MXPA97002768A

MXPA97002768A - New effective and high selectivity procedureanantiomerica for the production of ciclopentano-beta- aminoacidos enantiomericamente pu

Info

Publication number: MXPA97002768A
Application number: MXPA/A/1997/002768A
Authority: MX
Inventors: Mittendorf Joachim
Original assignee: Bayer Aktiengesellschaft
Priority date: 1996-05-03
Filing date: 1997-04-16
Publication date: 1998-07-03

Abstract

New procedure, effective and of high enantiomeric selectivity for the production of enantiomerically pure cyclopentane-α-amino acids. The process according to the invention for the production of enantiomerically pure cyclopentane-α-amino acids of general formula (I), in which A and D have the meanings mentioned in the description, is characterized in that mesodicarboxylic anhydrides are transformed by asymmetric alcoholysis with allyl alcohols and in the presence of a chiral aminated base, present in enantiomerically pure form, in inert solvents first through the enantiomerically pure intermediate salt phase, in the enantiomerically pure monoester of dicarboxylic acid, in another step in the sense of a Curtius transforms this monoester of the dicarboxylic acid by reaction with azides in the corresponding intermediate acid azides and then in the corresponding transposed isocyanates, the isocyanates are then converted with allylic alcohols to the compounds of the general formula (VII) and subsequently They have, by dissociation of the urethane and ester functions, the cyclopentane-α-amino acids of the general formula (

Description

NEW EFFECTIVE AND HIGH SELECTIVITY PROCEDURE ENANTIOMERICA FOR THE PRODUCTION OF CICLOPENTANO-BETA-AMINOACIDOS ENANTIOMERI CAMENTE PUROS FIELD OF THE INVENTION The present invention relates to an efficient and highly enantiomeric selectivity process for the production of enantiomerically pure cyclopentane-B-amino acids. BACKGROUND OF THE INVENTION For the publications EP 571,800, JP 021 7747 53 A2 and J. Antibiot. (1991), 44 (5), 546-9 cyclopentane-β-amino acids are known. In WO 95/19337 there is described a process for the production of enantiomerically pure cyclopentane- and -penteno-β-amino acids. These are obtained from the corresponding meso-dicarboxylic anhydrides in a synthesis of six stages, with overall yields of 28-40% of the theoretical, with an excess of the enantiomer of > 98%. DESCRIPTION OF THE INVENTION The object of the invention is an efficient and highly enantiomeric selectivity process for the production of enantiomerically pure cyclopentane-B-amino acids of the general formula (I) wherein A and D are the same or different and represent hydrogen, halogen, hydroxyl or straight or branched alkyl with REF: 24445 to 8 carbon atoms which, if appropriate, is mono- to di-substituted, by the same or different halogen substituents, hydroxyl, phenyl, benzyloxy, carboxy, or by alkoxy, acyl or alkoxycarbonyl, linear or branched, with up to 6 carbon atoms respectively, or by a group of formula -NR7R8, where R7 and R8 are the same or different and mean hydrogen, phenyl or linear or branched alkyl with up to 6 carbon atoms, R1: / A and D together represent a radical of formula C. R2 wherein R1 and R2 are the same or different and mean hydrogen, halogen or alkyl, alkoxy or oxyacyl, linear or branched, with up to 8 carbon atoms, benzyl or phenyl, which is characterized in that meso-dicarboxylic anhydrides of the general formula are transformed (II) wherein A and D have the meanings indicated above, by an asymmetric alcoholysis with allylic alcohols of general formula (III) wherein R3, R4 and R5 are the same or different and represent hydrogen or linear or branched alkyl with up to 5 carbon atoms or phenyl which, if appropriate, is trisubstituted by the same or different substituents halogen, cyano, trifluoromethoxy, nitro, trifluoromethyl or by alkyl or alkoxy, linear or branched, with up to 6 carbon atoms respectively, or R3 represents an aromatic heterocycle of 5-7 links with up to 3 heteroatoms of the group S, N and / or O, and in the presence of equimolar amounts of a chiral aminated base, present in enantiomerically pure form, in inert solvents, first through the intermediate enantiomerically pure salt stage of general formula (IV) E © 0 in which A, D, R3, R4 and R5 have the meanings indicated above and E represents the chiral aminated base, in the enantiomerically pure compounds of general formula (IVa) wherein A, D, R3, R4 and R5 have the meanings indicated above in another step are transformed, in the sense of a Curtius rearrangement, by reaction of the compounds of general formula (IVa) with azides of general formula ( V) (R60) 2-P (0) -N3 (V) in which R6 represents phenyl or linear or branched alkyl with up to 6 carbon atoms, in inert solvents and in the presence of a base, or by activation of the carboxyl group of the compounds of general formula (IVa) and subsequent reaction with alkaline azides or trialkylsilylazides, in the corresponding intermediate acid azides and then in the corresponding transposed isocyanates of the general formula (VI) wherein A, D, R3, R4 and R5 have the meanings indicated above, isocyanates are then transformed with compounds of general formula (III) into the compounds of general formula (VII) wherein R3, R4, R5, A and D have the meanings indicated above and then a dissociation of the urethane and ester functions is carried out in inert solvents and in the presence of a Pd and / or a phosphine catalyst and / or of a nucleophilic coadjuvant substance. The process according to the invention can be clarified in an exemplified manner by means of the following scheme of formulas: In the context of the invention heterocycle represents, in general, an aromatic heterocycle of 5 to 7 links, preferably of 5 to 6 links which can contain up to 3 heteroatoms of the group S, N and / or O. They are to be mentioned by way of example pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl or imidazolyl. Pyridyl and thienyl are preferred. Surprisingly, in the development of the process according to the invention, the chiral compounds of general formula (I) are obtained in an elegant manner with very high enantiomeric purity and, at the same time, with very good yields. In contrast to the state of the art indicated above, the process according to the invention makes possible, from the corresponding isodicarboxylic anhydride, through a Curtius rearrangement, a highly selective enantiomerically pathway for the synthesis of cyclopentane-β- enantiomerically pure amino acids in a shortened synthesis sequence of 6 to 3 stages, with an overall yield of > 45% of theory and an excess of enantiomer of > 99% Another advantage of the process according to the invention is that the volumetric yield in the synthesis of the dicarboxylic monoester (formula IVa) is substantially higher compared to that of the process of the document WO 95/19337. In addition, the intermediate isolation of the compounds of general formula (IV) is suppressed. Although the compounds of the general formula (IVa) are present with an enantiomer excess of only 80 to 97%, in the next step (Curtius rearrangement), however, in the crystallization of the compounds of the general formula (VI) , an enantiomer excess of > 99% The process according to the invention is further distinguished, as opposed to the state of the art, because the Hofmann rearrangement, introduction and dissociation of a protecting group, are replaced by an efficient Curtius rearrangement. In addition, the dissociation of the urethane and ester functions of the compounds of general formula (VII) is carried out in one step; the product crystallizes in the reaction mixture and, in opposition to the state of the art, can be isolated by a simple filtration. Another advantage of the process according to the invention is that the compounds of general formula (VII), in comparison with the compounds of formula (V) of WO 95/19337, are crystalline and generally crystallize in the reaction mixture. This makes possible a simple manipulation and achieve an enrichment of the enantiomeric purity by crystallization. As the solvent for the conversion of the dicarboxylic anhydrides of the general formula (II), all inert organic solvents which do not change under the reaction conditions are taken into consideration. These preferably include, but are not limited to, ether, ethyl ether, dioxane, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons such as toluene, benzene, xylene, hexane, cyclohexane or petroleum fractions, or chlorinated hydrocarbons such as chloroform or ethylene chloride, or amides such as dimethylformamide, di-ethylacetamide or triamide of hexamethylphosphoric acid, or glacial acetic acid, dimethyl sulfoxide, acetonitrile or pyridine. Preferred for the individual steps are diisopropyl ether, diethyl ether, dioxane, t-butyl methyl ether and toluene. The reaction temperatures may vary within a wide range. Generally, it is worked between -602C and + 202C, preferably between -202C and +252C. The transformations can be carried out at normal pressure, but also at elevated or reduced pressure (for example from 0.5 to 80 bar). In general, normal pressure is used. As alcohols for the alcoholysis and for the transformation in the sense of a Curtius rearrangement (formula III), suitable primary allyl alcohols, such as, for example, allyl alcohol or cinnamic alcohol, are suitable. Trans-cinnamic alcohol is especially preferred.

As chiral aminated bases, they are suitable for the process according to the invention, preferably alkaloids and cinchona alkaloids. They are . preferred especially cinchona alkaloids such as, for example (+), (-) - quinine, (+), (-) - hydroquinine, (+), (-) - cinchonidine, (+), (-) -epiquinidine, (+), (-) -epicinconidine, (+), (-) -cinconine, (+), (-) -epicinconin, (+), (-) -epiquinin, (+), (-) -hydroquinidine, (+), (-) 4-chlorobenzoate-epiquinine or (+) t (~) 4-chlorobenzoate-epicinconine. Especially preferred are (+), (-) - quinine and (+), (-) - quinidine. The chiral aminated bases are used in equivalent amounts, based on 1 mole of the dicarboxylic anhydrides of the general formula (II). As acids for the recovery of the free chiral aminated bases are suitable, for example, mineral acids such as hydrochloric acid, hydrobromic acid or sulfuric acid. The acid is generally used in an amount of 1 mol to 10 mol, preferably from 1.5 mol to 4 mol, based on 1 mol of the compounds of general formula (IV). The recovery takes place, in general, in a temperature range from oac to + 502C, preferred from 200C to 30SC and at normal pressure. The transposition of Curtius is carried out, in general, in one of the inert solvents indicated above. Preferred are cyclic hydrocarbons such as benzene, toluene or xylene or ethers such as dioxane or tetrahydrofuran. Toluene is preferred. Suitable amines for the Curtius rearrangement are organic amines such as N-ethylmorpholine, N-methylmorpholine, pyridine, triethylamine or N-methylpiperidine. Triethylamine is preferred. The base is generally used in an amount of 1 mol to 3 mol, preferably 1 mol to 1.5 mol, based on 1 mol of the compounds of the general formula (IVa). As azides of formula (V) for the Curtius rearrangement, phosphoric ester azides are suitable, for example, diphenyl ester azide of phosphoric acid, diethyl ester azide of phosphoric acid. The azide of the diphenyl ester of phosphoric acid is preferred. It is also possible to first convert the carboxylic acid with activating reagents such as (C, -C4) -alkylchloroformates in the presence of an amine, thionyl chloride, phosphorus pentachloride or phosphorus oxychloride, in the corresponding activated derivatives and then obtain , by transformation with alkaline azides, such as sodium azide or trialkylsilylazides, such as tri-ethylsilylazide, the carboxylic acid azides. The Curtius rearrangement is generally carried out in a temperature range from OdC to + 1302C, preferred from 602C to HOSC.

The transposition of Curtius is carried out, in general, at normal pressure. But it is also possible to carry out the process under reduced pressure or at elevated pressure (for example, in a range of 0.5 to 5 bar). Activation of the carboxyl groups of the compounds of the general formula (IVa) is usually carried out with ethyl chloroformate / triethylamine and, in general, in a temperature range of -30 to +252C. The acid azides obtained in this way are then converted by heating a solution in one of the inert solvents indicated above, at temperatures of 60 ° C. to 120 ° C., into the corresponding isocyanates of the general formula (VI). The isocyanates of formula (VI) can be isolated or transformed after their preparation with the alcohols of general formula (III). The dissociation of the urethane and ester functions in the compounds of the general formula (VII) is generally carried out in one of the inert solvents indicated above. Preferred are hydrocarbons such as toluene, benzene or xylene, ethers such as tetrahydrofuran or diethyl ether, esters such as ethyl acetate, alcohols such as ethanol, methanol, isopropanol, acetonitrile or dimethylformamide. Acetonitrile, dimethylformamide, ethyl acetate or ethanol are especially preferred. The dissociation is generally carried out in a temperature range of ose to + 100 ° C, preferred from 202 ° C to 800 ° C.

The dissociation is carried out, in general, at normal pressure. But it is also possible to carry out the process under reduced pressure or at elevated pressure (for example, in a range of 0.5 to 5 bar). Suitable nucleophilic agents for dissociation are, for example, carboxylic acids and their alkali metal salts (for example, formic acid, acetic acid, 2-ethylhexanoic acid, sodium 2-ethylhexanoate), organic amines such as morpholine, triethylamine. , pyrrolidine, dimethyltrimethylsilylamine, trimethylsilylmorpholine, n-butylamine, dimedon, sodium diethylmalonate, tributyltin hydride, N, N-dimethylbarbituric acid or ammonium formate. Morpholine is preferred. The auxiliary agent is generally used in an amount of 1 mol to 20 mol, preferably 1.1 mol to 3 mol, based on 1 mol of the compounds of the general formula (VII). Suitable Pd catalysts are, for example, tetrakistriphenylphosphinpalladium (O) (Pd (PPh3) 4 / PPH3, palladium-dibenzylidenaketone (Pd2 (dba) 3), Pd2 (dba) 3 x, for example, in the process according to the invention. CHC13, Pd (dba) 2, Cl2Pd, (AcO) 2Pd, PdCl2 (PhCN) 2, PdCl2 (CH3CN) 2 or PdCl2 (PPh3) 2. Palladium (II) acetate (AcO) 2Pd is preferred. in general, in an amount of from 0.0001 mol to 0.2 mol, preferably from 0.001 mol to 0.05 mol, based on 1 mol of the compounds of the general formula (VII) As phosphine, they are generally suitable. (C, -C 4) -trialkyl- and triarylphosphines such as triphenylphosphine, triisopropylphosphine or tri-o-tolylphosphine Triphenylphosphine is preferred Compounds of general formula (II) are known or obtainable by published methods. (III), (Illa) and (V) are known The compounds of general formula (VII) are new and can be obtained as described above. preferably, enantiomerically pure compounds of the general formula (I) are obtained, in which A and D are the same or different and represent hydrogen, fluorine or linear or branched alkyl with up to 6 carbon atoms, or R1 / A and D together represent a residue of formula C R2 wherein R1 and R2 are the same or different and denote hydrogen, fluorine, bromine or linear or branched alkyl with up to 6 carbon atoms, benzyl or phenyl. Preferably, enantiomerically pure compounds are obtained by way of the process according to the invention. of general formula (I), in which A and D are the same or different or represent hydrogen or linear or branched alkyl with up to 4 carbon atoms, R1 'A and D together represent a radical of formula - _C R2 in which R1 and R2 are the same or different and denote hydrogen, linear or branched alkyl with up to 4 carbon atoms The process according to the invention makes it possible to efficiently, elegantly and with high enantiomeric selectivity and at the same time with high yields, access to enantiomerically pure cyclopentane-β-amino acids of general formula (I), which are extremely valuable medications with antifungal and antibacterial action.

Preparation examples Example 1 Ester of 1- (E) -cinnazyl acid (IR, 2S> 4-methylene-cyclopentane-1,2-dicarboxylic acid) 4-Met i len-1,2-cyclopentanedicarboxylic anhydride (90.0 g, 591 mmol) is dissolved in toluene (2,400 mi), in an atmosphere of N2. At -152C quinine is added (191.7 g, 591 mmol) and, later, transcinnamic alcohol (119.2 g, 888 mmol). The reaction mixture is stirred at -15 ° C for at least 4 hours. Allow to warm to room temperature and wash with 1 N HCl (3 x 900 mL) and water (2 x 900 mL). The product is then extracted from the organic phase with 2% aqueous solution of C03K2 (1 x 4.5 1, 2 x 1.5 1). The combined aqueous phases are washed with ethyl acetate (2 x 11), covered with toluene (600 ml) and, under vigorous stirring, adjusted to pH 2 with 10% hydrochloric acid. After separation of the phases, it is extracted twice more with toluene (2 x 600 ml). The combined toluene phases are washed with water (2 x 400 ml) and concentrated in vacuo at 50 ° C./about 20 mbar. Yield: 159.1 g, 94% of theory.

Excess of enantiomer, e.e. > 85% (HPLC, Chiracel OD-H, eluent: n-heptane / isopropanol). If the product is then mixed with toluene (180 ml) and the resulting suspension is stirred for approximately 1 hour after filtration and evaporation of the filtrate in vacuo, the ester of 1- (E) -cinnamyl of the acid is obtained. (IR, 2S) -4-methylenecyclopentane-1,2-dicarboxylic acid (144.6 g, 85% of theory) with an excess of ee enantiomer > 98% (HPLC, Chiracel OD-H, eluent: n-heptane / isopropanol). C17H ,, 04 (286.3): Theoretical: C 71.31% H 6.34% Found: C 71.27% H 6.42% Example Ester of 1- (E) -cinamyl of (1S, 2R) -4-methylenecyclopentane-1 acid , 2-dicarboxylic A suspension of quinidine (179.4 g, 553 mmol) is cooled to -152 C under N2 and mixed successively with 4-methylenecyclopentane-1,2-dicarboxylic anhydride (84.0 g, 553 mmol) and transboundary alcohol. cinnamic (111.2 g, 829 mmol).

The reaction mixture is stirred at -15ac for at least 4 hours. The processing is carried out analogously to obtaining the compound of example 1. Yield: 147.3 g, 93% of theory. Excess of enantiomer, e.e. > 93% (HPLC, Chiracel OD-H, eluent: n-heptane / isopropanol). C17Hlg04 (286.3) Theoretical: C 71.31% H 6.34% Found: C 71.23% H 6.32% Example 2 (IR, 2S) -2N- ((E) -cinnaxyloxycarbonyl) amino-4 -metilen-l-cyclo-r pentane-carboxylate of (E) -cinomyl To the solution of the compound of Example 1 (10.0 g, 34.9 mmol, ee = 85%) in toluene (70 ml) is added successively, dropwise, under a nitrogen atmosphere, triethylamine (3.5 g). , 34.7 mmol) and azide of the phosphoric acid diphenyl ester (9.6 g, 34.9 mraol). The reaction mixture is heated at 90 ° C for about 30 minutes, until nitrogen is no longer evolved. Subsequently, trans-cinnamic alcohol (5.6 g, 41.9 mmol) is added dropwise at 90 ° C. and heated under reflux overnight under nitrogen. Allow the mixture to cool, stirring, to room temperature, continue cooling in a bath with ice to about 3 c, the precipitated product is filtered in vacuo, washed with a total of 50 ml of cold toluene and the product is dried empty at 50ac. Yield: 10.3 g, 70% of theory, white crystals. Excess of enantiomer, e.e. > 99% (HPLC, Chiracel OD-H, eluent: n-heptane / isopropanol + trifluoroacetic acid). P. of f. : 1368C. C26H27N04 (417.51) Theoretical: C 74.80% H 6.52% N 3.36% Found: C 74.88% H 6.44% N 3.51% If the reaction described above is carried out with the compound of Example 1, with an excess of ee enantiomer > 98% under otherwise analogous conditions, then the product is obtained with a yield of 11.7 g (80% of theory), with an excess of > 99% Example 2a (1S, 2R) -2N- ((E) -cinnaxyloxycarbonyl) amino-4-methylene-l-cyclopentane-carboxylate of (E) -cinnamyl The preparation is analogous to obtaining the compound of Example 2, starting from the compound of example la (30.0 g, 104.8 mmol). Yield: 34.6 g, 79.1% of theory. Excess of enantiomer, e.e. > 99% (HPLC, Chiracel OD-H, eluent: n-heptane / isopropanol + trifluoroacetic acid). C26H27N04 (417.51) Theoretical: C 74.80% H 6.52% N 3.36% Found: C 74.99% H 6.63% N 3.34% Example 3 (IR, 2S) -2N- ((E) -alkyl iloxycarbonyl) -amino-4-methylene-lf cyclopentane-carboxylic acid allyl The preparation is carried out from the 1-allyl ester of (IR, 2S) -4-methylenecyclopentane-1,2-dicarboxylic acid (DE 44 007 49 A1, 7.3 g, 34.9 mmol, e.e. = 96%), analogously to that described for example 2. Yield: 7.9 g, 66% of theory, white crystals.

C20H23NO4 (341.38) Theoretical: C 70.36% H 6.79% N 4.10% Found: C 70.25% H 6.97% N 4.08% Example 4 (-) - (IR, 2S) -2-amino-4-methylene-cyclopentane-1-carboxylic acid A solution of the compound of Example 2 (180.0 g, 431 mmol) in ethyl acetate (1500 ml) is mixed successively, under N2 with triphenylphosphine (5.38 g, 20.5 mmol), morpholine (75.1 g, 862 mmol) and palladium (II) acetate (0.97 g, 4.3 mmol). The reaction mixture is heated to reflux for 2 hours and after that it is cooled to about 60ac. The precipitated product is filtered under vacuum, washed with ethyl acetate and dried in vacuo. The crude product is crystallized twice from aqueous ethanol at 85% Yield: 42.6 g, 70% of theory, white crystals. P. of f. : 2223C. [a] 20D = 31.6 (c = 1, H20). C7HpN02 (141.2) Theoretical: C 59.56% H 7.85% N 9.92% Found: C 59.46% H 7.85% N 9.88% Analogously and with almost the same yields the production of the compound of Example 4 is obtained from the compound of Example 3. Example 4a Acid (+) - (1S , 2R) -2-amino-4-methylene-cyclopentane-1-carboxylic acid H2N CO, The preparation is analogous to obtaining the compound of Example 4, starting from the compound of the example 2a (60.3 g, 144.4 mmol). Yield: 12.4 g, 67.6% of theory. P. of f .: 233ac (decomp.). [a] 20D = +32.2 (c = l, 02, H20). Theoretical: C 59.56% H 7.85% N 9.92% Found: C 59.09% H 7.74% N 9.87% Example 5 Ester of 1- (E) -cinomyl of (IR, 2S) -cyclopentane-1,2-dicarboxylic acid A suspension of quinine (50.9 g, 157.1 mmol) in toluene (634 ml) is mixed successively, at -15ac under N2, with cyclopentane-1,2-dicarboxylic anhydride (22.0 g, 157.1 mmol) and trans-cinnamic alcohol (31.6 g, 235.7 mmol). The reaction mixture is stirred at -15ac for at least 4 hours. Allow to warm to room temperature and wash with 1 N HCl (2 x 240 mL) and water (240 mL). The product is then extracted from the organic phase with 2.2% aqueous solution of C03K2 (1 x 1210 ml, 1 x 400 ml). The combined aqueous phases are washed with ethyl acetate (2 x 260 ml), covered with toluene (260 ml) and, under vigorous stirring, adjusted to pH 2 with 10% hydrochloric acid. After separation of the phases, it is extracted once more with toluene (260 ml). The combined toluene phases are washed with water (2 x 130 ml) and concentrated in vacuo at 50 ° C. Yield: 40.2 g, (93% of theory). Excess of enantiomer, e.e. > 86% (HPLC). C16H1804 (274.3) Theoretical: C 70.06% H 6.61% Found: C 69.66% H 6.42% Example 6 (IR, 2S) -2N- ((E) -cinnaxyloxycarbonyl) amino-cyclopentane -1- (E) -cinamyl carboxylate To the solution of the compound of Example 5 (39.3 g, 143 mmol) in toluene (286 ml) is added successively, dropwise, under N2, triethylamine (14.3 g, 142 mmol) and sodium azide. Phosphoric acid diphenyl ester (39.4 g, 143 mmol). The reaction mixture is heated at 90 ° C for about 30 minutes and then trans-cinnamic alcohol (23.0 g, 172 mmol) is added dropwise at this temperature and the mixture is refluxed overnight. The mixture is allowed to cool, with stirring, to 30 ° C., the precipitated crude product (14.2 g) is filtered in vacuo and then washed with cold toluene (60 ml). The mother liquors are washed successively with 5% aqueous solution of citric acid (410 ml), water (410 ml), saturated NaCl solution (410 ml) and saturated NaCl solution (410 ml). After concentrating the organic phase in vacuo, more crude product is obtained (30.0 g). The crude product is then crystallized from isopropanol. Yield: 33.3 g (57.3% of theory), white crystals. Excess of enantiomer, e.e. > 99% (HPLC, Chiracel OD-H).

P. of f. : 84-858C. C25H27N04 (405, 5) Theoretical: C 74.05% H 6.71% N 3.45% Found: C 74.12% H 6.58% N 3.53% Example 7 (-) - (IR, 2S) -2-amino-cyclopentane-1-carboxylic acid A solution of the compound of Example 6 (44.8 g, 110.5 mmol) and triphenylphosphine (1.37 g, 5.2 mmol) in ethanol (127 ml), mixed under N2 with morpholine (19.3 g, 221 mmol) and palladium acetate (II ) (0.062 g, 0.28 mmol). The reaction mixture is refluxed for 2 hours, mixed with 3-mercapto-l, 2,4-triazole (1.12 g, 11.1 mmol), heated to reflux for an additional 1.5 hours and then from this it cools to 0-5ac. The precipitated crude product is filtered under vacuum, washed with ethanol and dried in vacuo. The crude product is crystallized from 85% aqueous ethanol, in the presence of 5% molar mercapto-1, 2,4-triazole. Yield: 9.4 g (66% of theory), white crystals. P. de f .: 218ac (decomp.). [a] 20D = 9.9 (c = 1, 0, H20). Theoretical: C 55.80% H 8.59% N 10.84% Found: C 55.53% H 8.24% N 10.83% It is noted that, in relation to this date, the best method known by The applicant for carrying out the said invention is the one that is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims

CLAIMS 1. Procedure for the production of enantiomerically pure cyclopentane-β- to innoacids,. of general formula (I) wherein A and D are the same or different and represent hydrogen, halogen, hydroxyl or straight or branched alkyl with up to 8 carbon atoms. carbon, which, if appropriate, is mono- to a -substituted, by the same or different substituents halogen, hydroxyl, phenyl, benzyloxy, carboxy, or by alkoxy, acyl or alkoxycarbonyl, linear or branched, with up to 6 carbon atoms respectively, or a group of formula -NR7R8, wherein R7 and R8 are the same or different and mean hydrogen, phenyl or straight or branched alkyl with up to 6 carbon atoms, or R1 / A and D together represent a moiety of formula C R2 in which R1 and R 2 are the same or different and mean hydrogen, halogen or alkyl, • alkoxy or oxyacyl, linear or branched, with up to 8 carbon atoms, benzyl or phenyl, characterized in that they are converted to dicarboxylic anhydrides of the general formula (II) wherein A and D have the meanings indicated above, by an asymmetric alcoholysis with allylic alcohols of general formula (III) wherein R3, R4 and R5 are the same or different and represent hydrogen or linear or branched alkyl with up to 5 carbon atoms or phenyl which, if appropriate, is trisubstituted by the same or different substituents halogen, cyano, trifluoromethoxy, nitro, trifluoromethyl or by alkyl or alkoxy, linear or branched, with up to 6 carbon atoms respectively ,. or R3 represents an aromatic heterocycle of 5-7 links with up to 3 heteroatoms of the group S, N and / or 0, and in the presence of equimolar amounts of a chiral aminated base, present in enantiomerically pure form, in inert solvents, first through of the enantiomerically pure salt intermediate stage of general formula (IV) wherein A, D, R3, R4 and R5 have the meanings indicated above and E represents the chiral aminated base, in the enantiomerically pure compounds of general formula (IVa) in which A, D, R3, R4 and R5 have the meanings indicated above in another step are transformed, in the sense of a Curtius rearrangement, by reaction of the compounds of general formula (IVa) with azides of general formula (V) _ (R60) 2-P (0) - N3 (V) in which R6 represents phenyl or linear or branched alkyl with up to 6 carbon atoms, in inert solvents and in the presence of a base, or, by activation of the carboxyl group of the compounds of general formula (IVa) and reaction with alkaline azides or trialkylsilylazides, in the corresponding intermediate acid azides and then in the corresponding transposed isocyanates of the general formula (VI) wherein A, D, R3, R4 and R5 have the meanings indicated above, the isocyanates are then transformed with compounds of general formula (III) / into the compounds of general formula (VII) wherein R3, R4, R5, A and D have the meanings indicated above and then a dissociation of the urethane and ester functions is carried out in inert solvents and in the presence of a Pd and / or a phosphine catalyst and / or of a nucleophilic coadjuvant substance. Process according to claim 1, characterized in that the conversion of the dicarboxylic anhydride of the general formula (I) is carried out in a temperature range between -60 ° c and + 40 ° C., preferably between -20 ° C. and + 25 ° C. Process according to claim 1, characterized in that the conversion of the dicarboxylic anhydride of the general formula (I) is carried out at a pressure in the range between 0.5 and 80 bar, preferably at normal pressure. Process according to claim 1, characterized in that the Curtius rearrangement is carried out in a temperature range between 0 and + 130ac, preferably between 6 and lioac. Process according to claim 1, characterized in that the Curtius rearrangement is carried out at a pressure in the range between 0.5 and 5 bar, preferably at normal pressure. Process according to claim 1, characterized in that in the Curtius rearrangement the base is used in an amount of 1 to 3 moles, preferably 1 to 1.5 moles, based on 1 mole of the compound of the general formula (IVa). Process according to claim 1, characterized in that the dissociation of the urethane and ester functions is carried out in a temperature range between oac and 100 ° C, preferably between 20 ° C and 80 ° C. Process according to claim 1, characterized in that the dissociation of the urethane and ester functions is carried out at a pressure comprised in the range between 0.5 and 5 bar, preferably at normal pressure. Enantiomerically pure compounds of general formula (IV) characterized in that A, D, R3, R4 and R have the meanings indicated in claim 1 and: E represents the chiral aminated base, enantiomerically pure compounds of general formula (IVa) characterized in that A, D, R3, R4 and R5 have the meanings indicated in claim 1. Enantiomerically pure compounds of general formula (VII) characterized in that R3, R4, R5, A and D have the meanings indicated in claim

1. SUMMARY OF THE INVENTION New, efficient and highly enantiomeric selectivity procedure for the production of enantiomerically pure cyclopentane-β-amino acids. The process according to the invention for the production of enantiomerically pure cyclopentane-β-amino acids, of general formula (I) wherein A and D have the meanings mentioned in the description is characterized in that isodicarboxylic anhydrides are transformed by asymmetric alcoholysis - with allylic alcohols and in the presence of a chiral aminated base, present in enantiomerically pure form, in inert solvents first through of the enantiomerically pure salt intermediate stage in the enantiomerically pure monoester of dicarboxylic acid, in another step in the sense of a Curtius rearrangement, this monoester of the dicarboxylic acid is converted by reaction with azides into the corresponding intermediate acid azides and then in the corresponding transposed isocyanates, the isocyanates are then converted with allylic alcohols to the compounds of general formula (VII) and then the cyclopentane-β-amino acids of general formula (I) are obtained by cleavage of the urethane and ester functions. .