IE56654B1 - A process for the resolution of racemates of optically active bicyclic imino-alpha-carboxylic esters,and the use of the compounds thus obtainable for the synthesis of carboxyalkyldipeptides - Google Patents
A process for the resolution of racemates of optically active bicyclic imino-alpha-carboxylic esters,and the use of the compounds thus obtainable for the synthesis of carboxyalkyldipeptidesInfo
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- IE56654B1 IE56654B1 IE210/84A IE21084A IE56654B1 IE 56654 B1 IE56654 B1 IE 56654B1 IE 210/84 A IE210/84 A IE 210/84A IE 21084 A IE21084 A IE 21084A IE 56654 B1 IE56654 B1 IE 56654B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/54—Spiro-condensed
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
Abstract
For the Contracting States BE CH DE FR GB IT LI LU NL SE 1. A process for resolving racemic mixtures of bicyclic imino-alpha-carboxylic esters into the components of the formula Ia and Ib see diagramm : EP0115345,P15,F1 in which R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or an araliphatic radical having 7 to 15 carbon atoms, a) A and B**1 denote hydrogen, and B**2 and C together form a chain of the formula -[CH2 ]n -, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, b) C and B**2 denote hydrogen, and A and B**1 together form a chain of the formula -[CH2 ]n -, with n bein 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, or c) A and C denote hydrogen, and B**1 and B**2 together form a chain of the formula -[CH2 ]m -, with m being 4, 5, 6 or 7, by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-aminocarboxylic acids which contain a phenyl nucleus, from the series phenylalanine, phenylglycine, beta-phenyl-alpha-aminobutyric acid, 3,4-dihydroxyphenylalalin, beta-phenylserine and tyrosine, recrystallizing them form an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogenous diastereomeric salts in a manner known per se, and isolating the enantiomers of the formula Ia or Ib, respectively, and where appropriate, converting the latter into the free acids by saponification or hydrogenolysis in a manner known per se. For the Contracting State AT 1. A process for resolving racemic mixtures of bicyclic imino-alpha-carboxylic esters into the components of the formula Ia and Ib see diagramm : EP0115345,P17,F1 in which R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or an araliphatic radical having 7 to 15 carbon atoms, a) A and B**1 denote hydrogen, and B**2 and C together form a chain of the formula -[CH2 ]n -, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, b) C and B**2 denote hydrogen, and A and B**1 together form a chain of the formula -[CH2 ]n -, with n being 3, 4, 5 or 6, or a chain of the formula -[CH2 ]p -CH=CH-[CH2 ]q -, with (p+q) being 1, 2, 3 or 4, or c) A and C denote hydrogen, and B**1 and B**2 together form a chain of the formula -[CH2 ]m -, with m being 4, 5, 6 or 7, by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters with optically active N-acylated R- or S-aminocarboxylic acids which contain a phenyl nucleus, from the series phenylalanine, phenylglycine, beta-phenyl-alpha-aminobutyric acid, 3,4-dihydroxyphenylalanin, beta-phenylserine and tyrosine, recrystallizing them form an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogenous diastereomeric salts in a manner known per se, and isolating the enantiomers of the formulae Ia or Ib, respectively, and, where appropriate, converting the latter into the free acids by saponification or hydrogenolysis in a manner known per se.
Description
This invention relates to a process for the resolution of racemates of optically active bicyclic imino-a-carboxylic esters, and the use of the compounds thus obtainable for the synthesis of carboxyalkyldipeptides.
The resolution of racemates of aminoacids via crystallization of diastereomeric salts is a widely used 4 , process (Review: Boyle, Quart. RcVo 25 (1971) 323)O Usually, N-acylated aminoacids are employed, the salts # with alkaloid bases are crystallized, and the homogeneous diastereomeric salts are decomposed by, for example, extraction of the N-acy l-aminoacids from the acidified solution (J. Amere Chem. Soc„ 71 ¢1949) 2541, 3251). It is also possible to carry out the converse process and to crystallize aminoacid esters or amides with optically active acids (Chemo Ber« 86 (1953) 1524).
Optically active compounds, such as 10-camphorsulfonic acid, abietic acid or tartaric acid or their 0derivatives, for example, are used for this purpose. This procedure is particularly appropriate when the intention is to employ optically active aminoacid esters as starting compounds for further $ynthesesD In this case, it is not advantageous initially to prepare a N-acyt compound and then undertake resolution of the racemate via salt formation with optically active bases, split off the acyl radical and then esterify the free aminoacid.
A process suitable for bicyclic imino-a-carboxylic I? esters has not hitherto been described. It emerged from experimental tests that all customary acids are unsuitable - 3 for resolution of the racemates, A process is known, from European Patent A 37,231, for octahydroindole-2-carboxylic acid, using which the N-benzoyl compound of the racemate can be resolved via the salt with optically active cc~ phenyIethyI amine„ However, for the reasons mentioned, this process is uneconomic when the esters are required as intermediates for further syntheses» It has now been found, surprisingly, that N-acyl derivatives of optically active R- or S-aminoacids which contain a phenyl nucleus, such as, for example, S-phenylalaninc, tyrosine or tyrosine 0-derivatives are suitable as chiral partners for bicyclic imiηο-α-carboxylie esters^ This is because the 15 and (R,S)-$alts remain in solution. It is possible, in just a single step, to achieve a greater than 95 per cent enrichment, and a single recrystallization leads to the optically homogeneous salts in high yield, and these are decomposed in a known manner.
Thus the invention relates to a process for resolving racemic mixtures of bicyclic imiηο-α-carboxyIic esters into the components of the formulae Ia and lb fe In which R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or an araliphatic radical having 7 to 15 carbon atoms, a) A and each denote hydrogen, and B and C together form a chain of the formula -CCH23n~«> with n being 3, 4, 5 or 6, or a chain of the formula -CCH23p-CH=CH-CCH23q-, «ith (p+q) being 1, 2, 3 or 4, b) C and each denote hydrogen, and A and together form a chain of the formula -CCH23n", with n being 3, 4, 5 or 6, or a chain of the formula -ECH2:ip-CH=CH-CCH2:iq-, with (p+q) being 1,2,3 or 4, or c) A and C each denote hydrogen, and and together form a chain of the formula with m being 4, 5, 6 or 7, by crystallization of diastereomeric salts, which process comprises preparing the salts of the racetnic esters with optically active N-acylated R- or S-aminocarboxylic acids which contain a phenyl nucleus, selected from phenylalanine, phenylglycine, β-pheny1-a-aminobutyric acid, 3,4-dihydroxyphenylalanine, β-phenylserine and tyrosine, and whose possibly present free OH-groups are optionally O-alkylated by alkyl having 1 to 6 carbon atoms, benzyl or other OHprotecting group customary in peptide chemistry, recrystallizing them from an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically homogeneous diastereomeric salts in a manner known per se, and isolating the enantiomers of the formulae Ia and lb and, where appropriate, converting the Latter into the froe acids by hydrolysis or hydrogenolysis in a manner knoan per se.
Resolution of racemates of compounds of the formula Za and Zb In which a) A and B^ each denote hydrogen, and B^ and C together form a chain of the formula -CCH23n"z with n being 3, 4, 5 or 6, or a chain of the formula -CCH23p-CH=CH-CCHjlq’ with (p+q) being 1, 2, 3 or 4, or b) C and B2 denote hydrogen, and A and together form one of the chains defined above under a) is preferred.
A particularly preferred variant of the process comprises precipitating, preferably as crystals, the salts of racemic bicyclic esters of the formulae Za and Zb 1n which the two bridgehead hydrogen atoms have the cis configuration and the COOR group Is oriented endo with respect to the bicyclic ring system» Particularly suitable imino-oe-carboxylic esters are esters with aliphatic, alicyclic or araliphatic alcohols, which can be cleaved by hydrogenolysis or hydrolysis, as are described in, for example, Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Volume XV/1, Stuttgart 1974, on pages 314-427, or Peptide Synthesis'1, by Bodanszky et 3.1., 2nd edition (1976), John Wiley & Sons. Esters of the formula la + Zb in which R represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms, uhich can optionally be substituted by N02, are preferred, in particular alkyl esters having up to 4 alkyl ™ 6 carbon atoms and aralkyl esters, such as benzyl, nitrobenzyl or benzhydryl esters,, Examples of suitable N-acylated aminocarboxyIic acids containing a phenyl nucleus are derivatives of R- or S-phenyLalanine, -C-phenylglycine, -β-phenyΙ-α-aminobutyric acid, .-3,4-dihydroxyphenylalanine', -β-phenylserine and -tyrosine* N-Acyl derivatives of R- or S-phenylalanine, ri -C-phenylglycine and -tyrosine are preferred,* The N-acyl protective groups which can be used are * the customary NH2 protective groups described in, for example, Houben-Weyl, Volume XV/1, pages 46-305 or Bodanszky et al., Peptide Synthesis", 2nd edition (1976), John UiLey & Sons,, Alkanoyl having 1 to 6 carbon atoms, in particular formyl, terto-butoxycarbonyl, and benzyloxycarbonyl are preferred. Any free OH groups present can, where appropriate, be O-alkylated by alkyl having 1 to 6 carbon atoms, in particular methyl, ethyl or tert.-butyl, by benzyl or by other OH protective groups customary in peptide chemistry (cf. for example Houben-Ueyl, Volume XV/1 or Bodans2ky et al., Peptide Synthesis, 2nd edition (1976), John Miley & Sons)» Suitable and preferred solvents are aprotic organic solvents, such as, for example, esters, ethyl acetate, cyclohexane and tetrahydrofuran, but it is also possible to use alcohols having up to 6 carbon atoms* Octahydroindole-2-carboxylic acid is known from * ILS. Patent 4,350,704« German Patent Application DE-A3 226 768 relates to 2-azabicyc loC3.3 „03octane-3-carbox- 0 ylic acid, and German Patent Application DE-A-3 210 496 'ν relates to 2,3,3a,4,5,7a-hexahydroC1H3indole-2-carboxylic acid» German Patent Application DE-A-3 211 676 relates to octahydroisoindole-1-carboxylic acid and 3-azabicycloC3.3e03octane-4-carboxyIic acid.
Racemic bicyclic cis, endo-imino-a-carboxylic acids of the formulae Ia * lb, in which C and each denote hydrogen, and A and E0 together denote the abovementioned chain, can be prepared from, for example, enamines of a cycloalkanone and N-acylated β-halogeno-α- aminocarboxylic esters of the formula IV, in which X' represents a nucleofugic group, preferably chlorine or bromine, Y’ represents alkanoyl having 1 to 5 carbon atoms, aroyl having 7 to 9 carbon atoms or other protective groups which are customary in peptide chemistry and which can be split off with ecid, and represents alkyl having 1 to 5 carbon atoms or aralkyl having 7 to 9 carbon atoms.
(IV) or with acrylic esters of the formula V, in which Y* and R4 have the abovementioned meaning.
CH COOR4 ini-y· (V) by reacting the in which A, , latter to give compounds of the formula VI and Y* have the abovementioned meaning, COOR NH-Y' (VI) cyclizing the latter using strong acids, uith cleavage of 5 the acrylamide and ester, to give compounds of the formula Vila or b, (Vila) H (Vllb) converting the latter, by catalytic hydrogenation in the 10 presence of transition metal catalysts or by reduction uith borane-amine complexes or complex borohydrides in lower alcohols, into compounds of the formulae Ia and lb in which R represents hydrogen, and esterifying the latter to give compounds of the formulae Ia and lb in which R has the meaning defined above» Racemic bicyclic imino-crcarboxyIic acids of the formulae Ia and lb, in which A and denote hydrogen and Hi t» B2 and C together denote the chain mentioned, can be prepared from, for example, compounds of the formula VIII (VXIX) in which the bridgehead hydrogen atoms are oriented cis or 5 trans with respect to one another, and B2 and C have the abovementioned meaning.
Compounds of the formula VIII uith n - 1 are known from Ro Griot, Helvo Chim. Acta 42, 67 (1959), and those with n = 2 are known from C.HU Rice et al., J. Org. Chem. 2^, 1687 (1955).
These compounds of the formula VIIX arc acylated in a known manner, an aliphatic or aromatic acyl radical, preferably an acetyl or benzoyl radical, being bonded to the nitrogen atom, and the resulting N-acylated compounds are subjected to anodic oxidation (in analogy to Liebigs Ann. Chem. 1978, page 1719) in an aliphatic alcohol, preferably an alcohol having 1 to 4 carbon atoms, in particular methanol, in the presence of a conducting salt, preferably at temperatures in the range from 0° to +40°C, with the formation of a compound of the formula IX in which B2 and C have the abovementioned meaning and R^ = C^-C^-alkyl.
Acyl The resulting compound of the general formula IX is reacted uith trimethylsilyl cyanide by the method of Tetrahedron Letters 1981, page 141, in a hydrocarbon or halogenated hydrocarbon, in ether or in THF, at temperatures in the range from -60°C to +20°C, preferably -40°C to t0°C, in the presence of a Lewis acid, such as, for example, ZnCl2/ SnClgz SnCl^, TiCl^ or BFj-etherate, preferably BF^-etherate, and the resulting compound of the formula X in which the bridgehead hydrogen atoms are cis or trans with respect to one another, the CH group being Located cis with respect to the bridgehead hydrogen atom on carbon atom (4+n), and in which n> B^ and C have the abovementioned meanings, is, after purification and resolution of the mixture of diastereomers by recrystallization or column chromatography, hydrolyzed in a known manner by the action of acids or bases to give a compound of the formulae la and Jb, with R - hydrogen, and the latter is esterified* HCl or HBr, in particular, is used as the acid for the acid hydrolysis of the nitrile group. In this instance and in those which follow, the esterification is carried out by the procedures customary in aminoacid chemistry.
The invention also relates to optically homogeneous compounds of the formula Ia or lb in which the two bridgehead hydrogen atoms have the cis configuration, the COOR group is oriented endo with respect to the bicyclic ring system, the carbon atom α to the COOR group has the R or S configuration, R represents alkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms, which can optionally be substituted by NO?, and A, b\ B2 and C are defined as above, and to those compounds of the formulae Ia or lb in which R denotes hydrogen and a) A and B^ each denote hydrogen, and B2 and C together form a chain of the formula -CCHjln' with n bein9 3, 4, 5 or 6, or a chain of the formula -CCH23p-CH=CH-CCH23q-, with being 1, 2, 3 or 4, or b) C and B2 each denote hydrogen, and A and together form one of the chains defined above a), with n being 3, 5 or 6 and (p+q> being 1, 2, 3 or 4, and their salts.
The invention also relates to diastereomeric salts of a bicyclic cis, endo-imiηο-α-carboxyIic ester of the formula Ia or lb, in which A, , B2, C and R have the meanings defined above as being preferred, and an optically active N-acylated R- or S-aminocarboxylic acid which contains a phenyl nucleus and which is protected as defined aboveo The invention also relates to the use of the opti5 colly pure compounds of the formula Ia or lb in a process for the preparation of optically pure compounds of the general formulae Ila or IXb 2 »' B C Xi COOH ''/H £ CH 1« NH ch - λη27γ C°2R2 Y C - X I z (Ila) € ch - x2 COaR Y I C - I I z (lib) in which it is possible for the carbon atoms labeled uith an asterisk (ή) each, independently of one another, to have the R- or the S-configuration, «1 a) A and B' each denote hydrogen, and B^ end C together form a chain of the formula -CCH2ln-, n being 3, 4, 5 or 6, or a chain of the formula -lCH2np-CH=CH-CCH23q- , (p+q) being 1, 2, 3 or 4, b> C and B2 each denote hydrogen, and A and B^ together form a chain of the formula -CCH23n-z with n being 3, 4, 5 or 6, or a chain of the formula -CCH23p-CH=CH-CCH23q-, with (p+q> being 1, 2, 3 or 4, or c) A and C each denote hydrogen, and and B2 together form a chain of the formula CCH23m-, with m being 4, 5, 6 or 7, 10 r denotes 0 or 1, R^ denotes hydrogen, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 3 to 9 carbon atoms, an optionally substituted a I icycIic-a I iphatic radical having 4 to 11 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms, which can also be partially hydrogenated, an optionally substituted araliphatic radical having 7 to 15 carbon atoms, an optionally substituted aroyl20 aliphatic radical having 8 to 13 carbon atoms, an optionally substituted monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, 1 or 2 of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms being nitrogen atoms, or a side chain of a naturally occurring aminoacid which is optionally protected, R^ denotes hydrogen, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, or ati optionally substituted araliphatic radical having 7 to 15 carbon atoms, Y denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen, and X denotes an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 5 to 9 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms, or indolyl, which process comprises reacting, in the presence of a condensing agent or, where appropriate, as an active ester, optically pure compounds of the formulae Ia or lb, in which A, B^z B2 and C have the abovementioned meanings, and R represents an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 4 to 10 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms or an optionally substituted araliphatic radical having 7 to 15 carbon atoms, with optically pure compounds of the formula III * γ (III) - X R* co2nr' Z in which the two carbon atoms labeled with an asterisk (*) have the (S,R), (R,S), (R,R) or, preferably, (S,S) configuration, and R, r\ R2, X, Y and Z have the abovementioned meanings, splitting off the radical R by hydrogeno lysis or hydrolysis, and, where appropriate, converting the optically HOOC - CH Ii NH - CH I pure compounds of the formulae IXa or lib into physiologically tolerated salts.
A preferred embodiment of the process according to the invention comprises preparing compounds of the for5 mulae Ila or lib, in which r denotes 0 or' 1, R denotes hydrogen, (C*j to C$)-alkyl or aralkyl having 7 to 9 carbon atoms, R*^ denotes hydrogen or (C-j to C^J-alkyl, which can 10 optionally be substituted by amino, (Cf to C$)-acyl~ amino or ben2oylamino, (Cg to C$)-aLkenyl, (C5 to Cg)cycloalkyl, (C5 to Cg)-cycloalkenyl, (C5 to Cyl-cycloalkyl-tC^ to Cjp-atkyl, aryl or partially hydrogenated aryl having 6 to 12 carbon atoms, each of which can be substituted by CC-j to C^l-alkyl, (C-j or Cg^alkoxy or halogen, (C$ £0 C-|2^-aryi-"ic1*c4^'’a or {c7"Ci3>"aroyl-CCi-C2>"eIky I, both of which can be substituted in the aryl radical as defined above, a monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respective ly, 1 or 2 of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms being nitrogen atoms, or an optionally protected side chain of a naturally occurring aminoac id, R2 denotes hydrogen, (C^ to C^-alkyl, (Cg to C$>alkenyl or -aryl-(Ci to C^J-alkyl, Y denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen, and X denotes The preparation of the S,S,S-compound$ of the formula Ila is preferred.
In this context as in the following, ai*yl is to 10 be understood preferably to include optionally substituted phenyl or naphthyl. Alkyl can be straight-chain or branched.
Examples of a monocyclic or bicyclic heterocycLic radical having 5 to 7 or 8 to 10 ring atoms respectively, in which the ring atoms have the abovementioned meanings, include thienyl, bcnzoCblthienyL, furyl, pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indoLyl, purinyl, quino lizinyI, isoquino I inyL, phthalazinyl, naphthyridinyL, quinoxa linyI, quinazolyl, cinnolinyl, pteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazoly I. It is also possible for these radicals to be partially or completely hydrogenated.
Where represents a side chain of a protected 25 naturally occurring α-aminoacid, such as, for example, protected or optionally substituted Ser, Thr, Asp, Asn, Glu, Gin, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp, His or Hyp, the preferred protective groups are those groups customary in peptide chemistry (cf. Houben-Weyl, Vol.XV/1 and XV/2)« In the case where denotes a protected side chain of a lysine, the known amino protective groups, but in particular (Ci"C$)-a IkanoyI, are preferred. Preferred 0-protective groups for tyrosine are methyl or ethyl.
In the procedures hitherto known for preparing mixtures of stereoisomers of compounds of the formulae Ila or lib, which started from mixtures of stereoisomers, it was necessary to use elaborate separating procedures to separate the reaction mixture in order to obtain the desired optically pure stereoisomers of the formula Ila or Ilbo By reacting the optically homogeneous imino-a-carboxylic esters of the formulae Ia or Ib according to the invention with optically homogeneous compounds of the formula III, specific synthesis of optically homogeneous compounds of the formula Ila or lib has become possible.
The desired compounds of the formulae Ila or lib are obtained in high yields without using elaborate separating techniques.
Compounds of the formula III are described in the abovementioned documents or are known from European Patent A 46,953, The reaction of a compound of the formula III with tert.-butyl 1-<2a,3ap,7a3)-octahydro-C1H3-indole-2carboxylate followed by elimination of a tert.-butytester, whereupon a correspond!ng octahydroindo le derivative of the formula lib results, is known from European Patent A 37,231» However, it has been necessary to restrict this reaction to reaction of a compound of the formula Ia or Ib with C and each being H and A + being (CH2>^, and it has hitherto only been possible to prepare this in a complicated manner via the N-benzoyl compound, crystallization of the diastereomeric salts with S-a-phenylethylamine, liberation of the N-benzoyl compound, elimination of the benzoyl group and esterification.
It has* not hitherto been possible to transfer this reaction sequence to the intermediates of the formula la and lb according to the invention. Nor has it been possible to resolve racemic mixtures of compounds of the formula IIa and lib by separating conventional diastereomeric salts with optically active carboxylic or sulfonic acids. The compounds of the formula Ia and lb have been made accessible for subsequent reactions for the first time by the procedure described above» The process according to the invention is particularly cost-effective, since compounds of the formula III can be prepared directly in an optically pure form by straightforward routes from German Patent Application DE-A-3 226 768» However, in this reference, it was still necessary for these intermediates to be reacted with a racemic aminoacid and to be converted into an opticalLy pure compound of the general formulae IIa and lib by an additional purification step.
The process according to the invention, which is preferably carried out with S,$ compounds of the formula III, thus represents by far the most cost-effective process for the preparation of the compounds covered since, in all the other known procedures, great losses have to be accepted due to the chromatography or crystallization of mixtures of stereoisomers, some of which are complex» The condensation step is carried out by one of the conventional processes of peptide synthesis which involve little racemization, such as are described in, for example, Houben-Weyl, Volume XV, or in The Peptides - Analysis, Synthesis, Biology, Vol.1 Major Methods of Peptide Bond Formation, Part A, Gross, Meierhofer, Academic Press Ν®Υ. (1979). The DCC/HOBt method of Chem. Ber» 103 (1979), pages 788-798, is particularly advantageous» In this context, it should be taken into account that reactive functional groups in the radical R^ must be temporarily pro tected by the known methods of peptide chemistry (for example Houben-Weyl, Volume XV, or Bodanszky et a£» in Peptide Synthesis, 2nd edition (1976), John Wiley fi Sons) The optically homogeneous compounds of the formula Ila or lib are obtained, after eliminating R and, where appropriate, R^, in high yield in a manner known per se without using elaborate separating techniques» The compounds of the formula Ila and lib and their salts have long-lasting and powerful hypotensive activity. They are potent inhibitors of angiotensin converting enzyme (ACE) and can be employed to control high blood pressure of a variety of etiologies. ACE inhibitors of this type are known from, for example, U.S. Patent 4,344,949, European Patent A 49,658, European Patent A 46,953, European Patent A 50,800 and European Patent A 79,022.
It is also possible to combine them with other compounds having hypotensive, vasodilator or diuretic activity. Typical representatives of these classes of active compounds are described in, for example, ErhardtRuschig, Arzneimittel (Drugs), 2nd edition, Meinhein, 1972» They can be administered intravenously, subcutaneously or ora I Ly.
The dosage on oral administration is generally 1-500 mg, preferably 1-100 mg, per single dose for an adult patient of normal weight» Zt is also possible to increase this in severe cases, since no toxic properties have hitherto been observed. It is also possible to reduce the dose and this is particularly appropriate when diuretics are administered concurrentLy.
The compounds according to the invention can be administered orally or parenterally in appropriate pharmaceutical formulations» For a form for oral use, the active compounds are mixed with the additives customary for this purpose, such as vehicles, stabilizers or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard gelatin capsules, aqueous, alcohol or oily suspensions or aqueous, alcohol or oily solutions. Examples of suitable inert vehicles which can be used are gum arabic, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch.. This can entail formulation either as dry or as moist granules. ExampLes of suitable oily vehicles or solvents are vegetable or animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds or their physiologically tolerated - 21 salts are converted into a solution, suspension or emulsion, where appropriate with the substances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Examples of suitable solvents for the new active compounds and the corresponding physiologically tolerated salts are: water, physiological saline or alcohols, for example ethanol, propanediol or glycerol, but also sugar solutions, such as glucose or mannitol solutions, or even a mixture of the various solvents or solutions mentioned.
The Examples which follow illustrate the process, but there is no intention to restrict the invention to these specific Examples» Example 1: Benzyl <1S, 3S, 5S)-2-azabicycloC3.3.OJoctane-3-carboxylate hyd roc h loride (abbreviated to (S)-Aoc-OBzl-HCI)__ ( A ) Hethy I 2-acetylamino-3-(2-oxocyclopentyI)propionate: 269 g of methyl 3-chloro-2-acetylaminopropionate and 257 g of eyelopentenopyrrolidine in 1.5 liters of DHF are kept at room temperature for 24 hours. The mixture is evaporated in vacuo, and the residue is taken up in a little water, the pH is adjusted to 2 with concentrated hydrochloric acid and the solution is extracted twice with 4 liters of ethyl acetate each time. A pale yellow oil remains on evaporating the organic phase.
Yield: 290 go ‘iH-NHR:2.02 (sz3H); 3.74 Ana lysi s: C H N calculated 58.1 7.54 6.16 f ound 58o5 7.2 6.5 (Β ) c j s,endc-2-AzabicycloC3.3. 03oct ane-3-carboxylie acid 5 hydroch tori de 270 g of the acetylamino derivative prepared under (A) in 1.5 liters of 2 N hydrochloric acid arc boiled under reflux for 45 minutes. The mixture is evaporated in vacuo, and the residue is taken up in glacial acetic acid, 5 g of Pt/C (10% Pt) are added and hydrogenation is carried under 5 bar. After filtration, the filtrate is evaporated and the residue is crystallized from chloroform/diisopropyL ether.
Melting point: 205-209°C, Yield: 150 g (C) Racemic Aoc- OBzI.H CI 1.2 liters (11.5 mol) of benzyL alcohol are cooled to -10°C. 126 ml (1.73 mol) of thionyl chloride are added dropwise, with cooling and stirring, and then 126.5 g (0.66 mole) of crude Aoc.HCl are added at -10cC, with stirring, and the mixture is then stirred at this temperature for 30 minutes. The temperature is then allowed to rise slowly to 20-25°C with stirring, the product dissolving within 5 hours. After standing overnight, the brown solution is run into 4.0 liters of diisopropyl ether with stirring. After 1 hour, the precipitated crystals are filtered off, washed with diisopropyl ether and dried in vacuo. A further precipitate separates out of the combined diisopropyl ether solutions overnight» Yield: 168.5 g (90.6%) (D) (S)-Aoc-OBzl.Z-Pho-OH 166.0 g (0.589 mol) of racemic Aoc-OBzl.HCl are suspended in 500 ml of methylene chloride and thoroughly shaken with 25 g (0.625 mol) of NaOH in 250 ml of water* A solution is produced. After a short time, the initially formed emulsion has separated» The methylene chloride phase is separated off, washed with 100 ml of 0«1 N NaOH and twice uith 50 ml of water each time and the combined aqueous phases are extracted twice with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated under mild conditions uith waterpump vacuum. The remaining oil is immediately taken up in 100 ml of ethyl acetate, and a solution of 117.6 g (0.39 mol) of N-benzyloxycarbonyl-Sphenylalanine (Z-Phe-OH) in 200 ml of ethyl acetate is added. The flask is rinsed with 100 ml of ethyl acetate. 1,600 ml of cyclohexane (= 4 times the amount by volume) are added, with stirring, to the clear solution at room temperature. After scratching, crystallization starts, and this is completed by standing overnight in a cold room. The crystalline precipitate is filtered off, washed with 250 ml of ethyl acetate/cyclohexane (1+4) and dried.
Yield: 133.6 g of (S)-Aoc-OBzl.Z-Phe-OH (50.9%, corresponding to 1022 of theory), melting point 101-103°C; Ca3^: -5.3° (c = 1, methanol).
After recrystallization from ethyl acetate/cyclo24 hexane <1 :1), the following data are found for the Z-Phe-OH salt: melting point: 103-104°C, -6.1° (c = 1, in methanol) ($)-Aoc-OBzI.HCI 63.0 g (0.142 mole) of the Z-Phe-OH salt obtained according to (D) are dissolved in 300 ral of methylene chloride and the solution is thoroughly shaken with 6.0 g (0.15 mole) of NaOH in about 150 ml of water·» Phase separation takes some time because of a small amount of 10 insolubles. The methylene chloride phase is separated off, washed with 50 ml of 0.1 N NaOH and twice with 50 ml of water each time and dried. The solution is evaporated to about 100 ml, diluted with 100 ml of diisopropyl ether and, with stirring, 25 ml of 6 N HCL in ether are added. After 1 hour, the mixture is filtered, and the precipitate is washed with diisopropyl ether and dried.
Yield: 32.5 g <81.3%) Melting point: 185-186°C -42.5° (c = 1, water) Methylene chloride is removed from the basic aqueous phase in vacuo, and it is acidified with concentrated HCL. The precipitated Z-Phe-OH is washed with water and dried.
The R compound and further Z-Phe-OH are obtained from the methylene chloride mother liquor from Example 1(0) in the manner described. ο ιη (J CM Ο Ο\ rr V II .2 fb •κ + Ο° <μ cn ου ι ο οκ ΙΓ> CM rn co κΟ co I in co o o o O O oOr- o o O O' •cm cn cn \O o CO CM sT • • CM cn O e-* o KO CO V* it m xr JT AT m CM σι KO 1 1 1 I 1 1 I 1 1 + o'< ra (u f-s, ώχ a J5 ου 'U JJ u u υ o a o o o o o o CM Kf> in in in m m Cn CO co co CO CO co in «—· I «·* 1 CM 1 sr sr Λ «4 1 CM cn *— CO CO co e*· co CO r- I— r" in S' Ό •r-.
U < d d !»* ·!* o o O o o_ o O o O o in °.- CO CM O sr sr sr m · * • ft « • m k- tn VO \O if O rn «- «— if + 4 1 + + I 1 4 1 1 + o'— •r-«s n ω S to ο E T5 cj < o U u o a u O u o u o o o o o o o o o o o o kO in sr xr o k0 in O' " >- CO —· o o o m CM o o CM O o *7 «— *7 »7 *7 r~ Ί Ί CM KO * lA 1 sr 1 m 1 CM 1 co 1 in 1 1 1 l·- ·— o o O CM CM o b CM O o r— r— ,~ w »— v~ »·· i— «— , — -%. >» V. •s. ·»» 01 r—C TO TO TO TO rl o Φ Φ TO 4J O4« +j M 4j +-» to Qf C <0 <9 TO (0 Qf t: TO TO TO +j £ f-1 4-» v & X K C rj 4-» t* tJ rl to to u κ ίΧ S X TO o 8 Φ TO <> X n. o l. 8 8 X TO c* t. «ο to £ to ft? <9 <0 TO <9 Φ (9 <9 Φ TO U to _/ Ό n. —j •6 -»δ (X _« —j 5 to .a •rl U X—» JC O o n £ 5 υ £ £ u £o O co £ £ u £ « to ΰ Kl UJ & UJ UJ & a & l-C uj a & a X X j X :r X o 1 X X trJ X X jt: o o o 6 o o O o .c ru o o o o a ό P« r-l v. ί 4> A £ -C P. I £ ( rc fe) ru Χ t-« >uJ I o 1 « ts] v— 1 1« £ £ | 1 £ Kl 1 kj ti Ki ti ii £ 1 1 1 rH rl rH «•1 rl rH rd rH 1 r-C cH r-l •S >1 >. >> >» >» o >» >. >, j: N N N M N N N C. Ν N .a C, n C C r: C r; *> n c SJ s r8 ii ii δ s <8 •Η «1 TO >*: .o cu TO cyclohexane Table KI O TO l-C »-< n H KI KI M KI »•1 H KI l-C > 1 > c KI n l-l KI X X X X X X X >: T ΙΛ IO Γ* eo Ch o r »— «· nf o CN The Ccis,endo3-imino-a"carboxylic esters in Table 1 are prepared and subjected to racemate resolution in an analogous manner,, This Table details their optically active crystallization partners, and the solvents, yields and properties of the salts and the final products in the form of the ester hydrochlorides or ester tosylates. Explanations of Table 1 (XI) and mirror image (XII) and mirror image (XIII) .COOR and mirror image The free iminocarboxylic acids can be prepared from the esters by hydrolysis or hydrogenolysis. Example 13 N- (1S-Carboethoxy-3-phenyIpropy1)-S-alanyl-2-cis,endo15 a zabi cycloC3,3.03 octane-3 S-ca rboxylic acid ( A ) Benzyl N-(2S-carbocthoxy-3-phenyIpropy l)-S-a lany Ιοί s,endo--2-azabi cyclo C3 ,3.03 octane-3S-carboxylate 14 g of the benzyl ester hydrochloride prepared according to Example 1 E arc converted into the free ester 5 by extracting by shaking the alkaline aqueous solution uith diethyl e.ther, and, after distilling out the ether, are reacted with 6 .7 g of HOBt, 13.8 g of N-(1S-carboethoxy-3-phenyIpropyI)-S-alanine and 10.2 g of dicyclohexylcarbodiimide in 200 ml of dimethylformamide. After stirring at room temperature for 3 hours, the precipitated dicyclohexylurea is filtered off, and the filtrate is evaporated, and the residue is taken up in 1 Liter of ethyl acetate and this solution is extracted by shaking with 3 x 500 rol of 5 per cent NaHCO^ solution. The organic* phase is evaporated. 22.4 g (90%) of product are obtained as an oil. 1HNMR of the S,S,S-compound, characteristic signals: 1.20 , 1.27 (t,2H), 4U17 7.18 (s,5H), 7.32 (s,5H) (d>Cl3> Analysis: C H Nc30H38N2°5 calculated 71»1 7.56 5.53 found 70.8 7.8 5.7 (B) H-(1S-Carboethoxy-3-phenyIpropyI)-S-aIanyl-cis,endo2-azabi cyc loC3.3.03 octane-3S-carboxy lie acid 8.0 g of the S,S,S-benzyl ester from Example 1 E are dissolved in 100 ml of ethanol, and the benzyl group is removed by hydrogenolysis under atmospheric pressure with the addition of 0.5 g of 10% Pd/C. This reaction can also be carried out under elevated pressure which involves - 28 shortening of the reaction timen After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated in vacuo, The zwitterion crystallizes from ether in a virtually quantitative yield: melting point: 110-112°C (decomposition) A hydrochloride (decomposition above 120°C) can be obtained by addition of an equivalent amount of hydrochloric * acid. Analysis: C H N *c23h32n2°5 calculated 66 .3 7.7 6.73 found 66.1 7.8 6.6 The NMR and mass spectra which are obtained are consistent with the structure indicated.
CoOq = +15.6° (c = 1, methanol).
Example 14 N-(1S-Ca rboethoxy-2-benzoylethyl)-0-ethyl-S-tyrosy Ιοί s ,endo-2-azabi eye loC3.3,03octane-3S-carboxyli c acid (A) H-(1S-Carboethoxy-3-phenyIpropy1)-0-ethyl-Styrosine benzyl ester g of ethyl benzoylacrylate in 100 ml of ethanol are reacted with 30 g of O-ethyl-S-tyrosine benzyl ester in the presence of 0.5 ml of triethylamine and, after evaporating the solution and digesting the residue with diethyl ether/petroleum ether (1:1) and drying in vacuo, g of RS,S compound ere obtained. Resolution of the diastereomers by chromatography on silica gel using the system ethyl acetate/cyclohexane (1:3).
Yield: 17 g of the S,S compound. (Β) Μ-(1S-Carboethoxy-3-phenylpropyj)-0-ethyl-S-tyrosine g of the compound obtained according to (A) in 800 ml of acetic acid are hydrogenated with 4 g of Pd/C (10%) under 100 bar and at room temperature. Yield after chromatography on silica gel using the solvent ethyl acetate/cyclohexane (1:3) and drying the residue from evapora tion: 12 g of title compound which is virtually homogeneous by thin-layer chromatography.
Melting point 205-213°C Analysis: C23H29WO3 (399.5) calculated C 69.15 H 7.31 N 3.50 found C 69.5 H 7.4 W 3.3 (C) M-(1S-Carboethoxy-3-phenyI propyl)-0-ethyl-S-tyrosyΙο i s ,endo-2-a2abi eye loE3.3 aQ3octane-3s-ca rboxy lie acid In analogy to Example 13 A, 8 g of the free benzyl ester obtained in accordance with Example 1 E and extracted from alkaline solution by shaking with diethyl ether are reacted with 8 g of the compound obtained in accordance with Example 14 B using 4.4 g of di eye lohexyIcarbodiimide in the presence of 2»? g of 1-hydroxybenzotriazole, and 14.3 g of oily benzyl ester are obtained as an intermediate The NMR and mass spectra are consistent with the structure indicated.
The benzyl ester in 50 mt of ethanol is catalytically hydrogenated on Pd/C under atmospheric pressure. After filtering off the catalyst and distiLling off the solvent, there remains a solid residue which is digested with diethyl ether/petroleum ether and is dried.
Yields 11.2 g Example 15 N-(1S-Carboethoxy-3-phenyIpropy1)-0-methyl-S-tyrosy Ιοί s, endo-2-a zabi eye loC3.3,03 octane-3S-ca rboxylic acid The procedure is carried out as described in Example 14, but in the stage analogous to (A) 0~methyl-Styrosine benzyl ester is used and the title compound is obtained, the NMR spectrum of which is consistent with the structure indicated. 1H NMR (CDCtj): 1.2-3.0 (m,15H>; 1.27 (t,3H>; 1.4 ; 3.0-4.3 (n),4H>; 3.8-4.2 ; 6.5-7.1 (2d,4H); 7.3 Example 16 N-(1S-Carboethoxy-3-phenyIpropy l>-S-alany1-2-azaspi ΓΟΕ 4 - 53 d e c a n e-3 S-ca r b ο x y I i c acid 15 CA) 1- (Diethoxyethy I)cyclohexanecarbonitrile 51.7 ml (0.5 mol) of anhydrous diethylamine are added dropwise, under protective gas at -10°C, to 312,.5 ml <0»5 mol) of a 15% strength solution of n-butyllithium in hexane» The mixture is stirred for 20 minutes and then cooled to -70°C. 54®6 g of eye lohexanecarbonitriLe are added dropwise over the course of 30 minutes and, after a further 30 minutes, 98θ5 g of bromoacetaldehyde diethyl acetal are added within 1 hour and the mixture is left at low temperature for 24 hours. It is then warmed to room temperature, 100 g of ice are added, and the mixture is extracted twice with 500 ml of ethyl acetate, and the organic phase is dried over sodium sulfate, evaporated in vacuo and the residue is subjected to vacuum distillation. Yield: 90 g (about 80% of theory), boiling point 78-*79°C at - 31 8 torr (10.7 mbar).
( B ) 1-Ami noroethy 1-1-(diethyIoxyethyl)cyclohexane g of diethyloxycyclohexanecarbonitrile are dissolved in 1 liter of ethanol, and 60 g of sodium are added. After the metal has dissolved, 100 ml of water are added and the solvent is largely removed in vacuo. 300 ml of water are added to the residue and the mixture is extracted 3 x with 200 ml of ether. The ethereal phase is dried over sodium sulfate, evaporated and distilled in vacuo.
Yield: 83 g (about 90% of theory), boiling point 69-72° at 8 torr (10o7 mbar) (C) 2-Azaspi roE4.53decane-3-carbonitrile 80.2 g of aminomethyLdiethyloxycyclohexane are stirred in a mixture of 300 ml of ethanol and 300 ml of 1 N hydrochloric acid under a protective gas (N2 or Ar) for about 1 hour.
After the starting product has been completely cleaved, the mixture is cooled to 0°C and the solution is rapidly adjusted to pH 5 by adding 2 N sodium hydroxide solution. 300 ml of glacial acetic acid are immediately added (pH about 3), and the mixture is cooled to *1O°C and 17.5 g of sodium cyanide are added. The reaction vessel is closed and left at room temperature for rbout 5 hours. Completion of reaction is checked using thin-layer chromatography (system ethyl acetate/petroleum ether 2:1) (Schiff's base Rf = 0.6-0.7; aminoacid nitrile Rf = 0«28) and the reaction solution is evaporated to dryness. The crude aminoacid nitrile is immediately processed further in accordance with Example 16 D or Eo CD) 2-Azaspi roC4»53deeane-3-carboxy lie acid 250 ml of 4 N hydrochloric acid arc added to one half of the aminoacid nitrile obtained in Example 16 C, and the mixture is heated under reflux for 4 hours. Traces of escaping hydrocyanic acid are made harmless in a suitable manner (freezing out, absorption in basic iron(ll) salt solution). The solution is neutralized, evaporated to dryness and extracted several times uith n-butanol. The residue from evaporation of the organic phase is a) crystallized from chloroform/diisopropyL ether to obtain the hydrochloride and, if necessary, again precipitated from a mixture uith ethanol or b) purified in aqueous solution by stirring with an ion exchanger, for example IR 45 (OH form) (Amber Iite) and, after removing the water, the zwitterion is crystallized from ethanol/ether.
Yield from a): 31-32 g (82%) Melting point 205°C (decomposition), hydrochloride (E) Benzyl.2-azaspi roC4,53decane-3-carboxy late hydrochloride Half of the aminoacid nitrile obtained in accordance with Example 16 C is taken up in 70 ml of benzyl alcohole A slow stream of HCl gas is passed through the solution at room temperature for 5 minutes, then it is maintained at room temperature for 2-3 hours, evaporated to a small volume in vacuo, and aqueous sodium bicarbonate solution is added until the pH is 8.5 and the benzyl ester is extracted into ethyl acetate. The organic phase is dried, an equivalent amount of ethereal hydrochloric acid is added and the mixture is evaporated. The residue crystallizes from diisopropyl ether and can be recrystallized from methylene chloride/diisopropyL ether.
Yield: 43 g (about 80%) Melting point 145°C (decomposition) ( F ) Benzyl 2-azaspiroE4.53decane-3S-carboxylate hydrochloride The racemic hydrochloride obtained in accordance uith Example 16 E is subjected fo racemate resolution in analogy to Examples 1 D and E„ (6) Benzy I N-( 1S-carboethoxy-3-phenylpropyl?-S-alanyl2 - a z a s p i r ο E 4.53nonane-3S-ca rboxylate .6 g of benzyl 2-azaspiroC4„53nonane-3S-carboxylate hydrochloride, 6a7 g of 1-hydroxybenzotriazole and 13.8 g of (S,S)-N-(1-ca rboet ho xy-3-ph eny IpropyDalanine are dissolved in 200 ml of DMF and reacted overnight with 10.2 g of dicyclohexylcarbodiimlde. Addition of tertiary bases, for example 6.4 ml of N-ethyImorpholine, increases the yield only ineonsiderablyB The precipitated DCurea is filtered off, the filtrate is evaporated in vacuo, the residue is taken up in ethyl acetate, and the solution is extracted by shaking with aqueous sodium bicarbonate solution, and the organic phase is dried over solid sodium sulfate and again evaporated. The NMR spectra (in CDCl^) confirm the structure.
(H) N-(1S-Carboethoxy-3-phenyIpropyI)-S-alany1-2-azaspi roC4 3 nonane-3s-ca rboxy li c acid The benzyL ester obtained in Example 16 <5 is taken up in 200 ml of methanol and the benzyl group is removed by hydrogenolysis with 1 g of Pd/C (102 Pd). After uptake of hydrogen is complete, the mixture is filtered and the filtrate is evaporated in vacuo. A solid, hygroscopic foam of the zwitterionic dipeptide derivative can be obtained in vacuo uith the addition of pentane,, ta^1 = 3B„3° (c = 1, methanol) Example 17 N-(1 S-Carboethoxy-3-phenyIpropyl)-S-alany l-cis,endo2,3,3a,4,5,7a-hexahydroC1H3indole-2S-carboxyli c acid (a) Methy l ci s-2,3 ,3a,4,5,7a-hoxahydroC1H3indole-2Scarboxylate hydrochloride Racemic methyl cis-2,3z3a,4,5,7a-hexahydroC1H3indole-2-carboxytate hydrochloride (obtainable in analogy to the procedure described in German Patent Application P 32 10 496.0) is subjected to racemate resolution in analogy to Examples 1 0 and E.
CoOp = +68.4° (c = 1, H20) ( B ) N- (1 S-Ca rboet hoxy-3-phenyIp ropy I )_-S-a I any l-c iszendo2,3,3a,4,5,7a-hexahydroC1H3 i ndole-2S-carboxy lie ecid hydrochlor1de The title compound is obtained by a procedure analogous to that described in Examples 13 A and Β» NMR data 0.9-3.0 (m, 17 H); 3n4-4„9 (m, 6 H); 5.2-6.0 (m, 2 H); 7„2 (s, 5 H)
Claims (9)
1.CLAIMS: 1« A process for resolving a racemic mixture of bicyclic imino-a-carboxylic esters into the components of the formulae la and Ib (la) (Ib) in which R represents an aliphatic radical having 1 to 6 carbon atoms, an alicyclic radical having 4 to 10 carbon atoms, an aromatic radical having 6 to 12 carbon atoms or an araliphatic radical having 7 to 15 carbon atoms, a) A and B^ each denote hydrogen, and and C together form a chain of the formula with n being 3, 4, 5 or 6, or a chain of the formula -CCH 2 3 p -CH-CH-CCH 2 3 q -, with being 1, 2, 3 or 4, b) C and B 2 each denote hydrogen, and A and together form a chain of the formula -CCH 2 3 n w , with n being 3, ’4, 5 or 6, or a chair, of the formula -CCH23 p -CH=CH-tCH 2 3 q -, with (p+q> being 1, 2, 3 or 4, or c) A and C each denote hydrogen, and B^ and B 2 together form a chain of the formula -Εε^Οβ,-, with m being 4, 5, ό or 7 by crystallization of diastereomeric salts, which process comprises preparing the salts of the racemic esters uith optically active N-acylated R- or S-aminocarboxylic acids which contain a phenyl nucleus, selected from phenylalanine, phenylglycine, 8-phenyl-a-aminobutyric acid, 3,4-dihydroxyphenylalanine, 0-phenylserine and tyrosine, and whose possibly present free OH-groups are optionally O-alkylated by alkyl having 1 to 6 carbon atoms, benzyl or other OHprotecting group customary in peptide chemistry, recrystal- * lizing them from an aprotic organic solvent or an alcohol having up to 6 carbon atoms, decomposing the precipitated, optically *· homogeneous diastereomeric salts in a manner known per se, and isolating the enantiomers of the formulae Ia and lb and, where appropriate, converting the latter into the free acids by saponification or hydrolysis in a manner known per se.
2. « A process as claimed in claim 1, wherein a) A and B^ each denote hydrogen, and B 2 and C together form a chain of the formula “CCHjl,,-, with n being 3, 4, 5 or 6, or a chain of the formula -CCH 2 3 p -CH=CH-CCH23 q - with (p+q) being 1, 2, 3 or 4, or b) C and B 2 each denote hydrogen, and A and together form one of the chains defined above under a) o
3. » A process as claimed in claim 2, wherein the salts of racemic esters of the formulae Ia and lb in which the two bridgehead hydrogen atoms have the cis configure- , tion and the COOR group is oriented endo with respect to the bicyclic ring system are precipitated. 4
4. » A process as claimed in one of claims 1 to 3, wherein R represents aLkyl having 1 to 6 carbon atoms, cycloalkyl having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon atoms uhich can optionally be substituted by W0 2 .
5. A process as claimed in one of claims 1 to 4, wherein the amino group of the N-acylated R- or S-amino 5 carboxylic acids which are used for salt formation is protected by alkanoyl having 1 to 6 carbon atoms, tert.butoxycarbonyI, benzyloxycarbonyl or another NH 2 protective group customary in peptide chemistry, and any free OH groups present in the N-acylated aminoacids are, where 10 appropriate, protected by rlkyl having 1 to 6 carbon atoms, benzyl or other OH protective groups customary in peptide chemistry.
6. A compound of the formula la or lb in which the two bridgehead hydrogen atoms have the cis configuration, 15 the COOR group is oriented endo with respect to the bicyclic ring system, the carbon atom a to the COOR group has the R or S configuration, and A, 10, B 2 and C have the meanings defined in claim 2, and R has that defined in claim 4, or a salt thereof. 20
7. A compound of the formula Ia or lb in which the two bridgehccd hydrogen atoms have the cis configuration, the COOR group is oriented endo with respect to the bicyclic ring system, the carbon atom a to the COOR group has the R or S configuration, and R denotes hydrogen or has the 25 meanings defined in cl?iro 4, a) A and f0 each denote hydrogen, and B 2 and C together form a chain of the formula -CCHgln’z with n being 3, 4, 5 or 6, or a chain of the formula “CCH23p~CH=CH-CCH23q-, with (p+q) being 1, 3 or 4, or b) C and B 2 each denote hydrogen, and A and B^ together form one of the chains defined above a), with n being 3, 5 or 6 and (p+q) being 1, 2 Z 3 or 4, or a salt thereof. 8o A compound as claimed in one of claims 6 or 7, wherein the carbon atom a to the COOR group has the S configuration. 9. A diastereomeric salt of a bicyclic imino-a-carboxylic ester of the formula Ia or lb as cLaimed in one of claims 6 or 8, in which R has the meanings defined in claim 4, and an N-acylated z optically active R- or Saminocarboxylic acid which contains a phenyl nucleus and is protected as defined in claim 5 e 10 B ci s z endo-2-Azabi cy c loC3 e 3.03octane-3S-carboxylie acid. 11« A cis z endo-2-azabicycLoC3.3.03octane-3S-carboxyLic ester in which R has the meaning defined in claim 4. 12e Benzyl cis,endo-2-azabicycloC3.3.OJoctane-35-carboxylat e, 13. A process as claimed in one of claims 1 to 4 for separating off cis,endo-octahydro[1H]indole2S-carboxylate. 14. A process as claimed in one of claims 1 to 4 for separating off benzyl cis,endo-octahydro[1HJindole2S-carboxylate. 15. A process for the preparation of an optically pure compound of the general formula Ila or lib CH co 2 n 2 γ ι C - X I z (XIa) (lib) Y * I CH - ZCH-7 ~ C - X I K 1 I 1 5> co^ir z in which it is possible for the carbon atoms labeled with an asterisk (*) each, independently of one another, to 5 have the R- or the S-configuration, a) A and B** each denote hydrogen, and B 2 and C together form a chain of the formula -CCH^In* with n being 3, 4, 5 or 6, or a chain of the formula -CCHgJp-CH-CH-tCHg^q*' , with 10 C and B 2 each denote hydrogen, and A and together form.a chain of the formula -CCH^lp-, with n being 3, 4, 5 or 6, or a chain of the formula -CCll23p'“CH = CH-CCH23 q -, with (p*q) 15 being 1, 2, 3 or 4, or c) A and C each denote hydrogen, and B and together form a chain of the formula -CCHj^ro/ with m being 4, 5, 6 or 7, r denotes 0 or 1, R^ denotes hydrogen, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 3 to 9 carbon a.toms, an optionally substituted a li eye I i c-a liphat i c radical having 4 to '11 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms, which can also be partially hydrogenated, an > optionally substituted araliphatic radical having 7 to 15 carbon atoms, an optionally substituted aroylaliphatic radical having 8 to 13 carbon atoms, an optionally substituted monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, 1 or 2 of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms being nitrogen atoms, or a side chain of a naturally occurring aminoacid which is optionally protected, R 2 denotes hydrogen, an optionally substituted aliphatic radical having 1 to 6 carbon atoms, or an optionally substituted araliphatic radical having 7 to 15 carbon atoms, Y denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen, and * X denotes an aliphatic radical having 1 to 6 carbon atoms, an aLicyclic radical having 5 to 9 carbon atoms, an optionally substituted aromatic radical having 6 to 12 41 carbon atoms, or indolyl, which process comprises reacting, in the presence ot a condensing agent or, where appropriate, as an active ester, an optically pure compound of the formula la or lb, in which A, B^, B^ and C have the abovementioned meanings, and R represents an optionally substituted aliphatic radical having 1 to 6 carbon atoms, an optionally substituted alicyclic radical having 4 to 10 carbon atoms, an optionally substituted aromatic radical having 6 to 12 carbon atoms or an optionaLly substituted araliphatic radicaL having 7 to 15 carbon atoms, with an optically pure compound of the formula 111 HOOC - CB - NH Ci! I CO ? R y C - X 7. (Ill) in which R, R^, R 2 , X, Y and Z. have the abovementioned meanings, splitting off the radical R by hydrogenolysis or hydrolysis, and, where appropriate, converting the optically pure compound of the formula la or Ib into a physiologically tolerated salt. 16. a process as claimed in cLaim 15, wherein there is prepared a conpound with the formula lla or lib in which r denotes 0 or 1, R denotes hydrogen, 7 to 9 carbon atoms, r1 denotes hydrogen or 1 to C 6 >-alkyl, which can optionally be substituted by amino, (C-j to C$>-acylamino or benzoylamino, (C 2 to C^I-alkenyl, (C5 to C9)- 42 cycloalkyl, (C5 to Cg)-cyc loa lkenyI, ¢¢5 to Cy)-cycloalkyl-(Cf to C^-alkyl, aryl or partially hydrogenated aryl having 6 to 12 carbon atoms, each of which can be substituted by (Cf to C4>-alkyl, (Cf or C 2 )-alkoxy 5 or halogen, (C$ to Cf 2 )-ary l-CCf-C^p-a Lkyl or (C7“Cf 3)- ar °y l-(Cf-C 2 )-a Iky I, both of which can be substituted in the aryl radical as defined above, a monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, 1 or 2 of *
8. 10 these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms being nitrogen atoms, or an optionally protected side chain of a naturally occurring aminoacid, R 2 denotes hydrogen, (Cf to C^)-alkyl, (C 2 to C 6 )f5 alkenyl or (C$ to Cf 2 )-aryI-(Cf to C4)*alkylz Y denotes hydrogen or hydroxyl, 2 denotes hydrogen, or Y and 2 together denote oxygen, and X denotes (Cf to C 6 )-alkyl, (C 2 to C6>-aLkeny I, 20 5 to C9>-cycloalkyl, (C^ t0 Cf 2 )-aryl, which can be mono-, di- or trisubstitued by -alkyl, (Cf to C4>-alkoxy, hydroxyl, halogen, nitro, amino, (Cf to €4)-8tkylamino, di-(Cf to C4)alkylamino and/or methylenedioxy, or 3-indolyl„ 25 17 e A process as claimed in one of claims 15 or 16, £ wherein there is prepared a ccxnpound of the formula Ila or lib i n whi ch ϊ a) A and B^ each denote hydrogen, and B 2 an d ς together form one of the chains defined in claim 15 (under a) or b) C and B 2 each denote hydrogen, and A and B^ together form one of the chains defined in claim 15 (under b> . 18. A process as claimed in one of claims 15-17, wherein the (S,S,S) compound is prepared. 19» A process as claimed in claim 17, wherein a cis,endo compound is prepared. 20. A process as claimed in one of claims 1-5, wherein the resulting compound of the formula Xa or Xb is further reacted by a process according to any one of claims 15-1
9. 21. & process recording to claim 1 for resolving a racemic mixture of bicyclic ioino-a-carboxylic esters into tbe cd^pooents of tbe formula© Is and Xb given and defined in claim 1, substantially ss hereinbefore described end exemplified. 22. a compound of the formula Xa or Xb given and defined in data .1, whenever obtained by a process daisied in any one of claim 1 to 5 or 21. 23. & compound according to claim 5, substantially as hereinbefore described and exemplified. 24. & process according to claim IS for the preparation of an optically pure compound of the general formula XXa or lib given end defined in claim 15, substantially as hereinbefore described and exemplified. 25. An optically pure compound of the general formula Ila or lib given and defined in claim 15, whenever prepared by a process claimed in any one of claims 15 to 20 or 24.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833303139 DE3303139A1 (en) | 1983-01-31 | 1983-01-31 | Process for the preparation of carboxyalkyldipeptides |
| DE19833303112 DE3303112A1 (en) | 1983-01-31 | 1983-01-31 | METHOD FOR RACEMATE SEPARATION OF OPTICALLY ACTIVE BICYCLIC IMINO (ALPHA) CARBONIC ACIDS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE840210L IE840210L (en) | 1984-07-31 |
| IE56654B1 true IE56654B1 (en) | 1991-10-23 |
Family
ID=25807929
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE210/84A IE56654B1 (en) | 1983-01-31 | 1984-01-30 | A process for the resolution of racemates of optically active bicyclic imino-alpha-carboxylic esters,and the use of the compounds thus obtainable for the synthesis of carboxyalkyldipeptides |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0115345B1 (en) |
| JP (1) | JPH0788358B2 (en) |
| KR (1) | KR910001438B1 (en) |
| AU (1) | AU566589B2 (en) |
| CA (2) | CA1283249C (en) |
| DE (1) | DE3468415D1 (en) |
| DK (1) | DK174386B1 (en) |
| ES (2) | ES529272A0 (en) |
| FI (1) | FI88153C (en) |
| GR (1) | GR82650B (en) |
| HU (1) | HU191120B (en) |
| IE (1) | IE56654B1 (en) |
| IL (1) | IL70830A (en) |
| MA (1) | MA20020A1 (en) |
| NO (1) | NO166641C (en) |
| NZ (1) | NZ206980A (en) |
| PT (1) | PT78036B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4500713A (en) * | 1982-09-23 | 1985-02-19 | Usv Pharmaceutical Corporation | Therapeutic dipeptides |
| DE3345355A1 (en) * | 1983-12-15 | 1985-06-27 | Hoechst Ag, 6230 Frankfurt | METHOD FOR RACEMATE CLEAVING BICYCLIC IMINO (ALPHA) CARBONIC ACID ESTERS |
| AU581919B2 (en) * | 1984-07-30 | 1989-03-09 | Schering Corporation | Process for the preparation of cis, endooctahydrocyclopenta (b) pyrrole-2-carboxylate |
| HU192914B (en) * | 1985-02-11 | 1987-07-28 | Richter Gedeon Vegyeszet | Process for producing new 3-/substituted amino/-5-phenyl-2/3h/-furanone derivatives and pharmaceutically acceptable salts |
| FR2620703B1 (en) * | 1987-09-17 | 1991-10-04 | Adir | PROCESS FOR THE INDUSTRIAL SYNTHESIS OF PERHYDROINDOLE CARBOXYLIC ACID - 2 (2S, 3AS, 7AS). APPLICATION TO THE SYNTHESIS OF CARBOXYALKYL DIPEPTIDES |
| HU904967D0 (en) * | 1988-04-22 | 1991-01-28 | Hoechst Ag | Process for producing new azabicyclo(3.3.o)octane-3-carboxylic acid-octylesther derivatives |
| US6407262B1 (en) | 2001-11-21 | 2002-06-18 | Brantford Chemicals Inc. | Process for the preparation of Ramipril |
| WO2006059347A2 (en) * | 2004-12-01 | 2006-06-08 | Morepen Laboratories Limited | Improved process for preparation of ramipril |
| EP2560493B1 (en) | 2010-04-20 | 2018-06-06 | Chiral Quest, Inc. | An enantioselective process for cycloalkenyl b-substituted alanines |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2503155A2 (en) * | 1980-10-02 | 1982-10-08 | Science Union & Cie | NOVEL SUBSTITUTED IMINO DIACIDES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS AN ENZYME INHIBITOR |
| IE52663B1 (en) * | 1980-04-02 | 1988-01-20 | Warner Lambert Co | Substituted acyl derivatives of octahydro-1h-indole-2-carboxylic acids |
| US4374847A (en) * | 1980-10-27 | 1983-02-22 | Ciba-Geigy Corporation | 1-Carboxyalkanoylindoline-2-carboxylic acids |
-
1984
- 1984-01-25 HU HU84312A patent/HU191120B/en unknown
- 1984-01-27 FI FI840350A patent/FI88153C/en not_active IP Right Cessation
- 1984-01-27 DE DE8484100858T patent/DE3468415D1/en not_active Expired
- 1984-01-27 EP EP84100858A patent/EP0115345B1/en not_active Expired
- 1984-01-28 KR KR1019840000396A patent/KR910001438B1/en not_active IP Right Cessation
- 1984-01-30 NO NO840350A patent/NO166641C/en not_active IP Right Cessation
- 1984-01-30 CA CA000446349A patent/CA1283249C/en not_active Expired - Lifetime
- 1984-01-30 IL IL70830A patent/IL70830A/en not_active IP Right Cessation
- 1984-01-30 ES ES529272A patent/ES529272A0/en active Granted
- 1984-01-30 GR GR73651A patent/GR82650B/el unknown
- 1984-01-30 PT PT78036A patent/PT78036B/en unknown
- 1984-01-30 DK DK198400415A patent/DK174386B1/en not_active IP Right Cessation
- 1984-01-30 IE IE210/84A patent/IE56654B1/en not_active IP Right Cessation
- 1984-01-30 NZ NZ206980A patent/NZ206980A/en unknown
- 1984-01-30 MA MA20241A patent/MA20020A1/en unknown
- 1984-01-31 AU AU23933/84A patent/AU566589B2/en not_active Expired
- 1984-04-04 ES ES531284A patent/ES531284A0/en active Granted
-
1988
- 1988-09-06 CA CA000576609A patent/CA1317067C/en not_active Expired - Lifetime
-
1991
- 1991-01-30 JP JP3027801A patent/JPH0788358B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| HUT34159A (en) | 1985-02-28 |
| CA1283249C (en) | 1991-04-16 |
| DK174386B1 (en) | 2003-01-27 |
| FI88153B (en) | 1992-12-31 |
| IE840210L (en) | 1984-07-31 |
| HU191120B (en) | 1987-01-28 |
| NZ206980A (en) | 1988-05-30 |
| ES8500228A1 (en) | 1984-10-01 |
| DE3468415D1 (en) | 1988-02-11 |
| PT78036B (en) | 1986-05-30 |
| AU2393384A (en) | 1984-08-02 |
| FI840350A0 (en) | 1984-01-27 |
| ES8501759A1 (en) | 1984-12-01 |
| ES531284A0 (en) | 1984-12-01 |
| FI840350A (en) | 1984-08-01 |
| NO166641C (en) | 1991-08-21 |
| PT78036A (en) | 1984-02-01 |
| GR82650B (en) | 1985-02-07 |
| DK41584D0 (en) | 1984-01-30 |
| EP0115345B1 (en) | 1988-01-07 |
| IL70830A (en) | 1988-02-29 |
| KR910001438B1 (en) | 1991-03-07 |
| ES529272A0 (en) | 1984-10-01 |
| EP0115345A1 (en) | 1984-08-08 |
| NO840350L (en) | 1984-08-01 |
| AU566589B2 (en) | 1987-10-22 |
| FI88153C (en) | 1993-04-13 |
| CA1317067C (en) | 1993-04-27 |
| MA20020A1 (en) | 1984-10-01 |
| JPH0788358B2 (en) | 1995-09-27 |
| JPH0517439A (en) | 1993-01-26 |
| DK41584A (en) | 1984-08-01 |
| IL70830A0 (en) | 1984-04-30 |
| NO166641B (en) | 1991-05-13 |
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