NOVEL PROCESS FOR THE PREPARATION OF CIS, ENDOOCTAHYDROCYCLOPENTA[b]PYRROLE-2-CARBOXYLATE

Abstract: Novel process for the preparation of cis,endo-octahydrocyclopenta[b]pyrrole-2-carboxylate (IIIa) wherein R<6> is hydroxy, lower alkoxy, lower alkenoxy, dilower alkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, arylloweralkoxy, amino, lower alkylamino, dilower alkylamino, hydroxyamino, aryllower alkylamino, or substituted aryloxy or substituted aryllower alkoxy wherein the substituent is methyl, halo or methoxy, which comprises catalytic reduction of compound (II), which further may comprise preparing the compound of formula (II) by the reaction of a halo pyruvate ester (V) with benzyliminocyclopentane. Compounds (IIIa) are useful intermediates for the preparation of certain ACE-inhibitors.

Description: NOVEL PROCESS FOR THE PREPARATION OF CIS,ENDO- OCTAHYDROCYCLOPENTACb1PYRROLE-2-CARBOXYLATE Inhibitors of angiotβnsin-converting enzymes are useful in the treatment of cardiovascular disorders especially as antihypertensive agents and also in the treatment of congestive heart failure and of glaucoma. Such ACE*inhibi ors have, for example, been described in the published European patent applications Nos. 50800 and 79022. Of particular interest as ACE-inhibitors are compounds of the general formula (I) — IC- and the pharmaceutically acceptable salts thereof, wherein R and R 6 are the same or different and are hydroxy, lower alkoxy, lower alkenoxy, diloweralkyl- amino lower alkoxy (e.g. dimethylaminoethoxy) , acylamino lower alkoxy (e.g. acetylaminoethoxy) , acyloxy lower alkoxy (e.g. pi aloyloxyethoxy ) , aryloxy (e.g. phenoxy.)., arylloweralkoxy (e.g. bβnzyloxy ) , amino, lower alkylamino, dilowβralkylamino, hydroxyamino, aryllower alkylamino (e.g. benzyla ino) , or substituted aryloxy or substituted arylloweralkoxy wherein the substituent is methyl, halo or methoxy; R 1 is hydrogen, alkyl of from 1 to 10 carbon atoms, including branched and cyclic and unsaturated (e.g. allyl) alkyl groups, substituted lower alkyl wherein the substituent is hydroxy, lower alkoxy, aryloxy (e.g. phenoxy), substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, lower alkylamino, dilowβralkylamino, acylamino, arylamino, substituted arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio (e.g. phenylthio) , substituted arylthio, carboxy, carbamoyl, lower alkoxycarbonyl, aryl (e.g. phenyl or naphthyl), substituted aryl, aralkyloxy, substituted aralkyloxy, aralkylthio, or substituted aralkylthio, wherein the aryl or heteroaryl portion of said substituted aryloxy, heteroaryloxy, arylamino, arylthio, aryl, aralkyloxy or aralkylthio groups is substituted with a group selected from halo, loweralkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano and sulfamoyl; and R 3 is hydrogen, lower alkyl, phenyl lower alkyl, a inomethylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl (e.g. benzoylamino lower alkyl or acetylamino lower alkyl), amino lower alkyl, dimethylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkylthio lower alkyl. As used herein, acyl includes - JC-R 12 wherein R 12 is lower alkyl, lower alkenyl or aryl. The lower alky or lower alktnyl groups except where noted otherwise are represented by any of the variables including straight and branched chain hydrocarbon radicals from one to six carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, isopentyl, hexy or vinyl, allyl, butenyl and the like. Cycloalkyl groups include bridged and non-bridged groups. The aralkyl groups represented by any of the above variables have from one to four carbon atoms in the alkyl portion thereof and include for example, benzyl, p-methoxybenzyl and the like. Halo means chloro, bromo, iodo or fluoro. Aryl, where it appears in any of the radicals, except where noted, represents phenyl or naphthyl. Heteroaryl groups where they appear include for example pyridyl, thienyl, furyl, indolyl,benzoΛ:hienyl, imidazolyl and thiazolyl. The R 1 and R substituted lower alkyl moieties are exemplified by groups such as HO-CH 2 -, HS-CB2-, B 2 N- ( CB 2 ) 4 -, ca 3 -s-(ca 2 ) 2 -, NB H 2 N-(CH 2 ) 3 -, a 2 N-C-NB-(Ca 2 ) 3 - and the like. Preferred compounds of formula I are those in which R is hydroxy or lower alkoxy, R 1 is lower alkyl or substituted lower alkyl wherein the substituent is aryl, R 3 is lower alkyl or aminoloweralkyl and R 6 is hydroxy. The aforementioned compounds of the formula I, as defined above, include all possible stereo- isomβrs. Preferred stβrβoisoaers are the cis,endo- oc tahydrocyclopβnt [ 1 yrrole-2 ( S ) -carboxy 1 ic ac ids , wherein preferably the absolute configuration at the carbon atoms marked by_double asterisk in the above formula I is most similar to that of natural L-amino acids, which usually are assigned the S-configuration. Particularly preferred compounds are l-[M-(l(S)-carboxy-3 phenylpropyl ) - ( S ) - alanyl] -c i s , endo-oc tahydroc yc lopen ta [b]-pyrrole-2(S)- carboxylic acid, 1-[N-(1(S ) - carboethoxy phenv lpropy 1 ) - ( S ) -alanyl 1 -c i s , endo- μ octahydrocycloyclopβntajb] pyrrole-2(S)-carboxylic acid, 1- [No- ( 1 ( S ) -carboethoxy-3-phenylpropyl ) - ( S ) -lysy 1] - c i s , endo-oc tahydrocyc lopen ta [b } yrrole-2 ( S ) -carboxyl ic ac id , 1- [Nα- ( 1 ( S ) -carboxy-3-phenylpropyl ) - ( S ) -lysy 1] - c is, endo-oc tahydrocyc lopenta [b] pyrrole-2 ( S ) -carboxyl ic ac id , 1- [N- ( 1 ( S ) -carboxybutyl ) - ( S ) -alanyll -cis,endo- octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid, 1- [N- ( 1 ( S ) -carboethoxybutyl ) - ( S ) -alanyl] -c is, endo- octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid, 1- [No- ( 1 ( S ) -carboethoxybutyl ) - ( S ) -lysyl ] -cis,endo- oc tahydrocyclopβnta [b] pyrrole-2(S) -carboxylic acid, and 1- [No- ( 1 ( S ) -carboxybutyl ) - ( S ) -l syl ] -cis,endo- octahydrocyclopentatb]pyrrole-2(S)-carboxylic acid or their hydrochloride salts. A most preferred compound is 1- [N- ( 1 ( S ) -carboethoxy-3-phenylpropyl ) - ( S ) -alanyl] - cis,endo-octahydrocyclopenta[b I pyrrole-2-(S) -carboxylic acid and its hydrochloride salt. These compounds can be prepared by known methods such as described in the above mentioned European published patent applications Nos. 50800 and 79022. One of the starting materials for the preparation of compounds of formula I is octahydro- σyclopenta[b]pyrrole-2-carboxylate. III, wherein R 6 is as defined above. Compounds of formula III consist of eight stereoisomers composed of four racemic pairs; the two cis epimers. Ilia and Ilϊb, and the two trans epimers, IIIc and Hid: Ilia (+> Hl (+) IIIC As used herein, the formulae Ilia, nib, IIIc and Hid are meant to comprise the relevant racemic pair of optical isomers. The compounds of formula III can be prepared by known methods, such as disclosed in the publications mentioned above, followed, if desired, by isolation of the racemic pairs of isomers or their individual component enantiomers according to resolution methods well described in the art. The present invention provides a novel process for the preparation of the compounds of the - ζ - general formula Ilia. This process comprises catalytic reduction of compound II II wherein R 6 is as defined above followed, if desired by the resolution of the racemic mixture to obtain the individual enantio er. Compound II can be prepared by the reaction of a halopyruvate ester (V) wherein R is as defined above and Hal stands for halogen, with benzyliminocyclopentane. This procedure can be exemplified by the following reaction scheme: -CH 2 -C 6 B 5 Br-CB,-C-C-R 6 IV V« (C 2 H 5 ) 3 N II Thβ process for preparing the novel compounds II t1-benzyl-l,4,5,6- etrahydrocyclopentanβ[b]pyrrole- 2-carboxylic acid or its esters) preferably uses a lower alkyl ester of bromo pyruvatβ (e.g. R 6 is ethoxy, methoxy or t-butoxy). Preferably, eguimolar amounts of reactants are used. The reaction is carried out in an inert solvent such as, for example, an alcohol (e.g. ethanol), acetonitrile or dimethylformamide in the presence of a base such as, for example, triethyl- amine. The reaction may be carried out at from 0-100 β C for 2-8 hours, but is preferably carried out at low temperatures (e.g. 0-5 β C) for approximately 2 hours, then at reflux (temperature depends on solvent) for 2 hours. The catalytic reduction of compound II to saturate the ring and remove the benzyl group is carried out in a solvent such as an alcohol (e.g. ethanol) in the presence of hydrogen gas and a catalyst such as Pd ' (OH) on carbon, Pd on carbon or other appropriate catalysts. The resultant product may be isolated by methods well known to those skilled in the art, e.g. by treating with an acid such as HC1 to prepare the salt, followed by removal of the salt (e.g. by basifying with sodium hydroxide) to obtain the compound of formula Ilia, followed, if desired by the isolation of the individual enantiomers. In the above reactions, the group R being other than hydrogen (especially aryllower alkyl) can be hydrogenolyzed to some extent. Consequently, an addi¬ tional esterification step may be required to obtain the desired compound. The above described process is stereospecific so that compounds Ilia (cis,endo-for )are obtained directly. These compounds are useful in the preparation of the preferred compounds of formula I (listed above) which are also the cis,endo-isomers. This is a great advantage over the known method for preparing compounds of formula III which- are not stereospecific so that additional process steps have to be carried out to isolate the desired isomer of the intermediate (III) or of the end product (I). Compounds Ilia as obtained by this process are racemic mixtures. The individual enantiomers can be obtained by conventional resolution methods well described in the art, such as fractional crystallization of appropriate diastereomeric salts, for example the fractional crystallization of compounds Ilia wherein R° is benzyloxy or its benzyloxycarbonyl-L-phenylalanine salt. The compounds of formulae Ilia (cis,endo- form) can be converted to the corresponding compounds having the cis,exo-form (111b). Such epimerizations are most conveniently carried out on the free base ester forms of these compounds, in the absence or presence of additional basic catalysts such as potassium t-butoxide, triethylamine and the like. The following examples illustrate the process of this invention, the preparation and use of the compounds of the present invention. The diasterioisomers prepared as set forth below may be isolated by column chromatography or by fractional crystallization. EXAMPLS 1 ETHYL CIS,ENDO-OCTAHYDROCYCLOPENTA[b]PYRROLE-2- CARBOXYLATE A. Ethyl 1-Benzyl-l ,4,5,β-Tetrahydrocyclopenta- [b]Pyrrole-2-Carboxylate. Add dropwise 3.9 gm of ethyl bromopyruvate in 50 ml of ethanol to a flask containing 3.46 gm of benzyliminocyclopβntanβ and 2.0g of triβthylaminβ in 50 ml of ethanol at 0°C, stir for 2 hours, then heat to reflux for 2 hours. Concentrate the reaction mixture and partition between IN HC1 and ether. Dry the ether extract over magnesium sulfate, filter, concentrate under high vacuum to obtain a brown oil and distill in a kugelrohr at 190-210V0.1 mm to obtain the title compound of Part A as a yellow oil. B. Ethyl Cis,Endo-octahydrocyclopentafb] yrrole-2- Carbox late Hydrochloride. Introduce hydrogen gas to a mixture of 2.3 gm of the pyrrole compound produced in part A ι of this Example and 1.5 gm of 20% Pd(0H) 2 /C in 200 ml of ethanol, and stir the reaction mixture. After 24 hours add an additional 0.8 gm of the palladium catalyst. After 600 ml of hydrogen gas is absorbed, filter the reaction mixture and concentrate to obtain a liquid and a solid. Take up the liquid in ether and filter. Treat the filtrate with 2.86N HCl/ether to obtain an oil which solidifies. Filter off the solid to obtain the hydrochloride salt of the title compound of Part B as a beige solid, m.p. 163 β -7°C. Recrystallization from CH 2 C1 2 and hexane raises the melting point to 171°-2°C. C. Cia,Endo-Octahvdrocyc opβntatb] yrrolβ-2-Carboxylic Acid. Stir a mixture of 10.7 g of ethyl cis,endo- octahydrocyclopβnta[b] yrrole-2-carbox late hydrochloride (from Part B above) and 175 ml of lN ^ sodium hydroxide at room temperature for 20 hours and then concentrate n. vacuo. Place the residue on a silica gel (1000 g, 60-200 mesh) column and elutβ with chloroform:isopropanol:7% ammonium hydroxide 1:1:1 (organic layer) to give cis,endo-octahydrocyclopβnta- [b]pyrrole-2-carboxylic acid, as a white solid, m.p. 220-222°C; TLC: R f 0.12 (0.25 mm silica; » —» CHC1 3 :isopropanol:7% NH 4 OH-l:l:l-lowβr phase); MS: 156, 155 (M + ), 126 (M-HCO), 111 (M-C0 2 ), 110 (M-C0 2 H; 100%), 93 [M-H(CH 2 ) 3 ], 82 (M-CH 2 »CHC0 2 H) , 80 (M- I 1 H 2 ,CH 2 »CHC0 2 H), 68 [M-C0 2 H, (CH 2 ) 3 ], 67 [M- J f HC0 2 H,(CH 2 ) 3 ] . NMR (400 MHz-D 2 0); S 4.39 (1H doublet of doublets J»llHz,8Hz); 4.20 (1H multiplet) ; 3.00 (1H multiplet) ; 2.66 (1H multiplet); 2.03-1.78 (6H multiplet); 1.57 (1H multiplet) . EXAMPLE 2 l-[N-(l(R,S)-CARBOETHOXY-3-PHENYLPROPYL)-(S)- ALANYL]-CIS,ENDO-OCTAHYDROCYCLOPENTA[b]PYRROLE-2(S)- CARBOXYLIC ACID A. To a solution of 10.0 g of ethyl-cis,endo- octahydrocyclopenta[b]pyrrole-2-carboxylate in 400 ml of ethyl acetate add 17.0 g of N-benzyloxycarbonyl-(S)- alanine, N-hydroxysuccinimide ester. Stir the reaction mixture at room temperature for 20 hours and concen- tratβ it _in , vacua. Place the residue on a column of silica gel (3000 g, 60-200 mesh) and βlutβ with chloroform:ethyl acetate 10:1 to obtain l-[N-benzyloxy- carbony1-(S)-alanyl]-cis,endo-octahydrocyclopβnta[b]- pyrrole-2-carboxylic acid, ethyl ester, a colorless oil [α] D 26 -32.6 β (C =» 0.5, ethanol). B. To a solution of 3.22 g of 1-[N-benzyloxy- carbonyl-(S)-alanyl]-cis,endo-octahydrocyclopβnta- [b]pyrrole-2-carboxylic acid, ethyl ester in 150 ml of methanol, add 20 ml of 2.5 N sodium hydroxide and stir the mixture at room temperature for 18 hours. Concentrate the mixture under nitrogen, dilute the residue with ice-water and then make the mixture acidic with concentrated hydrochloric acid. Extract the aqueous solution with ethyl acetate and dry the organic phase over magnesium sulfate. Concentrate the organic phase and place it on a column of silica gel (500 g., 60-200 mesh). Elute with chloroform:glacial acetic acid 9:1 and isolate l-[N-benzyloxycarbonyl-(S)- alanyl]-cis,endo-octahydrocyclo-penta[b] pyrrole-2(S)- carboxylic acid, as a colorless oil, [α] D 2 ^-26.4° (C = 0.5, ethanol). C. Dissolve 1.70 g of l-[N-benzyloxycarbonyl- (S)-alanyl]-cis,endo-octahydrocyclopenta[b] pyrrole- 2(S)-carboxylic acid in 100 ml of methanol. Add 0.40 g 10% palladium-on-charcoal and hydrogenate the mixture at atmospheric pressure. Filter the mixture and concentrate in vacuo to obtain 1-[(S)-alanyl]-cis,endo- octahydro-cyclopenta[b]pyrrole-2(S)-carboxylic acid. D* Dissolve l-[(S)-alanyl]-cis,endo-octahydro- cyclopenta[b]pyrrole-2(S)-carboxylic acid in 100 ml of absolute methanol. Add 1.10 g 2-oxo-4-phβnylbutyric acid, ethyl eater and 20 ml of 3 Angstrom molecular sieve pellets, and stir the resulting mixture at room temperature for eighteen hours. Filter the reaction mixture and treat the filtrate with 0.68 g sodium cyanoborohydridβ at. room temperature for two hours. Concentrate the mixture under nitrogen and dilute the oil with dilute hydrochloric acid and stir at room temperature for one hour. Absorb the aqueous solution on 200 ml of a XAD-2 (Rohm & Haas Co. resin). Ξlute the resin with 2000 ml of water and then with 2000 ml of methanol. Concentrate the methanol solution and place the residue on a column of silica gel (400 g, 60- 200 mesh) and elute with chloroform:isopropanol:7% ammonium hydroxide (1:1:1) (organic layer) to give 1- [N-(1(R ,S)-carboethoxy-3-phenylpropyl)-(S)-alanyl]- cis,endo-octahydrocyclopenta[b]pyrrole-2 (S)-carboxylic acid, as a colorless oil, [α] D | f -5.8° (C»10.6, ethanol) . EXAMPLE 3 1-[N-(1(S)-CARBOETHOXY-3-PHENYLPROPYL)-(S)-ALANYL]- CIS ,ENDO-OCTAHYDROCYCLOPENTA[b1 PYRROLE-2(S)- CARBOXYLIC ACID AND THE HYDROCHLORIDE SALT THEREOF Method I A. Cis,endo-Octahydrocyclopenta[b]pyrrole-2-Carboxylic Acid Hydrochloride Method I Add a 20% HC1 in dioxanβ solution (100 ml) to 5 g. of cis,endo- I | octahydrocyclopenta[b]pyrrole-2-carboxylic acid. Stir the resulting mixture at room temperature for 30 min. and then concentrate it in vacuo. Wash the white residue with anhydrous ether and dry in vacuo to obtain thβ title compound of Part A as a white solid, m.p. 209-211*. Method II Dissolve 0.2 g of ethyl cis,endo- octahydrocyclopβnta[b]pyrrolβ-2-carboxylatβ (free base or hydrochloride from Example 1 in 20 ml of 6N hydrochloric acid and reflux overnight. Cool the reaction mixture, remove the volatiles under high vacuum and obtain the title product of Part A. B. To 5.0 g of the product of Part A, add 50 ml of benzyl alcohol and 50 ml of thionyl chloride and stir at room temperature. Concentrate the reaction mixture in vacuo and recrystallize the residue from chloroform/ isopropanol to give benzyl cis,endo- octahydrocyclopenta[b]pyrrole-2-carboxγlate hydrochloride, m.p. 175°. C. To 5.5 g of the product of Part B, add 2.6 g of 1-hydroxybenzotriazole, 5.4 g of N[l(S)-carboethoxy- 3-phenylpropyl]-(S)-alanine and 4.0 g of dicyclohexyl- carbodiimide in 80 ml of dimethyl formamide. Stir the reaction mixture at room temperature for 18 hours. Filter the reaction mixture, and add ethyl acetate to the filtrate. Extract the ethyl acetate solution (3 X 200 ml) with 5% aqueous sodium bicarbonate. Concentrate the dried (MqS0 4 ) ethyl acetate solution in vacuo. Chromatograph the residue on a silica gel column (400 g, 60-200 mesh) and elute with ethyl acetate/petroleum ether (30-60°) 2:1. Isolate, as the first eluted material, 1-[N-(l(S)-carboethoxy-3- phenvlpropvl)-(S)-alanyl]-cis,βndo-octahydrocyclo- pβnta[b]pyrrolβ-2(S) -carboxylic acid benzyl ester. D. Hydrogenate 3.0 g of l-[N-(l(S)-carboethoxy- 3-phenylpropyl ) - ( S ) -alanyl] -cis,endo- oc tahydrocyclopen ta lb ] pyrrole-2 ( S ) -carboxyl ic ac id benzyl ester in 40 ml of ethanol containing 0.5 g of 10% Pd/C. Remove the catalyst by filtration and concentrate the filtrate in vacuo. Add absolute ether to crystallize l-[N-(l(S)-carboethoxy-3-phenylpropyl)- ( S ) -alanyl] -cis, endo-oc tahydrocyc lo penta [b ] pyrrole- 2(S) -carboxylic acid, m.p. 110-112°C(d) . Ξ. Add dropwise, with stirring, a solution of 1.3 M hydrochloric acid in ether to the product of Part D until the mixture is pH2. Add 100 ml of ether and continue to stir for 30 minutes, then filter to obtain 1- [N-l ( S ) -carboethoxy-3-phenylpropyl ) -( S ) -alanyl] - cis ,endo-octahydrocyclopenta [b ] pyrrole-2 ( S ) -carboxylic acid hydrochloride. Method II A. Stir a solution of 4.56 g of N-[1(S)- carboethoxy-3-phenylpropyl]-(S)-alanine, 2.20 g of N > hydroxy-succinimide and 3.80 g of l-(3-dimethylamino- propyl)-3-ethylσarbodiimide hydrochloride in 30 ml of dimethyl-formamidβ for 18 hours at room temperature. Dilute the reaction mixture with ethyl acetate and wash the ethyl acetate layer with saturated aqueous sodium chloride. Concentrate the dried (MqS0 4 ) ethyl acetate solution to give N-[l(S)-carboethoxy-3-phenylpropyl]- (S)-alanine N-hydroxysuccinimide ester. B. To a mixture of 3.76 g of the product of Part A and 1.55 g of cia,βndo-octahydrocyclopenta[b]- ρyrrolβ-2-carboxylic acid in 30 ml of I dimethylformaaide, add 1.5 ml of triβthylaminβ and stir the resulting mixture at room temperature for 18 hours. Concentrate the reaction mixture in vacuo and partition between ethyl acetate and H 2 0 (adjusted to pH 4). Wash the ethyl acetate solution with saturated aqueous sodium chloride. Concentrate the dried (MgS0 4 ) ethyl acetate solution _ir^ vacuo and chromatograph the residue on a silica gel (1000 ml) column using / •' : / CHCl 3 /iso-PrOB/7% NH 4 OH (organic phase). Isolate 1-[N- (1(S)-carboethoxy-3-phβnylpropy1)-(S)-alanyl]-cis,endo- octahydrocycloρenta[b]pyrrole-2(S)-carboxylie acid as a foam. EXAMPLE 4. STHYL CIS ,EXO-OCTAHYDROCYCLOPENTA[b]PYRROLE- 2-CARBOXYLATE Dissolve 0.4g of ethyl cis,endo-octahydro- cyclopenta[b]pyrrole-2-carboxylate (as prepared in Example 1) in 40 ml of ethanol and 7 ml of triethylaminβ. Reflux under nitrogen for five days. Remove the volatiles in vacuo and isolate. To obtain the hydrochloride salt of the product of this example, treat the free base with ethereal HC1. EXAMPLE 5 1-[N-(1(S)-CARBOXY-3-PHENYLPROPYL)-(S)-ALANYL]-CIS, ENDO-OCTAHYDROCYCLOPENTA[b]PYRROLE-2(S)-CARBOXYLIC ACID AND THE HYDROCHLORIDE SALT THEREOF A. To a solution of 0.80g of 1[N-(1(S)- carboethoxy-3-phenylpropyl)-(S)-alanyl]-cis,endo- octahydrocyclopβnta[b]pyrrolβ-2(S)-carboxylic acid from Example 3 in 100 ml of methanol at 0-5 β C, add 2.0 ml of 2.5N sodium hydroxide solution and stir at room temperature for 24 hours * Concentrate this solution in vacuo and absorb on 350 ml of AG50W-X2 Bio-Rad resin (100-200 mesh, hydrogen form). Wash the column with water until the eluatβ is neutral and elutβ the product with pyridinβ:H 2 0 (1:24). Concentrate the aluate in vacuo and chromatograph on a Lobar RP-8, size B column (Ξ. Merck) using acetonitrile: ater (2:3) as eluant to obtain the title compound of this example as the free amino acid. B. Treat an ethanol solution of the product of Part A with one equivalent of a IN solution of ethanolic hydrogen chloride. Remove the solvent in vacuo at room temperature to obtain the hydrochloride salt of the title compound of this example.

Claims: Claims 1. Process for the preparation of compounds of the general formula Il Ilia in the form of the racemic pair or of the individual enantiomers, wherein R δ is hydroxy, lower alkoxy, lower alkenoxy, dilower alkylamino lower alkoxy, acylamino lower alkoxy, acyloxy lower alkoxy, aryloxy, arylloweralkoxy, amino, lower alkylamino, dilower alkylamino, hydroxyamino, aryllower alkylamino, or substituted aryloxy or substituted aryllower alkoxy wherein the substituent is methyl, halo or methoxy, which comprises catalytic reduction of compound II II g wherein R is as defined above, followed if desired by the resolution of the racemic mixture to obtain the individual enantiomers. 2 » Process according to claim 1, which further comprises preparing the compound of formula II by the reaction of a halo pyruvate ester (V) Hal-CB 2 -C-C-R 6 whβrein R 6 is as defined above and Hal stands for halogen, with bβnzyli inocyclopentane. 3. Process according to claim 1 or 2 comprising carrying out the reduction in a solvent, using hydrogen gas and Pd(OH 2 ) on carbon or Pd on carbon. 4. Process according to claim 3 comprising carrying out the reduction step in an alcohol. 5. Process according to any one of claims 2 to 4 comprising carrying out the reaction of the halo pyruvate ester with benzyliminocyclopβntanβ in an inert solvent in the presence of a base at 0-100°C for about 2-8 hours. 6. Process according to any one of claims 2 to 5 comprising the use of brorao pyruvate ester (V) . 7. Process according to any one of claims 1 to 6 comprising the isolation of compound Ilia in the free form or in the form of its ethyl or benzyl ester. . Use of compound ( Ilia ) obtained according to any one of claim* 1 to 7 for the preparation of a cis , endo-oc tahydrocyc lopen a [bl yrrole-carboxylic ac id derivative of general formula ( I ) . wherein R β is as defined above, R is defined as R , is hydrogen, alkyl of from 1 to 10 carbon atoms, including branched and cyclic and unsaturated alkyl groups, substituted lower alkyl wherein the substituent is hydroxy, lower alkoxy, aryloxy substituted aryloxy, heteroaryloxy, substituted heteroaryloxy, amino, lower alkylamino, diloweralkyl- amino, acylamino, arylamino, substituted arylamino, guanidino, imidazolyl, indolyl, lower alkylthio, arylthio substituted arylthio, carboxy, carbamoyl, lower alkoxycarbonyl, aryl, substituted aryl, aralkyloxy, substituted aralkyloxy, aralkylthio, or substituted aralkylthio, wherein the aryl or heteroaryl portion of said substituted aryloxy, heteroaryloxy, arylamino, arylthio, aryl, aralkyloxy or aralkylthio groups is substituted with a group selected from halo, loweralkyl, hydroxy, lower alkoxy, amino, aminomethyl, carboxyl, cyano and sulfamoyl; R 3 is hydrogen, lower alkyl, phenyl lower alkyl, aminomethylphenyl lower alkyl, hydroxyphenyl lower alkyl, hydroxy lower alkyl, acylamino lower alkyl, amino lower alkyl, dimethylamino lower alkyl, guanidino lower alkyl, imidazolyl lower alkyl, indolyl lower alkyl, or lower alkylthio lower alkyl. and wherein preferably the absolute configuration at the carbon atoms marked by a single asterisk in the above formula I is the S-configuration, and at the carbon atoms marked by a double asterisk are most similar to that of natural L-amino acids. 9. Use of compound (Ilia) , preferably the S, S, S- form, according to claim 8 for the preparation of 1- [N-(l(S)-carboethoxy-3- phβnylpropyl)-(S)-alanyll- -cis,endo-octahydrocylopenta- [b] pyrrole-2(S)-carboxylic acid. 10. Compound of formula II II wherein R 6 is as defined above.

Inventors: GOLD ELIJAH HERMAN, NEUSTADT BERNARD RAY, SMITH ELIZABETH MELVA, GOLD, ELIJAH, HERMAN, NEUSTADT, BERNARD, RAY, SMITH, ELIZABETH, MELVA
Applicants: SCHERING CORP, SCHERING CORPORATION
Application year: 1985
Main classification: C07D209
IPC codes: C07D209, C07K1, C07K5, C07K14