general formula (III) compound, perhaps obtain general formula (XV) intermediate compound, these compounds can be cyclized into general formula (III) compound as described previously.

In addition, use or adopt known functionalized method usually, as an example: functional group's substitution reaction (for example by replacing hydrogen atom with the palladium coupling by cyano group), removal of alkylation reaction (is for example used BBr ₃), alkylated reaction (passes through BBr especially ₂Effect alkylation-ring formation reaction), by mutual-through type (I) or (III) the substituting group functionalization of the aromatic ring Ar of compound, can obtain corresponding general formula (I) or (III) compound.

Another one content of the present invention also relates to these compounds of general formula (XV):

R in the formula ₃, R ₄, R ₅With Ar in the general formula I definition, G ₁Represent benzyl, and R ₆Representative contains the alkyl of 1-3 carbon atom, and these compounds are racemize and their optically active isomer form.

General formula (IX) product that is racemize and their optically active isomer form, wherein R ₃, R ₄, R ₅, R ₆With Ar in the general formula I definition, G ₁Represent benzyl; can be by the N-trialkylsilkl methyl-N-alkoxy methyl-amine of band as the amine official energy blocking group of benzyl and so on; as N-trimethyl silyl methyl-(it can be at Chem.Pharm.Bull. for N-n-butoxy methyl-benzyl amine; prepare under 276 (1895) conditions of describing), obtain with following general formula cyclohexenone derivates reaction:

R ₃, R ₄, R ₅And R ₆Define as the front, these compounds are outer choosing or its optically active isomer form of disappearing.

Usually, in the organic solvent of the halogenated aliphatic hydrocarbon of like methylene dichloride and so on, in the presence of strong acid, to the reaction mixture refluxed temperature, carry out this reaction at 0 ℃ as trifluoroacetic acid and so on.

In the solvent that is selected from tetrahydrofuran (THF), dimethyl formamide, acetone Huo diox, operate, in the presence of the mineral acid of example hydrochloric acid or sulfuric acid and so on, at 0 ℃ to the reaction mixture refluxed temperature, by the fatty alcohol that contains 1-3 carbon atom, perhaps as 1,8-diazabicyclo [5,4,0] organic bases of 11 carbon-7-alkene and so on or exist down as the mineral alkali of cesium carbonate and so on, by alkyl halide (iodide), can be by R wherein ₃, R ₄, R ₅Obtain general formula (X) product as the defined 3-oxo in front-6-phenyl-hexamethylene-1-alkene-1-formic acid esterification.

R wherein ₃, R ₄, R ₅As the defined 3-oxo in front-6-phenyl-hexamethylene-1-alkene-1-formic acid, can adopt in temperature and heat down (according to " organic chemistry magazine " near 190 ℃, 1971, the 3707th page), or in the presence of tosic acid in toluene reflux, by hot dehydration, perhaps by at temperature 0-50 ℃ down as the effect of the mineral alkali of sodium hydroxide and so on, by R wherein ₃, R ₄, R ₅Obtain as the defined 3-oxo in front-6-phenyl-hexamethylene-1-alcohol-1-formic acid.

R wherein ₃, R ₄, R ₅As the defined 3-oxo in front-6-phenyl-hexamethylene-1-alcohol-1-formic acid, usually in medium as the water-alcohol solution of methanol-water mixtures and so on, in the presence of mineral alkali as sodium hydroxide and so on, can be by phenylpyruvic acid, or randomly corresponding ester, more preferably at R ₅Do not represent hydrogen atom, its phenyl ring is randomly by R ₃And R ₄Under the situation that the substituting group of definition replaces, obtain with the methyl ethylene reactive ketone (according to " organic chemistry magazine ", 1971, the 3707th page).

Phenylpyruvic acid, its phenyl ring is randomly by R ₃And R ₄The substituting group of definition replaces, more preferably at R ₅Do not represent under the situation of hydrogen atom, can be according to " organic synthesis ", nineteen forty-three, the 519th page, adopt and in hydrochloric acid, heat, by the corresponding a-kharophen of hydrolysis styracin, perhaps roll up according to Org.Synth.Coll. V, the 627th page, adopt and in 20% sodium hydroxide solution, heat, obtain by the corresponding benzylidene glycolylurea of hydrolysis.

A-kharophen styracin, its phenyl ring is randomly by R ₃And R ₄The substituting group of definition replaces; can be according to " organic synthesis "; nineteen thirty-nine, page 1 made by corresponding benzylidene aldehyde: in the presence of sodium acetate; under the condition that diacetyl oxide refluxes; by the effect of N-acetyl-glycine; then, reflux in aqueous acetone is hydrolyzed into a-kharophen styracin with the intermediate azlactone that so obtains.

The benzylidene glycolylurea, its phenyl ring is randomly by R ₃And R ₄The substituting group of definition replaces, according to Org.Synth.Coll. V volume, the 627th page, can be in the presence of organic bases as piperidines and so on, temperature near 130 ℃ under, corresponding phenyl aldehyde and glycolylurea heated obtain.

Phenylpyruvic acid, its phenyl ring is randomly by R ₃And R ₄The substituting group of definition replaces, more preferably at R ₅Do not represent hydrogen atom, and represent under the situation of alkyl or alkylthio, can be by phenyl wherein randomly by R ₃And R ₄The 2-phenyl alkanoic acid that the substituting group of definition replaces obtains by corresponding two anionic effects, generally in " tetrahedron communication ", 1981, operate under the condition of describing in the 2439-42 page or leaf, under approaching-70 ℃ of temperature, allow as just-organic bases of butyllithium and so on obtain with acid, with the ethyl oxalate reaction as described in two negatively charged ion.

General formula (III) product:

R represents following radicals in the formula:

(CH ₂) _m-X ₁(CH ₂) _n-Z

In the formula:

M equals 0,

X ₁Represent a key,

N equal 0 and

Z representative-COOR ₆Or-CON (R ₇) (R ₈)

Can be by the general formula of R representation carboxy (VIII) product wherein, under these conditions through esterification or amidate action, then the ring that acts as by trifluoromethanesulfonic acid obtains under these conditions.

R represents general formula (III) product of following radicals in the formula:

(CH ₂) _m-X ₁(CH ₂) _n-Z

In the formula:

M equals 1,

X ₁Represent a key,

N equal 0 and

Z representative-COOR ₆Or-CON (R ₇) (R ₈) or PO (OR ₉) ₂

Can obtain by following general formula product:

Ar, R in the formula ₃, R ₄Define G with R such as front ₁Represent amido protecting group (benzyl, benzyloxycarbonyl or tert-butoxycarbonyl), G ₂Representative is as the leavings group of trifluoromethyl sulfonyloxy and so on.

More preferably, in order to obtain general formula (III) product that R wherein represents following radicals:

(CH ₂) _m-X ₁(CH ₂) _n-Z

In the formula:

M equals 1,

X ₁Represent a key,

N equal 0 and

The Z representation carboxy ,-COOR ₆, R wherein ₆Represent alkyl, or-CON (R ₇) (R ₈),

Particularly advantageous is to obtain the said products by means of corresponding nitrile, in polar organic solvent as dimethyl sulfoxide (DMSO) and so on, temperature 0-50 ℃ of operation down, can obtain described nitrile by alkali metal cyanide and the reaction of general formula (XI) product, its hydrolysis generates corresponding acid, and this acid can be carried out esterification or amidation under common condition.

(CH ₂) _m-X ₁(CH ₂) _n-Z

In the formula:

M equals 1,

X ₁Represent a key,

N equal 0 and

Z represents PO (OR ₉) ₂

Particularly advantageous is to allow trialkyl phosphite and general formula (XI) product react, and randomly resulting phosphonic acid ester is changed into corresponding phosphonic acids then.

Following general formula (III) product:

In the formula:

-R represents (CH ₂) _m-X ₁(CH ₂) _n-Z, m equals 1, X ₁Represent a Sauerstoffatom or sulphur atom, n equals 1 or 2, and the Z representation carboxy ,-COOR ₆, R wherein ₆Represent alkyl, or-CON (R ₇) (R ₈),

-G ₁Represent the amine functional group blocking group

Can be in the organic solvent of diox and so on, in the presence of alkalimetal hydride, by following general formula ester or acid amides as sodium hydride and so on:

H-X ₁-(CH ₂) _n-Z

X wherein ₁, n and Z such as front define,

Obtain the saponification reaction of the general formula that randomly according to circumstances then so obtains (III) product with the reaction of general formula (XI) product.

Following general formula (III) product, in the formula:

-m equals 1,

-X ₁Represent a key,

-n equals 1, and methylene radical can be replaced by carboxyl or carbalkoxy or formamyl or alkyl-carbamoyl or dialkyl amido formyl radical,

-G ₁Represent the amine functional group blocking group and

-Z representation carboxy ,-COOR ₆, R wherein ₆Represent alkyl, or-CON (R ₇) (R ₈),

Can be in the organic solvent of diox and so on, in the presence of alkalimetal hydride as sodium hydride and so on, at 0 ℃ to the temperature of reaction mixture refluxed temperature, allow the propanedioic acid of anionization in advance, or malonate derivative, preferably diester obtains with the reaction of general formula (XI) product, and randomly the general formula that according to circumstances then will so obtain (III) product carries out saponification reaction, esterification, amidate action or decarboxylate reaction.

R representative-NH-CO-T and T general formula as defined above (III) product can by general formula T-CO-OH acid, obtain by the following general formula of amidation (III) product under the condition of above-mentioned amidation general formula (VI) product, in the formula:

-R ₃As above-mentioned definition,

-G ₁Represent the amine official can blocking group and

-R represents amino.

R represents amino general formula (III) product or general formula (VI) product in its formula, and the method that can not relate to the molecule rest part according to carboxyl being changed into amino obtains.

Usually, can by isocyanic ester with general formula (III) or (I) carboxyl of product change into amino, and isocyanic ester can obtain by the acid azide hydrolysis, acid azide itself can obtain by an alkali metal azide and corresponding carboxylic acid halides reaction.Normally, the middle isocyanic ester that so obtains can with the phenylcarbinol condensation, then under these conditions, perhaps adopt hydrogenolysis, perhaps adopt acidolysis, the carboxylamine benzyl ester that obtains is changed into amino.

Wherein R represents general formula (III) product of following formula group,

Can obtain by the derivative and the reaction of general formula (XII) product of pyridine and strong acid or this acid, wherein:

Ar, R in the formula ₃, R ₄And R ₅As above-mentioned definition, and G ₁Represent the amine functional group blocking group.

General formula (VII) product or general formula (XII) product can obtain by reduction general formula (I) product or general formula (III) product respectively, and wherein R represents general formula-COOR ₆, and R ₆Preferably representative contains 1-3 carbon atom alkyl.

Usually, in the ether organic solvent of like tetrahydrofuran (THF) and so on, under temperature 0-50 ℃, reduce by two hydride of lithium and aluminium.

According to the present invention, wherein Ar, R ₁, R ₂, R ₃, R ₄, R ₅, X and Y such as above-mentioned definition, R representative-COOR ₆Base, and R ₆General formula as defined above (I) product also can obtain R in its formula by general formula (IX) product ₃, R ₄, R ₅, R ₆As above-mentioned definition, and G ₁Represent hydrogen atom.

According to the present invention, general formula (IX) product

G in the formula ₁Represent hydrogen atom, at its G of above-mentioned preparation ₁Represent under the condition of general formula (III) product of hydrogen atom, can be by G wherein ₁Represent general formula (IX) product of amido functional group blocking group to obtain.

G wherein ₁Represent of the conversion of general formula (IX) product of hydrogen atom to following general formula product:

R in the formula ₁, R ₂, R ₃, R ₄, R ₅, X and Y such as above-mentioned definition, operate as follows according to the meaning of X and Y:

-wherein Y represents oxygen or sulphur atom, and X representative-CO-base, methylene radical, ethene two bases, alkene-1, and 1-two bases or cycloalkanes-1, general formula (XIII) product of 1-two bases can be at above-mentioned general formula (II) product and G wherein ₁Represent under the condition of general formula (III) product reaction of hydrogen atom and operate, by the acid of general formula (II), or its acyl chlorides, or its acid anhydrides and G wherein ₁Represent general formula (IX) the product reaction of hydrogen atom to obtain,

-wherein Y represents oxygen or sulphur atom, and the general formula of X represention oxygen atom (XIII) product can be at above-mentioned general formula (IV) product and G wherein ₁Represent under the condition of general formula (III) product reaction of hydrogen atom and operate, haloformate by general formula (IV) or halo thiocarboxylic and G wherein ₁Represent general formula (IX) the product reaction of hydrogen atom to obtain,

-wherein Y represents oxygen or sulphur atom, and X represents general formula (XIII) product of NH group, can be at above-mentioned logical formula V product and G wherein ₁Represent under the condition of general formula (III) product reaction of hydrogen atom and operate, isocyanic ester by logical formula V or lsothiocyanates and G wherein ₁Represent general formula (IX) the product reaction of hydrogen atom to obtain.

General formula (XIII) product can change into the product of following general formula by following method:

Ar, R in the formula ₁, R ₂, R ₃, R ₄, R ₅, R ₆, X and Y be as above-mentioned definition: under the condition of above-mentioned general formula Ar-Mg-X or Ar-Li organic-magnesium or organolithium derivative and the reaction of general formula (IX) product, operate, allow X wherein represent metal derivative and the effect of general formula (XIII) product of the general formula Ar-Mg-X or the Ar-Li of halogen atom.

Under the condition of above-mentioned trifluoromethanesulfonic acid or Lewis acid and the reaction of general formula (VIII) product, operate, allow the effect of trifluoromethanesulfonic acid or Lewis acid and general formula (XIV) product, can make general formula (XIV) product change into wherein Ar, R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, X and Y such as above-mentioned defined general formula (I) product.

As above-mentioned defined aromatic hydrocarbons or aromatic heterocycle Ar-H, in the presence of trifluoromethanesulfonic acid or Lewis acid, with wherein Ar, R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, X and Y such as the reaction of above-mentioned defined general formula (XIII) product, obtain general formula (I) product, Ar is as above-mentioned definition in its formula, and R represents COOR ₆Base, wherein R ₆Representative has the alkyl of 1-3 carbon atom.

According to the present invention, general formula (I) product, wherein:

-Ar, R ₁, R ₂, R ₃, R ₄, R ₅, R ₆, X and Y such as above-mentioned definition and

-R represents following radicals

(CH ₂) _m-X ₁(CH ₂) _n-Z

In the formula: m, n, X ₁With Z as above-mentioned definition,

Can prepare under the condition of general formula (III) product by general formula (XI) product above-mentioned, begin, after with the hydroxyl of replacing general formula (VII) product as the leavings group of trifluoromethane sulfonyloxy and so on, obtain by general formula (VII) product.

Adopt reaction mixture that above-mentioned different methods obtains to handle according to common physical method (for example evaporate, extraction, distillation, chromatogram, crystallization process) or chemical process (for example salify).

In as alcohol, ketone, ether or chlorinated solvents and so on organic solvent, can general formula (I) compound randomly be changed into additive salt with mineral acid or organic acid effect.

According to common separation method, can obtain the optically active isomer of general formula (I) compound by corresponding racemic product.Particularly advantageous is to adopt high performance liquid chromatography, uses the Pirkle type chiral stationary phase of modification, carries out described separation with the solvent elution that is fit to.

As preferred operable chiral stationary phase, it is chiral selector (preferably 3 wherein, 5-dinitrobenzene-phenylalanine) the aminoalkyl group arm by the organic 3-14 of containing of the amine that is fixed on an aminopropyl silicon-dioxide carbon atom and silicon-dioxide separate, and its free silanol functional is blocked by trialkylsilkl.

This chirality can be used following organization definition mutually:

Symbol R ' is identical or different in the formula, R, and " identical or different, their representatives contain the alkyl of 1-10 carbon atom, G ₃Represent electron-withdrawing group, and n representative comprises the integer of 3 and 13 3-13, its porosity is about 100 dusts.

This chirality can be prepared as follows mutually: allow aminopropyl silicon-dioxide with contain the anhydride reaction of the amino-alkane acid of 4-14 carbon atom; and the amine functional group of described acid anhydrides is then used as above-mentioned defined Si (R ') by the blocking group protection as tert-butoxycarbonyl and so on ₃Group blocking part silanol functional, after removing the amine functional group protecting group, carry out amidate action then by following general formula amino acid:

G in the formula ₃As above-mentioned definition, adopt at last as above-mentioned defined Si (R ") ₃The silanol functional that the group blocking-up is residual.

Usually, in anhydrous organic solvent,, allow the acid anhydrides and the aminopropyl silicon-dioxide of amino-alkane acid of protection react in the about 20 ℃ of down operations of temperature as dimethyl formamide and so on.

In organic solvent as methylene dichloride and so on, in the presence of alkaline reagents, allow halo trialkyl silicomethane and aminopropyl silicon dioxde reaction with the amino-alkane residue grafted as pyridine and so on, by as above-mentioned defined Si (R ') ₃Group blocking-up silanol functional.

Usually, when blocking group is tert-butoxycarbonyl, in organic solvent,, remove blocking group from the amino-alkane base by the effect of trifluoroacetic acid as methylene dichloride and so on.

In anhydrous organic solvent, operate,, under the existence of 2-dihydro-quinoline and so on condensing agent, carry out amidation by the protected phenylalanine of amine functional group as N-ethoxy carbonyl-2-oxyethyl group-1 as dimethyl formamide and so on.

Usually, in organic solvent, operate as methylene dichloride and so on, by the trialkylsilkl imidazoles, with as above-mentioned defined-Si (R ") ₃The silanol functional that the group blocking-up is residual.

Aminopropyl silicon-dioxide can be in the anhydrous organic solvent of the aromatic hydrocarbons of like toluene and so on, operation in the presence of imidazoles, by aminopropyl triethoxy-silicane and silicon-dioxide effect, wherein the silicon-dioxide porosity is about 100 dusts, can prepare aminopropyl silicon-dioxide.

Indicated as following embodiment, the method that new general formula (I) product suppresses farnesyl transferase and protein Ras turns usefulness into, has significant antitumor and antileukemie character.

A further object of the invention is any composition that contains at least a general formula (I) product and one or more inertia or biologic activity, pharmaceutically acceptable thinner or additive.

New general formula (I) product can be atoxic and form pharmacologically acceptable salts.Character according to general formula (I) compound, these non-toxic salts comprise the salt (hydrochloric acid, sulfuric acid, Hydrogen bromide, phosphoric acid, nitric acid) that generates with mineral acid, or the salt (acetate, propionic acid, succsinic acid, toxilic acid, hydroxymaleic acid, phenylformic acid, fumaric acid, methylsulfonic acid, trifluoroacetic acid or oxalic acid) that generates with organic acid, or the salt (sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide) that generates with mineral alkali, or the salt (tertiary amine is as triethylamine, piperidines, benzene methanamine) that generates with organic bases.

The invention still further relates to general formula of the present invention (I) compound be used for the preparation be used to suppress farnesyl transferase, more particularly suppress the purposes that oncogene ras method turns the pharmaceutical composition of usefulness into.Especially, the present invention relates to general formula of the present invention (I) compound and be used to prepare and be used for, especially especially for the pharmaceutical composition for the treatment of with any carcinogenic protein HRas of overexpression, N-Ras or K-Ras or having the relevant disease of cell proliferation that any corresponding oncogene ras suddenlys change by suppressing the pharmaceutical composition of the farnesyl transferase treatment disease relevant with cell proliferation.

The present invention relates to general formula of the present invention (I) compound especially and is used to prepare the pharmaceutical composition that is used for the treatment of with different tissues and/or organ cell's pernicious or benign cell propagation relative disease, wherein tissue and/or organ comprise muscle, bone or reticular tissue, skin, brain, lung, sexual organ, lymphsystem or kidney system, mammary cell or blood cell, liver, digestion organs, colon, pancreas and Tiroidina or suprarenal gland, also comprise following disease: psoriasis, restenosis, noumenal tumour, the Kaposi sarcoma, cancer, cholangiocarcinoma, villioma, sympathoblastoma, the Wilms knurl, king's evil suddenly, melanoma, teratocarcinoma, neurospongioma, multiple myeloma, chronic lymphocyte leukemia, acute or chronic granulocyte lymphoma and as the pancreas cancer, colorectal carcinoma, lung cancer, ovarian cancer, mammary cancer, the cancer of the brain, prostate cancer, liver cancer, cancer of the stomach, the cancer of bladder cancer or carcinoma of testis and so on.

The invention particularly relates to general formula of the present invention (I) compound, the compound of describing in the preferred embodiment 3, be used to prepare the cancer that is used for the treatment of as pancreas cancer, colorectal carcinoma, lung cancer, ovarian cancer, mammary cancer, the cancer of the brain, prostate cancer, liver cancer, cancer of the stomach, bladder cancer or carcinoma of testis and so on, the pharmaceutical composition that more advantageously is used for the treatment of colorectal carcinoma, pancreas cancer, especially colorectal carcinoma.

Compound of the present invention also can be used for preparing be used for the treatment of and/or prevention and farnesyl transferase relevant cell signal effect passage or with their medicine of consequence or the relevant disease of symptom.

Advantageously, can use compound of the present invention to be used for the treatment of and/or the medicine of the cell signal effect passage relative disease that prevention and Ras interrelate.Therefore, can use compound of the present invention to be used for the treatment of and/or prevent transplant rejection (as heteroplastic transplantation of the same race) (people such as O ' Donnel, nineteen ninety-five, Kidney International, the 48th volume, supplement 52, the S29-33 pages or leaves).

Equally, compound of the present invention can be used for preparing the medicine (people such as J.Rak who is used to suppress vasculogenesis and tumor growth is worked, cancer research, 55,4575-4580,1995), these angiogenesis inhibitor character also may be favourable for some blindness relevant with retinal vesselization of treatment;

Compound of the present invention also can be used for preparing the medicine that is used for the treatment of and/or prevents following disease:

-particularly including above-mentioned cancer with the relevant disease of apoptosis dysfunction (short-or anti--apoptosis);

-δ hepatitis and relevant virus (people such as J.S.Glenn, science, 256,1331-1333,1992), and without limitation, simplexvirus, poxvirus, epstein-barr virus, sindbis virus and adenovirus;

-inflammation and/or autoimmune disease, as without limitation, polyarthritis, multi-joint rheumatism, enteritis, pulmonary edema, myocardial infarction, fibrosis, lupus erythematosus are as Kaposi disease, immunity glomerulonephritis, autoimmune diabetes;

Restenosis after-cardiovascular disorder (arteriosclerosis or the infringement of other arteries), arterioplasty or the vascular operation;

-osteopathia, bone metabolism are regulated disease, for example Paget disease, hypercalcemia, metastatic tumor of bone, osteoporosis;

-the disease relevant with hypercholesterolemia is as hypercholesterolemia, hyperlipoidemia disease, hyperproteinemia, ephrosis hyperlipoidemia disease or atherosclerosis (people such as Massy, Lancet, 347,102-3,1996);

-neurodegenerative disease is as PakinsonShi disease, Alzheimer disease, amyotrophic lateral sclerosis, the sacred disease relevant with virus disease, as AIDS, the retinitis, spinocerebellum atrophy or degeneration;

And be used to prevent and/or treat following disease: AIDS especially, also has polycystic Kidney (people such as D.L.Schaffiner, American Journal of Pathology (American Journal ofPathology), 142,1051-1060,1993), neurofibroma, pulmonary fibrosis, sacroiliitis, psoriasis, glomerulonephritis, hypertrophic cicatrix form, endotoxin shock;

And myelodysplastic syndrome, aplastic anemia, the local asphyxia damage relevant, the damage of being correlated with cerebrovascular accident with infraction, and arrhythmia, arteriosclerosis, because the hepatic diseases that toxin or alcohol cause, particularly including the hemopathy of chronic or aplastic anemia, particularly including osteoporosis and arthritic Musculoskeletal degenerative disease, tumour fibrosis, multiple sclerosis, hepatic diseases, the pain relevant with cancer.

Can pass through to suppress tumor growth,, perhaps carry out described treatment by the tumor growth that suppresses expression activatory oncogene ras especially by suppressing farnesyl transferase.

Can also use other methods of treatment to carry out this treatment simultaneously, comprising antitumour drug, monoclonal antibody, immunotherapy or radiation treatment or biological response modifier.Reaction control agent comprises lymphokine and cytokine without limitation, as interleukin-, (α, β or δ) Interferon, rabbit and TNF.When treating the disease that causes owing to the improper propagation of cell, other effective chemotherapeutic comprises without limitation, alkylating agent as mustargen and so on, as chlormethine, endoxan, melphalan and Chlorambucil, alkyl sulfonate esters, as 1,4-dimethane sulfonoxybutane, nitrosourea, as carmustine, chlorethyl cyclohexyl nitrosourea, semustine and streptozocin, triazene is as Dacarbazine, metabolic antagonist, as folacin, as methotrexate, pyrimidine analogue, as Fluracil and cytarabine, purine analogue is as mercaptopurine and Tioguanine, natural product, as vinca alkaloids, as vincaleucoblastine, vincristine(VCR) and vendesine, epipodophyllotoxin is as Etoposide and teniposide, microbiotic, as gengshengmeisu, daunorubicin, Zorubicin, bleomycin, Plicamycin and mitomycin, enzyme is as L-Asnase, other medicaments, as the coordination complex of platinum,, replace urea as cis-platinum, as hydroxyurea, the methyl hydrazine derivative, as Procarbazine, the adrenal cortex inhibitor, as mitotane and aminoglutethimidium, hormone and antagonist are as adrenocortical steroid, as prednisone, Progesterone, as caproic acid hydroxyl progesterone ester, acetate methoxyl group corpus luteum ketone ester and acetate megestrol ester, oestrogenic hormon is as diethylstilbestrol and lynoral, estrogen antagonist, as tamoxifen, male sex hormone is as testosterone propionate ester and Ultandrene.

Another one purpose of the present invention is that general formula (I) product is cooperated with the compatibilized compound and/or any of radiation treatment of one or more pharmaceutical actives, so that reach synergistic therapeutic effect, described compound be known have suppress cell-proliferation activity, particularly treat the active active ingredient of cancer; The anti-proliferative compounds that they preferably work in some stage of oncogene ras signal pathway, as tyrosine kinase inhibitor, or other farnesyl transferase inhibitors, or HMG-Co-reductase inhibitor, or when the treatment cancer normally used cytotoxin compounds.

Product of the present invention can be used for prevention or delay disease symptoms occurring or occurring, or is used for the treatment of these disease symptomses.

That the present invention can adopt is oral, gi tract externally applied agent or intraperitoneal or rectal application, preferably adopts oral.

Oral compositions comprises tablet, pill, pulvis or granule.In these compositions, biologically active prod of the present invention can be mixed with one or more inert diluents, as sucrose, lactose or starch.These compositions can contain the material except that thinner, for example as the lubricant of Magnesium Stearate and so on.

As oral liquid composition, can use pharmaceutically emulsion, solution, suspension, the syrup accepted, contain elixir just like the inert diluent of water or paraffin oil and so on.

These compositions can also contain the material except that thinner, for example wetting agent, sweeting agent or perfume compound.

The gi tract externally applied agent of the present composition can be moisture or water-free solution, suspension or the emulsion of sterilization.As solvent or carrier, can use propylene glycol, polyoxyethylene glycol, vegetables oil, especially sweet oil or injectable organic ester, for example ethyl oleate.These compositions can also contain additive, particularly wetting agent, emulsifying agent and dispersion agent.Can adopt multiple mode to sterilize, for example adopt the bacterium filtration, in said composition, add disinfectant simultaneously, or adopt heat sterilization.They can also make sterilization solids composition form, in use, and can be in water or in any other injectable sterile medium with these composition dissolves.

The composition of rectal application is to fasten agent, and except biologically active prod, it can contain the vehicle just like Oleum Cocois and so on.

The dosage that is used to implement the inventive method is such, and this dosage makes prophylactic treatment or therapeutic response maximum.Its dosage can be decided with the characteristic of application method, selected specific product and object to be treated itself.Usually, these dosage should be that disease, the especially treatment to the inhibition cell that treatment is caused because of improper cell proliferation is effective.Can take product of the present invention by needed frequency of the result of treatment that will reach and time length.

Generally, people's dosage is to be every day the 0.1-10000 mg/kg, and preferably be the 100-2000 mg/kg every day, preferred oral.Should consider administrated method, patient body weight, general healthy state, age and any factor that may exert an influence to result of treatment when selecting optimal dosage.

Generally, according to the peculiar factor of age, body weight and any other object to be treated, the doctor can determine proper dosage.

Embodiment 105 explanations composition of the present invention.

Following embodiment illustrative and the present invention is described without limitation.

Embodiment 1

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

To 428 grams (1.98 moles) (RS)-3-oxo-6-phenyl hexamethylene-1-alkene-1-formic acid (can be according to " organic chemistry magazine ", 1971,36,3707 obtain) is at 4.5 centimetres ³Add 358 gram (2.52 moles) methyl iodide and 361 gram (2.38 moles) 1 in the solution in the acetone in succession, 8-diazabicyclo [5,4,0] 11 carbon-7-alkene, temperature rising reflux is 5 hours then.Boil off acetone then, again with resistates and 2.5 decimeters ³Water stirs together.After being cooled to 10 ℃, with the precipitation dehydration that generates, with the frozen water washing, then 30 ℃ of dryings.Obtain like this 423 the gram (93%) (RS)-3-oxo-6-phenyl hexamethylene-1-alkene-1-methyl-formiate, be the yellow powder shape, its feature is as follows:

-fusing point=66 ℃

-NMR composes (300MHz, CDCl ₃, represent δ with ppm): 2.1-2.4 (mt, 4H :), 3.72 (s, 3H:CH at 4 and 5 H ₃); (4.25 dt, 1H:6 position H); (6.88 s, 1H:2 position H); 7.2-7.52 (mt, 5H: aromatics).

Step B

With 170 grams (0.77 mole) (RS)-3-oxo-6-phenyl hexamethylene-1-alkene-1-methyl-formiate and 0.9 centimetre ³Trifluoroacetic acid is at 880 centimetres ³Solution temperature rising reflux in the methylene dichloride.Reflux add 15 minutes the time 256.3 gram (0.913 mole) N-n-butoxy methyl-[(trimethyl silyl) methyl-benzyl amine, the latter can be according to Chem.Pharm.Bull., 1985,276 obtain.At this moment reaction medium is cooled to 20 ℃.Adding 20 centimetres ³Behind the saturated sodium bicarbonate aqueous solution, the decant organic phase washes with water, stirs 30 minutes with 900 gram silicon-dioxide (63-200 order) then.Filter silicon-dioxide, use 1.5 centimetres again ³Washed with dichloromethane.Under reduced pressure after the concentrated solvent, obtain 270 gram brown oils, this oil is with 800 centimetres ³Hexanaphthene and 770 centimetres ³The dissolving of 1M aqueous methane sulfonic acid.After decant, organic phase is used 200 centimetres at every turn ³Twice of water washing.The water that merges is each with 200 centimetres ³The hexanaphthene washed twice is added the sodium bicarbonate neutralization then, uses 400 centimetres again ³Ethyl acetate extraction is used 200 centimetres then at every turn ³Twice of ethyl acetate extraction.The organic phase that merges with half saturated sodium chloride solution washing, is used dried over sodium sulfate again, under reduced pressure concentrates again.So obtain 248 grams (90%) (3aRS, 4SR 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate, are orange oily, and its feature is as follows:

-NMR composes (300MHz, CDCl ₃, represent d with ppm): 2.4-2.65 (mt, 4H:5 and 6 H), 2.85 (2dt, 2H:1 position H); (3.02 2dt, 2H:3 position H); (3.2 2dt, 1H:4 position H); (3.35 mt, 1H:7a position H); 3.5 (2dt, 2H: benzyl H); 7-7.3 (mt, 10H: aromatics).

Step C

With 5.1 centimetres ³4-bromo toluene and 1 gram cutting magnesium are at 100 centimetres ³Reflux is one hour in the ether.Add 100 centimetres ³Toluene, medium are heated to 60 ℃ under nitrogen gas stream.When being cooled near 5 ℃, (7aRS) 2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 80 centimetres for 3aRS, 4SR to add 10 grams ³Solution in the toluene.This reaction mixture stirred 1 hour down for about 20 ℃ in temperature, used 100 centimetres then ³Saturated aqueous ammonium chloride is hydrolyzed.Adopt the decantation water phase separated, and use 75 centimetres at every turn ³The ethyl acetate extraction secondary.Merge organic phase, and use 100 centimetres in succession ³Distilled water and 100 centimetres ³Dried over mgso is used in the saturated sodium-chloride water solution washing, under reduced pressure concentrates again.Using silicagel column flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out, obtain 9 gram (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-7-hydroxyl-7-(4-aminomethyl phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=164 ℃

- ¹HNMR composes (250MHz, CDCl ₃, represent d with ppm): 1.84 and 2.60 (d mt and mt, J=12.5Hz, each 1H:5 position CH ₂); 2.05-2.20 (mt, 2H:1 position CH ₂1H and 6 CH ₂1H); 2.32 (s3H:ArCH ₃); 2.40 and 2.95 (2d, J=10.5Hz, each 1H:3 position CH ₂); 2.45 (mt, 1H:6 position CH ₂Another H); 2.64 (mt, 1H:1 position CH ₂Another H); (2.85 mt, 1H:7a position H); 3.32 (s, 3H:COOCH ₃); 3.4 and 3.70 (2d, J=12.5Hz, each 1H:NCH ₂Ar); (3.50 dd, J=12.5 and 3Hz, 1H:4 position H); 6.68 (s; 1H:7 position OH); (7.00-7.50 mt, 10H:4 position aromatics H and benzyl aromatics H); 7.12 and 7.40 (2d, J=8Hz, each an aromatics ortho position, 2H:7 position and a position H).

Step D

Toward remain on 0 ℃ 20 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-7-hydroxyl-7-(4-aminomethyl phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate is at 200 centimetres ³In the solution in the methylene dichloride, drip 29 centimetres ³Trifluoromethanesulfonic acid and 100 centimetres ³The mixture of methylene dichloride.This reaction mixture stirred 30 minutes down for about 0 ℃ in temperature, stirred 2 hours for about 20 ℃ in temperature, was cooled to about 0 ℃ then.At this moment add 50 centimetres ³Distilled water is adjusted to 8-9 with the 4N aqueous sodium hydroxide solution with the pH of water again.Adopt decantation to separate organic phase, with 100 centimetres ³Distilled water and 100 centimetres ³Saturated sodium-chloride water solution washs in succession, with dried over mgso and under reduced pressure concentrated.In Virahol, obtain after the recrystallization 18.2 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=158 ℃

- ¹HNMR composes (250MHz, CDCl ₃, represent d with ppm): (3mts is respectively 1H-1H and 2H:CH to 1.61-1.90 and 2.67 ₂CH ₂); 2.50-2.60 (mt, 2H:1 position CH ₂1H and 3 CH ₂1H); 2.57 (s 3H:ArCH ₃); 2.95 (2d, J=10Hz, 1 CH ₂Another H); 3.37 (d, J=10Hz, 3 CH ₂Another H); (3.44 wide d, J=10Hz, 1H:9a position H); 3.54 and 3.85 (2d, J=12.5Hz, each 1H:NCH ₂Ar); (3.57 wide s, 1H:4 position H); 3.72 (s, 3H:COOCH ₃); 6.70 (wide d; J=7,5Hz, 1H:8 position H); (7.10-7.60 mt, an aromatics ortho position, H-9 position, H-7 position, H-6 position, 12H:5 position and a position H and benzyl aromatics hydrogen).

Step e

18 grams (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-methyl-formiate is at 250 centimetres ³Solution in the methyl alcohol in the presence of 2 gram 10% (w/w) palladium/carbon, reduces under 2 hours condition of reflux with 7.8 gram ammonium formiates.After cooling, the filtering separation catalyzer is used 50 centimetres at every turn ³Washed with methanol 3 times, and concentrated filtrate under reduced pressure.Resistates is dissolved in 200 centimetres ³In the ethyl acetate, organic phase is one after the other used 100 centimetres ³Saturated sodium bicarbonate aqueous solution, 100 centimetres ³Distilled water and 100 centimetres ³The saturated sodium-chloride water solution washing is with dried over mgso and under reduced pressure concentrated.At 100 centimetres ³Stir the oily crystallization that obtains in the pentane.Obtain after filtration 13.2 the gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=118 ℃

- ¹HNMR composes (250MHz, CDCl ₃, represent d with ppm): (3mts is respectively 1H-1H and 2H:CH to 1.56-1.78 and 2.24 ₂CH ₂); 2.42 (s, 3H:ArCH ₃); 2.79 and 2.96 (2dd is respectively J=12.5Hz and 5.5Hz and J=12.5 and 8Hz, each 1H:1 position CH ₂); 3.10 and 3.39 (2d, J=12.5Hz, each 1H:3 position CH ₂); (3.30 mt, 1H:9 position H); (3.51 wide s, 1H:4 position H); 3.60 (s, 3H:COOCH ₃); 6.56 (wide d; J=7,5Hz, 1H:8 position H); (6.95-7.45 mt, H-6 position, 7H:5 position H-7 position H and 9 aromatics ortho positions and a position H).

Step F

Restrain (2-p-methoxy-phenyl) acetate at 110 centimetres with 36.6 ³Suspension in two (dimethylamino) methane is cooled to 0 ℃ of temperature.Drip 110 centimetres ³Diacetyl oxide makes the temperature of reaction medium be no more than 40 ℃.Reaction mixture stirred 24 hours at about 20 ℃, was cooled to about 0 ℃ then.At this moment add 500 centimetres ³Distilled water continues to stir 2 hours for about 0 ℃ in temperature.The resulting solid of filtering separation is used 100 centimetres at every turn ³Distilled water wash three times, dry under 40 ℃ of decompressions.Obtain 23 gram 2-(2-p-methoxy-phenyl) vinylformic acid like this, be milk look solid state, its feature is as follows:

-fusing point=145 ℃

- ¹HNMR composes (200MHz, DMSO d6 represents d with ppm): 3.74 (s, 3H:ArOCH ₃); 5.71 and 6.15 (2d, J=0.5Hz, each 1H:=CH ₂); 6.90-7.50 (mt, 4H: aromatics H); 11.5-13.5 (mf of non-constant width, 1H:COOH).

Step G

Toward containing 5 N, 6.31 gram 2-(2-p-methoxy-phenyl) vinylformic acid of dinethylformamide are at 150 centimetres ³In the solution in the methylene dichloride, drip 3.05 gram centimeters ³Oxalyl chloride is at 150 centimetres ³Solution in the methylene dichloride.Reaction mixture stirred 2 hours down for about 20 ℃ in temperature, was cooled to about 0 ℃ of temperature then, and was added drop-wise to 12.3 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-methyl-formiate is at 250 centimetres ³Methylene dichloride and 10 centimetres ³In the solution in the triethylamine, solution temperature keeps about 0 ℃.This reaction mixture stirred 1 hour down for about 0 ℃ in temperature then, stirred 1 hour down, and pour 200 centimetres into for about 20 ℃ in temperature again ³In the distilled water.Adopt decantation to separate organic phase, use 200 centimetres at every turn ³Distilled water wash twice is used 200 centimetres again ³The saturated sodium-chloride water solution washing is with dried over mgso and under reduced pressure concentrated.With silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (second volumeter 70-30) wash-out, obtain 14.9 gram (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f]-isoindole-3a-methyl-formiate, the solid that is white in color, its feature is as follows:

-fusing point=152 ℃

- ¹HNMR composes (temperature 383K represents d with ppm for 250MHz, DMSO d6): (3mts is respectively 1H-1H and 2H:CH for 1.44-1.68 and 2.00-2.30 ₂CH ₂); 2.40 (s, 3H:ArCH ₃); 3.35-3.50 (mt, 3H:1 position CH ₂With 9a position H); (3.46 mt, 1H:4 position H); 3.55 (s, 3H:COOCH ₃); 3.60 and 4.10 (2d, J=12.5Hz, each 1H:3 position CH ₂); 3.73 (s, 3H; ArOCH ₃); 5.54 and 5.70 (2s, each 1H:=CH ₂); 6.46 (wide d; J=7,5Hz, 1H:8 position H); 6.90-7.40 (mt, H-6 position, 11H:5 position H-7 position H and 9 aromatics ortho positions and position H and OCH ₃Ortho position, Meta-and para-aramid H).

Embodiment 2

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid

At 400 centimetres ³In the ethanol, at 43.5 centimetres ³The 1M aqueous sodium hydroxide solution exists down, with 14.7 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-methyl-formiate reflux six hours.Reaction mixture under reduced pressure concentrates then, and resistates is dissolved in 250 centimetres ³In the distilled water.Water is each with 200 centimetres ³Ether washing three times is acidified to pH about 2 with the 4N aqueous hydrochloric acid then.The crystal that filtering separation obtains is used 400 centimetres at every turn ³Distilled water wash three times is used 200 centimetres again ³Petroleum ether at 40 ℃ of drying under reduced pressure, obtains 12.6 gram (3aRS like this; 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid, the solid state that is white in color, its feature is as follows:

-fusing point=142 ℃

- ¹HNMR spectrum (temperature 383K represents d with ppm for 250MHz, DMSO d6): 1.42-1.65-2.00 and 2.15 (4mts, each 1H:CH ₂CH ₂); 2.40 (s, 3H:ArCH ₃); 3.20-3.40 (mt, 3H:1 position CH ₂With 9a position H); 3.55 (mt1H:, 4 H); 3.60 and 4.06 (2d, J=12.5Hz, each 1H:3 position CH ₂); 3.68 (s, 3H; OCH ₃); 5.53 and 5.70 (2s, each 1H:=CH ₂); 6.45 (wide d; J=7,5Hz, 1H:8 position H); 6.95 (wide t, J=7.5Hz, 1H:OCH ₃Contraposition aromatics H); 7.03 (wide d, J=7.5Hz, 1H:OCH ₃Ortho position aromatics H); 6.90-7.30 (mt, H-6 position, 9H:5 position H-7 position H and OCH ₃Between position aromatics H and 9 aromatics ortho positions and a position aromatics H).

Embodiment 3

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid dextrorotation Separation of Enantiomers

500 milligrams of (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid chirality silica column, promptly (3; the 5-dinitrobenzoyl)-and the separation of S-phenylalanine grafting carrier, with methylene dichloride, Virahol and normal heptane mixture (by volume 85-10-5) wash-out.Reclaim second part of eluting fraction (retention time 60 minutes), obtain 220 milligrams of dextrorotation enantiomorphs after under reduced pressure concentrating, its feature is as follows:

-fusing point=225 ℃

-mass spectrum (IE): M/Z=493 (M ⁺) and 449 (M ⁺-CO ₂)

-specific rotation: [α] ₃₆₅ ²⁰=+63.3+/-1.0 ° (c=0.5/ methyl alcohol).

Chirality silicon-dioxide can prepare as follows:

At 6 decimeters ³In the there-necked flask, with 948 gram aminopropyl silicon-dioxide (100 dusts-10 μ m-NH ₂Macherey-Nagel) be suspended in 36 decimeters ³N is in the dinethylformamide.Add 180 gram uncle N--butoxy carbonyl amino-11-undecane acid anhydrides, and about 20 ℃ of following stirred reaction mixtures of temperature 18 hours.Filtering separation silicon-dioxide is one after the other used 2500 centimetres at every turn ³Washed with dichloromethane twice is used 2500 centimetres more at every turn ³N, the dinethylformamide washed twice.The silicon-dioxide of washing like this is re-suspended into 3 liters of N, in the dinethylformamide, and adds and to add 180 gram uncle N--butoxy carbonyl amino-11-undecane acid anhydrides again, and about 20 ℃ of following stirred reaction mixtures of temperature 18 hours.Filtering separation silicon-dioxide is one after the other used 2500 centimetres at every turn ³Washed with dichloromethane twice is used 2500 centimetres at every turn ³The tetrahydrofuran (THF) washed twice is used 2500 centimetres more at every turn ³Twice of methanol wash and each with 2500 centimetres ³The ether washed twice, dry under the about 20 ℃ of decompressions of temperature then.Obtain 971 grams like this and be called " BOC-C ₁₁-C ₃-silicon-dioxide " silicon-dioxide, it is Powdered to be white in color, its structure adopts infrared spectra to confirm, and results of elemental analyses (measured value) is C%=9.85; H%=2.05; N%=1.05.

At 6 decimeters ³In the there-necked flask, with 971 gram " BOC-C ₁₁-C ₃-silicon-dioxide " silicon-dioxide is suspended in 2500 centimetres ³In methylene dichloride and the 470 gram imidazoles.Drip 850 centimetres ³Dimethyl octyl group chloro silicomethane, reaction mixture stirred 16 hours down for about 20 ℃ in temperature.The resulting solid of filtering separation is one after the other used 2500 centimetres at every turn ³Washed with dichloromethane twice is used 2500 centimetres at every turn ³Methanol wash twice is used 2500 centimetres at every turn ³The tetrahydrofuran (THF) washed twice is used 2500 centimetres at every turn ³Twice of washed with dichloromethane and each with 2500 centimetres ³The ether washed twice, dry under the about 20 ℃ of decompressions of temperature then.Obtain 1179 gram title " BOC-C like this ₁₁-C ₃-silicon-dioxide-O-Si (CH ₃) ₂(CH ₂) ₇CH ₃" silicon-dioxide of expression, it is Powdered to be white in color, and its structure adopts infrared spectra to confirm, and results of elemental analyses (measured value) is C%=13.9; H%=2.83; N%=1.16.

At 6 decimeters ³In the there-necked flask, with 1178 gram " BOC-C ₁₁-C ₃-silicon-dioxide-O-Si (CH ₃) ₂(CH ₂) ₇CH ₃" silicon-dioxide is suspended in 2500 centimetres ³In the solution of 5% (volume) trifluoroacetic acid in methylene dichloride.20 ℃ are stirred down.Filtering separation silicon-dioxide is one after the other used 2500 centimetres at every turn ³Washed with dichloromethane twice is used 2500 centimetres at every turn ³Methylene dichloride-diisopropyl ethyl amine mixture (by volume 70-30) washed twice is used 2500 centimetres at every turn ³Washed with dichloromethane twice is used 2500 centimetres at every turn ³The tetrahydrofuran (THF) washed twice is used 2000 centimetres at every turn ³Twice of methanol wash and at every turn use 2000 centimetres ³The ether washed twice, dry under the about 50 ℃ of decompressions of temperature then.Obtain 1080.5 gram title " C like this ₁₁-C ₃-silicon-dioxide-O-Si (CH ₃) ₂(CH ₂) ₇CH ₃" silicon-dioxide of expression, it is Powdered to be white in color, and its structure adopts infrared spectra to confirm, and results of elemental analyses (measured value) is C%=12.6; H%=2.44; N%=1.05.

At 6 decimeters ³In the there-necked flask, with 1080 gram " C ₁₁-C ₃-silicon-dioxide-O-Si (CH ₃) ₂(CH ₂) ₇CH ₃" silicon-dioxide is suspended in 2500 centimetres ³With the N of 4 dust molecular sieve dryings, in the dinethylformamide.Add 108 gram N-benzoyls-3,5-dinitrobenzene-L-phenylalanine and 75 gram N-ethoxy carbonyl-2-oxyethyl groups-1,2-dihydroquinoline.Reaction mixture was stirred for 1 night.With fritted glass filter filtering separation silicon-dioxide, one after the other use 2500 centimetres then at every turn ³Washed with dichloromethane twice is used 2500 centimetres at every turn ³The tetrahydrofuran (THF) washed twice is used 2500 centimetres at every turn ³N, dinethylformamide washed twice and each with 2500 centimetres ³Twice of washed with dichloromethane.The silicon-dioxide that will so wash is re-suspended into 2500 centimetres then ³N, dinethylformamide.Add 108 gram N-benzoyls-3 in succession, 5-dinitrobenzene-L-phenylalanine and 75 gram N-ethoxy carbonyl-2-oxyethyl groups-1, the 2-dihydroquinoline stirred for 1 night at 20 ℃ then.With fritted glass filter filtering separation silicon-dioxide, one after the other use 2500 centimetres then at every turn ³Washed with dichloromethane twice is used 2500 centimetres at every turn ³The tetrahydrofuran (THF) washed twice is used 2500 centimetres at every turn ³Twice of methanol wash and each with 2500 centimetres ³The ether washed twice.Under the about 60 ℃ of decompressions of temperature (2.7 kPas), after the drying, obtain 1093.6 gram title " DNB-L-Phe-C ₁₁-C ₃-(silicon-dioxide)-O-Si (CH ₃) ₂(CH ₂) ₇CH ₃" silicon-dioxide of expression, being the pale yellow powder shape, its structure adopts infrared spectra to confirm, and results of elemental analyses (measured value) is C%=14.5; H%=2.4; N%=1.68.

At 4 decimeters ³In the there-necked flask, with 519 gram " DNB-L-Phe-C ₁₁-C ₃-(silicon-dioxide)-O-Si (CH ₃) ₂(CH ₂) ₇CH ₃" silicon-dioxide is suspended to 3000 centimetres ³With the N of 4 dust molecular sieve dryings, in the dinethylformamide.In 15 minutes, add 450 centimetres ³Trimethyl-silyl-imidazole stirred for 1 night then.Filtering separation silicon-dioxide, and one after the other use 1500 centimetres at every turn ³The tetrahydrofuran (THF) washed twice is used 1500 centimetres at every turn ³Methanol wash twice is used 1500 centimetres at every turn ³Twice of washing with acetone and each with 1500 centimetres ³Methylene dichloride ether washed twice.Under the about 60 ℃ of decompressions of temperature (2.7 kPas), after the drying, obtain 519 gram title " DNB-L-Phe-C ₁₁-C ₃-(silicon-dioxide)-[O-Si (CH ₃) ₂(CH ₂) ₇CH ₃]-[O-Si (CH ₃) ₃] " silicon-dioxide of expression, being the pale yellow powder shape, its structure adopts infrared spectra to confirm, and results of elemental analyses (measured value) is C%=15.3; H%=1.8; N%=2.6.

Can prepare N-tert-butoxycarbonyl-11-amino-undecane acid anhydrides as follows:

30.1 gram uncle N--butoxy carbonyl-11-amino-undecanoic acids are dissolved in 480 centimetres ³In the ethyl acetate.This solution is cooled to 5 ℃, remains on this temperature then simultaneously, added 10.63 grams 1 in 10 minutes, the 3-dicyclohexyl carbodiimide is at 120 centimetres ³Solution in the ethyl acetate.Stirred this reaction mixture 1 hour at 5 ℃, stirred 16 hours down at about 20 ℃ then.The precipitation that filtering separation generated, and with 30 centimetres ³The ethyl acetate washing.Concentrated filtrate under the about 30 ℃ of decompressions of temperature (2.7 kPas).Resulting solid carries out drying under 20 ℃ of decompressions (2.7 kPas).Obtain 31 gram N-tert-butoxycarbonyl-11-amino-undecane acid anhydrides like this, productive rate about 100%.

Can be according to the organic chemistry magazine, 41,1350 (1976) preparation N-tert-butoxycarbonyl-11-amino-undecanoic acids.

Embodiment 4

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9, the separation of 9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid levo-enantiomer

500 milligrams of (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid chirality silica column, promptly (3; the 5-dinitrobenzoyl)-and the separation of S-phenylalanine grafting carrier, with methylene dichloride, Virahol and normal heptane mixture (by volume 85-10-5) wash-out.Reclaim first part of eluting fraction (retention time 47 minutes), obtain 240 milligrams of levo-enantiomers after under reduced pressure concentrating, its feature is as follows:

-fusing point=225 ℃

-mass spectrum (IE): M/Z=493 (M ⁺) and 449 (M ⁺-CO ₂)

-specific rotation: [α] ₃₆₅ ²⁰=-76.0+/-1.2 ° (c=0.5/ methyl alcohol).

Embodiment 5

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid

Steps A

To 755 milligrams (2.17 mmoles) embodiment 1 step e obtain (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-methyl-formiate is at 20 centimetres ³In the solution in the methylene dichloride, add 362 milligrams of (2.17 moles) 2-anisole guanidine-acetic acids, 456 milligrams of (2.38 mmole) 1-ethyl-3-[(3-dimethylaminos in succession) propyl group] carbodiimide hydrochloride and 59 milligrams of (0.43 mmole) N-hydroxy benzotriazole hydrates.Add 15 centimetres after at room temperature stirring a night ³Methylene dichloride is used 15 centimetres at every turn ³Dried over mgso is used in water washing twice again, under reduced pressure boils off solvent.With silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 820 milligrams of (76%) (3aRS after the pressure reducing and steaming solvent; 4SR, 9SR, 9aRS)-4; 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(4-aminomethyl phenyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f]-isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=189 ℃

-mass spectrum (IE): M/Z=495 (M ⁺)

Step B

Operation as embodiment 2, but be to use 819 milligrams of (1.65 mmole) (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(4-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-methyl-formiate are at 17 centimetres ³1M aqueous sodium hydroxide solution and 17 centimetres ³Refluxed 18 hours in the methyl alcohol, at 25 centimetres ³Obtain 720 milligrams of (74%) (3aRS in the isopropyl ether after the recrystallization; 4SR, 9SR, 9aRS)-4; 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(4-aminomethyl phenyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid, it is Powdered to be white in color, and its feature is as follows:

-fusing point=182 ℃

- ¹HNMR spectrum (temperature 423K represents d with ppm for 400MHz, DMSO d6): 1.40-1.64-1.95 and 2.10 (4mts, each 1H:CH ₂CH ₂); 2.41 (s, 3H:ArCH ₃); 3.30-3.65 (mt, 6H:1 position CH ₂-NH ₂Ar-3 position CH ₂1H and 9a position H); (3.48 mt, 1H:4 position H); 3.75 (s, 3H:OCH ₃); 4.18 (d, J=12.5Hz, 1H:3 position CH ₂Another H); (6.46 wide d, J=7.5Hz, 1H:8 position H); 6.90 (wide t, J=7.5Hz, 1H:OCH ₃The fragrant H of contraposition; 6.96 (wide d, J=7.5Hz, 1H:OCH ₃Adjacent fragrance H); 7.00-7.35 (mt, H-6 position, 5H:5 position H-7 position H-OCH ₃Between the position fragrant H); (7.30 AB, the fragrant H of an aryl ortho position, 4H:9 position and a position).

Embodiment 6

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid

Steps A

With 2.07 centimetres ³(16.5 mmole) 4-bromo phenylmethylether and 402 milligrams (16.5 mmole) cutting magnesium are at 20 centimetres ³Solution in ether reflux three hours under argon atmospher.Be cooled to after 0 ℃, add 1.36 gram (5.5 mmole) anhydrous cerium chlorides, then temperature about 5 ℃ under argon atmospher, drip (5.5 mmoles) that 2 grams obtain at embodiment 1 step B (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 5 centimetres ³Solution in the anhydrous diethyl ether.Reaction mixture stirred 1 hour down at about 0 ℃, at room temperature stirred a night then.Being cooled to after 0 ℃, with 15 centimetres ³This reaction medium of saturated aqueous ammonium chloride hydrolysis.Adopt the decantation water phase separated, use 50 centimetres at every turn ³Twice of ethyl acetate extraction.Merge organic phase, one after the other use 25 centimetres ³Distilled water and 25 centimetres ³Dried over mgso is used in the saturated sodium-chloride water solution washing, under reduced pressure concentrates again.Adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 60-40) wash-out, obtain 1.345 gram (51%) (3aRS, 4SR, 7RS, 7aRS)-and 2-benzyl-7-hydroxyl-7-(4-p-methoxy-phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=136 ℃

Step B

As embodiment 1 step D, operate, but be to use 1.343 grams (2.85 mmole) (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-hydroxyl-7-(4-p-methoxy-phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate and 4.56 centimetres ³Trifluoromethanesulfonic acid is at 65 centimetres ³Solution in the methylene dichloride, following 30 minutes of about 0 ℃ of temperature, night at room temperature then, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 863 milligrams of (67%) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=127 ℃

Step C

As embodiment 1 step e, operate, but be to use 839 milligrams of (1.85 mmole) (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 0.35 gram (5.5 mmole) ammonium formiate, in the presence of 0.27 gram 10% (w/w) palladium/carbon, at 20 centimetres ³In the methyl alcohol, reflux 3 hours is at 30 centimetres ³Stir after the resulting sead albumen crisp skin sample material in the pentane, obtain 559 milligrams of (83%) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=112 ℃

Step D

As embodiment 5 steps A, operate, but be to use 548 milligrams of (1.51 mmole) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 251 milligrams of (1.51 mmole) 2-anisole guanidine-acetic acids, 318 milligrams of (1.66 mmole) 1-ethyl-3-[(3-dimethylaminos) propyl group] carbodiimide hydrochloride and 41 milligrams of (0.3 mmole) N-hydroxy benzotriazole hydrates are at 15 centimetres ³Solution in the methylene dichloride is adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out; obtain 575 milligrams of (75%) (3aRS, 4SR, 9SR; 9aRS)-4, ethanoyl 9-ethano--9-(4-p-methoxy-phenyl)-2-[(2-p-methoxy-phenyl)]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate; it is Powdered to be white in color, and its feature is as follows:

-fusing point=169 ℃

-mass spectrum (IE): M/Z=511 (M ⁺)

Step e

Operation as embodiment 2; but be to use 566 milligrams of (1.1 mmole) (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 11.5 centimetres ³1M aqueous sodium hydroxide solution and 7.5 centimetres ³Refluxed 18 hours in the methyl alcohol, at 10 centimetres ³After the recrystallization, obtain 385 milligrams of (75%) (3aRS, 4SR in the isopropyl ether; 9SR; 9aRS)-4, ethanoyl 9-ethano--9-(4-p-methoxy-phenyl)-2-[(2-p-methoxy-phenyl)]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; it is Powdered to be white in color, and its feature is as follows:

-fusing point=163 ℃

- ¹HNMR spectrum (temperature 393K represents d with ppm for 400MHz, DMSO d6): 1.36-1.61-1.90 and 2.07 (4mts, each 1H:CH ₂CH ₂); 3.30-3.65 (mt, 6H:1 position CH ₂-NCOCH ₂Ar-3 position CH ₂1H and 9a position H); (3.46 mt, 1H:4 position H); 3.73 (wide s, 3H:OCH ₃); 3.80 (s, 3H:9 position aromatics OCH ₃); 4.15 (d, J=12.5Hz, 1H:3 position CH ₂Another H); 6.45 (wide d; J=7,5Hz, 1H:8 position H); 6.90 (wide t, J=7.5Hz, 1H:OCH ₃Contraposition aromatics H); 6.96 (wide d, J=7.5Hz, 1H:OCH ₃Ortho position aromatics H); 7.06 (d, J=8Hz, 2H:9 position aromatics OCH ₃Ortho position H); 7.00-7.30 (mt, H-6 position, 5H:5 position H-7 position H and OCH ₃Between position aromatics H); 7.30 (d, J=8Hz, 2H:9 position aromatics OCH ₃Between position aromatics H).

Embodiment 7

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(4-methylthio group phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid

Steps A

As embodiment 6 steps A, operate, but be to use 1.34 gram (6.6 mmole) 4-bromo sulfo-phenylmethylethers and 161 milligrams (6.6 mmole) cutting magnesium at 4 centimetres ³Vlil in the ether three hours, add 543 milligrams of (2.2 mmole) anhydrous cerium chlorides then in succession, with 800 milligrams (2.2 mmoles) embodiment 1 step B obtain (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 2 centimetres ³Solution in the ether.Adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out, obtain 679 milligrams of (63%) (3aRS, 4SR, 7RS, 7aRS)-and 2-benzyl-7-hydroxyl-7-(4-methylthio group phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=124-6 ℃

Step B

As embodiment 1 step D, operate, but be to use 676 milligrams (1.39 mmoles) (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-hydroxyl-7-(4-methylthio group phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate and 2.22 centimetres ³Trifluoromethanesulfonic acid is at 34 centimetres ³Solution in the methylene dichloride, following 30 minutes of about 0 ℃ of temperature, at room temperature 70 hours then, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 366 milligrams of (56%) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-methylthio group phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=105-7 ℃

Step C

With 246 milligrams (0.52 mmoles) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-methylthio group phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is at 10 centimetres ³Solution in the methylene dichloride is cooled to 0 ℃ under argon atmospher.At this moment add 115 milligrams of (0.79 mmole) carbonochloridic acid 2-chloroethene esters, at room temperature stir a night then.Under reduced pressure after the concentrated solvent, resistates is at 10 centimetres ³Contain 1.5 centimetres ³Reflux is 4 hours in the methyl alcohol of 1M methanol hydrochloride solution.With the crystal dehydration that generates, use 1 centimetre at every turn ³The ice cold methanol washed twice is then at 10 centimetres ³0.1M stir neutralization in the sodium hydroxide solution.With dichloromethane extraction and be concentrated into do after, obtain 145 milligrams of (62%) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-methylthio group phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the sead albumen crisp skin sample material shape that is white in color, its feature is as follows:

-fusing point=90-4 ℃

Step D

As embodiment 5 steps A, operate, but be to use 145 milligrams of (0.38 mmole) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-methylthio group phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 64 milligrams of (0.38 mmole) 2-anisole guanidine-acetic acids, 91 milligrams of (0.42 mmole) 1-ethyl-3-[(3-dimethylaminos) propyl group] carbodiimide hydrochloride and 10 milligrams of (0.076 mmole) N-hydroxy benzotriazole hydrates are at 5 centimetres ³Solution in the methylene dichloride is adopting silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (80-20 of by volume elder generation; back 70-30) after the wash-out, obtains 182 milligrams of (90%) (3aRS, 4SR; 9SR, 9aRS)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(4-methylthio group phenyl)--2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=137 ℃

-mass spectrum (IE): M/Z=527 (M ⁺)

Step e

Operation as embodiment 2; but be to use 180 milligrams of (0.34 mmole) (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(4-methylthio group phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 3.7 centimetres ³1M aqueous sodium hydroxide solution and 3.7 centimetres ³Refluxed 18 hours in the methyl alcohol, at 5 centimetres ³After the recrystallization, obtain 144 milligrams of (81%) (3aRS, 4SR in the isopropyl ether; 9SR; 9aRS)-4, ethanoyl 9-ethano--2-[(2-p-methoxy-phenyl)]-9-(4-methylthio group phenyl)-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; it is Powdered to be white in color, and its feature is as follows:

-fusing point=145 ℃

- ¹HNMR spectrum (temperature 393K represents d with ppm for 250MHz, DMSO d6): 1.40-1.63-1.92 and 2.10 (4mts, each 1H:CH ₂CH ₂); 2.59 (s, 3H:SCH ₃); 3.30-3.70 (mt, 6H:1 position CH ₂-NCOCH ₂Ar-3 position CH ₂1H and 9a position H); (3.50 mt, 1H:4 position H); 3.73 (wide s, 3H:OCH ₃); 4.18 (d, J=12.5Hz, 1H:3 position CH ₂Another H); 6.48 (wide d; J=7,5Hz, 1H:8 position H); 6.92 (wide d, J=7.5Hz, 1H:OCH ₃Contraposition aromatics H); 7.00 (wide d, J=7.5Hz, 1H:OCH ₃Ortho position aromatics H); 7.05-7.35 (mt, H-6 position, 5H:5 position H-7 position H and OCH ₃Between position aromatics H); 7.35 and 7.45 (2 wide d, J=8Hz, the adjacent and position aromatics H of each 2H:9 position aromatics).

Embodiment 8

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-fluorophenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid

Steps A

As embodiment 6 steps A, operate, but be to use 6.1 centimetres ³The solution of 1M4-bromo phenyl-magnesium-bromide in ether, add 1.36 gram (5.5 mmole) anhydrous cerium chlorides then in succession, with 2 grams embodiment 1 step B resulting (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-phenyl octahydro isoindole-3a-methyl-formiate is at 20 centimetres ³Solution in the ether, adopting silica gel (230-400 order) flash chromatography purifying, use earlier hexanaphthene, the back obtains 507 gram (20%) (3aRS, 4SR with after hexanaphthene-ethyl acetate mixture (by volume 60-40) wash-out, 7RS, 7aRS)-and 2-benzyl-7-(4-fluorophenyl)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=163 ℃

Step B

As embodiment 1 step D, operate, but be to use 433 milligrams (0.94 mmoles) (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-(4-fluorophenyl)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate and 1.51 centimetres ³Trifluoromethanesulfonic acid is at 20 centimetres ³Solution in the methylene dichloride, following 30 minutes of about 0 ℃ of temperature, at room temperature 70 hours then, adopting silica gel (230-400 order) flash chromatography purifying, use earlier hexanaphthene, the back is with after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 360 milligrams of (86%) (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(4-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=157 ℃

Step C

As embodiment 1 step e, operate, but be to use 358 milligrams of (0.81 mmole) (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(4-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 153 milligrams of (2.43 mmole) ammonium formiates, in the presence of 120 milligram of 10% (w/w) palladium/carbon, at 20 centimetres ³In the methyl alcohol, reflux 3 hours is at 15 centimetres ³Stir in the pentane after the resulting sead albumen crisp skin sample material, obtain 236 milligrams (83%) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=163 ℃

Step D

As embodiment 5 steps A, operate, but be to use 235 milligrams of (0.67 milli rub 0 you) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 112 milligrams of (0.67 mmole) 2-anisole guanidine-acetic acids, 142 milligrams of (0.74 mmole) 1-ethyl-3-[(3-dimethylaminos) propyl group] carbodiimide hydrochloride and 19 milligrams of (0.076 mmole) N-hydroxy benzotriazole hydrates are at 10 centimetres ³Solution in the methylene dichloride is adopting silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (90-10 of by volume elder generation; back 80-20) after the wash-out, obtains 230 milligrams of (68%) (3aRS, 4SR; 9SR, 9aRS)-4,9-ethano--9-(4-fluorophenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=216 ℃

-mass spectrum (IE): M/Z=499 (M ⁺)

Step e

Operation as embodiment 2, but be to use 228 milligrams of (0.45 mmole) (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-fluorophenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 4.7 centimetres ³The 1 molar sodium hydroxide aqueous solution and 5 centimetres ³Refluxed 18 hours in the methyl alcohol, at 5 centimetres ³After the recrystallization, obtain 171 milligrams of (77%) (3aRS, 4SR in the isopropyl ether; 9SR; 9aRS)-4, ethanoyl 9-ethano--9-(4-fluorophenyl)-2-[(2-p-methoxy-phenyl)]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; it is Powdered to be white in color, and its feature is as follows:

-fusing point=250 ℃

- ¹HNMR spectrum (temperature 393K represents d with ppm for 400MHz, DMSO d6): 1.40-1.64-1.95 and 2.10 (4mts, each 1H:CH ₂CH ₂); 2.41 (s, 3H:ArCH ₃); 3.30-3.65 (mt, 6H:1 position CH ₂-NCOCH ₂Ar-3 position CH ₂1H and at 9a position H); (3.48 mt, 1H:4 position H); 3.75 (s, 3H:OCH ₃); 4.18 (d, J=12.5Hz, 1H:3 position CH ₂Another H); 6.46 (wide d; J=7,5Hz, 1H:8 position H); 6.90 (wide t, J=7.5Hz, 1H:OCH ₃Contraposition aromatics H); 6.96 (wide d, J=7.5Hz, 1H:OCH ₃Ortho position aromatics H); 7.00-7.35 (mt, H-6 position, 5H:5 position H-7 position H and OCH ₃Between position aromatics H); (7.30 restriction AB, an aromatics ortho position, 4H:9 position and a position aromatics H).

Embodiment 9

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid

Steps A

As embodiment 6 steps A, operate, but be to use 2.42 centimetres ³The solution of tolyl bromination magnesium in tetrahydrofuran (THF) between 1M, add 543 milligrams of (2.2 mmole) anhydrous cerium chlorides then in succession, (the 3aRS that obtains at embodiment 1 step B with 800 milligrams (2.2 mmoles), 4SR, 7aRS) 2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 10 centimetres ³Solution in the anhydrous diethyl ether.Adopting silica gel (230-400 order) flash chromatography purifying, use earlier hexanaphthene, the back is with after hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out, obtain 505 milligrams of (50%) (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-hydroxyl-7-(3-aminomethyl phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=117-9 ℃

Step B

As embodiment 1 step D, operate, but be to use 669 milligrams (1.47 mmoles) (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-hydroxyl-7-(3-aminomethyl phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate and 2.35 centimetres ³Trifluoromethanesulfonic acid is at 33 centimetres ³Solution in the methylene dichloride, following 30 minutes of about 0 ℃ of temperature, at room temperature 48 hours then, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 582 milligrams of (90%) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=113-5 ℃

Step C

As embodiment 1 step e, operate, but be to use 578 milligrams of (1.27 mmole) (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 241 milligrams of (3.82 mmole) ammonium formiates, in the presence of 185 milligram of 10% (w/w) palladium/carbon, at 20 centimetres ³In the methyl alcohol, reflux 3 hours is at 10 centimetres ³Stir in the pentane after the resulting sead albumen crisp skin sample material, obtain 412 milligrams (93%) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=103 ℃

Step D

As embodiment 6 steps A, operate, but be to use 409 milligrams of (1.18 mmole) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 196 milligrams of (1.18 mmole) 2-anisole guanidine-acetic acids, 248 milligrams of (1.29 mmole) 1-ethyl-3-[(3-dimethylaminos) propyl group] carbodiimide hydrochloride and 32 milligrams of (0.076 mmole) N-hydroxy benzotriazole hydrates are at 12 centimetres ³Solution in the methylene dichloride adopting silica gel (230-400 order) flash chromatography purifying, is used earlier hexanaphthene; the back obtains 509 milligrams of (86%) (3aRS, 4SR with after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out; 9SR, 9aRS)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(3-aminomethyl phenyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=132 ℃

-mass spectrum (IE): M/Z=495 (M ⁺)

Step e

Operation as embodiment 2; but be to use 506 milligrams of (1.02 mmole)-(3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(3-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 10.3 centimetres ³1M aqueous sodium hydroxide solution and 7 centimetres ³Refluxed 18 hours in the methyl alcohol, at 5 centimetres ³After the recrystallization, obtain 424 milligrams of (87%) (3aRS, 4SR in the isopropyl ether; 9SR; 9aRS)-4, ethanoyl 9-ethano--2-[(2-p-methoxy-phenyl)]-9-(3-aminomethyl phenyl)-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; it is Powdered to be white in color, and its feature is as follows:

-fusing point=138 ℃

- ¹HNMR spectrum (temperature 393K represents d with ppm for 250MHz, DMSO d6): 1.40-1.66-1.95 and 2.10 (4mts, each 1H:CH ₂CH ₂); 2.43 (s, 3H:ArCH ₃); 3.30-3.65 (mt, 6H:1 position CH ₂-NCOCH ₂Ar-3 position CH ₂1H and 9a position H); (3.48 mt, 1H:4 position H); 3.73 (wide s, 3H:OCH ₃); 4.18 (d, J=12.5Hz, 1H:3 position CH ₂Another H); 6.45 (wide d; J=7,5Hz, 1H:8 position H); 6.92 (wide t, J=7.5Hz, 1H:OCH ₃Contraposition aromatics H); 6.98 (wide d, J=7.5Hz, 1H:OCH ₃Ortho position aromatics H); 7.00-7.35 (mt, H-9 position, H-7 position, H-6 position, 8H:5 position aryl OCH ₃Between position aromatics H and CH ₃Ortho position and contraposition aromatics H); 7.40 (t, J=8Hz, 1H:9 position aryl CH ₃Between position aromatics H).

Embodiment 10

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(3-p-methoxy-phenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-formic acid

Steps A

As embodiment 6 steps A, operate, but be to use 1.56 centimetres ³(12.4 mmole) 3-bromo phenylmethylether and 302 milligrams (12.4 mmole) cutting magnesium are at 5 centimetres ³Refluxed one hour in the anhydrous diethyl ether, add 1.02 gram (4.13 mmole) anhydrous cerium chlorides then in succession, with 1.5 grams (4.13 mmole) embodiment 1 step B obtain (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 8 centimetres ³Solution in the ether.Adopting silica gel (230-400 order) flash chromatography purifying, use earlier hexanaphthene, use again after hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out, obtain 945 milligrams of (48%)-(3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-hydroxyl-7-(3-p-methoxy-phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=118 ℃

Step B

As embodiment 1 step D, operate, but be to use 941 grams (1.99 mmole)-(3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-hydroxyl-7-(3-p-methoxy-phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate and 3.19 centimetres ³Trifluoromethanesulfonic acid is at 45 centimetres ³Solution in the methylene dichloride, following 30 minutes of about 0 ℃ of temperature, at room temperature 48 hours then, adopting silica gel (230-400 order) flash chromatography purifying, use hexanaphthene, use then after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 755 milligrams of (83%) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(3-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=117 ℃

Step C

As embodiment 1 step e, operate, but be to use 747 milligrams of (1.65 mmole) (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(3-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 311 milligrams of (4.94 mmole) ammonium formiates, in the presence of 240 milligram of 10% (w/w) palladium/carbon, at 18 centimetres ³Reflux is 3 hours in the methyl alcohol, at 10 centimetres ³Stir after the resulting sead albumen crisp skin sample material in the pentane, obtain 501 milligrams of (83%) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=96-8 ℃

Step D

As embodiment 5 steps A, operate, but be to use 500 milligrams of (1.38 mmole) (3aRS, 4SR, 9SR, 9aRS) 4,9-ethano--9-(3-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 229 milligrams of (1.38 mmole) 2-anisole guanidine-acetic acids, 2 91 milligrams of (1.52 mmole) 1-ethyl-3-[(3-dimethylaminos) propyl group] carbodiimide hydrochloride and 37 milligrams of (0.27 mmole) N-hydroxy benzotriazole hydrates are at 14 centimetres ³Solution in the methylene dichloride adopting silica gel (230-400 order) flash chromatography purifying, is used hexanaphthene; use then after hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out, obtain 451 milligrams of (64%) (3aRS, 4SR; 9SR, 9aRS)-4,9-ethano--9-(3-p-methoxy-phenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=128 ℃

-mass spectrum (IE): M/Z=511 (M ⁺)

Step e

Operation as embodiment 2; but be to use 450 milligrams of (0.88 mmole) (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--9-(3-p-methoxy-phenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 4.7 centimetres ³1M aqueous sodium hydroxide solution and 5 centimetres ³Refluxed 18 hours in the methyl alcohol, at 10 centimetres ³After the recrystallization, obtain 391 milligrams of (89%) (3aRS, 4SR in the isopropyl ether; 9SR; 9aRS)-4, ethanoyl 9-ethano--9-(3-p-methoxy-phenyl)-2-[(2-p-methoxy-phenyl)]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; it is Powdered to be white in color, and its feature is as follows:

-fusing point=135 ℃

- ¹HNMR spectrum (temperature 393K represents d with ppm for 250MHz, DMSO d6): 1.40-1.63-1.94 and 2.10 (4mts, each 1H:CH ₂CH ₂); 3.35-3.70 (mt, 6H:1 position CH ₂-NCOCH ₂Ar-3 position CH ₂1H and 9a position H); (3.50 mt, 1H:4 position H); 3.73 (wide s, 3H:OCH ₃); 3.87 (s, 3H:9 position aromatics OCH ₃); 4.18 (d, J=12.5Hz, 1H:3 position CH ₂Another H); 6.48 (wide d; J=7,5Hz, 1H:8 position H); 6.85-7.35 (mt, H-6 position, 10H:5 position H-7 position H and OCH ₃Ortho position, Meta-and para-aramid H and 9 aryl OCH ₃Ortho position and contraposition aromatics H); 7.43 (t, J=8Hz, 1H:9 position aryl OCH ₃Between position aromatics H).

Embodiment 11

Preparation (3aRS, 4SR, 9SR, 9aRS) 9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f]-isoindole-3a-methyl-formiate

Steps A

With 2.3 centimetres ³4-bromo-o-Xylol and 0.42 gram cutting magnesium are at 20 centimetres ³Ether and 20 centimetres ³Vlil in the tetrahydrofuran compound one hour.Be cooled to after-7 ℃, (7aRS) 2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 20 centimetres for 3aRS, 4SR to add 3.11 grams ³Solution in the ether.Reaction mixture was stirred 4 hours down for about 25 ℃ in temperature, use 50 centimetres then ³The saturated aqueous ammonium chloride hydrolysis.Adopt the decantation water phase separated, and with 25 centimetres ³Ethyl acetate extraction.Merge organic phase, use dried over mgso, under reduced pressure concentrate again.Adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out, obtain 1.995 gram (3aRS, 4SR, 7RS, 7aRS)-and 2-benzyl-7-hydroxyl-7-(4-3,5-dimethylphenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate, its former state is used for following step, and feature is as follows:

-mass spectrum (IE)=M/Z=469 (M ⁺) and 410 (M ⁺-CO ₂).

Step B

As embodiment 1 step D, operate, but be to use 1.99 mixtures that obtain of gram above-mentioned steps at 100 centimetres ³Be maintained at about-5 ℃ solution and 3.7 centimetres in the methylene dichloride ³Trifluoromethanesulfonic acid stirred 72 hours down at about 25 ℃, obtained 1.63 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, be yellow oily, former state is used for following step, and its feature is as follows:

-mass spectrum (IE)=M/Z=451 (M ⁺)

Step C

As embodiment 1 step e, operate, but be to use 1.63 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is at 40 centimetres ³Solution in the methyl alcohol and 0.68 gram ammonium formiate, reflux is 2 hours in the presence of 0.41 gram 10% (w/w) palladium/carbon, obtain 0.79 gram (3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-mass spectrum (IE)=M/Z=361 (M ⁺)

Step D

As embodiment 5 steps A, operate, but be to use 0.79 gram (3aRS, 4SR, 9SR, 9aRS)-9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.44 gram 2-anisole guanidine-acetic acid, 0.5 gram 1-ethyl-3-[(3-dimethylamino) propyl group] carbodiimide hydrochloride and 0.35 gram N-hydroxy benzotriazole hydrate be at 35 centimetres ³Solution in the methylene dichloride; adopting 37 gram silica gel (230-400 order) flash chromatography purifying; use absolute dichloromethane; use again after dichloromethane-ethanol mixture (by volume 99-1) wash-out; obtain 0.7 gram (3aRS, 4SR, 9SR; 9aRS)-9-(3; the 4-3,5-dimethylphenyl)-4, ethanoyl 9-ethano--2-[(2-p-methoxy-phenyl)]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate; be sead albumen crisp skin shape, it is by following recrystallization: with this sead albumen crisp skin sample substance dissolves at 5 centimetres ³In the dehydrated alcohol, it is muddy up to occurring to add entry, cools off one hour to about 0 ℃.Obtain so the yellow powdered of 0.16g (3aRS, 4SR, 9SR, 9aRS)-9-(3; the 4-3,5-dimethylphenyl)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, its feature is as follows:

-fusing point=88 ℃

-mass spectrum (IE): M/Z=509 (M ⁺)

Embodiment 12

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 637 milligrams (3aRS, 4SR, 9SR, 9aRS)-9-(3; the 4-3,5-dimethylphenyl)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 1.9 centimetres ³1M aqueous sodium hydroxide solution and 60 centimetres ³Refluxed 18 hours in the ethanol, at 5 centimetres ³In the isopropyl ether after the recrystallization, obtain 176 milligrams (3aRS, 4SR, 9SR, 9aRS)-9-(3; the 4-3,5-dimethylphenyl)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, it is Powdered to be white in color, and its feature is as follows:

-fusing point=257 ℃

-mass spectrum (IE): M/Z=495 (M ⁺) and 451 (M ⁺-CO ₂).

Embodiment 13

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 3a-N-benzylamino formyl radical-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole

Restrain 1 (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid is at 10 centimetres ³Contain 1 N, in the solution in the methylene dichloride of dinethylformamide, drip 0.19 centimetre ³Oxalyl chloride is at 5 centimetres ³Solution in the methylene dichloride.Reaction mixture was stirred 2 hours for about 20 ℃ in temperature, be cooled to about 0 ℃ of temperature then, and be added drop-wise to 0.22 centimetre ³Benzene methanamine is at 10 centimetres ³Methylene dichloride and 0.57 centimetre ³In the solution in the triethylamine, keep about 0 ℃ of temperature simultaneously.Reaction mixture was stirred 15 minutes for about 0 ℃ in temperature, stirred 2 hours for about 20 ℃ in temperature then, pour 50 centimetres again into ³In the distilled water.Adopt decantation to separate organic phase, with 50 centimetres ³Distilled water wash is used 50 centimetres again ³The saturated sodium-chloride water solution washing is with dried over mgso and under reduced pressure concentrated.Adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 50-50) wash-out, obtain 0.8 gram (3aRS; 4SR, 9SR, 9aRS)-3a-N-benzylamino formyl radical-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-p-methoxy-phenyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole, it is Powdered to be white in color, and its feature is as follows:

-fusing point=227 ℃

- ¹HNMR spectrum (temperature 413K represents d with ppm for 300MHz, DMSO d6): 1.40-1.64-2.02 and 2.15 (4mts, each 1H:CH ₂CH ₂); 2.39 (s, 3H:ArCH ₃); 3.31 and 3.40 (be respectively mt and wide d, J=13Hz, each 1H:1 position CH ₂); 3.50 and 4.20 (be respectively mt and wide d, J=13Hz, each 1H:3 position CH ₂); (3.59 mt, 1H:9a position H); (3.61 wide s, 1H:4 position H); 3.71 (s, 3H:ArOCH ₃); 4.22 (restriction AB, 2H:CH ₂NAr); 5.52 and 5.67 (2s, each 1H:=CH ₂); 6.44 (wide d; J=7,5Hz, 1H:8 position H); 6.95 (wide t, J=7.5Hz, 1H:OCH ₃Contraposition aromatics H); 7.01 (wide d, J=7.5Hz, 1H:OCH ₃Ortho position aromatics H); 6.95-7.35 (mt, H-6 position, 14H:5 position H-7 position H-OCH ₃Between position aromatics aromatics ortho position, H-9 position and a position aromatics H and benzyl aromatics H); 7.75 (mf, 1H:CHNH).

Embodiment 14

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid benzyl ester

Operation as embodiment 13, but be to use 2.49 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid is at 20 centimetres ³Contain 2 N, the solution in the methylene dichloride of dinethylformamide, 0.48 centimetre ³Oxalyl chloride is at 5 centimetres ³Solution in the methylene dichloride and 0.8 gram O-benzyl hydroxylamine hydrochloride are at 2.1 centimetres ³Triethylamine and 20 centimetres ³Solution in the dichloromethane mixture.Obtain 2.4 the gram (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-p-methoxy-phenyl)-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid benzyl ester, the solid state that is white in color, its feature is as follows:

-fusing point=227 ℃

- ¹HNMR spectrum (temperature 413K represents d with ppm for 300MHz, DMSO d6): 1.38-1.61-1.98 and 2.10 (4mts, each 1H:CH ₂CH ₂); 2.39 (s, 3H:ArCH ₃); 3.26 and 3.38 (be respectively dd and non-constant width d, J=13Hz and 9Hz and J=13Hz, each 1H:1 position CH ₂); 3.46 and 4.14 (be respectively d and wide d, J=13Hz, each 1H:3 position CH ₂); (3.52 dt, J=9 and 3Hz, 1H:9a position H); 3.72 (s, 3H:ArOCH ₃); 4.63 and 4.70 (2d, J=11Hz, each 1H:OCH ₂Ar); 5.52 and 5.68 (be respectively s and wide s, each 1H:=CH ₂); 6.44 (wide d; J=7,5Hz, 1H:8 position H); 6.95 (wide t, J=7.5Hz, 1H:OCH ₃Contraposition aromatics H); 7.00-7.40 (mt, H-6 position, 14H:5 position H-7 position H-OCH ₃Between the position and aromatics ortho position, aromatics H-9 position, ortho position and a position H and benzyl aromatics H); 10.83 (mf, 1H:CHNH).

Embodiment 15

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 3a-formamyl-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole

Restrain 1.24 (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid is at 10 centimetres ³Contain 1 N, in the solution in the methylene dichloride of dinethylformamide, drip 0.24 centimetre ³Oxalyl chloride is at 5 centimetres ³Solution in the methylene dichloride.Reaction mixture was stirred 2 hours for about 20 ℃ in temperature, then concentrating under reduced pressure.Resistates is dissolved in 10 centimetres ³In the diox, be added drop-wise to 10 centimetres again ³2.5N in the ammonia soln, keep about 0 ℃ of temperature simultaneously.Reaction mixture the about 0 ℃ of restir of temperature 1 hour, is filtered then.One after the other use 50 centimetres at every turn ³Distilled water wash three times is used 50 centimetres again ³The isopropyl ether washing, dry under the about 40 ℃ of decompressions of temperature then.So in methyl alcohol, obtain 0.85 gram (3aRS behind the recrystallization; 4SR, 9SR, 9aRS)-3a-formamyl-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole, the solid state that is white in color, its feature is as follows:

-fusing point=＞260 ℃

- ¹HNMR spectrum (temperature 413K represents d with ppm for 300MHz, DMSO d6): 1.38-1.60-1.98 and 2.12 (4mts, each 1H:CH ₂CH ₂); 2.39 (s, 3H:ArCH ₃); 3.26 and 3.36 (be respectively dd and non-constant width d, J=13Hz and 9Hz and J=13Hz, each 1H:1 position CH ₂); 3.48 and 4.16 (be respectively d and wide d, J=13Hz, each 1H:3 position CH ₂); (3.50 dt, J=9 and 3Hz, 1H:9a position H); (3.56 mt, 1H:4 position H); 3.72 (s, 3H:ArOCH ₃); 5.52 and 5.68 (be respectively s and wide s, each 1H:=CH ₂); 6.42 (wide d; J=7,5Hz, 1H:8 position H); 6.70 (mf, 2H:CONH ₂); 6.95 (wide t, J=7.5Hz, 1H:OCH ₃Contraposition aromatics H); 7.03 (wide d, J=7.5Hz, 1H:OCH ₃Ortho position aromatics H); 7.00-7.40 (mt, H-6 position, 9H:5 position H-7 position H-OCH ₃Between position aromatics H and 9 aromatics ortho positions and a position H).

Embodiment 16

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid

Be cooled to approximately-15 ℃ 1.3 grams (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid benzyl ester is at 10 centimetres ³Nitromethane 99Min. and 10 centimetres ³In the solution in the dichloromethane mixture, add 0.61 centimetre ³Pmethoxybenzyl alcohol adds 0.72 gram aluminum chloride again.Reaction mixture was stirred one hour for about 20 ℃ in temperature, under reduced pressure concentrate then.With resistates with 50 centimetres ³The dissolving of 1M aqueous hydrochloric acid is used 50 centimetres more at every turn ³Dichloromethane extraction 2 times.Combining extraction liquid is one after the other used 50 centimetres ³Distilled water, 50 centimetres ³The saturated sodium-chloride water solution washing is with dried over mgso and concentrated under reduced pressure.Resistates adopts silica gel (230-400 order) flash chromatography purifying, with methylene chloride-methanol mixture (by volume 90-10) wash-out.In acetonitrile behind the recrystallization, obtain 0.75 gram (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid are creamy, and its feature is as follows:

-fusing point=252 ℃

- ¹HNMR composes (300MHz, (CD ₃) ₂SO d6, temperature 413K represents d with ppm): 1.36-1.60-1.98 and 2.08 (4mts, each 1H:CH ₂CH ₂); 2.39 (s, 3H:ArCH ₃); 3.26 and 3.30-3.45 (is respectively dd and mt, J=13Hz and 9Hz, each 1H:1 position CH ₂); 3.43 and 4.12 (be respectively d and wide d, J=13Hz, each 1H:3 position CH ₂); (3.50 dt, J=9 and 3Hz, 1H:9a position H); (3.56 mt, 1H:4 position H); 3.72 (s, 3H:ArOCH ₃); 5.52 and 5.68 (be respectively s and wide s, each 1H:=CH ₂); 6.42 (wide d; J=7,5Hz, 1H:8 position H); 6.95 (wide t, J=7.5Hz, 1H:OCH ₃Contraposition aromatics H); 7.03 (wide d, J=7.5Hz, 1H:OCH ₃Ortho position aromatics H); 7.00-7.40 (mt, H-6 position, 9H:5 position H-7 position H-OCH ₃Between position aromatics aromatics ortho position, H-9 position and a position H).At room temperature, we observe tradable signal: 8.70 (mf, 1H:CONH); 10.65 (mf, 1H:OH).

Embodiment 17

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide

Restrain 1.24 (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid is at 10 centimetres ³Methylene dichloride and a N in the solution in the dinethylformamide, drip 0.24 centimetre ³Oxalyl chloride is at 5 centimetres ³Solution in the methylene dichloride.Reaction mixture stirred two hours for about 20 ℃ in temperature, was cooled to about 0 ℃ of temperature then, and poured into and be cooled to about 0 ℃ 0.26 centimetre of temperature ³3-(aminomethyl) pyridine and 0.7 centimetre ³Triethylamine is at 10 centimetres ³In the solution in the methylene dichloride.Reaction mixture stirred 15 minutes down for about 0 ℃ in temperature, stirred two hours for about 20 ℃ in temperature then, poured 100 centimetres again into ³In the distilled water.Adopt decant method water phase separated, and use 50 centimetres at every turn ³Twice of dichloromethane extraction.Merge organic phase, earlier with 50 centimetres ³Distilled water, the back is with 50 centimetres ³Dried over mgso is used in the saturated sodium-chloride water solution washing, under reduced pressure concentrates again.Resistates adopts silica gel (230-400 order) flash chromatography purifying, with methylene chloride-methanol mixture (by volume 95-5) wash-out, in Virahol after the backflow crystallization; obtain 1.0 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide, its feature is as follows:

-fusing point=234 ℃

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6, temperature 393K represents d with ppm): (3mts is respectively 1H-1H and 2H:CH for 1.40-1.62 and 1.90-2.20 ₂CH ₂); 2.39 (s, 3H:ArCH ₃); 3.20-3.40 (restriction AB, 2H:1 position CH ₂); 3.44 (d, J=12.5Hz, 1H:3 position CH ₂1H); (3.55-3.65 mt, 2H:4 position CH, 9a position CH); 3.68 (s, 3H:ArOCH ₃); 4.10-4.35 (mt, 3H:3 position CH ₂Another H and NCH ₂Ar); 5.51 and 5.68 (2s, each 1H:=CH ₂); 6.42 (wide d; J=7.5Hz, 1H:8 position H); (6.90-7.50 mt, the H that H that the aromatics H-pyridyl of the aromatics H-4-aminomethyl phenyl of H-7 position, H-6 position, 13H:5 position H-2-p-methoxy-phenyl is 4 and pyridyl are 5); 8.05 ((mf, 1H:CONH); 8.39 (wide s, 1H: 2 H of pyridyl); 8.44 (wide d, J=5Hz, 1H: 6 H of pyridyl).

Embodiment 18

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide dextrorotation Separation of Enantiomers

By each 1 gram injection 12 times; restrain (3aRS, 4SR, the 9SR that embodiment 17 obtain with 12; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide is expelled to Whelk 01 (SS) chirality silicagel column to be separated, with normal heptane-methylene dichloride-propyl alcohol (by volume 50-50-2) wash-out.Reclaim first eluting fraction (retention time 42 minutes); under reduced pressure obtain 4.78 gram (3aRS, 4SR, 9SR after the concentrated solvent; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide dextrorotation enantiomorph, its feature is as follows:

-fusing point=210 ℃

-mass spectrum (IE)=M/Z=583 (M ⁺)

-specific rotation: [a] ₃₆₅ ²⁰+ 104.6+/-1.6 ° (c=0.5/ methyl alcohol).

Embodiment 19

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9, the separation of 9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide levo-enantiomer

By each 1 gram injection 12 times, restrain (3aRS, the 4SR that embodiment 17 obtain with 12; 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide; be expelled to Whelk 01 (SS) chirality silicagel column and separate, with normal heptane-methylene dichloride-propyl alcohol (by volume 50-50-2) wash-out.Reclaim second eluting fraction (retention time 65 minutes); under reduced pressure obtain 4.86 gram (3aRS, 4SR, 9SR after the concentrated solvent; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide levo-enantiomer, its feature is as follows:

-fusing point=210 ℃

-mass spectrum (IE)=M/Z=583 (M ⁺)

-specific rotation: [a] ₃₆₅ ²⁰=+102.2.6+/-1.5 ° (c=0.5/ methyl alcohol).

Embodiment 20

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(4-pyridylmethyl)-methane amide

Operation as embodiment 17; but be to use 1.24 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 1 N, dinethylformamide, 0.24 centimetre ³Oxalyl chloride, 0.26 centimetre ³4-(aminomethyl) pyridine and 0.7 centimetre ³Triethylamine.In Virahol and isopropyl ether equal-volume mixture after the crystallization; obtain 0.7 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(4-pyridylmethyl)-methane amide, its feature is as follows:

-fusing point=202 ℃

Embodiment 21

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid methyl esters

Restrain 1.24 (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid is at 10 centimetres ³Methylene dichloride and a N in the solution of dinethylformamide, drip 0.24 centimetre ³Oxalyl chloride is at 5 centimetres ³Solution in the methylene dichloride.Its reaction mixture stirred 2 hours down for about 20 ℃ in temperature, pour into then be cooled to 0 ℃ of temperature 0.21 gram O-methyl-azanol at 1.05 centimetres ³Trimethylamine 99 and 10 centimetres ³In the solution of dichloromethane mixture.Reaction mixture was stirred 30 minutes for about 0 ℃ in temperature, stirred one hour for about 20 ℃ in temperature then, pour 50 centimetres again into ³In the distilled water.Adopt the decant method to separate organic phase, use 50 centimetres more at every turn ³Distilled water wash twice is used 20 centimetres at every turn ³1 molar sodium hydroxide solution washing twice is with 50 centimetres ³Distilled water, 50 centimetres ³The saturated sodium-chloride water solution washing is with dried over mgso and concentrated under reduced pressure.At 20 centimetres ³After the backflow recrystallization, obtain 0.95 gram (3aRS, 4SR, 9SR in the Virahol; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid methyl esters, its feature is as follows:

-fusing point=256 ℃

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6, temperature 383K represents d with ppm): (3mts is respectively 1H-1H and 2H:CH for 1.38-1.62 and 1.90-2.20 ₂CH ₂); 2.40 (s, 3H:ArCH ₃); 3.15-3.45 (be respectively dd and mt, J=12Hz and 9Hz, 2H:1 position CH ₂); 3.30-3.60 (mt, 3H:9a position CH-4 position CH and 3 CH ₂1H); 3.48 (s, 3H:NOCH ₃); 3.71 (s, 3H:ArOCH ₃); 4.14 (wide d, J=12.5Hz, 1H:3 position CH ₂Another H); 5.52 and 5.69 (2s, each 1H:=CH ₂); 6.43 (wide d; J=7,5Hz, 1H:8 position H); (6.90-7.40 mt, the aromatics H of H-7 position, H-6 position, 11H:5 position H-2-p-methoxy-phenyl and the aromatics H of 4-aminomethyl phenyl).

Embodiment 22

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N ', N ' dimethyl methyl hydrazides

Restrain 1.24 (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid is at 10 centimetres ³Methylene dichloride and a N in the solution of dinethylformamide, drip 0.24 centimetre ³Oxalyl chloride is at 5 centimetres ³Solution in the methylene dichloride.Its reaction mixture stirred 2 hours down for about 20 ℃ in temperature, poured 0.2 centimetre that is cooled to 0 ℃ of temperature then into ³N, N-dimethylhydrazine and 0.7 centimetre ³Triethylamine is at 10 centimetres ³In the solution in the methylene dichloride.Reaction mixture was stirred 30 minutes for about 0 ℃ in temperature, stirred one hour for about 20 ℃ in temperature then, pour 50 centimetres again into ³In the distilled water.Adopt the decant method to separate organic phase, use 50 centimetres again ³Distilled water wash is used 25 centimetres at every turn ³1 molar sodium hydroxide solution washing twice is with 50 centimetres ³Distilled water, 50 centimetres ³The saturated sodium-chloride water solution washing is with dried over mgso and concentrated under reduced pressure.Adopting silica gel (230-400 order) flash chromatography purifying, with methylene chloride-methanol mixture (by volume 97.5-2.5) wash-out, and at 50 centimetres ³After the recrystallization, obtain 0.95 gram (3aRS, 4SR in the Virahol-isopropyl ether mixture (by volume 1-9); 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '; N ' dimethyl methyl hydrazides, its feature is as follows:

-fusing point=230 ℃

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6, temperature 383K represents d with ppm): (3mts is respectively 1H-1H and 2H:CH for 1.38-1.60 and 1.90-2.20 ₂CH ₂); 2.40 (s, 3H:ArCH ₃); 2.47 (s, 6H:N (CH ₃) ₂); 3.21 and 3.35 (be respectively dd and mt, J=12Hz and 9Hz, each 1H:1 position CH ₂); 3.40 and 4.19 (be respectively d and wide d, J=13Hz, each 1H:3 position CH ₂); (3.50-3.65 mt, 2H:9a position CH and 4 CH); 3.71 (s, 3H:ArOCH ₃); 5.51 and 5.69 (2s, each 1H:=CH ₂); 6.42 (wide d; J=7,5Hz, 1H:8 position H); (6.90-7.40 mt, the aromatics H of H-7 position, H-6 position, 11H:5 position H-2-p-methoxy-phenyl and the aromatics H of 4-aminomethyl phenyl); 8.41 (mf, 1H:CONH).

Embodiment 23

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-phenyl formyl hydrazine

Operation as embodiment 22, but be to use 0.5 gram (3aRS, 4SR; 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, a N; dinethylformamide, 0.095 centimetre ³Oxalyl chloride, 0.098 centimetre ³N-phenyl hydrazine and 0.28 centimetre ³Triethylamine is at 10 centimetres ³After the recrystallization, obtain 0.22 gram (3aRS, 4SR, 9SR in the isopropyl ether; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-phenyl formyl hydrazine, its feature is as follows:

-fusing point=220 ℃

Embodiment 24

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N ', N '-pentamethylene formyl hydrazine

Operation as embodiment 22, but be to use 0.5 gram (3aRS, 4SR; 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, a N; dinethylformamide, 0.095 centimetre ³Oxalyl chloride, 0.095 centimetre ³1-amino piperidine and 0.28 centimetre ³Triethylamine adopting silica gel (230-400 order) flash chromatography purifying, is used eluent ethyl acetate; in isopropyl ether, after the recrystallization, obtain 0.06 gram (3aRS, 4SR; 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-N ', N '-pentamethylene formyl hydrazine, its feature is as follows:

-fusing point=220 ℃

Embodiment 25

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-3a-benzenesulfonyl aminocarboxyl-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole

Restrain 0.5 (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid is at 5 centimetres ³Methylene dichloride and a N in the solution in the dinethylformamide, drip 0.096 centimetre ³Oxalyl chloride is at 0.5 centimetre ³Solution in the methylene dichloride.Reaction mixture was stirred 2 hours down for about 20 ℃ in temperature, pour the suspension and 0.31 of 0.12 gram, 60% sodium hydride in Vaseline then into and restrain benzsulfamide at 5 centimetres ³N is in the mixture in the dinethylformamide.Reaction mixture was stirred 3 days down for about 20 ℃ in temperature.Add 10 centimetres then ³Distilled water, this mixture is each with 20 centimetres ³Twice of dichloromethane extraction.Merge organic phase, use 20 centimetres again ³Distilled water wash is used 20 centimetres then ³The saturated sodium-chloride water solution washing is with dried over mgso and concentrated under reduced pressure.Adopting silica gel (230-400 order) flash chromatography purifying, with methylene chloride-methanol mixture (by volume 98-2) wash-out, and in isopropyl ether after the recrystallization; obtain 0.005 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)--3a-benzenesulfonyl aminocarboxyl-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole, its feature is as follows:

-fusing point=about 166 ℃

- ¹HNMR composes (400MHz, (CD ₃) ₂SO d6, temperature 393K represents d with ppm): 1.35-1.58-1.97 and 2.09 (4mts, each 1H:CH ₂CH ₂); 2.39 (s, 3H:ArCH ₃); 3.20 and 3.31 (be respectively dd and wide d, J=12.5Hz and 9Hz and J=12.5Hz, each 1H:1 position CH ₂); (3.40-3.50 mt, 1H:9a position CH); 3.45 and 4.14 (be respectively dd and wide d, J=13Hz, each 1H:3 position CH ₂); (3.59 mt, 1H:4 position CH); 3.66 (s, 3H:ArOCH ₃); 5.45 and 5.65 (2s, each 1H:=CH ₂); (6.35 mt, 1H:8 position H); (6.85-7.60 mt, position aromatics H and phenyl sulfonyl contraposition aromatics H between the aromatics H-benzenesulfonyl of the aromatics H-4-aminomethyl phenyl of H-7 position, H-6 position, 14H:5 position H-2-p-methoxy-phenyl); 7.77 (d, J=8Hz, 2H: benzenesulfonyl ortho position aromatics H); 8.00 (wide s, 1H:CONH).

Embodiment 26

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(N-oxo-3-pyridyl) methylformamide

Restrain 0.29 (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide is at 8 centimetres ³In the solution in the chloroform, add 0.20 gram yellow soda ash and 6 centimetres ³Distilled water.Reaction mixture is cooled to about 0 ℃ of temperature, adds 0.11 gram metachloroperbenzoic acid.Reaction mixture was stirred 1 hour down for about 2 ℃ in temperature, stirred 22 hours down for about 20 ℃ in temperature then.Add 0.22 gram metachloroperbenzoic acid again, reaction mixture was stirred 4 hours down for about 20 ℃ in temperature, use 10 centimetres then ³The methylene dichloride dilution.Adopt the decant method to separate organic phase, use 5 centimetres at every turn ³10% sodium sulfite aqueous solution washing three times is used 5 centimetres at every turn ³10% saturated sodium bicarbonate aqueous solution and with 5 centimetres ³Distilled water wash three times is with dried over mgso and concentrated under reduced pressure.Resistates is at 8 centimetres ³In the isopropyl acetate after the recrystallization; obtain 0.25 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(N-oxo-3-pyridyl) methylformamide, its feature is as follows:

-fusing point=250 ℃

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6, temperature 383K represents d with ppm): (3mts is respectively 1H:1H and 2H:CH for 1.40-1.62 and 1.90-2.25 ₂CH ₂); 2.40 (s, 3H:ArCH ₃); 3.20-3.50 (restriction AB, 2H:1 position CH ₂); 3.44 (d, J=12.5Hz, 1H:3 position CH ₂1H); (3.50-3.65 mt, 1H:9a position CH); (3.57 mt, 1H:4 position CH); 3.70 (s, 3H:ArOCH ₃); 4.00-4.30 (mt, 3H:3 position CH ₂Another H and NCH ₂Ar); 5.51 and 5.68 (2s, each 1H:=CH ₂); (6.41 wide d, J=7.5Hz, 1H:8 position H); (6.90-7.40 mt, 5 H of 4 H-N-oxo pyridines of aromatics H-N-oxo pyridine base base of H-7 position, H-6 position, 13H:5 position H-2-p-methoxy-phenyl and 4-aminomethyl phenyl aromatics H); (8.00 wide s, 2 H of 1H:N-oxo pyridine base); (8.05 wide d, J=5Hz, 6 H of 1H:N-oxo pyridine base); 8.11 (wide t, J=5Hz, 1H:CONH).

Embodiment 27

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-(4-p-methoxy-phenyl) formyl hydrazine

Restrain 0.49 (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid is at 10 centimetres ³In the solution in the methylene dichloride, add 0.21 gram 4-p-methoxy-phenyl hydrazonium salt hydrochlorate, 0.23 gram 1-ethyl-3-[(dimethylamino in succession) propyl group] carbodiimide hydrochloride, 0.08 gram N-hydroxy benzotriazole hydrate and 0.17 gram triethylamine.Reaction mixture stirred 20 hours down for about 20 ℃ in temperature, used 10 centimetres then ³The methylene dichloride dilution.Organic phase is each with 10 centimetres ³Distilled water wash three times, in the presence of 3S is black with dried over mgso and concentrated under reduced pressure.By at 10 centimetres ³In the isopropyl acetate after the recrystallization; obtain 0.36 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-(4-p-methoxy-phenyl) formyl hydrazine, its feature is as follows:

-fusing point=180 ℃

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6, temperature 383K represents d with ppm): (3mts is respectively 1H:1H and 2H:CH for 1.40-1.62 and 1.90-2.25 ₂CH ₂); 2.38 (s, 3H:ArCH ₃); 3.25 (dd, J=12 and 9Hz, 1H:1 position CH ₂1H); 3.39 (wide d, J=12Hz, 1H:1 position CH ₂Another H); 3.48 and 4.22 (be respectively d and wide d, J=12.5Hz, each 1H:3 position CH ₂); (3.56 mt, 1H:9a position CH); (3.60-3.75 mt, 1H:4 position CH); 3.68 (s, 6H:2 ArOCH ₃); 5.52 and 5.69 (2s, each 1H:=CH ₂); (6.42 wide d, J=7.5Hz, 1H:8 position H); 6.56 and 6.69 (2d, J=8Hz, each 2H:OCH ₃An ortho position and a position aromatics H); 6.80 (wide s, 1H:ArNH); (6.90-7.40 mt, the aromatics H of H-7 position, H-6 position, 11H:5 position H-2-p-methoxy-phenyl and the aromatics H of 4-aminomethyl phenyl); 9.46 (wide s, 1H:-CONH).

Embodiment 28

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-methyl-N '-phenyl formyl hydrazine

Operation as embodiment 27, but be to use 0.49 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 0.14 centimetre ³N-methyl-N-phenyl hydrazine, 0.23 gram 1-ethyl-3-[(dimethylamino) propyl group] carbodiimide hydrochloride, 80 milligrams of N-1-hydroxy benzotriazole hydrates and 0.17 gram triethylamine.At 5 centimetres ³In the Virahol after the recrystallization; obtain 0.22 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-methyl-N '-phenyl formyl hydrazine, its feature is as follows:

-fusing point=240 ℃

Embodiment 29

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-(2-aminomethyl phenyl) formyl hydrazine

Operation as embodiment 27; but be to use 0.4 gram (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2; 3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 0.16 gram N-(2-aminomethyl phenyl) hydrazonium salt hydrochlorate, 0.19 gram 1-ethyl-3-[(dimethylamino) propyl group] carbodiimide hydrochloride, 60 milligrams of N-1-hydroxy benzotriazole hydrates and 0.14 gram triethylamine.At 7.5 centimetres ³In the isopropyl acetate after the recrystallization; obtain 0.28 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-(2-p-methoxy-phenyl) formyl hydrazine, its feature is as follows:

-fusing point=235 ℃.

Embodiment 30

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) ethanoyl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation Separation of Enantiomers

Operation as embodiment 3 is with carrier band N-(3, the 5-dinitrobenzoyl)-phenylalanine grafted chirality silica column; be separated in (the 3aRS that embodiment 5 obtains; 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) ethanoyl]-9-(4-aminomethyl phenyl)-2; 3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid.Reclaim second cut with methylene dichloride, Virahol and normal heptane mixture (by volume 85-10-5) institute wash-out; obtain 70 milligrams of (3aRS, 4SR, 9SR after under reduced pressure concentrating; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) ethanoyl]-9-(4-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph, its feature is as follows:

-fusing point=205 ℃

-mass spectrum (IE)=M/Z=481 (M ⁺)

-specific rotation: [a] ₃₆₅ ²⁰=+59.5.6+/-0.9 ° (c=0.5/ methyl alcohol).

Embodiment 31

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

With 6.3 stable grams of amylene (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 60 centimetres ³In solution in, under argon atmospher, add 7.1 centimetres ³1, the 4-benzodioxan; This solution cools off with ice-water bath, and pours 10.7 centimetres in 5 minutes ³99% trifluoromethanesulfonic acid.After in cryostat, stirring, temperature is raised to about 20 ℃ again, under argon atmospher, was stirring 21 hours under this temperature.At this moment pour 200 centimetres into ³Distilled water, 300 centimetres then ³Ethyl acetate.Adopt the decant method to separate organic phase, use 180 centimetres more at every turn ³The 1N aqueous sodium hydroxide washes is washed three times, uses 240 centimetres again ³Dried over mgso is used in the saturated sodium-chloride water solution washing then.After filtration, the vapourisation under reduced pressure organic phase obtains 10.8 gram oil.This oil carries out the flash chromatography purifying with the post that 430 gram silica gel (230-400 order) are housed of 8 centimetres of diameters, uses 1 decimeter in succession ³Hexanaphthene-ethyl acetate mixture (by volume 98-2) is used 2 decimeters again ³Hexanaphthene-ethyl acetate mixture (by volume 95-5), hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out then, reclaiming each cut is 30 centimetres ³A plurality of cuts.Under reduced pressure after the concentrated solvent, obtain impure (3aRS, the 4SR of 5.41 grams, 9SR, 9aRS)-2-benzyl-9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the sead albumen crisp skin shape that is white in color, but former state is used for following step, and its feature is as follows:

-mass spectrum (IE)=M/Z=481 (M ⁺)

- ¹HNMR composes (300MHz, CDCl ₃, represent d with ppm): (3mts is respectively 1H:1H and 2H:CH for 1.45-1.65 and 2.40-2.55 ₂CH ₂); 2.31 and 3.20 (2d, J=10Hz, each 1H:3 position CH ₂); 2.35-2.45 (mt, 1H:1 position CH ₂1H); 2.81 (d, J=10,1H:1 position CH ₂Another H); (3.00-3.20 mt, 1H:9a position CH); 3.30-3.45 and 3.71 (be respectively mt and wide d, J=13Hz, each 1H:NCH ₂Ar); (3.39 wide d, 1H:4 position CH); 3.55 (s, 3H:COOCH ₃); 4.31 (s, 4H:OCH ₂CH ₂O); (6.63 wide d, J=7.5Hz, 1H:8 position H); (6.85-7.40 mt, the aromatics H of H-7 position, H-6 position, 11H:5 position H-benzyl aromatics H and 1-4-benzodioxan).

Step B

As embodiment 1 step e, operate, but be to use 5.4 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 2.16 gram ammonium formiates, 1.35 gram 10% (w/w) palladium hydroxide/carbon are at 80 centimetres ³Refluxed 5 hours in the methyl alcohol, obtain the impure 3aRS of 4 grams, 4SR, 9SR, 9aRS)-9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the sead albumen crisp skin shape that is white in color, but former state is used for following step, and its feature is as follows:

-mass spectrum (DCI): M/Z=392 (M+H ⁺)

Step C

As embodiment 1 step G, operate, but be to use 0.275 gram 2-(2-p-methoxy-phenyl) vinylformic acid at 5 centimetres ³Contain 4 N, the solution in the methylene dichloride of dinethylformamide drips 0.2 centimetre ³Oxalyl chloride is at 7 centimetres ³Solution in the methylene dichloride.Reaction mixture stirred 2 hours down for about 20 ℃ in temperature, was cooled to about 0 ℃ of temperature then; At this moment in 20 minutes, add 0.73 gram impure (3aRS, 4SR, 9SR, 9aRS)-9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is at 15 centimetres ³Solution in the methylene dichloride adds 0.4 centimetre then ³Triethylamine.Reaction mixture stirred one hour under uniform temp, poured 100 centimetres into ³Distilled water; Dilute so that make organic phase reach about 200 centimetres with methylene dichloride ³By adding 10 centimetres ³32% ammonia soln is raised to 11 with pH, the decant water, and organic phase is one after the other used 100 centimetres then ³The washing of 1N aqueous hydrochloric acid is used 100 centimetres then ³Distilled water wash is used 100 centimetres again ³The saturated sodium-chloride water solution washing.After with dried over mgso, boil off organic phase, obtain 0.75 gram oil, this oil is used hexanaphthene-ethyl acetate mixture (by volume 60-40) wash-out with silica gel (230-400 order) flash chromatography purifying, and reclaiming each cut is 10 centimetres ³A plurality of cuts.(140-650 centimetre of the cut that will contain good product ³) merge, and evaporation, but be not evaporated to driedly, obtain a kind of oil, again this oil is dissolved in the isopropyl ether, obtains 465 milligrams of (3aRS, 4SR like this, 9SR, 9aRS)-9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) phenyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=184 ℃,

-mass spectrum (IE): M/Z=551 (M ⁺)

- ¹HNMR composes (400MHz, (CD ₃) ₂SO d6, temperature 403K represents d with ppm): 1.40-1.58-1.96 and 2.12 (4mts, each 1H:CH ₂CH ₂); 3.25-3.45 (mt, 3H:1 position CH ₂With 9a position CH); (3.42 mt, 1H:4 position CH); 3.52 (s, 3H:COOCH ₃); 3.60 and 4.06 (be respectively d and wide d, J=13Hz, each 1H:3 position CH ₂); 3.73 (s, 3H:ArOCH ₃); 4.31 (s, 4H:OCH ₂CH ₂O); 5.54 and 5.68 (2s, each 1H:=CH ₂); (6.51 wide d, J=7.5Hz, 1H:8 position H); (6.75-7.35 mt, H-7 position, H-6 position, 10H:5 position H-2-p-methoxy-phenyl aromatics H and 1-4-benzodioxan base aromatics H).

Embodiment 32

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 5.43 gram (3aRS, the 4SR that obtain at the foregoing description; 9SR, 9aRS)-9-(2,3-dihydro-1; 4-benzo two oxa-s English-6-yl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 40 centimetres ³The 1M aqueous sodium hydroxide solution is at 150 centimetres ³Refluxed 16 hours in the diox, add 50 centimetres then ³The 1M aqueous sodium hydroxide solution refluxed 4 hours, added 3.5 centimetres again ³The 10N aqueous sodium hydroxide solution refluxed 16 hours, obtained 3.76 gram terra brown solids in isopropyl ether after the dissolving.By being dissolved in 50 centimetres ³In the dehydrated alcohol, use 12.5 centimetres then ³Distilled water diluting obtains 2.64 gram (3aRS, 4SR; 9SR, 9aRS)-9-(2,3-dihydro-1; 4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; it is Powdered to be white in color, and its feature is as follows:

-fusing point=78 ℃

-mass spectrum (IE)=M/Z=537 (M ⁺)

- ¹HNMR composes (250MHz, (CD ₃) ₂SO, temperature 383K represents d with ppm): 1.38-1.57-1.94 and 2.11 (4mts, each 1H:CH ₂CH ₂); 3.20-3.45 (mt, 3H:1 position CH ₂With 9a position CH); (3.42 mt, 1H:4 position CH); 3.59 and 4.06 (be respectively d and wide d, J=13Hz, each 1H:3 position CH ₂); 3.73 (s, 3H:ArOCH ₃); 4.31 (s, 4H:OCH ₂CH ₂O); 5.54 and 5.69 (2s, each 1H:=CH ₂); (6.50 wide d, J=7.5Hz, 1H:8 position H); (6.75-7.40 mt, H-7 position, H-6 position, 10H:5 position H-2-p-methoxy-phenyl aromatics H and 1-4-benzodioxan aromatics H).

Embodiment 33

Preparation (3aRS, 4SR, 9SR, 9aRS)-9-(2; 3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide

Operation as embodiment 13, but be to use 0.5 gram (3aRS, 4SR; 9SR; 9aRS)-9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 0.24 centimetre ³Oxalyl chloride, 0.5 centimetre ³N, dinethylformamide is at 20 centimetres ³In the methylene dichloride 2 hours, be evaporated to driedly then, be dissolved in 20 centimetres ³In the methylene dichloride, add 0.09 centimetre ³3-aminomethyl pyridine and 0.26 centimetre ³Triethylamine is at 15 centimetres ³Solution in the methylene dichloride; After the about 20 ℃ of following stirrings of temperature 18 hours, pour 50 centimetres in succession into then ³Distilled water and 40 centimetres ³The 1M aqueous sodium hydroxide solution; With 200 centimetres ³The methylene dichloride dilution; Decant is also each with 100 centimetres ³1M aqueous hydrochloric acid washing organic phase twice is used 200 centimetres again ³The saturated sodium-chloride water solution washing, use dried over mgso at last, obtain the 0.38 gram Huang-crisp skin sample of green protein material, its recrystallization in isopropyl ether obtains 249 milligrams of yellow solids, this solid is used MERCK 60F254 preparation of silica gel plate purifying again, with methylene chloride-methanol mixture (by volume 90-10) wash-out.Obtain orange oil like this, it is dissolved in the isopropyl ether, obtain 165 milligrams of (3aRS; 4SR, 9SR, 9aRS)-9-(2; 3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) acid amides, it is Powdered to be white in color, and its feature is as follows:

-fusing point=228 ℃

-mass spectrum (IE)=M/Z=627 (M ⁺)

- ¹HNMR composes (250MHz, (CD ₃) ₂SOd ₆, temperature 373K represents d with ppm): 1.38-1.56-1.93 and 2.10 (4mts, each 1H:CH ₂CH ₂); 3.20-3.55 (mt, 3H:1 position CH ₂With 9a position CH); 3.43 (d, J=12.5Hz, 1H:3 position CH ₂1H); (3.57 wide s, 1H:4 position CH); 3.71 (s, 3H:ArOCH ₃); 4.05-4.30 (mt, 3H:3 position CH ₂Another H and NCH ₂Ar); 4.31 (s, 4H:OCH ₂CH ₂O); 5.52 and 5.70 (2s, each 1H:=CH ₂); (6.48 mt, 1H:8 position H); (6.75-7.45 mt, H-7 position, H-6 position, 12H:5 position H-2-p-methoxy-phenyl aromatics H-1-4-benzodioxan aromatics 4 H of H-pyridyl and 5 H of pyridyl); 8.10 (mt, 1H:CONH); 8.38 (wide s, 1H: 2 H of pyridyl); 8.45 (wide d, J=5Hz, 1H: 6 H of pyridyl).

Embodiment 34

(3aRS, 4SR, 9SR, 9aRS)-9-(2; 3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide dextrorotation Separation of Enantiomers

Operation as embodiment 18, but be to use 17 gram (3aRS, 4SR; 9SR, 9aRS)-9-(2,3-dihydro-1; 4-benzo two oxa-s English-6-yl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide divide to be expelled in succession for 10 times on Whelk 01 (SS) the chirality silicagel column; with normal heptane-ethanol-triethylamine mixture (by volume 70-30-0.05) wash-out; and isolate first eluting fraction (retention time=45 minute), under reduced pressure obtain 8.4 gram (3aRS, 4SR after the concentrated solvent; 9SR; 9aRS)-9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide dextrorotation enantiomorph, it is Powdered to be white in color, and its feature is as follows:

-mass spectrum (IE)=M/Z=627 (M ⁺)

-specific rotation: [a] ₃₆₅ ²⁰=+103.2+/-1.5 ° (c=0.5/ methyl alcohol).

Embodiment 35

(3aRS, 4SR, 9SR, 9aRS)-9-(2; 3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a, 4,9, the separation of 9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide levo-enantiomer

Operation as embodiment 19, but be to use 17 gram (3aRS, 4SR; 9SR, 9aRS)-9-(2,3-dihydro-1; 4-benzo two oxa-s English-6-yl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide divide to be expelled in succession for 10 times on Whelk 01 (SS) the chirality silicagel column; with normal heptane-ethanol-triethylamine mixture (by volume 70-30-0.05) wash-out; and isolate second eluting fraction (retention time=67 minute), under reduced pressure obtain 6.6 gram (3aRS, 4SR after the concentrated solvent; 9SR; 9aRS)-9-(2,3-dihydro-1,4-benzo two oxa-s English-6-yl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide levo-enantiomer, it is Powdered to be white in color, and its feature is as follows:

-mass spectrum (IE)=M/Z=627 (M ⁺)

-specific rotation: [a] ₃₆₅ ²⁰=-102+/-1.5 ° (c=0.5/ methyl alcohol).

Embodiment 36

Preparation (3aRS, 4SR, 9SR, 9aRS)-9-(2; 3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(2-thienyl methyl) methane amide

Operation as embodiment 33, but be to use at 20 centimetres ³In the methylene dichloride 0.5 gram (3aRS, 4SR, 9SR, 9aRS)-9-(2; 3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 0.24 centimetre ³Oxalyl chloride, 0.1 centimetre ³N, dinethylformamide is added in 15 centimetres then ³In the methylene dichloride 0.1 centimetre ³2-(aminomethyl) thiophene, 0.26 centimetre ³Triethylamine obtains 29 milligrams of (3aRS, 4SR after freeze-drying; 9SR, 9aRS)-9-(2,3-dihydro-1; 4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-thienyl methyl) methane amide; be Powdered, its feature is as follows:

-fusing point=134 ℃

-mass spectrum (IE)=M/Z=632 (M ⁺).

Embodiment 37

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(3,4, the 5-trimethylphenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Steps A

As embodiment 31 steps A, operate, but be to use stable 3.49 the restraining down of amylene (3aRS, 4SR, 7aRS)-the 2-[(2-p-methoxy-phenyl) ethanoyl]-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 40 centimetres ³Solution in the methylene dichloride, 3.34 centimetres ³1 and 5.1 centimetres ³Trifluoromethanesulfonic acid; After 18 hours, add 2.8 centimetres in the about 20 ℃ of following stirrings of temperature ³Trifluoromethanesulfanhydride anhydride, restir 18 hours.Obtain 263 milligrams of (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl like this]-9-(3; 4, the 5-trimethylphenyl)-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=159 ℃,

-mass spectrum (IE)=M/Z=523 (M ⁺).

Step B

As embodiment 2 the operation, but be to use 192 milligrams (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(3,4, the 5-trimethylphenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 0.55 centimetre ³1N aqueous sodium hydroxide solution and 20 centimetres ³Refluxed 18 hours in the ethanol, at 5 centimetres ³Obtain 69.3 milligrams of (3aRS, 4SR, 9SR in the Virahol after the recrystallization; 9aRS)-4, ethanoyl 9-ethano--2-[(2-p-methoxy-phenyl)]-9-(3,4; the 5-trimethylphenyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, it is Powdered to be white in color, and its feature is as follows:

-fusing point=＞260 ℃,

-mass spectrum (IE)=M/Z=509 (M ⁺).

Embodiment 38

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Steps A

As embodiment 1 step C, operate, but be to use 1.33 centimetres ³2-bromo toluene, 0.27 gram cutting magnesium and 2 gram (3aRS, 4SR, 7aRS) 2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate, adopting silica gel (230-400 order) flash chromatography purifying, with obtaining 2.2 gram (3aRS after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, 4SR, 7RS, 7aRS)-2-benzyl-7-hydroxyl-7-(2-aminomethyl phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate, but the faint yellow sead albumen crisp skin of synthetic sample material shape after being former state and being used for.

Step B

Keep 2.2 grams of 0 ℃ of temperature (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-hydroxyl-7-(2-aminomethyl phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate is at 20 centimetres ³In the solution in the methylene dichloride, drip 3.2 centimetres ³Trifluoromethanesulfonic acid and 3 centimetres ³Dichloromethane mixture.Reaction mixture was stirred 30 minutes down for 0 ℃ in temperature, stirred 20 hours down for 20 ℃ in temperature then, be cooled to 0 ℃ of temperature again.By adding the 1M aqueous sodium hydroxide solution pH of mixture is transferred to 8.Adopt decant method water phase separated, use 50 centimetres at every turn ³Dichloromethane extraction 3 times.Merge organic phase, use 100 centimetres more at every turn ³3 times, 100 centimetres of distilled water washs ³Saturated sodium-chloride water solution washing 3 times is with dried over mgso and under reduced pressure concentrated.Obtain like this 1.9 grams (3aRS, 4SR)-2-benzyl-7-(2-aminomethyl phenyl)-4-phenyl-1,3,3a, 4,5,6-six hydrogen isoindole-3a-methyl-formiate is oily, but that former state is used for is later synthetic, its feature is as follows:

- ¹HNMR composes (250MHz, CDCl ₃Add several CD ₃COODd4 represents d with ppm): 1.90 (mt, 1H:5 position CH ₂1H); 2.17 (s, 3H:ArCH ₃); 2.40-2.55 (mt, 2H:5 position CH ₂Another H and at 6 CH ₂1H); 2.66 (mt, 1H:6 position CH ₂Another H); (3.08 dd, J=11 and 2.5Hz, 1H:4 position CH); 3.32 (mt, 1H:1 position CH ₂1H); 3.63 (s, 3H:COOCH ₃); 3.60-3.70 (mt, 1H:3 position CH ₃1H); 3.75 (d, J=11.5Hz is at 1 CH ₂Another H); 3.92 (d, J=10Hz, 3 CH ₂Another H); 3.98 and 4.32 (2d, J=11Hz, each 1H:NCH ₂Ar); (6.90-7.40 mt, 14H: phenyl aromatics H-benzyl aromatics H and 2-aminomethyl phenyl aromatics H).

Step C

To remain on 0 ℃ 1.9 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-7-(2-aminomethyl phenyl)-4-phenyl-1,3,3a, 4,5,6-six hydrogen isoindole-3a-methyl-formiate is at 50 centimetres ³In the solution in the methylene dichloride, Dropwise 5 .8 centimetre ³Trifluoromethanesulfonic acid and 5 centimetres ³The mixture of methylene dichloride.Reaction mixture stirred 1 hour down for about 0 ℃ in temperature, stirred 96 hours down for about 20 ℃ in temperature then, was cooled to 0 ℃ of temperature then.By adding the 1M aqueous sodium hydroxide solution pH of mixture is transferred to 8.Adopt the decant method to separate organic phase, with 100 centimetres ³Distilled water, 100 centimetres ³The saturated sodium-chloride water solution washing is with dried over mgso and under reduced pressure concentrated.Adopting silica gel (230-400 order) flash chromatography purifying, with obtaining 0.85 gram (3aRS, 4SR after hexanaphthene-ethyl acetate mixture (by volume 95-5) wash-out, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(2-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, be oily, but former state is used for later synthesizing.

Step D

As embodiment 1 step e, operate, but be to use 0.85 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(2-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.37 gram ammonium formiate and 0.15 gram 10% (w/w) palladium/carbon are adopting silica gel (230-400 order) flash chromatography purifying, with obtaining 0.6 gram (3aRS after hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out, 4SR, 9SR, 9aRS)-4,9-ethano--9-(2-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are colorless oil, but former state is used for later synthesizing.

Step e

As embodiment 1 step G, operate, but be to use 0.6 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(2-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.31 gram 2-(2-p-methoxy-phenyl) vinylformic acid and 0.15 centimetre ³Oxalyl chloride is adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out; obtain 0.51 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-aminomethyl phenyl)-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate; be micro white sead albumen crisp skin shape, but former state is used for later synthesizing

Step F

Operation as embodiment 2, but be to use 0.51 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-aminomethyl phenyl)-2,3,3a; 4,9,1.5 centimetres of 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate ³1M aqueous sodium hydroxide solution and 15 centimetres ³Ethanol after the recrystallization, obtains 0.22 gram (3aRS, 4SR, 9SR in Virahol; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, its feature is as follows:

-fusing point:＞260 ℃

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6, temperature 393K represents d with ppm): 1.15-1.50 and 2.05-2.35 (2mts, each 2H:CH ₂CH ₂); 2.25 (s, 3H:ArCH ₃); 3.13 (dd, J=12 and 9Hz, 1H:1 position CH ₂1H); 3.31 (wide d, J=12Hz, 1H:1 position CH ₂Another H); (3.44 mt, 1H:4 position CH); 3.60 and 4.05 (be respectively d and wide d, J=12.5Hz, each 1H:3 position CH ₂); 3.75 (s, 3H:ArOCH ₃); 5.54 and 5.69 (mt, H-7 position, H-6 position, 11H:5 position H-2-p-methoxy-phenyl aromatics H and 2-aminomethyl phenyl aromatics H).

Embodiment 39

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

Restrain 4-trifluoromethyl-bromobenzenes at 40 centimetres 7.2 ³In the solution in the anhydrous diethyl ether, add 0.8 gram cutting magnesium.The spontaneous temperature rising reflux of reaction mixture 10 minutes, reflux is 20 minutes then.Then with reaction medium cooling, and (7aRS) 2-benzyl-7-oxo-4-phenyl octahydro diindyl-3a-methyl-formiate is at 40 centimetres for 3aRS, 4SR to add 5.6 grams in 15 minutes under about 10 ℃ of temperature ³Solution in the anhydrous diethyl ether.Reaction mixture was stirred 10 minutes down for about 10 ℃ in temperature, pour 150 centimetres then into ³In the saturated aqueous ammonium chloride.Adopt decant method water phase separated, use 75 centimetres at every turn ³Extracted with diethyl ether three times.Merge organic phase, one after the other use 75 centimetres at every turn ³Distilled water wash three times also under reduced pressure concentrates with dried over mgso in the presence of 3S is black.At 25 centimetres ³In the pentane after the recrystallization, obtain 5.2 grams (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-hydroxyl-7-[(4-trifluoromethyl) phenyl]-4-phenyl octahydro isoindole-3a-methyl-formiate, be the beige solid shape, its feature is as follows:

-fusing point=164 ℃.

Step B

Be cooled to 0 ℃ 20 centimetres ³In the trifluoromethanesulfonic acid, adding 4 grams (3aRS, 4SR, 7RS, 7aRS)-and 2-benzyl-7-hydroxyl-7-[(4-trifluoromethyl) phenyl]-4-phenyl octahydro isoindole-3a-methyl-formiate.Reaction mixture was stirred 3 hours down for about 20 ℃ in temperature, be cooled to about 10 ℃ of temperature then.At this moment add 50 centimetres ³Distilled water is transferred to 8-9 by adding 30% aqueous sodium hydroxide solution with the pH of its water then, with the cryostat that ethanol-dry ice mixture is housed its temperature is remained at about 10-15 ℃ simultaneously.Adopt decant method water phase separated, use 75 centimetres at every turn ³Ethyl acetate extraction 3 times.Merge organic phase, use 75 centimetres more at every turn ³Distilled water wash 3 times also under reduced pressure concentrates with dried over mgso in the presence of 3S is black.In sherwood oil after the recrystallization, such 3.4 gram (3aRS, 4SR that obtain for twice, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4,9,9-six hydrogen isoindole-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point: 132 ℃.

Step C

As embodiment 1 step e, operate, but be to use 3.4 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4,9,9-six hydrogen isoindole-1H-benzo [f] isoindole-3a-methyl-formiate, 1.3 gram ammonium formiates and 0.4 gram 10% (w/w) palladium/carbon.Obtain 2.2 grams (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point: 172 ℃

Step D

As embodiment 1 step G, operate, but be to use 1.4 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.62 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.94 centimetre ³Triethylamine and 0.3 centimetre ³Oxalyl chloride is adopting silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 50-50) wash-out; after crystallization in isopropyl ether, obtain 1.3 gram (3aRS, 4SR; 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2; 3; 3a, 4,9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, its feature is as follows:

-fusing point: 163 ℃.

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6 under the temperature 373K, represents d with ppm): (3mts is respectively 1H:1H and 2H:CH for 1.45-1.72 and 1.95-2.25 ₂CH ₂); 3.20-3.45 (mt,, 3H:1 position CH ₂With 9a position CH); (3.48 mt, 1H:4 position CH); 3.55 (s, 3H:COOCH ₃); 3.61 and 4.11 (be respectively d and wide d, J=12.5Hz, each 1H:3 position CH ₂); 3.70 (s, 3H:ArOCH ₃); 5.55 and 5.68 (2S, each 1H:=CH ₂); (6.36 wide d, J=7.5Hz, 1H:8 position H); (6.90-7.40 mt, H-7 position, H-6 position, 7H:5 position H-2-p-methoxy-phenyl aromatics H); 7.59 and 7.83 (2 wide d, J=8Hz, the aromatics H of each 2H:4-trifluoromethyl).

Embodiment 40

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 1.1 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 9.8 centimetres ³1M aqueous sodium hydroxide solution and 20 centimetres ³Methyl alcohol, in isopropyl ether after the crystallization, by acidic matrix and in isopropyl ether recrystallization; obtain 0.65 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, its feature is as follows:

-fusing point=153 ℃.

Embodiment 41

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation Chiral Separation

With embodiment 40 obtain 11 the gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-[4-(trifluoromethyl) phenyl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid divide to be expelled in succession for 4 times to be loaded with (R) N-(3; the 5-dinitrobenzoyl)-phenylalanine grafted chirality silicagel column on; use normal heptane; methylene dichloride and alcohol mixture (by volume 50-50-1) wash-out obtains 5 gram (3aRS, 4SR after under reduced pressure concentrating; 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph; it is Powdered to be white in color, and its feature is as follows:

-fusing point=228 ℃,

-mass spectrum (IE)=M/Z=547 (M ⁺)

-specific rotation: [a] ₃₆₅ ²⁰=+63.1+/-1.2 ° (c=0.5/ methyl alcohol).

Be loaded with (R)-N-(3; the 5-dinitrobenzoyl)-phenylalanine grafted chiral stationary phase can be according to the synthetic method preparation of embodiment 3 descriptions; but replace (S) N-(3, the 5-dinitrobenzoyl)-phenylalanine with (R) N-(3, the 5-dinitrobenzoyl)-phenylalanine.

Embodiment 42

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide

Restrain 1.1 (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid is at 20 centimetres ³In the solution in the methylene dichloride, add 0.24 centimetre in succession ³3-(aminomethyl) pyridine, 0.46 gram 1-ethyl-3-[(3-dimethylamino) propyl group] inferior diamine hydrochloride of carbonization and 0.16 gram N-hydroxy benzotriazole hydrate.Reaction mixture stirred 48 hours for about 20 ℃ in temperature.Organic phase is each with 10 centimetres ³Distilled water wash three times is again with dried over mgso and under reduced pressure concentrated.At 15 centimetres ³In the Virahol behind the recrystallization; obtain 0.95 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide, its feature is as follows:

-fusing point=214 ℃.

Embodiment 43

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-benzoyl-formyl hydrazine

Restrain 0.55 (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid is at 10 centimetres ³In the solution in the methylene dichloride, add 0.16 gram benzoyl hydrazine, 0.23 gram 1-ethyl-3-[(3-dimethylamino in succession) propyl group] the inferior diamine hydrochloride of carbonization and 81 milligrams of N-hydroxy benzotriazole hydrates.Reaction mixture stirred 20 hours for about 20 ℃ in temperature, filtered with fritted glass filter then.Precipitation is one after the other used 1.5 centimetres at every turn ³Washed with dichloromethane 3 times is used 2.5 centimetres then ³Distilled water wash three times.Obtain like this 0.34 the gram (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-the 9-[(4-trifluoromethyl) phenyl]-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-benzoyl-formyl hydrazine, its feature is as follows:

-fusing point=275 ℃.

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6 under the temperature 383K, represents d with ppm): 1.44-1.70-2.01 and 2.18 (4mts, each 1H:CH ₂CH ₂); 3.20-3.40 (restriction AB, 2H:1 position CH ₂); 3.55-3.85 (mt, 3H:3 position CH ₂1H-9a position CH and 4 CH); 3.72 (s, 3H:ArOCH ₃); 4.36 (wide d, J=12.5Hz, 3 H:CH ₂Another H); 5.57 and 5.70 (2s, each 1H:=CH ₂); (6.34 wide d, J=7.5Hz, 1H:8 position H); (6.85-7.60 mt, position aromatics H-benzoyl hydrazides contraposition aromatics H and 2-p-methoxy-phenyl aromatics H between the H-benzoyl hydrazides of H-7 position, H-6 position, 10H:5 position); 7.60 and 7.85 (2d, J=8Hz, the aromatics H of each 2H:4-trifluoromethyl); 9.66 and 9.91 (2 wide s, each 1H:CONHNHCO).

Embodiment 44

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-trifluoromethyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-phenyl-formyl hydrazine

Restrain 0.55 (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-trifluoromethyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid is at 10 centimetres ³In the solution in the methylene dichloride, add 0.12 gram phenyl hydrazine, 0.23 gram 1-ethyl-3-[(3-dimethylamino in succession) propyl group] the inferior diamine hydrochloride of carbonization and 81 milligrams of N-hydroxy benzotriazole hydrates.Reaction mixture stirred 20 hours for about 20 ℃ in temperature.With reaction mixture with 15 centimetres ³The methylene dichloride dilution is used 15 centimetres at every turn ³Distilled water wash three times also under reduced pressure concentrates with dried over mgso in the presence of 3S is black.At 10 centimetres ³Behind the recrystallization, obtain 0.21 gram (3aRS, 4SR, 9SR in the Virahol; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-trifluoromethyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-phenyl-formyl hydrazine, its feature is as follows:

-fusing point=226 ℃.

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6 under the temperature 383K, represents d with ppm): (3mts is respectively 1H-1H and 2H:CH for 1.44-1.69 and 1.95-2.25 ₂CH ₂); 3.20-3.45 (restriction AB, 2H:1 position CH ₂); 3.52 and 4.26 (be respectively d and wide d, J=12.5Hz, each 1H:3 position CH ₂); (3.63 mt, 1H:9a position CH); 3.69 (s, 3H:ArOCH ₃); (3.75 mt, 1H:4 position CH); 5.55 and 5.68 (2s, each 1H:=CH ₂); (6.35 wide d, J=7.5Hz, 1H:8 position H); 6.60 (d, J=7,5Hz, 2H: phenyl hydrazides ortho position aromatics H); 6.70 (t, J=7.5Hz, 1H: phenyl hydrazides contraposition aromatics H); (6.90-7.45 mt, position aromatics H-2-p-methoxy-phenyl aromatics H and ArNH between the H-phenyl hydrazides of H-7 position, H-6 position, 10H:5 position); 7.61 and 7.82 (2d, J=8Hz, the aromatics H of each 2H:4-trifluoromethyl); 9.52 (wide s, 1H:CONH).

Embodiment 45

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-naphthyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-the methyl-formiate that obtains at 40 gram embodiment 1 step B is at 300 centimetres ³In the solution in the ethanol, add 21.4 gram hydrazine hydrate, temperature rising reflux is 2 hours 30 minutes then.Under reduced pressure after the concentrated solvent, with its resistates of water dissolution and use dichloromethane extraction.The decant organic phase washes and uses dried over mgso with water.After under reduced pressure concentrating, obtain 38.73 grams (93%) (3aRS, 4SR 7aRS)-2-benzyl-7-hydrazono--4-phenyl octahydro isoindole-3a-methyl-formiate, are brown oily, and its feature is as follows:

-mass spectrum (IE): M/Z=377 (M ⁺)

-IR spectrum (with the dichloromethane solution form):

3400cm ^-1?????????????????????n?NH

3080,3060,3045,3030cm ^-1N aromatics CH

2950,2800cm ^-1N aliphatic series CH

2730cm ^-1?????????????????????n?CHN(CH ₂) ₃

1720cm ^-1N methyl esters C=O

1605,1495,1455,1435cm ^-1The aromatic ring breathing vibration

1435cm ^-1d _sMethyl esters CH ₃

1220cm ^-1N methyl esters O-C=O

Step B

37.75 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-hydrazono--4-phenyl octahydro isoindole-3a-methyl-formiate is at 200 centimetres ³Tetrahydrofuran (THF) and 43 centimetres ³In the solution in the triethylamine, Dropwise 5 2.07 gram iodine are at 250 centimetres ³Solution in the tetrahydrofuran (THF).After adding, at room temperature keep stirring 1 hour.At this moment add 1 decimeter ³Water and 1 decimeter ³Ethyl acetate.Adopt the decant method to separate organic phase, one after the other, wash and use dried over mgso with saturated nacl aqueous solution then with saturated sodium sulfite solution washing.Under reduced pressure after the concentrated solvent.Its resistates adopts silica gel (230-400 order) flash chromatography purifying, with hexanaphthene and ethyl acetate mixture (by volume 95-5) wash-out.Obtain like this 22.25 grams (47%) (3aRS, 4SR, 7aRS)-2-benzyl-7-iodo-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate are the yellow solid state of sticking with paste, its feature is as follows:

-mass spectrum (IE): M/Z=473 (M ⁺)

-IR spectrum (with the carbon tetrachloride solution form):

3080,3060,3030cm ^-1N aromatics CH

2950,2800cm ^-1N aliphatic series CH

2730cm ^-1??????????????????????n?CHN(CH ₂) ₃

1730cm ^-1N methyl esters C=O

1600,1495,1455,1435cm ^-1The aromatic ring breathing vibration

1435cm ^-1d _sMethyl esters CH ₃

1210cm ^-1N methyl esters O-C=O

700cm ^-1G aromatics CH

Step C

To 2 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-iodo-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate is at 40 centimetres ³In the solution in the toluene, add 240 milligrams of tetrakis triphenylphosphine palladiums, add 0.69 then and restrain with the isolating 2-naphthyl of trimer anhydride form boric acid at 20 centimetres ³Solution in the methyl alcohol.Drip 45 centimetres ³2N aqueous sodium carbonate, and temperature rising reflux 4 hours.After cooling, add 80 centimetres ³Water and 60 centimetres ³Ethyl acetate.Adopt the decant method to separate organic phase, wash with water up to neutral and use dried over mgso.Under reduced pressure after the concentrated solvent, its resistates adopts silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out.Obtain like this 1.33 grams (67%) (3aRS, 4SR, 7aRS)-2-benzyl-7-(2-naphthyl)-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the sead albumen crisp skin sample material that is white in color, its feature is as follows:

-mass spectrum (IE): M/Z=473 (M ⁺).

Step D

As embodiment 38 step C, operate, but be to use 1.66 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-(2-naphthyl)-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 1.9 centimetres ³Trifluoromethanesulfonic acid is at 20 centimetres ³Solution in the anhydrous methylene chloride at room temperature four hours, is adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 95-5) wash-out, isolate 1.22 grams (51%) and mainly contain (measuring about 90%) (3aRS, 4SR with NMR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(2-naphthyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, but former state is used for later synthesizing, and its feature is as follows:

- ¹HNMR composes (300MHz, CDCl ₃, represent d with ppm): 1.40-2.0 and 2.52 (mts, each 2H:CH ₂CH ₂); 2.20-2.40 (mt, 2H:1 position CH ₂1H and 3 CH ₂1H); 2.68 (wide d, J=10Hz, 1H:1 position CH ₂Another H); 3.21 (wide d, J=10Hz, 3 CH ₂Another H); 3.31 and 3.67 (d, J=12.5Hz, 2H:NCH ₂Ar); (3.36 mt, 1H:9a position CH); (3.45 wide d, 1H:4 position CH); 3.58 (s, 3H:COOCH ₃); (6.61 wide d, J=7,5Hz, 1H:8 position H); (6.91-8.00 mt, H-6 position, 15H:5 position H-7 position H-naphthyl aromatics and benzyl aromatics H).

Step e

1.2 gram (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(2-naphthyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is at 50 centimetres ³Methanol solution and 2 centimetres ³The 2M hydrogen chloride methanol solution in the presence of 115 milligram of 10% (w/w) palladium/carbon, under normal atmosphere hydrogen, stirred 5 hours at 50 ℃.After filtering catalyst, decompression is concentrated solvent down.Obtain like this 0.96 the gram (91%) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(2-naphthyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are the cream-coloured powder shape, its feature is as follows:

-fusing point＞260 ℃

-mass spectrum (IE): M/Z:383 (M ⁺)

Step F

As embodiment 1 step G, operate, but be to use 0.96 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(2-naphthyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride, 0.41 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.2 centimetre ³Oxalyl chloride and 0.64 centimetre ³Triethylamine is at 60 centimetres ³Solution in the methylene dichloride at room temperature 20 hours, is adopting silica gel (230-400 order) flash chromatography purifying; after hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out, obtain 1.15 gram (78%) (3aRS, 4SR; 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-naphthyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=140-2 ℃

-mass spectrum (IE): M/Z=473 (M ⁺).

Embodiment 46

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-naphthyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid sodium salt

As embodiment 2 one operations, but be to use 1.15 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-naphthyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 6.3 centimetres ³1M aqueous sodium hydroxide solution and 40 centimetres ³Refluxed 5 hours in the ethanol; adopting silica gel (230-400 order) flash chromatography purifying; with methylene dichloride and carbinol mixture (by volume 95-5) wash-out; carry out high-efficient liquid phase chromatogram purification with grafting C18 Waters silica gel then; after water and acetonitrile (by volume 70-30) wash-out, obtain 50 milligrams of (4.8%) (3aRS, 4SR; 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(2-naphthyl)-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid sodium salt; the solid state that is white in color, its feature is as follows:

-fusing point＞260 ℃

-mass spectrum (IE): M/Z=529 (M ⁺).

Embodiment 47

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(5-methyl-2-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 31 steps A, operate, but be to use 2 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate, 0.8 centimetre ³2-thiotolene and 3 centimetres ³Trifluoromethanesulfonic acid is at 30 centimetres ³In the methylene dichloride at room temperature 5 hours, adopting silica gel (230-400 order) flash chromatography purifying, with hexanaphthene and the ethyl acetate mixture (95-5 of by volume elder generation, back 90-10) wash-out obtains 0.49 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(5-methyl-2-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

- ¹HNMR composes (300MHz, CDCl ₃, represent d with ppm): (3mts is respectively 1H:1H and 2H:CH for 1.14-1.66 and 2.35-2.55 ₂CH ₂); 2.29 and 3.18 (d, J=10Hz, each 1H:3 position CH ₂); 2.35-2.55 and 3.00 (be respectively mt and d, J=10Hz, each 1H:1 position CH ₂); 2.52 (s, 3H:ArCH ₃); (3.10 wide d, J=8Hz, 1H:9a position CH); 3.30-3.40 (mt, 2H:4 position H and NCH ₂The 1H of Ar); 3.54 (s, 3H:COOCH ₃); 3.74 (d, J=12.5Hz, 1H:NCH ₂Another H of Ar); (6.71 mt, 1H:8 position H); 6.71 and 6.74 (be respectively mt and d, J=4Hz, each 1H: thienyl aromatics H); (6.95-7.45 mt, H-6 position, 8H:5 position H-7 position H and benzyl aromatics H).

Step B

0.48 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(5-methyl-2-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 0.17 centimetre ³The carbonochloridic acid vinyl acetate is at 5 centimetres ³Solution in the dichloro hexane at room temperature stirred 18 hours.Under reduced pressure after the concentrated solvent, its resistates adopts the flash chromatography on silica gel purifying, with hexanaphthene and ethyl acetate mixture (85-15 of by volume elder generation) wash-out, obtains 0.37 gram sead albumen crisp skin shape product, and this product is dissolved in 7 centimetres ³In the methyl alcohol.At this moment add 1.65 centimetres ³1M aqueous hydrochloric acid, and temperature rising reflux 3 hours.After concentrated solvent, with resistates recrystallization in Virahol and isopropyl ether mixture (by volume 50-50).Obtain like this 0.3 the gram (70%) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(5-methyl-2-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride are the light green solid state, its feature is as follows:

-fusing point=226-30 ℃

-mass spectrum (IE): M/Z=353 (M ⁺).

Step C

As embodiment 1 step G, operate, but be to use 0.58 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(5-methyl-2-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride, 0.27 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.13 centimetre ³Oxalyl chloride and 0.42 centimetre ³Triethylamine is at 35 centimetres ³Solution in the methylene dichloride at room temperature 20 hours, is adopting silica gel (230-400 order) flash chromatography purifying; after hexanaphthene and ethyl acetate mixture (by volume 80-20) wash-out, obtain 0.53 gram (69%) (3aRS, 4SR; 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(5-methyl-2-thienyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are the cream-coloured powder shape, and its feature is as follows:

-fusing point=112-5 ℃

-mass spectrum (IE): M/Z=513 (M ⁺).

Embodiment 48

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(5-methyl-2-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 0.45 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(5-methyl-2-thienyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 2.6 centimetres ³1M aqueous sodium hydroxide solution and 15 centimetres ³Refluxed 5 hours in the ethanol, in isopropyl ether, after the recrystallization purifying, obtain 285 milligrams of (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(5-methyl-2-thienyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid are the beige solid shape, and its feature is as follows:

-fusing point=164-6 ℃

-mass spectrum (IE): M/Z=499 (M ⁺).

Embodiment 49

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(4-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 45 step C, operate, but be to use 1 gram (3aRS, 4SR, 7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a, 4,5,7a-six hydrogen isoindole-3a-methyl-formiate is at 20 centimetres ³Solution in the toluene, 120 milligrams of tetrakis triphenylphosphine palladiums, 0.46 gram 4-bromophenyl boric acid are at 10 centimetres ³Solution in the methyl alcohol and 15 centimetres ³The 2N aqueous sodium carbonate, reflux 18 hours.Adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene and ethyl acetate mixture (by volume 90-10) wash-out, obtain 0.77 gram (73%) (3aRS, 4SR, 7aRS)-2-benzyl-7-(4-bromophenyl)-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate, the sead albumen crisp skin shape that is white in color, its feature is as follows:

-mass spectrum (IE): M/Z=502 (M ⁺).

Step B

As embodiment 38 step C, operate, but be to use 0.77 gram (3aRS, 4SR, 7aRS)-2-benzyl-7-(4-bromophenyl)-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate and 1.18 centimetres ³Trifluoromethanesulfonic acid is at 20 centimetres ³Solution in the methylene dichloride at room temperature 18 hours, obtains 0.71 gram (92%) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(4-bromophenyl)-4,9 ethano-s-2,3,3a, 4,9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate are the cream-coloured powder shape, but former state is used for following synthesizing, and its feature is as follows:

-mass spectrum (IE): M/Z=502 (M ⁺).

Step C

As embodiment 47 step B, operate, but be to use 0.71 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(4-bromophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate and 0.4 centimetre ³The carbonochloridic acid vinyl acetate is at 20 centimetres ³Solution in the methylene dichloride.At room temperature 72 hours, enriched material is dissolved in 40 centimetres then ³Methyl alcohol and 5 centimetres ³In the solution in the 6M hydrogenchloride Zai diox, refluxed 3 hours, in isopropyl ether after the crystallization, obtain 0.45 gram (77%) (3aRS, 4SR, 9SR, 9aRS)-9-(4-bromophenyl)-4,9 ethano-s-2,3,3a, 4,9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate hydrochloride, the lenticular that is white in color, its feature is as follows:

-mass spectrum (IE): M/Z=412 (M ⁺).

Step D

As embodiment 1 step G, operate, but be to use 0.45 gram (3aRS, 4SR, 9SR, 9aRS)-and 9-(4-bromophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate hydrochloride, 0.21 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.10 centimetre ³Oxalyl chloride and 0.33 centimetre ³Triethylamine is at 30 centimetres ³Solution in the methylene dichloride at room temperature 20 hours, is adopting silica gel (230-400 order) flash chromatography purifying; after hexanaphthene and ethyl acetate mixture (by volume 70-30) wash-out, obtain 0.25 gram (40%) (3aRS, 4SR; 9SR, 9aRS)-9-(4-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-isoindole-3a-methyl-formiate, it is Powdered to be oldlace, and its feature is as follows:

-fusing point=190-2 ℃

-mass spectrum (IE): M/Z=572 (M ⁺).

Embodiment 50

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(4-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 0.19 gram (3aRS, 4SR, 9SR; 9aRS)-and 9-(4-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 0.44 centimetre ³1M aqueous sodium hydroxide solution and 10 centimetres ³Refluxed 3 hours in the ethanol, in isopropyl ether, after the recrystallization purifying, obtain 120 milligrams of (66%) (3aRS; 4SR, 9SR, 9aRS)-9-(4-bromophenyl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, the solid state that is white in color, its feature is as follows:

-fusing point=169 ℃

-mass spectrum (IE): M/Z=558 (M ⁺).

Embodiment 51

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-dichlorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Steps A

As embodiment 39 steps A, operate, but be to use 3.6 grams 3,4-two chloro-bromobenzenes, at 20 centimetres ³In the ether 0.4 gram cutting magnesium, 2.9 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 20 centimetres ³Solution in the ether is at 35 centimetres ³In the Virahol after the recrystallization, obtain 1.8 grams (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-(3, the 4-dichlorophenyl)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=144 ℃

To do additionally to obtain 0.6 gram with isopropyl ether to anhydrous filtrate crystallization.Adopt this second batch of filtrate of silica gel (230-400 order) flash chromatography purifying,, in isopropyl ether, can access 0.25 gram after the crystallization with hexanaphthene and ethyl acetate mixture (by volume 80-20) wash-out.

Step B

As embodiment 1 step D one operation, but be to use 1.2 grams (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-(3, the 4-dichlorophenyl)-7-hydroxy-4-phenyl-1,3,3a, 4,5,6-six hydrogen isoindole-3a-methyl-formiate, 3 centimetres ³Trifluoromethanesulfonic acid and 45 centimetres ³Methylene dichloride, obtain 1.1 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(3, the 4-dichlorophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the sead albumen crisp skin shape former state that is white in color can be used for following synthesizing.

Step C

Restrain 0.7 (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-9-(3, the 4-dichlorophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is at 7.5 centimetres ³In the solution in the methylene dichloride, add 0.18 centimetre ³The carbonochloridic acid vinyl acetate.Reaction mixture was stirred 20 hours down for about 20 ℃ in temperature, under reduced pressure concentrate then.Its resistates is with 7.5 centimetres ³The methyl alcohol dilution.In this solution, add 14 centimetres ³The solution of 1M hydrogen chloride gas in ether.Reaction mixture stirred 20 hours down for about 20 ℃ in temperature, under reduced pressure concentrated then.Resistates is dissolved in 25 centimetres ³Methylene dichloride and 20 centimetres ³In the mixture of saturated sodium bicarbonate aqueous solution.Adopt the decant water phase separated, and use 15 centimetres at every turn ³Extracted with diethyl ether 2 times.Merge organic phase, use 15 centimetres at every turn ³Distilled water wash 3 times is with dried over mgso and under reduced pressure concentrated.Adopting silica gel (230-400 order) flash chromatography purifying, with hexanaphthene and ethyl acetate mixture (by volume 80-20) wash-out with at 5 centimetres ³In the isopropyl ether after the crystallization, then obtain 0.21 gram (3aRS, 4SR, 9SR, 9aRS)-9-(3, the 4-dichlorophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=185 ℃.

Step D

As embodiment 1 step G, operate, but be to use 0.20 gram (3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-dichlorophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.1 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.04 centimetre ³Oxalyl chloride and 0.14 centimetre ³Triethylamine after the crystallization, obtains 0.19 gram (3aRS in isopropyl ether; 4SR, 9SR, 9aRS)-9-(3; the 4-dichlorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate; the solid state that is white in color, its feature is as follows:

-fusing point=150 ℃.

Step e

Operation as embodiment 2, but be to use 0.16 gram (3aRS, 4SR, 9SR; 9aRS)-and 9-(3, the 4-dichlorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 1.4 centimetres ³1M aqueous sodium hydroxide solution and 3 centimetres ³Methyl alcohol is at 2.5 centimetres ³Recrystallization in the isopropyl acetate, obtain 0.1 gram (3aRS, 4SR, 9SR, 9aRS)-9-(3; the 4-dichlorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, its feature is as follows:

-fusing point=168 ℃.

Embodiment 52

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-chloro-phenyl-)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

Operate as embodiment 1 step C, (7aRS) 2-phenyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 25 centimetres for 3aRS, 4SR but be to use 9.58 gram 4-chloro-bromobenzenes, 1.2 gram cutting magnesium and 9.1 grams ³In the Virahol after the recrystallization, obtain 7.9 grams (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-(4-chloro-phenyl-)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=189 ℃

Step B

As embodiment 1 step D, operate, but be to use 7.5 grams (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-(4-chloro-phenyl-)-7-hydroxy-4-phenyl-2,3,3a, 4,5,6-six hydrogen isoindole-3a-methyl-formiate, 25 centimetres ³Trifluoromethanesulfonic acid and 80 centimetres ³Methylene dichloride is at 100 centimetres ³In the Virahol after the crystallization, obtain 6.35 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(4-chloro-phenyl-)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=142 ℃

Step C

As embodiment 51 step C, operate, but be to use 2.29 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(4-chloro-phenyl-)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 0.98 centimetre ³The carbonochloridic acid vinyl acetate is at 7.5 centimetres ³Solution in the methylene dichloride is used 8.5 centimetres then ³Solution-treated in the 6M hydrogen chloride gas Zai diox is diluted in 25 centimetres ³Intermediate product in the methyl alcohol.Adopting silica gel (230-400 order) flash chromatography purifying,, obtaining 0.8 gram (3aRS with methylene chloride-methanol mixture (by volume 98-2) wash-out, 4SR, 9SR, 9aRS)-9-(4-chloro-phenyl-)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are sead albumen crisp skin shape, but former state is used for following synthesizing.

Step D

As embodiment 1 step G, operate, but be to use 0.75 gram (3aRS, 4SR, 9SR, 9aRS)-and 9-(4-chloro-phenyl-)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.36 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.17 centimetre ³Oxalyl chloride and 0.57 centimetre ³Triethylamine, obtain 0.8 gram (3aRS, 4SR, 9SR, 9aRS)-9-(4-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, its feature is as follows:

-fusing point=90 ℃.

Embodiment 53

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(4-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 0.7 gram (3aRS, 4SR, 9SR; 9aRS)-and 9-(4-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 2 centimetres ³1M aqueous sodium hydroxide solution and 30 centimetres ³Ethanol is adopting silica gel (230-400 order) flash chromatography purifying, after methylene chloride-methanol mixture (by volume 98-2) wash-out; obtain 0.45 gram (3aRS, 4SR, 9SR; 9aRS)-9-(4-chloro-phenyl-)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, its feature is as follows:

-fusing point: about 160 ℃.

Embodiment 54

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-methoxyl group-3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Steps A

As embodiment 31 steps A, operate, but be to use 2 grams (3aRS, 4SR, 7aRS) 2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate, 2 gram 2-methyl phenylmethylethers and 2.9 centimetres ³Trifluoromethanesulfonic acid is at 30 centimetres ³Solution in the methylene dichloride is adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 2.3 gram (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(4-methoxyl group-3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, be micro white sead albumen crisp skin sample material, but former state is used for following synthesizing.

Step B

As embodiment 1 step e, operate, but be to use 2.3 gram (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(4-methoxyl group-3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.93 gram ammonium formiate and 0.5 gram 10% (w/w) palladium/carbon, adopting silica gel (230-400 order) flash chromatography purifying, with methylene chloride-methanol mixture (by volume 99-1) wash-out with at 20 centimetres ³In the Virahol after the recrystallization, obtain 0.5 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-methoxyl group-3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=123 ℃.

Step C

As embodiment 1 step G, operate, but be to use 1.1 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-methoxyl group-3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.52 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.25 centimetre ³Oxalyl chloride and 0.82 centimetre ³Triethylamine is adopting silica gel (230-400 order) flash chromatography purifying, with methylene chloride-methanol mixture (by volume 99-1) wash-out with at 5 centimetres ³After the recrystallization, obtain 0.85 gram (3aRS, 4SR, 9SR in the Virahol; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-methoxyl group-3-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, its feature is as follows:

-fusing point=125 ℃.

Step D

Operation as embodiment 2, but be to use 0.8 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-methoxyl group-3-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 2.25 centimetres ³1M aqueous sodium hydroxide solution and 40 centimetres ³Ethanol is adopting silica gel (230-400 order) flash chromatography purifying, after methylene chloride-methanol mixture (by volume 97.5-2.5) wash-out; obtain 0.45 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-methoxyl group-3-aminomethyl phenyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid are amorphous white solid.

-mass spectrum (IE): M/Z=523 (M ⁺).

Embodiment 55

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-indyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 31 steps A, operate, but be to use 3.63 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate, 3.85 gram 1-phenyl sulfonyl indoles and 5.3 centimetres ³Trifluoromethanesulfonic acid is at 30 centimetres ³Solution in the methylene dichloride, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out, obtain 2.1 gram crude products, the crude product of this crude product with second batch of test carrying out with same amount merged.Adopt this mixture of silica gel (230-400 order) flash chromatography purifying,, obtain 1 gram (3aRS with hexanaphthene-ethyl acetate mixture (by volume 95-5) wash-out, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(3-indyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are micro white sead albumen crisp skin sample material, but former state is used for following synthesizing, and its feature is as follows:

- ¹HNMR composes (300MHz, CDCl ₃, represent d with ppm): 1.30-1.60 and 2.55 (2mts, each 2H:CH ₂CH ₂); 2.11 and 2.65 (be respectively dd and d, J=10 and 9Hz and 10Hz, each 1H:1 position CH ₂); 2.31 and 3.21 (2d, J=10Hz, each 1H:3 position CH ₂); 3.37-3.51 (2d, J=12,5Hz, each 1H:NCH ₂Ar); (3.42 wide s, 1H:4 position CH); (3.50-3.70 mt, 1H:9a position CH); 3.59 (s, 3H:COOCH ₃); (6.81 wide d, J=7.5Hz, 1H:8 position H); (6.90-7.60 mt, H-7 position, H-6 position, 13H:5 position H-indoles aromatics H and benzyl aromatics H); 8.11 (wide s, 1H:NH).

Step B

As embodiment 51 step C, operate, but be to use 1 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(3-indyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 0.285 centimetre ³The carbonochloridic acid vinyl acetate is at 20 centimetres ³Solution in the methylene dichloride is used 21.4 centimetres then ³The solution-treated of 1M hydrogen chloride gas in ether is dissolved in 20 centimetres ³Intermediate product in the methyl alcohol is adopting this mixture of silica gel (230-400 order) flash chromatography purifying, after methylene chloride-methanol mixture (by volume 97.5-2.5) wash-out, obtain 0.3 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-indyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, be orange sead albumen crisp skin sample material, but former state is used for following synthesizing.

Step C

As embodiment 1 step G, operate, but be to use 0.3 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-indyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.145 gram 2-(2-p-methoxy-phenyl) vinylformic acid and 0.07 centimetre ³Oxalyl chloride is adopting silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 50-50) wash-out with in isopropyl ether after the crystallization; obtain 0.16 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-indyl)-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, its feature is as follows:

-mass spectrum (IE): M/Z=532 (M ⁺)

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6, temperature 383K represents d with ppm): 1.46 and 2.16 (2mts, each 2H:CH ₂CH ₂); 3.30-3.80 (mt, 4H:1 position CH ₂-9a position CH and 3 CH ₂1H); (3.47 mt, 1H:4 position CH); 3.57 (s, 3H:COOCH ₃); 3.71 (s, 3H:ArOCH ₃); 4.10 (wide d, J=12.5Hz, 1H:3 position CH ₂Another H); 5.52 and 5.67 (2s, each 1H:=CH ₂); (6.65 wide d, J=7.5Hz, 1H:8 position H); (6.90-7.88 mt, H-7 position, H-6 position, 12H:5 position H-indoles aromatics H and 2-p-methoxy-phenyl aromatics H).

Embodiment 56

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-isopropyl phenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Steps A

As embodiment 1 steps A, operate, but be to use 6 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 60 centimetres ³Solution in the anhydrous diethyl ether and by 4 gram 4-bromo-isopropyl benzenes and 0.52 gram cutting magnesium at 7 centimetres ³The solution of the 4-isopropyl phenyl magnesium bromide of instant preparation in the ether, at room temperature 18 hours, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 98-2 to 80-20) wash-out, obtain 3.3 gram (41%) (3aRS, 4SR, 7RS, 7aRS)-and 2-benzyl-7-(4-isopropyl phenyl)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate, be yellow oily, its feature is as follows:

-mass spectrum (IE): M/Z=483 (M ⁺)

Step B

As embodiment 1 step D, operate, but be to use 1.7 grams (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-(4-isopropyl phenyl)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate and 2.3 centimetres ³Trifluoromethanesulfonic acid is at 22 centimetres ³In the methylene dichloride at room temperature 3 hours, obtain 1.44 gram (90%) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-isopropyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, be brown thickness oily, but former state is used for following synthesizing, its feature is as follows:

-mass spectrum (IE): M/Z=465 (M ⁺).

Step C

As embodiment 45 step C, operate, but be to use 1.4 gram (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(4-isopropyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, with 140 milligram of 10% (w/w) palladium/carbon, at 125 centimetres ³Methyl alcohol and 3.3 centimetres ³In the 1M aqueous hydrochloric acid, under normal atmosphere hydrogen and room temperature 4 hours, in isopropyl ether, obtain 1.03 gram (86%) (3aRS after the crystallization, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-isopropyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride are the cream-coloured powder shape, and its feature is as follows:

-mass spectrum (IE): M/Z=375 (M ⁺).

Step D

As embodiment 5 steps A, operate, but at 55 centimetres ³Use 500 milligrams of (3aRS in the methylene dichloride, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-isopropyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride, 240 milligrams of 2-anisole guanidine-acetic acids, 280 milligrams of 1-ethyl-3-[(3-dimethylaminos) propyl group] carbodiimide hydrochloride, 16 milligrams of N-1-hydroxy benzotriazole hydrates and 0.2 centimetre ³Triethylamine is adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out; obtain 460 milligrams of (76%) (3aRS, 4SR, 9SR; 9aRS)-4, ethanoyl 9-ethano--9-(4-isopropyl phenyl)-2-[(2-p-methoxy-phenyl)]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate; it is Powdered to be white in color, and its feature is as follows:

-fusing point=85-7 ℃

-mass spectrum (IE): M/Z=523 (M ⁺).

Step e

As embodiment 2 one operations, but be to use 0.379 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-isopropyl phenyl)-2-[(2-p-methoxy-phenyl) ethanoyl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 0.85 centimetre ³1M aqueous sodium hydroxide solution and 15 centimetres ³Refluxed in the ethanol 3 hours, and in the presence of silica gel (230-400 order), in ethyl acetate, stirred purifying, then in pentane after the recrystallization; obtain 170 milligrams of (47%) (3aRS, 4SR, 9SR; 9aRS)-4, ethanoyl 9-ethano--9-(4-isopropyl phenyl)-2-[(2-p-methoxy-phenyl)]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; the solid state that is white in color, its feature is as follows:

-fusing point=135-6 ℃

-mass spectrum (IE): M/Z=509 (M ⁺).

Embodiment 57

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-isopropyl phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

As embodiment 1 step G, operate, but (the 3aRS that is to use 0.53 gram embodiment, 56 step C to obtain, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-isopropyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride, 0.25 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.12 centimetre ³Oxalyl chloride and 0.4 centimetre ³Triethylamine is at 30 centimetres ³Solution in the methylene dichloride; at room temperature 20 hours; adopting silica gel (230-400 order) flash chromatography purifying; with hexanaphthene-ethyl acetate mixture (by volume 98-2 to 70-30) gradient elution with in isopropyl ether after the crystallization; obtain 0.375 gram (54%) (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--9-(4-isopropyl phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=98-100 ℃

-mass spectrum (IE): M/Z=535 (M ⁺).

Operation as embodiment 2, but be to use 0.32 gram (54%) (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-isopropyl phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 0.71 centimetre ³1M aqueous sodium hydroxide solution and 15 centimetres ³Refluxed in the ethanol 2 hours, and in the presence of silica gel (230-400 order), in ethyl acetate, stirred purifying, then in pentane after the recrystallization; obtain 190 milligrams of (59%) (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-isopropyl phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; it is Powdered to be white in color, and its feature is as follows:

-fusing point=168-70 ℃

-mass spectrum (IE): M/Z=521 (M ⁺).

Embodiment 58

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 45 step C, operate, but be to use 1.2 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a, 4,5,7a-six hydrogen isoindole-3a-methyl-formiate is at 30 centimetres ³Solution in the toluene, 150 milligrams of tetrakis triphenylphosphine palladiums, 0.35 gram 3-thienyl boric acid.At 15 centimetres ³Methyl alcohol and 28 centimetres ³Refluxed 3 hours in the 2N aqueous sodium carbonate.Adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 85-15) wash-out, obtain 0.99 gram (93%) (3aRS, 4SR, 7aRS)-2-benzyl-4-phenyl-7-(3-thienyl)-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate are yellow oily, and its feature is as follows:

-mass spectrum (IE): M/Z=429 (M ⁺).

Step B

As embodiment 38 step C, operate, but be to use 1.1 grams (3aRS, 4SR, 7aRS)-2-benzyl-4-phenyl-7-(3-thienyl)-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate and 1.4 centimetres ³Trifluoromethanesulfonic acid is at 15 centimetres ³In the methylene dichloride at room temperature 10 hours, obtain 0.62 gram (56%) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(3-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, be the cream-coloured powder shape, but former state is used for following synthesizing, its feature is as follows:

-mass spectrum (IE): M/Z=429 (M ⁺).

Step C

As embodiment 47 step B, operate, but be to use 0.62 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(3-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 0.19 centimetre ³The carbonochloridic acid vinyl acetate is at 10 centimetres ³In the methylene dichloride at room temperature 72 hours, enriched material is dissolved in 20 centimetres then ³Methyl alcohol and 2.7 centimetres ³In the solution of 5M spirit of salt in Virahol, refluxed two hours, in isopropyl ether, obtain 0.48 gram (89%) (3aRS after the crystallization, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride, the solid state that is white in color, its feature is as follows:

-mass spectrum (IE): M/Z=339 (M ⁺).

Step D

As above-mentioned 1 step G, operate, but be to use 0.48 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-thienyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride, 0.27 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.12 centimetre ³Oxalyl chloride and 0.36 centimetre ³Triethylamine is at 35 centimetres ³Solution in the methylene dichloride; at room temperature 20 hours; adopting silica gel (230-400 order) flash chromatography purifying; with hexanaphthene-ethyl acetate mixture (by volume 60-40) wash-out; then in isopropyl ether, after the recrystallization, obtain 0.40 gram (63%) (3aRS, 4SR; 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-thienyl)-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate; the solid state that is white in color, its feature is as follows:

-fusing point=174 ℃

-mass spectrum (IE): M/Z=499 (M ⁺).

Step e

Operation as embodiment 2, but be to use 0.35 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-thienyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 2.1 centimetres ³1M aqueous sodium hydroxide solution and 12 centimetres ³Refluxed 3 hours in the ethanol, in sherwood oil (40-65 ℃), after the recrystallization purifying, obtain 340 milligrams of (88%) (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-thienyl)-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, the solid state that is white in color, its feature is as follows:

-fusing point=170 ℃

-mass spectrum (IE): M/Z=485 (M ⁺).

Embodiment 59

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-ethylphenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 45 step C, operate, but be to use 1.35 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a, 4,5,7a-six hydrogen isoindole-3a-methyl-formiate is at 20 centimetres ³Solution in the toluene, 340 milligrams of tetrakis triphenylphosphine palladiums, 0.38 gram 4-ethylphenyl boric acid trimerization acid anhydrides are at 10 centimetres ³Methyl alcohol and 15 centimetres ³Refluxed 18 hours in the 2N aqueous sodium carbonate.Adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 0.92 gram (72%) (3aRS, 4SR, 7aRS)-2-benzyl-7-(4-ethylphenyl)-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate are yellow thickness oily, and its feature is as follows:

-mass spectrum (IE): M/Z=451 (M ⁺).

Step B

As embodiment 38 step C, operate, but be to use 0.92 gram (3aRS, 4SR, 7aRS)-2-benzyl-7-(4-ethylphenyl)-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate and 1.18 centimetres ³Trifluoromethanesulfonic acid is at 18 centimetres ³In the methylene dichloride at room temperature 6 hours, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 95-5) wash-out, obtain 0.68 gram (74%) (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(4-ethylphenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, be yellow thickness oily, its feature is as follows:

-mass spectrum (IE): M/Z=451 (M ⁺).

Step C

As embodiment 1 step e, operate, but be to use 0.68 gram (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(4-ethylphenyl)--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 0.27 gram ammonium formiate are at 40 centimetres ³In the methyl alcohol, in the presence of 200 milligram of 3% (w/w) palladium/carbon, refluxed 4 hours, obtain 0.47 gram (87%) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-ethylphenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are yellow pasty solid, and its feature is as follows:

-mass spectrum (IE): M/Z=461 (M ⁺).

Step D

As embodiment 5 steps A, operate, but be to use 0.47 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-ethylphenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.23 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.3 gram 1-ethyl-3-[(3-dimethylamino) propyl group] the inferior diamine hydrochloride of carbonization, 20 milligrams of N-1-hydroxy benzotriazole hydrates, at 30 centimetres ³In the methylene dichloride at room temperature 6 hours, adopting silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out; obtain 0.26 gram (38%) (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-ethylphenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate; it is Powdered to be white in color, and its feature is as follows:

-fusing point=90-2 ℃

-mass spectrum (IE): M/Z=521 (M ⁺).

Embodiment 60

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-ethylphenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 0.18 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-ethylphenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 0.43cm ³1M aqueous sodium hydroxide solution and 10 centimetres ³Refluxed 3 hours in the methyl alcohol, in sherwood oil, obtain 59 milligrams of (34%) (3aRS, 4SR after the recrystallization purifying; 9SR; 9aRS)-4,9-ethano--9-(4-ethylphenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; the solid state that is white in color, its feature is as follows:

-fusing point=141 ℃

-mass spectrum (IE): M/Z=507 (M ⁺).

Embodiment 61

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(2,3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 31 steps A, operate, but be to use 2.5 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate is at 250 centimetres ³Solution in the methylene dichloride, 2.4 centimetres ³2,3-Dihydrobenzofuranes and 4.25 centimetres ³Trifluoromethanesulfonic acid; After the about 20 ℃ of following stirrings of temperature 18 hours, obtain 1.56 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(2,3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are orange-yellow oily, but former state is used for following step, and its feature is as follows:

-mass spectrum (IE): M/Z=465 (M ⁺).

Step B

As embodiment 1 step e, operate, but be to use 1.56 gram (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-9-(2,3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.63 gram ammonium formiate and 0.2 gram 10% (w/w) palladium/carbon are at 30 centimetres ³Refluxed 5 hours in the methyl alcohol, obtain impure (3aRS, the 4SR of 0.995 gram, 9SR, 9aRS)-9-(2,3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are orange lacquer shape, but former state is used for following step, and its feature is as follows:

-mass spectrum (DCI): M/Z=376 (M ⁺+ H ⁺).

Step C

As embodiment 1 step G, operate, but be to use 0.45 gram 2-(2-p-methoxy-phenyl) vinylformic acid at 20 centimetres ³Contain 4 N, the solution in the methylene dichloride of dinethylformamide, 0.54 centimetre ³Oxalyl chloride, is evaporated to dry doubling and is dissolved in 20 centimetres again after about 20 ℃ of next nights in temperature ³In the methylene dichloride, then this solution is poured at 20 centimetres ³In the methylene dichloride and added 0.31 centimetre ³0.99 gram (3aRS, 4SR, the 9SR that the step in front of triethylamine obtains; 9aRS)-and 9-(2,3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2; 3,3a, 4; 9, in the solution of 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, obtain 39 milligrams of (3aRS; 4SR; 9SR, 9aRS)-9-(2,3-Dihydrobenzofuranes-5-yl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are the beige solid shape, and its feature is as follows:

-fusing point=200 ℃ (decomposition)

-mass spectrum (IE): M/Z=535 (M ⁺).

Embodiment 62

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(2,3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2; but be to use (3aRS, 4SR, the 9SR of 7.21 gram the foregoing description preparations; 9aRS)-9-(2; 3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 50 centimetres ³1M aqueous sodium hydroxide solution and 100 centimetres ³Diox refluxed 3 hours, at 80 centimetres ³After the crystallization, obtain 3.44 gram (3aRS, 4SR in the ethanol-water mixture (by volume 75-25); 9SR, 9aRS)-9-(2,3-Dihydrobenzofuranes-5-yl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, the crystal powder powder that is white in color, its feature is as follows:

-fusing point=241 ℃

-mass spectrum (IE): M/Z=521 (M ⁺).

Embodiment 63

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(2,3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide

Preparation as embodiment 42, but at 15 centimetres ³Use in the methylene dichloride 522 milligrams (3aRS, 4SR, 9SR, 9aRS)-9-(2; 3-Dihydrobenzofuranes-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 0.122 centimetre ³3-(aminomethyl) pyridine, 0.23 gram 1-ethyl-3-[3-(dimethylamino) propyl group]-the inferior diamine hydrochloride of carbonization and 80 milligrams of N-1-hydroxy benzotriazole hydrates, obtain 462 milligrams of (3aRS, 4SR; 9SR, 9aRS)-9-(2,3-Dihydrobenzofuranes-5-yl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl) methane amide, it is Powdered to be white in color, and its feature is as follows:

-fusing point=238 ℃ (decomposition)

-mass spectrum (IE): M/Z=611 (M ⁺).

- ¹HNMR composes (400MHz, (CD ₃) ₂SO d6, temperature 383K represents d with ppm): 1.40-1.60-1.99 and 2.14 (4mts, each 2H:CH ₂CH ₂); 3.29 and 3.41 (be respectively dd and wide d, J=12 and 9Hz and J=12Hz, each 1H:1 position CH ₂); 3.26 (wide t, J=8,5Hz, the ArCH of 2H:2-3 Dihydrobenzofuranes ₂); 3.47 and 4.17 (2d, J=12.5Hz, each 1H:3 position CH ₂); (3.53 mt, 1H:9a position CH); (3.56 wide s, 1H:4 position CH); 3.70 (s, 3H:ArOCH ₃); 4.22 (AB, J=15 and 6Hz, 2H:NCH ₂Ar); 4.60 (t, J=8.5Hz, the CH of 2H:2-3 Dihydrobenzofuranes ₂O); 5.52 and 5.68 (2s, each 1H:=CH ₂); (6.48 mt, 1H:8 position H); (6.75-7.50 mt, H-7 position, H-6 position, 12H:5 position H-2-p-methoxy-phenyl aromatics H-2-3 dihydroxyl benzo furans aromatics 4 H of H-pyridyl and 3 H of pyridyl); 7.96 (mt, 1H:CONH); 8.38 (wide s, 1H: 2 H of pyridyl); 8.44 (wide d, J=5 and 1.5Hz, 1H: 6 H of pyridyl).

Embodiment 64

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 39 steps A, operate, but be to use 2.8 gram 4-fluoro-bromobenzenes, at 20 centimetres ³In the ether 0.4 gram cutting magnesium and at 20 centimetres ³In the ether 2.9 gram (3aRS, 4SR, 9RS, 9aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate, in Virahol-isopropyl ether mixture (by volume 50-50) after the crystallization, obtain 1.2 gram (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-(4-fluorophenyl)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=130 ℃.

Adopt this filtrate of silica gel (230-400 order) flash chromatography purifying, can obtain 1.2 gram products in addition with hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out.

Step B

As embodiment 38 step C, operate, but be to use 2.2 grams (3aRS, 4SR)-2-benzyl-7-(4-fluorophenyl)-7-hydroxy-4-phenyl-2,3,3a, 4,5,6-six hydrogen isoindole-3a-methyl-formiate, 6.3 centimetres ³Trifluoromethanesulfonic acid and 21 centimetres ³Methylene dichloride is at 24 centimetres ³Obtain after the recrystallization in the isopropyl ether 1.0 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=135 ℃.

By concentrated this filtrate with at 25 centimetres ³Crystallization in the sherwood oil obtains 0.75 gram product in addition.

Step C

As embodiment 1 step e, operate, but be to use 1.5 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.64 gram ammonium formiate and 0.2 gram 10% (w/w) palladium/carbon obtain 1.0 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=145 ℃.

Step D

As embodiment 1 step G, operate, but be to use 1.0 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.51 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.24 centimetre ³Oxalyl chloride and 0.79 centimetre ³Triethylamine is at 16 centimetres ³In the Virahol after the crystallization, obtain 0.7 gram (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--9-(4-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=165 ℃.

Embodiment 65

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 0.85 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 8.5 centimetres ³1M aqueous sodium hydroxide solution and 15 centimetres ³Methyl alcohol obtains 0.65 gram (3aRS, 4SR, 9SR after the crystallization in acidic aqueous medium; 9aRS)-4,9-ethano--9-(4-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, its feature is as follows:

-fusing point=170 ℃.

Embodiment 66

Preparation (3aRS.4SR.9SR, 9aRS)-9-(4-chloro-3-fluorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 1 step C, operate, but be to use 6.3 gram 4-chloro-3-fluoro-bromobenzenes, 0.73 gram cutting magnesium and 5.45 gram (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate, adopt silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 95-5) wash-out and at 75 centimetres ³In the Virahol after the recrystallization, obtain 4.8 grams (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-(4-chloro-3-fluorophenyl)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=175 ℃.

Step B

As embodiment 1 step D, operate, but be to use 4.6 grams (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-(4-chloro-3-fluorophenyl)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate, 12.4 centimetres ³Trifluoromethanesulfonic acid and 50 centimetres ³Methylene dichloride is at 25 centimetres ³In the Virahol after the crystallization, obtain 3 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(4-chloro-3-fluorophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=136 ℃.

Step C

As embodiment 51 step C operation, but be to use at 40 centimetres ³In the methylene dichloride 2.8 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(4-chloro-3-fluorophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 1.95 centimetres ³The carbonochloridic acid vinyl acetate is used 59 centimetres then ³The solution-treated of 1M hydrogen chloride gas in ether is dissolved in 40 centimetres ³Intermediate product in the methyl alcohol is adopting silica gel (230-400 order) flash chromatography purifying, after methylene chloride-methanol mixture (by volume 97.5-2.5) wash-out, obtain 1 gram (3aRS, 4SR, 9SR, 9aRS)-and 9-(4-chloro-3-fluorophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, be the crisp skin sample of xanthoprotein material, but former state is used for following synthesizing.

Step D

As embodiment 1 step G, operate, but be to use 1.4 gram (3aRS, 4SR, 9SR, 9aRS)-and 9-(4-chloro-3-fluorophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.67 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.33 centimetre ³Oxalyl chloride and 1.06 centimetres ³Triethylamine is adopting silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out; after recrystallization in Virahol-isopropyl ether mixture (by volume 1-1), obtain 1.5 gram (3aRS, 4SR; 9SR, 9aRS)-9-(4-chloro-3-fluorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3; 3a, 4,9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, its feature is as follows:

-fusing point=173 ℃.

Embodiment 67

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(4-chloro-3-fluorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 1.2 gram (3aRS, 4SR, 9SR; 9aRS)-and 9-(4-chloro-3-fluorophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 3.3 centimetres ³LM aqueous sodium hydroxide solution and 20 centimetres ³Ethanol is at 5 centimetres ³Obtain after the recrystallization in the Virahol 1.15 grams (3aRS, 4SR, 9SR, 9aRS)-9-(4-chloro-3-fluorophenyl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, its feature is as follows:

-fusing point=170 ℃

Embodiment 68

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 1 step C, operate, but be to use 3.68 centimetres ³3-toluene bromide, 0.73 gram cutting magnesium and 5.45 gram (3aRS, 4SR, 7aRS)-and 2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate, adopt silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 95-5) wash-out and at 75 centimetres ³In the Virahol after the recrystallization, (7RS 7aRS)-2-benzyl-7-hydroxyl-7-(3-aminomethyl phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate, is orange-yellow sead albumen crisp skin sample material for 3aRS, 4SR, but that former state is used for is following synthetic to obtain 4.2 grams.

Step B

As embodiment 38 step C, operate, but be to use 4.2 grams (3aRS, 4SR, 7RS, 7aRS)-2-benzyl-7-hydroxyl-7-(3-aminomethyl phenyl)-4-phenyl octahydro isoindole-3a-methyl-formiate, 12.4 centimetres ³Trifluoromethanesulfonic acid and 42 centimetres ³Methylene dichloride, obtain 4 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are orange sead albumen crisp skin sample material, but former state is used for following synthesizing.

Step C

As embodiment 1 step e, operate, but be to use 4 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 1.73 gram ammonium formiates and 0.75 gram 10% (w/w) palladium/carbon obtain 3 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, be the crisp skin sample of xanthoprotein material, but former state is used for following synthesizing.

Step D

As embodiment 1 step G, operate, but be to use 3 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 1.54 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.74 centimetre ³Oxalyl chloride and 2.45 centimetres ³Triethylamine is adopting silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 50-50) wash-out with at 10 centimetres ³After the recrystallization, obtain 2.5 gram (3aRS, 4SR, 9SR in the Virahol; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, its feature is as follows:

-fusing point=142 ℃.

Embodiment 69

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 2.2 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 8.7 centimetres ³1M aqueous sodium hydroxide solution and 22 centimetres ³Ethanol is at 50 centimetres ³Obtain after the recrystallization in the Virahol 1.75 grams (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-aminomethyl phenyl)-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, its feature is as follows:

-fusing point=252 ℃

Embodiment 70

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(1,3-benzo two divinylene oxides-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Steps A

As embodiment 31 steps A, operate, but be to use at 26 centimetres ³In the methylene dichloride 5.9 gram (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate, 2.5 centimetres ³Veratrole and 6.3 centimetres ³Trifluoromethanesulfonic acid is adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 1.8 gram (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-9-(3, the 4-Dimethoxyphenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are colorless oil, but former state is used for following synthesizing.

Step B

At 22.3 centimetres ³Be cooled in the boron tribromide of about-50 ℃ of temperature, and adding 1.8 grams (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-9-(3, the 4-Dimethoxyphenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is at 20 centimetres ³Solution in the methylene dichloride.Reaction mixture was stirred 1 hour under about-50 ℃ temperature, add 75 centimetres then ³Saturated sodium bicarbonate aqueous solution.Adopt decant method water phase separated, and use 25 centimetres at every turn ³Dichloromethane extraction 2 times.Merge organic phase, use 15 centimetres more at every turn ³Distilled water wash 3 times is with dried over mgso and under reduced pressure concentrated.Its resistates adopts silica gel (230-400 order) flash chromatography purifying, with methylene chloride-methanol mixture (by volume 97.5-2.5) wash-out.Obtain 0.8 gram (3aRS, 4SR, 9SR like this, 9aRS)-and 2-benzyl-9-(3, the 4-dihydroxy phenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are orange oily, but former state is used for following synthetic and 1.0 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(3-hydroxyl-4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-hydroxy 3-methoxybenzene base)-2,3,3a, 4,9, the mixture of 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is orange oily, but former state is used for following synthesizing.

Step C

Restrain 0.58 (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-9-(3, the 4-dihydroxy phenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is at 4 centimetres ³In the solution in the methylene dichloride, add 1.8 gram salt of wormwood at 4 centimetres ³Solution in the distilled water adds 60 milligrams of Adogen 464 then.Reaction mixture is reflux 90 minutes under agitation, is cooled to about 20 ℃ of temperature then, with 25 centimetres ³The methylene dichloride dilution.Adopt decant method water phase separated, and use 15 centimetres at every turn ³Dichloromethane extraction 2 times.Merge organic phase, use 15 centimetres more at every turn ³Distilled water wash 3 times is with dried over mgso and under reduced pressure concentrated.Obtain 0.8 gram crude product like this, with 0.4 gram crude product merging of this crude product and the 2nd batch of test.Adopt this mixture of silica gel (230-400 order) flash chromatography purifying,, obtain 0.45 gram (3aRS with hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, 4SR, 9SR, 9aRS)-9-(1,3-benzo two divinylene oxides-5-yl)-and 2-benzyl-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the sead albumen crisp skin sample material that is white in color, but that former state is used for is following synthetic, and its feature is as follows:

- ¹HNMR composes (400MHz, CDCl ₃, temperature 333K represents d with ppm): (3mts is respectively 1H:1H and 2H:CH to 1.43-1.65 and 2.47 ₂CH ₂); 2.25-2.40 (mt, 1H:1 position CH ₂1H); 2.36 (d, J=10Hz, 1H:3 position CH ₂1H); 2.77 (wide d, J=9.5Hz, 1H:1 position CH ₂Another H); (3.15-3.25 mt, 1H:9a position CH); 3.21 (d, J=10Hz, 1H:3 position CH ₂Another 1H); (3.39 wide s, 1H:4 position CH); 3.43 and 3.67 (2d, J=13Hz, each 1H:NCH ₂Ar); 3.55 (s, 3H:COOCH ₃); 5.98 (restriction AB,, 2H:OCH ₂O); (6.63 wide d, J=7.5Hz, 1H:8 position H); 6.85 and 6.91 (2 wide d, J=8.5Hz,, each 1H:6 position H and 7 H of 1-3 benzo two oxa-cyclopentadienyls); (6.96 wide s, 4 H of 1H:1-3 benzo two oxa-cyclopentadienyls); (7.00-7.35 mt, H-6 position, 8H:5 position H-7 position H and benzyl aromatics H).

Step D

As embodiment 1 step e, operate, but be to use 0.5 gram (3aRS, 4SR, 9SR, 9aRS)-9-(1,3-benzo two divinylene oxides-5-yl) 2-benzyl-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.21 gram ammonium formiate and 70 milligram of 10% (w/w) palladium/carbon, obtain 0.25 gram (3aRS, 4SR, 9SR, 9aRS)-9-(1,3-benzo two divinylene oxides-5-yl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, but that former state is used for is following synthetic.

Step e

As embodiment 1 step G, operate, but be to use 0.25 gram (3aRS, 4SR, 9SR, 9aRS)-9-(1,3-benzo two divinylene oxides-5-yl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.12 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.06 centimetre ³Oxalyl chloride and 0.19 centimetre ³Triethylamine is adopting silica gel (230-400 order) flash chromatography purifying, after methylene chloride-methanol mixture (by volume 97.5-2.5) wash-out; obtain 0.26 gram (3aRS, 4SR, 9SR; 9aRS)-and 9-(1,3-benzo two divinylene oxides-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the sead albumen crisp skin sample material that is white in color, but former state is used for following synthesizing.

Step F

Operation as embodiment 2, but be to use 0.26 gram (3aRS, 4SR, 9SR, 9aRS)-9-(1; 3-benzo two divinylene oxides-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 2.4 centimetres ³1M aqueous sodium hydroxide solution and 5 centimetres ³Methyl alcohol is adopting silica gel (230-400 order) flash chromatography purifying, with methylene chloride-methanol mixture (by volume 97.5-2.5) wash-out and at 2.5 centimetres ³In the isopropyl ether after the crystallization, obtain 80 milligrams (3aRS, 4SR, 9SR, 9aRS)-9-(1; 3-benzo two divinylene oxides-5-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, its feature is as follows:

-fusing point=204 ℃

Embodiment 71

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 31 steps A, operate, but be to use at 40 centimetres ³In the methylene dichloride 10.34 gram (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate, 50 centimetres ³O-Xylol, 24 centimetres ³99% trifluoromethanesulfonic acid and 6.5 centimetres ³Trifluoromethanesulfanhydride anhydride following 23 hours of about 20 ℃ of temperature, obtains the impure (3aRS of 7.27 grams under argon gas atmosphere, 4SR, 9SR, 9aRS)-2-benzyl-9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, but former state is used for following step, is colorless oil, and its feature is as follows:

-mass spectrum (DCI): M/Z=452 (M+H ⁺)

Step B

As embodiment 1 step e, operate, but at 150 centimetres ³Methyl alcohol and 100 centimetres ³(3aRS, 4SR, the 9SR that use 9.51 grams as above-mentioned step to obtain in the diox, 9aRS)-and 2-benzyl-9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 4 gram ammonium formiates, 0.5 gram 10% (w/w) palladium/carbon, following six hours of about 50 ℃ of temperature,, one after the other use 1 decimeter adopting 500 gram flash chromatography on silica gel purifying ³Absolute dichloromethane, 1 decimeter ³Dichloromethane-ethanol mixture (by volume 98-2), 1 decimeter ³Dichloromethane-ethanol mixture (by volume 95-5), 1 decimeter ³Dichloromethane-ethanol mixture (by volume 90-10), dichloromethane-ethanol mixture (by volume 80-20) wash-out obtain 5.79 gram (3aRS, 4SR, 9SR, 9aRS)-9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, but former state is used for following step, be the no colored paint shape that is covered with sead albumen crisp skin sample material a little, its feature is as follows:

-mass spectrum (DCI): M/Z=361 (M ⁺).

Step C

As embodiment 1 step G, operate, but be to use 2.67 gram 2 (2-p-methoxy-phenyl) vinylformic acid at 50 centimetres ³Solution in the methylene dichloride, this solution contain 2 N, and dinethylformamide added 1.31 centimetres in two hours ³Oxalyl chloride and 5.075 gram above-mentioned steps obtain (3aRS, 4SR, 9SR, 9aRS)-9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 4.4 centimetres ³Triethylamine is at 100 centimetres ³Solution in the methylene dichloride was poured 100 centimetres into after 1 hour ³Water, obtain 3.4 grams (3aRS, 4SR, 9SR, 9aRS)-9-(3; the 4-3,5-dimethylphenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=163 ℃ (decomposition)

-mass spectrum (IE): M/Z=521 (M ⁺).

Embodiment 72

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but (3aRS, the 4SR that are to use 4.736 gram above-mentioned steps to obtain; 9SR; 9aRS)-and 9-(3, the 4-3,5-dimethylphenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3; 3a, 4,9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 36 centimetres ³The 1M aqueous sodium hydroxide solution is at 50 centimetres ³Ethanol and 100 centimetres ³In the diox,, obtain 3.375 gram (3aRS following 16 hours of about 70 ℃ of temperature; 4SR, 9SR, 9aRS)-9-(3; the 4-3,5-dimethylphenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; it is Powdered to be white in color, and its feature is as follows:

-fusing point=200 ℃, 245 ℃ then,

-NMR composes No.127748

-mass spectrum (IE): M/Z=507 (M ⁺).

Embodiment 73

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 31 steps A, operate, but be to use at 120 centimetres ³In the methylene dichloride 11.5 gram (3aRS, 4SR, 7aRS)-2-benzyl-7-oxo-4-phenyl octahydro isoindole-3a-methyl-formiate, 13.1 centimetres ³Phenylmethylether and 21.2 centimetres ³Trifluoromethanesulfonic acid is adopting silica gel (230-400 order) flash chromatography purifying, with obtaining 12 gram (3aRS behind hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, its feature is as follows:

-fusing point=150 ℃.

Step B

As embodiment 1 step e, operate, but be to use 11.4 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 4.76 gram ammonium formiates and 1 gram 10% (w/w) palladium/carbon, obtain 9 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, but former state is used for following synthesizing.

Step C

As embodiment 1 step G, operate, but 8.9 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 4.36 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 2.1 centimetres ³Oxalyl chloride and 6.9 centimetres ³Triethylamine is adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 50-50) wash-out; obtain 0.47 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate; the sead albumen crisp skin sample material shape that is white in color, its feature is as follows:

-fusing point=90 ℃.

Embodiment 74

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 11 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 42 centimetres ³1M aqueous sodium hydroxide solution and 100 centimetres ³Methyl alcohol is adopting silica gel (230-400 order) flash chromatography purifying, after methylene chloride-methanol mixture (by volume 100-0 to 98-2) wash-out; obtain 2.15 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, its feature is as follows:

-fusing point=165 ℃.

Embodiment 75

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation Chiral Separation

9.2 (3aRS, 4SR, 9SR that gram obtains at embodiment 74; 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid are annotated for 5 times in succession and are had (R)-N-(3; the 5-dinitrobenzoyl)-phenylalanine grafted chirality silica column on, separate with normal heptane-methylene chloride-methanol mixture (by volume 50-50-3) wash-out.Reclaim first eluting fraction (retention time 42 minutes), under reduced pressure obtain 3.51 gram (3aRS, 4SR after the concentrated solvent; 9SR; 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph; it is Powdered to be white in color, and its feature is as follows:

-fusing point=203 ℃

-mass spectrum (IE): M/Z=507 (M ⁺),

-specific rotation: [a] ₃₆₅ ²⁰=+71.7+/-1.2 ° (c=0.5/ methyl alcohol).

Embodiment 76

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide

Operation as embodiment 42, but be to use 1 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 0.24 centimetre ³3-(aminomethyl) pyridine, 0.46 gram 1-ethyl-3-[(3-dimethylamino) propyl group] inferior diamine hydrochloride of carbonization and 0.16 gram N-1-hydroxy benzotriazole hydrate, at 11 centimetres ³After the middle crystallization of Virahol-isopropyl ether (by volume 10-90); obtain 0.72 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide, its feature is as follows:

-fusing point=121 ℃.

Embodiment 77

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-phenyl formyl hydrazine

Operation as embodiment 27, but be to use 1 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 0.25 centimetre ³N-phenyl hydrazine, 0.45 gram 1-ethyl-3-[(3-dimethylamino) propyl group] inferior diamine hydrochloride of carbonization and 0.16 gram N-1-hydroxy benzotriazole hydrate, at 11 centimetres ³After the middle crystallization of Virahol-isopropyl ether (by volume 10-90); obtain 0.9 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-phenyl formyl hydrazine, its feature is as follows:

-fusing point=180 ℃.

Embodiment 78

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid

Steps A

At 2.2 gram (3aRS; 4SR; 9SR; 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 1 gram 1-ethyl-3-[(3-dimethylamino) propyl group] the inferior diamines of carbonization and 0.35 gram N-1-hydroxy benzotriazole hydrate be at 10 centimetres ³In the solution in the methylene dichloride, add 0.83 gram O-benzyl oxyamine and 0.73 centimetre ³Triethylamine is at 10 centimetres ³Solution in the methylene dichloride.Reaction mixture was stirred 24 hours down for about 20 ℃ in temperature, add 15 centimetres then ³Distilled water.Adopt decant to separate organic phase, with 20 centimetres ³Distilled water wash is with dried over mgso and under reduced pressure concentrated.Its resistates is at 25 centimetres ³Crystallization in Virahol-isopropyl ether (by volume 20-80).Obtain like this 2.03 the gram (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid benzyl ester, the solid state that is white in color, its feature is as follows:

-fusing point=201 ℃.

Step B

Operation as embodiment 16; but be to use 1.84 gram (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid benzyl ester, 1 gram aluminum chloride and 0.98 centimetre ³Phenylmethylether is adopting silica gel (230-400 order) flash chromatography purifying, after methylene chloride-methanol mixture (by volume 90-10) wash-out; obtain 0.5 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid; the solid state that is white in color, its feature is as follows:

-fusing point=165 ℃.

Embodiment 79

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-(3-pyridyl) formyl hydrazine

Operation as embodiment 27; but be to use 1 gram (3aRS; 4SR; 9SR; 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; 0.26 gram N-(3-pyridyl) hydrazine; 0.45 propyl group gram 1-ethyl-3-[(3-dimethylamino)] inferior diamine hydrochloride of carbonization and 0.16 gram N-1-hydroxy benzotriazole hydrate; adopting silica gel (230-400 order) flash chromatography purifying; after the recrystallization, obtain 0.6 gram (3aRS with methylene chloride-methanol mixture (by volume 95-5,90-10 then) wash-out and in Virahol; 4SR; 9SR, 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2; 3; 3a, 4,9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-(3-pyridyl) formyl hydrazine, its feature is as follows:

-fusing point=180 ℃.

Embodiment 80

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-thienyl methyl) methane amide

Operation as embodiment 42; but be to use 1 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 0.2 gram 3-amino methyl thiophene, 0.45 gram 1-ethyl-3-[(3-dimethylamino) propyl group] inferior diamine hydrochloride of carbonization and 0.16 gram N-1-hydroxy benzotriazole hydrate, at 11 centimetres ³After the middle recrystallization of Virahol-isopropyl ether mixture (by volume 10-90); obtain 1 gram (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-thienyl methyl) methane amide, its feature is as follows:

-fusing point=130 ℃.

Embodiment 81

Preparation 2-{ (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-carbonylamino } phenylacetic acid

Steps A

Operation as embodiment 42; but be to use 1.27 gram (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 0.61 gram phenyl glycine methyl ester hydrochloride, 0.59 gram 1-ethyl-3-[(3-dimethylamino) propyl group] the inferior diamine hydrochloride of carbonization, 0.42 centimetre ³Triethylamine and 0.2 gram N-1-hydroxy benzotriazole hydrate; adopting silica gel (230-400 order) flash chromatography purifying; after methylene chloride-methanol mixture (by volume 99-1) wash-out; obtain 1 gram (RS) and (SR)-2-{ (3aRS; 4SR; 9SR; 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-carbonylamino } the phenylacetic acid mixtures of methyl esters; but former state is used for following synthesizing, and is sead albumen crisp skin sample material.

Step B

Operation as embodiment 2, but be to use at 1.83 centimetres ³1M aqueous sodium hydroxide solution and 20 centimetres ³In the ethanol 0.6 gram (RS) and (SR)-2-{ (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-carbonylamino } the phenylacetic acid mixtures of methyl esters, obtain 0.5 gram crude product, this crude product and second batch of 0.65 gram crude product merging of test in addition.By at 50 centimetres ³This mixture of recrystallization purifying in the Virahol-isopropyl ether mixture (by volume 50-50); obtain 1.05 gram (RS) and (SR)-2-{ (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-carbonylamino } molar mixture such as phenylacetic acid, its feature is as follows:

-fusing point=196 ℃,

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6, temperature 383K represents d with ppm).We observe the mixture of two kinds of diastereomers, and its ratio is 50/50.

* 1.38-1.60-1.98 and 2.14 (4mts, each 1H:CH ₂CH ₂); 3.15-3.80 (mt, 5H:1 position CH ₂-3 CH ₂1H-9a position CH and 4 CH); 3.64-3.71 and 3.84 (3s, 6H:2 ArOCH altogether ₃); 4.20-4.55 (mt, 1H:3 position CH ₂Another H); 5.19 (mt, 1H:NCHAr); 5.47-5.51-5.66 and 5.69 (4 wide s, 2H:=CH altogether ₂); (6.42 mt, 1H:8 position H); (6.80-7.50 mt, H-7 position, H-6 position, 16H:5 position H-4-p-methoxy-phenyl aromatics H-2-p-methoxy-phenyl aromatics H and phenyl aromatics H); 7.98 and 8.02 (2 wide s, 1H:CONH altogether).

Embodiment 82

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-Trifluoromethoxyphen-l)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Steps A

As embodiment 45 step C, operate, but be to use 1.51 gram (3aRS, 4SR, 7aRS)-and 2-benzyl-7-iodo--4-phenyl-2,3, a, 4,5,7a-six hydrogen isoindole-3a-methyl-formiate, 0.17 gram tetrakis triphenylphosphine palladium, 0.73 gram as operation obtains with the trimer anhydride form in the DE4218614 patent 4-Trifluoromethoxyphen-l boric acid and 1.5 gram yellow soda ash are at 15 centimetres ³Toluene and 13 centimetres ³Refluxed 2 hours in the methyl alcohol, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out, obtain 1.2 gram (79%) (3aRS, 4SR, 7aRS)-2-benzyl-4-phenyl-7-(4-Trifluoromethoxyphen-l)-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate, be light yellow oily, its feature is as follows:

-mass spectrum (IE): M/Z=507 (M ⁺).

Step B

As embodiment 38 step C, operate, but be to use 0.48 gram (3aRS, 4SR, 7aRS)-2-benzyl-4-phenyl-7-(4-Trifluoromethoxyphen-l)-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate and 1.18 centimetres ³Trifluoromethanesulfonic acid is at 2 centimetres ³In the methylene dichloride at room temperature 2 hours, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 1.43 gram (89%) (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(4-Trifluoromethoxyphen-l)-2,3,3a, 4,5,7a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, but former state is used for following step, is cream-coloured pasty state, and its feature is as follows:

-mass spectrum (IE): M/Z=507 (M ⁺)

Step C

As embodiment 47 step B, operate, but be to use 0.83 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-Trifluoromethoxyphen-l)-2,3,3a, 4,5,7a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 0.29 centimetre ³The carbonochloridic acid vinyl acetate is at 10 centimetres ³In the methylene dichloride at room temperature 18 hours, then its enriched material is dissolved in 20 centimetres ³Refluxed in the solution of 1M hydrogen chloride gas in Virahol 1 hour, after with the neutralization of 1M aqueous sodium hydroxide solution, then with dichloromethane extraction and concentrated solvent under reduced pressure, obtain 0.59 gram (75%) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-Trifluoromethoxyphen-l)-2,3,3a, 4,5,7a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, but former state is used for following step, the sead albumen crisp skin shape that is white in color, and its feature is as follows:

-mass spectrum (IE): M/Z=417 (M ⁺)

Step D

As embodiment 5 step e, operate, but be to use 0.59 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-Trifluoromethoxyphen-l)-2,3,3a, 4,5,7a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.25 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.2 gram 1-ethyl-3-[(3-dimethylamino) propyl group] the inferior diamine hydrochloride of carbonization and 27 milligrams of N-1-hydroxy benzotriazole hydrates, at 15 centimetres ³In the methylene dichloride at room temperature 18 hours; adopting silica gel (230-400 order) flash chromatography purifying; after hexanaphthene-ethyl acetate mixture (by volume 60-40) wash-out; obtain 0.41 gram (53%) (3aRS; 4SR; 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-Trifluoromethoxyphen-l)-2; 3; 3a, 4,9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate; but former state is used for following step, is the oldlace pasty state, and its feature is as follows:

-fusing point=86 ℃,

-mass spectrum (IE): M/Z=577 (M ⁺).

Step e

Operation as embodiment 2, but be to use 0.38 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-Trifluoromethoxyphen-l)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 13 centimetres ³0.1M aqueous sodium hydroxide solution and 13 centimetres ³Refluxed 4 hours in the methyl alcohol, in pentane, obtain 200 milligrams of (54%) (3aRS, 4SR after the recrystallization; 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-Trifluoromethoxyphen-l)-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; the solid state that is white in color, its feature is as follows:

-fusing point=160 ℃,

-mass spectrum (IE): M/Z=563 (M ⁺).

Embodiment 83

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 45 step C, operate, but be to use 11.61 gram (3aRS, 4SR, 7aRS)-2-benzyl-7-iodo--4-phenyl-2,3, a, 4,5, the 3-bromophenyl boric acid that 7a-six hydrogen isoindole-3a-methyl-formiate, 1.13 gram tetrakis triphenylphosphine palladiums, 5.46 grams obtain with the trimer anhydride form, with 11.5 gram yellow soda ash, at 70 centimetres ³Toluene and 50 centimetres ³Refluxed 2 hours in the methyl alcohol, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out, obtain 8.5 gram (75%) (3aRS, 4SR, 7aRS)-2-benzyl-7-(3-bromophenyl)-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate, be light yellow oily, its feature is as follows:

-mass spectrum (IE): M/Z=502 (M ⁺).

Step B

As embodiment 38 step C, operate, but be to use 8.6 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-(3-bromophenyl)-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate and 25 centimetres ³Trifluoromethanesulfonic acid is at 25 centimetres ³In the methylene dichloride room temperature 2 hours, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 4.58 gram (64%) (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-9-(3-bromophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, be the cream-coloured powder shape, its feature is as follows:

-fusing point=74 ℃,

-mass spectrum (IE): M/Z=502 (M ⁺).

Step C

As embodiment 47 step B, operate, but be to use 1.88 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(3-bromophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 0.6 centimetre ³The carbonochloridic acid vinyl acetate is at 15 centimetres ³In the methylene dichloride at room temperature 2 hours, then with its enriched material in 30 centimetres ³Refluxed 3 hours in the solution of 2M hydrogen chloride gas in methyl alcohol, in isopropyl ether, obtain 1.72 gram (76%) (3aRS, 4SR after the crystallization, 9SR, 9aRS)-and 9-(3-bromophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride, the lenticular that is white in color, its feature is as follows:

-mass spectrum (IE): M/Z=412 (M ⁺).

Step D

As embodiment 5 step e, operate, but be to use 1.72 gram (3aRS, 4SR, 9SR, 9aRS)-9-(3-bromophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride, 0.68 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.73 gram 1-ethyl-3-[(3-dimethylamino) propyl group] the inferior diamine hydrochloride of carbonization, 50 milligrams of N-1-hydroxy benzotriazole hydrates and 0.54 centimetre ³Triethylamine is at 15 centimetres ³In the methylene dichloride at room temperature 18 hours, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out; obtain 0.58 gram (27%) (3aRS, 4SR, 9SR; 9aRS)-and 9-(3-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate; it is Powdered to be oldlace, and its feature is as follows:

-fusing point=184-5 ℃,

-mass spectrum (IE): M/Z=572 (M ⁺).

Embodiment 84

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use 0.50 gram (3aRS, 4SR, 9SR; 9aRS)-and 9-(3-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 70 centimetres ³0.1M aqueous sodium hydroxide solution and 70 centimetres ³Refluxed 4 hours in the methyl alcohol, in water and alcohol mixture (by volume 90-10), after the recrystallization purifying, obtain 170 milligrams of (35%) (3aRS; 4SR, 9SR, 9aRS)-9-(3-bromophenyl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, the solid state that is white in color, its feature is as follows:

-fusing point=164 ℃,

-mass spectrum (IE): M/Z=558 (M ⁺).

Embodiment 85

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(3-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 1 step C, operate, but be to use 2 gram cutting magnesium, 9.1 centimetres ³3-fluoro-bromobenzene is at 60 centimetres ³In the ether, then at 20 centimetres ³In the toluene, re-use 15 grams at 60 centimetres ³(3aRS in the toluene, 4SR, 7aRS)-2-benzyl-7-oxo--4-phenyl octahydro isoindole-3a-methyl-formiate, obtain impure (3aRS, 4SR, the 9SR of 21.29 grams, 9aRS)-2-benzyl-7-(3-fluorophenyl)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate, be brown oily, but former state is used for following step, its feature is as follows:

-mass spectrum (DCI): M/Z=460 (M+H ⁺).

Step B

As embodiment 1 step D, operate, but be to use 21.29 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-7-(3-fluorophenyl)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate and 40 centimetres ³99% trifluoromethanesulfonic acid is at 300 centimetres ³In the methylene dichloride, in argon atmospher, assigned 43 hours for about 20 ℃, obtain the impure (3aRS of 14.38 grams in temperature, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(3-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are brown oily, but former state is used for following step, and its feature is as follows:

-mass spectrum (IE): M/Z=441 (M ⁺).

Step C

As embodiment 1 step e, operate, but be to use 14.38 gram (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(3-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 5.53 gram ammonium formiate and 1.8 gram 10% (w/w) palladium/carbon are at 200 centimetres ³Refluxed in the methyl alcohol 16 hours, obtain 10.36 grams impure (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate be brown oily, but former state are used for following step, and its feature is as follows:

-mass spectrum (IE): M/Z=351 (M ⁺).

Step D

As embodiment 1 step G, operate, but be to use 5.66 gram 2-(2-p-methoxy-phenyl) vinylformic acid at 50 centimetres ³Solution in the methylene dichloride, this solution contain 2 N, N-two crystallization methane amides, 2.75 centimetres ³Oxalyl chloride, add again in two hours that 10.36 grams obtain in above-mentioned steps (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-fluorophenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 7.3 centimetres ³Triethylamine is at 100 centimetres ³Solution in the methylene dichloride after the crystallization, obtains 3.59 gram (3aRS then in sherwood oil (40-60 ℃); 4SR, 9SR, 9aRS)-4; 9-ethano--9-(3-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are the cream-coloured powder shape, and its feature is as follows:

-fusing point=151 ℃,

- ¹HNMR composes (250MHz, (CD ₃) ₂SO represents d with ppm): 1.43-1.67-2.00 and 2.14 (4mts, 1H:CH ₂CH ₂); 3.30-3.45 (mt, 3H:1 position CH ₂With 9a position CH); (3.46 mt, 1H:4 position CH); 3.54 (s, 3H:COOCH ₃); 3.61 and 4.09 (be respectively d and wide d, J=12.5Hz, each 1H:3 position CH ₂); 3.71 (s, 3H:ArOCH ₃); 5.5 and 5.68 (2s, each 1H:CH ₂); (6.41 wide d, J=7.5Hz, 1H:8 position H); (6.90-7.40 mt, H-7 position, 10H:6 position H-3-fluorophenyl aromatics H); (7.54 wide q, J=7.5Hz, the H that the 1H:3-fluorophenyl is 5).

-mass spectrum (IE): M/Z=511 (M ⁺)

Embodiment 86

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(3-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2; but be to use 1.02 gram (3aRS, 4SR, the 9SR that obtain in above-mentioned steps; 9aRS)-4; 9-ethano--9-(3-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 24 centimetres ³The 1M aqueous sodium hydroxide solution is at 30 centimetres ³Refluxed in the diox 18 hours, obtain 0.71 gram (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--9-(3-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, it is Powdered to be white in color, and its feature is as follows:

-fusing point=161 ℃,

-mass spectrum (IE): M/Z=497 (M ⁺).

Embodiment 87

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(3-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide

Operation as embodiment 42, but be to use 0.52 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(3-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 0.128 centimetre ³3-(aminomethyl) pyridine, 0.24 gram 1-ethyl-3-[(3-dimethylamino) propyl group] the inferior diamine hydrochloride of carbonization and 85 milligrams of N-1-hydroxy benzotriazole hydrates, at 30 centimetres ³In the methylene dichloride, after following 16 hours of about 20 ℃ of temperature, obtain 183.6 milligrams of (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--9-(3-fluorophenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide, it is Powdered to be true qualities, and its feature is as follows:

-fusing point=223 ℃.

-mass spectrum (IE): M/Z=587 (M ⁺).

Embodiment 88

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 1 step C, operate, but be to use 2 gram cutting magnesium, 9.75 centimetres ³3-chloro-bromobenzene is at 60 centimetres ³In the ether, then at 20 centimetres ³In the toluene, re-use 15 grams at 60 centimetres ³(3aRS in the toluene, 4SR, 7aRS)-2-benzyl-7-oxo--4-phenyl octahydro isoindole-3a-methyl-formiate, obtain impure (3aRS, 4SR, the 9SR of 31.2 grams, 9aRS)-2-benzyl-7-(3-chloro-phenyl-)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate, be yellow oily, but former state is used for following step, its feature is as follows:

-mass spectrum (DCI): M/Z=476 (M+H ⁺).

Step B

As embodiment 1 step D, operate, but be to use that 31.2 grams obtain in above-mentioned steps (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-7-(3-chloro-phenyl-)-7-hydroxy-4-phenyl octahydro isoindole-3a-methyl-formiate and 40 centimetres ³99% trifluoromethanesulfonic acid is at 300 centimetres ³In the methylene dichloride, in argon atmospher,, obtain the impure (3aRS of 23.88 grams following 4 days of about 20 ℃ of temperature, 4SR, 9SR, 9aRS)-2-benzyl-9-(3-chloro-phenyl-)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are oily, but former state is used for following step, and its feature is as follows:

-mass spectrum (IE): M/Z=457 (M ⁺).

Step C

As embodiment 47 step B, operate, but be to use 23.88 grams impure (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(3-chloro-phenyl-)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 5.4 centimetres ³Carbonochloridic acid vinyl acetate and 11.5 gram salt of wormwood are at 200 centimetres ³In the methylene dichloride,, obtain the impure (3aRS of 24.4 grams following 16 hours of about 20 ℃ of temperature, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-chloro-phenyl-)-2-ethylene oxy carbonyl-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are used for following step but be the oily former state, and its feature is as follows:

-mass spectrum (IE): M/Z=437 (M ⁺).

With this oil be placed on reached 18 hours in the solution in the 6N hydrogen chloride gas Zai diox after, obtain impure (3aRS, the 4SR of 18.28 grams, 9SR, 9aRS)-7-(3-chloro-phenyl-)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride, be brown dense oily, but former state is used for following step, its feature is as follows:

-mass spectrum (IE): M/Z=368 (M ⁺).

Step D

As embodiment 1 step G, operate, but be to use 8.76 gram 2-(2-p-methoxy-phenyl) vinylformic acid at 50 centimetres ³Solution in the methylene dichloride, this solution contain 2 N, dinethylformamide and 4.21 centimetres ³Oxalyl chloride after 2 hours 30 minutes, adds (3aRS, 4SR that 18.5 grams obtain in above-mentioned steps again, 9SR, 9aRS)-7-(3-chloro-phenyl-)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride and 11.5 centimetres ³Triethylamine is at 100 centimetres ³Solution in the methylene dichloride was poured 100 centimetres into after 42 hours ³Water, obtain 0.95 gram (3aRS, 4SR, 9SR, 9aRS)-9-(3-chloro-phenyl-)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are the cream-coloured powder shape, and its feature is as follows:

-fusing point=159 ℃,

-mass spectrum (IE): M/Z=527 (M ⁺).

Embodiment 89

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2; but be to use 795 milligrams of (3aRS as in above-mentioned steps, obtaining; 4SR, 9SR, 9aRS)-9-(3-chloro-phenyl-)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 30 centimetres ³1N aqueous sodium hydroxide solution and 30 centimetres ³Diox refluxed 18 hours, obtained 0.77 gram (3aRS, 4SR, 9SR; 9aRS)-and 9-(3-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, it is Powdered to be white in color, and its feature is as follows:

-fusing point=170 ℃,

-mass spectrum (IE): M/Z=513 (M ⁺).

Embodiment 90

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide

Operation as embodiment 42, but be to use 0.46 gram (3aRS, 4SR, 9SR; 9aRS)-and 9-(3-chloro-phenyl-)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, 0.11 centimetre ³3-(aminomethyl) pyridine, 0.21 gram 1-ethyl-3-[(3-dimethylamino) propyl group] the inferior diamine hydrochloride of carbonization and 70 milligrams of N-1-hydroxy benzotriazole hydrates, at 30 centimetres ³In the methylene dichloride, after following 16 hours of about 20 ℃ of temperature, obtain 269.8 milligrams of (3aRS; 4SR, 9SR, 9aRS)-9-(3-chloro-phenyl-)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-pyridylmethyl)-methane amide are broken white powder, and its feature is as follows:

-fusing point=244 ℃.

-mass spectrum (IE): M/Z=603 (M ⁺).

Embodiment 91

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3-N, N-dimethylamino phenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 45 step C, operate, but be to use 2.5 gram (3aRS, 4SR, 7aRS)-and 2-benzyl-7-iodo-4-phenyl-2,3,3a, 4,5, the 3-N that 7a-six hydrogen isoindole-3a-methyl-formiate, 0.30 gram tetrakis triphenylphosphine palladium, 0.77 gram obtain with the trimer anhydride form, N-Dimethylaminobenzene ylboronic acid and 20 centimetres ³The 2M aqueous sodium carbonate is at 20 centimetres ³Toluene and 10 centimetres ³Refluxed 7 hours in the methyl alcohol.Adopt silica gel (230-400 order) flash chromatography purifying,, obtain 2.09 gram (85%) (3aRS like this with hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, 4SR, 9SR, 9aRS)-2-benzyl-7-(3-N, the N-dimethylamino phenyl)-4,9-ethano--2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate, be orange pasty solid, but former state is used for following step, its feature is as follows:

-mass spectrum (IE): M/Z=466 (M ⁺).

Step B

As embodiment 39 step B, operate, but be to use 2.09 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-(3-N, N-dimethylamino phenyl)-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate and 20 centimetres ³Pure trifluoromethanesulfonic acid, at room temperature 4 days.In the presence of methylene dichloride, after with the neutralization of 30% aqueous sodium hydroxide solution, the decant organic phase washes with water again, uses dried over mgso, stirs 1 hour with 20 gram silica gel (230-400 order) then.Under reduced pressure after the concentrated solvent, obtain 1.74 gram (83%) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(3-N, N-dimethylamino phenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are yellow pasty solid, but former state is used for following step, and its feature is as follows:

-mass spectrum (IE): M/Z=466 (M ⁺).

Step C

As embodiment 47 step B, operate, but be to use 2.21 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(3-N, N-dimethylamino phenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate, 3 centimetres ³Carbonochloridic acid vinyl acetate and 4.6 centimetres ³Triethylamine is at 20 centimetres ³In the methylene dichloride at room temperature 7 hours.After hydrolysis, the decant organic phase also under reduced pressure concentrates.Adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 85-15) wash-out, obtain 0.27 gram (27%) (3aRS, 4SR, 7aRS)-and 9-(3-N, N-dimethylamino phenyl)-4,9-ethano--2-ethylene oxy carbonyl-2,3,3a, 4,9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate, with its centimetre ³Make solution in the methyl alcohol, and at 5 centimetres ³In the presence of the solution in the 5M hydrogen chloride gas Zai diox, reflux 5 hours.In isopropyl ether after the crystallization, obtain like this 0.68 gram (98%) (3aRS, 4SR, 7aRS)-9-(3-N, N-dimethylamino phenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate dihydrochloride, the solid state that is white in color, its feature is as follows:

-mass spectrum (IE): M/Z=376 (M ⁺).

Step D

As embodiment 5 step e, operate, but be to use 0.68 gram (3aRS, 4SR, 9SR, 9aRS)-9-(3-N, the N-dimethylamino phenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate dihydrochloride, 0.29 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.38 gram 1-ethyl-3-[(3-dimethylamino) propyl group] the inferior diamine hydrochloride of carbonization, 20 milligrams of N-1-hydroxy benzotriazole hydrates and 0.42 centimetre ³Triethylamine is at 15 centimetres ³In the methylene dichloride; at room temperature 24 hours; adopting silica gel (230-400 order) flash chromatography purifying; after hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out, recrystallization in pentane obtains 0.27 gram (33%) (3aRS then; 4SR; 9SR, 9aRS)-9-(3-N, N-dimethylamino phenyl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=95 ℃,

-mass spectrum (IE): M/Z=536 (M ⁺).

Embodiment 92

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3-N, N-dimethylamino phenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Operation as embodiment 2, but be to use (3aRS, 4SR, 9SR, 9aRS)-9-(3-N; the N-dimethylamino phenyl)-4,9-ethano--2[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 2 centimetres ³1M aqueous sodium hydroxide solution and 5 centimetres ³Refluxed 5 hours in the ethanol, in methylene dichloride and pentane admixture (by volume 50-50), after the recrystallization purifying, obtain (3aRS; 4SR, 9SR, 9aRS)-9-(3-N; the N-dimethylamino phenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; the solid state that is white in color, its feature is as follows:

-fusing point=194 ℃,

-mass spectrum (IE): M/Z=522 (M ⁺).

Embodiment 93

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3-aminophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride

Steps A

As embodiment 45 step C, operate, but be to use 2.5 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a, 4,5,7a-six hydrogen isoindole-3a-methyl-formiate, 0.30 gram tetrakis triphenylphosphine palladium, 0.72 gram 3-aminophenyl boric acid and 20 centimetres ³The 2M aqueous sodium carbonate is at 20 centimetres ³Toluene and 10 centimetres ³Refluxed 7 hours in the methyl alcohol.Adopt silica gel (230-400 order) flash chromatography purifying,, obtain 1.60 gram (70%) (3aRS with hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out, 4SR, 7aRS)-and 7-(3-aminophenyl)-2-benzyl-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate are the orange solids shape, but former state is used for following step, and its feature is as follows:

-mass spectrum (IE): M/Z=438 (M ⁺).

Step B

As embodiment 39 step B, operate, but be to use 0.20 gram (0.4 mmole) (3aRS, 4SR, 7aRS)-7-(3-aminophenyl)-2-benzyl-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate and 5 centimetres ³Pure trifluoromethanesulfonic acid, at room temperature 3 days.In the presence of methylene dichloride, after with the neutralization of 30% aqueous sodium hydroxide solution, the decant organic phase washes with water then, uses dried over mgso again, stirs 1 hour with 20 gram silica gel (230-400 order).Under reduced pressure obtain 0.16 gram (80%) (3aRS, 4SR, 9SR after the concentrated solvent, 9aRS)-2-benzyl-9-(3-aminophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are yellow oily, but former state is used for following step, and its feature is as follows:

-mass spectrum (IE): M/Z=438 (M ⁺).

Step C

As embodiment 45 step e, operate, but be to use 1.5 gram (3aRS, 4SR, 9RS, 9aRS)-and 9-(3-aminophenyl)-2-benzyl-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate, 0.6 gram 10% (w/w) palladium/carbon are at 100 centimetres ³Methyl alcohol and 3.5 centimetres ³In the solution of 1M hydrogen chloride gas in methyl alcohol, under nitrogen atmosphere 50 ℃ 8 hours, in isopropyl ether after the crystallization, obtain 1.27 gram (79%) (3aRS, 4SR, 9RS, 9aRS)-and 9-(3-aminophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate dihydrochloride, the solid state that is white in color, its feature is as follows:

-mass spectrum (IE): M/Z=348 (M ⁺).

Step D

As embodiment 1 step G, operate, but be to use 0.74 gram (3aRS, 4SR, 9RS, 9aRS)-9-(3-aminophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate dihydrochloride, 0.41 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.22 centimetre ³Oxalyl chloride and 0.76 centimetre ³Triethylamine is at room temperature at 10 centimetres ³In the methylene dichloride 20 hours, adopting silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 50-50) wash-out; in isopropyl ether, after the recrystallization, obtain 0.20 gram (21%) (3aRS, 4SR then; 9RS, 9aRS)-9-(3-aminophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride, it is Powdered to be white in color, and its feature is as follows:

-fusing point=186 ℃,

-mass spectrum (IE): M/Z=508 (M ⁺).

Embodiment 94

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(4-N, N-dimethylaminophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 45 step C, operate, but be to use 1.15 grams (3aRS, 4SR, 7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a, 4,5,7a-six hydrogen isoindole-3a-methyl-formiate, 0.12 gram tetrakis triphenylphosphine palladium, 0.44 gram 4-N, N-dimethylaminophenyl boric acid and 15 centimetres ³The 2M aqueous sodium carbonate is at 20 centimetres ³Toluene and 10 centimetres ³Refluxed 4 hours in the methyl alcohol.Adopt silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 80-20) wash-out, obtain 0.93 gram (82%) (3aRS, 4SR, 7aRS)-2-benzyl-7-(4-N, N-dimethylaminophenyl)-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate, be orange oily, but former state is used for following step, its feature is as follows:

-mass spectrum (IE): M/Z=466 (M ⁺).

Step B

As embodiment 39 step B, operate, but be to use 0.53 gram (3aRS, 4SR, 7aRS)-2-benzyl-7-(4-N, N-dimethylaminophenyl)-4-phenyl-2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate and 10 centimetres ³Pure trifluoromethanesulfonic acid, at room temperature 2 days.In the presence of methylene dichloride, after with the neutralization of 30% aqueous sodium hydroxide solution, the decant organic phase washes with water then, uses dried over mgso again.Under reduced pressure after the concentrated solvent, its resistates adopts silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 0.34 gram (64%) (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-9-(4-N, N-dimethylaminophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are colorless oil, and its feature is as follows:

-mass spectrum (IE): M/Z=466 (M ⁺).

Step C

As embodiment 45 step e, operate, but be to use 0.34 gram (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-9-(4-N, N-dimethylaminophenyl)-4,9-ethano--2,3,3a, 4,5,7a-six hydrogen-1H-isoindole-3a-methyl-formiate, 0.15 gram 10% (w/w) palladium/carbon are at 20 centimetres ³Methyl alcohol, 10 centimetres ³Chloroform and 1.5 centimetres ³In the solution of 1M hydrogen chloride gas in methyl alcohol, under nitrogen atmosphere 40 ℃ 5 hours, in isopropyl ether after the crystallization, obtain 0.31 gram (96%) (3aRS, 4SR, 9SR, 9aRS)-and 9-(4-N, N-dimethylaminophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate dihydrochloride are the light green solid state, and its feature is as follows:

-mass spectrum (IE): M/Z=376 (M ⁺).

Step D

As embodiment 1 step G, operate, but be to use 0.30 gram (3aRS, 4SR, 9SR, 9aRS)-9-(4-N, the N-dimethylaminophenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate dihydrochloride, 0.13 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.07 centimetre ³Oxalyl chloride and 0.3 centimetre ³Triethylamine is at room temperature at 5 centimetres ³In the methylene dichloride 18 hours, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate-28% ammonia solution mixture (by volume 60-40-0.2) wash-out; obtain 0.18 gram (50%) (3aRS, 4SR, 9SR; 9aRS)-and 9-(4-N, N-dimethylaminophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=86-90 ℃,

-mass spectrum (IE): M/Z=536 (M ⁺).

Embodiment 95

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(4-cyano-phenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Steps A

5.02 grams that obtain among the embodiment 49 step B under remaining on argon atmospher (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-9-(4-bromophenyl)-4,9-ethano--2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is at 50 centimetres ³In the solution in the dimethyl formamide, add 1.15 gram tetrakis triphenylphosphine palladiums and 5.84 gram zinc cyanides, temperature rising reflux 5 hours, all the time in argon atmospher, at room temperature restir is 18 hours then.After adding water and ethyl acetate, the decant organic phase, organic phase washes with water, with dried over mgso and under reduced pressure concentrated.Resistates adopts silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 95-5) wash-out, obtains 3.09 gram (69%) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(4-cyano-phenyl)-4,9-ethano--2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=158 ℃,

- ¹HNMR composes (300MHz, CDCl ₃, represent d with ppm): (3mts is respectively 1H:1H to 1.46-1.70 and 2.49,2H:CH ₂CH ₂); 2.25-2.40 and 2.63 (be respectively mt and d, J=10Hz, each 1H:1 position CH ₂); 2.31 and 3.21 (2d, J=10Hz, each 1H:3 position CH ₂); (3.23 mt, 1H:9a position CH); 3.41 and 3.63 (2d, J=12.5Hz, each 1H:NCH ₂Ar); (3.45 wide s, 1H:4 position CH); 3.55 (s, 3H:COOCH ₃); (6.43 d, J=7.5Hz, 1H:8 position H); (6.95-7.80 mt, H-7 position, H-6 position, 12H:5 position H-4-cyano-phenyl aromatics H and benzyl aromatics H).

-mass spectrum (IE): M/Z=448 (M ⁺).

Step B

As embodiment 47 step B, operate, but be to use 0.80 gram (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(4-cyano-phenyl)-4,9-ethano--2,3,3a, 4,, 9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate and 1 centimetre ³The carbonochloridic acid vinyl acetate is at 20 centimetres ³In the methylene dichloride at room temperature 24 hours.After hydrolysis, the decant organic phase, and under reduced pressure concentrate.Adopt silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 0.69 gram (91%) (3aRS, 4SR, 7aRS)-and 9-(4-cyano-phenyl)-4,9-ethano--2-ethylene oxy carbonyl-2,3,3a, 4,, 9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate, with it at 20 centimetres ³Make solution in the methyl alcohol, and at 5 centimetres ³In the presence of the solution in the 5M hydrogen chloride gas Zai diox, reflux 5 hours.In isopropyl ether, obtain after the crystallization like this 0.62 gram (98%) (3aRS, 4SR, 9SR, 9aRS)-9-(4-cyano-phenyl)-4,9-ethano--2,3,3a, 4,9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate hydrochloride, the solid state that is white in color, its feature is as follows:

-mass spectrum (IE): M/Z=358 (M ⁺).

Step C

As embodiment 1 step G, operate, but be to use 0.72 gram (3aRS, 4SR, 9SR, 9aRS)-9-(4-cyano-phenyl)-4,9-ethano--2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride, 0.32 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.175 centimetre ³Oxalyl chloride and 0.55 centimetre ³Triethylamine is at room temperature at 20 centimetres ³In the methylene dichloride 18 hours, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out; obtain 0.52 gram (55%) (3aRS, 4SR, 9SR; 9aRS)-and 9-(4-cyano-phenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=90-2 ℃,

-mass spectrum (IE): M/Z=518 (M ⁺).

Step D

Operation as embodiment 2, but be to use 0.50 gram (3aRS, 4SR, 9SR, 9aRS)-9-(4-cyano-phenyl)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4;, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 1.1 centimetres ³1M aqueous sodium hydroxide solution and 20 centimetres ³Refluxed 5 hours in the ethanol, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 95-5 to 50-50) gradient elution; obtain 220 milligrams of (45%) (3aRS, 4SR, 9SR; 9aRS)-and 9-(4-cyano-phenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, the solid state that is white in color, its feature is as follows:

-fusing point=182 ℃,

-mass spectrum (IE): M/Z=504 (M ⁺).

Embodiment 96

Preparation (3aRS, 4SR, 9SR, 9aRS)-and 9-(3-cyano-phenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

As embodiment 95 steps A, operate, but (3aRS, the 4SR that are to use 2.69 grams in embodiment 83 step B, to obtain, 9SR, 9aRS)-and 2-benzyl-9-(3-bromophenyl)-4,9-ethano--2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.62 gram tetrakis triphenylphosphine palladium and 3.14 gram zinc cyanides are at 50 centimetres ³Refluxed 5 hours in the dimethyl formamide, under room temperature and argon atmospher, refluxed again 18 hours then, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 90-10) wash-out, obtain 2.0 gram (83%) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(3-cyano-phenyl)-4,9-ethano--2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=88 ℃,

-mass spectrum (IE): M/Z=448 (M ⁺).

Step B

As embodiment 47 step B, operate, but be to use 2.0 grams (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-9-(3-cyano-phenyl)-4,9-ethano--2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and 0.6 centimetre ³The carbonochloridic acid vinyl acetate is at 20 centimetres ³In the methylene dichloride at room temperature 4 hours, allow its enriched material then at 20 centimetres ³Methyl alcohol and 10 centimetres ³Refluxed 2 hours in the solution of 1M hydrogen chloride gas in Virahol,, obtain 1.22 gram (77%) (3aRS with the neutralization of 5N aqueous sodium hydroxide solution and after with extracted with diethyl ether, 4SR, 9SR, 9aRS)-9-(3-cyano-phenyl)-4,9-ethano--2,3,3a, 4,, 9,9a-six hydrogen-1H-isoindole-3a-methyl-formiate, the sead albumen crisp skin sample material that is white in color, but former state is used for following step, and its feature is as follows:

-mass spectrum (IE): M/Z=358 (M ⁺).

Step C

As embodiment 1 step G, operate, but be to use 1.22 gram (3aRS, 4SR, 9SR, 9aRS)-and 9-(3-cyano-phenyl)-4,9-ethano--2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 0.61 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.3 centimetre ³Oxalyl chloride and 0.96 centimetre ³Triethylamine is at 25 centimetres ³In the methylene dichloride at room temperature 2 hours, adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 95-5 is 80-20 then) wash-out; obtain 0.75 gram (48%) (3aRS, 4SR, 9SR; 9aRS)-and 9-(3-cyano-phenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a, 4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, it is Powdered to be white in color, and its feature is as follows:

-fusing point=176-8 ℃,

-mass spectrum (IE): M/Z=518 (M ⁺).

Embodiment 97

Preparation (3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(3-hydroxyl-4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Steps A

As embodiment 1 step e, operate, but be to use 3.1 gram (3aRS, the 4SR that in embodiment 70 step B, obtain, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(3-hydroxyl-4-p-methoxy-phenyl)-2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-hydroxy 3-methoxybenzene base)-2,3,3a, 4,9, the mixture of 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 1.25 gram ammonium formiate and 0.4 gram 10% (w/w) palladium/carbon obtain 2.1 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-hydroxyl-4-p-methoxy-phenyl)-2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-hydroxy 3-methoxybenzene base)-2,3,3a, 4,9, the mixture of 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is used for following synthetic but be the colorless oil former state.

Step B

As embodiment 1 step G, operate, but be to use 2.1 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(3-hydroxyl-4-p-methoxy-phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate and (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-hydroxy 3-methoxybenzene base)-2,3,3a, 4,, 9, the mixture of 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 1.0 gram 2-(2-p-methoxy-phenyl) vinylformic acid, 0.47 centimetre ³Oxalyl chloride and 1.5 centimetres ³Triethylamine, adopting silica gel (230-400 order) flash chromatography purifying, for the first time with methylene chloride-methanol mixture (by volume 96.5-3.5) wash-out, for the second time with methylene chloride-methanol mixture (by volume 99-1) wash-out, use methylene chloride-methanol mixture (by volume 99.5-0.5) wash-out for the third time, and at 25 centimetres ³After the recrystallization, obtain 0.4 gram and contain 5% (3aRS, 4SR in the acetonitrile; 9SR, 9aRS)-4,9-ethano--9-(4-hydroxy 3-methoxybenzene base)-2-[2-(2-p-methoxy-phenyl) acryl]-2; 3,3a, 4; 9, (3aRS, the 4SR of 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate; 9SR; 9aRS)-4,9-ethano--9-(3-hydroxyl-4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a; 4,, 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, its feature is as follows:

-fusing point=242 ℃.

Step C

Operation as embodiment 2, but be to use 0.35 gram (3aRS, 4SR, 9SR; 9aRS)-4,9-ethano--9-(3-hydroxyl-4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a; 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, 3.25 centimetres ³1M aqueous sodium hydroxide solution and 5 centimetres ³Methyl alcohol is at 6 centimetres ³In the Virahol after the recrystallization, obtain 0.24 gram (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--9-(3-hydroxyl-4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4;, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, its feature is as follows:

-fusing point=278 ℃,

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6, temperature 383K represents d with ppm): 1.38-1.56-1.96 and 2.12 (4mts, each 1H:CH ₂CH ₂); 3.20-3.50 (mt, 3H:1 position CH ₂, 9a position CH); (3.42 mt, 1H:4 position CH); 3.59 and 4.06 (be respectively d and wide d, J=12.5Hz, each 1H:3 position CH ₂); 3.73 and 3.86 (2s, each 3H:2 ArOCH ₃); 5.54 and 5.69 (be respectively d and wide s, J=1Hz, each 1H:=CH ₂); (6.52 wide d, J=7.5Hz, 1H:8 position H); (6.73 dd, J=8 and 2Hz, 1H:3-hydroxyl-6 H of 4-p-methoxy-phenyl); (6.86 d, J=2Hz, 1H:3-hydroxyl-2 H of 4-p-methoxy-phenyl); (6.90-7.40 mt, H-7 position, H-6 position, 8H:5 position H-3-hydroxyl-5 H of 4-p-methoxy-phenyl and 2-p-methoxy-phenyl aromatics H); 8.20-8.90 (wide mf, 1H:ArOH).

Embodiment 98

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate

Steps A

Be cooled to 0 ℃ 178 gram (0.917 mole) (2-p-methoxy-phenyl) pyruvic acid (can be, 1939,19, the method for describing among the 1-3 obtains) at 970 centimetres according to " organic synthesis " ³In the solution in the methyl alcohol, add 77.5 gram (1.1 moles) ethylene methacrylic ketone and 1.1 decimeters in succession ³The 1M aqueous sodium hydroxide solution stirred 2 hours down for about 20 ℃ in temperature then.With 1.1 decimeters ³After neutralization of 1M aqueous hydrochloric acid and the concentrated methyl alcohol, the precipitation dehydration of generation washes with water, then 20 ℃ of dryings, obtains 189.7 gram (78%) 6-(2-p-methoxy-phenyl)-3-oxo-hexamethylene-1-alcohol-1-formic acid like this, is the yellow powder shape, and its feature is as follows:

-fusing point=204 ℃,

- ¹HNMR composes (250MHz, CDCl ₃, represent d with ppm): 1.20 (t, J=7Hz, 3H: the CH of ethyl ₃); 1.47 (d, J=7Hz, 3H:CH ₃); 4.17 (q, J=7Hz, 2H: the OCH of ethyl ₂); 4.49 (q, J=7Hz, 1H:ArCH); 7.15-7.45 (mt, 5H: aromatics H).

Step B

With 396.7 gram (1.5 moles) 6-(2-p-methoxy-phenyl)-3-oxo-hexamethylene-1-alcohol-1-formic acid, in the presence of 39.7 gram tosic acid, at 13.3 decimeters ³Reflux is 2 hours in the toluene.Reaction mixture is under reduced pressure concentrated again, filter the precipitation that generates, with the isopropyl ether washing, then 50 ℃ of dryings.Obtain like this 288 the gram (78%) (RS)-6-(2-p-methoxy-phenyl)-3-oxo-tetrahydrobenzene-1-formic acid, be chestnut color solid, its feature is as follows:

-fusing point=177 ℃,

-mass spectrum (IE): M/Z=246 (M ⁺),

- ¹HNMR composes (300MHz, CDCl ₃, represent d with ppm): 2.10-2.50 (mt, 4H:CH ₂CH ₂); 3.70 (s, 3H:COOCH ₃); 3.90 (s, 3H:ArOCH ₃); 4.61 (mt, 1H:ArCH); 6.80-7.00 and 7.25 (2mt, 5H:=CH and aromatics H altogether).

Step C

288 grams (1.17 moles) (RS)-6-(2-p-methoxy-phenyl)-3-oxo-tetrahydrobenzene-1-formic acid is at 2.5 decimeters ³Solution in the acetone one after the other drips 235 gram (1.66 moles) methyl-iodides and 212 gram (1.39 moles) 1.8-diazabicyclos [5.4.0], 11-7-alkene, and temperature rising reflux is 1 hour then.Reconcentration acetone, resistates and 1 decimeter ³Water stirs together.Be cooled to after 10 ℃, the dehydration of the precipitation of generation is used petroleum ether, again 50 ℃ of dryings.Obtain like this 289 the gram (95%) (RS)-6-(2-p-methoxy-phenyl)-3-oxo-tetrahydrobenzene-1-methyl-formiate, be mustard toner end, its feature is as follows:

-fusing point=76 ℃,

-mass spectrum (IE): M/Z=260 (M ⁺)

Step D

With 6 grams (0.023 mole) (RS)-6-(2-p-methoxy-phenyl)-3-oxo-tetrahydrobenzene-1-methyl-formiate and 0.3 centimetre ³Trifluoroacetic acid is at 185 centimetres ³Solution temperature rising reflux in the methylene dichloride.At this moment drip 7.7 gram (0.0275 mole) N-n-butoxy methyl-N-trimethyl silyl methyl-benzyl amine, this amine can be according to " chemicals circular " (Chem.Pharm.Bull.), and reported method obtains in 1985,276, and temperature rising reflux 3 hours.Reaction medium is cooled to 20 ℃.After about 5 gram salt of wormwood stir 1 hour, concentrate organic phase, the yellow oil that obtains adopts silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 95-5) wash-out, obtain 6.1 gram (68%) (3aRS, 4SR, 7aRS) 2-benzyl-4-(2-p-methoxy-phenyl)-7-oxo-octahydro isoindole-3a-methyl-formiates like this, be yellow oily, its feature is as follows:

-mass spectrum (IE): M/Z=393 (M ⁺).

Step e

With 166.6 the gram (0.424 mole) (3aRS, 4SR, 7aRS)-2-benzyl-4-(2-p-methoxy-phenyl)-7-oxo-octahydro isoindole-3a-methyl-formiate and 84.5 the gram (1.69 moles) hydrazine hydrate at 2.8 decimeters ³Solution temperature rising reflux in the methyl alcohol 2 hours.Under reduced pressure concentrate after the methyl alcohol, resistates is with 2 decimeters ³The methylene dichloride dissolving is used 1 decimeter at every turn ³Distilled water wash 4 times is with dried over mgso and under reduced pressure concentrated.Obtain like this 175.2 grams (3aRS, 4SR 7aRS)-2-benzyl-7-hydrazono--4-(2-p-methoxy-phenyl)-octahydro-isoindole-3a-methyl-formiate, are yellow oily, and its feature is as follows:

-mass spectrum (IE): M/Z=407 (M ⁺).

Step F

85 grams (0.209 mole) (3aRS, 4SR, 7aRS)-2-benzyl-7-hydrazono--4-(2-p-methoxy-phenyl)-octahydro-isoindole-3a-methyl-formiate is at 2 decimeters ³In the solution in the tetrahydrofuran (THF), drip 106.1 gram (0.418 mole) iodine at 1.1 decimeters ³Solution in the tetrahydrofuran (THF).Adding 2 decimeters ³After the ethyl acetate, organic phase is used 1 decimeter at every turn ³Saturated sodium bicarbonate aqueous solution washing 2 times is used 1 decimeter at every turn ³Saturated aqueous sodium thiosulfate washing 2 times is again with dried over mgso and under reduced pressure concentrated.Adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 95-5) wash-out, obtain 51 gram (48%) (3aRS, 4SR, 7aRS)-2-benzyl-7-iodo-4-(2-p-methoxy-phenyl)-1,2,3,4,5,7a-six hydrogen-isoindole-3a-methyl-formiate are chestnut color oily, and its feature is as follows:

-mass spectrum (IE): M/Z=503 (M ⁺).

Step G

(7aRS)-2-benzyl--7-iodo-4-(2-p-methoxy-phenyl)-1,2,3,4,5,7a-six hydrogen-isoindole-3a-methyl-formiate and 0.15 (0.13 mmole) four (tribenzyl phosphine) palladium is at 30 centimetres for 3aRS, 4SR at 1.37 grams (2.7 mmole) ³In the solution in the toluene, add 0.41 gram (2.99 mmole) 4-aminomethyl phenyl boric acid in succession at 13 centimetres ³Solution in the methyl alcohol and 30 centimetres ³The 2N aqueous sodium carbonate, temperature rising reflux is 2 hours then.Get back to after about 20 ℃ in temperature, reaction mixture is with 100 centimetres ³Ethyl acetate extraction is used 50 centimetres at every turn ³Distilled water wash 2 times is used dried over mgso, under reduced pressure concentrates then.Resulting chestnut color resistates adopts silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 95-5) wash-out, obtain 1.2 gram (93%) (3aRS, 4SR like this, 7aRS)-2-benzyl-4-(2-p-methoxy-phenyl)-7-(4-aminomethyl phenyl)-1,2,3,4,5,7a-six hydrogen-isoindole-3a-methyl-formiate are yellow oily, and its feature is as follows:

-mass spectrum (IE): M/Z=467 (M ⁺).

Step H

(7aRS)-2-benzyl-4-(2-p-methoxy-phenyl)-7-(4-aminomethyl phenyl)-1,2,3,4,5,7a-six hydrogen-isoindole-3a-methyl-formiate is at 750 centimetres for 3aRS, 4SR to be maintained at about 0 ℃ 66.4 grams (0.142 mole) in temperature ³In the solution in the methylene dichloride, drip 94 centimetres ³Trifluoromethanesulfonic acid.Reaction mixture was stirred 3 hours down for about 20 ℃ in temperature, be cooled to about 0 ℃ of temperature then.At this moment add 700 centimetres ³The unsaturated carbonate aqueous solutions of potassium.Adopt the decant method to separate organic phase, one after the other use 150 centimetres at every turn ³Distilled water wash 3 times is used 100 centimetres at every turn ³Saturated sodium-chloride water solution washing 2 times is with dried over mgso and under reduced pressure concentrated.In isopropyl ether, after the washing, obtain 54.9 gram (82%) (3aRS, 4SR then, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--5-methoxyl group-9-(4-aminomethyl phenyl)-2,3,3,4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, be broken white solid, its feature is as follows:

-fusing point=129 ℃,

- ¹HNMR composes (250MHz, CDCl ₃, represent d with ppm): (3mts is respectively 1H-1H and 2H:CH for 1.41-1.73 and 2.40-2.60 ₂CH ₂); 2.30-2.40 (mt, 2H:1 position CH ₂1H, 3 CH ₂1H); 2.39 (s, 3H:ArCH ₃); 2.75 (wide d, J=10Hz, 1H:1 position CH ₂Another H); 3.23 (d, J=9.5Hz, 1H:3 position CH ₂Another H); (3.26 mt, 1H:9a position CH); 3.41 and 3.65 (2d, J=12.5Hz, each 1H:NCH ₂Ar); 3.55 (s, 3H:COOCH ₃); 3.81 (s, 3H:ArOCH ₃); (3.96 mt, 1H:4 position CH); (6.21 d, J=7.5Hz, 1H:8 position H); (6.71 d, J=7.5Hz, 1H:6 position H); (6.99 t, J=7.5Hz, 1H:7 position H); (7.15-7.40 mt, 9H:4-aminomethyl phenyl aromatics H and benzyl aromatics H).

Step I

Use 0.54 gram (1.1 mmole) (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--5-methoxyl group-9-(4-aminomethyl phenyl)-2,3,3,4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is at 100 centimetres ³Solution in the methyl alcohol in the presence of 54 milligram of 10% (w/w) palladium/carbon, stirred 1 hour down for 40 ℃ at atmospheric hydrogen and temperature, at filtering catalyst and after under reduced pressure concentrating, obtain 0.5 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--5-methoxyl group-9-(4-aminomethyl phenyl)-2,3,3,4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride are the beige solid shape, and its feature is as follows:

-fusing point＞260 ℃,

-IR composes (KBr):

3050-2250cm ^-1NN ⁺H+n aromatics and aliphatic CH

2833cm ^-1????????????????????nCHOCH ₃

1738cm ^-1N methyl ester C=O

1603,1584,1514,1477cm ^-1The aromatic ring breathing vibration

1258cm ^-1N methyl ester O-C=O+n _aEther C-O

824cm ^-1The phenyl aromatics CH of g para-orientation

776,755cm ^-1G trisubstd phenyl aromatics CH

Step J

Restrain 2-(2-p-methoxy-phenyl) vinylformic acid at 5 centimetres 0.12 ³In the solution in the methylene dichloride (this solution contains 3 N, dinethylformamide), drip 0.058 centimetre ³Oxalyl chloride is at 5 centimetres ³Solution in the methylene dichloride.Reaction mixture was stirred 2 hours down for about 20 ℃ in temperature, be cooled to about 0 ℃ of temperature then, and be added drop-wise to 0.25 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--5-methoxyl group-9-(4-aminomethyl phenyl)-2,3,3,4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride is at 7 centimetres ³Methylene dichloride and 0.19 centimetre ³In the solution in the triethylamine, keep about 0 ℃ of temperature simultaneously.Reaction mixture was stirred 1 hour for about 0 ℃ in temperature, stir 1 night down, and pour 15 centimetres at 20 ℃ then ³In the distilled water.Adopt the decant method to separate organic phase, use 15 centimetres at every turn ³Distilled water wash 2 times is again with saturated sodium-chloride water solution washing 2 times, with dried over mgso and under reduced pressure concentrated.Adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out, obtain 0.17 gram (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2; 3,3,4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the solid state that is white in color, its feature is as follows:

-fusing point=185 ℃,

-mass spectrum (IE): M/Z=537 (M ⁺),

Embodiment 99

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

With 0.365 gram (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3,4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is at 0.82 centimetre ³The 1M aqueous sodium hydroxide solution exists down, at 30 centimetres ³Reflux is 3 hours in the ethanol.Reaction mixture is under reduced pressure concentrated, and resistates is dissolved in 10 centimetres ³In the distilled water.Water is each with 10 centimetres ³Washed with dichloromethane 2 times is about 2 with the acidifying of 1M aqueous hydrochloric acid up to pH, with 30 centimetres ³Dichloromethane extraction is used distilled water wash, uses dried over mgso, under reduced pressure concentrates then.Resulting orange solids adopts silica gel (230-400 order) flash chromatography purifying, with methylene chloride-methanol-acetate mixture (by volume 98-1.5-0.5) wash-out, obtains 0.09 gram (26%) (3aRS like this; 4SR, 9SR, 9aRS)-4; 9-ethano--5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4;, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid; the solid state that is white in color, its feature is as follows:

-fusing point＞260 ℃

- ¹HNMR composes (250MHz, (CD ₃) ₂SO d6, temperature 383K represents d with ppm): (3mts is respectively 1H-1H and 2H:CH for 1.32-1.60 and 1.85-2.20 ₂CH ₂); 2.38 (s, 3H:ArCH ₃); 3.34 (mt, 3H:1 position CH ₂With 9a position CH); 3.62 and 4.04 (2d, J=12.5Hz, each 1H:3 position CH ₂); 3.72 and 3.81 (2s, each 3H:ArOCH ₃); (3.93 mt, 1H:4 position CH); 5.52 and 5.66 (2 wide s, each 1H:=CH ₂); (6.06 d, J=7.5Hz, 1H:8 position H); (6.82 d, J=7.5Hz, 1H:6 position H); (6.90-7.10 mt, 3H:7 position H and 2-p-methoxy-phenyl aromatics 2H); (7.20-7.40 mt, 6H:2-p-methoxy-phenyl aromatics 2H and 4-p-methoxy-phenyl aromatics H).

Embodiment 100

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation Separation of Enantiomers

Divide 4 times one after the other with 6.5 gram embodiment, 99 resulting (3aRS, 4SR, 9SR; 9aRS)-4; 9-ethano--5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4;, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid injects and is loaded with (R)-N-(3; the 5-dinitrobenzoyl) on the phenylalanine grafted chirality silicagel column, and with normal heptane-dichloromethane-ethanol mixture (by volume 50-50-1) wash-out.Reclaim first eluting fraction (retention time 30 minutes), after under reduced pressure concentrating, obtain 2.81 gram (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4;, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph; it is Powdered to be white in color, and its feature is as follows:

-mass spectrum (IE): M/Z=523 (M ⁺),

-specific rotation: [a] ₃₆₅ ²⁰=+36.5+/-1 ° (c=0.5/ methylene dichloride).

Embodiment 101

Preparation (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-4-methyl-9-(4-p-methoxy-phenyl)-2,3,3a, 4,, 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Steps A

Be cooled to-70 ℃ 33 grams (0.220 mole) (RS)-2-phenyl-propionic acid is at 220 centimetres ³Tetrahydrofuran (THF) and 44 centimetres ³N in the solution in N '-Tetramethyl Ethylene Diamine, drips the solution of 1.6N n-Butyl Lithium in hexane.After-70 ℃ are stirred 3 hours, turn back to 20 ℃ of temperature again, pour the solution that obtains into 75 centimetres ³(0.55 mole) oxalyl chloride is at 110 centimetres ³Solution in the tetrahydrofuran (THF) keeps temperature to reach 1 hour for about-75 ℃ simultaneously.Reaction mixture is with 800 centimetres ³Saturated sodium bicarbonate aqueous solution is hydrolyzed, with 100 centimetres ³Ethyl acetate extraction 3 times is used 50 centimetres at every turn ³1M aqueous hydrochloric acid washing 3 times is with dried over sodium sulfate and under reduced pressure concentrated.Obtain like this 44 the gram (97%) (RS)-2-oxo-3-phenyl-ethyl butyrate, be orange oily, its feature is as follows:

- ¹HNMR composes (250MHz, CDCl ₃, represent d with ppm): 1.20 (t, J=7Hz, the CH of ethyl ₃); 1.47 (d, J=7Hz, 3H:CH ₃); 4.17 (q, J=7Hz, 2H: the CH of ethyl ₂); 4.49 (q, J=7Hz, 1H:ArCH); 7.15-7.45 (mt, 5H: aromatics H).

Step B

Be cooled to 7 ℃ 6.7 grams (32.5 mmole) (RS)-2-oxo-3-phenyl-ethyl butyrate is at 68 centimetres ³In the solution in the ethanol, one after the other add 3.5 centimetres ³(39 mmole) methyl vinyl ketone and 72 centimetres ³(71.5 mmole) 1M aqueous sodium hydroxide solution stirred 2 hours down for about 20 ℃ in temperature then.Reaction mixture is cooled to 15 ℃, adds 72 centimetres ³The 1M aqueous hydrochloric acid.After concentrating ethanol, the precipitation dehydration with generating washes with water, then 50 ℃ of dryings.Obtain like this 4.4 grams (50%) (1RS 2RS)-2-methyl-5-oxo-2-phenyl-hexamethylene-1-alcohol-formic acid, is the cream-coloured powder shape, and its feature is as follows:

- ¹HNMR composes (300MHz, CDCl ₃, represent d with ppm): 1.79 (s, 3H:CH ₃); 2.00-2.25 and 2.25-2.55 (2mts, each 2H:CH ₂CH ₂); 3.59 (s, 3H:COOCH ₃); 6.72 (s, 1H:=CH); 7.15-7.35 (mt, 5H: aromatics H).

Step C

With 4.4 grams (17.6 mmole) (1RS, 2RS)-2-methyl-5-oxo-2-phenyl-hexamethylene-1-alcohol-formic acid is at 100 centimetres ³In the toluene, reflux is 1 hour in the presence of 0.34 gram tosic acid.Reaction mixture is cooled to 0 ℃, and the precipitation of generation is filtered, and is with the ether washing, dry down at 50 ℃ then.Obtain like this 2.8 the gram (69%) (RS)-2-methyl-5-oxo-2-phenyl-tetrahydrobenzene-1-alcohol-formic acid, be rose-colored solid state, its feature is as follows:

-fusing point=206 ℃

-mass spectrum (IE): M/Z=230 (M ⁺).

Step D

2.3 grams (10 mmole) (RS)-2-methyl-5-oxo-2-phenyl-tetrahydrobenzene-1-alcohol-formic acid is at 20 centimetres ³In the solution in the acetone, one after the other drip 0.88 centimetre ³(14 mmole) methyl iodide and 1.8 centimetres ³(12 mmole) 1,8-diazabicyclo [5.4.0] 11-7-alkene are then with reaction mixture reflux 2 hours.Concentrate acetone then, again with resistates and 100 centimetres ³Water stirs together, uses 30 centimetres then at every turn ³Ethyl acetate extraction 3 times.After under with dried over mgso and decompression, concentrating, obtain 2.3 grams (94%) (RS)-2-methyl-5-oxo-2-phenyl-tetrahydrobenzene-1-methyl-formiate, be orange oily, its feature is as follows:

-mass spectrum (IE): M/Z=224 (M ⁺).

Step e

With 18.3 grams (0.075 mmole) (RS)-2-methyl-5-oxo-2-phenyl-tetrahydrobenzene-1-methyl-formiate and 0.57 centimetre ³Trifluoroacetic acid is at 145 centimetres ³Vlil in the methylene dichloride.Drip 31.4 gram (0.112 mole) N-n-butoxy methyl-N-trimethyl silyl methyl-benzyl amine then, this amine can be according to " chemicals circular ", and reported method obtains in 1985,276, and temperature rising reflux 4 hours.Reaction medium is cooled to 20 ℃ then.After about 15 gram salt of wormwood stir 1 hour, concentrate organic phase, the yellow oil that obtains crystallization in pentane.After filtering, obtain 19 restrain (67%) (3aRS, 4SR 7aRS)-2-benzyl-4-methyl-7-oxo-4-phenyl-octahydro isoindole-3a-methyl-formiate, are the yellow solid shape, and its feature is as follows:

-fusing point=115 ℃,

-mass spectrum (IE): M/Z=377 (M ⁺).

Step F

With 3 grams (7.95 mmole) (3aRS, 4SR, 7aRS)-2-benzyl-4-methyl-7-oxo-4-phenyl-octahydro isoindole-3a-methyl-formiate and 1.55 centimetres ³(31.8 mmole) hydrazine hydrate is at 30 centimetres ³Solution temperature rising reflux in the methyl alcohol 2 hours.Under reduced pressure concentrate after the methyl alcohol, resistates dissolves with methylene dichloride, uses 30 centimetres at every turn ³Distilled water wash 3 times is with dried over mgso and under reduced pressure concentrated.Obtain like this 2.8 grams (89%) (3aRS, 4SR 7aRS)-2-benzyl-7-hydrazono--4-methyl-4-phenyl-octahydro isoindole-3a-methyl-formiate, are chestnut color oily, and its feature is as follows:

- ¹HNMR composes (300MHz, CDCl ₃, represent d with ppm): 1.33 (s, 3H:CH ₃); 1.86-2.24-2.48 and 2.84 (4mts, each 1H:5 position CH ₂With 6 CH ₂); 2.43 and 3.47 (2d, J=9Hz, each 1H:3 position CH ₂); 2.67 and 3.19 (2t, J=8.5Hz, each 1H:1 position CH ₂); 3.10 (s, 3H:COOCH ₃); 3.53 and 3.71 (2d, J=13Hz, each 1H:NCH ₂Ar); (3.78 t, J=8.5Hz, 1H:7a position H); 4.98 (wide s, 2H:NH ₂); (7.10-7.35 mt, 10H: phenyl aromatics H and benzyl aromatics H).

Step G

2.8 grams (7 mmole) (3aRS, 4SR, 7aRS)-2-benzyl-7-hydrazono--4-methyl-4-phenyl-octahydro isoindole-3a-methyl-formiate is at 80 centimetres ³In the solution in the tetrahydrofuran (THF), add 2.95 centimetres ³Triethylamine also drips 3.6 gram (14.1 mmole) iodine at 40 centimetres ³Solution in the tetrahydrofuran (THF).After adding ethyl acetate, use 50 centimetres at every turn ³Saturated aqueous solution of sodium bicarbonate washing 2 times is used 50 centimetres at every turn ³Saturated aqueous sodium thiosulfate washing 2 times is then with dried over mgso and under reduced pressure concentrated.Adopt silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 85-15) wash-out, obtain 2.4 gram (69%) (3aRS, 4SR, 7aRS)-2-benzyl-7-iodo-4-(2-p-methoxy-phenyl)-1,2,3,4,5,7a-six hydrogen-isoindole-3a-methyl-formiate are yellow oily, and its feature is as follows:

-mass spectrum (IE): M/Z=487 (M ⁺).

Step H

(7aRS)-2-benzyl-7-iodo-4-(2-p-methoxy-phenyl)-1,2,3,4,5,7a-six hydrogen-isoindole-3a-methyl-formiate and 7 gram four (trimethyl-phosphine) palladiums are at 30 centimetres for 3aRS, 4SR at 58.6 grams (0.12 mole) ³In the solution in the toluene, one after the other add 20.1 gram (0.132 mole) 4-anisole ylboronic acids at 580 centimetres ³The solution of methyl alcohol and 1170 centimetres ³The 2N aqueous sodium carbonate, temperature rising reflux is 24 hours then.After turning back to about 20 ℃ of temperature, the reaction mixture ethyl acetate extraction is used distilled water wash, uses dried over mgso, under reduced pressure concentrates then.The resistates that obtains adopts silica gel (230-400 order) flash chromatography purifying, with hexanaphthene-ethyl acetate mixture (by volume 98-2) wash-out, obtain 29 gram (52%) (3aRS, 4SR like this, 7aRS)-2-benzyl-7-(4-p-methoxy-phenyl)-4-methyl-4-phenyl-1,2,3,4,5,7a-six hydrogen-isoindole-3a-methyl-formiate are chestnut color Powdered, and its feature is as follows:

-fusing point=132 ℃,

- ¹HNMR composes (250MHz, CDCl ₃, represent d with ppm): 1.60 (s, 3H:4 position CH ₃); 2.03 (dd, J=9 and 5Hz, 1H:5 position CH ₂1H); 2.40-2.90 (mt, 1H:5 position CH ₂Another H); 3.56 (s, 3H:COOCH ₃); 3.40-3.95 (mt, 2H:NCH ₂Ar); (3.79 mt, 1H:7a position CH); 3.83 (s, 3H:ArOCH ₃); 6.08 (mt, the 1H:6 position=CH); (6.75-7.45 mt, 14H:4-p-methoxy-phenyl aromatics H-benzyl aromatics H and phenyl aromatics H).

Step I

(7aRS)-2-benzyl-7-(4-p-methoxy-phenyl)-4-methyl-4-phenyl-1,2,3,4,5,7a-six hydrogen-isoindole-3a-methyl-formiate is at 700 centimetres for 3aRS, 4SR remaining on 54.7 about 5 ℃ (0.117 moles) of temperature ³In the solution in the methylene dichloride, drip 105 centimetres ³Trifluoromethanesulfonic acid.Reaction mixture was stirred 3 hours down for about 20 ℃ in temperature, be cooled to about 0 ℃ of temperature then.At this moment add 100 centimetres ³The 10N aqueous sodium hydroxide solution.Separate organic phase, one after the other use 100 centimetres at every turn ³Distilled water wash 3 times is with dried over mgso and under reduced pressure concentrated.In sherwood oil, obtain after the washing like this 50 grams (92%) (3aRS, 4SR, 9SR, 9aRS)-2-benzyl-4,9-ethano--9-(4-p-methoxy-phenyl)-4-methyl-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate, the gray solid state, its feature is as follows:

-fusing point=143 ℃,

- ¹HNMR composes (400MHz, CDCl ₃, represent d with ppm): 1.21-1.79-2.36 and 2.53 (4mts, each 1H:CH ₂CH ₂); 1.41 (s, 3H:CH ₃); 2.37 and 2.55 (2mts, each 1H:1 position CH ₂); 2.74 and 3.14 (2d, J=10Hz, each 1H:3 position CH ₂); (3.19 mt, 1H:9a position CH); 3.44 (s, 3H:COOH ₃); 3.47 and 3.61 (2d, J=13Hz, each 1H:NCH ₂Ar); 3.86 (s, 3H:ArOCH ₃); (6.59 d, J=7,5Hz, 1H:8 position H); 6.96 (wide d, J=7,5Hz, 2H:OCH ₃Ortho position aromatics H); (7.05-7.25 mt, H-6 position, 3H:5 position H-7 position H); 7.25-7.45 (mt, 7H:OCH ₃Between position aromatics H and benzyl aromatics H).

Step J

Use 13 grams (0.028 mole) (3aRS, 4SR, 9SR, 9aRS)-and 2-benzyl-4,9-ethano--9-(4-p-methoxy-phenyl)-4-methyl-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate is at 260 centimetres ³Solution in the methyl alcohol, in the presence of 1.7 gram 10% (w/w) palladium/carbon, stirring is 4 hours under 40 ℃, the hydrogen of barometric point, after filtering catalyst also under reduced pressure concentrates, obtain 10.2 gram (97%) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-4-methyl-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride are the yellow solid shape, and its feature is as follows:

-IR composes (KBr):

3050-2250cm ^-1N N ⁺H+n aromatics and aliphatic CH

2842cm ^-1????????????????????nCHOCH ₃

1737cm ^-1N methyl ester C=O

1611,1571,1516,1460cm ^-1The aromatic ring breathing vibration

1253cm ^-1N methyl ester O-C=O+n _aEther C-O

825cm ^-1The disubstituted phenyl aromatics of g contraposition CH

768cm ^-1G ortho position disubstituted phenyl aromatics CH

Step K

Restrain (0.026 mole) 2-(2-p-methoxy-phenyl) vinylformic acid at 100 centimetres 4.62 ³Solution in the methylene dichloride wherein contains 2 N, in the dinethylformamide, drips 3.1 centimetres ³Oxalyl chloride is at 50 centimetres ³Solution in the methylene dichloride.Reaction mixture was stirred 2 hours down for about 20 ℃ in temperature, be cooled to about 0 ℃ of temperature then, and be added drop-wise to 8.3 gram (0.024 mole) (3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--9-(4-p-methoxy-phenyl)-4-methyl-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate hydrochloride is at 100 centimetres ³Methylene dichloride and 6.1 centimetres ³In the solution in the triethylamine, keep about 0 ℃ of temperature simultaneously.Reaction mixture was stirred 1 hour for about 0 ℃ in temperature, stirred for 1 night down at 20 ℃ then.Each with 100 centimetres ³After the distilled water wash 2 times, adopt the decant method to separate organic phase, one after the other use 100 centimetres at every turn ³1M aqueous hydrochloric acid washing 2 times is washed 2 times with 100 milliliters of 1M aqueous sodium hydroxide washes more at every turn, with dried over mgso and under reduced pressure concentrated.Adopting silica gel (230-400 order) flash chromatography purifying, after hexanaphthene-ethyl acetate mixture (by volume 70-30) wash-out, obtain 9.1 gram (3aRS; 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-4-methyl-9-(4-p-methoxy-phenyl)-2; 3,3,4; 9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are the orange solids shape, and its feature is as follows:

-fusing point=141 ℃,

- ¹HNMR composes (300MHz, (CD ₃) ₂SO d6 represents d with ppm): 0.95-1.25 and 1.55-2.10 (2mts, 4H:CH altogether ₂CH ₂); 1.38 and 1.46 (s, 3H:CH altogether ₃); 3.05-3.35 (mt, 3H:1 position CH ₂With 9a position CH); 3.30-3.40 and 3.41 (be respectively mt and s, altogether 3H:COOCH ₃); 3.62-3.72-3.80 and 3.83 (4s, 6H:ArOCH altogether ₃); 3.80-4.20 (mt, 2H:3 position CH ₂); 5.43-5.56-5.60 and 5.78 (4s, 2H:=CH altogether ₂); 6.39 and 6.42 (2d, J=7.5Hz, 1H:8 position H altogether); (6.85-7.45 mt, H-7 position, H-6 position, 11H:5 position H-4-p-methoxy-phenyl aromatics H and 2-p-methoxy-phenyl aromatics H).

Step L

With 13.4 the gram (0.025 mole) (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-4-methyl-9-(4-p-methoxy-phenyl)-2,3,3,4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate are at 52 centimetres ³The 1M aqueous sodium hydroxide solution exists down, and reflux is 3 hours in 250 ethanol.Reaction mixture under reduced pressure concentrates then, and resistates is dissolved in 250 centimetres ³In the distilled water.Water is each with 100 centimetres ³Ether washing 2 times is with 60 centimetres ³The acidifying of 1M aqueous hydrochloric acid is used 150 centimetres at every turn ³Dichloromethane extraction 2 times is used dried over mgso, under reduced pressure concentrates then.The white solid that obtains is at 100 centimetres ³Purifying is carried out in washing in the pentane.Obtain like this 10.8 the gram (83%) (3aRS, 4SR, 9SR, 9aRS)-4; 9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-p-methoxy-phenyl)-4-methyl-2,3,3,4; 9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid, the solid state that is white in color, its feature is as follows:

-fusing point=157 ℃,

-mass spectrum (IE): M/Z=523 (M ⁺).(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-p-methoxy-phenyl)-4-methyl-2,3,3,4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation Separation of Enantiomers

Divide 4 times with 17.6 gram (3aRS; 4SR; 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-p-methoxy-phenyl)-4-methyl-2; 3; 3,4,9; 9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid injects on Whelk 01 (SS) the chirality silicagel column and separates, with normal heptane-methylene dichloride-propanol mixture (by volume 50-48-2) wash-out that contains 0.05% trifluoroacetic acid.Reclaim first eluting fraction (retention time 38 minutes), obtain 7.01 gram (3aRS, 4SR after under reduced pressure concentrating; 9SR; 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-p-methoxy-phenyl)-4-methyl-2,3; 3; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph; it is Powdered to be white in color, and its feature is as follows:

-fusing point=238 ℃,

-mass spectrum (IE): M/Z=523 (M ⁺).

Specific rotation [a] ₃₆₅ ²⁰=+74.4+/-1.3 ° (c=0,5/ methyl alcohol).

Embodiment 102

The active evaluation of the farnesyl transferase of The compounds of this invention

The farnesyl transferase activity can by the K-ras substrate or corresponding to the derive flow measurement of farnesylation of the substrate that obtains of its this peptide of C-end parts, farnesyl group be provided by method pyrophosphate (FPP).

Definitely, the biotinylation substrate of employed representative K-ras: BIOT-(β A) ₃-S-K-D-G-(K) ₆-S-K-T-K-C-V-I-M, [ ³H] FPP exist down by farnesyl transferase on its halfcystine C, carry out [ ³H] farnesylation.Allow itself and PVT then ^*-streptoavidin pearl (AMERSHAM) ^Contact, and, carry out quantitative assay by the approaching flicker (SPA mensuration) between tritium and PVT pearl by streptoavidin/vitamin H interaction.

In test, in order to carry out this mensuration, will be diluted to such concentration according to the farnesyl transferase of the scheme purifying of enclosing, promptly base consumption is lower than 30%.The final volumetric molar concentration of every kind of substrate all is adjusted to their Km separately: biotinylated peptide K ras is 50nM, and FPP is 120nM, and volume is 20 microlitres, with pH7.5 50mM HEPES, 5mM MgCl ₂, 40mMKCl, 5mM dithiothreitol (DTT), 0.01%Triton X100 damping fluid be adjusted to 100 microlitres with the reaction mixture final volume.

The 1mM inhibitor to be tested that begins to be dissolved in the suitable solvent (DMF or DMSO) is diluted in the mensuration damping fluid, and joins in the reaction mixture with 10 microlitres (3 parts of the same form) and 10 times of concentration to final concentration.

Add enzyme and be enabled in OPTIPLATES 96 ^Reaction in the titer plate, and under 37 ℃, kept 60 minutes.Can by add 150 microlitres contain 200 microgram PVT-streptoavidin pearls, by 0.2M H ₃PO ₄, 1.5mM MgCl ₂, the pH4 stop buffer mixture that constitutes of 0.5% (weight/volume) BSA, 0.05% (weight/volume) sodiumazide stops this reaction.

Slowly stirring 30 minutes (removing chemoluminescence) afterwards, for by a gram decay flicker have toner (cancellation) convert it into [ ³H] the microplate TOP COUNT of DPM ^(PACKARD), with the flicker computer with [ ³H] CPM reads these plates.

Deducting after any blank that contains substrate and damping fluid suppress percent value, calculate inhibition percentage ratio with respect to the damping fluid that does not have inhibitor.

Use Enzfitter ^Or Grafit ^Software is used by 9 resulting restraining effect of different concentration and is calculated or determine IC ₅₀The IC that lists among the result ₅₀Be twice IC ₅₀The mean value of measuring and calculating.Resulting result collects in the Table I.

Table I

Product	Vitro inhibition activity (KiRas) IC ₅₀(μM)
Product	Vitro inhibition activity (KiRas) IC ₅₀(μM)	Embodiment 1	?????0.305
Embodiment 2	?????0.045	Embodiment 1	?????0.305
Embodiment 2	?????0.045	Embodiment 3	?????0.028
Embodiment 4	?????1.80	Embodiment 3	?????0.028
Embodiment 4	?????1.80	Embodiment 5	?????0.050
Embodiment 6	?????0.0575	Embodiment 5	?????0.050
Embodiment 6	?????0.0575	Embodiment 7	?????0.050
Embodiment 8	?????0.100	Embodiment 7	?????0.050
Embodiment 8	?????0.100	Embodiment 9	?????0.055
Embodiment 10	?????0.160	Embodiment 9	?????0.055
Embodiment 10	?????0.160	Embodiment 11	?????0.345
Embodiment 12	?????0.045	Embodiment 11	?????0.345
Embodiment 12	?????0.045	Embodiment 13	?????0.140
Embodiment 14	?????0.210	Embodiment 13	?????0.140
Embodiment 14	?????0.210	Embodiment 15	?????0.170
Embodiment 16	?????0.360	Embodiment 15	?????0.170
Embodiment 16	?????0.360	Embodiment 17	?????0.235
Embodiment 18	?????0.050	Embodiment 17	?????0.235
Embodiment 18	?????0.050	Embodiment 19	?????0.181
Embodiment 20	?????0.140	Embodiment 19	?????0.181
Embodiment 20	?????0.140	Embodiment 21	?????0.111
Embodiment 22	?????0.131	Embodiment 21	?????0.111
Embodiment 22	?????0.131	Embodiment 23	?????0.277
Embodiment 24	?????0.084	Embodiment 23	?????0.277

Embodiment 25	????0.193
Embodiment 25	????0.193	Embodiment 26	????0.145
Embodiment 27	????0.009	Embodiment 26	????0.145
Embodiment 27	????0.009	Embodiment 28	????0.054
Embodiment 29	????0.140	Embodiment 28	????0.054
Embodiment 29	????0.140	Embodiment 30	????0.074
Embodiment 31	????0.101	Embodiment 30	????0.074
Embodiment 31	????0.101	Embodiment 32	????0.106
Embodiment 33	????0.242	Embodiment 32	????0.106
Embodiment 33	????0.242	Embodiment 34	????＜0.02
Embodiment 35	????0.084	Embodiment 34	????＜0.02
Embodiment 35	????0.084	Embodiment 36	????0.120
Embodiment 37	????0.088	Embodiment 36	????0.120
Embodiment 37	????0.088	Embodiment 38	????0.099
Embodiment 39	????0.273	Embodiment 38	????0.099
Embodiment 39	????0.273	Embodiment 40	????0.083
Embodiment 41	????0.009	Embodiment 40	????0.083
Embodiment 41	????0.009	Embodiment 42	????0.083
Embodiment 43	????0.590	Embodiment 42	????0.083
Embodiment 43	????0.590	Embodiment 44	????0.369
Embodiment 45	????0.181	Embodiment 44	????0.369
Embodiment 45	????0.181	Embodiment 46	????0.132
Embodiment 47	????0.207	Embodiment 46	????0.132
Embodiment 47	????0.207	Embodiment 48	????0.095
Embodiment 49	????0.229	Embodiment 48	????0.095
Embodiment 49	????0.229	Embodiment 50	????0.059
Embodiment 51	????0.068	Embodiment 50	????0.059
Embodiment 51	????0.068	Embodiment 52	????0.181

Embodiment 53	????0.020
Embodiment 53	????0.020	Embodiment 54	????0.078
Embodiment 55	????0.558	Embodiment 54	????0.078
Embodiment 55	????0.558	Embodiment 56	????0.589
Embodiment 57	????0.280	Embodiment 56	????0.589
Embodiment 57	????0.280	Embodiment 58	????0.138
Embodiment 59	????0.408	Embodiment 58	????0.138
Embodiment 59	????0.408	Embodiment 60	????0.124
Embodiment 61	????0.178	Embodiment 60	????0.124
Embodiment 61	????0.178	Embodiment 62	????0.036
Embodiment 63	????＜0.020	Embodiment 62	????0.036
Embodiment 63	????＜0.020	Embodiment 64	????0.325
Embodiment 65	????0.040	Embodiment 64	????0.325
Embodiment 65	????0.040	Embodiment 66	????0.379
Embodiment 67	????0.101	Embodiment 66	????0.379
Embodiment 67	????0.101	Embodiment 68	????0.431
Embodiment 69	????0.053	Embodiment 68	????0.431
Embodiment 69	????0.053	Embodiment 70	????0.067
Embodiment 71	????0.335	Embodiment 70	????0.067
Embodiment 71	????0.335	Embodiment 72	????0.098
Embodiment 73	????0.460	Embodiment 72	????0.098
Embodiment 73	????0.460	Embodiment 74	????0.048
Embodiment 75	????0.008	Embodiment 74	????0.048
Embodiment 75	????0.008	Embodiment 76	????0.244
Embodiment 77	????0.204	Embodiment 76	????0.244
Embodiment 77	????0.204	Embodiment 78	????0.048
Embodiment 79	????0.045	Embodiment 78	????0.048
Embodiment 79	????0.045	Embodiment 80	????0.067

Embodiment 81	????0.018
Embodiment 81	????0.018	Embodiment 82	????0.097
Embodiment 83	????0.319	Embodiment 82	????0.097
Embodiment 83	????0.319	Embodiment 84	????0.008
Embodiment 85	????0.508	Embodiment 84	????0.008
Embodiment 85	????0.508	Embodiment 86	????0.005
Embodiment 87	????0.064	Embodiment 86	????0.005
Embodiment 87	????0.064	Embodiment 88	????0.404
Embodiment 89	????0.005	Embodiment 88	????0.404
Embodiment 89	????0.005	Embodiment 90	????0.068
Embodiment 91	????0.183	Embodiment 90	????0.068
Embodiment 91	????0.183	Embodiment 92	????0.028
Embodiment 93	????0.786	Embodiment 92	????0.028
Embodiment 93	????0.786	Embodiment 94	????0.557
Embodiment 95	????0.177	Embodiment 94	????0.557
Embodiment 95	????0.177	Embodiment 96	????0.955
Embodiment 97	????0.040	Embodiment 96	????0.955
Embodiment 97	????0.040	Embodiment 98	????0.663
Embodiment 99	????0.018	Embodiment 98	????0.663
Embodiment 99	????0.018	Embodiment 100	????＜0.019
Embodiment 101	????＜0.019	Embodiment 100	????＜0.019

Embodiment 103

Suppress the activity that the ability of growing in the agar also can be estimated The compounds of this invention that is cloned in by described compound from people's tumour system.For example, to be cell containing 2mM L-glutaminate, 200U/ ml penicillin, 200 mcg/ml Streptomycin sulphates, be supplemented with growth in the substratum (the Eagle substratum of Dubelcco modification) of 10% (volume) heat inactivation foetal calf serum the people's who is provided by ATCC colorectal carcinoma.Cell with exponential growth carries out tryptic digestion, washs and is diluted to final concn with PBS and be 5000 cells/ml in perfect medium.In Zhi Bei the 2.5 ml cells suspension, add 50 microlitres and wait to test inhibitor or control solvent in front, add 0.4 milliliter of agar (Noble Difco) solution that remains on 45 ℃ then, mix then.The substratum that obtains like this is injected in the Petri culture dish at once, remain on 4 ℃ 5 minutes, then at 5%CO ₂Cultivate at 37 ℃ under the atmosphere.At 5%CO ₂Cultivate 12 days counting cells clone (＞50 cell) numbers afterwards at 37 ℃ under the atmosphere.With ultimate density in the agar 10,1,0.1,0.01 and 0.001 mcg/ml revision test every kind of inhibitor.These results generate inhibition percentage ratio with the clone with respect to untreated control and represent.Determine to suppress dosage IC by the semilog mean value diagram of the resulting value of each concentration ₅₀

The method that the concentration of product of the present invention between 0.1nM-100nM suppresses 50% protein Ras turns usefulness into.

Embodiment 104

Can also be according to the test of usually adopting and method (people such as Corbett, cancer research, 42,1707-1715 (1982); People such as Corbett, cancer treatment report, 66,1187-1200 (1982); People such as Corbett, 40,2660-2680 (1977)), adopt anti-tumor activity at the intravital evidence The compounds of this invention of mouse.

Studied to mouse and used The compounds of this invention influence in people's cancer growth of the subcutaneous vaccinations of these mouse.

Test the 0th day, the usefulness trochar is subcutaneous injection tumor fragment (30-60 milligram) in both sides.The both sides implantation tumour guarantees that the tumor weight of every mouse is more even, can reduce by every group size of animal like this.Then these mouse are divided into handle with do not handle not on the same group in.

Product is made suspension in the aqueous solution, its concentration is the 0.01-1200 mg/ml, is the 0.1-10000 mg/kg corresponding to dosage.

Adopt oral administration every day or give their optional vehicle, maximum volume is 0.2 milliliter, takes the time limit to depend on tumour doubling time.

According to carry out two kinds of measurements in millimeter, measure tumour 2-3 time by vernier callipers weekly, according to following formula its measuring result changed into tumor weight then:

Tumor weight (milligram)=length (millimeter) * width ²(millimeter ²)/2

Biologically active prod is the product that can limit tumor growth after using.

Can enumerate the unrestricted the present invention of following example with explanation the present invention:

Use is HCT116 (people such as Brattain, cancer research, 41 by the people's that ATCC provides colon tumor, 1751-1756 (1981)) the mouse of subcutaneous vaccination, by the product of oral embodiment 3, its dosage is that 400 mg/kg are inferior, can reach the static stabilization of tumour.

Embodiment 105

Embodiment A

Prepare the capsule that dosage is 50 milligrams of biologically active prods according to routine techniques with following composition:

50 milligrams of-active products

18 milligrams of-Mierocrystalline celluloses

55 milligrams of-lactose

1 milligram of-colloid silica

10 milligrams of-sodium starch glycolatees

10 milligrams of-talcum powder

1 milligram of-Magnesium Stearate

Embodiment B

Prepare the tablet that dosage is 50 milligrams of biologically active prods according to routine techniques with following composition:

50 milligrams of-biologically active prods

104 milligrams of-lactose

40 milligrams of-Mierocrystalline celluloses

10 milligrams of-polyvinylpyrrolidones

22 milligrams of-sodium starch glycolatees

10 milligrams of-talcum powder

2 milligrams of-Magnesium Stearates

2 milligrams of-colloid silicas

-Walocel MT 20.000PV, glycerine, titanium dioxide

Mixture (72-3.5-24.5) in right amount to 1 tablet be 245 milligrams

Embodiment C

Preparation contains the solution with following composition of 50 milligrams of biologically active prods: 1.6 milliliters-water of 80 milligrams of 24 milligrams-propane diols of 0.4 milliliter-NaOH of-95% ethanol of 0.06 milliliter-Sodium Benzoate of 80 milligrams-phenmethylol of 50 milligrams-benzoic acid of-biologically active prod is in right amount to 4 milliliters

Claims

1, the compound of general formula I:

In the formula:

-Ar representative:

-by the one or more identical or different atoms or the phenyl of group replacement; described atom or group are selected from halogen atom and contain the alkyl of 1-4 carbon atom; as methyl; the alkenyl that contains 2-4 carbon atom; hydroxyl; sulfydryl; alkylthio; alkyl sulphonyl or alkyl sulphinyl; amino; alkylamino; or dialkyl amido; formyl radical; alkyl-carbonyl; carboxyl; alkoxy carbonyl; formamyl; alkyl-carbamoyl or dialkyl amido formyl radical; cyano group or trifluoromethyl; the alkoxyl group that contains 1-4 carbon atom; as methoxyl group; its moieties is randomly by perhalogenation; as trifluoromethoxy, or

-with the phenyl of the heterocycle condensation that contains the one or more heteroatomic 4-7 of having chain links, wherein heteroatoms is selected from oxygen, nitrogen and sulphur,

Many cyclic groups of-aromatics or non-aromatics,

-contain the aromatics or the non-aromatic heterocycle of the one or more heteroatomic 5-12 of having chain links; wherein heteroatoms is selected from oxygen; nitrogen and sulphur atom; and heterocyclic radical is connected with condensed ring by C-C; described group can be replaced by one or more identical or different atoms or group; these atoms or group are selected from halogen atom and alkyl; the alkenyl that contains 2-4 carbon atom; hydroxyl; contain 1-4 carbon atom alkoxy; sulfydryl; alkylthio; alkyl sulphonyl or alkyl sulphinyl; amino; alkylamino or dialkyl amido; formyl radical; alkyl-carbonyl; carboxyl; alkoxy carbonyl; formamyl; alkyl-carbamoyl or dialkyl amido formyl radical; cyano group or trifluoromethyl

Wherein the alkyl in all these groups all contains 1-4 carbon atom,

-R represents the group of following general formula:

-(CH ₂) _m-X ₁-(CH ₂) _n-Z

In the formula:

-X ₁Represent singly-bound or oxygen or sulphur atom,

The integer that-m representative equals 0 or 1,

The integer that-n representative equals 0,1 or 2,

-one or more methylene radical can be replaced by carboxyl, alkoxy carbonyl, formamyl, alkyl-carbamoyl, dialkyl amido formyl radical, amino, alkylamino, dialkyl amido, and the alkyl in all these groups contains 1-4 carbon atom,

-Z representative:

-carboxyl,

-COOR ₆Base, wherein R ₆Representative contains the straight or branched alkyl of 1-3 carbon atom, as methyl, or

-Shi CON (R ₇) (R ₈) group, in the formula

-R ₈Representative:

-hydrogen atom,

-hydroxyl,

-aryl sulfonyl, as phenyl sulfonyl, it is randomly replaced by one or more identical or different atoms or group, and wherein atom or group are selected from halogen atom and alkyl, alkoxyl group, and the alkyl of all these groups contains 1-4 carbon atom,

-contain the alkyl of 1-4 carbon atom,

-aryl, as phenyl, it is randomly replaced by one or more identical or different groups, and described group is selected from alkyl, alkoxyl group, and the alkyl of all these groups contains 1-4 carbon atom,

-contain one or more heterocyclic radicals that are selected from the heteroatoms of nitrogen, oxygen or sulphur atom and have 5-7 chain link,

-aryl carbonyl, as benzoyl, it is randomly replaced by one or more identical or different groups, and this group is selected from alkyl, alkoxyl group, and the alkyl of all these groups contains 1-4 carbon atom,

-contain the straight or branched alkyl of 1-6 carbon atom; as methyl; it is randomly replaced by following group: amino; alkylamino; dialkyl amido; hydroxyl; the alkoxyl group that contains 1-4 carbon atom; sulfydryl; alkylthio; alkoxy carbonyl; carboxyl; cyano group; optional replace have a 5-12 chain link contain or do not contain one or more heteroatomic lists-or polycyclic aromatic group; described heteroatoms is selected from oxygen; nitrogen and sulphur atom; maybe can also be randomly by one or more halogen atoms or by one or more hydroxyls; the phenyl that amino or trifluoromethyl replace; or by one or more alkyl or alkenyl; alkoxyl group; alkylthio; alkylamino; alkyl-carbonyl or C2-C4 alkoxy carbonyl; formamyl; wherein moieties is alkyl-carbamoyl or the dialkyl group formyl radical of C1-C8; formyl radical; or the phenyl of 1-naphthyl or 2-naphthyl substituted

-Z representative:

Its gegenion is a negatively charged ion, as the triflate ion,

Alkyl in all groups that propose in the Z definition all contains 1-4 carbon atom,

-R ₁And R ₂Identical or different, they represent hydrogen atom, halogen atom or alkyl, alkoxyl group, and as methoxyl group, each group is randomly replaced by dialkyl amido, its each moieties contains 1-4 carbon atom or constitutes the saturated heterocyclic of 5 or 6 chain links with nitrogen-atoms, alkylthio, alkoxy carbonyl or

Be positioned at adjacent R ₁And R ₂Constitute and contain 1 or 2 heteroatomic saturated or unsaturated heterocycle, wherein heteroatoms is selected from nitrogen and oxygen, and randomly replaced or replaced by alkyl or alkoxyl group by halogen atom,

All are at R ₁And R ₂Alkyl in the group that proposes in the definition all contains 1-4 carbon atom,

All are at R ₃And R ₄Alkyl in the group that proposes in the definition all contains 1-4 carbon atom,

-R ₅Represent hydrogen atom or alkyl, alkylthio, and at R ₅In the definition, alkyl contains 1-4 carbon atom,

-X represention oxygen atom or sulphur atom or-NH-,-CO-, methylene radical, alkene-1,1-two bases as ethene two bases, or contain the cycloalkanes-1 of 3-6 carbon atom, 1-two bases,

With

-Y represention oxygen atom or sulphur atom,

General formula (I) product is the salt of racemize or their optically active isomer form and general formula (I) product.

2, compound according to claim 1, it is characterized in that Ar represents 2,3-dihydro-1,4-benzo two oxa-s English-6-base, 2,3-Dihydrobenzofuranes-5-base, 2,3-dihydrobenzopyrans-6-base, 1-or 2-naphthyl, 5-(2, the 3-indanyl) or 1,2,3,4-naphthane-6-base or by methyl, trifluoromethyl or methoxyl group phenyl 4 replacements.

3, require according to aforesaid right in each described compound, it is characterized in that the R representation carboxy, or-the COOMe group or-CON (R ₇) (R ₈) group, wherein R ₇Represent hydrogen atom, and R ₈Representative is by the methyl of 2-, 3-or 4-pyridyl or N-pyridine oxide replacement.

4, according to each described compound in the aforesaid right requirement, it is characterized in that Ar represents 2,3-dihydro-1,4-benzo two oxa-s English-6-base or 2,3-Dihydrobenzofuranes-5-base, or by methyl, trifluoromethyl or the methoxyl group phenyl 4 replacements.

5, according to each described compound in the aforesaid right requirement, it is characterized in that the R representation carboxy, or-the COOMe group, or-CON (R ₇) (R ₈) group, wherein R ₇Represent hydrogen atom, and R ₈The methyl that representative is replaced by the 3-pyridyl.

6, according to each described compound in the aforesaid right requirement, it is characterized in that symbol R ₁Or R ₂In one represent hydrogen atom, and another one representation methoxy.

7, according to each described compound in the aforesaid right requirement, it is characterized in that R ₃Or R ₄Each all represents hydrogen atom, or R ₃Or R ₄In one represent hydrogen atom, and R ₃Or R ₄In the another one representation methoxy.

8, according to each described compound in the aforesaid right requirement, it is characterized in that R ₅Represent hydrogen atom or methyl.

9, according to each described compound in the aforesaid right requirement, it is characterized in that X represents methylene radical or ethene two bases.

10, according to each described compound in the aforesaid right requirement, it is characterized in that the Y represention oxygen atom.

11, compound is characterized in that it is selected from following compound alone:

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) propenyl]-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-(2-p-methoxy-phenyl) propenyl-9-(4-tolyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--2-[(2-p-methoxy-phenyl) ethanoyl]-9-(3-aminomethyl phenyl) 2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid benzyl ester,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(4-pyridylmethyl)-methane amide,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid methyl esters,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N ', N '-dimethyl methyl hydrazides,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-phenyl formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N ', N '-pentamethylene formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-3a-phenyl sulfonyl amino carbonyl-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(N-oxo-3-pyridylmethyl)-methane amide,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-(4-p-methoxy-phenyl) formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-methyl-N '-phenyl formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N '-(2-aminomethyl phenyl) formyl hydrazine,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-aminomethyl phenyl) acryl]-9-(2-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-and 9-(4-bromophenyl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-methyl-formiate,

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(3-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-hydroxamic acid,

(3aRS, 4SR, 9SR, 9aRS)-4, and 9-ethano--9-(4-p-methoxy-phenyl)-2-[2-(2-p-methoxy-phenyl) acryl]-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-N-(3-thienyl methyl) methane amide,

Above-claimed cpd is racemize or their optically active isomer form and their salt.

12, compound is characterized in that it is

Be racemize or their optically active isomer form and their salt.

13, compound is characterized in that it is

Be racemize or their optically active isomer form and their salt.

14, compound is characterized in that it is

Be racemize or their optically active isomer form and their salt.

15, compound is characterized in that it is

Be racemize or their optically active isomer form and their salt.

16, compound is characterized in that it is

Be racemize or their optically active isomer form and their salt.

17, compound is characterized in that it is

Be racemize or their optically active isomer form and their salt.

18, compound is characterized in that it is (3aRS, 4SR, 9SR; 9aRS)-4 ,-9 ethano-s-5-methoxyl group-2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a; 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid

Be racemize or their optically active isomer form and their salt.

19, compound is characterized in that it is

Be racemize or their optically active isomer form and their salt.

20, according to each described compound in the aforesaid right requirement, it is characterized in that they are dextrorotatory form.

21, compound is characterized in that it is

(3aRS, 4SR, 9SR, 9aRS)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-9-(4-aminomethyl phenyl)-2,3,3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a-formic acid dextrorotation enantiomorph.

22, compound is characterized in that it is

(3aRS, 4SR, 9SR, 9aRS)-9-(2; 3-dihydro-1,4-benzo two oxa-s English-6-yl)-4,9-ethano--2-[2-(2-p-methoxy-phenyl) acryl]-2,3; 3a, 4,9,9a-six hydrogen-1H-benzo [f] isoindole-3a--N-(3-pyridylmethyl)-methane amide dextrorotation enantiomorph.

23, the preparation method of each general formula (I) compound among the claim 1-22, wherein Y represents oxygen or sulphur atom, and X representative-CO-group, methylene radical, alkene-1,1-two bases as ethene two bases, or contain the cycloalkanes-1 of 3-6 carbon atom, 1-two bases, it is characterized in that methyl esters or derivative, as carboxylic acid halides or acid anhydrides by the acid of following general formula (II), this acid

R in the formula ₁, R ₂Such as claim 1 definition, and X such as front define, Y represents oxygen or sulphur atom,

Obtain with the reaction of following general formula (III) product,

Ar, R, R in the formula ₃, R ₄And R ₅Such as claim 1 definition, and G ₁Represent hydrogen atom.

24, the preparation method of each general formula (I) compound among the claim 1-22, wherein Y represents oxygen or sulphur atom, and the X represention oxygen atom, it is characterized in that allowing the haloformate or the halo thiocarboxylic of following general formula (IV), product reaction with the general formula (III) that limits as claim 23

Y represents oxygen or sulphur atom, R in the formula ₁, R ₂Such as claim 1 definition, Hal represents halogen atom.

25, the preparation method of each general formula (I) compound among the claim 1-22, wherein Y represents oxygen or sulphur atom, and X represents the NH group, it is characterized in that allowing the isocyanic ester or the lsothiocyanates of following logical formula V, with general formula (III) the product reaction that limits as claim 23

Y represents oxygen or sulphur atom in the formula, and R ₁And R ₂Such as claim 1 definition.

26, the preparation method of each general formula (I) compound among the claim 1-22, R represents the group of following general formula in its formula

-(CH ₂) _m-X ₁-(CH ₂) _n-Z

X wherein ₁, m and n such as front define,

Z representative-CON (R ₇) (R ₈) group,

R ₈Representative

-hydrogen atom

-hydroxyl

-aryl sulfonyl, as phenyl sulfonyl, it is randomly replaced by one or more identical or different atoms or group, and described atom or group are selected from halogen atom and alkyl, alkoxyl group, and alkyl all contains 1-4 carbon atom in these groups,

-containing the heterocycle of the one or more heteroatomic 5-7 of having chain links, described heteroatoms is selected from nitrogen, oxygen or sulphur atom, and described heterocycle can connect by heteroatoms,

-randomly by the amino of one or two identical or different group replacement, described group is selected from following group:

-contain the alkyl of 1-4 carbon atom,

-aryl, as phenyl, it is randomly replaced by one or two identical or different group, and described group is selected from alkyl, alkoxyl group, and alkyl all contains 1-4 carbon atom in these groups,

-aryl carbonyl, as benzoyl, it is randomly replaced by one or more identical or different groups, and described group is selected from alkyl, alkoxyl group, and alkyl all contains 1-4 carbon atom in these groups,

-contain 1-6 carbon atom straight chain or branched-chain alkyl; as methyl; it is randomly replaced by following groups: amino; alkylamino; dialkyl amido; hydroxyl; the alkoxyl group that contains 1-4 carbon atom; sulfydryl; alkylthio; alkoxy carbonyl; carboxyl; cyano group; optional monocycle that contains or do not contain the one or more heteroatomic 5-12 of having chain links or the polycyclic aromatic group that replaces; its heteroatoms is selected from oxygen; nitrogen and sulphur atom; maybe can also be randomly by one or more halogen atoms or by one or more hydroxyls; the phenyl that amino or trifluoromethyl replace; or by one or more alkyl or alkenyl; alkoxyl group; alkylthio; alkylamino; C2-C4 alkyl-carbonyl or alkoxy carbonyl; formamyl; its moieties is alkyl-carbamoyl or the dialkyl amido formyl radical of C1-C8; the phenyl of formyl radical or 1-naphthyl or 2-naphthyl substituted

It is characterized in that allowing the product of following general formula:

HN(R ₇)(R ₈)

R in the formula ₇, R ₈As above-mentioned definition

With the wherein general formula of Z representation carboxy (I) product reaction.

27, the preparation method of each general formula (I) compound among the claim 1-22, wherein R represents general formula-NHCO-T group, the alkyl (1-6 carbon atom) that T represents hydrogen atom or randomly replaced by amino, carboxyl, alkoxy carbonyl, hydroxyl, alkoxyl group, sulfydryl or alkylthio in the formula, it is characterized in that allowing the acid of general formula T-CO-OH, T reacts with following general formula (VI) product as defined above in the formula:

Ar, R in the formula ₁, R ₂, R ₃, R ₄, R ₅, X and Y such as claim 1 definition.

28, the preparation method of each general formula (I) compound among the claim 1-22, R represents the group of following general formula in its formula:

It is characterized in that allowing the derivative of excessive pyridine and strong acid or this acid and following general formula product react:

29, by the method for general formula (IX) compound general formula (III) compound:

R in the formula ₃, R ₄, R ₅, Ar and R as defined in claim 1, and G1 represents benzyl:

R in the formula ₃, R ₄, R ₅, R ₆And G ₁Define as the front, it is characterized in that by generating following general formula (XV) intermediate product:

R in the formula ₃, R ₄, R ₅, R ₆, Ar and G ₁Define as the front, by Friedel-Crafts type intramolecular condensation, this intermediate product transforms general formula (III) product that obtains as qualification in the claim 23.

30, compound is characterized in that it is represented by following general formula (XV):

R in the formula ₃, R ₄, R ₅, and Ar such as claim 1 defined in, G ₁Represent benzyl, and R ₆Representative contains the alkyl of 1-3 carbon atom, and its compound is racemize and their optically active isomer form.

31, the preparation method of the general formula of claim 29 (XV) compound is characterized in that general formula (IX) compound:

R in the formula ₃, R ₄, R ₅, and Ar such as claim 1 defined in, G ₁Represent benzyl, and R ₆Representative contains the alkyl of 1-3 carbon atom, be reflected at 7 or change into the vinyl iodide derivative by Barton, perhaps change into the triflate of enol, carry out the coupled reaction with palladium then, carry out so-called Suzuki reaction or carry out so-called Stille reaction with the aryl stannane with aryl boric acid.

32, prepare the method for the described general formula of claim 23 (III) compound, wherein Ar preferably represents:

-be powered subbase group at the phenyl ring that contraposition, position-contraposition or position-contraposition-position replaces,

-be rich in the heterocyclic radical of electronics,

-be powered subbase to roll into a ball the heterocyclic radical that suitably replaces

It is characterized in that in organic solvent, in the presence of excessive strong acid or excessive Lewis acid, by the intermolecular cyclization annulation of Friedel-Crafts type, intramolecularly annulation then, aromatic hydrocarbon or heterocyclic hydrocarbon Ar-H and general formula (IX) compound react, wherein R ₃, R ₄, R ₅, and Ar such as claim 1 defined in, G ₁Represent benzyl, and R ₆Representative contains the alkyl of 1-3 carbon atom.

33, the preparation method of following general formula (III) compound:

R wherein ₃, R ₄, R ₅, and Ar such as claim 1 defined in, G ₁Represent benzyl, R representation carboxy or general formula COOR ₆Group, and R ₆Representative contains the alkyl of 1-3 carbon atom, it is characterized in that the intramolecularly annulation by the Friedel-Crafts type, allows trifluoromethanesulfonic acid and following general formula (VIII) product react:

In the formula:

Ar, R ₃, R ₄And R ₅Such as claim 1 definition, G ₁Represent benzyl, R ₆Representative contains the alkyl of 1-3 carbon atom,

Then or pass through hydrogenolysis, then randomly in organic solvent, replace hydrogen atom by the effect of tert-butoxycarbonyl acid anhydrides with tert-butoxycarbonyl, or replace hydrogen atom with benzyloxycarbonyl by the effect of benzyloxycarbonyl chlorine, perhaps by the effect of carbonochloridic acid alkyl ester, then the carbamate that generates in the middle of the acidolysis is replaced G with hydrogen atom ₁Group is randomly followed the resulting product of saponification.

34, the preparation method of general formula (VIII) compound, Ar, R in its formula ₃, R ₄, R ₅, R ₆And G ₁Such as claim 33 qualification, it is characterized in that by following general formula (IX) compound:

R in the formula ₃, R ₄, R ₅, R ₆And G ₁Defined in claim 32,

Perhaps in organic solvent, between the reaction mixture refluxed temperature, in the presence of anhydrous cerium chloride (III), by the effect of general formula Ar-Mg-X organic-magnesium derivative, wherein Ar such as front define 0 ℃ of temperature, and X represents halogen atom,

Perhaps in organic solvent, temperature-78 ℃ to-20 ℃ under, by the effect of general formula Ar-Li organolithium derivative.

35, as the preparation method of claim 31 or 34 general formula that is limited (IX) compounds, R in its formula ₃, R ₄, R ₅With Ar such as claim 1 qualification, G ₁Represent benzyl, R ₆Representative contains the alkyl of 1-3 carbon atom, it is characterized in that allowing having N-trialkylsilkl methyl-N-alkoxy methyl-amine that the amine official can blocking group and the cyclonene of following general formula reacts:

R in the formula ₃, R ₄, R ₅Such as claim 1 qualification, and R ₆Representative contains the alkyl of 1-3 carbon atom.

36, pharmaceutical composition is characterized in that it contains match with one or more inert or bioactive pharmaceutically acceptable thinner or additive at least a and require the described product of 1-22 discipline according to aforesaid right.

37, be used to prepare the purposes of the pharmaceutical composition that suppresses farnesyl transferase according to each compound among the claim 1-22.

38, the purposes that is used to prepare the pharmaceutical composition for the treatment of following disease according to each compound among the claim 1-22: with different tissues and/or organ cell's the relevant disease of pernicious or benign cell propagation, wherein tissue and organ comprise muscle, bone or reticular tissue, skin, brain, lung, sexual organ, lymphsystem or kidney system, mammary cell or blood cell, liver, digestion organs, colon, pancreas and Tiroidina or suprarenal gland, comprise following disease: psoriasis, restenosis, noumenal tumour, the Kaposi sarcoma, cancer, cholangiocarcinoma, villioma, neuroblastoma, the Wilms knurl, king's evil suddenly, melanoma, teratocarcinoma, neurospongioma, multiple myeloma, chronic lymphocyte leukemia, acute or chronic granulocyte lymphoma and as the pancreas cancer, colorectal carcinoma, lung cancer, ovarian cancer, mammary cancer, the cancer of the brain, prostate cancer, liver cancer, cancer of the stomach, the cancer of bladder cancer or carcinoma of testis and so on.

39, be used to prepare the purposes for the treatment of the pharmaceutical composition of the disease relevant by the inhibition farnesyl transferase according to each general formula (I) compound among the claim 1-22 with cell proliferation.

40, be used to prepare the purposes of the pharmaceutical composition for the treatment of cancer according to each general formula (I) compound among the claim 1-22.

41, compound according to claim 21 is used to prepare the purposes of the pharmaceutical composition for the treatment of cancer.

42, be used to prepare the purposes of the pharmaceutical composition for the treatment of colorectal carcinoma according to each general formula (I) compound among the claim 1-22.

43, be used to prepare the purposes of the pharmaceutical composition for the treatment of the pancreas cancer according to each general formula (I) compound among the claim 1-22.

44, compound according to claim 21 is used to prepare the purposes of the pharmaceutical composition for the treatment of colorectal carcinoma.

45, compound according to claim 21 is used to prepare the purposes of the pharmaceutical composition for the treatment of the pancreas cancer.

46, match with the compatibilized compound of one or more pharmacologically actives and/or with radiation treatment according to each described product among the claim 1-22, so that reach synergistic therapeutic effect.