HK1051189A - Process for preparing 2-azadihydroxybicyclo[2.2.1]heptane compounds and the l-tartaric acid salt of the compound - Google Patents

Description

Process for preparing 2-azadihydroxybicyclo [2.2.1] heptane compounds

This application is a continuation-in-part application of U.S. patent application Ser. No. 08/655395, filed 5/30/1996, which in turn is a continuation-in-part application of U.S. patent application Ser. No. 08/476156, filed 6/7/1995.

Technical Field

The present invention relates to a process for preparing 2-azadihydroxybicyclo [2.2.1] heptane compounds. The invention also relates to L-tartrate salts of the diastereomer of the 2-azadihydroxybicyclo [2.2.1] heptane compound (1R) and preparation thereof. Furthermore, the invention relates to a process for the di-O-protection of diastereomers of the 2-azadihydroxybicyclo [2.2.1] heptane compound (1R) and to a process for the oxidation of diastereomeric derivatives of the 2-azadihydroxybicyclo [2.2.1] heptane compound (1R) to the corresponding lactam compounds.

US 5284769 discloses lactam compounds that can be used as synthons in the preparation of pharmaceutically active substances, including the lactam compounds prepared according to the present invention. Chen et al, tetrahedron letters (Tet. Lett.), 305543 (1989) disclose lactam compounds useful in the preparation of compounds having adenosine agonist activity, including lactam compounds prepared according to the present invention. Reported progress

Chui, synthetic communication (syn.comm.), 26(3), 577(1996) discloses the resolution of diastereomeric mixtures of bicycloheptenamine compounds of formulae (i) and (ii) by fractional crystallization using L-dibenzoyltartaric acid.This document does not disclose a method for resolving dihydroxylated products of a mixture of diastereomers.

S.j.c.taylor et al, tetrahedron: asymmetry (Tetrahedron: Asymmetry), 4(6), 1117(1993), discloses enzymatic resolution of lactams of formula (iii)To form the enantiomers of formulae (iv) and (v),s.j.c.taylor et al do not disclose any method for resolving the dihydroxylated products of lactam (iii).

US 5284769 discloses enzymatic resolution of lactams of formula (vi)To give enantiomers of said lactam. US 5284769 does not disclose any method for resolving the dihydroxylation product of lactam (iv).

Summary of The Invention

The invention relates to 2-azadihydroxybicyclo [2.2.1] of the formula]A process for the preparation of a heptane compound,wherein denotes an R chirality, denotes an S chirality, R is hydrogen, or are each a group of the formula:wherein R is₁Is an alkyl group, Ar is an optionally substituted aryl group, the process comprising adding to about 0.1 mol% to about 5 mol% of a metal salt of osmium compound or about 0.06 mol% to about 0.07 mol%Bicyclo [2.2.1] of the formula]The dihydroxylation of the heptane compound is carried out,wherein:' and R are as defined above.

The invention also relates to the treatment of 2-azadihydroxybicyclo [2.2.1] wherein R is a group of formula II with L-tartaric acid]The (1R) diastereomer of heptane compound (I), and the resulting L-tartrate salt product. The invention also relates to the preparation of 2-azadihydroxybicyclo [2.2.1]The (1R) diastereomer of the heptane compound or its salt undergoes an acid-catalyzed acetalization or ketalization reaction in isopropanol, resulting in the protection of its dihydroxy moiety. In addition, the present invention also relates to RuO at about 0.01 mol% to about 1 mol%₂Or a hydrate thereof, with about 3 equivalents of an oxidizing agent]The di-O-protected derivative of the heptane compound (1R) diastereomer is oxidized to the corresponding lactam to produce a lactam compound having an enantiomeric excess ("ee") of greater than or equal to about 95%.

Detailed Description

Unless otherwise defined, the following terms used above and throughout the specification of the present invention shall be understood to have the following meanings.

"alkyl" refers to a straight or branched chain aliphatic hydrocarbon group containing from 1 to about 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, isopropyl and tert-butyl.

"optionally substituted methylene" means-CH₂-or a residue in which the hydrogen atoms are substituted by one or two groups, respectively, which may be the same or different, and are selected from alkyl or phenyl, or in which the hydrogen atoms are simultaneously substituted and form, together with the carbon atom of the methylene group, a cycloalkyl group.

"aryl" refers to optionally substituted phenyl or optionally substituted alpha-or beta-naphthyl. Substituted aryl is aryl substituted with one or more aryl substituents, which may be the same or different, including halogen, alkyl, alkoxy, and nitro.

"alkoxy" refers to an alkyl-O-group wherein the alkyl group is as previously described. Examples of alkoxy groups include methoxy, ethoxy, isopropoxy and tert-butoxy.

"cycloalkyl" refers to an aliphatic ring of about 5 to 6 carbon atoms. An example of cycloalkyl is cyclohexyl.

"acyl" refers to an alkyl-CO-group wherein the alkyl group is as previously described. Examples of acyl groups include acetyl and propionyl.

"aroyl" refers to an aryl-CO-group in which the aryl group is as previously described. An example of aroyl is benzoyl.

"halogen" means fluorine, chlorine, bromine or iodine. Fluorine and chlorine are preferred.

"oxidizing agent capable of regenerating osmium tetraoxide" means that a metal osmate (Os) can be converted into a metal osmate⁺⁶) Is oxidized into osmium tetroxide (Os)⁺⁸) Or reoxidizing the reduced osmium tetroxide in the double hydroxylation reaction into osmium tetroxide (Os)⁺⁸) An oxidizing agent of (1). Examples of oxidizing agents which can regenerate osmium tetroxide include N-methylmorpholine oxide or triethylamine oxide and potassium ferricyanide (K)₃FeCN₃) N-methylmorpholine oxide is preferred.

The "metal salt of osmium" means a compound consisting of Mⁿ⁺A metal cation wherein n is 1 or 2, and an osmium oxide anion complex [ OsO₄]^-2A salt compound formed or a hydrate thereof. Preferred osmium metal salts are osmium acid alkali metal or alkaline earth metal salts, including sodium, potassium, rubidium, cesium, calcium and barium salts, more preferably K₂OsO₄·2H₂And O. Methods for preparing metal salts of osmium are described, for example, in B.N.Ivanov-Emin et al, Zh.Neorg.Khim.31(5)1238(1986), H.C.Jewiss, J.C.S.Dalton Trans.199(1985), B.N.Ivanov-Emin et al, Zh.Neorg.Khim.29(4)1241(1984), B.N.Ivanov-Emin et al, Zh.Neorg.Khim.28(5)1246 (1983).

By "salt thereof" is meant that the compound with a basic moiety is neutralized with an acid to form the corresponding acid addition salt. Acids which may be used in the preparation of acid addition salts preferably include those which, when combined with the free base, form a pharmaceutically acceptable salt, by which is meant a salt whose anion is non-toxic to the patient, and whose subsequent use does not affect the ability of the compound to undergo further chemical reactions. Acid addition salts can be used, for example, to regenerate a base compound by treatment with a base, such as a strong base, for purification and/or identification purposes, or to convert to another acid addition salt by ion exchange methods. Examples of acid addition salts include the following acids: inorganic acids such as hydrobromic acid, hydrochloric acid, sulfuric acid, phosphoric acid or sulfamic acid; organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, dibenzoyltartaric acid, malonic acid, succinic acid, 2, 3-dimethoxysuccinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like.

Description of the preferred embodiments

A particular embodiment of the dihydroxylation process of the invention is that in which R is a radical of the formula II or II'.

A preferred embodiment of the dihydroxylation process of the invention is that wherein R is₁Is methyl or ethyl, and Ar is phenyl unsubstituted or substituted with one or more methyl or methoxy groups.

A more preferred embodiment of the dihydroxylation process of the invention is that wherein R is₁Is methyl and Ar is phenyl.

One preferred embodiment for carrying out the double hydroxylation is to use from about 0.06 mol% to about 0.07 mol% osmium tetroxide, more preferably about 0.06 mol%.

Another preferred embodiment for carrying out the dihydroxylation is to use from about 0.1 mol% to about 5 mol% of the metal salt of osmium, more preferably from about 0.2 mol% to about 0.5 mol%.

A further preferred embodiment for carrying out the dihydroxylation is the use of alkali metal or alkaline earth metal salts of osmium acid as osmiumMetal salt, more preferably K₂OsO₄·2H₂O。

According to the invention, 2-azabicyclo [2.2.1] s are prepared]L-tartrate salt of diastereomer of heptane Compound (1R), i.e., Compound of formulaIn which R is a group of the formula II.

According to the invention, 2-azabicyclo [2.2.1] s are prepared]A preferred embodiment of the L-tartrate salt of the (1R) diastereomer of the heptane compound is where R is₁Is methyl and Ar is phenyl.

Another embodiment of the present invention is the preparation of the L-tartrate salt of the substantially enantiomerically pure diastereomer of the 2-azabicyclo [2.2.1] heptane compound (1R) in the presence of the diastereomer of the 2-azabicyclo [2.2.1] heptane compound (1S).

According to the present invention, a preferred embodiment of the preparation of the L-tartrate salt of the diastereomer of the 2-azadihydroxybicyclo [2.2.1] heptane compound (1R) is that the preparation is carried out in an aqueous-organic solvent mixture.

A more preferred embodiment of the process for preparing the L-tartrate salt of the diastereomer of the 2-azadihydroxybicyclo [2.2.1] heptane compound (1R) according to the invention is wherein the organic solvent is Isopropanol (IPA).

A more preferred embodiment of the preparation of the L-tartrate salt of the (1R) diastereomer of the 2-azadihydroxybicyclo [2.2.1] heptane compound according to the invention is that the preparation is carried out in a water-IPA solvent mixture having a volume ratio of from about 30: 70 to about 15: 85, more preferably about 25: 75.

One embodiment of carrying out the acid-catalyzed acetalization or ketalization reaction in accordance with the present invention relates to a process for preparing a compound of formula IVWherein R is as defined above, R_3’And R_3”Is hydrogen, alkyl orPhenyl, or R_3’And R_3”Taken together with the carbon atom to which they are attached to form a cycloalkyl group, which process comprises reacting a compound of formula VWherein R is_4’And R_4”Is alkoxy or taken together with the carbon atom to which they are attached to form a carbonyl group, with a 2-azadihydroxybicyclo [2.2.1] as described herein]The (1R) diastereomer of the heptane compound or its salt undergoes an acid-catalyzed acetalization or ketalization reaction in IPA.

A preferred embodiment for carrying out the acid-catalyzed acetalization or ketalization reaction is that wherein R is_4’And R_4”Is methoxy, R_3’And R_3”Is methyl.

Another preferred embodiment for carrying out the acid-catalyzed acetalization or ketalization reaction is one in which the acid catalysis is carried out with trifluoroacetic acid (TFA).

Another preferred embodiment for carrying out the acid-catalyzed acetalization or ketalization reaction is where R is a group of formula II.

A more preferred embodiment for carrying out the acid catalyzed acetalization or ketalization reaction is that wherein R is₁Is methyl and Ar is phenyl.

Yet another preferred embodiment for carrying out the acid catalyzed acetalization or ketalization reaction is where the (1R) diastereomer of the 2-azadihydroxybicyclo [2.2.1] heptane compound is in the form of its L-tartrate salt.

A particular embodiment of the preparation of lactams according to the invention relates to a process for the preparation of lactam compounds of formula VI,wherein R is₁' and R₁"independently of one another are acyl or aroyl, or together form an optionally substituted methylene group, G₁Is hydrogen or an amino protecting group, which process comprises reacting a di-O-protected 2-azadihydroxybicyclo [2.2.1] of formula VII](1R) diastereomer of heptane compoundRuO at about 0.1 mol% to about 1 mol%₂Or a hydrate thereof, with about 3 equivalents of an oxidizing agent to produce a lactam compound having an enantiomeric excess of greater than or equal to about 95%.

A preferred embodiment of the process for the preparation of lactams is that, wherein RuO₂Is present in an amount of about 0.5 mol%.

Another preferred embodiment of the lactam production process is where the enantiomeric excess of the lactam compound formed is greater than or equal to about 99%.

General parameters of the preparation process are as described above and below.

Generally, the dihydroxylation reaction is carried out under the conditions described in V.VanRhenen et al, Tetrahedron Letters, Vol.23, 1973-1976 (1976). The oxidizing agent is necessary to cause the dihydroxylation reaction to proceed exogenously. More specifically, the oxidation reaction can be carried out by using potassium permanganate or osmium tetroxide or metal salts of osmium in N-methylmorpholine or triethylamine oxide or potassium ferricyanide (K)₃FeCN₆) In the presence of (a).

According to the present invention, osmium tetroxide is used in catalytic amounts, so that the residual amount of osmium in the product can be controlled more effectively. The reaction with osmium can be carried out at as little as about 0.06 mol% to about 0.1 mol% for about 21 to about 5 hours, respectively. The reaction is preferably carried out in the presence of about 0.06 mol% osmium tetroxide. The oxidation reaction may be carried out in a water-organic solvent such as water-t-butanol or water-acetone, more preferably water-acetone. When the oxidation reaction is carried out in a water-acetone solvent system, an ether solvent such as tert-butyl methyl ether or diisopropyl ether may also be present. The preferred range for the volumetric amount of the ether/acetone/water solvent mixture is from about 1.9: 16.7: 1 ether/acetone to about 11.1: 7.4: 1; more preferably from 11.1: 16.7: 1 to 16.7: 1.

The dihydroxylation reaction can also be carried out in the same manner on a mixture of diastereomers (I) and (I'), i.e., without separation thereof prior to carrying out the dihydroxylation reaction.

The diastereomer of formula I (1R), wherein R is a group of formula II, can be isolated in the form of an optically active organic acid salt, in particular from a mixture of diastereomer compounds of formula I and I' by diastereoselective crystallization with the optically active organic acid. One useful optically active organic acid is L-dimethoxysuccinic acid. The salt formation using L-dimethoxysuccinic acid is carried out in a suitable organic solvent such as a ketone or an aliphatic alcohol, with IPA being particularly preferred. According to the present invention, L-tartaric acid is another useful optically active organic acid. The salt formation using L-tartaric acid is carried out in a solvent such as a water-organic solvent mixture, wherein the organic solvent is, for example, an aliphatic alcohol such as IPA. The yield and enantiomeric purity of the desired diastereomer (I) can be increased by using L-tartaric acid.

The dihydroxy moiety of the compound of formula I, wherein R is hydrogen or a group of formula II, may be protected in the form of an ester or acetal/ketal to produce a product of formula VIIIWherein R is hydrogen or a group of formula II, R'₁And R "₁As defined above.

Typically, protection of the hydroxyl group is carried out under esterification or acetalization/ketalization conditions. Esterification is effected, for example, by reaction with an acyl-containing substance, such as acetic acid or propionic acid, in the presence of p-toluenesulfonic acid, in an organic solvent, such as an aromatic hydrocarbon, e.g. benzene or toluene, and gradual separation of the water formed (e.g. azeotropy). Acetalization/ketalization is accomplished, for example, by reaction with an aldehyde or ketone (possibly in the form of a ketal) in the presence of an acid such as TFA, in an organic solvent such as an aliphatic alcohol, e.g., IPA, an aromatic hydrocarbon, e.g., benzene or toluene, an ether, e.g., t-butyl methyl ether or diisopropyl ether, at a temperature of from about 50 ℃ to about the boiling point of the reaction mixture. When an ether solvent is used, acetic acid may also be present, which may form a salt with the compound of formula IV, which may be extracted with water. Preferred ketalization solvents according to the present invention include the use of 2, 2-dimethoxypropane, TFA and IPA to increase the yield and enantiomeric excess of the product. The reaction was carried out at about 70 ℃.

The product of formula VIII, wherein R is a group of formula II, may be converted to a product of formula VIII wherein R is hydrogen by hydrogenolysis. Typically, the hydrogenolysis is carried out with hydrogen, optionally pressurized, in the presence of a catalyst such as palladium on carbon, in an organic solvent such as an alcohol, e.g., methanol, ethanol or IPA, at about 0 ℃ to about 50 ℃. The product of formula VIII wherein R is hydrogen may also be prepared using a salt of a compound of formula IV wherein R is a group of formula II, under the same hydrogenolysis reagents and conditions.

The product of formula VIII, wherein R is hydrogen, may be converted to a product of formula IX by selective introduction of a suitable protecting group,wherein R'₁And R "₁As defined above, G₂Is an amino protecting group.

The protecting groups are selected from those which can be selectively removed subsequently. These protecting groups include the following particularly suitable protecting groups: t-butoxycarbonyl, chloroacetyl, methoxymethyl, trichloro-2, 2, 2-ethoxycarbonyl, t-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, diphenylmethyl, trialkylsilyl, allyloxycarbonyl and benzyloxycarbonyl, wherein the phenyl ring is optionally substituted by halogen, alkyl or alkoxy. Among the particularly suitable protecting groups, mention may be made of those described in t.w.greene and p.g.m.wuis, "protecting groups in organic synthesis" chapter 7, 2 nd edition, John Wiely & Sons (1991). Particularly preferred is t-butoxycarbonyl.

Wherein G is₂The product of formula IX which is a tert-butoxycarbonyl group may be obtained directly from a product of formula VIII wherein R is a group of formula II by simultaneous hydrogenolysis and tert-butoxycarbonylation.

For example, the reaction may be accomplished by reacting a compound of formula VIII, wherein R is a group of formula II, in an organic solvent such as an alcohol, e.g., methanol, ethanol or IPA, at about 0 deg.C to about 50 deg.C, simultaneously with hydrogen and di-tert-butyl dicarbonate in the presence of a catalyst such as palladium on charcoal. R'₁And R "₁Are combined together to form an arbitraryThis reaction is particularly useful with optionally substituted methylene groups.

Or, wherein G₂A compound of formula IX which is t-butyloxycarbonyl may be obtained in two steps from a compound of formula VIII wherein R is a group of formula II: the group of formula II is first removed by hydrogenation to give the corresponding product in which R is hydrogen, which is then tert-butoxycarbonylated. Hydrogenation to remove the group of formula II is carried out as described above, tert-butyloxycarbonylation under basic conditions with (Boc)₂O is carried out in water.

The product of formula IX is then oxidized to a product of formula X,wherein R'₁、R”₁And G₂As defined above.

In general, ruthenium oxide (RuO) is used for oxidation reaction₄) Optionally from precursors thereof such as RuO₂Or RuCl₃Generated in situ in the presence of an oxidizing agent selected from periodates such as sodium periodate, hypohalites such as hypochlorite or sodium hypobromite, bromates such as sodium bromate or organic tertiary amine oxides such as N-methylmorpholine oxide or triethylamine oxide. The reaction is carried out in a solvent such as water or a homogeneous or heterogeneous water-organic solvent such as a water-ethyl acetate mixture.

The oxidation reaction can also be carried out using sodium hypochlorite alone or potassium permanganate or sodium tungstate in the presence of an oxidizing agent such as sodium hypochlorite, hydrogen peroxide or alkyl hydroperoxides.

The product of formula X can also be prepared by the following process: oxidizing a compound of formula VIII wherein R is hydrogen under the conditions described above, and then protecting the nitrogen atom of the lactam of formula XI with the protecting group described aboveWherein R'₁And R "₁As defined above.

The products of the formulae X and XI are particularly suitable for preparing carbosaccharides of the formula XIIWherein R is₂Is carboxy, alkoxycarbonyl, N-alkylaminocarbonyl, hydroxymethyl or alkoxymethyl, R 'and R' may be the same or different and are each hydrogen, acyl or aroyl, or R 'and R' taken together with the carbon atom to which they are attached form an optionally substituted methylene group, the carbon atom of which is optionally substituted by one or two groups, which may be the same or different, selected from alkyl or phenyl, or two alkyl groups taken together may form cycloalkyl, G₁Is hydrogen or an amino protecting group G₂. More preferably R₂Is ethylaminocarbonyl or hydroxymethyl, R' and R "taken together form isopropylidene.

May be substituted by a substituent R suitable for the requisite introduction₂The product of formula X is converted to a product of formula XII under conditions of nature.

Wherein R is₂The product of formula XII which is a carboxyl group may be prepared by reacting the product of formula X with an inorganic base such as sodium hydroxide, and then replacing the protecting group G with hydrogen₂And optionally replacing the radical R 'with hydrogen'₁And R "₁To prepare the compound.

Wherein R is₂The product of formula XII being a carboxyl group can be prepared by reacting the protecting group G of the product of formula X₂Substituted by a hydrogen atom, then treated with an inorganic base such as sodium carbonate and optionally substituted by hydrogen for the radical R'₁And R "₁To prepare the compound.

Wherein R is₂The product of formula XII, which is an alkoxycarbonyl group, can be prepared by reacting the product of formula X with an alkali metal alkoxide, and then replacing the protecting group G with hydrogen₂And optionally replacing the radical R 'with hydrogen'₁And R "₁To prepare the compound.

Wherein R is₂A product of formula XII which is an alkoxycarbonyl group can be prepared by reacting a protecting group G of a product of formula X₂Substituted by a hydrogen atom, then treated with an alkali metal alkoxide and optionally replacing the radical R 'by hydrogen'₁And R "₁To prepare the compound.

Wherein R is₂The product of the formula XII which is an N-alkylaminocarbonyl radical can be prepared by reacting a product of the formula XWith alkylamines, and then replacing the protecting group G with hydrogen₂And optionally replacing the radical R 'with hydrogen'₁And R "₁To prepare the compound.

Wherein R is₂The product of formula XII, which is an N-alkylaminocarbonyl group, can be prepared by reacting the protecting group G of the product of formula X₂Substituted by a hydrogen atom, then treated with an alkylamine and optionally replacing the radical R 'by hydrogen'₁And R "₁To prepare the compound.

Wherein R is₂The product of formula XII, which is hydroxymethyl, may be prepared by reacting the product of formula X with a reducing agent such as a borohydride, e.g. sodium or potassium borohydride, and then replacing the protecting group G with hydrogen₂And optionally replacing the radical R 'with hydrogen'₁And R "₁To prepare the compound.

Wherein R is₂A product of formula XII which is hydroxymethyl may be prepared by reacting a protecting group G of a product of formula X₂Substituted by a hydrogen atom, then treated with a reducing agent such as sodium or potassium borohydride and optionally replacing the group R 'by hydrogen'₁And R "₁To prepare the compound.

The invention also includes a process for separating the (1S) diastereomer of the compound of formula I' using an optically active organic acid having the opposite configuration to that described for the optically active organic acid for separating the (1R) diastereomer of the compound of formula I. According to the present invention, the (1S) diastereomer of the compound of formula I' can be converted into the corresponding (1S) diastereomer of formulae IV, VI, VII, VIII, IX and X by a process for preparing the (1R) diastereomer of the compound of corresponding formula.

The starting materials and intermediates can be prepared by known methods or modifications thereof.

Compounds of formula XIII and XIIIWherein R, R', R₁And Ar is as previously defined, can be prepared by Diels-Alder reaction between a mixture of a homochiral amine of the formula, formaldehyde and cyclopentadiene in salt form, preferably in salt form with a mineral acid such as hydrochloric acid,wherein R, R', R₁And Ar as previously defined, reaction conditions as described in s.d. larsen and p.a. grieco, journal of the american society for chemistry (j.amer. chem.soc.), volume 107, 1768-1769 (1985). These methods yield a mixture of two diastereomers. The diastereomer can be isolated using L-dibenzoyltartaric acid as described in c.k. -f.chiu, synthetic communication (syn.comm.)26(3), 577 (1996).

Compounds of formulae III and III 'wherein R is hydrogen may be prepared by hydrogenolysis of compounds of formulae XIII and XIII' in a two-step process. The compound is first treated with 2, 2, 2-trichloroethoxycarbonyl (Troc) chloride or β - (trimethylsilyl) ethoxycarbonyl (Teoc) chloride to give the corresponding Troc or Teoc derivative (carbamate), which is then treated with Zn in an alcoholic solvent such as ethanol with heating or in an organic acid solvent such as acetic acid at room temperature.

The preparation of the compounds of the present invention is further illustrated by the following non-limiting examples.

In Nuclear Magnetic Resonance (NMR) spectra, chemical shifts are expressed in ppm relative to tetramethylsilane. The abbreviations therein have the following meanings: s is singlet; d is a doublet, t is a triplet; m is multiplet; dd ═ doublet; ddd is a split doublet of doublets; dt is double triplet; b is broad peak.

Example 1a preparation of 2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] hept-5-ene

To a 2L reactor was added 255g of (S) - (-) - α -methylbenzylamine and 300 ml of water. The suspension is cooled to-5 ℃ and a solution of 185 ml of concentrated hydrochloric acid in 100 ml of water is added over 1 hour with stirring. The pH of the mixture was adjusted to between 5 and 6.5. Stirring was continued for 30 minutes, then 242 ml of 37% formaldehyde solution were added. After stirring for a further 40 minutes, cyclopentadiene (about 270 ml) was distilled directly into the reaction mixture. The resulting mixture was stirred vigorously at-5 ℃ overnight. The end of the reaction was determined by High Performance Liquid Chromatography (HPLC). The two phases formed are separated and the aqueous layer is diluted with 250 mlWashed with heptane and then basified with 168ml of 50% sodium hydroxide solution and crushed ice to pH 11. The organic mixture was then extracted with 2 × 500 ml and 2 × 300 ml of ethyl acetate. The combined extracts were washed successively with 200ml of cold water and 200ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The clear filtrate was rotary evaporated to give 408.4g (97.4%) of 2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] as a yellow oil]Hept-5-ene, diastereomer ratio 77.1: 22.9, desired isomer excess.¹H NMR(500MHz，CDCl₃): δ 1.35(d, 2H); 1.46(d, 1H); 1.62(d, 1H); 2.89(d, 1H); 3.05(m, 1H); 4.13(s, 1H); 6.11(d, 1H); 6.32(m, 1H); 7.26(d, 2H); 7.33(d, 2H); MS (EI, 70eV) m/z (relative intensity): 199(M +, 70)

Example 1b preparation of 2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] hept-5-ene

A solution of 20g of (S) - (-) - α -methylbenzylamine (165mmol) in 60ml of water was added under an argon atmosphere to a 250 ml three-neck flask equipped with a cooling device and a stirring system, and the pH of the solution was adjusted to 6.1 by adding 17ml of 36% hydrochloric acid (W/V). After cooling to 5 ℃ 20 ml of 37% (W/V) aqueous formaldehyde solution were added. The solution was stirred at 5 ℃ for 5 minutes, then 21.8g of cyclopentadiene (330mmol) were added. The mixture was stirred at-5 ℃ to 0 ℃ for 16 hours. The aqueous phase is separated off by decanting and washed with 50 ml of pentane. The pH is brought to 8 by addition of concentrated sodium hydroxide solution. Then extracted twice with 70 ml each time of ethyl acetate. The pH of the aqueous phase was adjusted to 11 by addition of concentrated sodium hydroxide solution and then extracted twice with 70 ml of ethyl acetate each time. The organic phases are combined and then washed twice with 50 ml of water and dried over sodium sulfate. Filtration and concentration to dryness under reduced pressure gave 33.1g of 2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] hept-5-ene as a pale yellow oil.

EXAMPLE 25 preparation of R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane

To a solution containing 20g of 2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] at about 25 ℃]Solution of hept-5-ene (75.34mmol) in 220 ml tert-butanol, containingA500 ml three-necked flask with a cooling device and a stirring system was charged with a solution of 12g N-methylmorpholine oxide in 32 ml of water, followed by slow addition of 6.3ml of 25% (W/V) osmium tetroxide (OsO)₄) Is added to the mixture. Stirring was continued at about 20 ℃ for 2 hours and then at 65 ℃ for 3 hours. After evaporation of the tert-butanol under reduced pressure, the residue was redissolved in 350 ml of IPA. Concentrated to dryness under reduced pressure to give 24g of cis-5, 6-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] as an oil]Heptane. Crystallization from cyclohexane gave 14g of 5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1]Heptane, having an isomer purity of 95% or more.

The NMR spectrum measured in deuterated chloroform has the following shift values (δ): 1.21(3H, d); 1.38(1H, d); 1.59(1H, d); 2.22(2H, m); 2.45(1H, dd); 2.95(1H, s); 3.99(1H, q); 3.78(1H, d); 3.90(1H, d); 7.28(5H, m).

Example 3a preparation of 5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane

A mixture of 0.5mmol of 5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane and 5S, 6R-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane (molar ratio 78/22) and a solution of 0.5mmol of L-dimethoxysuccinic acid in 1ml of IPA were stirred for 24 hours at a temperature in the range from 25 ℃ to 5 ℃ and initially at a temperature of 25 ℃. The crystals formed were isolated by filtration and dried. This gave 110mg of 5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane with an enantiomeric excess of 97%.

A mixture of 5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane and 5S, 6R-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane (molar ratio 78/22) can be prepared as follows:

to a solution containing 7g of 2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] at about 25 ℃]A solution of hept-5-ene (35mmol) in 70 mL t-butanol, a 250 mL three-neck round bottom flask equipped with a coolant and a stirring system, was charged with 4.12g N-methylmorpholine oxide in 11 mL waterThe solution was then slowly added 360ml of 2.5% (p/v) osmium tetroxide (OsO)₄) Is added to the mixture. The mixture was stirred at about 20 ℃ for 1 hour and then at 65 ℃ for 4 hours. After evaporation of the tert-butanol under reduced pressure, the residue was recovered in 150 ml of IPA. Concentration to dryness under reduced pressure gives 8.27g of the product, which is 5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] as indicated by proton NMR spectrum]Heptane and 5S, 6R-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1]A mixture of heptanes (molar ratio 78/22).

Example 3b preparation of 5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane

To a 50 ml single neck round bottom flask with magnetic stirrer and cooling bath was added 1g of 2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1]Hept-5-ene (5mmol), 2.5ml diisopropyl ether, 2.5ml acetone, 0.9ml 58% by weight aqueous N-methylmorpholine oxide solution and 0.15ml water. The mixture was stirred for 5 minutes, then 9mg of solid K were added in one portion₂OsO₄·2H₂O and stirring was continued at room temperature for 25 minutes. The mixture was then stirred at reflux for 7.5 hours. HPLC showed 95% completion of the oxidation reaction at this point. The brown mixture was cooled to room temperature and a solution of 630mg sodium sulfite in 4ml water was added. The biphasic mixture was stirred at room temperature for 1 hour. Most of the organic solvent was distilled off under reduced pressure. 5ml of diisopropyl ether were added. The aqueous phase is separated off by decanting and extracted again with 2X 5ml of diisopropyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated under reduced pressure to give 1.04g (89%, corrected yield ═ 86%) of 5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] as an oil]Heptane, which forms a precipitate upon standing. In CDCl₃In (1) on¹H NMR indicated that the product was 95 mol% pure (4 mol% N-methylmorpholine +0.6 mol% starting material).

Example 3 preparation of c5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane L-tartrate

To a 2L reactor was added 210g of 2- (. alpha.) (alpha.)-S-methylbenzyl) -2-azabicyclo [2.2.1]Hept-5-ene, 1200ml 2-methyl-2-propane and 182ml 4-methylmorpholine oxide. To this mixture was added dropwise 8ml of a 2.5% osmium tetroxide solution in tert-butanol. The mixture was heated at 62 ℃ for 22 hours under nitrogen with vigorous stirring. The reaction mixture was concentrated by rotary evaporation at 60 ℃. 300 ml IPA was added and the solution was concentrated again at 60 deg.C to give 246g of 5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] as a dark brown syrup]Heptane. The crude product was suspended in 1.8L of 75% IPA at 40 deg.C. To this suspension 158.2g L-tartaric acid was added with vigorous stirring. Stirring was continued at 40 ℃ for 2.5 hours. The mixture was cooled to 30 deg.C, filtered, washed with 500 ml of 75% IPA and 200ml IPA and then dried under vacuum at 70 deg.C for 16 h to give 269.5g of the desired L-tartrate salt as a cream solid (MP 143-145 deg.C, diastereomer ratio 94.2: 5.8).¹H NMR(500MHz，CDCl₃): δ 1.3(d, 3H); 2.5(m, 2H); 4.18(s, 2H); 7.36(t, 2H); 7.4(t, 2H); MS (EI, 70eV) m/z (relative intensity): 233(M +, 13)

Example 4a preparation of 5R, 6S-isopropylidenedioxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane

To a solution containing 18.4g of 5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1]A500 ml three-necked flask with a cooling device and a stirring system, containing a solution of heptane (76mmol) in 130ml of toluene, was charged with 31.7g of 2, 2-dimethoxypropane (304mmol) and then slowly with 13g of TFA (114 mmol). The mixture was heated at 65 ℃ for 4 hours and 10 minutes. After cooling to 30 ℃ and concentration in a rotary evaporator to remove toluene, excess 2, 2-dimethoxypropane and part of TFA, the reaction mixture is taken up in dichloromethane and then neutralized by addition of 100 ml of 2N sodium hydroxide. After decanting, the organic phase is dried over sodium sulfate, filtered, treated with decolorizing charcoal (30g) at the boiling point of dichloromethane for 30 minutes, and treated with Clarcel^Filtration and concentration to dryness under reduced pressure gave 18.8g of 5R, 6S-isopropylidenedioxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1]Heptane, the structure of which was characterised by proton NMR spectroscopy in deuterated chloroformThe NMR spectrum measured had the following shift values (δ): 1.22(3H, d); 1.23(6H, s); 1.31(1H, d); 1.57(1H, d); 2.08(1H, d); 2.34(1H, broad s); 2.45(1H, dd); 3.06(1H, s); 3.40(1H, q); 4.09(1H, d); 4.19(1H, d); 7.26(5H, m).

Example 4b preparation of 5R, 6S-isopropylidenedioxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane

To a 2L four-necked jacketed cylindrical reactor with thermocouple, overhead stirrer and condenser was added 223g of 5R, 6S-dihydroxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1]Heptane L-tartrate, then 1200ml IPA was added. Stirring was started and 286 ml of 2, 2-dimethoxypropane and 44.6ml of TFA were added to the flask. The suspension was heated to 72 ℃ until all solids were dissolved. After 5 hours, the reaction was cooled to 65 ℃ and its contents transferred to a 3L round bottom flask. About 1100 ml of solvent were distilled off at about 48 ℃ and under a vacuum of 124 mbar. To an initial 2L four-necked jacketed cylindrical reactor, 1.2L of 2M sodium hydroxide solution was added with stirring at 25 ℃. To the sodium hydroxide solution was added the residue of the above distillation (about 700 ml solution). The tan colored solution was cooled to 25 ℃ over 40 minutes. At about 28 ℃, a precipitate began to precipitate out of solution. The suspension was stirred for several hours and then filtered using an 11cm buchner funnel fitted with Whatman #1 filter paper. The filter cake was washed with 300 ml of water. The off-white solid was slurried in water for 13 hours, then re-filtered, washed with water and dried. The solid was dried in vacuo at 50 ℃ to give 112g of 5R, 6S-isopropylidenedioxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] as a white solid]Heptane, the product was diastereomerically pure by HPLC.¹H NMR(500MHz，CDCl₃): δ 1.28(s, 3H); 1.27(d, 3H); 1.39(s, 3H); 1.63(d, 1H); 2.27(d, 1H); 2.4(d, 1H); 2.51(dd, 1H); 3.12(s, 1H); 3.46(q, 1H); 4.2(dd, 2H); 7.28(m, 5H); MS (EI, 70eV) m/z (relative intensity): 273(M +, 8.4)

EXAMPLE 5a preparation of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptane

To a 250 ml three-necked flask with a stirring system were charged 0.5g of 5% palladium on carbon, 5g of 5R, 6S-isopropylidenedioxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [2.2.1] heptane, 3.98g of di-tert-butyl dicarbonate and 36 ml of methanol. The apparatus was purged with argon, then with hydrogen, and then placed under a hydrogen atmosphere at 25 ℃. The reaction was continued for 5 hours, with purging with hydrogen every 15 minutes to remove the carbon dioxide formed.

By Clarcel^Filtration and concentration under reduced pressure to dryness gave 4.84g of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1]Heptane by dissolving in DMSO-d₆The structure was identified by measuring the NMR spectrum, which had the following shift values (δ): 1.16(s, 3H); 1.28(s, 3H); 1.32(s, 1H); 1.34(s, 3H); 1.65(d, 1H); 2.38(m, 1H); 2.65(d, 1H); 2.99(m, 1H); 3.84(m, 1H); 3.94(d, 1H); 4.16(d, 1H).

EXAMPLE 5b preparation of 5R, 6S-isopropylidenedioxy-2- (tert-butyloxycarbonyl) -2-azabicyclo [2.2.1] heptane

140g of 5R, 6S-isopropylidenedioxy-2- (. alpha. -S-methylbenzyl) -2-azabicyclo [ 2.2.1) are added in succession to a 2L four-necked jacketed cylindrical reactor with thermocouple, overhead stirrer, gas bag and nitrogen and hydrogen inlet baffle]Heptane, 13.4g 10% Pd/C and 900 ml methanol. The stirred suspension was purged with nitrogen at 25 ℃ for 10 minutes and then with hydrogen for 10 minutes. This procedure was repeated every 30 minutes and the reaction was monitored by TLC (silica gel, ethyl acetate, developed with iodine). After 3 hours, TLC showed 50% completion of the reaction. To this partially reduced solution was added over 10 minutes 56g of di-tert-butyl dicarboxylate, followed by a nitrogen/hydrogen purge as described above. A further 10g of di-tert-butyl dicarboxylate were added every 30 minutes, followed by a nitrogen/hydrogen purge, until a total of 112g of di-tert-butyl dicarboxylate (56g + several 10g additions) had been added. The reaction mixture was stirred at 25 ℃ overnight. The Pd/C suspension was filtered through a 9cm Buchner funnel fitted with #54 filter paper and a 5g pad of Celite and the reactor and filter cake were filtered through 100 mmL of methanol was washed. The filtrate was placed in a 2L single-neck round-bottom flask and 750 ml of solvent were distilled off at 40 ℃ and 105 mbar (approximately 250 ml of pale yellow solution remained). To the initial reaction vessel was added 1L of water cooled to 10 ℃. The residue of the above distillation was added to cooled water all at once. The 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] S was precipitated from the solution as a white solid]Heptane. The slurry was stirred at 6 ℃ for 30 minutes, then filtered and washed with water. The white solid formed was dried in vacuo at 60 ℃ to give 129.6g of a white solid which was enantiomerically pure by HPLC.¹H NMR(500MHz，CDCl₃): δ 1.28(s, 3H); 1.4(s, 3H); 1.45(s, 9H); 1.87(d, 1H); 2.53(s, 1H); 2.82(d, 1H); 3.17(dd, 1H); 4.09(m, 2H); 4.2(m, 2H); MS (FAB-LRP) m/z (relative intensity): 270((M + H) +, 9.4)

EXAMPLE 6a preparation of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptan-3-one

To a 30ml tube was added 270mg of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1]Heptane (1mmol) and 40mg RuO₂·H₂O (0.3 equiv.). 10ml of ethyl acetate and 720mg of water (40 equiv.) are added. Then, 2.14g of sodium periodate (10 equivalents) were added and the tube was sealed. Stirring was continued at 50 ℃ for 16 hours. Subjecting the reaction mixture to Clarcel^Filtered and then extracted twice with 20 ml of ethyl acetate each time. The organic phase was dried over sodium sulfate. Filtered and concentrated to dryness under reduced pressure to give 245mg of a solid containing 68% of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1]]Heptan-3-one and 32% of raw materials. By reaction in DMSO-d₆The structure of the product was identified by measuring the NMR spectrum having the following chemical shift values (δ): 1.38(s, 9H); 1.23(s, 3H); 1.33(s, 3H); 1.85(d, 1H); 1.93(d, 1H); 2.69(s, 1H); 4.24(s, 1H); 4.41(d, 1H); 4.51(d, 1H). Example 6b5R, 6S-isopropylidenedioxy-2- (tert-butyloxycarbonyl) -2-azabicyclo [2.2.1]Preparation of hept-3-ones

To carry heatThe couple, overhead stirrer and condenser were added sequentially in a 2L four-necked jacketed cylindrical reactor under stirring: 120g of 5R, 6S-isopropylidenedioxy-2- (tert-butyloxycarbonyl) -2-azabicyclo [2.2.1]Heptane, 0.3g RuO₂201.2g of sodium bromate, 960 ml of ethyl acetate and 1000 ml of water. The reaction mixture was heated to 45 ℃ and stirred at this temperature for 15 hours. The stirring was stopped and the aqueous layer was discarded. Saturated sodium chloride solution (500 ml) was added to the reactor and the suspension was stirred for 10 minutes. The stirring was stopped again, the layers were allowed to separate and the aqueous layer was removed. A 33% solution of maleic acid disodium salt (500 ml) was added to the reactor, the suspension was stirred for 5 minutes and the layers were separated again. The organic layer was filtered through a pad of celite to remove the catalyst and the solvent was evaporated in vacuo. The resulting solid was dried in vacuo to give 117g of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] as a white solid]Heptan-3-one, which contains 5% of raw materials. The 115g sample was dissolved in 350 ml of 85 ℃ heptane, cooled to 25 ℃ over about 3 hours, then cooled to 5 ℃ and filtered, and dried under vacuum at about 60 ℃. 92g (74%) of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] are obtained as white crystalline solids]Hept-3-one.¹H NMR: δ 1.32(m, 3H); 1.48(m, 12H); 1.82(m, 1H); 2.1(m, 1H); 4.43(m, 1H); 4.48(m, 1H); 4.6(m, 1H); MS (FAB-LRP in nitrobenzyl alcohol): 284((M + H) +, 10%)

Example 7a preparation of 2R, 3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonyl-cyclopentanebenzoate

568mg of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] are added to a Berghoff tube]Hept-3-one and 10ml of a 70% by weight aqueous solution of ethylamine. The mixture was heated at 60 ℃ for 4 hours with stirring. After cooling, excess ethylamine and water were distilled off under reduced pressure. After concentration to dryness under reduced pressure, 650mg of 2R, 3S-isopropylidenedioxy-4R-tert-butoxycarbonylamino-1S-ethylaminocarbonyl-cyclopentane was obtained in 98% yield, and the structure was confirmed by proton NMR spectroscopy, which was the optical rotation [ alpha ], [ alpha ]]^D ₂₀15.0(c 1; methanol).

To a solution of 200mg 2R, 3S-isopropylidenedioxy-4R-tert-butoxycarbonylamino-1S-ethylaminocarbonyl-cyclopentane in 1.6ml dry dichloromethane was added 275 ml TFA. The mixture was stirred at a temperature of about-5 ℃ overnight. The reaction mixture was poured into 4ml of a 2.5N aqueous sodium carbonate solution. The organic layer was concentrated under reduced pressure below 25 ℃. 125mg of the product thus obtained are dissolved in 0.5ml of tetrahydrofuran. To this solution 70mg of benzoic acid was added. The resulting solution was cooled to about 0 ℃, the crystals formed were isolated by filtration and washed with pentane. This gave 138mg of 2R, 3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonyl-cyclopentanebenzoate.

Example 7b preparation of 2R, 3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonyl-cyclopentane trifluoroacetate

Into a 25 ml autoclave equipped with a magnetic stirrer was charged 1.47g of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1]]A solution of hept-3-one in 10ml of anhydrous toluene, followed by the addition of about 0.7ml of ethylamine. The autoclave was sealed and then heated at a temperature of 90-100 ℃ for 21 hours. After cooling, the toluene is evaporated off and dissolved with 10ml of dichloromethane and 10ml of water. After decanting, the organic phase was washed with 10ml of water. The combined aqueous layers were washed with 10ml of dichloromethane. The combined organic phases are washed with 10ml of saturated sodium chloride solution and then dried over sodium sulfate. Filtration and concentration to dryness under reduced pressure gave 1.58g of product containing 95% 2R, 3S-isopropylidenedioxy-4R-tert-butoxycarbonylamino-1S-ethylaminocarbonyl cyclopentane by reaction in DMSO-d₆The structure was identified by measuring the NMR spectrum having the following chemical shift values (δ): 0.95(t, 3H); 1.14(s, 3H); 1.31(s, 12H); 1.55(m, 1H); 2.11(m, 1H); 2.64(m, 1H); 3.00(q, 2H); 3.77(m, 1H); 4.23(m, 1H); 4.54(m, 1H); 7.07(d, 1H); 8.12(t, 1H).

Into a 25 ml flask, 1.22g of 2R, 3S-isopropylidenedioxy-4R-tert-butoxycarbonylamino-1S-ethylaminocarbonyl cyclopentane and 10ml of methylene chloride were charged. At about 25 deg.C, 0.85g TFA was added with stirring. Stirring for 6 hr, and concentrating to dry to obtainTo 1.16g of 2R, 3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonyl-cyclopentane trifluoroacetate by reaction in DMSO-d₆The structure was identified by measuring the NMR spectrum having the following chemical shift values (δ): 0.79(t, 3H); 1.03(s, 3H); 1.19(s, 3H); 1.42(m, 1H); 2.05(m, 1H); 2.52(m, 1H); 2.89(q, 2H); 3.04(m, 1H); 4.16(m, 1H).

Example 7 preparation of c2R, 3S-isopropylidenedioxy-4R-amino-1S-ethylamino-carbonyl-cyclopentane

To a solution of 167mg of 5R, 6S-isopropylidenedioxy-2- (tert-butoxycarbonyl) -2-azabicyclo [2.2.1] heptan-3-one in 1ml of dichloromethane cooled to 0 ℃ was added 90. mu.L of TFA. The temperature was raised to 23 ℃ over 40 minutes and then stirred at this temperature for 22 hours. 90 μ L of TFA was again added and stirring was continued for 1 hour at 23 ℃. After evaporation under reduced pressure, 123mg of 5R, 6S-isopropylidenedioxy-2-azabicyclo [2.2.1] heptan-3-one were obtained, which was approximately 92% pure by HPLC and whose structure was identified by proton NMR spectroscopy.

A solution of 10g of 5R, 6S-isopropylidenedioxy-2-azabicyclo [2.2.1] heptan-3-one in 100 ml of a 70% aqueous solution (by weight) of ethylamine was heated at 110 ℃ for 20 hours under normal pressure. After cooling, the excess ethylamine was distilled off under reduced pressure and then the unreacted starting material was removed by washing with dichloromethane. The aqueous layer was concentrated and dried. This gave 10.54g of 2R, 3S-isopropylidenedioxy-4R-amino-1S-ethylaminocarbonylcyclopentane.

The invention can be carried out in other ways without departing from the spirit or scope of the invention.

Claims (9)

1. A process for the preparation of a compound of the formulaWherein R is hydrogen, or a group of the formula:

wherein R is₁Is alkyl, Ar is optionally substituted aryl, R_3’And R_3”Is hydrogen, alkyl or phenyl, or R_3’And R_3”Taken together with the carbon atom to which they are attached to form a cycloalkyl group,

the method comprises reacting a compound of the formulaWherein R is_4’And R_4”Is alkoxy or taken together with the carbon atom to which they are attached to form a carbonyl group, with a 2-azabicyclo [2.2.1] ring of the formula]Acid catalyzed acetalization or ketalization of the (1R) diastereomer of a heptane compound or a salt thereof in isopropanolWherein denotes the R chirality.

2. The method of claim 1, wherein R_4’And R_4”Is methoxy, R_3’And R_3”Is methyl.

3. The process of claim 1 wherein the acid catalysis is with trifluoroacetic acid.

4. The method of claim 1, wherein R is a group of the formula:

5. the method of claim 4, wherein R₁Is methyl and Ar is phenyl.

6. The process of claim 1 wherein the (1R) diastereomer of the 2-azadihydroxybicyclo [2.2.1] heptane compound is in the form of its L-tartrate salt.

7. A process for the preparation of a lactam compound of the formula,wherein R is₁' and R₁"independently of one another are acyl or aroyl, or together form an optionally substituted methylene group, G₁Is hydrogen or an amino protecting group, which process comprises reacting a di-O-protected 1R-2-azadihydroxybicyclo [2.2.1]Heptane compoundWith 0.1 mol% to 1 mol% of RuO₂Or a hydrate thereof, in the presence of 3 equivalents of an oxidizing agent to produce a lactam compound having an enantiomeric excess of greater than or equal to 95%.

8. The method of claim 7, wherein RuO₂The content of (B) is 0.5 mol%.

9. The process of claim 7, wherein the enantiomeric excess of the lactam compound formed is greater than or equal to 99%.