IE840244L - Preparing n-alkylated amino acids and esters thereof - Google Patents

Preparing n-alkylated amino acids and esters thereof

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Publication number
IE840244L
IE840244L IE840244A IE24484A IE840244L IE 840244 L IE840244 L IE 840244L IE 840244 A IE840244 A IE 840244A IE 24484 A IE24484 A IE 24484A IE 840244 L IE840244 L IE 840244L
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optionally substituted
carbon atoms
radical
alkyl
benzyl
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IE840244A
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IE56751B1 (en
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Hoechst Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

For the Contracting states : BE, CH, DE, FR, GB, IT, LU, NL, SE 1. A process for preparing compounds of the formula I see diagramm : EP0117448,P21,F1 in which n = 1 or 2, R denotes, hydrogen, carboxy, carbamoyl, an optionally substituted aliphatic radical having 2-8 carbon atoms, an optionally substituted cycloaliphatic radical having 3-9 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an OR**4 or SR**4 radical in which R**4 represents an optionally substituted aliphatic radical having 1-4 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms or an optionally substituted heteroaromatic radical having 5-10 ring atoms, or an optionally substituted heteroaromatic radical having 5-10 ring atoms, R**1 denotes hydrogen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted cycloaliphatic radical having 3-9 carbon atoms, an optionally substituted cycloaliphatic-aliphatic radical having 4-13 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-16 carbon atoms, an optionally substituted heteroaromatic radical having 5-10 ring atoms or the side chain of an optionally protected naturally occuring alpha-amino acid, R**2 and R**3 are identical or different and denote hydrogen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted cycloaliphatic radical having 3-9 carbon atoms, an optionally substituted cycloaliphatic-aliphatic radical having 4-12 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms or an optionally substituted araliphatic radical having 7-16 carbon atoms, which comprises reacting compounds of the formulae II ou III see diagramm : EP0117448,P22,F2 in which n, R, R**1, R**2 and R**3 have the abovementioned meanings, with compounds of the formulae IV or V see diagramm : EP0117448,P22,F3 in which R, R**1, R**2, R**3 and n have the abovementioned meanings, if desired eliminating ester groups by hydrolysis or if desired esterifying free carboxyl groups in a manner known per se. For the Contracting state : Austria 1. A process for preparing compounds of the formula see diagramm : EP0117448,P25,F1 in which n = 1 or 2, R denotes, carbamoyl, hydrogen, carboxy an optionally substituted aliphatic radical having 2-8 carbon atoms, an optionally substituted cycloaliphatic radical having 3-9 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an OR**4 or SR**4 radical in which R**4 represents an optionally substituted aliphatic radical having 1-4 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms or an optionally substituted heteroaromatic radical having 5-10 ring atoms, or an optionally substituted heteroaromatic radical having 5-10 ring atoms, R**1 denotes hydrogen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted cycloaliphatic radical having 3-9 carbon atoms, an optionally substituted cycloaliphatic-aliphatic radical having 4-13 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-16 carbon atoms, an optionally substituted heteroaromatic radical having 5-10 ring atoms or the side chain of an optionally protected naturally accuring alpha-amino acid, R**2 and R**3 are identical or different and denote hydrogen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted cycloaliphatic radical having 3-9 carbon atoms, an optionally substituted cycloaliphatic-aliphatic radical having 4-12 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms or an optionally substituted araliphatic radical having 7-16 carbon atoms, which comprises reacting compounds of the formulae II or III see diagramm : EP0117448,P26,F2 in which n, R, R**1, R**2 and R**3 have the abovementioned meanings, with compounds of the formulae IV or V see diagramm : EP0117448,P26,F3 in which R, R**1, R**2, R**3 and n have the abovementioned meanings, if desired eliminating ester groups by hydrolysis or hydrogenolysis or if desired esterifying free carboxyl groups in a manner known per se.

Description

The invention relates to a process for preparing compounds of the formula I (X) in which n 1 or 2, R denotes hydrogen, carboxy, carbamoyl an optionally substituted aliphatic radicaL having 2-8 carbon atoms, an optionally substituted eye loa I iphatic radical having 3-9 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an OR^ or SR^ r-adical in which represents an optionally substituted aliphatic radical having 1-4 carbon atoms, an optionally substituted aromatic radical having 6-1? carbon atons or an optionally substituted heteroaromotic radical having 5-10 ring atoms, or an optionally substituted heteroaromatic radical having 5-10 ring atoms, an optionally substituted aliphatic radical having 1-6 carbon atonis, an optionally substituted cycloaliphatic radical hsvinp 3-9 carbon atons, an optionally substituted cyc loaIiphatic-a Iiphatic denotes hydrogen. radical having 4-13 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical S having 7-16 carbon atoms, an optionally substituted heteroaromatic radical having 5-10 ring atoms or the side chain of an optionally protected naturally occurring a-amino acid, 10 and R3 are identical or different and each denotes hydrogen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted eyeloaIiphatic radical 15 having 3-9 carbon atoms, an optionally substituted eye loaIiphatic-aIiphatic radical having 4-12 carbon atoms, an optionally r-ubstitutcd aromatic radical having 6-12 carbon atoms or 20 an optionally substituted araliphatic radical having 7-16 carbon atoms, uhich comprises reacting compounds of the formulae II or III n-icw../ — cir «? n O-so2CF3 " C-OR II 0 2 i r -ch o-so2-ck3 S-OK- (II) Patent Application P 32 26 768„1 relates, a-keto esters are reacted with amino esters and the resulting imino compounds are reduced with various reducing agents,. If sodium cyanoborohydride is used, the working-up becomes technically complicated because of the formation of hydroThe literature (for example US-PS 4,350,704 In a further process, to which, inter alia, German cyanic acid* Even If optically pure amino esters are used as starting materials/ this process only produces diastereoisomerlc mixtures uhich are, if desired, separated into their components in a technically complicated May.
The process of the invention is free of the disadvantages listed.
Xn a preferred embodiment the compounds prepared have the formula £ In uhich n = 1 or 2, R denotes hydrogen, alkyl having 2-8 carbon atoms, alkenyl having 2"6 carbon atoms, cycloalkyl having 3-9 carbon atoms, aryl uhich has 6-12 carbon atoms and can be mono- to trl-substituted by -aryl- -alkyl, guanidino-(C^-C^)-alkyl, imida201yI, indolyl, (C^-C^J-alkylthio, (C^-C^J-alkylthio-tC'j-C^J-alkyl, (C^-C^^arylth io-CC^-C^J-alkyl uhich can be substituted in the aryl moiety as described above for aryl, CC^-Cij^ary^^C^-C^J-alkylthio uhich can be substituted in the aryl moiety as described above for aryl, cnrboxy-(C^-C^)-a IkyL, carboxyl, carbamoyl, carbamoyl-CC^-C^J-alkyl, (C^-C^)-alkoxycarbonyl-(C^-C^)-alkyl, (C1-C,)-alkoxycarbonyl) (C^-C^25"arylc"~aryl--aroyl°*y--«lky.l# C4-C^2>"aryloxycarbonyloxy-(Ci-C4)-alkyl/ aryl having 6-12 carbon atoms, 10 (C£~Ci2>~aryl-~-alkyl, n a particularly preferred embodiment of the process, the compounds prepared have the formula I in 1S uhich n = 1 or 2, R denotes (C2 to C$)-alkyl, (C2 to )-a I kcnyI, (C3 to C^J-cycloalkyl, amino-(C^-C^)-a Iky I, i^2~ CjJ-acylEmino-CCi-C^J-alkyl, (C^-C^J-aroylamino-20 (C-j-C^J-alkyl, (C.j-C4 >~a I koxy c a rbony I am i no- (C-j-C^J-a Iky I, (C6 to C12>-ary I-(C1-C4)-a Ikoxy-carbonylamino-CC^-C^J-alkyl, (C5 to Ci2'~ary'-which can be mono- to trisubstituted by (C^ to C^J-alkyl, (C^ to C4)-25 alkoxy, hydroxyl, halogen, nitro, amino, (C1 to C^-alkylamino, d i-(C.j-C^J-a Iky I am i no and/or methyl-enedioxy, or 3-indolyl, in particular ethyl, cyclohexyl, t e rt „-bu to xy c a rbony I an i no-( C-j-C^ )-a I k y I , ben?oyloxycarbonylamino-(C^-C4>-alkyl or phenyl which can mono- or disubstituted by phenyl (C-j to C2)-alkyl, CC•] or C2>-alkony, hydroxy, fluorine, chlorine, bromine, amino, -alkylamino, nitro and/or ncthyl-enedioxy or, in the case of methoxy, trisubsti-tuted, denotes hydrogen or (C-j to C$)-alfcyl uhich can be optionally substituted by amino, (Ci to C$)~ acylamino or benzoyl amino, (C2 to C^J-alkenyl, (C3 to C9>-cycloalkyl, (C5 to C^-cycloalkenyl, (C3 to C^)-cycloalkyl-(C1 to C4>-alkyl, (C^ to C12)-aryl or partially hydrogenated aryl, either of uhich can be substituted by (C^ to C^J-alkyl, (C-aryl-(C.j to C4)-alkyl, but in particular hydrogen, (C^ to C^)-alkyl or benzyl.
Here, and belon, aryl is preferably to be understood as meaning optionally substituted phenyl, biphenylyl or naphthylo This also applies to radicals derived from aryl, such as aryloxy or arylthio. Aroyl is to be understood as meaning in particular benzoyl,, Aliphatic radicals can be straight-chain or branched.
A monocyclic or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, of which 1 or 2 ring atoms represent sulfur or oxygen atoms and/or of which 1 to A ring atoms represent nitrogen atoms, is to be understood as meaning, for example, thienyl, benzo-Cb3thienyl, furyl, pyranyl, benzofuryl, pyrrolyl, inidaz-olyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, inda-zolyl, isoindolyl, indolyl, purinyl, quinoIizinyI, iso-quinolinyl, phtha IazinyI, naphthyridiny I, quinoxaIinyI, quinazolyl, cinnolinyl, pteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl. These radicals can also have been partially or completely hydrogenated* Naturally occurring «-amino acids are described, for example, in Houben-Weyl, Methoden der Organischen Chemie CMethods of Organic Chemistry!, Volumes XV/1 and XV12.
If R^ represents a side, chain of a protected naturally occurring a-amino acid, such as, for example, protected ser, t h r, asp, asn, g lu, gin, arg, ly s, hyl, cys, orn, cit, tyr, trp, his or hyp, the protective groups are preferably those customary in peptide chemistry (cf.
Houben-Weyl, Volumes HW/1 and JtV/2)„ In the case uhere Rs denotes the protected lysine side chain, the knoun amino-protective groups, but in particular X, BoC or (C-j-C^)-alkanoylo The O-protective groups for tyrosine can * 5 preferably be (C^-C^J-alkyl, but in particular methyl or ethyl.
• The process of the invention, depending on uhich chiral starting compounds have been used, can produce compounds of the formula X in uhich the chirality center 10 formed in this SN2 reaction is in the S- or R-configur-ation or racemic.
The reaction uhich takes place in the process of the invention proceeds stereochemicaIly unambiguously.
This fact is also confirmed by studies of the stercochcmi- 15 cal course of>the reaction of a-trifluoromethanesulfonyl-oxycarboxy I ates with optically active amines (Effenberger et al„, Angew. Chem. 95_ (1983) 50)o The following chart illustrates the stereochemi-cal course of the reaction in the process of the invention: 20 a b Starting compounds —J* R^0-C~Cli-NH-CH-/CHo7 -R ' I 1 | n d n (I) R' co^R2 £ (R)-XV (H)-IV + + (R)-II (S)-II ~5> (Ra' (R)-II ~9 (Sa» V -1 (S)-IV V (S)-II (Sa' v -1 (R)-III V (R)-V Sb5 - 1 (S)-III + (K)-V (Ra' Rb> - I (S)-III + (S)-Y —> S, ) - I - 12 - The following compounds can be obtained particu- larly advantageously by the process of the invention.
Benzyl N-(1-S-carbethoxy-3-phenyIpropyI)l.-S-alanlne, benzyl H-O-R-ca rbet hoxy-3-pheny IpropyI)-S-alanine, 5 benzyl N-(1-S-carbethoxy-3-phenyIpropyl)-R-alanine, benzyl H-(1-R-carbethoxy-3-phenyIpropyD-R-aIanine, benzyl N-(1-R,S-carbethoxy-3-phenyIpropyl)-S-aIani ne, benzyl M-(1-R,S™carbethoxy-3-phenyIpropyl)-R-alanine, benzyl N-<1-S-carbethoxy-3-phenyIpropyl)-R,S-aI anine, 10 benzyl N~<1-R-carbethoxy-3-phenyIpropyl)-R,S-alanine, benzyl N-(1-R,S~carbethoxy-3-phenyIpropyI>-R,S-aI anine, tert.-butyl N .-(1-S-carbethoxy-3-pheny Ipropy l)-N -benzyl-oc oxycarbonyl-S-lysine, benzyl -(1-S-carbethoxy-3-phenyIpropyI)-N£ -tert.-15 butoxycarbonyl-S-lysine, benzyl N-(1-S-carbethoxy-3-phenyIpropy I)-0-ethyl-S-tyros ine, benzyl N-(1-S-carbethoxy-3-phenylpropyl>-0-methyl-S-tyros ine, 20 benzyl N-(1-S-carbethoxy-3-phenyIpropyI)-S-tyrosine, benzyl N-(1-S-carbethoxy-3-[4-fluorophenyID-propyI)-S-alanine, benzyl N-(1-S-carbethoxy-3-C4-methoxyphenyl]-propy 13-S-alanine, 25 benzyl N- (1-S-carbethoxy-3-C4-chIoropheny13-propyI)-S-alanine, benzyl N-(1-S-carbethoxy-3-C2-methylphenyl3-propyI)-S-alanine, benzyl M-(1-S-carbethoxy-3-C3,4-dimethoxyphenyl3-propyD- S-alanlne, benzyl <1-S-eorbethoxybutyU-S-alanine, benzy I M- (1-S-carbet hoxy-3-Ccyc lohexy l3*»propy D-S-'alanine, benzyl K=(1-S-carbethoxy-3-C4-phenyIpheny13-propyl)~S-5 alanine^ benzyl W-(1~S-carbethoxy»3-C4~fluoropheny13-propyl)-0-wettiy l-S-ty ros Ine, benzyl 85-(1-S-carbethoxy~C4-fluoropheny13-propyI)-O-ethyl-S-tyros ine, 10 benzyl M-(1"'S"carbethoxy-3**C4-rnethoxyphenyl3«propyl)-0-ethyl-S-tyrosine, benzyl N»(1",S->carbethoxy-3-C4-chloropheny13-propyIheathy l-S- tyros ine, benzyl H™ (1-S-c a rbet hoxy-3-C2-ine thy Ipheny 13-propy I)-0-15 ethyl-S-tyrosine, benzyl M-(1-S-carbethoxjr-3-C3,4-dimethoxypheny13-propyI)-0-ethyl-S=tyrosine, benzyl W-<1-S-carbethoxybuty l)-0-ethyl-S-tyrosine, benzyl N-(1-S-carbethoxy-3-eyelohexyIpropyl)-0-ethyl-S-20 tyrosine, benzyl N-(1-S-carbethoxy~3-C4-methoxypheny13-propyI)-0-methyl-S-tyrosine, benzyl N-(1-S-carbethoxy-3-C4-chloropheny13-propyI)-0-methyl-S-tyrosine, 25 benzyl N-(1-S-carbethoxy-3-C2-methyIpheny13-propyI cornet hy l-S~ty ros ine, benzyl N- (1-S-c a rbet hoxy-3 -C3,4-di met hoxypheriy 13-propy I) 0-ncthyl-S-tyrosine, benzyl N-(1-S-carbethoxybutyI)-0-methyl-S~tyrosine. benzyl M-C1-S-carbethoxy~3-CcyclohexyI3-propyl)-0-methyl-S-tyrosine, tert.-butyl N -<1-S-carbethoxy-3-C4~fluoropheny13-propyl)-E-alkyl, (C2™C5)~aeyla,nino-"(Ci-C^-ethyI, (Cy-C^)- aroylaraino-(C^-C^)™alkyI, (C-j-C4)-alkoxycarbony l- amino-tC^-C^j-alkyI, CC^—C-j2)~aryl™(C^-Ct)~ alkoxycarbonylamino-(C~aryI-(Cj to C^)-alkyl or (C7 to C^3)"aroyl-(C^-C2)-alkyl, either of uhich 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, of which 1 or 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen atoms, or a side chain of a naturally occurring, protected a-amino acid and and R3 each denote hydrogen (C1 to Cg)-alkyl, (C2 to C^J-alkenyl or (C^-C-]2>-aryl-(C.j to C,;)-alkyl„ Those compounds of the formula II and III are - 16 - preferred In wfi"ich n ~ Zf R denotes methyl, cyclohexyl, tert.-butoxycarbonyl- arjiino-(C^-C^)-a Iky I, benzy loxyc arbony I ami no- (C-j-C^)-S alkyl or phenyl which can be monosubstituted or disubstituted by phenyl, CC-j or CgJ-alkyl, (C1 or CjJ-alkoxy, hydroxyl, fluorine, chlorine, bromine, amino, (C-j to C4 )-a Iky I am i no, di-(Ci to C4>~ a Iky I ami no, nitro and/or methylenedia>:y or, in the 10 case of methoxy, trisubstituted, denotes hydrogen, (Cj or CjJ-alkyl, (Cg or CjJ-alkenyl, the protected side chain of lysine, 4-methoxybenzyI, 4"ethoxybenzyI, phcnethyl, 4-aminobutyl or benzoy Imethy I, 15 r2 and R3 each denote hydrogen, (C1 to CA)-alkyl or benzyl, but in particular compounds of the formulae II and III in which' n 2, 20 R denotes methyl, tcrt.-butoxycarbonylaminoethyl, benzyloxycarbony I aminoethy I, phenyl or fluorinp-and/or ch lorine-monosubstituted or -disubstituted phenyl, R denotes ethyl, phenyl, the acylated side chain 25 of lysine or the 0~(C^-C^)-a IkyLated side chain of tyrosine, and o 3 R and R each denote hydrogen, methyl, ethyl, tert.- butyI or benzyl.
The trifluoromethanesulfonates of the formulae II - 17 - and II! are obtained by reacting a-hydroitycarboxy I ic acid derivatives of the formulae VI or VII R - /cH_/ - CH* , „ *■ 2 n (Wt) * R1 - CH OH -C-OR3 (WI3£> II 0 in which n, R, R^, R^ and R^ have the abovementioned meanings, with a trifluoromcthanesulfonating agent, such as, for example, trifluoromethanesulfonic anhydride or tri-fluoromethanesulfonyl chloride, in an inert solvent.
To trap the acid formed in the course of the reaction, it is advantageous to carry out the reaction in the presence of a base. Suitable for this purpose arc inorganic salts, such as carbonates (for example KgCOj, Na2C03 or NaHC03>, S3a2SO^ or organic bases, such as, for example, t r iethy lamine or pyridine., The base can be used in a stoichiometric amount or in excess.
Suitable solvents are those uhich cannot react with the trifluoromethanesulfonatino agent and the tri-fluoromethanesuIfonic acid derivatives. Examples of such solvents are methylene chloride, chloroform, carbon tetrachloride, other halogenated hydrocarbons and even hydrocarbons, such as, for example, hexane. The reaction can be carried out within the temperature range from -80°C to +80°C. The reaction ic particularly advantageous in - 18 - methylene chloride, chloroform or carbon tetrachloride, and trifluoromethanesuIfonic anhydride is reacted with the a-hydroxycarboxylic acid derivative at temperatures between -80°C and room temperature in the presence of 5 pyridine. Trif luoromethanesulfonic anhydride can also be used In excess..
If optically active compounds of the formulae VI or VII are used, the configuration on the chiral carbon atom is preserved on conversion into compounds of the 10 formulae II or III.
The trifluoromethanesulfonic acid derivatives of the formulae II or III react smoothly with amino esters of the formulae IV or V respectively to give compounds of the formula I„ To trap the resulting trifluoromethane-15 sulfonic acid, the reaction is preferably carried out in the presence of one equivalent of a base uhich cannot react uith compounds of the formulae II or III* Tertiary amines, such as triethyI amine or pyridine, have been found to be advantageous. Ever, the amino acid derivatives thero-20 selves can serve as acid acceptors. Also suitable are inorganic salts, such as, for example, NazCOj, IC2CO3, NaHCOj or Na^SO^.
The reaction is carried out in an aprotic polar solvent or non-polar solvent. Examples of suitable sol-25 vents are methylene chloride, chloroform, carbon tetrachloride, dimethyIformamide, ethyl acetate,'dimethoxy-ethane, hexane, ether and tet rahydrof urari.
The reaction temperature is within the range between -80 and +150°C„- The range from -20 to +80°C has - i9 - been found to be particularly advantageous., The uorfcing-up Is very simple. The solvent is Hashed uith water to remove the salts formed. The organic solution is dried and then concentrated, In the course 5 of uhich the compounds of the formula % are obtained in a pure form and can, if required, be highly purified by general purification methods, such as, for example, inter alia,, filtration or chromatography over silica gel.
If optically pure compounds of the formulae II 10 or 111 are used in the reaction, the substitution of the trifluoromethanesulfonic acid ester by the amino acid derivative of the formula IV or V is accompanied by inversion of configuration. Optically pure starting materials, without racemization, give optically pure end 15 products. A diastereoisomeric mixture is obtained by, for example, reacting racemic compounds of the formula II or III uith optically pure amino acid derivatives, or vice versa, or reacting racemic compounds of the formula II or III uith racemic amino acid derivatives* The re-20 suiting diastereoisomers can be separated by generally customary separating methods, such as, for example, inter alia, fractional crystallization of the salts or column chromatography over silica gel. Even if one of the starting components is racemic, the process of the invention, 25 by virtue of the high yields and purity, offers great advantages over existing processes.
The compounds of the formulae I, II and III are valuable intermediates in preparing compounds of the formula VIII - 20 - R I *" — - /CH J - R (VIII) c - CH - NH - CH - .
II I, I 0 R CO 1 2 OR • in which nf R, and R^ have the abovementioned meanings and R*' represents the radical of a monocyclic, bicyclic or tricyclic imino-oc-carboxylic acid bonded to the rest 5 of the molecule via the imino nitrogen aton. Compounds of the formula VIII are known, for example, from US-PS 4,350,704; US-PS 4,344,949; US-PS 4,374,847; EP-A 50,800, EP-A 31,741, EP-A 51,020, EP-A 49,658, EP-A 49,605, 10 EP-A 29,483, EP-A 46,953 and EP- A 52,870n They are also the subject-matter of German Patent Applications P 32 26 768,1, P 31 51 690.4, P 32-10 496.0, P 32 11 397.8, P 32 11 676.4, P 32 27 055.0, P 32 42 151„6, P 32 46 503„ and P 32 46 757.5. 15 The compounds of the formula VIII are inhibitors of the angiotensin converting enzyme (ACE) and can be used for controlling hypertension of different etiologies.
Compounds of the formula VIII arc obtained by reacting the corresponding a-iminocarboxylic acids R^-H 20 or derivatives thereof with compounds of "the formula I by known amide formation methods of peptide chemistry.
The following examples will illustrate the process of the invention without limiting the invention to the substances mentioned ar. representative therein.
Example Is Benzy I BS-O-S-carbethoxy-S-pheny I propyl )-$*=• a I an ine a) Ethyl 2-R^S-trifluoromethanesulfonyloxy-4-phenyl~ butyrate 5 ft solution of 2„37 g (30 mmoles) of dry pyridine and 9»73 g (34.5 mraoles) of trifluoromethanesulfonic anhydride in 8 ml of dry methylene chloride is added drop-wise uith stirring at 0°C 1n the course of one hour to a solution of 6.24 g (30 mmoles) of ethyl 2-R,S-hydroxy-10 4-phenylbutyrate in 30 ml of dry methylene chloride.
When the dropuise addition is complete, the mixture is stirred at 0°C for a further 15 minutes,, The precipitate is then filtered off uith suction, and the methylene chloride solution is uashed tuice uith water, is dried 15 over MgSO^ and is concentrated.
Yield: 8.6 g = 84.3% of theory® Rf: 0.37 (Si02; eye lohexane/ethyI acetate (4:1); irolyb-datophosphoric acid 15% in methanol). b) Benzyl N-(1-S-carbethoxy-3-phenylpropyl)-S-alanine 20 4.4 g (24.68 mmoles) of benzyl S-alanine and 2.5 g (24.-7 mmoles) of triethylamine are dissolved in 20 ml of dry methylene chloride. 8.4 g of ethyl 2-P.,S-trifluoro-methanesulfonyloxy-4-phenyIbutyrate of Example la in 10 ml of dry methylene chloride are added dropuise uith stirring 25 at room temperature. Afterwards the mixture is stirred at room temperature for a further 40 minutes. The methylene chloride solution is washed three times with water, is dried over NajSO^, and is concentrated in vacuo* Yield: 9.0 g (99% of theory) of benzyl M-(1-R,S-carbethoxy- ■ 22 - 3~phenyIpropyl)™S-alanine mixed diastereoisomers Rf of diastereoisomer Is 0.12 Rf of diastereoisomer II; 0,07 2; eyelohexane/ethyI acetate (9:1); molybdatophos-phoric acid 15% in methanol)o The two diastereoisomers can be easily separated from each other over silica gel by means of the eluent mixture of eyelohexane/ethyl acetate (9:1)„ The slow isomer has the S,S-configuration.
Example II; 8enzyI H-(1-S~earbethoxy-3-phenyIpropyl)"S-alanine a) Ethyl 2-R-trifluoromethanesulfonyloxy-4-phenyl-butyrate The compound is obtained from ethyl 2-R-hydroxy-4-phenylbutyrate and trifluoromethanesuIfonic anhydride analogously to the preparation method of Example la. The ethyl ester is prepared analogously to Biquard's method in Annales de Chimie 20, 147 (1933), front 2-R-hydrcxy-4-phenylbutyric acid (fliquard, Annales de Chimie 20, page 145 (1933)) and absolute ethanol by passing dry hydrogen chloride gas into the solution heated up on the waterbath. Rf: 0o11 (SiOg; eye lohexane/ethyl acetate <9;1))„ Vield: 90% of theory. b) Benzyl N-(1-S-carbethoxy-3-phenyIpropyI)-S-alanine Ethyl 2-R-trifluoromethanesulfonyloxy-4-phenyl- butyrate is reacted with benzyl- S-alanine analogously to Example lb. The configuration in the butyric acid moiety inverts to give the desired S,S-compound in a 92% yield„ Rfi 0.07 (SiOj, eyelohexane/ethyl acetate (9:1)). - 23 - The configuration was determined as follows,, If the compounds obtained in Example lb (diastereoisomer IS) and Example 21b are hydrogenated in ethanol by means of 10% palladium on carbon,, this gives in each case N-O-S-carbethoxy-3-phenylpropyl)-S-alanine having an angle of optical rotation of //^^D = +28° (c = 1, CH3OH). This value is in good agreement with the literature value (European Patent A 37,231,, page 30) of -?31° (c = 1, CM3OH). The 270-HHz ^H-NMR shows no contamination by the R/S-dia™ stereoi somer.
Example III; Benzyl N-(1-R,S-carbethoxy~3-phenyIpropyI)-0-ethyl-S-tyrosine 6.1 g of ethyl 2-R/S-trifluoromethanesulfonyloxy-4-plienyIbutyrate of Example la art; reacted analogously to Example lb with 5„A g of benzyl 0-ethy l-S-ty ros i 11c and 1„8 g of triethylamine in methylene chloride.
Yield: 95% of theory of a 1:1 diastereoisoneric mixture of S,S and R,S-compounds.
Rf of diastereoisomer I: 0„46 (SiOg; cyclohcxane/diiso-propyl ether (1:1)) Rf of diastereoisomer II: 0.39 (SiOg; cyclohexane/diiso-propyl ether (1:1)).
The two diastereoisomers . can be easily separated from each other over silica gel using cyclohexane/diiso-propyl ether (8:2)„ The slow diastereoisomer has the S,S-conf i guration.
Eitampte IV Benzyl M-(1~S-carbethoxy-3-phenyIpropyl)-0»ethyl-S-tyrosine The compound is obtained by reacting ethyl 2■-R-trifluoromethanesulfonyloxy-4-phenylbutyrate of Example 5 Ha, benzyl O-ethyl-S-tyrosine and triethylamine in dry methylene chloride analogously to Example lb.
• Yield: 95^ of theory.
Rf: 0„39 (Si02; eyelohexane/diisopropyI ether (1:1)). Example V 10 Benzyl H-CI-R/S-corbethoxy-S-phenylpropyO-O-methyl-S-tyrosine The diastereoisomeric mixture is obtained by reacting ethyl 2-R,S~trifluoromethanesulfonyloxy-4-phenyl-butyrate of Example la with benzyl 0-methyl-S-tyrosine 15 and triethy I amine in methylene chloride analogously to Example Ib„ Yield: 92% of theory of diastereoisomeric mixture Rf of diastereoisomer I: 0,23 (SiOg; eyelohexane/ethyl acetate (9:1)). 20 Rf of diastereoisomer II: 0.19 (SiOg; eyelohexane/ethyl acetate (9:1)).
The diastereoisomers can be easily separated from each other over silica gel using cyclohexane/diisopropyl ether. The slow isomer has the S^.S-conf 1 guration„ 25 Example VI Benzyl N-(1-S-carbethoxy-3-phenyIpropyI)-0-methyl-S-tyrosine The compound is obtained by reacting ethyl 2-R-trifluoromethanesuIfonyloxy-4-phenyIbutyrate of Example - 25 - Xla with benzyl O-methyl-S-tyrosine and triethylamine in methylene chloride analogously to Example lb.
Yields 94X of theory Rf: 0.19 (SiO^; eyelohexane/ethyl acetate (9:1)). 5 Example VII Tert.-butyl N -(1-R,S-carbethoxy-3-phenylpropyl)-Hr - CC ' . benzyloxycarbonyl-S-lysine The diastereoisomeric mixture is obtained by reacting ethyl 2-R,S-trifluoromethanesulfonyloxy-4-phenyl-10 butyrate of Example la with tert.-butyl -benzyloxy- carbonyl-S-lysine and triethy I amine in methylene chloride analogously to Example lb.
Yield: 95% of theory m/e: 526 15 Example VIII Tcrt.-butyl N - (1-S-carbethoxy-3-phenyIpropyI)-N -a c benzyloxyc arbonyl-S-lysine The compound is obtained by reacting ethyl 2-R-trifluoromethanesulfonyloxy-4-phcnyIbutyratc of Exanple 20 Ila with tert.-butyI N£ -benzyloxycarbonyl-S-lysine and triethylanine in methylene chloride analogously to Example Ib„ Yield: 82% of theory m/e: S26 25 Example XX Benzyl N-(1-R,S-carbethoxy-3-phenyIpropyI)-S-a tanine a) Benzyl 2-R-trifluoromethanesulfonyloxypropionate The compound is obtained by reacting benzyl D-lactate with t r i f luoromet hanesu I f on i c arihydrido anc) pyridine - 26 - in methylene chloride analogously to Example Xa.
Yield; 95% of theory. b) Benzyl N-<1-R,S-carbethoxy-3-phenyIpropy I )-S- alanine The diastereoisomeric mixture is obtained by reacting benzyl 2-R"trifluoromethanesulfonyloxypropionate aith ethyl R,S-homophenylalanine and triethylamine in methylene chloride analogously to Example Ib° Yield: 90% of theory Rf of diastereoisomer I: 0.12 (Si02; eye lohexane/ethyl acetate (9:1)) Rf of diastereoisomer II: 0.07 (Si02; eye lohexane/ethyl acetate (9:1)).
The physical data agree uith those of the dias-tereoisomers of Example lb.
Example X Benzyl N-(1-S~carbethoxy-3-phenylpropyl)-S~alanine The compound is obtained by reacting benzyl 2-R-trif luoromethanesuIfonyIoxypropionate with ethyl S-homo-phenylalanine and triethylamine in carbon tetrachloride analogously to Example lb.
Yield: 9855 of theory Rf: 0.07 (SiOj; eyelohexane/ethyl acetate (9:1)).
The physical data agree with those of the compound of Example lib.
Exaii.plo XI Ethyl -(1-S-carbobenzyIoxyethy1)-Ne -tert.-butoxycai— bonyl-S- l> s i ne The compound is obtained by reacting benzyl 2-R- - 27 - trifluoromethanesulfonyloxypropionate of Example Ixa with ethyl -tert.-butoxycarbonyl-S-lysine and triethylamine in methylene chloride analogously to Example lb.
Yield; 82% of theory 5 m/e: 436 Example XXI Benzyl N-(1-R,S-carbethoxy-3-phenyIpropyI)-R-aIani ne The diastereoisomeric mixture is obtained by reacting benzyl 2-R,S«trifluoroniethanesulfonyloxybutyrate 10 aith benzyl R-alan1ne and triethylamine in methylene chloride analogously to Example lb and by reacting benzyl 2" S-trifluoromethanesulfonyloxylactate and ethyl R,S-homo-phenylalanine analogously to Example lb.
Yield; 92% of theory IS Rf of diastereoisomer I: 0.13 (SiO^; cyclohexane/ethyl acetate (9:1)) Rf of diastereoisomer IX: 0„07 (SiOj; cyclohexane/ethyl acetate (9:1)).
Example XIII 20 Benzyl N-(1-S-carbethoxy-3-phenyIpropyl)-R-a lanine The compound is obtained by reacting benzyl 2-S-trifluoronethanesulfonyloxypropionate, prepared from benzyl L-laetate, trifluoromethanesulfonic anhydride and pyridine in methylene chloride analogously to Example la, uith 25 ethyl S-homophenyIalanine and triethylamine in methylene chloride analogously to Example lb.
Yield: 955! of theory Rf.: 0.08 (SiOj; eye lohoxane/ethyI acetate (9:1>)„ Example XXV Ethyl Ma -(1-S-carboxy-tert„-butoxyethyl)~Ne -benayloxy-carbonyl-S-lys ine The compound is obtained by reacting tert*-butyl 5 2-R-trifluororaethanesuIfonyloxypropionate and ethyl -benzyloxycarbonyl-S-lysine and triethylamine in methylene chloride analogously to Example lb.
The following triflates are prepared by the above-mentioned methods from the corresponding 2-hydroxycarboxyl-10 ates uhich ore used in the R or S or R,S-form (preferabLy the R and R,S-forms): ethyl 2-R,S-trifluoromethanesuIfonyloxy-A-(4-fluoropheny15-butyrate, ethyl 2-R-trffluororaethanesuIfonyloxy-4-(4-fluorophenyI)-15 butyrate, ethyl 2-R,S-trif luoromethanesulfonyloxy-4-(4-methoxypheny I)-butyrate, ethyl 2-R-trifluoro#iethanesulfonyloxy-4-(4-methoxyphenyl>-butyrate, 20 ethyl 2-R,S-trifluoromethanesulfonyloxy-4-(4-chlorophenyl)-butyrate, ethyl 2-R-trifluoromethanesulfonyloxy-4-(4-chlorophenyl)-butyrate, ethyl 2-R,S-trifluoronethanesuIfonyloxy-4-(3,4-dichloro-25 pheny I )-butyrate, ethyl 2-R-trifluoromethanesulfonyloxy-4-(3,4-dichloro-phenyD-butyrate, etliyl 2-R,S-trifluororaethene>;ulfonyloxy-4-(2-methylphenyl)-butyrate. - 29 - ethyl 2-R-trifluoromethanesuIfonyloxy-4-(2-methyIphenyl)~ butyrate, ethyl 2-R,S-trifluoromethanesuIfonyloxy-4-(3,4-diwethoxy™ pheny l)~butyrate^ 5 ethyl 2-R-trifluoromethanesulfonyloxy-4-(3,4-dimethoxy-phenyl>-butyrate, ethyl 2-R,S-tri fluoromethanesuIfonyloxy-4-<4-phenyIphenyI) butyrate, ethyl 2-R-t rifluoromethanesulfonyloxy-4-(4-phenyIphenyl>-10 butyrate, ethyl 2-R,S-trifluoromethanesulfonyloxybutyrate, ethyl 2-R"trifluoromethanesuIfonyloxybutyrate, ethyl 2-R,S~trifluoromethanesuIfonyloxy-4-cyelohexyl-butyrate, 15 ethyl 2-R-trifluoromethanesulfonyloxy-4-cyclohexyl-butyrate, ethyl 2-R,S-trifluoromethanesuIfonyloxy-3--propionate, ethyl 2-R-trifluoromethanesulfonyloxy-3-(indol-3-yO-20 propionate, ethyl 2-R,S-trifluoromethanesulfonyloxy-3-(N-trifluoromethanesulf ony I indol-3-yI)-propionate, ethyl 2-R-trifluororaethanesulfonyloxy-3-(N-trifluoro-methanesulfonylindol-3-y O-propionat e. 25 The 2--R,S-hydroxycarboxy lates required for pre paring the triflates are obtained by reducihg the corresponding a-keto esters uith Kaney nickel and hydrogen in ethanol. In a further method of preparation used, the corresponding cyanohydrins are acid-hydrolyzed and the resulting 2-hydroxycarboxylic acids are converted into the ethyl esters by conventional esterification methods.
The racemic 2-hydroxycarboxylic acids are racemic" ally resolved either via diastereoisomeric salt formation 5 uith optically active amines or amino esters and fractional crystallization or by esterificat ion uith optically active alcohols, such as, for example, menthol, and separating the esters by column chromatography or by fractional crystallization. The esterification to the optically active 10 2-hydroxycarboxylates is effected by the conventional esterification methods.
The 2-trifluoromethanesulfonyloxycarboxylates described above are reacted uith the corresponding amino esters analogously to the method given in Example lb or 15 lib to give the following compounds: benzyl N-(1-S-carbethoxy-3-C4-fluorophenylD-propyO-S-alan ine, benzyI N™(1-S-carbethoxy-3-C4-mothoxyphenyID-propy I)-S-alanine, 20 benzyl N-(1-S-carbethoxy-3-C4~chloropheny13-propyI)-S-alanine, benzyl N-(1-S-carbethoxy-3-L2-methy Ipheny 13-propy I)-S-alanine, benzyl N-(1-S-carbethoxy-3-C3,4-dimethoxypheny13-propyI)-25 S-alanine, benzyl N-(1-S-carbethoxybutyl)-S-alanine, benzyl N-(1-S-carbethoxy~3-cyclohexylpropyl)-S~aLanine, benzy I N-(1-S-carbethoxy-3-C4-phenyIpheny13-propyI)-S-alanine. benzyl M-(1-S-carbethoxy-3-C4-fluorophenyl3"propyI)-0-raethyl-S-tyros ine, benzyl N-(1-S-carbethoxy-3-C4-fluoropheny13-propyI)-0-ethyl-S-syrosIne, 5 benzyl M-CI~S-carbethoxy-3~C4-sne'£hoxypheny 13-propyl)-0-& thyl-S-tyrosine, ' benzyl H-(1-S-carbethoxy-3"C4->aethoxyphenyl3-propyl)~0-methyl-S"tyrosine, benzyl N-(1-S-carbethoxy-3-C2,6-diehloropheny13-propyI)-10 O-ethyl-S-tyrosine, benzyl W-(1-S-carbethoxy-3-C2,6-dichloropheny13-propyl)-0-methyl-S-tyros ine, benzyl N-(1-S-carbethoxy-3-C2,6-dichloropheny13-propyI)-S-alanine, 15 benzyl M-(1-S-carbethoxy-3-C4™chloropheny13-propyI^fleetly l~S- tyros ine, benzyl N-(1-S-carbethoxy-3-C4-chloropheny13-propyI)-0-methyl-S-tyros1ne, benzyl N-(1-carbethoxy-3-C2-methyIpheny13-propyl>-0-ethyl-20 S-tyrosine, benzyl N-(1-S-carbethoxy-3-C2~methyIpheny13-propyI)-0-methy l-S-ty ros'ine, benzyl N-(1-S-carbethoxy-3-C3,4-dinethoxypheny13-propyI)-0-ethyl-S-tyrosine, 25 benzyl N-(1 -S-carbethoxy-3-t3,4-dimethoxypheny 13-propyl)-0-methyl-S-tyrosine, benzyl N-(1-S-carbethoxybutyl>=0-ethyl-S-tyrosine, benzyl N-(1-S-carbethoxybutyl)-C-raethyl-S-tyrosine, benzyl N-(1-S-carbethoxy-3-cyclohexylpropyl)-0-ethyl-S- - 32 - tyrosine,, benzyl M-(1-S-carbethoxy-3-eyelohexyIpropyl)-0-methyl-S*-tyrosine, benzyl N -(1-S-carbethoxy-3-C4-methoxyphenyl3-propyl>™ a 5 fte-tert»~butoxycarbonyl-S-lysine, tertn-butyI M ~(1~S-carbethoxy~3-C4-chlorophenyl3"propyl>-a W -benzyloxycarbonyl-S-lysine, c benzyl N^(1-S-carbethoxy-3-C4-chloropheny13-propyl)-Me-tert„-butoxycarbonyl-S-lysine, 10 benzyl Na-(1-S=carbethoxy-3-C2,6-dichlorophenyl3-propyl>-Ne~tert.-butoxycarbonyl-S-lysine, tert«-butyl N -(1-S-carbethoxy-3-C2,6-dichlorophenyl3- a propy I)-M^benzyloxycarbonyl-S™lysine, tert.-butyl N -(1-S-carbethoxy-3-[2-methylpheny13-propyI>-15 H£-benzyIoxycarbonyl-S-lysine, benzyl (I - (1 -S-ca rbet hoxy-3-C2-met hy I pheny 13-propy I >-Hf-tcrt.-butoxycarbonyl-S-lysine, benzyl N -(1-S-carbethoxy-3-C3,4-dimethoxypheny13-propy I)-N -tert.-butoxycarbonyl-S-lysine, 20 terto-butyl N^-(1-S-carbet hoxy-3-C3 ,4-dimet'noxy pheny 13-propy I >-Nf-benzy I o xyca rb ony l-S-lys ine, tert.-butyl N -11-S-carbethoxybutyl)-N -benzyloxycarbonyl-a e S-lysine, benzyl M^- (1-S-carbethoxybutyl)-Ne-tert«-butoxycarbonyl-25 S-lysinc, benzyl N^-(1-S-carbethoxy-3-eyelohexylpropyl)-N£-tert„-butoxycarbonyl-S-lysine, tert»-butyl N -(1-S-carbethoxy-3-cyclohexyIpropyI>-N a c benzyloxycarbonyl-S-lysine, - 33 - ethyl N -(1-S-carbobenzyloxyethyl)~ti! -tert."butoxycarbonyI ft t S-lys ine, ethyl ES ^»<1-S-carbo-ters.-butoxy~2--C<>-ethoxypheny I3~ethy I) N e-benzyloxycarbony l-S-» lysine, 5 ethyl -C1-S-carbo-tert„-butoxy=2-C4-methoxypheny 13-a ethyI)™We"benzyloxycarbonyl-S-lysine.
SI the corresponding tert.-butyl S-amino acid ester educts are used, the tert.-butyl ester end products are obtained in place of the benzyl ester products. 10 If the racemic triflate educts are used, the cor responding S-amino acid esters with the R,S-configuration in the N-aIkyI moiety are obtained. -34 -

Claims (10)

1. claims: 1„ A process for preparing a compound of the formula'
2. I r3o-c-ch-nh-ch-/ch>7 -n
3. •I t i • * 2"n 0 R C=0
4. I 2 OR
5. In which n = 1 or 2, R denotes hydrogen, carboxy, carbamoyl, an optionally substituted aliphatic radical having 2"8 carbon atoms, 10 an optionally substituted cycloaliphatic radical having 3-9 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an OR^ or SR^ radical in which R^ represents an optionally substituted aliphatic 15 radical having 1-4 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms or an optionally substituted heteroaroipatic radical having 5-10 ring atoms, or an optionally substituted heteroaromatic radical 20 having 5-10 ring atoms, 4 R denotes hydrogen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted cycloaIiphatic radical 25 having 3-9 carbon atoms,. an optionally substituted eye I oa I iphat i c--a I i phat • c radical having 4-13 carbon atoraSj, an optionally substituted aromatic radical having
6. -12 carbon atoms, an optionally substituted araliphatic radical 5 having
7. -16 carbon atoms, an optionally substituted heteroaromatic radical having 5~10 ring atoms or the side chain of an optionally protected naturally occurring oc-amino acid,? 10 and are identical or different and each denotes hydrogen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted cycloaliphatic radical *5 having 3-9 carbon atoms, an optionally substituted cycloaliphatic-aliphatic radical having 4-12 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atons or 20 an optionally substituted araliphatic radical having 7-16 carbon atoms, which process comprises reacting a compound of the formula II or III R- (in) - 36 - in uhich n, R, 'R^, R^ and R^ have the abovementioned meanings, with a compound of the formula IV or V KV{-M-»1.2 »Vc-fH-KK2 OR 6 /CH_/ ~ R d n (IV) CV) ir> tjhich 8, R**, R^, R^ and n have the abovement ioned meanings, if desired eliminating ester groups by hydrolysis or hydrogenolysis or if desired esterifying free carboxyl groups in a manner known per se. 2, A process as claimed in claim 1, wherein n = 1 or 2, R denotes hydrogen, alityl having 2-8 carbon atoms, alkenyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, aryl which has 6-12 carbon atoms and can be mono- to tri-substituted by (C^-C^)-a I ky I, (C -|-C^)-a I koxy , hydroxyl, halogen, nitro, amino, aminonethyI, (Ci~C4>-alkylaraino, di-(Ci-C4)-alkylamino, (C^-C^)-acylamino, preferably
8. -10 ring atoms respectively, of which 1 or 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atons represent nitrogen and which can be substituted as described above 5 for aryl, aaino--alfeyl, -alkoxycarbonylamino-(C.rC4>-alkyl, 10 CC^-C-jj^-ary l'--'(C.j-C4)-alkoxyca^bonylamino-* "a Iky I, (c6"c12)"aryl~tci"C4>-alkyIamino-tC^-C^)-alkyl, ™alkylaBiino-(C^-C4)-alky I, 15 di-(C^-C^)"alkylamino-(C^~C4>-alkyI, guanidino-(C1-C4>-alkyl, inidazolyI, indolyl, (C^-C/^J-alkylthio, CC.j-C^J-alkylthio-CC.j-^J'-alkyl, 20 (C£-Ci2'""ary Ithio- (Ci-C^J-alky I uhich can be substituted in the aryl moiety as described above for aryl, (C^-C^2'_ary^~'ci~c4i™aIkyIthio uhich can be substituted in the aryl moiety as 25 described above for aryl, carboxy-tC-j-C^J-alky I, carboxyl, carbamoyl, carbamoyl-(C^-C4)-alkyI, (C -C )-alkoxycarbonyl-(C„-C, )-alkyl, 14 i * - 38 - (C^j-C^J-alfcoxyc arbony I, *c$"Ci2,-aryloxy-(C^-C4>-alkyI uhich can be substituted in the aryl moiety as described above for aryl or — eye l°a Ikenyl — — — a Iky I ^ optionally partially hydrogenated aryl uhich has 6-12 carbon atoms and can be substituted as described above for R, l" CC-j-C^J-a Ikyl or tCy-CigJ-aroyl-CC^ or C2)~alkyL either of uhich can be substituted like the aryl above, monocyclic or bicyclic optionally partially hydrogenated hcteroaryl uhich has 5-7 or 8-10 ring atoms respectively, of uhich 1 or 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen atoms, and which can be substituted like ary'. above, or the side chain of an optionally protected naturally occurring a -amino acid of the formula R^-CHCNH^)- ■ 3
9. - COOH, and R"* are Identical or different and each denotes hydrogen, alkyl having 1-6 carbon atoms-,, alkenyl having 2-6 carbon atoms, di - (C^-C^J-alfcy I ami no- (C-j-C-*alkyl, (C^-C5)-alkanoy loxy-(C-j-C4>-alky I, CC-j-C$)-a Ikoxycarbony I oxy- -a Ikoxy-carbony I ami no- (C^-C^J-alkyl, (Cj- CijJ-aroylamino-CC^-C^J-alkyl, (C$ to which can be mono- to trisubs- tituted by ~cycloalityl-(C^ to C^-alkyl, ~aryI— -alicoxycarbonyl-amino-(C^-C4>-aIkyl, cyclohexyl or phenyl, which can be mono- or disubstituted by phenyl, (C^ or C2>-alkyl, or C2)-alkoxy, hydroxyl, fluorine, chlorine, bromine, amino, (C^ to Cjp-alkylapino, d i — < Ci to C4>-a Iky I amino, nitro cmC/ or methylenedioxy or, in the case of nethoxy, tt i-substituted. denotes hydrogen, (C-j to CjJ-alkyl, (C2 or CjJ-alkenyl, the optionally protected side chain of lysine* benzyl,, ^-methoxybenzyI, 4-ethoxybenzyI, phenethyl, 4=aminobutyl or benzoyImethyI, and and R3 denote identical or different radicals selected from hydrogen, (C^ to C4)-alkyl and benzyl. A compound of the formula IX . = 2, denotes (c^ to C^J-alkyl, (Cg to C^)-alkenyl, -acy I am i no-( C •)-C^-alkyl, (Cy-C^jJ-aroylamino-(Ci-C4)-alkyI, (C^™C4>-8lkoxycarbonylamino--aryl which can be mono-to trisubstituted by (Cj to C4)-alkyl, (C-j to C^J-alkoxy.hydroxy, halogen, nitro, amino, (C^ to C^-alkylamino, di-(C.j to C^)-alkyI amino and/ or methylenedioxy, or 3-indolyl, and denotes hydrogen, (C.j to C^>-alkyl, (Cg to C6)-alicenyl or (C^ to C.j2>~aryl, *C1 t0 c4)_ alkyl. A compound of the formula III 3 0 (II) which - 42 - (1X1) which denotes hydrogen or (C2 to C$)-aIkyI, uhich can be optionally substituted by amino, (C^ to C$>-acyl-amino or benzoylaroino, -alkyl or -aroyl-(C1~C2>-alkyl, either of uhich- 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 of uhich 1 or 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen atoms, or a side chain of a naturally occurring protected a~ amino acid, and R3 denotes hydrogen, (C.) to C^J-alkyl, (C2 to C6)-alkenyl or (C^"C12)-aryI-(C^ to C4)~alkyl» A compound as claimed in claim 5, wherein denotes ethyl, tert„-butoxycarbonylamino-(C^~C4>-alkyl, benzy I oxy c arbony I am ino-CC^-C/, )-a I ky I , cyclo-hexyl or phenyl which can be mono- or - 43 - di subscituted by phenyl, C C-j or CgJ-alkyl,, (C-j or CgJ-al&oxy, hydroxyl, fluorine, chlorine,. bromine, amino, CC^ to C^)"al!;ylaroino, di«CC^ to C^J-alkylamino, nitro and/or methylenedioxy or, in she case of 5 siethoxy^, t ri subs t i tut ed, and • R2 denotes hydrogen,, "alkyl or benzyI, 8. A compound as claimed in claim 6, wherein 8^ denotes hydrogen, (C% or CjJ-alkyl, (C^ or 10 CjJ-alkenyl, the protected side chain of lysine, 4~methoxybenzyI, 4-ethoxybenzyI, phenethyl, 4-aminobutyl or benzoyImethyl and R^ denotes hydrogen, (C^ to C^)-alkyl or benzyl. 9„ A compound as claimed in claim 5, wherein 15 r denotes phenyl or fluorine- and/or chlorine- mono- or disubstituted phenyl and R2 denotes hydrogen, methyl, ethyl, tert„-butyl or benzyl.
10. A compound as claimed in claim 6, wherein 20 R^ denotes the acylated side chain of lysine or the 0-(C'}-C^)-alkylated side chain of tyrosine and ft3 denotes hydrogen, Methyl, ethyl, tert.-butyl or benzyl. 25 11® A process for preparing a compound of the formula IX or III, which comprises reacting an a-hydroxycarboxyllc acid derivative of the formula VI or VII - 1,1, ~ »- - OH coir u. o CVS) ft ^-0H (VIX) r1 _ CH^ C-OR3 II 0 12 3 in which n, R, R , R and R have the meanings given in Claim 1, with a trifluoromethanesulfonating agent in the presence or absence of a base. 12. A process according to Claim 1 for preparing a compound of the formula I given and defined in Claim 1, substantially as hereinbefore described and exemplified. 13. A compound of the formula I given and defined in Claim 1, whenever prepared by a process Claimed in any one of claims 1-4 or 12. 14. A compound of the formula II given and defined in Claim 5, which is any one of those specifically hereinbefore mentioned. 15. A compound of the formula III given and defined in Claim 6, which is any one of those specifically hereinbefore mentioned. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.
IE244/84A 1983-02-02 1984-02-01 A process for preparing n-alkylated amino acids and esters thereof IE56751B1 (en)

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DE19833303344 DE3303344A1 (en) 1983-02-02 1983-02-02 METHOD FOR PRODUCING N-ALKYLATED AMINO ACIDS AND THEIR ESTERS

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IE244/84A IE56751B1 (en) 1983-02-02 1984-02-01 A process for preparing n-alkylated amino acids and esters thereof

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JPS63170344A (en) * 1987-01-09 1988-07-14 Daicel Chem Ind Ltd N-alkylation of amino acid ester
JP2535001B2 (en) * 1987-01-13 1996-09-18 ダイセル化学工業株式会社 Process for producing N-alkylated amino acid ester
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CN1585744A (en) 2001-03-27 2005-02-23 兰贝克赛实验室有限公司 Process for the preparation of benazepril
WO2008032463A1 (en) * 2006-09-12 2008-03-20 Wako Pure Chemical Industries, Ltd. Process for production of sulfonic acid ester
HUE040323T2 (en) 2012-12-21 2019-02-28 Epizyme Inc Prmt5 inhibitors and uses thereof

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DE3303344A1 (en) * 1983-02-02 1984-08-02 Hoechst Ag, 6230 Frankfurt METHOD FOR PRODUCING N-ALKYLATED AMINO ACIDS AND THEIR ESTERS

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PT78047B (en) 1986-07-15
EP0117448A1 (en) 1984-09-05
DK49492A (en) 1992-04-13
IE56751B1 (en) 1991-12-04
ES8500215A1 (en) 1984-10-01
CA1292236C (en) 1991-11-19
KR850000384A (en) 1985-02-27
EP0117448B1 (en) 1986-09-03
ES529302A0 (en) 1984-10-01
ZA84740B (en) 1984-09-26
AU7830487A (en) 1987-12-17
DK45584A (en) 1984-08-03
CA1267903A (en) 1990-04-17
JPH0587499B2 (en) 1993-12-16
DK49492D0 (en) 1992-04-13
ATE21890T1 (en) 1986-09-15
DK166619B (en) 1993-06-21
GR79751B (en) 1984-10-31
AU566053B2 (en) 1987-10-08
DK173770B1 (en) 2001-09-24
DE3460578D1 (en) 1986-10-09
JPH06102646B2 (en) 1994-12-14
KR910008135B1 (en) 1991-10-10
JPS59172442A (en) 1984-09-29
AU588483B2 (en) 1989-09-14
DE3303344A1 (en) 1984-08-02
IL70847A (en) 1991-04-15
PT78047A (en) 1984-03-01
DK45584D0 (en) 1984-02-01
IL70847A0 (en) 1984-05-31
JPH05320119A (en) 1993-12-03
DK166619C (en) 1993-11-08
AU2399884A (en) 1984-08-09

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