HK1055118B

HK1055118B - Novel intermediates and process for the manufacture of camptothecin derivatives (cpt-11) and related compounds

Info

Publication number: HK1055118B
Application number: HK03107416.8A
Authority: HK
Inventors: K‧E‧汉尼格; J‧C‧赛
Original assignee: 法玛西雅厄普约翰美国公司
Priority date: 1995-04-07
Filing date: 2003-10-15
Publication date: 2009-05-15

Description

Intermediates and processes for the preparation of camptothecin derivatives (CPT-11) and related compounds

Technical Field

Novel intermediates and methods for the synthesis of camptothecin derivatives, such as irinotecan, and other compounds involved in the synthesis of CPT-11 are disclosed and claimed. Related methods and novel methods of making compounds, such as mappicine, are also disclosed.

Disclosure of the literature

Compounds identified in this document as 14CPT are mentioned in Tetrahedron, 1973, 1949-1954, M.Shamma, D.A.Smithers, V.St.George.

The asymmetric synthesis of this compound, with the code number 14CPT, has been reported in the following literature (grouped by author name):

group 1

H.Terasawa，M.Sugimori，A.Ejima，H.Tagawa，Chem.Pharm.Bull.，1989，37，3382-3385。

A.Ejima，H.Terasawa，M.Sugimori，H.Tagawa，J.C.S.PerkinI，1990，27-31。

H.tagawa, h.teragawa, a.ejima, US4,778,891 (10 months and 18 days 1988).

H.tagawa, h.teragawa, a.ejima, EP 220601 (10 months and 14 days in 1986).

Group 2

M.C.Wani，A.W.Nicholas，M.E.Wall，J.Med.Chem.1987，2317-2319。

M.c. wani, a.w. nicholas, m.e. wall, US 5,053,512 (10 months and 1 day 1990).

M.e.wall, m.c.wani, a.w.nicholas, g.manikumar, US4,894,456 (16/1/1990).

M.e.wall, m.c.wani, a.w.nicholas, and g.manikumar, WO90/03169 (28/9/1988).

Background

Camptothecin derivatives such as irinotecan are potent anticancer agents. The present invention describes efficient synthetic methods for the synthesis of various camptothecin derivatives, including irinotecan or CPT-11, as well as other useful compounds such as mappicine.

Disclosure of Invention

The invention includes compounds, methods, reactions, and reagents shown in the various diagrams, structures, and figures herein. The compounds, methods, reactions and reagents are useful for the preparation of camptothecin derivatives such as CPT-11 and other related compounds such as mappicine.

Specific compounds selected from the compounds described and labeled in the specification are those labeled as 2G, 3G, 4G, 5G, 6G, 7GG, 7GA, 8GG, 8GA, 8GB, 9GG, 9GA, 10G (S), 10G (R), 11G (S), 11G (R), 12GA-1(S), 12GA-1(R), 12GA-2(S), 12GA-2(R), 12GB-1(S), 12GB-1(R), 12GB-2(S), 12GB-2(R), 12G (S), 12G (R), 13G (S) or 13G (R) in the figures,

wherein R1 is any optionally substituted C_1-8Alkyl, including lower alkyl, C_3-10Cycloalkyl, lower alkyl-C_3-10Cycloalkyl, alkenyl, aryl, substituted aryl, alkaryl, or substituted alkaryl, including benzyl and substituted benzyl;

wherein R is₂Is H;

a) any optionally substituted alkyl, including C_1-8Alkyl, alkaryl, including C_1-6Alkyl-aryl, C_1-8alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl;

b)-C(O)-R₃-, or

c)-C(R₇)₂-O-R₃Wherein each R is₇Are independent of each other;

wherein R is₃Is H, optionally substituted C_1-8Alkyl, including lower alkyl, cycloalkyl, alkenyl, aryl, substituted aryl, and alkaryl or substituted alkaryl, including benzyl and substituted benzyl;

wherein R is₄Is H, optionally substituted C_1-8Alkyl, including lower alkyl, C_3-10Cycloalkyl, lower alkyl-C_3-10Cycloalkyl, alkenyl, aryl, substituted aryl, alkaryl, or substituted alkaryl include benzyl and substituted benzyl;

wherein R is₅Is H, optionally substituted C_1-8Alkyl, including lower alkyl, aryl, substituted aryl, or two R₅The groups may be joined together to form cyclopentane or cyclohexane, or substituted derivatives thereof;

wherein R is₆Optionally substituted C_1-8Alkyl, lower alkyl, including ethyl, aryl, substituted aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl, lower alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl;

wherein R is₇Independently H, optionally substituted C_1-8Alkyl includes lower alkyl, aryl, substituted aryl, alkaryl, substituted alkaryl, or both R₇The groups may be joined together to form cyclopentane or cyclohexane or substituted derivatives thereof;

wherein R is₈Optionally substituted C_1-6Alkyl includes lower alkyl (including t-butyl), C_3-10Cycloalkyl, lower alkyl-C_3-10Cycloalkyl, alkenyl, aryl, substituted aryl, alkaryl, or substituted alkaryl include benzyl and substituted benzyl.

Other specific compounds of the invention selected from the group consisting of those described and labeled in the specification are 2CPT, 3CPT, 4CPT, 5CPT, 6CPT, 7CPTA, 8CPTG, 8CPTA, 8CPTAB, 9CPTG, 9CPTA, 9CPTB, 10CPT (S), 10CPT (R), 11CPT (S), 11CPT (R), 12CPTA-1(S), 12CPTA-1(R), 12CPTA-2(S), 12CPTA-2(R), 12CPTB-1(S), 12CPTB-1(R), 12CPTB-2(S), 12CPTB-2(R), 12CPT (S), 12T (R),13CPT, 13CPT (S) or 13CPT (R), wherein R₁-R₉As defined above.

Other specific compounds of the invention selected from the compounds described and labeled in the specification are 6MG, 7MG, 8MG, 9MG, 10MG, 11MG, 12MG, 13MG, excluding R₆Is C_1-2Alkyl 13MG, wherein the variable groups are as defined above for the variable groups.

Other specific compounds of the invention selected from the group consisting of compounds described and labeled in the specification are 5MM, 6MM, 7MM, 8MM, 9MM, 10MM, 11MM or 12 MM.

In addition to the compounds described above, various methods of labeling in the steps are described and claimed. Those steps include those depicted and labeled in the specification chart G, which include: step 2, or step 3, or step 4, or step 5a, or step 5b, or step 6, or step 7GG, or step 7GA, or step 8GG, or step 8GA, or step 8GB, or step 9GG, or step 9GA, or step 9GB, or step 10GG, or step 10GA, or step 10 split, or step 11, or step 12, or step 13, or step 14, or any combination of two or more thereof.

Those steps described and labeled in the specification chart CPT are also described and claimed, which include: step 7G, or step 7A, or step 8G, or step 8A, or step 8B, or step 9G, or step 9A, or step 9B, or step 10G, or step 10A, or step 11, or step 12, or step 13, or step 14, or any combination of two or more thereof.

Those steps described and labeled in the specification figures M-G are also described and claimed, including: step 5, or step 6, or step 7, or step 8, or step 9, or step 10, or step 11, or step 12, or step 13, or any combination of two or more thereof.

Those steps described and labeled in the specification diagrams M-M are also described and claimed, including: step 5, or step 6, or step 7, or step 8, or step 9, or step 10, or step 11, or step 12, or step 13, or any combination of two or more thereof.

Other descriptions of the invention and descriptions of preferred embodiments.

The compounds of the invention are represented in two ways: the structural formulae of the various chemical entities are indicated by illustrative names and by reference. Suitable stereochemistry is also described in appropriate places, by words or in the form of structures. In some cases, when a molecule has two chiral centers, the stereochemistry at only one chiral center is specified, and the other chiral center is unresolved or racemic unless the stereochemistry at the other chiral center is specified. All temperatures are expressed in degrees Celsius, either in degrees or C. Minutes can be written as m or min. Hours can be written as H or H. Unless otherwise indicated, various abbreviations are standard or obvious to the chemist. When a compound is added to or contacted with another compound in any way, it may be said to "mix" them with those compounds. Generally, the purpose of mixing the compounds is to facilitate the reaction of one or more of the compounds being mixed. The following terms may also be used. The term "substituted" or "optionally substituted" is usually first present in "C_1-8Alkyl "before, but is understood to be all modifications of all variations of the r group. The term means that the group is substituted with halogen, lower alkyl, mono-or di (lower alkyl) -substituted lower alkyl, (lower alkyl) thio, halogen-substituted lower alkyl, amino-substituted lower alkyl, mono-or di (lower alkyl) -substituted amino, lower alkenyl, lower alkynyl, halogen, lower alkoxy, aryloxy, aryl (lower alkyl), hydroxy, cyano, amino, mono-and di (lower alkyl) amino or nitro, etc. One of ordinary skill in the art would know when and how to make the various substitutions described above.

Alkyl radicalThe term in parentheses (C)_n-C_mAlkyl) is inclusiveE.g. (C)₁-C₈) The compounds include compounds of 1-8 carbon atoms and isomeric forms thereof. Each carbon moiety is an aliphatic hydrocarbon group and includes branched or straight chain forms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl, and the isomeric forms thereof.

N-alkyl radicalThe term in parentheses (C)_n-C_mN-alkyl) are inclusive, e.g. (C)₁-C₈) The compounds include compounds in the straight chain unbranched form of 1 to 8 carbon atoms.

Lower alkylThe term "lower alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. Typical examples of such groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, the various isomeric forms of pentyl, the various isomeric forms of hexyl and the like.

(lower alkyl) thioThe term "(lower alkyl) thio" refers to a lower alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom. Typical (lower alkyl) sulfides include methylthio, ethylthio, propylthio, isopropylthio and the like.

Alkoxy radicalAlkoxy with-OR₁Is represented by (wherein R is₁Is (C)₁-C₈) Alkyl) refers to an alkyl group attached to the remainder of the molecule through an oxygen, including branched or straight chain forms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, n-hexoxy, isohexoxy, n-heptoxy, isoheptoxy, and n-octoxy, and the like.

Lower alkoxyThe term "lower alkoxy" means an alkyl group, as defined above, appended to the parent molecule through an oxygen atom, typical examples of which include methoxy, ethoxy, butoxy, and the like.

Alkenyl radicalAlkenyl means an aliphatically unsaturated hydrocarbon radical having at least one double bond, including branched and straight-chain forms, e.g. vinyl, - (CH ═ CH)₂) 1-methyl-1-ethenyl, 1-propenyl, (-CH)₂-CH＝CH₂) 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-butenyl, 1-pentenyl, allyl, 3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 3-methyl-1-pentenyl, 3-methylallyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 1-methyl-4-hexenyl, 3-methyl-1-hexenyl, 3-methyl-2-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-methyl-4-heptenyl, 3-methyl-1-heptenyl, 3-methyl-2-heptenyl, 1-octenyl, 2-octenyl or 3-octenyl, etc.

Alkynyl radicalAlkynyl refers to monovalent branched or straight chain hydrocarbon groups containing at least one carbon-carbon triple bond such as ethynyl, propynyl, and the like.

Cycloalkyl radicalsThe term in parentheses (C)_n-C_mCycloalkyl) is inclusive, e.g. (C)₃-C₁₀) The compounds include saturated cyclic hydrocarbon groups having 3 to 10 carbon atoms in their ring chain. The term may also include alkyl-substituted cycloalkyl groups such as cyclopropyl, 2-methylcyclopropyl, 2-dimethylcyclopropyl, 2, 3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, cyclopentyl, 2-dimethylcyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and the like. Each of the above groups may be substituted as desired.

Heteroalkyl radicals"heteroalkyl" refers to an alkyl group as described above wherein at least one, two, or three non-adjacent carbon atoms are replaced with heteroatoms such as nitrogen, sulfur, and oxygen.

Aryl radicals(C_6-12) Aryl means a basic structure of 6 to 12 carbon atoms, one or two fused or non-fused aromatic rings, which may be unsubstituted or optionally substituted1-3 hydroxy, C₁-C₃Alkoxy radical, C₁-C₃Alkyl, trifluoromethyl, fluoro, chloro or bromo groups. Examples of "aryl" are: phenyl, m-methylphenyl, p-trifluoromethylphenyl, alpha-naphthyl, beta-naphthyl, (o-, m-, p-) tolyl, (o-, m-, p-) ethylphenyl, 2-ethyltolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-, m-, p-) propylphenyl, 2-propyl- (o-, m-, p-) tolyl, 4-isopropyl-2, 6-xylyl, 3-propyl-4-ethylphenyl, (2, 3, 4-, 2, 3, 6-or 2, 4, 5-) trimethylphenyl, (o-, m-, p-) fluorophenyl, M-or p-trifluoromethyl) phenyl, 4-fluoro-2, 5-xylyl, (2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-) difluorophenyl, (o-, m-, p-) chlorophenyl, 2-chloro-p-tolyl, (3-, 4-, 5-or 6-) chloro-o-tolyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chlorophenyl, 4-chloro-3-fluorophenyl, (3-or 4-) chloro-2-fluorophenyl, (o-, m-or p-) trifluorophenyl, (o-, m-, p-) ethoxyphenyl, (4-or 5-) chloro-2-methoxyphenyl and 2, 4-dichloro (5-or 6-) methylphenyl, and the like. Each of the above groups may be substituted as desired.

Alkylaryl radicalAlkylaryl refers to alkyl chains having from 1 to 8 carbon atoms and substituted with aryl groups of 6 to 12 carbon atoms as described above and isomeric forms thereof.

Heterocyclic ringsExamples of heterocycles include: (2-, 3-or 4-) pyridyl, imidazolyl, indolyl, Nin-formylindolyl, Nin-C₂-C₅alkyl-C (O) -indolyl, [1, 2, 4 [ ]]-triazolyl, (2-, 4-, 5-) pyrimidinyl, (2-, 3-) thienyl, piperidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, quinolinyl, isoquinolinoyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furanyl, purinyl (puryl), phenazinePhenyl, carbazolyl, thienyl, benzothienyl, thienyl, indolyl, isoquinolyl and the like. Each of the above groups may be substituted as desired.

Heteroaryl radicalHeteroaryl refers to a monocyclic or bicyclic ring structure having 5 to 12 ring atoms, wherein at least one ring is aromatic and only 1, 2 or 3 non-adjacent carbon atoms on the aromatic ring are replaced by heteroatoms such as nitrogen, sulfur and oxygen. Examples thereof may include pyridine, thiophene, furan, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinoxalinyl, 1- (2, 3-naphthyridine) yl, 2-imidazolyl, 4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 3-pyrazolyl, etc, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl, 2-benzofuranyl, 3-benzofuranyl, 2-furanyl (furyl), 3-furyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1, 2, 4-oxadiazol-3-yl, 1, 2, 4-oxadiazol-5-yl, 1, 2, 4-thiadiazol-3-yl, 1, 2, 4-thiadiazol-5-yl, 1, 2, 4-triazol-3-yl, 1, 2, 4-triazol-5-yl, 1, 2, 3, 4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1, 2, 3-triazol-1-yl, 1, 2, 4-triazol-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 1-purinyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl, and the like. Each of the above groups may be substituted as desired.

ChiralityThe compounds of the present invention may contain one or more chiral centers and may exist in optically active forms, including cis-/trans-and/or R-and S-isomeric forms and mixtures thereof, as will be apparent to those skilled in the art. The scope of the invention includesAll of these forms, enantiomers or diastereomers of these compounds, including optically active forms, may be in pure form or as mixtures of enantiomers or diastereomers, including cis-/trans-isomeric forms. The therapeutic properties of the compounds may be more or less dependent on the stereochemistry of the particular compound. Resolution may be carried out using resolving agents such as optically active dibenzoyltartaric acid, camphorsulfonic acid, di-o-toluoyltartaric acid, tartaric acid and diacetyltartaric acid.

Optical purityOptical purity is sometimes expressed in "% ee".

The methods and compounds of the invention

The following methods relate to the compounds and structural formulae shown in the figures.

Detailed Description

Methods, reactions, and compounds in Chart G

General description of the reaction

All variables in the following methods are as defined in the summary and definitions of the invention. More preferred substituents are as follows.

Step 1 (citrazinic acid → 1G)

The starting material dichloroisonicotinic acid is a compound and can be readily prepared from commercially available citrazinic acid.

Methods of preparation and acceptable ranges of conditions are known and included in the following references: m.e.baizer, m.dub, s.gist, n.g.steinberg, j.am.pharm.assoc, 1956, 45, 478-; the use of tetraalkylammonium and tertiary amine salts in such reactions is described in the following documents: chemical abstracts CA 97, 216024 and east de patent DD 154,538 to e.schroetter, h.schick, h.niedrich, p.oehme and l.piescheche. See also w.h.levelt and j.p.wibaut, rec.trav.chem, 1929, 44, 466.

In a preferred method, citrazinic acid is heated with phosphorus oxychloride and either tetraalkylammonium chloride or tertiary amine hydrochloride, most preferably tetramethylammonium chloride, to a temperature of 120-. This mixture was then reacted with water to give the product 1 CPT.

Step 2(1G → 2G)

2, 6-dichloroisonicotinic acid is dissolved or suspended in an ether solution, such as diethyl ether, tetrahydrofuran or 1, 2-dimethoxyethane, and reacted with an excess of ethylmagnesium halide or ethyllithium in the diethyl ether or tetrahydrofuran solution at a temperature of about-30 ℃ to about +10 ℃. The excess ethylmagnesium halide or ethyllithium is decomposed by reaction with a dilute acid, such as hydrochloric acid, or by reaction first with an ester, such as methyl formate, or a ketone, such as acetone, and then with a dilute acid, such as hydrochloric acid.

Alternatively, 2, 6-dichloroisonicotinic acid may be converted to the acid chloride and then to the Weinreb amide by reaction with thionyl chloride or phosphorus pentachloride. See, s.nahm and s.m.weinreb, tet.lett, 1981, 3815-. The Weinreb amide is then dissolved in and reacted with an ether solution such as diethyl ether, tetrahydrofuran or 1, 2-dimethoxyethane, and then reacted with an excess of ethylmagnesium halide or ethyllithium in diethyl ether or tetrahydrofuran solution at a temperature of from about-30 ℃ to about +10 ℃. The product is isolated after reaction of the intermediate complex with a dilute acid such as hydrochloric acid. Preferred R₆Is lower alkyl including C_1-4Alkyl and ethyl, aryl and substituted aryl, alkaryl and substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl, preferably C_1-4Alkyl, ethyl, benzyl.

Step 3(2G → 3G)

The alkyl ketones 2G, referred to page 1 in diagram G, are reacted with an alcohol or diol in the presence of trimethylchlorosilane. The alcohol may be a diol such as ethylene glycol, 1, 3-propanediol, or 2, 2-dimethyl-1, 3-propanediol, or an alcohol such as methanol. The preferred alcohol is ethylene glycol. When ethylene glycol is used to produce ethylene glycol ketals, other alcohols can be used to produce other ketals. Can be added intoA solvent such as dichloromethane. The reaction is carried out at a temperature of about 0 ℃ to about 60 ℃, preferably at about 40 ℃. Preferred R₆Is lower alkyl including C_1-4Alkyl and ethyl, aryl and substituted aryl, alkaryl and substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl, preferably C_1-4Alkyl, ethyl, benzyl.

Step 4(3G → 4G)

Compound 3G on page 1 of chart G is reacted with a sodium or potassium alkoxide in an excess of an alcohol or solvent such as tetrahydrofuran or 1, 2-dimethoxyethane. The reaction is carried out at a temperature of about 20 ℃ to about 80 ℃. Alkoxide or preferred R in diagram G₁The radicals may be any of the previously defined lower alkyl, cycloalkyl, C_3-10Cycloalkyl, alkenyl, aryl and aralkyl groups include benzyl and substituted benzyl. More preferred R₁Are methyl and benzyl.

Step 5a (optional) and step 5b (4G → 5G)

Step 5a review of the ortho-metallation reactions is described in V.Snieckus, chem.Rev., 1990, Vol.90, pp. 879-933, which is incorporated herein by reference,

Compound 4G, page 1 of scheme G, is dissolved in a solvent and reacted with an alkyl lithium base or an aryl lithium base to form a pyridyl anion. The resulting anion is then reacted with an electrophile and the product isolated after further reaction with dilute acid. Suitable reaction solvents are ethers such as diethyl ether, tetrahydrofuran or 1, 2-dimethoxyethane or hydrocarbons such as toluene, hexane, heptane, cyclohexane or isooctane, or mixtures of any of these or similar solvents.

The alkyllithium may be methyllithium, n-butyllithium, sec-butyllithium or tert-butyllithium. The reaction temperature may be from about-40 ℃ to about +50 ℃. The electrophile may be an alkyl halide such as methyl iodide, dimethyl sulfate, chloromethyl methyl ether, benzyl chloromethyl ether or benzyl bromide; aldehydes or ketones such as formaldehyde, acetone, benzaldehyde or other similar compounds; or amides such as formamide including dimethylformamide, N-formylpiperidine, or N-formylmorpholine or N-methyl-N-formanilide or similar formamide. The acid used for product isolation may be hydrochloric acid, acetic acid, sulfuric acid, or other moderate to strong acids.

The preferred solvent is heptane, the preferred base is N-butyllithium, and the preferred amide is N-methylpiperidine. The reaction is preferably carried out at a temperature of from about-5 ℃ to about +5 ℃. Purification can be carried out by crystallization, chromatography, or by formation of a bisulfite addition compound which can be decomposed by reaction with an acid or base.

Note that: step 5a may be omitted and step 5b may be used instead of step 5a to prepare 5G.

Step 5b

The aldehyde of step 5a is reduced to the alcohol with a hydride reducing agent such as sodium borohydride. The reaction may be carried out using an alcohol such as methanol or 2-propanol as a solvent, or may be carried out under biphasic conditions, with water and an organic phase consisting of heptane, dichloromethane or methyl tert-butyl ether, or a mixture of these and similar solvents. A phase transfer catalyst such as tetrabutylammonium chloride may be used, but this is not required.

Step 5a and step 5b (4G → 5G)

R shown in graph G₂Preferably H, or a) optionally substituted C_1-8Alkyl, alkaryl, C_1-8The alkylaryl group including C_1-8alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl; b) -C (O) -R₃Or C) -C (R)₇)₂-O-R₃Wherein each R is₇Are independent of each other; and wherein R₃And R₇As defined in the summary of the invention. Only when R is₂Is b) -C (O) -R₃Or C) -C (R)₇)₂-O-R₃(wherein each R is₇Independent of each other), the series of reactions proceeds directly according to the method of step 6, page 2, of the following graph G. When R is₂Is H or optionally substituted C_1-8Alkyl, alkaryl, C_1-8The alkylaryl group including C_1-8alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl; the reaction proceeds according to the methods of schemes M-G and M-M, and mappicine or mappicine analogs can be prepared.

Step 6(5G → 6G) (Chart G-continuation)

The alcohol is reacted with a base and an alkylating agent in a suitable solvent to provide the product. The base may be a hydride, such as sodium hydride or potassium hydride, or an alkoxide base, such as potassium tert-butoxide.

Suitable solvents are ether solvents such as tetrahydrofuran or 1, 2-dimethoxyethane or alcohols such as tert-butanol. The temperature may be from about 15 ℃ to about 80 ℃. The preferred base is potassium tert-butoxide, the preferred solvent is THF or MTBE, and the preferred temperature is from about 20 ℃ to about 40 ℃.

Alternatively, the reaction may be carried out under phase transfer conditions using water and an organic solvent such as dichloromethane or a hydrocarbon such as hexane, heptane or toluene or the like. The base may be a hydroxide such as sodium or potassium hydroxide, or sodium or potassium carbonate. A phase transfer catalyst such as tetrabutylammonium chloride may be added and the preferred temperature is about 10 ℃ to about 30 ℃.

Optional step

Step 7 there are 2 different reactions, namely the 7GG and 7GA series; step 8 has 3 different reactions, namely 8GG, 8GA and 8GB series; step 9 has 3 different reactions, namely 9GG, 9GA and 9GB series; step 10 there are 2 different reactions, namely the 10GG and 10GA series, followed by the step 10 resolution method. See diagram G, pages 2, 3, 4.

Step 7GG and step 10GA (6G → 7GG) and (9GA → 10G)

Carbonylation of aryl halides catalyzed with palladium-0 is well known, see j.k.stille and p.k.wong, j.org.chem., 1975, 40, 532-propan 534, but aryl halides are generally less active in these reactions. In contrast to simple aryl chlorides, 2-chloropyridines are known to readily undergo an insertion reaction with palladium-0. Various coupling reactions with palladium-0 catalyzed 2-chloropyridines are known, but the carbonylation of 2-chloropyridines with palladium-0 is not reported in the literature.

The compound of formula 6G is reacted with carbon monoxide and an alcohol in the presence of a soluble palladium (II) salt (e.g. palladium acetate), a phosphine ligand (e.g. 1, 3-bis diphenylphosphinopropane) and a base such as sodium or potassium acetate, sodium or potassium carbonate, triethylamine or tri-n-butylamine in a polar aprotic solvent such as dimethylformamide or acetonitrile.

Preferred R of the alcohols shown on pages 2 and 3 of the graph G₃The groups may be any of the above definitions, H, lower alkyl, cycloalkyl, alkenyl, aryl and aralkyl including benzyl and substituted benzyl. More preferred R₃Are methyl and benzyl.

Preferred R of the alcohols shown on pages 2 and 3 of the graph G₄The groups may be any of the above definitions, H, lower alkyl, cycloalkyl, alkenyl, aryl and aralkyl including benzyl and substituted benzyl. More preferred R₄Is n-propyl. The temperature is from about 50 ℃ to about 80 ℃.

Preferred R₇Independently is H, lower alkyl, aryl, alkaryl, substituted aryl, substituted alkaryl, or two R₇The groups may be joined together to form cyclopentane or cyclohexane or substituted derivatives thereof.

Some references describing the insertion reaction mentioned in step 7 above are: a) isobe and s.kawaguchi, Heterocycles, 1981, 16, 1603-; b) sato, A.Hayakawa and R Takeuchi, J.het.chem.1990, 503-506; c) m.ishikura, m.kamada and m.terashima, Synthesis, 1984, 936-938; and d) K.Isobe, K.Nanjo, Y.Nakamura and S.Kawaguchi, Bul.chem.Soc.Japan, 1986, 59, 2141-.

Step 7GA and step 8GG (6G → 7GA) also relate to (7GG → 8GG)

The ketal is hydrolyzed by reaction with water in the presence of a strong acid, such as trifluoroacetic acid. The concentration of trifluoroacetic acid can be between about 50% and 90% and the reaction temperature between about 15 ℃ and about 30 ℃. Alternatively, the ketal can be removed by an exchange reaction with a ketone, e.g., acetone or 2-butanone, catalyzed by a strong acid, e.g., p-toluenesulfonic acid, or an acidic ion exchange resin, e.g., amberlyst A-15 macroporous resin. The preferred temperature for the exchange reaction is about the reflux temperature of the ketone.

Step 8GA (7GA → 8GA)

Compound 8GA was dissolved in a solvent and reacted with a vinyl lithium halide or vinyl magnesium. Suitable solvents are ethers such as diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane or MTBE, which can be used individually or in the form of mixtures, or mixtures of these solvents with hydrocarbons such as toluene, heptane or cyclohexane. The reaction temperature is from about-78 ℃ to about 25 ℃. The product is isolated after further reaction with a dilute acid such as hydrochloric acid, sulfuric acid or acetic acid. The preferred reagent is vinylmagnesium bromide in tetrahydrofuran solvent at a temperature of about-40 ℃ to about 25 ℃, followed by termination with hydrochloric acid (quenching). Preferred R₅Independently is H, lower alkyl, aryl, substituted aryl, or two R₅The groups may be joined together to form cyclopentane or cyclohexane or substituted derivatives thereof.

Step 8GB and step 9GG (7GA → 8GB and 8GG → 9GG)

Wittig reaction is carried out by reacting a ketone with a solution of a ylium salt prepared from a methyltriphenylphosphonium salt, preferably bromide, and a strong base such as n-butyllithium, potassium tert-butoxide or potassium bistrimethylsilylamide in a solvent such as diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane or DMF. The preferred base is potassium bistrimethylsilylamide and the preferred solvent is DMF. The reaction temperature is from about-5 ℃ to about 25 ℃. The reaction time is from about 5 minutes to about 2 hours.

Step 9GA (8GA → 9GA)

The intermediate was prepared by dissolving 9GA in a solvent and reacting with ozone. Depending on the composition of the solvent, the intermediate may be an ozonide or a hydroperoxide. The intermediate is reacted with a suitable reducing agent to produce the product, either directly or via a stepwise preparation of the intermediate aldehyde. The reaction temperature may be from about-78 ℃ to about 25 ℃. Suitable reaction solvents are chlorinated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, 1, 2-dichloroethane, or other polychlorinated ethanes or ethylene derivatives, which may be used alone, in mixtures, or in mixtures with alcohols such as methanol. The preferred solvent is a mixture of methylene chloride and methanol, the initial reaction with ozone is at a temperature of about-78 ℃ to about-40 ℃, and the temperature of the intermediate reduction is at a temperature of about 0 ℃ to about 25 ℃. The preferred reducing agent is sodium borohydride.

Step 9GB and step 10GG (8GB → 9GA and 9GG → 10GG)

Alkenes are converted to diols under standard conditions (see v.vanrhenen, r.c. kelley and d.y. cha, tet.lett., 1976, 1973) by osmium alkylation (osmylation) with catalytic osmium tetroxide and a stoichiometric amount of a co-oxidant such as trimethylamine N-oxide or N-methylmorpholine-N-oxide in aqueous THF or preferably in tert-butanol solvent. The reaction temperature may be about 15 ℃ to about 50 ℃, preferably about 40 ℃ and the reaction time may be about 12 to 48 hours.

For the racemate, another osmium reaction was the use of an asymmetric osmium reaction, as described by Sharpless, to convert 9CPT directly to 10G (R) or (S). Specific references to Sharpless asymmetric osmium reactions are: G.A.Crispino, A.Makita, Z. -M.Wang, K.B.Sharpless, Tet.Lett., 1994, 543-; g.a. criping, k. — s.jeong, h.c. kolb, z. — m.wang, d.xu, k.b. sharp, j.org.chem., 1993, 3785-. Sharp, w.k.amberg, US 5,227,543; k.b. sharp, m.beller, b.blackburn, y.kawanami, h.l.kwong, y.ogino, t.shibata, y.ukita, l.wang, PCT WO 92/20677; hartung, k.b. sharpless, PCT WO 93/07142.

Step 10 splitting (10G → 10G (R or S))

Racemic diol 10G was treated with an acetylating agent such as vinyl acetate, isopropenyl acetate, acetic anhydride or ethyl acetate in an organic solvent in the presence of a lipase. Possible solvents include ethers or hexanes and the lipase may be cepacia such as Pseudomonas cepacia (Pseudomonas cepacia). With this method, a single acetic acid isomer and a single diol isomer can be obtained. The reaction is generally carried out at a substrate concentration of 15 to 40 mg/ml at a temperature of 25 to 45 ℃. The reaction product can be isolated by crystallization using common organic solvents, or by conventional silica gel chromatography. The optical purity (% ee) of each enantiomer can be determined by NMR using a chiral transfer reagent or by chiral HPLC analysis.

Steps 11 to 14

The following reactions can be carried out using single enantiomers, racemic mixtures or mixtures of enantiomers in other ratios. The reaction products depend on the starting materials. For convenience and exemplary purposes, chart G, pages 4 and 5 and the following steps relate to a single enantiomer. The single enantiomer is usually indicated by the capital letter "R" or "S". One example is "10 g (r)". Racemic mixtures are usually followed by the capital letter "G". One example is "10G". See chart G. Of course, the reactions of the present invention are not limited to only those shown in the diagrams, e.g., diagram G does not show the reaction steps 11-13 of the racemic mixture, but they are implicit in the diagrams and description herein. Likewise, the "R" series is not shown as complete as the "S" series. The figures are merely provided to aid in the description and do not indicate the entire invention.

Step 11(10G → 11G)

The diols are oxidized to hydroxyaldehydes by oxidation in the presence of Swern-type conditions such as DMSO, oxalyl chloride, and triethylamine in an aprotic solvent such as dichloromethane at temperatures from about-78 ℃ to about 25 ℃. Alternatively, the oxidation reaction can be carried out using sodium hypochlorite solution in a two-phase system consisting of water and an aprotic solvent such as dichloromethane, catalysed by TEMPO or substituted TEMPO such as 4-acetoxy-TEMPO. The reaction temperature is preferably from about-5 ℃ to about +25 ℃ and the reaction time is from about 30 minutes to about 2 hours.

Swern conditions were as described in a.j.manuso and d.swern Synthesis, 1981, 165-185. Two-phase systems consisting of water and an aprotic solvent are described in p.l. anelli, c.biffi, f.montanari and s.quick, j.org.chem, 1987, 52, 2559-. The above documents are incorporated herein by reference.

Step 12(11G → 12G)

Several different methods have been used to convert the hydroxyaldehyde 11G to 12G. In the first method, the hydroxyaldehyde 11G is oxidized to the hydroxyacid 12GA-1 with sodium chlorite. The hydroxy acid can then be converted to 12G by reaction with trimethylsilyl iodide in a single reaction pot. The advantage of this process is that 11G can be converted to 12G in one step. See graph G, page 5, step 12, pathway a, part 2, pathway a. The disadvantage of this one-stage conversion process is the low yield and the uncertain reaction time.

The higher yield process is to first remove the benzyl group by hydrogenation or by reaction with boron tribromide, and then remove the methoxy group by reaction with trimethylsilyl iodide. See graph G, page 5, step 12, pathway A, part 2 pathways b-1 and b-2. Obviously, the order of deprotection can be reversed.

A second method for converting 11G to 12G is to change the order of oxidation and deprotection steps. See diagram G, page 5, step 12, route B. Removal of the benzyl group by hydrogenation gives the lactol. Then the lactitol is oxidized with sodium hypochlorite, catalyzed with TEMPO. The methoxy group is then cleaved with trimethylsilyl iodide. See graph G, page 5, step 12, route B, sections 1, 2, and 3. The advantage of this process is that the use of sodium chlorite oxidation and the nuisance associated therewith is avoided.

Pathways A and B, preferably pathway B, will be described in more detail below. See table G, pages 4 and 5.

Step 12Route A(11G → 12G route A)

Pathway a includes two parts, part 1 and part 2, part 2 following part 1. Part 2 also includes two pathways, pathway a and pathway b. Route a, part 2 of route a, has only one step. While route b of route a, part 2, has two steps. Referring to graph G, page 4, note that only one stereoisomer is shown, as are the other stereoisomers and racemates.

Part 1

Preferably, the hydroxy acid is formed by oxidation with sodium chlorite under conditions described in the literature. See b.s.bal, w.e.childers, h.w.pinnick, Tetrahedron, 1981, 2091-. Other additives such as hydrogen peroxide or sulfamic acid are also used to prevent chlorine dioxide formation. Thereby producing 12 GA-1.

Section 2

Pathway a

Benzyl and methyl groups are removed in one step with trimethylsilyl iodide, which is preformed or generated in situ with trimethylsilyl chloride and sodium iodide in dichloromethane or acetonitrile. See t.morita, y.okamoto, h.sakurai, j.c.s.chem.comm, 1978, 874-. Pyridine may be added, but is not required. The reaction temperature is about 15 ℃ to about 50 ℃ and the reaction time is 12-48 hours. Thereby producing 12G.

Pathway b

Part 1 of pathway b-1The two steps of removing the benzyl and methyl groups are performed in two ways. The benzyl groups are removed by hydrogenation with a catalyst, preferably a palladium on carbon catalyst or other porous material or palladium black is used. The preferred solvent is an alcohol, most preferably methanol. The reaction is carried out under a hydrogen atmosphere at a pressure of about 1 to about 4 atmospheres at a temperature of about 15 ℃ to about 40 ℃ for about 2-4 hoursThen (c) is performed.

Alternatively, the benzyl group can be removed by reaction with boron tribromide in a solvent such as dichloromethane at a temperature of from about-5 ℃ to about 20 ℃ for from about 30 minutes to about 2 hours. Thereby producing 12GA-2, or 12 GB-2.

Part 2 of pathway b-2The methoxy group can be cleaved with trimethylsilyl iodide as described above to give 12G. (this step is the same as step 3 of route B described below.)

Step 12Route B(11G → 12G, route B)

Route B has 3 steps.

Part 1The benzyl group or other suitable group is removed by hydrogenation with a catalyst, preferably a palladium on carbon catalyst or other porous material or palladium black is used. The preferred solvent is an alcohol, most preferably methanol. The reaction is carried out under a hydrogen atmosphere at a pressure of about 1 to about 4 atmospheres at a temperature of about 15 ℃ to about 40 ℃ for about 12 to about 96 hours. Thereby producing 12 GB-1.

Section 2The lactitol is then oxidized under the same conditions as for the formation of the hydroxyaldehyde, using Swern conditions, for example, in the presence of DMSO, oxalyl chloride and triethylamine in an aprotic solvent such as dichloromethane at a temperature of from about-78 deg.C to about 25 deg.C.

Alternatively, the oxidation reaction can be carried out using sodium hypochlorite solution in a two-phase system consisting of water and an aprotic solvent such as dichloromethane, catalyzed by TEMPO or substituted TEMP0 such as 4-acetoxy-TEMPO. The reaction temperature is from about-5 ℃ to about +25 ℃ and the reaction time is from about 30 minutes to about 2 hours. Thereby producing 12GB-2 or 12 GB-1.

Section 3Methyl groups are removed with trimethylsilyl iodide, which is preformed or generated in situ with trimethylsilyl chloride and sodium iodide in dioxane or acetonitrile. The conditions are as described above. This gave 12G.

Step 13(12G → 13G)

12G is reacted with an acrylate ester, such as methyl, ethyl or tert-butyl acrylate, in the presence of a base, such as potassium hydride, sodium hydride, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate or a tertiary amine, such as diisopropylethylamine, in a polar aprotic solvent, such as dimethyl sulfoxide, DMF or acetonitrile, at a temperature of about 20 ℃ to 100 ℃. See diagram G, page 5. Preferred conditions are reaction with t-butyl acrylate and cesium carbonate in DMSO and about 50 ℃. The product can be isolated as a solvate of toluene. The ketoester, compound 13G, is obtained.

Step 14(13G → 14G)

Ketoesters, which exist predominantly or exclusively in the enol form, are converted to 14G by reaction with a strong acid, such as trifluoroacetic acid, at a temperature of from about 80 c to about 110 c for a time period of from about 10 minutes to about 6 hours. A solvent such as toluene may be added. Preferred conditions are the use of a mixture of toluene and trifluoroacetic acid at a reaction temperature of 100 ℃ and 110 ℃ for a reaction time of 1-4 hours.

All references cited in describing the figures are incorporated herein by reference. One skilled in the art should be able to prepare the compounds of the invention and carry out the reactions of the invention using the methods described above and substituting the appropriate starting materials. One embodiment of the present invention will be described by the reaction, method and structure of the chart CPT-11. This embodiment is merely illustrative and not restrictive of the invention in any way.

Chart CPT-11 methods, reactions, and compounds

Step 1 (citrazinic acid → 1CPT)

Citrazinic acid (152.0 g, 0.98 mol) and tetramethylammonium chloride (107.71 g, 1.02 mol) were suspended in phosphorus oxychloride (450 g, 273 ml, 2.9 mol) and heated in a hot bath at 130 ℃. When the internal temperature reached about 75 ℃, the solid dissolved with a slight exotherm to give a clear brown solution. The reaction was heated at 130 ℃ for 18 hours and then to 145 ℃ for 2 hours. The mixture was cooled to room temperature, poured into 2 kg of ice and stirred for 2 hours. The solid was dissolved in 1.5 l ethyl acetate. The organic solution was dried over sodium sulfate, filtered, and evaporated to give 146.9 g (78%) of a light brown solid.

mp 195-197℃(dec).(lit.¹mp.205-207℃).

¹H NMR(300.13MHz，DMSO-d₆)δ7.80(s，2H).

¹³C NMR(75.47MHz，DMSO-d₆)δ122.87，144.60，150.13，163.66.

Nominal mass spectrum: calculated value m/z 192, found value m/z 192.

Reference documents:

1.M.E.Baizer，M.Dub，S.Gister，N.G.Steinberg，J.Am.Pharm.Assoc，1956，45，478-480。

2. the use of tetramethylammonium salts in such reactions is described in DDR patent 154538.

Step 2(1CPT → 2CPT)

1CPT (6.6 g, 0.034 mol) was mixed with 82 ml THF and the mixture was cooled to-40 ℃. Ethyl magnesium chloride (52 ml, 104 mmol, 2M in THF) was added over about 15 minutes, maintaining the internal temperature of the reaction at least below-30 ℃. The cooling bath was removed and the resulting dark brown mixture was warmed to 0 ℃ and stirred at 0 ℃ for 1 hour. The reaction mixture was cooled to-25 ℃ again and methyl formate (3.2 ml, 52 mmol) was added. After 15 minutes of reaction at-25 ℃, 20 ml of 6M hydrochloric acid was added and the mixture was warmed to room temperature. The phases are separated, the lower aqueous phase is extracted with 3X 10 ml of THF, and the combined THF phases are washed once with 2 parts of a mixture of 15 ml of 1N sodium hydroxide and 15 ml of saturated sodium chloride and then with 15 ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate and then concentrated to an oil. Toluene (50 ml) was added and the mixture was concentrated to an oil and the process was repeated to give 6.01 g (84%) of a brown oil which was crystallized in vacuo.

mp 60-63℃.

¹H NMR(300.13MHz，CDCl₃)δ1.17(t，J＝7.1Hz，3H)，2.88(q，J＝6.6Hz，2H)，7.61(s，2H).

¹³C NMR(75.47MHz，CDCl₃)δ7.50，32.61，120.88，147.66，151.83，197.15.

Nominal mass spectrum: calculated value m/z 204, found value m/z 204.

Step 3(2CPT → 3CPT)

2CPT (90.2 g, 0.44 mol), ethylene glycol (650 ml) and trimethylsilyl chloride (140 ml, 1.1 mol) were mixed and stirred at room temperature. White crystals gradually formed in the mixture. The reaction was complete after about 12 hours. The reaction was neutralized by addition of 1 l of 1N sodium hydroxide solution and extracted with 3X 250 ml of 1: 1 ethyl acetate/heptane. The organic extracts were combined, dried over sodium sulfate and evaporated. The crystalline residue was dried under high vacuum to give 109.71 g (100%) of product.

¹H NMR(300.13MHz，CDCl₃)δ0.80(t，J＝7.4Hz，3H)，1.78(q，J＝7.4Hz，2H)，3.72(t，J＝7.0Hz，2H)，3.99(t，J＝7.0Hz，2H)，7.27(s，2H).

¹³C NMR(75.47MHz，CDCl₃)δ7.45，32.77，65.10，108.94，120.30，150.57，158.06.

Nominal mass spectrum: calculated value m/z 248, found value m/z 248.

Step 4(3CPT → 4CPT)

3CPT (57.5 g, 0.23 mol) was dissolved in methanol (170 mL). Sodium methoxide (80 ml, 0.35 mol, 25 wt% solution in methanol) was added and the reaction was refluxed in an oil bath at 85 ℃. After 20 hours, the reaction mixture was cooled to room temperature and then quenched with 250 ml of water. The two-phase mixture was diluted with 200 ml of dichloromethane and the phases were separated. The aqueous phase is extracted with two or more 100 ml portions of dichloromethane. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to an amber oil which was crystallized by seeding to give 50.43 g (89%) of a light yellow solid.

¹H NMR(300.13MHz，CDCl₃)δ0.88(t，J＝7.4Hz，3H)，1.85(q，J＝7.5Hz，2H)，3.78(t，J＝6.9Hz，2H)，3.93(s，3H)，4.02(t，J＝7.1Hz，2H)，6.73(s，1H)，6.98(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ7.62，32.53，54.04，64.79，106.25，109.23，113.83，148.33，157.27，163.94.

Nominal mass spectrum: calculated value m/z 243, found value m/z 244(m + 1).

Step 5(4CPT → 5CPT)

4CPT (73.05 g, 0.299 mol) was dissolved in 1400 ml heptane and cooled to-10 ℃. N-butyllithium (294 ml, 0.588 mol, 2.5M in hexane) was added over 10 minutes, maintaining the internal temperature < 5 ℃. After the butyl lithium addition was complete, the organic mixture was stirred at 0 ℃ for 30 minutes. The mixture was then cooled to-30 ℃ and N-formylpiperidine (66.0 ml, 0.588 mol) was added. The mixture was warmed to 0 ℃ and stirred at 0 ℃ for 1 hour. The dark red mixture was quenched by the addition of 600 ml of 1N hydrochloric acid. The phases were separated and the aqueous phase was extracted with 2X 250 ml of MTBE. The organic phases were combined to give a solution of 5 aCPT. A portion of this solution was chromatographed on silica gel with 4: 1 hexane/ethyl acetate to give a pure sample of 5aCPT, which was used to determine its properties.

To the 5aCPT solution were added water (250 mL), tetrabutylammonium chloride (8.3 g, 0.029 mol), and sodium borohydride (11.3 g, 0.29 mol), and the mixture was stirred vigorously at room temperature. The reduction reaction was complete after about 18 hours. 20 ml of acetone were added and the mixture was stirred at room temperature for 30 minutes. The aqueous phase was removed and the organic phase was washed 1 time with 500 ml of water. The organic phase was evaporated to give an oil. The oil was chromatographed on 800 g of silica gel with 4: 1 hexane/ethyl acetate. The product was obtained in 57.30 g with 71% chemical yield. 15.0 g (20%) of substantially pure 4CPT were also recovered.

¹H NMR(300.13MHz，CDC1₃)δ0.96(t，J＝9.0Hz，3H)，2.03(q，J＝9.0Hz，2H)，3.75(m，2H)，4.00(m，2H)，4.00(s，3H)，7.13(s，1H)，10.44(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ7.32，33.28，54.81，64.78，109.66，114.67，117.20，150.83，157.52，161.75，190.80.

Nominal mass spectrum: calculated m/z 271, found m/z 271.

¹H NMR(300.13MHz，CDCl₃)δ0.84(t，J＝7.5Hz，3H)，1.87(q，J＝7.0Hz，2H)，3.74(m，2H)，3.92(s，3H)，3.97(m，2H)，4.72(s，1H)，7.05(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ7.46，33.01，54.50，56.16，64.98，110.25，114.53，119.15，147.39，154.50，163.00.

Nominal mass spectrum: calculated m/z 273, found m/z 273.

Step 6(5CPT → 6CPT, Chart CPT page 2)

In a 12 l flask equipped with a mechanical stirrer, addition funnel and thermocouple with adapter, 5CPT (503.98 g, 1.841 mol) was dissolved in 1330 ml THF. The internal temperature was maintained below 30 ℃ and 1188 ml of a 20% potassium tert-butoxide solution in THF was added to the flask. The mixture was stirred for 30 minutes, then benzyl bromide (230.0 ml, 2.117 mol) was added via an addition funnel, maintaining the internal temperature below 30 ℃. After the benzyl bromide addition was complete, the mixture was stirred at 20-30 ℃ for 1 hour. After 1 hour, 38 ml of 40% aqueous dimethylamine solution were added and the mixture was stirred at 20-30 ℃ for 30 minutes. 276 ml of 1N hydrochloric acid and 2 l of ethyl acetate are added and the phases are separated. The organic phase was washed with 3X 1 l of water and then evaporated to give an oil. Yield of the product: 663.5 g, 99.3% chemical yield.

¹H NMR(300.13MHz，CDCl₃)δ0.75(t，J＝7.4Hz，3H)，1.82(q，J＝7.4Hz，2H)，3.61(m，2H)，3.82(s，3H)，3.85(m，2H)，4.48(s，2H)，4.57(s，2H)，6.97(s，1H)，7.23(m，5H).

¹³C NMR(75.47MHz，CDCl₃)δ7.50，32.96，54.47，62.83，64.73，73.20，110.12，114.8，116.42，127.54，127.76，128.24，138.43，147.91，155.62，163.74.

Nominal mass spectrum: calculated m/z 363, found m/z 364(m + 1).

There are two different possible reactions for step 7, i.e. series G and a, and three different possible reactions for step 8. See page 2 of chart CPT.

Step 7G (6CPT → 7CPTG)

The flask was charged with 6CPT (66.45 g, 183 mmol), palladium acetate (2.05 g, 9.13 mmol), DPPP (4.14 g, 10.0 mmol), potassium carbonate (37.86 g, 274 mmol), n-propanol (665 ml) and DMF (332 ml). The flask was purged with nitrogen and then with carbon monoxide. The mixture was added to 90 ℃ for about 16 hours under a carbon monoxide atmosphere. The reaction was then cooled and vented. The solids were removed by filtration through celite (celite), and the celite was washed with 350 ml THF. The combined filtrate and washings were concentrated to a volume of about 400 ml. Water (700 ml) and MTBE (700 ml) were added. The aqueous phase was separated and extracted with 350 ml MTBE. The combined MTBE solution was extracted with 4X 350 ml of water, dried over sodium sulfate and evaporated to yield 68.03 g (89% chemical yield) of a light orange oil after purification by column chromatography (silica gel: 230-400 mesh, eluent: 80: 20 heptane/ethyl acetate).

¹H NMR(300.13MHz，CDCl₃)δ0.87(t，J＝7.4Hz，3H)，0.98(t，J＝7.4Hz，3H)，1.77(m，2H)，1.93(q，J＝7.4Hz，2H)，3.71(m，2H)，3.94(m，2H)，3.99(s，3H)，4.26(t，J＝6.7Hz，2H)，4.59(s，2H)，4.74(s，2H)，7.29(m，5H)，7.82(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ7.5，10.42，22.02，33.08，54.07，63.08，64.72，66.98，73.29，110.26，117.05，122.14，127.51，127.99，128.22，138.45，144.70，153.62，163.88，165.29.

Nominal mass spectrum: calculated m/z 415, found m/z 416(m + 1).

Step 7A (6CPT → 7CPTA)

6CPT (50.0 g, 0.137 mol) was dissolved in 50% aqueous trifluoroacetic acid (250 ml) and stirred at room temperature for 48 hours. Water (200 ml) and ethyl acetate (200 ml) were added. The phases were separated and the aqueous phase was extracted with ethyl acetate (3 × 200 ml). The combined organic phases were washed with saturated sodium bicarbonate solution (500 ml) until residual TFA was removed, then with water (200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to give 42.6 g (97%) of product.

¹H NMR(300.13MHz，CDCl₃)δ1.04(t，7.2Hz，3H)，2.71(q，7.2Hz，2H)，3.95(s，3H)，4.47(s，2H)，4.56(s，2H)，6.77(s，1H)，7.29(m，5H).

¹³C NMR(75.47MHz，CDCl₃)δ7.39，36.15，54.56，63.16，73.43，113.35，115.73，127.86，127.97，128.51，137.50，147.81，153.07，161.38，204.47.

Nominal mass spectrum: calculated m/z 319, found m/z 320(m + 1).

There are three different possible reactions for step 8, series G, A and B, see pages 2 and 3 of the chart CPT.

Step 8G (7CPTG → 8CPTG)

7CPTG (68.02 g, 163.7 mmol) was dissolved in 384 ml of 50% aqueous TFA at room temperature. The mixture was stirred at room temperature for 21 hours. 880 ml of water were added and the mixture was extracted with 2X 500 ml of ethyl acetate. The organic phases are combined and washed with 2 × 500 ml of water and then neutralized with saturated sodium bicarbonate solution. The organic phase was then dried over sodium sulfate and evaporated, yielding 59.86 g (98.4%) of the product as a pale yellow oil.

¹H NMR(300.13MHz，CDCl₃)δ0.96(m，6H)，1.72(m，2H)，2.68(q，J＝7.2Hz，2H)，3.96(s，3H)，4.23(t，J＝6.7Hz，2H)，4.42(s，2H)，4.58(s，2H)，7.24(m，5H)，7.48(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ7.55，10.41，21.99，36.21，54.13，63.83，67.22，73.56，115.50，121.49，127.86，127.97，128.19，128.37，137.32，144.87，150.96，161.31，164.54.

Nominal mass spectrum: calculated value m/z 371, found m/z 372(m + 1).

Step 8A (7CPTA → 8CPTA)

7CPTA (1.00 g, 3.13 mmol) was dissolved in 5 mL THF and cooled to-40 ℃ under a nitrogen atmosphere. Vinylmagnesium bromide (2.9 ml, 4.4 mmol, 1.5M in THF) was added. The reaction was held at-40 ℃ for 1 hour and then allowed to warm to room temperature. After 1 hour at room temperature, the reaction mixture was quenched with saturated aqueous ammonium chloride (10 ml) and diluted with ethyl acetate (10 ml). The aqueous layer was extracted with 10 ml of ethyl acetate and the extracts combined with the previous organic layer and dried over sodium sulfate. Filtration and concentration gave 1.098 g (100% yield) of a light amber oil.

¹H NMR(300.133MHz，CDCl₃)：δ0.87(t，J＝7.32Hz，3H)，1.79-2.00(m，2H)，3.93(s，3H)，4.54(s，2H)，4.83(s，2H)，5.16(dd，J＝0.99Hz，10.59Hz，1H)，5.25(dd，J＝0.99，17.23Hz，1H)，6.01(dd，J＝10.59，17.23Hz，1H)，6.94(s，1H)，7.30-7.37(m，5H).

¹³C NMR(75.468MHz，CDCl₃)：δ7.7，34.2，54.5，62.6，72.4，78.0，114.0，115.6，115.9，127.9，128.0，137.2，143.0，148.2，159.2，163.1.

Nominal mass spectrum: calculated m/z 347, found m/z 348(m + 1).

There are three different possible reactions for step 9, series G, A and B, see page 3 of the chart CPT.

Step 9G (8CPTG → 9CPTG)

Methyltriphenylphosphonium bromide (2.14 g, 6.0 mmol) was dissolved in 15 ml DMF and stirred at rt. A solution of potassium bis-trimethylsilylamide (10 ml, 5.0 mmol, 0.5M in toluene) was added and the yellow solution with suspended white solid was stirred at room temperature for 10 min. A solution of 8CPTG (1.48 g, 4.0 mmol) in 5 mL THF was added in one portion, producing a dark red color and rapidly fading to a brown color. The mixture was stirred for 10 minutes. Additional ylide solution was added until all 8CPTG was consumed. The reaction was stopped by adding 10 ml of 1N hydrochloric acid. 20 ml of MTBE were added and the phases were separated. The aqueous phase is extracted with 2X 20 ml of MTBE. The combined organic phases are washed with 3 × 20 ml of water, the organic phase is dried over sodium sulfate and evaporated to a volume of about 15 ml (small amount of triphenylphosphine oxide crystallized). This solution was chromatographed on silica gel (ca. 20 g) using 4: 1 hexane/ethyl acetate to give 1.39 g of product (92% chemical yield).

¹H NMR(300.13MHz，CDCl₃)δ0.85(m，6H)，1.59(m，2H)，2.20(q，J＝7.4Hz，2H)，3.89(s，3H)，4.12(t，J＝6.7Hz，2H)，4.33(s，2H)，4.42(s，2H)，4.89(s，1H)，5.06(s，1H)，7.17(m，5H)，7.35(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ10.43，12.07，22.02，30.23，53.95，63.79，67.00，73.03，114.66，118.67，121.40，127.60，127.90，128.26，138.21，144.49，147.58，155.33，163.11，165.25.

Nominal mass spectrum: calculated m/z 369, found m/z 369.

Step 9A (8CPTA → 9CPTA)

8CPTA (0.500 g, 1.43 mmol) was dissolved in 40 mL of 1: 1 methanol: dichloromethane and cooled to-70 ℃ before purging with oxygen for 15 minutes. A flow of ozone in a Welsbach ozone generator was passed through the solution until the solution turned blue. The solution was then purged with oxygen for 5 minutes to remove excess ozone, followed by a nitrogen purge for 10 minutes. The-78 ℃ solution was treated with a solution of sodium borohydride (0.250 g, 6.61 mmol) in 5 ml of 50% aqueous methanol. After 15 minutes, the reaction was allowed to warm to room temperature over 1 hour. After 1 hour at room temperature, the reaction was quenched with 1M hydrochloric acid solution (10 ml) and the phases were separated. The aqueous phase was extracted with 20 ml and 10 ml of dichloromethane, respectively, combined with the initial organic layer and dried over sodium sulfate. Filtration and concentration gave 0.491 g (99% chemical yield) of 9 CPTA.

¹H NMR(300.133MHz，CDCl₃)：δ0.82(t，J＝7.20Hz，3H)，1.86(dd，J＝7.20Hz，14.71Hz，2H)，3.69(s，2H)，3.96(s，3H)，4.19-4.31(m，2H)，4.28(s，2H)，4.59(s，2H)，7.20(s，1H)，7.40-7.29(m，5H).

¹³C NMR(75.468MHz，CDCl₃)：δ7.61，35.44，54.50，62.97，73.40，75.26，84.72，113.71，114.13，127.91，128.18，128.35，137.48，148.56，158.01，163.46.

Nominal mass spectrum: calculated value m/z 351, found value m/z.

Step 9B (8CPTB → 9CPTA)

Similar reagents and conditions were used as described in step 9 CPTG.

Step 10G (9CPTG → 10CPTG)

To the flask were added 9CPTG (100.0 g, 0.271 mol), trimethylamine N-oxide dihydrate (90.24 g, 0.81 mol), and osmium tetroxide (0.68 g, 2.7 mmol) and 300 ml of t-butanol. The mixture was heated to 40 ℃. After 24 hours, the mixture was cooled to 20-25 ℃. 300 ml of water and 110 g of sodium metabisulfite were added and the mixture was stirred at room temperature for 30 minutes. The mixture was extracted with 4X 200 ml of ethyl acetate. The organic phases were combined and stirred with 50 g of 70-230 mesh silica gel for 1 hour. The silica gel was filtered and washed with 100 ml of ethyl acetate. The filtrate was stirred with 100 g of magnesium acid silicate for 30 minutes, and then the resulting slurry was filtered over 50 g of magnesium acid silicate. The filtrates were combined and concentrated to an oil. 200 ml of toluene and 800 ml of heptane were added and the mixture was crystallized at-20 ℃ for 18 hours. The resulting solid was filtered and washed with 200 ml heptane. 83.5 g of 10CPT are obtained. Additional 10CPT was recovered from the filtrate and washed by chromatography.

¹H NMR(300.13MHz，CDCl₃)δ0.74(t，J＝7.4Hz，3H)，1.03(t，J＝7.4Hz，3H)，1.80(m，4H)，3.69(d，J＝11.2Hz，1H)，3.86(d，J＝11.2Hz，1H)，4.01(s，3H)，4.31(t，J＝6.7Hz，2H)，4.88(d，J＝10.7Hz，1H)，4.96(d，J＝10.7Hz，1H)，7.33(m，5H)，7.64(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ7.55，10.41，22.01，31.71，54.16，62.95，67.13，70.86，72.69，80.12，117.83，122.25，128.00，128.42，137.14，144.74，155.82，163.16，165.23.

Nominal mass spectrum: calculated m/z 403, found m/z 404(m + 1).

Step 10A (9CPTA → 10CPTA)

In a flask equipped with a gas sparge tube and magnetic stirrer, 9CPTA (2.13 g, 6.0 mmol) was dissolved in 1-propanol (25 ml) and DMF (50 ml). To the flask was added solid potassium carbonate (1.24 g, 9.0 mmol), palladium (II) acetate (67 mg, 0.3 mmol), and DPPP (124 mg, 0.3 mmol), then purged with carbon monoxide and heated to 85 ℃ for 15 minutes. The reaction mixture was then cooled to room temperature and purged with nitrogen. The resulting solution was filtered through celite, and the celite was washed with ethyl acetate (3 × 50 ml). The combined filtrate and washings were concentrated in vacuo to an oil. The oil was diluted with ethyl acetate (100 ml) and the resulting solution was washed with water (50 ml) and then concentrated in vacuo. The product was separated by column chromatography (silica gel, 230-400 mesh, 1: 4 ethyl acetate: hexane eluent) to give 1.40 g (58%) of 10 CPT.

After step 10, the optical isomers can be resolved, which involves resolution in step 10 of the chart, see page 4 of the chart CPT.

Step 10 splitting

To 10CPT (8.0 g, 20 mmol) suspended in 200 mL of methyl tert-butyl ether were added 8.0 g of PS-30 catalyst (Pseudomonas cepacia lipase immobilized on an equal weight of Celite 521) and 1.85 mL (20 mmol) of vinyl acetate. The resulting suspension was magnetically stirred at room temperature for 24 hours. The catalyst was filtered off, washed with methyl tert-butyl ether (3X 100 ml) and the organic solvent was concentrated in vacuo to about 25 ml. The solution was maintained at 0-5 deg.C, the resulting solid was collected by filtration and washed with hexane (3X 25 mL) to give 2.75 g of 10CPT (s-enantiomer), [ a ]]_D ²⁵+3.25 °, in chloroform (> 99% ee HPLC Chiralpak AD column, 90: 10 hexane-isopropanol, 1 ml/min, 254 nm).

Step 11(10CPT → 11CPT)

The flask was charged with 10CPT (0.565 g, 1.4 mmol), 4-acetoxy-TEMPO (0.006 g, 0.028 mmol), potassium bromide (0.0167 g, 0.14 mmol) and sodium bicarbonate (0.0153 g, 0.182 mmol). Dichloromethane (7 ml) and water (1 ml) were added and the mixture was stirred at room temperature for 5 minutes. Sodium hypochlorite solution (1.6 ml, 0.95M) was added via syringe pump over about 40 minutes. After the addition was complete, the reaction was terminated by the addition of 5% aqueous sodium metabisulfite. The aqueous phase was separated and extracted with 2 x 5 ml dichloromethane. The combined organic phases were dried over sodium sulphate and evaporated, yielding 0.601 g of a brown syrup. The chemical yield was essentially 100%.

¹H NMR(300.13MHz，CDCl₃)δ0.91(t，J＝7.5Hz，3H)，1.03(t，J＝7.5Hz，3H)，1.83(m，2H)，2.10(m，2H)，4.02(s，3H)，4.35(t，J＝6.6Hz，2H)，4.55(s，2H)，4.68(d，J＝11.7Hz，1H)，4.87(d，J＝11.7Hz，1H)，7.35(m，5H)，7.78(s，1H)，9.62(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ7.24，10.43，22.02，29.72，54.30，63.2，67.24，73.12，82.37，117.45，122.48，128.23，128.55，136.67，145.05，150.55，162.88，164.93，200.14.

Nominal mass spectrum: calculated value m/z 401, found value m/z 402(m + 1).

Alternative reactions

Step 12 has two different reaction pathways, referred to as pathway a or pathway B. Route a is in two parts. The second part of pathway a, part 2, has two reaction pathways, pathway a-one-step and pathway b-two-step. Pathway B has a total of three segments. The 2 nd intermediate 12GA-2 produced by pathway B-1 in part 2 of pathway A is identical to the 2 nd intermediate 12GB-2 produced by pathway B in part 2. Part 3 of pathway B is the same as step 2 of pathway B-2 of part 2 of pathway A. See diagram CPT page 5.

Step 12 route A, part 1 (11CPT → 12CPT A-1)

A solution of 11CPT (0.206 g, 0.5 mmol) in 6 mL of t-butanol was mixed with NaH₂PO₄A solution of (0.035 g) in 2 ml of water was mixed and cooled to 0 ℃. A 50% hydrogen peroxide solution (0.043 ml) was added followed by a single addition of a solution of sodium chlorite (0.076 g, 0.675 mmol) in 0.5 ml of water. After 5 minutes, the reaction was stopped by adding 1.8 ml of a 10% aqueous solution of sodium metabisulfite. The mixture was partitioned between water and dichloromethane and the aqueous phase was extracted with 2 parts dichloromethane. The combined organic phases were evaporated to give 0.200 g (93%) of product 12 CPTA-1.

¹H NMR(300.13MHz，CDCl₃)δ1.02(m，6H)，1.82(m，2H)，2.23(m，2H)，3.99(s，3H)，4.32(t，J＝6.9Hz，2H)，4.53(d，J＝11.7Hz，1H)，4.62(d，J＝11.7Hz，1H)，4.68(d，J＝11.7Hz，1H)，4.97(d，J＝11.7Hz，1H).7.32(m，5H)，7.90(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ7.83，10.41，22.01，32.15，54.36，62.62，67.31，72.95，79.21，117.39，121.82，128.21，128.52，136.52，145.25，152.55，162.97，165.01，176.06.

Nominal mass spectrum: calculated m/z 417, found m/z 418(m + 1).

Step 12 route A, part 2, route a (one-step method) (12CPT A-1 → 12CPT)

A solution of 12A-1CPT (0.17 g, 0.40 mmol) and pyridine (0.05 mL, 0.6 mmol) in 5 mL acetonitrile was stirred at room temperature. Trimethylsilyl iodide (0.2 ml, 1.4 mmol) was added and the mixture was stirred at room temperature overnight, then the mixture was heated at 45 ℃ for 48 hours. Hydrochloric acid (5 ml, 6N) was added and the mixture was stirred at room temperature for 15 minutes. The mixture was extracted with 3X 5 ml of ethyl acetate and the combined extracts were washed with 5% sodium bisulfite solution. The ethyl acetate solution was dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel with 95: 5 dichloromethane/methanol to give 0.083 g (69%) of the product as a pale yellow oil.

¹H NMR(300.13MHz，CDCl₃)δ1.02(m，6H)，1.80(m，4H)，4.36(t，J＝6.0Hz，2H)，5.22(d，J＝16.5Hz，1H)，5.60(d，J＝16.5Hz，1H)，7.40(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ7.66，10.33，21.84，31.88，66.07，68.68，72.32，107.10，124.45，134.41，149.99，159.80，173.26，176.63.

Nominal mass spectrum: calculated m/z 295, found m/z 296(m + 1).

Step 12, route A, part 2, route b-1(12CPT A-1 → 12CPT A-2)

A solution of hydroxy acid 12CPT a-1(2.64 g, 6.3 mmol) in 50 ml of methanol was stirred with 10% palladium on carbon (0.264 g) under hydrogen atmosphere at atmospheric pressure and room temperature for 2 hours. The catalyst was filtered off over celite and washed with 10 ml of methanol. The combined filtrate and washings were evaporated to give the product as a pale yellow, very viscous oil (1.82 g, 93%).

¹H NMR(300.13MHz，CDCl₃)δd 0.88(t，J＝7.5Hz，3H)，0.97(t，J＝7.6Hz，3H)，1.76(m，4H)，4.0(s，3H)，4.25(t，J＝6.9Hz，2H)，5.23(d，J＝16.2Hz，1H)，5.52(d，J＝16.2Hz，1H)，7.85(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ7.49，10.32，21.89，31.88，54.08，65.53，67.22，72.72，114.79，115.22，146.01，148.91，158.50，164.51，173.53.

Step 12, route A, part 2, route b-2(12CPT A-2 → 12CPT)

A solution of the hydroxy lactone 12CPT A-2(1.93 g, 6.2 mmol) and sodium iodide (1.86 g, 12.4 mmol) in 30 mL of acetonitrile was stirred at 0 ℃. Trimethylsilyl iodide (1.6 ml, 12.4 mmol) was added, the mixture was stirred and allowed to warm to room temperature over 12 hours. Sodium iodide (0.9 ml, 6.2 mmol) and trimethylsilyl chloride (0.8 ml, 6.2 mmol) were added further and stirring was continued for 6 hours. 1N hydrochloric acid (10 ml) and sodium metabisulfite (0.6 g) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (30 ml) was added and the aqueous phase was extracted with a further 30 ml of ethyl acetate. The combined organic phases were washed with water, dried over sodium sulfate and evaporated to give the product as a pale yellow solid (1.84 g, 100%).

Nominal mass spectrum: calculated m/z 295, found m/z 296(m + 1).

Step 12, route B, part 1 (11CPT → 12CPT B-1)

Hydroxyaldehyde 11CPT (2.62 g, 6.6 mmol) was dissolved in 30 ml of methanol and stirred with palladium on carbon (0.26 g) under a hydrogen atmosphere and atmospheric pressure. After 96 hours, the reaction was complete. The catalyst was filtered off over celite and washed with 10 ml of methanol. The combined filtrate and washings were evaporated to give 1.97 g (96%) of the product as a white solid.

¹H NMR(300.13MHz，CDCl₃)δ，0.84(t，J＝7.5Hz，3H)，0.95(t，J＝7.4Hz，3H)，1.73(m，4H)，3.89(s，3H)，4.24(t，J＝6.7Hz，2H)，4.57(d，J＝17.2Hz，1H)，4.73(d，J＝17.2Hz，1H)，7.86(s，1H).

¹³C NMR(75.47MHz，CDCl₃)δ7.53，10.36，21.94，31.70，53.69，58.31，67.04，70.68，93.26，116.57，120.38，143.54，148.98，158.48，165.34.

Step 12, route B, part 2(12CPT B-1 → 12CPT B-2)

A solution of 12CP TB-1(1.94 g, 6.2 mmol) in 37 ml dichloromethane was stirred at room temperature with a solution of TEMPO (0.04 g, 0.25 mmol), sodium bicarbonate (0.081 g, 0.96 mmol) and potassium iodide (0.088 g, 0.74 mmol) in 3 ml water. Sodium hypochlorite solution (12%, about 12 ml) was added dropwise over 30 minutes. Sodium bisulfite (1.0 g) was added to destroy excess sodium hypochlorite. The aqueous phase was extracted with dichloromethane (10 ml) and the combined organic phases were washed once with water (10 ml) and dried over sodium sulfate. The solvent was evaporated to give the product as an oil (1.90 g, 99%) which solidified on standing.

Nominal mass spectrum: calculated value m/z, found value m/z.

Step 12, route B, part 3(12 CPT B-2 → 12CPT)

This step and the method used are the same as in step 12.

Step 13, route A, part 2, route b-2(12CPT → 13CPT)

12CPT (10.1 g, 0.339 mol), cesium carbonate (22.0 g, 0.067 mol), tert-butyl acrylate (25 mL, 0.169 mol) and DMSO (150 mL) were stirred at 47-50 ℃ for 19 h. The mixture was cooled and 20 ml of concentrated hydrochloric acid and 180 ml of water were added. The mixture was extracted 4 times with a total of 500 ml of a 4: 1(v/v) mixture of toluene and ethyl acetate. The combined extracts were washed three times with water and then evaporated to give an oil. The solution was concentrated by the addition of 200 mL of toluene to give the solvate of 13CPT as a crystalline 1: 1 toluene solvate (11.5 g, 67%).

¹H NMR(300.13MHz，CDCl₃)δ0.92(t，J＝7.4Hz，3H)，1.50(s，9H)，1.71-1.79(m，2H)，2.28(s，3H)，4.59(s，2H)，5.16(d，J＝17.8Hz，1H)，5.61(d，J＝17.8Hz，1H)，6.94(s，1H)，7.0-7.2(m，5H).

¹³C NMR(75.47MHz，CDCl₃)δ7.64，21.38，28.20，31.41，49.27，66.13，72.50，83.55，97.80，105.69，118.59，125.22，128.14，128.95，137.78，143.82，149.48，156.84，159.26，166.02，173.60.

Step 14(13CPT → 14CPT)

13 CPT-toluene solvate (70.3 g, 0.153 mol) was dissolved in 1400 ml of toluene and 140 ml of trifluoroacetic acid and heated at 110 ℃ for 2 hours. The solution was cooled and concentrated in vacuo to a volume of about 350 ml. Ethyl acetate (1 l) was added and the mixture was cooled to-20 ℃. Filtration gave 14CPT as a light brown crystalline solid (37.92 g, 93.4%).

¹H NMR(300.13MHz，CDCl₃)δ0.98(t，J＝7.5Hz，3H)，1.80(q，J＝6.0Hz，2H)，2.96(m，2H)，4.36(t，J＝6Hz，2H)，5.24(d，J＝15Hz，1H)，5.66(d，J＝15Hz，1H)，7.27(s，1H).

¹H NMR(300.13MHz，DMSO-d₆)δ0.80(t，J＝7.3Hz，3H)，1.81(m，2H)，2.89(t，J＝6.3Hz，2H)，4.13(t，J＝6.3Hz，2H)，5.34(d，J＝17.1Hz，1H)，5.41(d，J＝17.1Hz，1H)，6.86(s，1H).

¹³C NMR(75.47MHz，DMSO-d₆)δ7.52，30.31，33.71，42.56，65.20，71.92，98.49，123.81，140.19，149.05，156.97，172.03，197.93.

Nominal mass spectrum: calculated m/z 263, found m/z 264(m + 1).

Other reactions disclosed

The following reactions, methods and structural formulae in the following table are also included in the present invention.

The following references may be used to understand the above "other published reactions". Preparation of u-503 from native camptothecin is described in US4,473,692 (25.9.1984, t.miyasaka, s.sawada, k.nokata, e.siguno, m.mutai). U-440 prepared from U-503 is described in U.S. Pat. No. 4,604,463 (8.8.5.1986, T.Miyasaka, S.Sawada, K.Nokata, E.Siguno, M.Mutai). The conversion of U-440 to CPT-11 is described in the following references: S.Sawada, R.Okajima, R.Aiyama, K.Nokata, T.Furuta, T.Yokohura, E.Siguno, K.Yamaguchi, T.Miyasaka, chem.Pharm.Bull, 1991, Vol.39, p.1446-1454.

The reactions shown in the "other published reactions" diagram above are described below.

Preparation of U-503 and U-440

U-727 and U-772 were reacted in a mixture of toluene and acetic acid at 95-100 ℃ for about 48 hours. The toluene and acetic acid are distilled off to give U-503, which is converted to U-440 without purification.

Unpurified U-503 was dissolved in pyridine and reacted with 4-piperidinopiperidinocarbamoyl chloride dissolved in dichloromethane at 20-25 ℃. The dichloromethane and pyridine were distilled off, the crude U-440 was redissolved in dichloromethane and treated with saturated aqueous sodium bicarbonate. U-440 was then chromatographed on silica gel, eluting with a mixture of dichloromethane and methanol, and isolated as a crystalline solid by crystallization from a mixture of dichloromethane and ethanol.

U-503. U-727(1.05 g, 4.0 mmol), U-772(0.62 g, 3.8 mmol) and p-toluenesulfonic acid monohydrate (0.02 g) were mixed with toluene (10 ml) and acetic acid (10 ml) and heated at 95-100 ℃ for 18-24 hours. During the reaction, U-503 gradually precipitated out. When the reaction was complete, toluene and acetic acid were removed by distillation under reduced pressure to give U-503 as a solid.

U-440. Pyridine (15 ml) was added to unpurified U-503, and the mixture was stirred at 20-25 ℃ for 15 minutes to dissolve U-503. 4-Piperidinopiperidinecarbamyl chloride (1.32 g, 5.7 mmol) dissolved in dichloromethane (5 ml) was added. The mixture was stirred at 20-25 ℃ for 2 hours until the reaction was complete. The mixture was distilled to dryness under reduced pressure. Toluene (20 ml) was added and the mixture was distilled under reduced pressure to near dryness.

Unpurified U-440 was dissolved in dichloromethane (25 ml), saturated aqueous sodium bicarbonate solution (5 ml) was added, and the mixture was stirred at room temperature for 5 minutes. The phases were stabilized and the dichloromethane phase was removed. The aqueous phase was extracted with dichloromethane (10 ml). The dichloromethane phases were combined and distilled to give crude solid U-440.

The crude solid U-440 was dissolved in 95: 5 dichloromethane-methanol (v/v, 10 ml) and chromatographed on a column containing 30 g 230-400 mesh silica gel, eluting with 95: 5 dichloromethane-methanol (v/v). The products containing the fractions were combined and distilled to a volume of about 10 ml at atmospheric pressure. At the end of the distillation some product crystallized. Ethanol (15 ml) was added and the resulting slurry was left at-20 ℃ for 24 hours. The product was filtered, washed with ethanol (10 ml) and dried to yield 1.34 g (62% chemical yield, calculated from 16 CPT) of U-140.

Processes, reactions and compounds of diagrams M-M and M-G

Mappicine synthesis and chiral reduction of related compounds are shown in the diagrams M-G and M-M. Precursors of these compounds are described in the previous reaction of scheme G.

There are many reagents suitable for reducing ketones to produce chiral secondary alcohols. Aryl-alkyl ketones structurally similar to the intermediates shown in the mappicine diagram are particularly advantageous chiral reduction substrates. Among these agents, effective for such reduction is the Noyori binaphthol-lithium aluminum hydride complex¹Complexes of boranes and chiral amino alcohols produced by Itsuno²Borane reduction catalyzed by chiral oxazaborolidines³And complexes of lithium aluminum hydride with darvon alcohol⁴。

The reaction products and intermediates described above can then be subjected to a significantly modified Friedlander type condensation reaction to yield the desired product, such as those shown in the following chart.

4.N.Cohen，R.J.Lopresti，C.Neukom，G.Saucey，J.Org.Chem.1980，45，582.

R.noyori, i.tomino, and y.tanimoto, j.am.chem.soc, 1979, 101, 3129; noyori, U.S. patent 4,284,581.

S.itsuno, k.ito, a.hirao, and s.nakahama, j.chem.soc.chem.comm., 1983, 469; s.itsuno, m.nakano, k.miyazaki, h.masuda, k.ito, a.hirao, and s.nakahama, j.chem.soc.perkin I, 1985, 2039.

3.E.J.Corey，R.K.Bakshi，S.Shibate，J.Am.Chem.Soc.1987，5551.

The following is a detailed embodiment illustrating the reaction conditions shown in the graphs M-G and M-M.

5 MM. 4CPT (10.0 g, 41.0 mmol) was dissolved in 500 ml heptane. The solution was cooled to 0 ℃ and 24.4 ml of a hexane solution of n-butyllithium (2.10M, 51.2 mmol) were added while maintaining the reaction temperature at 0 ℃. The resulting bright orange slurry was stirred at 0 ℃ for 1.75 hours. Dimethyl sulfate (4.8 ml, 51.2 mmol) was added while maintaining the reaction temperature below 10 ℃. The reaction was stirred at 0 ℃ for 2 hours, then treated with 1.5 ml of concentrated aqueous ammonia and then stirred for a further 1 hour. Water (40 ml) and ethyl acetate (75 ml) were added. After 15 minutes, the phases were separated and the aqueous phase was extracted with 3X 50 ml of ethyl acetate. The organic extracts were combined, dried over sodium sulfate, filtered and concentrated to give a red oil. Purification by flash chromatography (dichloromethane) gave 5MM (6.97 g, 66%) as a clear colorless oil:

MS(EI)m/z 257，259；MS(CI)m/z(-NH₃ ⁺)258，260；¹H NMR(300.14MHz，CDCl₃)δ7.08(s，1H)，4.05-4.01(m，2H)，3.97(s，3H)，3.80-3.75(m，2H)，2.28(s，3H)，1.93(dd，J＝7.4，14.9Hz)，0.91(t，J＝7.4Hz)；¹³C NMR(75.47MHz)δ162.9，153.3，144.9，116.9，114.4，110.1，64.5，54.2，31.5，12.0，7.4.

6 MM. 5MM (12.0 g, 46 mmol) was dissolved in 25 ml aqueous TFA (64% v/v) and heated to 40 ℃. After 4 hours, the reaction mixture was cooled and quenched with 50 mL of water and 75 mL of 2: 1(v/v) ethyl acetate: heptane. The phases were separated and the aqueous phase was extracted with 3X 40 ml of 2: 1 ethyl acetate: heptane. The organic extracts were combined and washed with 200 ml of 9% (w/v) aqueous sodium bicarbonate solution for neutralization. The phases were separated and the aqueous phase was extracted with 3X 50 ml of ethyl acetate. The organic phases were combined, dried (sodium sulfate), filtered and concentrated to give 10g of a pale yellow oil. The crude product was used directly in the next reaction. A small portion of which was purified to determine its properties:

MS(EI)m/z 213，215；MS(CI)m/z(-NH₃ ⁺)214，216；¹H NMR(300.14MHz，CDCl3)δ6.88(s，1H)，3.99(s，3H)，2.82(dd，J＝7.2，14.5Hz)，2.16(s，3H)，1.19(t，J＝7.2Hz)；¹³C NMR(75.47MHz)δ204.2，162.6，150.5，145.5，116.3，113.0，54.4，35.9，11.8，7.6.

6 bMM. Crude 6MM (10g, about 46 mmol) was dissolved in 100 ml methanol and cooled to 0 ℃. Freshly prepared 2.18 g NaBH was added in one portion₄(58 mmol) in 20 ml of 50% aqueous methanol. After 20 minutes, the reaction was quenched with 50 ml of aqueous hydrochloric acid (1M, 50 mmol) and then diluted with 100 ml of dichloromethane and 10 ml of water. The phases were separated and the aqueous phase was extracted with 3X 50 ml of dichloromethane. The organic extract was concentrated to give a white solid. The solid material was recrystallized from hexane to give 7MM (8.54 g, 85%, calculated from 5 MM) as long needles:

mp＝97.0-97.5℃；MS(EI)m/z 215，217；MS(CI)m/z(-NH₃ ⁺)216，218；¹H NMR(300.14MHz，CDCl₃)δ7.05(s，1H)，4.85-4.81(m，1H)，3.95(s，3H)，2.08(s，3H)，1.76-1.63(m，2H)，0.98(t，J＝7.4Hz)；¹³C NMR(75.47MHz)δ161.8，155.6，145.4，115.0，113.1，71.0，54.1，30.4，10.5，9.8.

7MM (4.00 g, 18.5 mmol) and sodium hydride (1.55 g, 64.6 mmol) were stirred with 40 ml of THF for 30 minutes. Benzyl bromide (2.3 ml, 18.9 mmol) was added and the mixture was stirred at room temperature for 8 h. Saturated ammonium chloride solution (10 ml), 10 ml water and 20 ml dichloromethane were added. The phases are separated and the pH of the aqueous phase is adjusted to neutrality with 1M hydrochloric acid and then extracted with 3X 20 ml of dichloromethane. The organic phases were combined, dried (sodium sulfate), filtered and concentrated to a yellow oil. Flash chromatography on silica gel gave 8MM (5.09 g, 90%) as a clear oil:

MS(EI)m/z 305，307；MS(CI)m/z(-NH₃ ⁺)306，308；¹H NMR(300.14MHz，CDCl₃)δ7.38-7.32(m，5H)，7.07(s，1H)，4.53-4.46(m，2H)，4.26(d，J＝11.7Hz，1H)，4.00(s，3H)，2.09(s，3H)，1.83-1.62(m，1H)，0.98(t，J＝7.3Hz，3H)；¹³CNMR(75.47MHz)δ162.0，154.0，145.6，137.9，128.4，127.8，127.7，116.3，113.8，78.0，71.0，54.2，29.5，10.5，10.1.

8MM (4.00 g, 13.1 mmol), potassium acetate (1.92 g, 19.6 mmol), palladium acetate (0.147 g, 0.65 mmol) and DPPP (0.268 g, 0.65 mmol) were stirred with 80 ml DMF and 40 ml n-propanol. The flask was purged with CO and then heated to 85 ℃ under a CO atmosphere. After 25 minutes, the mixture was cooled and purged with nitrogen. The solution was filtered through celite, and the filtrate was concentrated and then partitioned between 80 ml water and 160 ml MTBE. The aqueous phase was further extracted with 3X 50 ml of MTBE. The organic extracts were combined, washed with 4 × 25 ml of water, dried (sodium sulfate), filtered and concentrated. Purification by flash chromatography using dichloromethane as eluent gave 9MM (4.14 g, 89%) as a clear colorless oil:

MS(EI)m/z 358；

MS(CI)m/z(-NH₃ ⁺)358，360；¹H NMR(300.14MHz，CDCl₃)δ7.88(s，1H)，7.38-7.28(m，5H)，4.57-4.53(m，1H)，4.48(d，J＝11.6Hz，1H)，4.36-4.32(m，2H)，4.25(d，J＝11.6Hz，1H)，4.09(s，3H)，2.18(s，3H)，1.90-1.80(m，3H)，1.78-1.64(m，2H)，1.06(t，J＝7.4Hz)，0.97(t，J＝7.4Hz)；¹³C NMR(75.47MHz)δ165.5，162.3，151.5，142.8，138.0，128.3，127.8，127.7，122.9，116.5，78.1，70.9，66.8，53.8，29.5，22.0，11.3，10.4，10.2.

9MM A solution of sodium iodide (1.89 g, 12.6 mmol) and 8MM (3.00 g, 8.4 mmol) in 30 ml of CH3CN was cooled to 0 ℃ and trimethylsilyl chloride (1.6 ml, 12.6 mmol) was added. After 15 minutes, the reaction mixture was allowed to warm to room temperature. After 24 hours, 4.2 ml of 6M hydrochloric acid, 5.3 ml of saturated sodium chloride solution, 10.6 ml of water, 0.4 ml of 38% Na were added in this order₂S₂O₅The reaction was quenched with aqueous solution and 20 ml of ethyl acetate. After stirring at room temperature for 30 minutes, the phases were separated and the aqueous phase was extracted with 3X 10 ml of ethyl acetate. The organic solutions were combined and washed with 7 ml of saturated sodium bicarbonate and 0.25 ml of 38% sodium bisulfite. After stirring for 15 minutes, the phases are separated and the organic solution is washed with 2X 10 ml of saturated aqueous sodium chloride solution. The solution was dried over sodium sulfate, then filtered and concentrated to give 2.80 g (97%) of 9MM as a waxy off-white solid:

MS(EI)m/z 343，344；MS(CI)m/z(-NH₃ ⁺)344，345；¹HNMR(300.14MHz，CDCl₃)δ9.82(broads)，7.39-7.29(m，6H)，4.51-4.46(m，1H)，4.35-4.26(m，2H)，2.14(s，3H)，1.87-1.75(m，3H)，1.71-1.57(m，1H)，1.05-0.95(m，6H)；¹³C NMR(75.47MHz)δ162.42，161.28，150.41，137.63，133.04，130.54，128.40，127.87，108.01，77.76，71.13，67.95，28.80，21.84，12.04，10.29，10.06.

10MM A mixture of 9MM (3.22 g, 9.4 mmol), cesium carbonate (6.12 g, 18.8 mmol), tert-butyl acrylate (13.5 g, 92.3 mmol) and 50 ml DMSO was heated to 65 ℃ under a nitrogen atmosphere. After 3 hours, the reaction mixture was cooled to 0 ℃ and then quenched by the slow addition of 60 ml of 0.5M hydrochloric acid, keeping the internal reaction temperature at 15 ℃ or below 15 ℃ all the time. The mixture was diluted with 30 ml of 1: 4 ethyl acetate: toluene (v/v) and partitioned. The aqueous phase is extracted with 2X 30 ml of the above-mentioned solvent. The combined organic extracts were washed with 3 × 30 ml of water, dried over sodium sulfate, filtered and concentrated to give 4.57 g of a yellow oil. Purification by column chromatography gave 3.28 g of 10MM as a beige foamy solid (85%):

MS(EI)m/z 411，412；MS(CI)m/z(-NH₃ ⁺)412，413；¹H NMR(300.14MHz，CDCl₃)δ9.91(br s)，7.39-7.29(m，5H)，6.91(s，1H)，4.67(s，2H)，4.52-4.48(m，2H)，4.26(d，J＝11.8Hz，1H)，2.18(s，3H)，1.87-1.78(m，1H)，1.73-1.53(m，2H)，1.59(s，9H)，0.97(t，J＝7.4Hz，3H)；

¹³C NMR(75.47MHz)δ166.61，160.77，160.28，150.69，140.25，137.89，128.35，127.77，127.69，126.63，103.99，99.13，82.95，78.02，70.88，49.08，29.01，28.25，27.87，11.84，10.07.

11MM A solution of 10MM (0.25 g, 0.61 mmol), trifluoroacetic acid (0.45 ml) and toluene (18 ml) was heated to 75 ℃. After 24 hours, the solution was concentrated to a thick oil using a rotary evaporator. The oil was diluted with 20 ml of toluene and concentrated to a thick oil. The oil was purified by flash chromatography (5% methanol in dichloromethane) to give 0.138 g of 11MM as a yellow foamy solid (73%):

MS(EI)m/z；MS(CI)m/z(-NH₃ ⁺)；¹H NMR(300.14MHz，CDCl₃)δ7.27-7.18(m，5H)，7.04(s，1H)，4.43-4.38(m，2H)，4.23-4.13(m，3H)，2.80(t，J＝6.9Hz)，2.09(s，3H)，1.75-1.47(m，2H)，0.86(t，J＝7.4Hz，3H)；¹³C NMR(75.47MHz)δ196.91，161.48，150.48，137.67，136.95，132.94，128.36，127.71，102.40，77.77，70.97，41.92，33.69，28.90，12.41，9.98.

12MM A solution of 11MM (0.135 g, 0.43 mmol), N-Boc o-aminobenzaldehyde (0.14 g, 0.63 mmol), p-toluenesulfonic acid (0.010 g, 0.06 mmol), glacial acetic acid (5 ml) and toluene (25 ml) was heated to 100 ℃. After 36 hours, the solution was concentrated to dryness in vacuo. The residue was dissolved in 25 ml of toluene and then concentrated to give 0.333 g of a reddish brown solid. The material was purified by flash chromatography (2% methanol in dichloromethane) to afford 0.123 g of 12MM as a yellow foamy solid (72%):

MS(EI)m/z 396，398；MS(CI)m/z(-NH₃ ⁺)397，399；¹H NMR(300.14MHz，CDCl₃)δ8.33(s，1H)，8.22(d，J＝8.5Hz，1H)，7.90(d，J＝8.1Hz，1H)，7.80(t，J＝7Hz，1H)，7.64-7.57(m，2H)，7.38-7.29(m，5H)，5.28(s，2H)，4.64-4.54(m，2H)，4.32(d，J＝12Hz，1H)，2.25(s，3H)，1.99-1.67(m，1H)，1.02(t，J＝7.3Hz)；¹³C NMR(75.47MHz)δ161.51，153.51，151.30，148.78，142.67，138.12，130.67，130.12，129.56，128.64，128.33，127.98，127.76，127.60，127.29，126.87，99.51，78.18，70.81，49.91，29.08，11.99，10.19.

graph table

The figures used to illustrate the invention are briefly described herein in the following pages. The above is described in detail. Panel G is a general illustration showing the homogeneous structures involved in the reaction. After the preparation of the 4G compound, two distinct reaction pathways are available. One route is to continue with diagram G and ultimately produce camptothecin or related compounds. The other pathway is the diagrams M-G, ultimately producing mappicine or related compounds.

Chart CPT-11 is a specific embodiment of chart G, showing specific reactions and intermediates for the preparation of camptothecin. Panels M-M are a specific embodiment of panel M, in which specific reactions and intermediates for making mappicine are shown.

The resolution of the enantiomers is shown by step 10 and CPT-11 in scheme G. Although only one enantiomer is shown, it is also contemplated to split the other enantiomer with appropriate starting materials and making the necessary changes will be apparent to those skilled in the art. Methods applicable to either enantiomers or mixtures of enantiomers are desirable.

When there is only one asymmetric center, the method (with appropriate modifications as required) can be used to prepare any one enantiomer. When two asymmetric centers are present, the stereochemistry of only one of the two centers is shown. When there are two asymmetric centers in a molecule, only one asymmetric center is typically resolved using the methods herein, and the second asymmetric center is typically unresolved. All four stereoisomers with two asymmetric center molecules can be fully resolved by appropriate modification of the methods described herein in combination with methods common to those of ordinary skill in the art.

The diagrams M-G and G-G show one enantiomer, the orientation of which is indicated by a bold line, but the other enantiomer can be prepared and isolated entirely by methods known to those skilled in the art. Suitable methods for the enantiomers or mixtures thereof may be selected. The other enantiomers in the diagrams M-G and G-G are shown in some claims, their orientation being shown in bold or dashed lines.

The hydrogen atoms and their linkages are not generally shown in the following chart or in any structural formula used herein. Sometimes only the carbon atom is represented by a chemical bond, not by the letter "c".

The various charts are as follows.

Graph G p.1

Graph G p.2

Graph G p.3

Chart G p.4

Graph G p.5

Chart CPT p.1

Chart CPT p.2

Chart CPT p.3

Chart CPT p.4

Chart CPT p.5

Chart M-G p.1

Chart M-G p.2

Chart M-mp.1

Graph M-mp.2

1. Described in this specification are compounds labelled 2G, 3G, 4G, 5G, 6MG, 6bMG, 7GG, 7GA, 7MG, 8GG, 8GA, 8GB, 8MG, 9GG, 9GA, 9MG, 10G (S), 10G (R), 10MG, 11G (S), 11G (R), 11MG, 12GA-1(S), 12GA-1(R), 12GA-2(S), 12GA-2(R), 12GB-1(S), 12GB-1(R), 12GB-2(S), 12GB-2(R), 12G (S), 12G (R), 13G (S), 13G (R) or 13MG (G), (S),

wherein R is₁Optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₂Is a compound of formula (I) wherein the compound is H,

a) any optionally substituted alkyl group includes C_1-8Alkyl, alkaryl radicals including C_1-6alkyl-C₆-C₁₂Aryl radical, C_1-8alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl;

b)-C(O)-R₃or is or

c)-C(R₇)₂-O-R₃Wherein each R is₇Are independent of each other;

wherein R is₃Is H, optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl, cycloalkyl, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl and alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₄Is H, optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₅Is H, optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, or two R₅The groups may be joined together to form cyclopentane or cyclohexane, or substituted derivatives thereof;

wherein R is₆Optionally substituted C_1-8Alkyl radical, C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted aryl, alkaryl, substituted C₆-C₁₂Aryl radicals including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl;

wherein R is₇Independently H, optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl, or both R₇The groups may be joined together to form cyclopentane or cyclohexane or substituted derivatives thereof;

wherein R is₈Optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl includes t-butyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups include benzyl and substituted benzyl groups.

2. The compound of item 1, represented by the following structural formula,

formula 2G

Wherein R is₆Optionally substituted C_1-8The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl.

3. The compound of the claim 2, wherein,

wherein R is₆Is C₁-C₆The alkyl group includes ethyl and C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl radicals including benzyl or substituted C₁-C₆Alkyl substituted C₆And (4) an aryl group.

4. The compound of the item 3 in the above-mentioned formula,

wherein R is₆Is C_1-4Alkyl includes ethyl or C₆And (4) an aryl group.

5. The compound of the item 4 in which,

wherein R is₆Is C_1-2An alkyl group.

6. The compound of item 5, represented by the following structural formula,

7. the compound of item 1, represented by the following structural formula,

formula 3G

8. The compound of the item 7 in which,

wherein R is₆Optionally substituted C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl radical, C₁-C₆alkyl-C₆Aryl, substituted C₁-C₆alkyl-C₆-aryl or benzyl.

9. The compound of the item 8, wherein,

wherein R is₆Is C₁-C₆Alkyl includes ethyl, or C₆And (4) an aryl group.

10. The compound of the claim 9, wherein,

wherein R is₆Is C_1-3An alkyl group.

11. The compound of item 10, represented by the following formula 4CPT,

12. the compound of item 1, represented by the following structural formula,

formulae 4G and 5G

wherein R is₂Is a compound of formula (I) wherein the compound is H,

a) any optionally substituted C_1-8The alkyl group comprising C_1-6Alkyl, alkaryl, C_1-6Alkylaryl group, C_1-6alkyl-C₆Aryl includes substituted benzyl and unsubstituted benzyl;

b)-C(O)-R₃or is or

c)-C(R₇)₂-O-R₃Wherein each R is₇Are independent of each other;

wherein R is₆Is C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl.

13. A compound of the item 1,

wherein R is₁Optionally substituted C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, or substituted C₆-C₁₂Aryl or benzyl;

wherein R is₂Is H, any optionally substituted alkyl group including C_1-8The alkyl group comprising C_1-6Alkyl radical, C_1-6alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl;

b)-C(O)-R₃or is or

c)-C(R₇)₂-O-R₃Wherein each R is₇Are independent of each other; and wherein R₃And R₇Is any optionally substituted alkyl group including C_1-6Alkyl radical, C_1-6alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl; or

Wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl radical, C₁-C₆alkyl-C₆Aryl, substituted C₁-C₆alkyl-C₆-aryl or benzyl.

14. The compound of the claim 13, wherein,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₂Is H, C_1-3An alkyl group; or

Wherein R is₆Is C₁-C₆Alkyl includes ethyl, or C₆And (4) an aryl group.

15. The compound of the claim 13, wherein,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₂Is H, methyl, ethyl; or

Wherein R is₆Is C_1-3An alkyl group.

16. The compound of item 13, represented by the following formula 4CPT,

17. the compound of item 13, represented by the following formula 5CPT,

17a, the bisulfite adduct of the compound of item 13, represented by the following formula 5aCPT,

(bisulfite adduct)

The compound of item 13, represented by the following formula 5CPT,

18. the compound of item 13, represented by the following formula 5MM,

19. the compound of item 1, represented by the following structural formula,

formula 6G

wherein R is₆Is H, optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substitutedC₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl; or

Wherein R is₇Independently H, C₁-C₆Alkyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl-substituted alkaryl, or two R₇The groups may be joined together to form cyclopentane or cyclohexane or substituted derivatives thereof.

20. The compound of the claim 19, wherein,

wherein R is₁Is any C₁-C₆An alkyl group;

wherein R is₇Independently is H or C₁-C₆An alkyl group;

wherein R is₃Is C₁-C₆Alkyl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl; or

Wherein R is₆Is C₁-C₆An alkyl group.

21. The compound of item 20, represented by the following formula 6CPT,

22. the compound of item 1, represented by the following structural formula,

formula 7GG

wherein R is₄Is any C_1-6The alkyl group comprising C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₆Is H, optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl; or

Wherein R is₇Independently H, C₁-C₆Alkyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl, or both R₇The groups may be bonded together to form cyclopentane or cyclohexane or substituted derivatives thereof.

23. The compound of the claim 22, wherein,

wherein R is₁Optionally substituted C₁-C₆An alkyl group;

wherein R is₃Optionally substituted C₁-C₆Alkyl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₄Is H, C₁-C₆Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₆Is H, or C₁-C₆An alkyl group; or

Wherein R is₇Independently is H, or C₁-C₆An alkyl group.

24. The compound of item 23, represented by the following formula 7CPTG,

25. the compound of item 1, represented by the following structural formula,

formula 7GA

wherein R is₆Is C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆Alkyl radical C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl; or

Wherein R is₇Independently H, optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl, or both R₇The groups may be joined together to form cyclopentane or cyclohexane or substituted derivatives thereof.

26. The compound of the claim 22, wherein,

wherein R is₁Is any optionally substituted C₁-C₆An alkyl group;

wherein R is₃Is H, optionally substituted C₁-C₆Alkyl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₆Optionally substituted C_1-4An alkyl group; or

Wherein R is₇Independently H, or optionally substituted C_1-4An alkyl group.

27. The compound of item 23, represented by the following structural formula,

28. a compound of the formula,

formula 8GG

wherein R is₃Optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl, cycloalkyl, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl and alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl;

wherein R is₇Independently H, C₁-C₆Alkyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl, or both R₇The groups may be joined together to form cyclopentane or cyclohexane or substituted derivatives thereof.

29. The compound of claim 28, wherein the compound of formula (I),

wherein R is₁Optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₁-C₆alkyl-C_3-6Cycloalkyl radical, C₂-C₈Alkenyl, aryl or substituted aryl, or benzyl;

wherein R is₃Optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl and C_1-6alkyl-C_1-6-aryl or substituted C_1-6alkyl-C_1-6Aryl includes benzyl and substituted benzyl;

wherein R is₄Is H, optionally substituted C₁-C₆Alkyl, cycloalkyl, C₆-C₁₂Aryl, substituted C₆-C₁₂An aryl group;

wherein R is₆Optionally substituted C₁-C₆The alkyl group includes ethyl and C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, substituted C₁-C₆alkyl-C₆-aryl or benzyl; or

Wherein R is₇Independently H, optionally substituted C₁-C₆An alkyl group.

30. The compound of the claim 29, wherein,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₃Is benzyl or substituted benzyl;

wherein R is₄Is H, C₁-C₆An alkyl group;

wherein R is₆Is C₁-C₆Alkyl includes ethyl, or C₆-C₁₂An aryl group; or

Wherein R is₇Is H, C_1-3An alkyl group.

31. The compound of item 30, represented by the following structural formula,

32. the compound of item 1, represented by the following structural formula,

formula 8GA

wherein R is₅Independently H, optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, or two R₅The groups may be joined together to form cyclopentane or cyclohexane, or substituted derivatives thereof;

wherein R is₆Optionally substituted C_1-8Alkyl radicalComprising C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl;

33. The compound of the claim 32, wherein,

wherein R is₁Optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₁-C₆alkyl-C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl or substituted C₆-C₁₂Aryl, or benzyl;

wherein R is₃Optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, and C_1-6alkyl-C_1-6Aryl, or substituted C_1-6alkyl-C_1-6Aryl includes benzyl and substituted benzyl;

wherein R is₆Optionally substituted C₁-C₆The alkyl group includes ethyl and C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, substituted C₁-C₆alkyl-C₆-aryl, or benzyl.

34. The compound of the item 33 which is,

wherein R is₁Optionally substituted C₁-C₆Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₃Is benzyl or substituted benzyl; or

Wherein R is₆Optionally substituted C₁-C₆Alkyl includes ethyl, or C₆-C₁₂And (4) an aryl group.

35. The compound of the claim 34, wherein,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₃Is benzyl or substituted benzyl; or

Wherein R is₆Is C_1-3Alkyl includes ethyl, or C₆-C₁₂And (4) an aryl group.

36. The compound of item 35, represented by the following formula 8CPTA,

37. the compound of item 1, represented by the following structural formula,

formula 8GB

wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl; or

38. The compound of the item 37 which is,

wherein R is₃Optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl and C_1-6alkyl-C_1-6Aryl or substituted C_1-6alkyl-C_1-6Aryl includes benzyl and substituted benzyl; or

Wherein R is₆Optionally substituted C₁-C₆The alkyl group includes ethyl and C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, substituted C₁-C₆alkyl-C₆-aryl, or benzyl; or

Wherein R is₇Independently H, optionally substituted C₁-C₆An alkyl group.

39. The compound of item 38, wherein,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₃Is benzyl or substituted benzyl;

Wherein R is₇Is H.

40. The compound of item 39, represented by the following formula 8CPTB,

41. the compound of item 1, represented by the following structural formula,

formula 9GG

wherein R is₄Is H, optionally substituted C_1-8The alkyl group comprising C_1-6The alkyl group comprising C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted aryl C₁-C₆Alkyl radical C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl;

wherein R is₇Independently H, optionally substituted C₁-C₆Alkyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl, or both R₇The groups may be joined together to form cyclopentane or cyclohexane or substituted derivatives thereof.

42. The compound of item 41, wherein,

wherein R is₁Is any optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₁-C₆alkyl-C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, or benzyl;

wherein R is₆Optionally substituted C₁-C₆The alkyl group includes ethyl and C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, substituted C₁-C₆alkyl-C₆-aryl, or benzyl;

wherein R is₇Independently H, C₁-C₆An alkyl group.

43. The compound of item 42, wherein,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₃Is benzyl or substituted benzyl;

wherein R is₄Is H, C₁-C₆An alkyl group;

Wherein R is₇Is H.

44. The compound of item 43, represented by the following structural formula,

45. the compound of item 1, represented by the following structural formula,

formula 9GA

wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl radicals including ethyl, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl;

46. The compound of the item 45 in the above-mentioned formula,

wherein R is₃Optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, and C_1-6alkyl-C_1-6Aryl, or substituted C_1-6alkyl-C_1-6Aryl includes benzyl and substituted benzyl; or

47. A compound of the item 46,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₃Is benzyl or substituted benzyl; or

Wherein R is₆Is C₁-C₆Alkyl includes ethyl, or C₆-C₁₂And (4) an aryl group.

48. The compound of item 47, wherein,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₃Is benzyl or substituted benzyl; or

Wherein R is₆Is C_1-3An alkyl group.

49. The compound of item 48, represented by the following formula 9CPTA,

50. the compound of item 1, represented by the following structural formula,

formula 10G

wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl radicalsAlkylaryl, substituted alkylaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl;

51. The compound of the item 50 which is,

wherein R is₁Optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₁-C₆alkyl-C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, or substituted C₆-C₁₂Aryl, or benzyl;

wherein R is₄Is H, optionally substituted C_1-6The alkyl group comprising C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₁-C₆alkyl-C_3-6Cycloalkyl radical, C₆Aryl, substituted C₆Aryl radical, C₃Alkyl radical C₆Aryl or substituted C₃Alkyl radical C₆Aryl includes benzyl and substituted benzyl;

wherein R is₆Optionally substituted C₁-C₆The alkyl group includes ethyl and C₆Aryl, substituted C₆Aryl, heteroaryl, and heteroaryl,C₁-C₆alkyl-C₆Aryl, substituted C₁-C₆alkyl-C₆-aryl, or benzyl; or

Wherein R is₇Independently H, optionally substituted C₁-C₆Alkyl radical, C₆-C₁₂Aryl, or two R₇The groups may be joined together to form cyclopentane or cyclohexane or substituted derivatives thereof.

52. The compound of the claim 51, wherein,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₃Is benzyl or substituted benzyl;

wherein R is₄Is any C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C₁-C₆alkyl-C_3-6A cycloalkyl group; or

Wherein R is₇Independently H, C₁-C₆Alkyl, or two R₇The groups may be joined together to form cyclopentane or cyclohexane or substituted derivatives thereof.

53. The compound of item 52 wherein,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₃Is benzyl or substituted benzyl;

wherein R is₄Is any C_1-4An alkyl group;

wherein R is₆Is C_1-3An alkyl group; or

Wherein R is₇Is H.

54. The compound of item 53, represented by the following formula 10CPT,

55. a compound of item 54, represented by the following formula 10CPT (R),

56. the compound of item 55, represented by the following formula 10CPT (S),

57. the compound of item 1, represented by the following structural formula,

formula 11G

Wherein R is₁Optionally substituted C_1-8Alkyl radical, C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cyclic group, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₃Optionally substituted C_1-8Alkyl radical, C₁-C₆Alkyl, cycloalkyl, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl and alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₄Is H, optionally substituted C_1-8Alkyl radical, C₁-C₆Alkyl radical, including C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₆Optionally substituted C_1-8Alkyl radical, C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl;

wherein R is₇Independently H, optionally substituted C_1-8Alkyl radical, C₁-C₆Alkyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl, or both R₇The groups may be joined together to form cyclopentane or cyclohexane or substituted derivatives thereof.

58. A compound of the item 57,

Wherein R is₇Independently is H, or C₁-C₆An alkyl group.

59. The compound of the claim 58, wherein,

wherein R is₁Is C₁-C₆Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₃Is benzyl or substituted benzyl;

wherein R is₄Is H, C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C₁-C₆alkyl-C_3-6A cycloalkyl group;

wherein R is₆Is C₁-C₆An alkyl group; or

Wherein R is₇Independently is H.

60. A compound of the formula (I) in item 59,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₃Is benzyl or substituted benzyl;

wherein R is₄Is C_1-4An alkyl group;

wherein R is₆Is ethyl.

61. The compound of item 60, represented by the following formula 11CPT,

62. the compound of item 61, represented by the following formula 11CPT (R),

63. the compound of item 62, represented by the following formula 11CPT (S),

64. the compound of item 1, represented by the following structural formula,

formula 12GA-1

Wherein R is₁Optionally substituted C_1-8Alkyl radical, C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₃Optionally substituted C_1-8Alkyl radical, C₁-C₆Alkyl, cycloalkyl, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl and alkylaryl or substituted alkylaryl groups, C₁-C₆Alkyl, including benzyl and substituted benzyl;

wherein R is₄Is H, optionally substituted C_1-8Alkyl radical, C₁-C₆Alkyl radicals including C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₆Optionally substituted C_1-8Alkyl radical, C₁-C₆Alkyl radicals including ethyl, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl;

65. The compound of the item 64 which is,

wherein R is₁Is any optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₁-C₆alkyl-C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, or substituted C₆-C₁₂Aryl, or benzyl;

wherein R is₄Is H, optionally substituted C_1-4Alkyl radical, C_3-6Cycloalkyl radical, C₁-C₆Alkyl radical C_3-6A cycloalkyl group;

Wherein R is₇Independently H, or optionally substituted C_1-6An alkyl group.

66. A compound of the item 65 which is,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₃Is benzyl or substituted benzyl;

wherein R is₄Is H, C_1-4An alkyl group;

Wherein R is₇Independently H, C_1-3An alkyl group.

67. The compound of item 66 wherein the compound is,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₃Is benzyl or isA substituted benzyl group; or

Wherein R is₆Is C_1-3An alkyl group; or

Wherein R is₇Is H.

68. The compound of item 67, represented by the following formula 12CPTA-1,

69. the compound of item 68, represented by the following formula 12CPTA-1(R),

70. the compound of item 69, represented by the following formula 12CPTA-1(S),

71. the compound of item 1, represented by the following structural formula,

12GB-1

wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl.

72. The compound of the item 71,

wherein R is₄Is H, optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₁-C₆alkyl-C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl or substituted C₆-C₁₂Aryl, or benzyl;

wherein R is₆Optionally substituted C₁-C₈The alkyl group includes ethyl and C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, substituted C₁-C₆alkyl-C₆-aryl, or benzyl.

73. The compound of the claim 72, wherein,

wherein R is₁Is C_1-4Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₄Is C_1-4C₁-C₆Alkyl radical, C_3-6A cycloalkyl group; or

Wherein R is₆Is C_1-4Alkyl includes ethyl, or C₆-C₁₂And (4) an aryl group.

74. The compound of item 73 wherein the compound of formula,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₄Is C_1-3An alkyl group; or

Wherein R is₆Is C_1-3An alkyl group.

75. The compound of item 74, represented by the following formula 12CPTB-1,

76. the compound of item 75, represented by the following formula 12CPTB-1(R),

77. the compound of item 76, represented by the following formula 12CPTB-1(S),

78. the compound of item 1, represented by the following structural formula,

formula 12GA-2 or

Formula 12GB-2

wherein R is₄Is H, optionally substituted C_1-8Alkyl includes optionally substituted C_1-6The alkyl group comprising C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

79. The compound of the item 78,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₁-C₆alkyl-C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, or substituted C₆-C₁₂Aryl, or benzyl;

wherein R is₄Is H, C₁-C₆Alkyl, aryl, heteroaryl, and heteroaryl,C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, and C_1-6alkyl-C_1-6Aryl, or substituted C_1-6alkyl-C_1-6Aryl includes benzyl and substituted benzyl; or

Wherein R is₆Is C₁-C₆The alkyl group includes ethyl and C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, substituted C₁-C₆alkyl-C₆-aryl, or benzyl.

80. A compound of the item 79,

wherein R is₁Is C_1-4Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₄Is H, C_1-4Alkyl radical, C_3-6A cycloalkyl group; or

81. The compound of the claim 80, wherein,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₃Is benzyl or substituted benzyl;

wherein R is₆Is C_1-3An alkyl group.

82. The compound of item 81, represented by the following formula 12CPTA-2 or 12CPTB-2,

83. the compound of item 82, represented by the following formula 12CPTA-2(R) or 12CPTB-2(R),

84. a compound of item 83, represented by the following formula 12CPTA-2(S) or 12CPTB-2,

85. the compound of item 1, represented by the following structural formula,

formula 12G

86. The compound of the item 85, wherein,

wherein R is₄Is H, optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, and C_1-6alkyl-C_1-6Aryl, or substituted C_1-6alkyl-C_1-6Aryl includes benzyl and substituted benzyl; or

87. The compound of item 86 which is a pharmaceutically acceptable salt thereof,

wherein R is₁Is C_1-4Alkyl radical, C_3-6A cycloalkyl group;

wherein R is₄Is C_1-4Alkyl radical, C_3-6A cycloalkyl group; or

88. The compound of item 87, wherein the compound of formula (I),

wherein R is₁Is C_1-3An alkyl group;

wherein R is₄Is C_1-3An alkyl group; or

Wherein R is₆Is C_1-3An alkyl group.

89. The compound of item 88, represented by the following formula 12CPT,

90. a compound of item 89, represented by the following formula 12CPT (R),

91. the compound of item 90, represented by the following formula 12CPT (S),

92. the compound of item 1, represented by the following structural formula,

formula 13G

Wherein R is₆Optionally substituted C_1-8The alkyl group comprising C_1-6The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl; or

Wherein R is₈Optionally substituted C_1-8The alkyl group comprising C_1-6Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl; or substituted derivatives thereof.

93. The compound of the claim 92, wherein,

Wherein R is₈Optionally substituted C₁-C₆Alkyl radical, C_3-6Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, and C_1-6alkyl-C_1-6Aryl, or substituted C_1-6alkyl-C_1-6Aryl includes benzyl and substituted benzyl.

94. The compound of claim 93, wherein the compound of formula (I),

wherein R is₆Is C₁-C₆Alkyl includes ethyl, or 1-6 aryl; or

Wherein R is₈Is C₁-C₆Alkyl includes ethyl, or C_1-6And (4) an aryl group.

95. The compound of claim 94, wherein the compound of formula,

wherein R is₆Is a butyl group; or

Wherein R is₈Is C₁-C₆Alkyl includes ethyl, or C_1-6And (4) an aryl group.

96. The compound of item 95, represented by the following formula 13CPT,

97. a compound of item 96, represented by the following formula 13CPT (R),

98. the compound of item 97, represented by the following formula 13CPT (S),

98a, toluene solvates of the compounds of items 92-98.

99. The compound of item 1, represented by the following structural formula,

formula 5MG

Wherein R is₁Optionally substituted C_1-8The alkyl group comprising C_1-6Alkyl radical, C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₂Is H, optionally substituted C_1-8The alkyl group comprising C_1-6Alkyl, alkaryl radicals including C_1-6Alkyl-aryl, C_1-6alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl;

100. The compound of the item 99 which is,

wherein R is₁Optionally substituted C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₂Is H, optionally substituted C₁-C₆An alkyl group; or

Wherein R is₆Optionally substituted C₁-C₆Alkyl, ethyl, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl including benzyl and substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10A cyclic aryl, heteroaryl or substituted heteroaryl.

101. The compound of the claim 100, wherein,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl, alkaryl, or substituted C₁-C₆Alkyl radical C₆Aryl includes benzyl and substituted benzyl;

wherein R is₂Is C_1-6An alkyl group; or

Wherein R is₆Is C₁-C₆Alkyl, ethyl, C₆Aryl, substituted C₆Aryl radical, C₁-C₆Alkyl radical C₆Aryl, substituted C₁-C₆Alkyl radical C₆Aryl groups include benzyl and substituted benzyl.

102. The compound of the claim 101, wherein,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₂Is C_1-3An alkyl group; or

Wherein R is₆Is C_1-3The alkyl group includes ethyl.

103. The compound of item 102, represented by the following formula 5MM,

104. the compound of item 1, represented by the following structural formula,

formula 6MG

wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl, benzyl, substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl.

105. The compound of the claim 104, wherein,

wherein R is₁Optionally substituted C₁-C₆Alkyl radical, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₂Optionally substituted alkyl includes C_1-6Alkyl, benzyl and substituted benzyl;

wherein R is₆Optionally substituted C₁-C₆Alkyl, ethyl, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl, benzyl, substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10-cycloalkyl, heteroaryl or substituted heteroaryl.

106. The compound of the claim 105, wherein,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, or substituted alkaryl include benzyl or substituted benzyl;

wherein R is₂Is C_1-4An alkyl group;

wherein R is₆Is C₁-C₆Alkyl, ethyl, C₆Aryl, substituted C₆Aryl radical, C₁-C₆Alkyl radical C₆Aryl, substituted C₁-C₆Alkyl radical C₆Aryl, benzyl, substituted benzyl.

107. The compound of the claim 106 wherein said compound is,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₂Is C_1-3An alkyl group; or

Wherein R is₆Is C_1-3The alkyl group includes ethyl.

108. The compound of item 107, represented by the following formula 6MM,

109. the compound of item 1, represented by the following structural formula,

formula 7MG

110. The compound of the formula (I) according to item 109,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl groups include benzyl and substituted benzyl;

wherein R is₂Is H, C_1-6Alkyl radical, C_1-6alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl;

wherein R is₃Is H, C₁-C₆Alkyl radical, C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆alkyl-C₆Aryl includes benzyl and substituted benzyl;

wherein R is₆Is any C₁-C₆The alkyl group includes ethyl and C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl groups include benzyl and substituted benzyl.

111. The compound of the claim 110, wherein,

wherein R is₁Is any C₁-C₆Alkyl radical, C_3-7A cycloalkyl group;

wherein R is₂Is C_1-4An alkyl group;

wherein R is₃Is H, C₁-C₆Alkyl radical, C₁-C₆alkyl-C_3-7A cycloalkyl group;

112. The compound of item 111, wherein,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₂Is C_1-3An alkyl group;

wherein R is₃Is H; or

Wherein R is₆Is C_1-3The alkyl group includes ethyl.

113. The compound of item 112, represented by the following formula 6bMM,

114. the compound of item 111, represented by the following formula 7MM,

115. the compound of item 1, represented by the following structural formula,

formula 8MG

wherein R is₃Is H, optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl, cycloalkyl, C₂-C₈Alkenyl radical C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl and alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₄Is H, optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl, cycloalkyl, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl, ethyl, C₆-C₁₂Aryl radical, aryl radicalGeneration C₆-C₁₂Aryl, alkaryl, substituted alkaryl, benzyl, substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl.

116. The compound of the item 115, wherein,

wherein R is₁Optionally substituted C_1-8The alkyl group comprising C_1-6Alkyl radical, C₁-C₆Alkyl radical C₁-C₆Alkyl radical, C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl groups include benzyl and substituted benzyl;

wherein R is₂Is H, optionally substituted C_1-8The alkyl group comprising C_1-6Alkyl radical, C_1-6alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl;

wherein R is₃Is H, optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl radical, C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl includes benzyl and substituted benzyl;

wherein R is₄Is H, optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl radical, C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl or substituted C₁-C₆Alkyl radical C₆Aryl radicals including benzylAryl and substituted benzyl;

wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl groups include benzyl and substituted benzyl.

117. The compound of the claim 116, wherein,

wherein R is₁Optionally substituted C₁-C₆Alkyl radical, C_3-7A cycloalkyl group;

wherein R is₂Is H, C_1-6Alkyl, substituted benzyl and unsubstituted benzyl;

wherein R is₃Is H, any optionally substituted C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl includes benzyl and substituted benzyl;

wherein R is₄Is H, optionally substituted C₁-C₆Alkyl radical, C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl or substituted C₁-C₆Alkyl radical C₆Aryl includes benzyl and substituted benzyl;

wherein R is₆Optionally substituted C₁-C₆Alkyl, ethyl, C₆Aryl, substituted C₆Aryl radical, C₁-C₆Alkyl radical C₆Aryl radicalsSubstituted C₁-C₆Alkyl radical C₆Aryl, benzyl, substituted benzyl.

118. The compound of item 117 wherein the compound is,

wherein R is₁Is C_1-3An alkyl group;

wherein R is₂Is C_1-3An alkyl group;

wherein R is₃Is H, C₁-C₆alkyl-C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl includes benzyl and substituted benzyl; or

Wherein R is₄Is C_1-3An alkyl group; or

Wherein R is₆Is C_1-3The alkyl group includes ethyl.

119. The compound of item 118, represented by the following formula 8MM,

120. the compound of item 1, represented by the following structural formula,

formula 9MG

Wherein R is₂Is H, optionally substituted C_1-8The alkyl group comprising C_1-6Alkyl, alkaryl radicals including C_1-8Alkyl-aryl, C_1-8alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl;

121. The compound of the claim 120, wherein,

wherein R is₂Is H, optionally substituted C_1-6Alkyl radical, C_1-6alkyl-C₆Aryl includes substituted benzyl and unsubstituted benzyl;

wherein R is₃Is H, optionally substituted C₁-C₆Alkyl radical, C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl includes benzyl and substituted benzyl;

wherein R is₆Optionally substituted C₁-C₆The alkyl group includes ethyl and C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl groups include benzyl and substituted benzyl.

122. The compound of the formula (I) in item 121,

wherein R is₂Is H, optionally substituted C_1-4An alkyl group;

wherein R is₃Is H, optionally substituted C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl includes benzyl and substituted benzyl;

wherein R is₆Optionally substituted C₁-C₆The alkyl group includes ethyl and C₆Aryl, substituted C₆Aryl radical, C₁-C₆Alkyl radical C₆Aryl, substituted C₁-C₆Alkyl radical C₆Aryl, benzyl, substituted benzyl。

123. The compound of item 122, wherein,

wherein R is₂Is H or C_1-3An alkyl group;

wherein R is₃Is H, any C₁-C₆alkyl-C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl includes benzyl and substituted benzyl; or

Wherein R is₄Is H or C_1-3An alkyl group; or

Wherein R is₆Is C_1-3The alkyl group includes ethyl.

124. The compound of item 123, represented by the following formula 9MM,

125. the compound of item 1, represented by the following structural formula,

formula 10MG

wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl, benzyl, substituted benzyl, C_3-10Cycloalkyl radical, C₁-C₆Alkyl radical C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl;

wherein R is₈Optionally substituted C_1-8The alkyl group comprising C₁-C₆Alkyl includes t-butyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl groups include benzyl and substituted benzyl groups.

126. The compound of item 125, wherein,

wherein R is₂Optionally substituted C_1-6Alkyl radical, C_1-6alkyl-C₆Aryl, including substituted benzyl and unsubstituted benzyl;

wherein R is₆Optionally substituted C₁-C₆The alkyl group includes ethyl and C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl radicalsOr substituted C₁-C₆Alkyl radical C₆Aryl groups include benzyl and substituted benzyl; or

Wherein R is₈Optionally substituted C₁-C₆Alkyl includes t-butyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10A cycloalkyl group.

127. The compound of item 126 wherein,

wherein R is₂Is H, or C_1-4An alkyl group;

wherein R is₃Is H, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl includes benzyl and substituted benzyl;

wherein R is₆Is C₁-C₆Alkyl, ethyl, C₆Aryl, substituted C₆Aryl radical, C₁-C₆Alkyl radical C₆Aryl, substituted C₁-C₆Alkyl radical C₆Aryl, benzyl, substituted benzyl; or

Wherein R is₈Is any C₁-C₆Alkyl includes t-butyl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10A cycloalkyl group.

128. The compound of item 127, wherein the compound of formula (I),

wherein R is₂Is C_1-3An alkyl group;

wherein R is₃Is H, C₁-C₆alkyl-C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl includes benzyl and substituted benzyl;

wherein R is₆Is C_1-3Alkyl groups include ethyl; or

Wherein R is₈Is any C₁-C₆Alkyl groups include t-butyl.

129. The compound of item 128, represented by the following formula 10MM,

130. the compound of item 1, represented by the following structural formula,

formula 11MG

wherein R is₃Is H, optionally substituted C_1-8The alkyl group comprising C_1-6The alkyl group comprising C₁-C₆Alkyl, cycloalkyl, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl and alkaryl or substituted alkaryl groups including benzyl and substituted benzyl;

131. The compound of the claim 130, wherein,

wherein R is₂Is H, optionally substituted C_1-8The alkyl group comprising C_1-6Alkyl radical, C_1-6alkyl-C₆Aryl includes substituted benzyl and unsubstituted benzyl;

wherein R is₆Optionally substituted C_1-8The alkyl group comprising C₁-C₆The alkyl group includes ethyl and C_3-7Cycloalkyl radical, C₁-C₆alkyl-C3-7 cycloalkyl, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl groups include benzyl and substituted benzyl.

132. The compound of the claim 131, wherein,

wherein R is₂Is C_1-4An alkyl group;

wherein R is₃Is H, optionally substituted C₁-C₆Alkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C_3-7Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆Aryl includes benzyl and substituted benzyl; or

133. The compound of item 132 wherein the compound is,

wherein R is₂Is C_1-3An alkyl group;

wherein R is₃Are benzyl and substituted benzyl;

wherein R is₆Is C_1-3The alkyl group includes ethyl.

134. The compound of item 133, represented by the following formula 11MM,

135. the compound of item 1, represented by the following structural formula,

formula 12MG

Wherein R is₂Is H, optionally substituted C_1-8The alkyl group comprising C_1-6Alkyl, alkaryl radicals including C_1-6Alkylaryl group, C_1-6alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl;

wherein R is₃Is H, optionally substituted C_1-8The alkyl group comprising C_1-6Alkyl, cycloalkyl, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl and alkaryl or substituted alkaryl, benzyl, substituted benzyl; or

136. The compound of claim 135, wherein the compound of formula,

wherein R is₂Is H or optionally substituted C_1-6Alkyl radical, C_1-6alkyl-C₆Aryl, substituted benzyl and unsubstituted benzyl;

wherein R is₃Is H, optionally substituted C_1-6The alkyl group comprising C₁-C₆Alkyl, cycloalkyl, C₆Aryl, substituted C₆Aryl, and C_1-6Alkyl radical C₆Aryl, or substituted C_1-6Alkyl radical C₆Aryl includes benzyl and substituted benzyl; or

137. The compound of item 136 wherein the compound of formula,

wherein R is₂Is H, C_1-6An alkyl group;

wherein R is₃Is H, optionally substituted C_1-6Alkyl radical, C_1-6alkyl-C₆Aryl includes benzyl and substituted benzyl; or

Wherein R is₆Optionally substituted C₁-C₆Alkyl, ethyl, C₆Aryl, substituted C₆Aryl radical, C₁-C₆Alkyl radical C₆Aryl, substituted C₁-C₆Alkyl radical C₆Aryl, benzylSubstituted benzyl groups.

138. The compound of item 137 which is a pharmaceutically acceptable salt thereof,

wherein R is₂Is C_1-3An alkyl group;

wherein R is₃Is substituted benzyl and unsubstituted benzyl;

wherein R is₆Is C_1-3The alkyl group includes ethyl.

139. The compound of item 138, represented by the following formula 12MM,

140. a process for the preparation of a compound of formula 2G as described in item 2 comprising either 1) mixing 2, 6-dichloroisonicotinic acid with a nucleophile which is either a grignard reagent or an alkyl lithium and an ether solvent and then contacting the reaction product with a dilute acid, or 2) converting 2, 6-dichloroisonicotinic acid to an acid chloride which is then converted to a Weinreb amide which is then mixed with a nucleophile which is either a grignard reagent or an alkyl lithium and an ether solvent and then contacting the reaction product with a dilute acid.

141. The method of item 140, wherein the reactants are maintained at about-30 ℃ to about +10 ℃.

142. The method of item 141, wherein the compound produced is described in item 6, see formula 2 CPT.

143. The process of item 140 for preparing a compound of formula 3G of item 7, starting with the product of item 140, formula 2G and mixing the product with an alcohol or diol in the presence of chlorotrimethylsilane.

144. The method of item 143, wherein the alcohol or glycol is ethylene glycol.

145. The method of item 143, wherein the compound prepared is described in item 11, is formula 3CPT,

146. the method of item 143, wherein the alcohol or glycol is ethylene glycol and the temperature is maintained at from about 0 ℃ to about +60 ℃.

147. The compound of item 143 for use in preparing the compound of item 12, see formula 4G, starting from the product of item 143, formula 3G, and mixing the product with a sodium or potassium alkoxide in a solvent.

148. The compound of item 147, wherein the reactants are maintained at a temperature in the range of about 20 ℃ to about 80 ℃.

149. The process of item 147 for preparing the compound of formula 5G of item 12 from the product of item 147 formula 4G-wherein R₂Starting with hydrogen and mixing the product with a solvent and an alkyl or aryl lithium base to form a pyridyl anion, which is then mixed with an electrophile, after which the product is mixed with an acid and the final product is isolated.

150. The process of item 149, wherein the solvent is selected from diethyl ether, tetrahydrofuran or 1, 2-dimethoxyethane or a hydrocarbon such as toluene, hexane, heptane, cyclohexane or isooctane, or a mixture of these solvents.

151. The process of item 149, wherein the alkyllithium is selected from methyllithium, n-butyllithium, sec-butyllithium, tert-butyllithium, or any mixture thereof.

152. The method of item 149, wherein the electrophile is a formamide comprising dimethylformamide, N-formylpiperidine or N-formylmorpholine or N-methylformanilide or similar formamide or mixtures thereof.

153. The method of item 149, wherein the reactants are maintained at a temperature in the range of about-40 ℃ to about +50 ℃.

154. The method of item 153, wherein the reactants are maintained at a temperature in the range of about-5 ℃ to about +5 ℃.

155. The process of item 153, wherein the product is isolated with dilute acid.

156. The process of clause 155, wherein the dilute acid is selected from a medium strength acid to a strong acid such as hydrochloric acid, acetic acid, or sulfuric acid, or any mixture thereof.

The method of item 155, 156a, wherein sodium bisulfite is mixed with the product of item 155 and the compound formed is a bisulfite adduct.

157. The method of item 156, wherein the product compound is represented by formula 5 aCPT.

The method of item 156a, wherein the 5aCPT bisulfite adduct is further combined with an acid or base to produce a compound represented by formula 5 aCPT.

158. The process of item 147 for preparing a compound of formula 4G or 5G of item 12 from the product of item 147 formula 4G-wherein R₂Is hydrogen or the product of item 149 formula 5G begins and the product is mixed with a reducing agent.

159. The method of item 158, wherein the reducing agent is a hydride.

160. The method of item 159, wherein the hydride is sodium borohydride.

161. The method of item 158, wherein the reactants are mixed in an alcohol or under biphasic conditions.

162. The process of item 161, wherein the alcohol is methanol or 2-propanol, or the biphasic conditions are water and an organic phase.

163. The process of item 162, wherein the organic phase is heptane, dichloromethane or methyl tert-butyl ether, or a mixture of these solvents.

164. The method of item 158, wherein the compound produced is represented by formula 5CPT described in item 17.

165. The method of item 158, wherein the compound produced is represented by formula 5MM as described in item 18.

166. The process of item 158, for preparing the compound of formula 6G of item 19, starting from the product of formula 5G of item 58 and either a) mixing the product with a base and an alkylating agent in a solvent, or b) mixing the product under phase transfer conditions using water and an organic solvent.

167. The process of item 166, wherein the base is a hydride such as sodium or potassium hydride or an alkoxide base such as potassium tert-butoxide or a mixture of such bases.

168. The process of item 167, wherein the base is potassium tert-butoxide.

169. The process of item 167, wherein the solvent is selected from an ether solvent such as Tetrahydrofuran (THF), methyl tert-butyl ether (MTBE) or 1, 2-dimethoxyethane or an alcohol such as tert-butanol.

170. The process of item 169, wherein the solvent is THF or MTBE and the temperature is about 20 ℃ to about 40 ℃.

171. The process of item 166, wherein the organic solvent is selected from dichloromethane, or a hydrocarbon such as hexane, heptane or toluene, and wherein the base is selected from a hydroxide such as sodium hydroxide or potassium hydroxide or a carbonate such as sodium carbonate or potassium carbonate.

172. The method of item 166, wherein the compound prepared is represented by formula 6CPT described in item 21.

173. The method of item 166 for preparing a compound of formula 7G or 7GG of item 22, starting with the product of item 166 formula 6G and combining the product with carbon monoxide and an alcohol in a polar aprotic solvent in the presence of a soluble palladium II salt, a phosphine ligand and a base.

174. The method of item 173, wherein the soluble palladium II salt is selected from palladium acetate.

175. The process of item 174, wherein the phosphine ligand is selected from 1, 3-bis diphenylphosphinopropane.

176. The process of item 175, wherein the base is selected from the group consisting of sodium or potassium acetate, sodium or potassium carbonate, triethylamine or tri-n-butylamine.

177. The method of item 176, wherein the polar aprotic solvent is selected from dimethylformamide or acetonitrile.

178. The method of item 177, wherein the compound prepared is represented by formula 7CPTG described in item 24.

179. The process of item 173, used for preparing the compound of formula 7GA of item 25, starting from the product of item 173, formula 6G and then removing the ketal by a) mixing the product with water in the presence of a strong acid, or b) removing the ketal by an exchange reaction.

181. The method of item 180, wherein the acid concentration is about 50 to 90%.

180. The method of item 179, wherein the temperature of the method is about 15 ℃ to about 80 ℃.

182. The process of item 181, wherein the strong acid is trifluoroacetic acid.

183. The method of item 182, wherein the compound prepared is represented by 7CPTA described in item 27.

184. The method of clause 179, wherein the exchange reaction is catalyzed by a strong acid using a ketone or is carried out on an acidic ion exchange resin.

185. The process of item 184, wherein the ketone is acetone or 2-butanone, or wherein the acidic ion exchange resin is, for example, amberlystA-15 macroporous resin.

186. The method of item 185, wherein the compound prepared is represented by formula 7CPTA described in item 27.

187. The method of clause 179, for preparing a compound of formula 8GG of clause 28, starting from the product of clause 173, formula 7G or 7GG, and then removing the ketal by a) mixing the product with water in the presence of a strong acid, or by b) removing the ketal using an exchange reaction.

188. The process of item 187, wherein the process temperature is about 15 ℃ to about 80 ℃.

189. The method of item 188, wherein the concentration of the acid is about 50-90%.

190. The process of clause 189, wherein the strong acid is trifluoroacetic acid.

191. The method of item 190, wherein the compound produced is represented by 8CPTG described in item 31.

192. The method of item 187, wherein the exchange reaction is catalyzed by a strong acid using a ketone or is performed on an acidic ion exchange resin.

193. The process of item 192, wherein the ketone is acetone or 2-butanone, or wherein the acidic ion exchange resin is, for example, amberlystA-15 macroporous resin.

194. The method of item 193, wherein the compound produced is represented by formula 8CPTG described in item 31.

195. The process of item 179 or 187, for preparing a compound of formula 8GA of item 32, starting from the product of item 179 or 187, formula 7GA and dissolving the product in a solvent, mixed with a lithium vinyl halide or magnesium vinyl halide.

196. The process of item 195, wherein the solvent is selected from ethers such as diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane or MTBE, and these solvents can be used alone or in a mixture, or in a mixture with a hydrocarbon such as toluene, heptane or cyclohexane.

197. The process of item 196, wherein the temperature of the process is about-78 ℃ to about 25 ℃.

198. The process of clause 197, wherein the product is isolated with dilute acid after the reaction.

199. The process of item 198, wherein the dilute acid is hydrochloric acid, sulfuric acid, or acetic acid

200. The method of item 199, wherein the compound prepared is represented by 8CPTA described in item 36.

201. The process of item 179, for the preparation of a compound of formula 8GB of item 37, starting from the product of item 179, formula 7GA and mixing this product in an ylide solution and a solvent of a wittig reaction.

202. The method of item 201, wherein the ylide solution is prepared from a methyltriphenylphosphonium salt and a strong base in a solvent.

203. The process of item 202, wherein the solvent is diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane or DMF.

204. The process of item 203, wherein the strong base is selected from n-butyllithium, potassium tert-butoxide, or potassium bistrimethylsilylamide.

205. The process of item 204, wherein the methyltriphenylphosphonium salt is a bromide salt, the base is potassium bistrimethylsilylamide, and the solvent is DMF.

206. The process of item 205, wherein the process temperature is about-5 ℃ to about 25 ℃ and the reaction is carried out for about 5 minutes to about 2 hours.

207. The method of item 206, wherein the compound prepared is represented by 8CPTB as described in item 40.

208. Process according to item 187 for the preparation of a compound of formula 9GG according to item 41 starting from the product of item 187 formula 8GG and mixing this product in an ylium solution and a solvent of a wittig reaction.

209. The method of item 208, wherein the ylide solution is prepared from a methyltriphenylphosphonium salt and a strong base in a solvent.

210. The process of item 209, wherein the solvent is diethyl ether, tetrahydrofuran, 1, 2-dimethoxyethane or DMF.

211. The process of item 210, wherein the strong base is selected from n-butyllithium, potassium tert-butoxide, or potassium bistrimethylsilylamide.

212. The process of item 211, wherein the methyltriphenylphosphonium salt is a bromide salt, the base is potassium bistrimethylsilylamide, and the solvent is DMF.

213. The process of item 212, wherein the process temperature is from about-5 ℃ to about 25 ℃ and the reaction is carried out for from about 5 minutes to about 2 hours.

214. The method of item 213, wherein the compound produced is represented by 9CPTG described in item 44.

215. The process of item 195 for preparing a compound of formula 9GA of item 45 by mixing the product of item 195, starting with formula 8GA, with a solvent and ozone to produce an intermediate, which is reduced to 9GA directly or via an intermediate.

216. The method of item 195, wherein the solvent is selected from chlorinated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, or other polychlorinated ethanes or ethylene derivatives, used alone or in a mixture, or in a mixture with an alcohol such as methanol.

217. The process of item 216, wherein the process temperature is from about-78 ℃ to about-25 ℃.

218. The method of item 217, wherein the reducing agent is sodium borohydride.

219. The process of item 218, wherein the solvent is selected from the group consisting of a mixture of dichloromethane and methanol, and wherein the initial reaction temperature with ozone is from about-78 ℃ to about-40 ℃, and the temperature of the reduced intermediate is from about 0 ℃ to about 25 ℃.

220. The method of item 219, wherein the compound prepared is represented by 9CPTA described in item 49.

221. The method of item 208, for preparing a compound of formula 10G of item 50, starting from the product of item 208, formula 9GG, and converting the diol by conducting an osmium reaction under standard conditions.

222. The process of item 221, wherein the temperature of the process is from about 15 ℃ to about 50 ℃.

223. The method of item 222, wherein the compound prepared is represented by 10CPT described in item 54.

224. The method of item 208 for preparing a compound of formula 10GG of item 50, starting from the product of item 208 formula 9GG and converting the diol by conducting an osmium reaction under standard conditions.

225. The process of item 224, wherein the temperature of the process is about 15 ℃ to about 50 ℃.

226. The method of item 224, wherein the compound prepared is represented by formula 10CPT described in item 54.

227. The process of item 215, for preparing the compound of formula 10G of item 50, starting with the product of item 215, formula 9GA and combining the product with carbon monoxide and an alcohol in a polar aprotic solvent in the presence of a soluble palladium II salt, a phosphine ligand, and a base.

228. The method of item 227, wherein the soluble palladium II salt is selected from palladium acetate.

229. The process of item 228, wherein the phosphine ligand is selected from the group consisting of 1, 3-bis diphenylphosphinopropane.

230. The process of item 229, wherein the base is selected from sodium or potassium acetate, sodium or potassium carbonate, triethylamine or tri-n-butylamine.

231. The method of item 230, wherein the polar aprotic solvent is selected from dimethylformamide or acetonitrile.

232. The method of item 231, wherein the compound prepared is represented by formula 10CPT described in item 54.

233. The process of resolution of the compound of formula 10G described in item 50 by treatment of racemic diol with an acetylating agent.

234. The process of item 233, wherein the acetylating agent is selected from vinyl acetate, isopropenyl acetate, acetic anhydride or ethyl acetate in an organic solvent with a suitable lipase.

235. The process of item 234, wherein the organic solvent is diethyl ether and the lipase is Pseudomonas.

236. The method of item 234, wherein the lipase is Pseudomonas cepacia.

237. The process of item 233, wherein the lipase is Pseudomonas cepacia, the process is carried out at 25 ℃ to 45 ℃ at a substrate concentration of 15-40 mg/ml, and the resolved compound is represented by formula 10CPT (R) or 10CPT (S) as described in items 55 and 56.

238. A process for preparing a compound of formula 11G as described in item 57 by oxidizing a compound of formula 10G as described in item 50 to a hydroxyaldehyde either under a) Swern type conditions or b) in a two-phase system comprising water and an aprotic solvent.

239. The process of item 238, wherein Swern conditions are DMSO, oxalyl chloride, and triethylamine in an aprotic solvent at a temperature in the range of about-78 ℃ to about 25 ℃.

240. The process of item 239, wherein the aprotic solvent is dichloromethane.

241. The process of item 238, wherein the two-phase system comprising water and aprotic solvent is a sodium hypochlorite solution catalyzed by TEMPO or a substituted TEMPO such as 4-acetoxy-TEMPO and the other phase is dichloromethane.

242. The process of clause 241, wherein the process temperature is from about-5 ℃ to about +25 ℃ and the reaction time is from about 30 minutes to about 2 hours.

243. The process of item 242 for preparing a compound of formula 11CPT described in item 61, a compound of formula 11CPT (r) described in item 62, or a compound of formula 11CPT(s) described in item 63.

244. The process of item 238, oxidizing the product of item 238, formula 11G, for preparing the compound of formula 12GA-1 of item 64.

245. The method of item 242, wherein the temperature is about 10 ℃ to about 20 ℃ and the reaction time is about 1 hour.

246. The method of item 242, wherein the oxidizing agent is sodium chlorite.

247. The process of item 244, making the compound of formula 12CPTA-1 as described in item 68, the compound of formula 12CPTA-1(R) as described in item 69, or the compound of formula 12CPTA-1(S) as described in item 70.

248. The process of item 238, removing the leaving group from the product of item 238, formula 11G, to produce the compound of formula 12GB-1 of item 71.

249. The method of item 248, wherein the leaving group is removed by hydrogenation with a catalyst.

250. The method of item 249, wherein the catalyst is palladium.

251. The process of item 248 wherein the compound prepared is represented by formula 12CPTB-1 as described in item 75, formula 12CPTB-1(R) as described in item 76, or formula 12CPTB-1(S) as described in item 76.

252. The process of item 244, removing the leaving group from the product of item 244, formula 12GA-1, to produce a compound of formula 12GA-2 or 12GB-2 of item 78.

253. The method of item 252, wherein the leaving group is removed by hydrogenation with a catalyst.

254. The method of item 253, wherein the catalyst is palladium.

255. The method of item 252, wherein the compound prepared is represented by formula 12CPTA (B) -2 as described in item 82, formula 12CPTA (B) -2(R) as described in item 83, or formula 12CPTA (B) -2(S) as described in item 84.

256. The process of item 248, oxidizing the product of item 248, the lactitol of formula 12GB-1, to produce a compound of formula 12GA-2 or 12GB-2 of item 78.

257. The process of item 256, wherein the lactitol is oxidized under a) Swern conditions, or b) in a two-phase system comprising water and an aprotic solvent.

258. The method of clause 257, wherein the Swern conditions are DMSO, oxalyl chloride, and triethylamine in an aprotic solvent at a temperature in the range of about-78 ℃ to about 25 ℃.

259. The process of item 258, wherein the aprotic solvent is dichloromethane.

260. The method of item 256, wherein the compound prepared is represented by formula 12CPTA (B) -2 as described in item 82, formula 12CPTA (B) -2(R) as described in item 83, or formula 12CPTA (B) -2(S) as described in item 84.

261. The process of item 244, removing the leaving group from the product of item 244, formula 12GA-1, by mixing the compound with trimethylsilyl iodide to prepare a compound of formula 12G of item 85.

262. The process of clause 261, wherein the trimethylsilyl group is preformed or produced in situ from trimethylsilyl chloride and sodium iodide in dichloromethane or acetonitrile and the process temperature is in the range of about 15-50 ℃ and the reaction time is 12 to 48 hours.

263. The process of item 261, wherein the compound prepared is represented by formula 12CPTA described in item 89, formula 12CPT (R) described in item 90, or formula 12CPT (S) described in item 91.

264. The process of item 252, removing the leaving group from the product of item 252, formula 12GA-2 or 12GB-2, by mixing the compound with trimethylsilyl iodide to produce a compound of formula 12G of item 85.

265. The process of item 264, wherein the trimethylsilyl group is preformed or produced in situ from trimethylsilyl chloride and sodium iodide in dichloromethane or acetonitrile and the temperature of the process is in the range of about 15-50 ℃ and the reaction time is 12 to 48 hours.

266. The process of item 265 wherein the compound prepared is represented by formula 12CPTA described in item 89, formula 12cpt (r) described in item 90, or formula 12cpt(s) described in item 91.

267. A method for preparing compound 13G of item 92, comprising mixing the compound of item 85, formula 12G, and an acrylate in the presence of a base.

268. The process of item 267, wherein the acrylate is methyl, ethyl or tert-butyl acrylate.

269. The process of item 268, wherein the base is potassium hydride, sodium hydride, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate or a tertiary amine including diisopropylethylamine in a polar aprotic solvent such as dimethyl sulfoxide, DMF or acetonitrile.

270. The process of clause 267, wherein the acrylate is t-butyl acrylate and the base is cesium carbonate in DMSO at a reaction temperature of about 20-100 ℃, preferably 50 ℃, wherein the compound prepared is represented by formula 13CPT as described in clause 96, formula 13CPT (R) as described in clause 97, or formula 13CPT (S) as described in clause 98.

270a, 267 in which the variable parameters are as defined above, wherein the ketoester is converted to the compound of formula 14G by mixing 13G with a strong acid.

270b. the method of item 270a, wherein a solvent such as toluene is added to the acid, ketoester mixture.

270c. the process of clause 270b, wherein the solvent is toluene and the acid is trifluoroacetic acid.

271. The method of item 149, wherein the electrophile is a methylating agent comprising dimethyl sulfate, methyl iodide, methyl bromide, or methyl triflate.

272. The method of item 271, wherein the reactants are maintained at a temperature in the range of about-40 ℃ to about +50 ℃.

273. The method of item 271, wherein the reactants are maintained at a temperature in the range of about-5 ℃ to about +5 ℃.

274. The process of item 271, wherein the product is isolated with dilute acid.

275. The process of clause 271, wherein the methylating agent is dimethyl sulfate and the dilute acid is selected from the group consisting of medium to strong acids such as hydrochloric, acetic or sulfuric acid or any mixture of these acids.

276. The method of item 271, wherein the compound prepared is represented by formula 5 MM.

277. A method of preparing the compound 6MG of item 104, comprising de-ketalizing (deketalizing) the compound 5MG of item 99.

278. The method of item 277, wherein the step of deketalizing is performed under acidic conditions.

279. The method of item 278, wherein the compound prepared is represented by formula 6MM as described in item 108.

280. The method of item 279, wherein the product 6MG produced by the method of item 277 is reduced to produce the compound of item 109 wherein R is₃A compound of formula 7MG that is hydrogen.

281. The compound of item 280, wherein the compound prepared is described in item 113, as formula 6bMM, as a racemate or any one isomer.

282. The method of item 277, wherein R is prepared according to item 109₃A compound of formula 7MG that is hydrogen consisting of item 277 wherein R₃The compound of formula 7MG, which is hydrogen, is started and the product is mixed with a base and an alkylating agent in a solvent.

283. The method of item 282, wherein the product prepared is described as 7MM in item 114 as the racemate or any one of the isomers.

284. The process of item 282, wherein the base is a hydride such as sodium or potassium hydride or an alkoxide base such as potassium tert-butoxide or a mixture of such bases and the alkylating agent is an alkyl halide.

285. The process of item 284, wherein the base is potassium tert-butoxide and the alkylating agent is benzyl bromide.

286. The process of item 282, for preparing a compound of formula 8MG of item 115, starting with the product of item 276, formula 7MG and combining the product with carbon monoxide and an alcohol in a polar aprotic solvent in the presence of a soluble palladium II salt, a phosphine ligand, and a base.

287. The method of item 286, wherein the soluble palladium II salt is selected from palladium acetate.

288. The method of item 286, wherein the phosphine ligand is selected from the group consisting of 1, 3-bis diphenylphosphinopropane.

289. The process of item 286, wherein the base is selected from the group consisting of sodium or potassium acetate, sodium or potassium carbonate, triethylamine, and tri-n-butylamine.

290. The process of item 289, wherein the polar aprotic solvent is selected from dimethylformamide or acetonitrile.

291. The method of item 286, wherein the compound prepared by the method is represented by formula 8MM, item 119, as any one of the isomers or racemates.

292. The process of item 286, for preparing the compound of formula 9MG of item 120, by removing the leaving group from the product of item 286, formula 8MG, and mixing the compound with trimethylsilyl iodide.

293. The process of clause 292, wherein the trimethylsilyl group is preformed or generated in situ from trimethylsilyl chloride and sodium iodide in dichloromethane or acetonitrile.

294. The process of item 292, wherein the process temperature is in the range of about 15-50 ℃ and the reaction time is 12 to 48 hours.

295. The method of item 292, wherein the compound prepared is represented by formula 9MM as described in item 124.

296. The process of item 292 for preparing a compound of formula 10MG of item 125 by combining the compound of formula 9MG prepared in item 292 with an acrylate in the presence of a base in a polar aprotic solvent.

297. The method of item 296, wherein the acrylate is methyl acrylate, ethyl acrylate, or tert-butyl acrylate.

298. The process of item 296, wherein the base is potassium hydride, sodium hydride, methyl tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate or a tertiary amine including diisopropylethylamine in a polar aprotic solvent such as dimethylsulfoxide, DMF or acetonitrile.

299. The method of item 296, wherein the compound produced is represented by the compound of formula 10MM as depicted in item 134, as any one of isomers or racemates.

300. The process of item 296, mixing the compound of formula 10MG prepared in item 296 with a strong acid to prepare the compound of item 130.

301. The process of clause 300, wherein the strong acid is trifluoroacetic acid.

302. The method of item 300, wherein the compound prepared is represented by the compound of formula 11MM as described in item 134, as any one of isomers or racemates.

303. The process of clause 300, starting from the product of clause 300, formula 11MM, using a Friedlander condensation reaction to produce a significant product comprising a suitably modified significant intermediate of formula 12MG and a suitably modified significant intermediate, produces a compound of formula 12MG of clause 135.

304. The process of item 303, wherein the obvious intermediate of suitable modification for Friedlander condensation is a compound shown below,

305. the process of item 303, wherein the obvious intermediate of suitable modification for Friedlander condensation is a compound shown below,

306. the method of item 304 or 305, wherein the compound prepared is represented by formula 12MM, as racemates and all isomers.

307. The process of item 303 for preparing a MG compound of formula 13, starting from the product of item 303 and removing the leaving group.

308. The method of item 307, wherein the leaving group is removed by mixing the product of item 303 with hydrogen in the presence of a catalyst.

309. The method of item 308, wherein the catalyst is palladium.

310. The method of item 309, wherein the compound prepared by the reaction is mappicine.

Claims

1. A compound represented by the following structural formula,

wherein R is₂Is H, optionally substituted C_1-7Alkyl, alkaryl or substituted benzyl;

wherein R is₃Is H, optionally substituted C_1-8Alkyl radical, C_3-10Cycloalkyl radical, C₂-C₈Alkenyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl or substituted alkaryl; and

wherein R is₆Optionally substituted C_1-8Alkyl radical, C₆-C₁₂Aryl, substituted C₆-C₁₂Aryl, alkaryl, substituted alkaryl, C_3-10Cycloalkyl radical, C₁-C₆alkyl-C_3-10Cycloalkyl, heteroaryl or substituted heteroaryl,

the alkylaryl group means C having 1 to 8 carbon atoms and being substituted by the above-mentioned 6 to 12 carbon atoms₆-C₁₂An alkyl group substituted with an aryl group,

by heteroaryl is meant a monocyclic or bicyclic ring structure having 5 to 12 ring atoms in which at least one ring is aromatic and only 1, 2 or 3 non-adjacent carbon atoms on the aromatic ring are replaced by heteroatoms,

said substituted C_1-8The substituents of alkyl, substituted alkylaryl, substituted heteroaryl, substituted benzyl being halogen, C_1-6Alkyl, mono-or di-C_1-6Alkyl substituted C_1-6Alkyl radical, C_1-6Alkylthio, halogen substituted C_1-6Alkyl, amino substituted C_1-6Alkyl, mono-or di-C_1-6Alkyl-substituted amino, C_2-6Alkenyl radical, C_1-6Alkoxy, aryloxy, aryl C_1-6Alkyl, hydroxy, cyano, amino or nitro,

said substituted C₆-C₁₂The substituent of the aryl group is selected from 1-3 hydroxyl groups and C₁-C₃Alkoxy radical, C₁-C₃Alkyl, trifluoromethyl, fluoro, chloro and bromo groups.

2. A compound according to claim 1, which is a pharmaceutically acceptable salt thereof,

wherein R is₂Is H, optionally substituted C_1-6Alkyl radical, C_1-6alkyl-C₆Aryl or substituted benzyl;

wherein R is₃Is H, optionally substituted C_1-6Alkyl radical, C_3-10Cycloalkyl radical, C₆Aryl, substitutedC₆Aryl radical, C_1-6Alkyl radical C₆Aryl, or substituted C_1-6Alkyl radical C₆An aryl group; and

wherein R is₆Is any C₁-C₆Alkyl radical, C_3-7Cycloalkyl radical, C₁-C₆alkyl-C_3-7Cycloalkyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆alkyl-C₆Aryl, or substituted C₁-C₆Alkyl radical C₆An aryl group, a heteroaryl group,

said substituted C₁-C₆Alkyl radical C₆The substituents for aryl being halogen, C_1-6Alkyl, mono-or di-C_1-6Alkyl substituted C_1-6Alkyl radical, C_1-6Alkylthio, halogen substituted C_1-6Alkyl, amino substituted C_1-6Alkyl, mono-or di-C_1-6Alkyl-substituted amino, C_2-6Alkenyl radical, C_1-6Alkoxy, aryloxy, aryl C_1-6Alkyl, hydroxy, cyano, amino or nitro.

3. A compound according to claim 2, which is a pharmaceutically acceptable salt thereof,

wherein R is₂Is H, C_1-6Alkyl, benzyl or substituted benzyl;

wherein R is₃Is H, optionally substituted C_1-6Alkyl radical, C_1-6alkyl-C₆Aryl or substituted benzyl; and

wherein R is₆Is C₁-C₆Alkyl radical, C₆Aryl, substituted C₆Aryl radical, C₁-C₆Alkyl radical C₆Aryl or substituted C₁-C₆Alkyl radical C₆And (4) an aryl group.

4. A compound according to claim 3, which is a pharmaceutically acceptable salt thereof,

wherein R is₂Is C_1-3Alkyl, benzyl or substituted benzyl;

wherein R is₃Is substituted benzyl or unsubstituted benzyl;

wherein R is₆Is C_1-3An alkyl group.

5. The compound of claim 1, wherein R₂Is C_1-6alkyl-C_6-12An aryl group; r₆Is ethyl, benzyl or substituted benzyl.

6. The compound of claim 4, represented by the following formula 12MM,

7. a process for the preparation of the MG compound of formula 12 of claim 1, comprising the steps of:

reacting a compound of formula 11MG

Wherein R is₂Is H, optionally substituted C_1-8Alkyl, alkaryl or substituted benzyl;

said substituted C₆-C₁₂The substituent of the aryl group is selected from 1-3 hydroxyl groups and C₁-C₃Alkoxy radical, C₁-C₃Alkyl, trifluoromethyl, fluoro, chloro and bromo groups;

mixing with a compound A of the formula

A compound A.

8. A process for the preparation of the MG compound of formula 12 of claim 1, comprising the steps of:

reacting a compound of formula 11MG

by heteroaryl is meant a monocyclic or bicyclic ring structure having 5 to 12 ring atoms, wherein at least one ring is aromatic and only 1, 2 or 3 non-adjacent carbon atoms on the aromatic ring are replaced by heteroatoms,

mixing with a compound B of the formula

And (B) a compound B.

9. The method of claim 7 or 8, wherein the compound prepared is represented by a compound described by formula 12 MM:

10. use of a compound of formula 12MG according to claim 1 for the preparation of a compound of formula 13MG, characterized in that a leaving group is removed from a compound of formula 12MG according to claim 1 to obtain a compound of formula 13MG,

wherein R is₂And R₆As defined in claim 1.

11. Use according to claim 10, wherein the leaving group is removed by mixing a compound of formula 12MG according to claim 1 with hydrogen in the presence of a catalyst.

12. The use of claim 11, wherein the catalyst is palladium.

13. The use of claim 12, wherein the compound prepared by the reaction is: