IE56751B1 - A process for preparing n-alkylated amino acids and esters thereof - Google Patents

A process for preparing n-alkylated amino acids and esters thereof

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Publication number
IE56751B1
IE56751B1 IE244/84A IE24484A IE56751B1 IE 56751 B1 IE56751 B1 IE 56751B1 IE 244/84 A IE244/84 A IE 244/84A IE 24484 A IE24484 A IE 24484A IE 56751 B1 IE56751 B1 IE 56751B1
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carbon atoms
optionally substituted
radical
alkyl
aryl
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IE244/84A
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IE840244L (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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  • General Chemical & Material Sciences (AREA)
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  • 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)
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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 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 cycloaliphatic 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 atoms or an optionally substituted heteroaromatic radical having 5-10 ring atoms, or an optionally substituted heteroaromatic radical having 5-10 ring atoms, denotes hydrogen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted cycloaliphatic radical heving 3-9 carbon atoms, an optionally substituted cycloaliphatic-aliphatic - 3 10 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 occurring CC-amino acid, r2 and r3 are identical or different and each 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 cyc Loa Iiphatic-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 O-SO2-Ci'3 * S' R-cir R-ZC1L? — CH n (II) (III) In which n, R, R^, R^ and R^ have the abovementioned meanings, with compounds of the formulae IV or V (IV) in which R, r\ R^, * ro-c-ch-nh2 8 tao - r n (V) R*> 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.
The literature (for example US-PS 4,350,704 and EP-A 49,605 and 46,953) discloses processes for preparing compounds of the formula I by reacting α-halogenocarboxyLates or the corresponding tosyloxy or mesyloxy compounds with amino esters. The reaction requires an elevated reaction temperature. The yields are low because of the drastic reaction conditions, which lead to side reactions. In many cases it is necessary to catalyze the reaction with silver ions, as, for example, when «-halogeno compounds are reacted, and the catalysis can improve the yield, but is more expensive. What is nore, racemic products are obtained when optically active ffhaIogenocarboxyI ates are used.
In a further process, to which, inter alia, German Patent Application P 32 26 768*1 relates, cc-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 hydro- 5 cyanic add® Even If optically pure amino esters are used as starting materials, this process only produces diastereoisomerlc mixtures which are, If desired, separ^ ated into their components in a technically complicated * 5 way® The process of the invention is free of the dis~ « advantages Listed® In a preferred embodiment the compounds prepared have the formula X in which ΊΟ 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 which has 6-12 carbon atoms and can be mono- to trisubstituted by "alky I, -alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C^-C^I-alkylamino, di-lC-j-C^J-alkyt amino, t)-acyLamino, preferably (C^-C^J-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy having 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and which can be substituted as described above for aryl, monocyclic or bicyclic heteronryloxy which has 57 or 6-10 ring atoms respectively of which 1 or 2 ring atoms represent sulfur or oxygen atoms and/or to 4 ring atoms represent nitrogen and which can be substituted as described above for aryl, amino-(C^-€4)-a Ikyl, (C j*=*C4)a lkanoy lam ino-a Iky I, 1-C4>-alkyl, (C^C^-aryl-CC^C^-atkylami no- (C-j -C4)alkyl, (¢-)-04)-3 Iky lamino- (C^-C4>-a I kyl, di-(C^"C4)-alkylamino-(C^-C4>-alkyl, guanidino-(C^-C4)-alkyl, imidazolyl, indolyl, (C-)-C4>-alkylthio, (Cl"C4)alkyLthio-(C-j"C4)"alkylz ^c0c12^ary*‘tli'’o'~^c1"c4^’’a’,ky'‘ which can be substituted in the aryl moiety as described above for aryl, (C4-Ci2>~aryl-(Ci-C4)-alkylthi° which can be substituted in the aryl moiety as described above for aryl, ca rboxy-(C·)-C4)-a Lky L, carboxyl, carbamoyl, carbamoyl-(C-|-C4>-alkyl> (C<]-C4)-alkoxycarbonyl~(Ci-C4)-alkyl, (C.-Cj)-alkoxycarbonyl) (c1-c12)-aryioxy-(c1-C4>-aikyi which can be substituted in the aryl moiety as R1 R2 - 7 described above for aryl or (C6"c12^"ary*·" >-aLkoxy which can be substituted In the aryl moiety as described above for aryl, denotes hydrogen, alkyl having 1-6 carbon atoms,* alkenyl having 2=-6 carbon atoms, alkynyl having 2->6 carbon atoms, cycloalkyl having 3-9 carbon atoms, cycloalkenyl having 5-9 carbon atoms, (Cj-C^I-cycloalkyl-CC-j-C^I-alkyl, (C^-C^)"cycloalkenyl- (C^**C^)-alky I, optionally partially hydrogenated aryl which has 6-12 carbon atoms and can be substituted as described above for R, _aryl*(Ci~C4>~alkyl or (Cy-C^)-aroyl ^C6 C12)-aryloxyca rbony loxy- CC^-C^-alkyl, aryl having 6-12 carbon atoms, ic6‘*Ci2>-ary I- In a particularly preferred embodiment of the process, the compounds prepared have the formula I in which n = 1 or 2, R denotes (C2 to C^)-alkyl, 2 to C^)-alkenyl, 3 to C9>-cycloalkyl, ami no-CC-j-C^ )-a Iky L, 2CjjJ-acylamino-iC-i-C^-alkyl, (Cy-C-|3)-aroylamino(C-j-C^J-alkyl, (C-j -C^-alkoxy carbony lami no(C-j-C^-a Iky I, (C6 to C12^9ryl- 2>"aryl which can be mono- to trisubstituted by CC-j to C^)-alkyl, (C^ to C^)alkoxy, hydroxyl, halogen, nitro, amino, (C1 to C^>-olkylamino, di-(C-j-C^)"alkylamino and/or mcthylenedioxy, or 3-indolyl, in particular ethyl, < cyclohexyl, t e rt e-bu to xy c a rbony I am i no- < C -j-C^,)-a I k y I , benzoyloxycarbonylamino-(C^"C^)-alkyl or phenyl R2 which can mono- or disubstituted by phenyl CC-j to C2)-alkyl, "»lkouy, hydroxy, fluorine, chlorine, bromine, amino, (C^ to C^)alkylamino, di-CC-j to C&)~a Iky lam ino, nl t ro and/or niethylenedioxy or, in the case of methoxy, trisubstituted, denotes hydrogen or 2 to C^)-alkenyl, (Cg to Cg)-cycloalkyI, (C5 to Cg)-cycloalkenyl, (Cj to Cy)-cycloalkyl-(C^ to C^-alkyl, (C$ to C12)-aryl or partially hydrogenated aryl, either of which can be substituted by (C-j to C^J-alkyl, (C2>"alkoxy or halogen, (C^"C^2)-aryl-(C^ to C^)-alkyl or )-aroyI-(C^-C2)-aIkyL, 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, 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 optionally protected cc-amino acid, but in particular* hydrogen, (C-j to CjJ-alkyl, (C2 or )-aIkenyL, the optionally protected side chain of Lysine, benzyl, 4-methoxybenzyl, 4*=*ethoxybenzy I, phenethyl, 4-aminobutyI or benzoylmethyl, and and R denote identical or different radicals selected fron hydrogen, (C^ to C^i-alkyt, (Cg to C^)-alkenyl and (C^ to - 10 C^2>-aryl-(C-j to QJ-alkyl, but in particular hydrogen, Here, and below, aryl is preferably to be understood as meaning optionally substituted phenyl, biphenylyl or naphthyl® This also applies to radicals derived from «· aryl, such as aryloxy or arylthio. Aroyl is to be understood as meaning in particular benzoyl® Aliphatic radi- * cals 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 ano'/or of which 1 to 4 ring atoms represent nitrogen atoms, is to be understood as meaning, for example, thienyl, benzoCbDthienyl, furyl, pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, quino Ii2iny I, isoquinolinyl, phthalaziny I, naphthyridiny I, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxazolyl, isoxazolyi, 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 [Methods of Organic Chcmistryl, Volumes XV/1 and XV/2.
If R^ represents a side, chain of a protected naturally occurring «-amino acid, such as, for example, pro< tected tier, thr, asp, asn, glu, gin, arg, lys, hyl, cys, orn, cit, tyr, trp, his or hyp, the protective groups are preferably those customary in peptide chemistry (cf® Houben-Weyl, Volumes XV/1 and XV/2)« Xn the case where R^ denotes the protected lysine side chain, the known amino-protective groups, but in particular 2, BoC or (C a Th© O-protective groups for tyrosine can * 5 preferably be (Cj-C^)-alkyl, but in particular methyl or ethyl* ’ The process of the invention, depending on which chiral starting compounds have been used, can produce compounds of the formula ΐ in which the chirality center formed in this S^2 reaction is in the S- or R-configuration or racemic.
The reaction which takes place in the process of the invention proceeds stereochemlcally unambiguously.
This fact is also confirmed by studies of the stereocbcmi15 cal course of ^the reaction of α-trifluoromethanesulfonyIoxycarboxylates uith optically active amines (Effenberger et al., Angew. Chem. 95 (1983) 50).
The following chart illustrates the stereochemical course of the reaction in the process of the invention: a b Start ing compounds R^0oC-Cli«-NH-CH-/'CHo7 -R c ι · | o c n (I) R1 CO.. FT (R)-IV (R)-II(Ra-Sb> - I (R)-IV + (S)-II -5>(Ra· V - I (S)-IV (R)-II(Sa’Sb> - I (S)-IV T (S)-II(Sa·Kb> - I (R)-III ·«· (R)-V(Sa’ V - I (R)-III + (S)-V(Sa·sb> - I (S)-III + (R)-V(Ra’ 'V - I (S)-III + (S)-V -H> - Ϊ The following compounds can be obtained particularly advantageously by the process of the invention* Benzyl N-d-S-carbethoxy-3-phenyIpropyl>L-S-alanine, benzyl N-d-R-carbethoxy-3-phenylpropyI)-$"alanine, benzyl W"d-S-carbethoxy"3-phenyIp ropyI)Ra Ianine, benzyl M-d-R-c a rbet hoxy**3-pheny IpropyI )-R-alanine, benzyl N-d-R,S-carbethoxy-3-phenyIpropyI)"S-alanine^ benzyl W-d-R,S-carbethoxy-3-phenylpropy L)-R-alanine, benzyl N-d"S-carbethoxy-3-phenylpropyl)-R,S-alanine, benzyl (1-R-carbethoxy-3-phenyIpropyl)-R,$-atanine, benzyl N-d-R,S= carb ethoxy-3-phenyIpropyI>-R,S-aI anine, tert.-butyl N .- d-S-carbethoxy-3-pheny Ipropy l)-N -benzylOC coxycarbonyl-S-lysine, benzyl Νβ -d-S-carbethoxy-3-phenyIpropyI)-N£ -tertebutoxycarbonyL-S- lysine, benzyl N-d-S-carbethoxy-3-phenyIpropyI)-0-ethyl-Styros ine, benzyl N-d-S-carbethoxy-3-pheny Ipropy I >-0-methy l-Styrosine, benzyl N-d-S-carbethoxy-3-phenylpropyl>-$-tyrosine, benzyl N-(1-S-carbethoxy-3-C4-fluorophenyU-propyI)-Salanine, benzyl N-d-S-carbethoxy-3-C4-methoxyphenyl3-propyI)-Salanine, benzyl N-d-S-carbethoxy-3-C4-chIorophenyI3-propyL)-Salanine, benzyl N-d-S-carb ethoxy-3-C2-inethy Ipheny Ll-pr opy I)-Salanine, benzyl M- d-S’*carbethoxy-3-C3 ,4-d imethoxy pheny 13-propy D S-alanine, benzyl fcHd-S-e&rbethoxybutyI)-S-alanine, benzyl 83-(1-S-carbethoxy-3** CcycLohexyLJ^propy1)^5^alanine benzyl 81-(1-S-carbethoxye3"C4"phenyIphenyU-propyL)"S~ * 5 alanine, benzyl M-C1-S-carbethoxy«3-C4-fluoropheny13-propy1)-01 methyl^S-tyrosine, benzyl W-(1-S-ca r bet hoxy-[4-floor opheny 13-pr opy L) "0-ethy I S-tyrosine, benzyl ^-G-S-carbethoxy-S^E^methoxypheny I3~propy 1)-0ethyL"S"tyros ine, benzyl N^O^S-earbethoxy^S-C^-ch loropheny 13-pr opy 1)-0ethyl^S-tyrosine, benzyl 81·"<1-S-carbetboxy"3-C2-roethyIpheny13-propyl)"ΟΙ 5 ethyl"S"tyrosine, benzyl W-(1-S-carbetho^y-3-C3,4-dimethoxyphenyI3-propyDO-ethyl-S"tyrosine, benzyl W-G-S-carbethoxybutyI)-0-ethyl-S-tyrosine, benzyl N-(1-S-carbethoxy-3-eyeLohexyIpropyI)-0-ethyl-S20 tyrosine, benzyl N-(1-S-carbethoxy3-C4~methoxyphenyl3-propyl)-0methyl-S-tyrosine, benzyl N-(1-3-carbethoxy-3-C4-chLorophenyI□—propy 1)-0methyI-S-tyrosine, benzyl N-G-S*carbethoxy-3-C2-methylpheny 13-pr opy 1)-0methyl-S-tyrosine, benzyl N-G-S-carbethoxy-3-C3,4-dimethoxypheriy 13-propy I)· 0-methyL-S-tyrosine, benzyl N-G-S-carbeth'oxybutyD-O-methy I-S-tyrosine, benzyL N-d-S-carbethoxy-3-Ccyclohexy 13-propy U-0-me thy lS-tyro$ine, terto-butyl N -d-S-carbethoxy-3-C4-fluoropheny13-propyl)N £-benzyloxycarbonyl-S-lysine, tert.-butyl N* ed-S-carbethoxy-3-C4-methoxyphenyL3-propyL>N £-be.nzyloxycarbonyl-S-lysine, tert®"butyl N & "d-S~carbethoxy-3-C4-chlorophenyL3-propy1)i N -benzyloxycarbonyl-S-lysine, terto-butyl N -d~S-carbethoxy-3-C4-methylpheny 13-propy ΟΝ e -benzyloxycarbonyl-S-lysine, W ed-S~carbethoxy-3-C3,4-dimethoxypheny13-propyt, tertff-butyl N £ -benzyloxycarbonyL-S-lysine, ethyl M -(1-S-carbobenzyLoxyethyL)-N -tert.-butoxycarCl t* bonyl-S-Lysine, ethyl N^-d-S-carbo-tert®-butoxyethyl)-N£ -benzyloxycarbonyl-S-lysine, tert.-butyl N* -d-S-carbethoxybutyl)-N £ -benzyLoxycarbony l-S-lysine, tert.-butyl .-d-S-carbethoxy-3-Ccyc LohexyLJ-propyUN e -benzyloxycarbonyL-S- lysine, ethyl N & -d-S-carbo-tert.-butoxy-2-C4-ethoxyphenyl3ethyl)-Ne -benzyloxycarbonyl-S-lysine, ethyl N -d-S-carbo-tert®-butoxy-2-C4-methoxypheny13E"benzyloxycarbonyL-S-Lysine.
The invention also relates to compounds of the formulae II and III in which n = 2, R denotes (C-, to C^)-alkyl, (C2 to C^)-alkenyI, -alkyl, Λ R1 e(C-j-C^^ethyI, (Cy-C-jg)" aroylatnino-(C^"C^)-alkyI, (0^C^)"aIkoxycarbonylami no*’ (C^C^) "a Iky I, (C^CjgJ'-ary1"" alkoxycarbonylamino-U^-C^^aLkyl, (0^ to C-j2)-aryl which can be mono- to trisubstituted by (C-j to C^J-alkyl, (C-j to 0^)alkoxy, hydroxyl, halogen, nitro, amino, (C-j to C^J-alkylamino, di-CC-j to C^)ualkylamino and/or methylenedioxy, or 3-indolyl, denotes hydrogen or CCg to C^-alkyl, which can be optionally substituted by amino, (C^ to C^)" acylamino or benzoylamino, (¢3 to C^)-alkenyl, (¢3 to C^-cyeloalkyl, (C5 to C^J-cycloalkenyl, (Cj to Cy )" cy c I oa I ky I-( C to C^^alkyl, (C^ to C-)2^" aryl or partially hydrogenated aryl, either of which can be substituted by (C-j to C^J-atkyl, (C-j or C2>"alkoxy or halogen, (¢4 to C-j2>-ary 1-(03 to C^J-alkyl or (Cy to C-j-j )« ar oy I-)" a Iky I, either 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, 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 ( Cg-0 -j 2 a ry 1’ (C 1 to C^J-alkyl.
Those compounds of the formula II and III are *2 preferred in which n 2, R denotes methyl, cyclohexyl, tert®-butoxycarbonyI™ amino-(C-pC^J-a Ikyl, benzy Loxycarbony I am ino-(CpC^) alkyl or phenyl which can be monosubstituted or disubstituted by phenyl, (C-j or C2>-alkyl, 2)-alkoxy, hydroxyl, fluorine, chlorine, bromine, amino, (C-j to C4)-a Iky Lamino, di-(C-j to Chalky I am ino, nitro and/or methylenedioxy or, in the case of methoxy, trisubstituted, R^ denotes hydrogen, 2 or CjJ-alkyl, (C2 or CjJ-alkenyl, the protected side chain of lysine, 4-methoxybenzyI, 4-ethoxybenzyI, phenethyl, 4aminobutyl or benzoylmethyI, r2 and R3 each denote hydrogen, (¢^ to C4)-alkyl or ben2yI, but in particular compounds of the formulae II and III in which n 2, R denotes methyl, terta-butoxycarbonylaminoethyl, ben2yloxycarbonylaminoethyI, phenyl or fluorineand/or chlorine-monosubstituted or -disubstituted phenyl, denotes ethyL, phenyl, the acylated side chain of lysine or the O-(CpC^)-alkylated side chain of tyrosine, and Rc and R each denote hydrogen, methyl, ethyl, tert·butyl or benzylB The trifluoromethanesulfonates of the fornulae XX (VI) and XXI are obtained by reacting α-hydroxycarboxyIic acid derivatives of the formulae VI or VXX II in which n, R, r\ R^ and R^ have the abovementioned mean ings, with a trifluoromethanesulfonating agent, such as, for example, trifluoromethanesulfonic anhydride or trifluoromethanesulfonyl chloride, in an inert solvent.
To trap the acid formed in the course of the reaction, if 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 K2CO3, Nd2C03 or NaHC03>, Na2s04 or organic bases, such as, for example, triethylamine or pyridineu The base can be used in a stoichiometric amount or in excess..
Suitable solvents are those uhich cannot react with the trifluoromethanesulfonating agent and the trifluoromethanesulfonic acid derivatives. Examples of such solvents are methylene chloride, chloroform, carbon tetra chloride, 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 methylene chloride, chloroform or carbon tetrachloride, and trifluoromethanesulfonic anhydride is reacted with the α-hydroxycarboxylic acid derivative at temperatures between -80°C and room temperature in the presence of pyridine- Trifluoromethanesulfonic 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 formulae II or IIIThe trifLuoromethanesulfonic acid derivatives of the formulae IX or III react smoothly uith amino esters of the formulae IV or V respectively to give compounds of the formula I- To trap the resulting trifluoromethanesulfonic acid, the reaction is preferably carried out in the presence of one equivalent of a base which cannot react with compounds of the formulae II or HI. Tertiary amines, such as triethylamine or pyridine, have been found to be advantageous- Ever, the amino acid derivatives themselves can serve as acid acceptors. Also suitable are inorganic salts, such as, for example, NazCt^, K2CO3, NaHCO-j or NazSO^ The reaction is carried out in an aprotic polar solvent or non-polar solvent- Examples of suitable solvents are methylene chloride, chloroform, carbon tetrachloride, dimethylformamide, ethyl acetate,’dimethoxycthane, hexane, ether and tetrahydrofuranThe reaction temperature is within the range between -80 and +150°Cft- The range from -20 to +80°C has been found to be particularly advantageous® The working-up is very simple® The solvent is washed with wafer to remove the salts formed® The organic solution is dried and then concentrated, in the course of which the compounds of the formula X are obtained in a pure form and can, if required, be highly purified by general purification methods, such as, for exanple, inter alia, filtration or chromatography over silica gel® If optically pure compounds of the formulae II or III are used in the reaction, the substitution of the trifLuoromethanesulfonie 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 products® A diastereoisomeric mixture is obtained by, for example, reacting racemic compounds of the formula II or III with optically pure amino acid derivatives, or vice versa, or reacting racemic compounds of the formula II or III uith racemic amino acid derivatives® The resulting 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, by virtue of the high yields and purity, offers great advantages over existing processes® The compounds of the formulae 1, II and III are valuable intermediates in preparing compounds of the formula VIII NH - CH (VIII) CO 1 2 OR * in which n, R, and R2 have the abovementioned meanings and R^ represents the radical of a monocyclic, bicyclic or tricyclic imino-a-carboxylic acid bonded to the rest of the molecule via the imino nitrogen atom® 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 52,870® They ere also the subject- -matter of German Patent Applications P 32 26 768,1, p 31 51 690.4, P 32 496®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.
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 VUI arc obtained by reacting the corresponding α-iminocarboxylic acids R^-H or derivatives thereof with compounds of 'the formula I by known amido formation methods of peptide chemistry® The following examples will illustrate the process of the invention without limiting the invention to the substances mentioned as representative therein. θ 21 Example Is Benzyl fil-(1-Scarbethoxy"3-pheny IpropyI)S~a Ianine a) Ethyl 2-R^S^tri fluoromethanesutfonyloxy-4-phenyH butyrate A solution of 2-37 g (30 mmoles) of dry pyridine and 9-73 g (34-5 mmoles) of trifluoromethanesulfonic anhydride in 8 ml of dry methylene chloride is added dropwise with stirring at 0°C in the course of one hour to a solution of 6-24 g (30 mmoles) of ethyl 2-R,S-*hydroxy^ 4-phenylbutyrate in 30 ml of dry methylene chlorideWhen the dropwise addition is complete, the mixture is stirred at 0°C for a further 15 minuteso The precipitate is then filtered off with suction, and the methylene chloride solution is washed twice with water, is dried over MgSO^ and is concentratedYield: 8-6 g = 84-3% of theory» Rfs 0-37 (SiOg; cyclohexane/ethyl acetate (6:1); molybdatophosphoric acid 15% in methanol)» b) Benzyl N-(1-S-carbethoxy-3-phenyIpropyI)-S-alanine 4*4 g (24068 mmoles) of benzyl S-alanine and 2O5 g (24-7 mmoles) of triethylamine are dissolved in 20 ml of dry methylene chloride- 8-4 g of ethyl 2-R,$-trifluoromethanesulfonyloxy-4-phenyIbutyrate of Exatnple Ia in 10 ml of dry methylene chloride are added dropwise with stirring 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 NagSOj^, and is concentrated in vacuoYield: 9-0 g (99% of theory) of benzyl U-(1-R,S-carbethoxy22 3pheny Ipropy L)‘3S-aLanine mixed diastereoisomers Of of diastereoisomer 2s 0®12 Rf of diastereoisomer Ils 0®07 (Si02; eyelohexane/ethyI acetate (9:1); molybdatophosphoric acid 15% in methanol)® 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)n The slow isomer has the S,S-configuration® Example II: Benzyl N-(1-S~carbethoxy-3-phenyIpropyt)«S~atanine a) Ethyl 2-R-trifIuoromethanesulfonyLoxy*4-phenylbutyrate The compound is obtained from ethyl 2-R-hydroxy·3 4-phenylbutyrate and tri f luoromethancsulfonic anhydride analogously to the preparation method of Example la® The ethyl ester is prepared analogously to Biquard's method in Annales de Chinle 20, 147 (1933), from 2-R-hydroxy-4-t phenylbutyric acid (Biquard, 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 (Si02; eyelohexane/ethyl acetate (9:1))« Yield: 90% of theory® b) Benzyl M- (1-S*carbethoxy-3-phenylpropyl)-S-alanine Ethyl 2-R-trifLuoromethanesulfonyloxy-4-phenylbutyrate is reacted with benzyl S-alanine analogously to Example 2b® The configuration in the butyric acid moiety inverts to give the desired S,S-compound in a 92% yield» Rf: 0®07 (SiO2, eyeLohexane/ethyl acetate (9:1))« «- 23 cThe configuration was determined as follows. Xf the compounds obtained in Example Xb (diastereoisotner XX) and Example XXb are hydrogenated in ethanol by means of 10% palladium on carbon, this gives in each case W-O-Scarbethoxy-3-phenyIpropyU-S-alanine having an angle of optical rotation of //^¾ = ^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, CII3OH). The 270"HHz ^H-NWR shows no contamination by the R,S-diastereoi somer* Example Ills Benzyl W*(1-R,S-carbethoxy-3-phenyI propyl)-0-ethyl-Styrosine 6.1 g of ethyl 2-RzS-trifluoromethanesuIfonyloxy4-phenylbutyrate of Example Ia are reacted analogously to Example lb with 5.4 g of benzyl O-ethyl-S-tyrosine and 1.8 g of triethylamine in methylene chloride.
Yield: 95% of theory of a 1:1 diastereoisomeric mixture of S,S and R,S-compounds.
Rf of diastereoisotner 1: 0.46 (SiO^; cyclohcxane/diisopropyl ether (1:1)) Rf of diastereoisotner XX: 0.39 (SiO^; cyclohexane/di isopropyl ether (1:1)).
The tuo diastereoisomers can be easily separated from each other over silica gel using cyclohexane/diisopropyl ether (8:2). The slow diastereoisotner has the S,Sconf i gurat ion*. - 24 Example XV Benzyl W-(1S-carbethoxy-3-phenyIpropyL)"0~ethytyrosine The compound is obtained by reacting ethyl 2-Rtrifluoromethanesulfonyloxy-4-phenyIbutyrate of ExampLe Ila, benzyl 0-ethyl^S-tyrosine and triethylamine in dry methylene chloride analogously to Example Xb, Yield: 95% of theory® RfS 0o39 (Si02; cyclohexane/diisopropyI ether (1s1))o Example V BenzyL N-(1-RzS-carbethoxy-3-phenyIpropy1)-0-methyl-Styrosine The diastereoisomeric mixture is obtained by reacting ethyl 2-R,Strifluoromethanesutfonyloxy-4-phenylbutyrate of Example la with benzyL O-methyL-S-tyrosine and triethylamine in methylene chloride analogously to ExampLe lb® Yield: 92% of theory of diastereoisomeric mixture Rf of diastereoisomer I: 0,23 (SiO^; cyclohexane/ethyI acetate (9:1)?® Rf of diastereoisomer II: 0„19 (SiOg; cyclohexane/ethyI acetate (9:1))® The diastereoisomers can be easily separated from each other over silica gel using cyclohexane/diisopropyt ether. The slow isomer has the S,S-configuration® Example VI Benzyl N-(1-S-carbethoxy-3-phenyIpropyI)-0-methyl-Styrosine The compound is obtained by reacting ethyl 2-RtrifluoromethanesuIfonyloxy-4-phenyIbutyrate of Example - 25 Iia with benzyl 0-methyl-S-tyrosine and triethylamine in methylene chloride analogously to Example IbQ Yields 94% of theory RfS 0o19 (SiO^p cyclohexane/ethyl acetate <9s1))0 Example VII Tert.-butyl H "(1-R,S-carbethoxy-5-phenyIpropyl)-N_ cc c benzyloxycarbonyl-S"lysine The diastereoisomerlc mixture is obtained by reacting ethyl 2"R,$"trifluororaethanesulfonyloxy-4-phenylbutyrate of Example la with tert®-butyl -benzyloxycarbonyl-S-lysine and triethylamine in methylene chloride analogously to Example lb.
Yields 95% of theory m/e: 526 Example VI ΐ I Tert.-butyl N -G-S-carbethoxy-3-pheny Ipropy I)-N a . c benzyloxycarbonyl-S-lysine The compound is obtained by reacting ethyl 2-Rtrifluoromethanesulfonyloxy-4-phenylbutyratc of Exanple Ila with tert.-butyl H -benzyloxycarbonyl-S-lysine and triethylamine in methylene chloride analogously to Example lb® Yield: 82% of theory m/e: S26 Example IX Benzyl N-G*RzS-carbethoxy-3-pheny t propy I)-S-a I an ine a) Benzyl 2-R-trifluoromethanesulfonyloxypropionate The compound is obtained by reacting benzyl Dlactate with trifluoromethanesuIfonic anhydride and pyridine in methylene chloride analogously to Example XaYield; 95% of theory0 b) Benzyl N-O-R,S-carbethoxy-3-phenylpropyl)-Salanine The diastereoisomeric mixture is obtained by reacting benzyl 2-R~trifluoromethar.esutf ony loxypropionate -» with ethyl R,$-homophenylalanine and triethylamine in methylene chloride analogously to Example Ibo « Yield: 90% of theory Rf of diastereoisotner X: 0-12 (Si02; cyclohexane/ethyl acetate (9:1)) Rf of diastereoisomer IX: 0-07 (SiOj>; cyclohexane/ethyl acetate ¢9:1)),, The physical data agree with those of the diastereoisomers of Example Ib„ Example X Benzyl N-(1-S-carbethoxy-3-phenyIpropyI)-S-alanine The compound is obtained by reacting benzyl 2-RtrifLuoromethane sulfonyloxypropionate with ethyl S-homophenylalanine and triethylamine in carbon tetrachloride analogously to Example lbYield: 98% of theory Rf: 0-07 (SiOgi cyclohexane/ethyl acetate (9:1))The physical data agree with those of the compound of Example lib.
Exatuple XI Ethyl N -(1-S-carbobenzyloxyethyl)-N -tert--butoxycarff Ε , bonyl-S-lys ine The pompoundis obtained by reacting benzyl 2-Rtrifluoromethanesulfonyloxypropionate of Example Xxa with ethyl - tert®-butoxycarbonyl-S-Lysine and triethylamine in methylene chloride analogously to Example lb® Yield; 82% of theory m/e: 436 Example XII Benzyl N-<1-R,S-carbethoxy-3-phenylpropyI)-R"alanine The diastereoisomeric mixture is obtained by reacting benzyl i-R^S^trifluoromethanesulfonyLoxybutyrate with benzyl R-alanine and triethylamine in methylene chloride analogously to Example Xb and by reacting benzyl 2" S-trifluoromethanesulfonyloxylactate and ethyl R,S-homophenylalanine analogously to Example Xb® Yield; 92% of theory Rf of diastereoisomer I: 0.13 (Si02; eyelohexane/ethyl acetate (9:1)) Rf of diastereoisomer II: 0.07 (Si02; eyelohexane/ethyI acetate (9:1))® Example XIII Benzyl N~(1-S-carbethoxy-3-phenylpropyL)-R-alanine The compound is obtained by reacting benzyl 2-Strifluoromethanesulfonyloxypropionate, prepared from benzyl L-lactate, trifluoromethanesulfonic anhydride and pyridine in methylene chloride analogously to Example Ia, with ethyl S-homophenylalanine and triethylamine in methylene chloride analogously to ExampLe lb.
Yield: 95% of theory Rf.: O.OS (SiO2; eye lohexane/ethy I acetate (9:1>)o Example XIV Ethyl -O-S-carboxy-tert.-butoxyethyl)*N£ -benzyloxycarbony l-S-lys ine The compound is obtained by reacting tert.-butyl 2-R-trifluoromethanesuLfonyloxypropionate and ethyl N benzyloxycarbo-nyl-S-lysine and triethylamine in methylene chloride analogously to Example lb.
The following triflates are prepared by the abovementioned methods from the corresponding 2-hydroxycarboxy lates which are used in the R or S or R,S-form (preferabLy the R and R,S-forms): ethyl 2-R,S-trifLuoromethanesuIfonyLoxy-4-(4-fluoropheny 1)butyrate, ethyl 2-R-t rifluoromethanesuIfonyloxy-4-(4-fluorophenyI)butyrate, ethyl 2-R,S-trifluoromethanesuIfonyLoxy-4-(4-methoxypheny 1)butyrate, ethyl 2-R-trif LuoromethanesuIfonyloxy-4-(4-methoxypheny1)butyrate, ethyl 2-R,S-trif luoromethanesuIfonyloxy-4-(4-chloropheny1)butyrate, ethyl 2-R-t rifLuoromethanesulfonyloxy-4-(4-chlorophenyl)butyrate, ethyl 2-R,S-trifluoromsthanesulfonyloxy-4-(3,4-dich lorophenyl) -butyrate, ethyl 2-R-trifluoromethanesuIfonyloxy-4-(3,4-di chlorophenyl) -butyrate, ethyl 2-R,S-trifIuoromethane*uIionyIoxy-4-(2-methyIpheny1)butyrate. ethyl 2OTR-tr1fLuoromethanesuLfonyLoxy-4=(2-methylphenyI butyrate, ethyl 2-R,S-trIfluoromethanesuLfonyLoxy-4-(3,4-dimethoxye phenyO-butyrate, ethyl 2-R-trifluoromethanesulfonylo«y-4-(3,4-dimethoxypheny l>-buty rate, ethyt 2-R,S"trifluoromethanesulfonyloxy-4-<4-phenyIphenyl) butyrate, ethyl 2-R-t r if luoromet hanesu If ony loxy-4- (4-ph eny I pheny D'butyrate, ethyl 2-R,$-trifluoromethanesuIfonyloxybutyrate, ethyl 2-RtrifLuoromethanesuIfonyloxybutyrate, ethyl 2~R,S~trifluoromethanesuIfonyloxy-4-cyclohexylbutyrate, ethyl 2-R-trifluoromethanesuIfonyLoxy-4-cyclohexyIbutyrate, ethyl 2-R,S-trifluoromethanesuIfonyLoxy-3- The 2-*R,S-hydroxycarboxylates required for preparing the triflates are obtained by reducing the corresponding α-keto esters with Raney 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 with optically active amines or amino esters and fractional crystallization or by esterification with optically active * z alcohols, such as, for example, menthol, and separating the esters by column chromatography or by fractional crystallization. The esterification to the optically active 2-hydroxycarboxylates is effected by the conventional esterification methods.
The 2-trifluoromethanesulfonyloxycarboxylates described above are reacted with the corresponding amino esters analogously to the method given in Example lb or IXb to give the following compounds: benzyl N- (1-S"carbethoxy-3-C4-fluorophenyl3-propy1)-Salan i ne, benzyL N- (1-S-carbethoxy-3-C4~methoxypheny13-propy I)-Salanine, benzyL N-(1-S-carbethoxy-3-C4«chlorophenyL3-propyl)-Salanine, benzyL N-(1-S-carbethoxy-3-L2-methy Ipheny 13-p ropy I) -Salanine, benzyl N-<1-S-carbethoxy-3-C3,4-dimethoxypheny13-pr opy1)S-alanine, benzyl N-(1-S-carbethoxybutyl)-S-alanine, benzyl N-(1-S-c a rbethoxy-3-cyc LohexyIp ropyl)-S-aLanine, benzyl N-(1-S-carbethoxy-3-C4-phenyIpheny13-p ropy I)-Sa I anine. benzyl M"(1-S-c a rbe tho xy-3-04-·?luorophenyI3~propyl)-0& methyl-S-tyros ine, benzyl M-(1-S®capbeihoxye*3‘-t4-?luoropheny 13-propy 1)-0ethyl-S-tyros1ne, benzyl N-(1-S-c a rbethoxy-3"C4-met hoxypheny 13-propyl)-0ethyl-S-tyrosine, benzyl M-(1carbethoxy-3-C4~aethoxypheny13-propy1)-0methyl-S«tyrosine, benzyl N-(1-S-carbethoxy-3-C2,6-dichIoropheny13-propy1)O-ethyl-S-tyrosine, benzyl N-(1-S-carbethoxy-3^C2,6-dichlorophenyl3~propyl)" Dimethyl-S-tyros ine, benzyl N-(1-S-carbethoxy-3*C2,6-dichloropheny 13-propy 1)S-alanine, benzyl M- G-S-carbethoxy-S-t^chlorophenyU-propy I toothy l*S-tyros ine, benzy I W-(1-S-carbethoxy-3-C4-ch lorophenyl3-propyl)-0methyl-S-tyrosine, benzyl N-(1-carbethoxy-3-C2*methylpheny13-propyI)-D-ethyl S-tyrosine, benzyl N-(1"S-carbethoxy-3-C2-methylphenyl3-propyl)-0methyl-S-tyros ine, benzyl N-(1-S-carbethoxy~3*[3,4-dimethoxypheny13-propy ΟΟ-ethyl-S-tyrosine, benzyl N-(1-S-carbethoxy-3-C3,4-dimethoxypheny13-propyD0-methyL-S-tyrosine, benzyl N-(1-S-carbethoxybutyl)-0-ethyI-S-tyrosine, benzyl N-(1-S-carbethoxybutyl)~C-methyl-S-tyrosine, benzyl N-(1-S-c arbethoxy-3-eyelohexylp ropy I)-0-et hyl-Styrosine, benzyl N-¢1-S-carbethoxy-3-eyelohexyIpropyL)-0-methylS-tyrosine, benzyl N -(1"Scarbethoxye3"[4~methoxypheny13-propyI)™ a W g-tertft~butoxycarbonyL-S- lysine, tertm^butyl M -(1~S-carbethoxy~3-C4-chlorophenyl3~propyθα W -benzyIoxycarbonyl-S-lysine, e benzyL <1-S-carbethoxy-3-C4-chloropheny13*propy1)W tert.-butoxycarbonyl-S-Lys ine, benzyl N&-(1-S~carbethoxy-3-[2,6-dichlorophenyL3-propy ΟΝ e-tert.-butoxycarbonyl-S-lysine, tert.-butyl N -<1-S-carbethoxy-3-C2,6-di chloropheny13α propy I )-Mebenzy loxy carbony l-S-3 Lysine, tert.-butyl N^-(1-S-carbethoxy-3-C2-methyIphenyl3-propyL>He-benzyIoxycarbonyL-S-lysine, benzyl N^-(1-S-carbethoxy-3-t2-methyIpheny13-propy1)Nf-tert.-butoxycarbonyl-S-lysine, benzyl N (1 -S-c a r bet hoxy-3-C3,4-d ime thoxy pheny 13-propy ΟΝ terte-butoxycarbonyl-S-lysine, tert0-butyl N -(1-S-carbethoxy-3-C3z4*dimethoxypheny13propy I)-N^-benzyloxycarbonyl-S-lys ine, tert.-butyl N -G-S-carbethoxybutyD-N -benzy loxy carbony Ια ε S-lysine, benzyl N&- (1-S-cerbethoxybuty D-N^te rt «-but oxy carbony 1S-lysinc, benzyl N -G-S-carbethoxy-3-cyc Lohexy Lpropyl)-N -tertnα t» butoxycarbonyl-S-lysine, tert.-butyl N -G-S-carbethoxy-3-cycIohexyIpropy I)-N α ε benzyloxycarbonyl-S-lysine, ethyl M "(l-S-carbobenzyloxyethy1)-¾ -tert«-butoxycarbonyI ff ε - lys ine, ethyl &3 ^<1-S-carbo-terto-butoxy"2"C4*ethoxyphenyl3"ethyl) N ^benzyloxycarbonyl-S- lysine, ethyl &J (1-S" carbo-terto-bu to xy-2-C4-m< thoxy phenyl) ethylM_-benzyloxycarbonyl-S-lysine® s. ε Xf the corresponding terto-butyl S®amino acid ester educts are used, the terto-butyl ester end products are obtained in place of the benzyl ester products.» Xf the racemic triflate educts are used, the corresponding $-amino acid esters with the R,S-configuration in the N-alfcyl moiety are obtained®

Claims (15)

CLAIMS :
1. - 1 or 2, denotes ethyl, (C-j-C^J-alkoxy carbony I aini no- (C^C 4 )-alkyl, (C 6 *C 12 >-a ry I (C-j-C/, >-a I koxycarbony lami no-(C^-C 4 )-a Ikyl, cyclohexyl or phenyl, which can be mono- or disubstituted by phenyl, (C-j or C 2 >-alkyl, (C-j or C 2 >-alkoxy, hydroxyl, fluorine, chlorine, bromine, amino, (¢^ to c 4>-alkylariino, di-CC-j to C^-atkylamino, nitro and/ or methylenedioxy or, in the case of methoxy, trisubstituted, - 41 R^ denotes hydrogen, (C^ to C^-alkyl, (Cg or Cj)-alkenyI, the optionally protected side chain of lysine, benzyl, 4-methoxybenzyI, 4-ethoxybenzyI, phenethyl, 4-aminobutyl or benzoyImethyI, and 1 r, A process for preparing a compound of the formula I 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* or SR^ radical in which R^ 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 heteroaroinatic radical having 5-10 ring atoms, or an optionally substituted heteroaromatic radical having 5-10 ring atoms, R 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 θ 35
5. ® A compound of the formuLa XX . °' S °2 CK 3 {-OK* (X I> in which 5 R 2 and R 3 denote identical or different radicals selected frcm hydrogen, (C^ to C^)-alkyl and benzyl. 5 for aryl, amino- (0-3-04)“ alkyl, (Cj-C4)“alkanoyla«ino“(Ci-C4>*alkyl9 (Cy-C-jTp-aroy I ami no-(0-3-04)-8 Iky I, (¢-3-04)-^ Ikoxy carbony I ami no-(€-3 ^04)-8 Iky I,
6. « A compound of the formula III - 42 R - in which denotes hydrogen or (C 2 to C^)-alkyl, which can be optionally substituted by amino, (Cf to C$>acylamino or benzoyLamino, (C 2 to C^l-aLkenyI, 3 to Cg)-cycloaIkyL, (C§ to C^-cycloalkenyl, (C3 to C 2 >-cycloalkyl-(Cf to C^-alkyl, (C$ to Cf 2 >aryl or partially hydrogenated aryl, either of which can be substituted by (Cf to C^)-alkyl, (Cf or C 2 )-alkoxy or halogen, (C^ to Cf 2 J-aryl-(C 2 to C^>-alkyl or 2 >-alkyl, either 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 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 aamino acid, and R 3 denotes hydrogen, (Cf to C 6 )-alkyl, (C 2 to C^)-alkenyl or (C$Cf 2 )-aryl-(Cf to C^-alkyl. 6-12 carbon atoms and can be substituted as described above for R, (C^-Cf^J-ary L-(Cf-C^-a Lkyl or (Cy*C^ 3 )-aroyl-(Cf or C 2 )-alkyL either of which can be substituted Like the aryl above, monocyclic or bicyclic optionally partially hydrogenated heteroaryl which has 5-7 or 8-10 ring atoms respectively, of which 1 or 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen atoms, and which can be substituted Like ary*, above, or the side chain of an optionally protected naturally occurring oc -amino acid of the formula R^-CHCNH^)- 39 ri COOH, and are Identical or different and each denotes hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, di - (C-p-C/. )*aIkyIami no- (C^-C^^alkyl, (C <3 Cj alkanoy loxy-(C^-Q >~a Iky I, (C-j-C^)-a lkoxy carbony loxy- 7 C 3 >“aroyloxy-(C.j“C4>*“alky I, (C^-C^jp-ary Loxycarbony loxy- ~a lkyl, aryl having 6-12 carbon atoms, -aryl“(C.j~C4>~alkyl, (Cj-C^^cycloalkyl or CCj-Cg-cycloalkyl-CC^-C/J-alkyI® A process as claimed in claim 1, wherein * 1 or 2, denotes (Cg to C$)-alkyl, (Cg to C^)-alkenyl, (Cj to C^J-cycloalkyl, amino-CC-j-C^J-alkyl, (CgCj)”acylamino-(C^-C4>“alkyI, (CpC^J-a Ikoxycarbonylamino-(C^-C^-alky I, (C$ to Cjg>~aryl(C-j-c^J-a lkoxy-carbony lamino- (C-j-C^-alkyl, (CyC^^-aroylamino-lC-j-C^-alkyl, -aryl which can be mono- to trisubstituted by CC-j to C^J-alkyl, 2 to C^J-alkcnyl, (Cj to Cg)-cycloalkyl, (Cj to CgJ-cycloalkenyl, (Cj to Cy>~cycloaIkyI-(C^ to C^)-alkyl, (C$ to C^ 2 )-aryl or partially hydrogenated aryl, either of which can be substituted by (C^ to C^)-alkyl, 2 >-alkoxy or halogen, 6 -Ci 2 >~ary l-(C-| to C^)-alkyl or (Cy-C-jj )-aroyI- 2 )-alkyI, 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, 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 optionally protected Ct-amino acid, and denote identical or different radicals selected from hydrogen, 2 to C$)-alkenyl and (C^ to C-j 2 )aryl-(C^ to C^J-alkyU A process as claimed in claim 1, wherein 6-12 carbon atoms or an optionally substituted araliphatic radical having 7-16 carbon atoms, process comprises reacting a compound of the formula III ll C-OR 3 II 2 and R^ have the abovementioned meanings, with a compound of the formula IV or V R J 0i-if NH. 0 R (IV) R^O-G-CH-NHp kcH 2 ?„ (V) in which R, r\ R 2 , 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 sg2 O A process as claimed in claim 1, wherein n = 1 or 2, R denotes hydrogen, alkyl having 2-S 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 trisubstituted by (Cf-C4>-alkyI, (C-j-C^J-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C-j-C^J-alkyl amino, di-(C-|-C4>-a lkyl amino, (Cf-C^l-acylamino, preferably (C^-C^J-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy having 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and which can be substituted as described above for aryl, monocyclic or bicyclic heteroaryloxy which has 525 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-16 carbon atoms, an optionally substituted heteroaromatic radical having 5 u 10 ring atoms or the side chain of an optionally protected naturally occurring a* ami no acid, and R^ are identical or different and each 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 4-12 carbon atoms, an optionally substituted aromatic radical having
7. ® A compound as claimed in claim 5, wherein R denotes ethyl, tert n -butoxycarbonylamino-lCf-C^)atkyl, benzyloxycarbonylamino-(Cf-C/ t )-alkyl z cyclohexyl or phenyl which can be mono- or - 43 10 disubstituted by phenyl, (C^ or Cz^-alkyl, (¢^ or CgJ-alkoxy, hydroxyl, fluorine, chlorine, bromine, amino, (C^ to C^-alkylamino, di~(C<| to ¢¢)-31 icy lamino, nitro and/or methylenedioxy or, in the case ot methoxy, trisubstituted, and R 2 denotes hydrogen, (C-j to Q^alkyl or benzyl* 7 or 8-10 ring atoms respectively, of which 1 or 2 ring atoms represent sulfur or oxygen atoms and/or 1 to 4 ring atoms represent nitrogen and which can be substituted as described above
8. A compound as claimed in claim 6, wherein denotes hydrogen, (c 2 or Cj^alkyl, (Cg or Cjl-alhenyl, the protected side chain of lysine, 4-methoxybenzyI, 4-ethoxybenzyI, phenethyl, 4aminobutyl or benzoyImethyl and fP denotes hydrogen, (¢^ to C^)“alkyl or benzyl*
9. * A compound as claimed in claim 5, wherein R denotes phenyl or fluorine- and/or chlorinemono- or disubstituted phenyl and R 2 denotes hydrogen, methyl, ethyL, tert.-butyl or benzyl. IO. A compound as claimed in claim 6, wherein R^ denotes the acylated side chain of lysine or the O-(Ci“C^)-alkylated side chain of tyrosine and denotes hydrogen, methyl, ethyl, tert.-butyl or benzyl*
10. 1/ whenever prepared by a process Claimed in any one of claims 1-4 or 12. 10 n = 2, R denotes (C^ to C^i-alkyl, (Cg to C^)-alkenyl, 3 to C 9 )“cyc loa lky I, CCg-CjJ-acylamino-lC-i” C4>-alkyl, (Cy-CaroyI ami no- (C-j-C^-alky I, (C-j-C^-alkoxycarbonylamino-CCq-C^-alky I, (C$15 c ^ 2 )-ary I-(C^-C^)-alkoxycarbony lamino-lC-j-C^)alkyl, (C5 to C-j 2 ^~ ary( · w ^ ch can be mono ~ to trisubstituted by (C* to C*)-alkyl, (C-j to C^J-alkoxy.hydroxy, halogen, nitro, amino, (C^ to C^-alkylamino, di-(C^ to C^-alky I amino and/ 20 or methylenedioxy, or 3-indolyl, and R 2 denotes hydrogen, (C^ to C 6 )-alkyl, (Cg to C 6 )-alkenyl or (C$ to C^g)-aryl, (C^ to C4)a Ikyl0 10 (C 6 “C-3g)“ary 1-(0^-04)-alkoxy carbony lami no“ (C«|-C4>~alkyl, (¢¢^0 «ig) *ry I- (¢^-04)-8 Iky I ami no“ (€.3-04)alkyl, (0^-04)-8 IkyI ami no-(¢^-04)-a Ikyl, 15 di-(¢.3-04)-0 Iky I ami no-(¢.3-04 )-a Iky I, guanidino-(0^-04)-3 IkyI, imidazolyl, indolyl, (0^-04)-alkyIthio, (C«|-C4)-alkylthio-(Cq“C4>-alkyl, 20 (C^-C-jg)-ary Ithio- (€-3-04)-8 Iky I which can be substituted in the aryl moiety as described above for aryl, (¢4-0-3 2 )-ary I-(0.3-04)-8 Iky Ithio uhich can be substituted in the aryl moiety as 25 described above for aryl, carboxy- (C-j-€4)·^ a I kyl, carboxyl, carbamoyl, carbamoyl-(0-3-04)-8 Iky I, (0 C >-alkoxyearbonyl-(C -C, )-alkyt, 10 R 2 radical having 4-13 carbon atoms, an optionally substituted aromatic radical having 10 R 2
11. B A process for preparing a compound of the formula It or III, uhich comprises reacting an a-hydroxycarboxylic acid derivative of the formula VI or VIX - 44 (VXX) R - CH ’ - /CHj/» OH COR ll. (VX) OH
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. 12 3 in which n, R, Η , R and R have the meanings given in Claim 1, with a trifluoromethanesulfonating agent in the 5 presence or absence of a base.
13. A compound of the formula I given and defined in Claim
14. A compound of the formula II given and defined in Claim 5, which is any one of those specifically hereinbefore mentioned. 14 1 A - 38 tkoxycarbony I, (C^-C^ 2 )”aryloxy-(C^-C^J-alkyl which can be substituted in the aryl moiety as described above for aryl or (C^-C^l-ary L^CC-j-C^J-alkoxy which can be substituted in the aryl moiety as described above for aryl, denotes hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, cycloalkenyl having 5-9 carbon atoms, (C^-C^-cyctoalkyl-CC^-C^-alkyl, (Cj-CoJ-cycloalkenyl-CC-i-C^J-alkyl, optionally partially hydrogenated aryl which has
15. 15. A compound of the formula III given and defined in Claim 6, which is any one of those specifically hereinbefore mentioned.
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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