TRIFLUOROMETHANESULFONATES AND A PROCESS FOR THEIR PREPARATION

TRIFLUOROMETHANESULFONATES, ET LEUR PREPARATION

English Abstract

ABSTRACT
The invention relates to trifluoromethane-
sulfonates of the formulae II and III
<IMG>
(II)
<IMG>
(III)
in which
n = 2,
R represents (C1 to C6-alkyl, (C2 to C6)-alkenyl,
(C3 to C9)-cycloalkyl, (C2-C5)-acylamino-(C1-
C4)-alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl,
(C1-C4)-alkoxycarbonylamino-(C1-C4)-alkyl, (C6-
C12)-aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4)-
alkyl, (C6 to C12)-aryl which can be monosubstituted,
dissubstrituted or trisubstituted by one or more of (C1-C4)-alkyl,
(C1 to C4)-alkoxyhydroxy, halogen, nitro, amino,
(C1 to C4)-alkylamino, di-(C1 to C4)-alkylamino and
methylenedioxy, or 3-indolyl,

R1 represents hydrogen or (C2 to C6)-alkyl, which can
be optionally substituted by amino, (C1 to C6)-acyl-
amino or benzoylamino, (C2 to C6)-alkenyl, (C3 to
C9)-cycloalkyl, (C5 to C9)-cycloalkenyl, (C3 to
C7)-cycloalkyl-(C1 to C4)-alkyl, (C6 to C12)-
aryl or partially hydrogenated aryl, either of
which can be substituted by (C1 to C4)-alkyl, (C1
or C2)-alkoxy or halogen, (C6 to C12)-aryl-(C2 to
C4)-alkyl or (C7-C13)-aroyl-(C1-C12)-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 which can
be thienyl, benzo-[b]thienyl, furyl, pyranyl,
benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl,
purinyl, quinolizinyl, isoquinolinyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl,
pteridinyl, oxazolyl, isoxazolyl, thiazolyl or
isothiazolyl, or a side chain of a naturally
occurring protected .alpha.-amino acid,
R2 represents hydrogen, (C1 to C6)-alkyl, (C2 to
C6)-alkenyl or (C6 to C12)-aryl- (C1 to C4)-
alkyl, and
R3 represents hydrogen, (C1 to C6)-alkyl, (C2 to
(C6)-alkenyl or (C6-C12)-aryl-(C1 to C4)-alkyl

and processes for their preparation. The compounds of
the formula II and III are intermediates for the preparation
of inhibitors of the angiotensin converting enzyme.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the formula
<IMG>
wherein Ra denotes hydrogen or (C2 to C6)-alkyl, which can
be optionally substituted by amino, (C1 to C6)-acyl-
amino or benzoylamino, (C2 to C6)-alkenyl, (C3 to
C9)-cycloalkyl, (C5 to C9)-cycloalkenyl, (C3 to
C7)-cycloalkyl-(C1 to C4)-alkyl, (C6 to 12)-
aryl or partially hydrogenated aryl, either of
which can be substituted by (C1 to C4)-alkyl, (C1
or C2)-alkoxy or halogen, (C6 to C12)-aryl-(C2 to
C4)-alkyl or (C7-C13)-aroyl-(C1-C2)-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 atom and/or 1
to 4 ring atoms represent nitrogen atoms which can
be thienyl, benzo-[b]thienyl, furyl, pyranyl,
benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl,
purinyl, quinolizinyl, isoquinolinyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl,
pteridinyl, oxazolyl, isoxazolyl, thiazolyl or
isothiazolyl, or a side chain of a naturally
occurring protected .alpha.-amino acid, or R-CH2CH2 wherein
34

R denotes (C1 to C6)-alkyl, (C2 to C6)-alkenyl,
(C3 to C9)-cycloalkyl, (C2-C5)-acylamino-(C1-
C4)-alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl,
(C1-C4)-alkoxycarbonylamino(C1-C4)-alkyl, (C6-
C12)-aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4)-
alkyl, (C6 to C12)-aryl which can be monosubstituted,
disubstituted or trisubstituted by one or more of (C1 to C4)-alkyl,
(C1 to C4)-alkoxyhydroxy, halogen, nitro, amino,
(C1 to C4)-alkylamino, di-(C1 to C4)-alky(amino and
methylenedioxy, or 3-indolyl, and
Rb denotes hydrogen, (C1 to C6)-alkyl, (C2 to
C6)-alkenyl or (C6 to C12)-aryl- (C1 to C4)-
alkyl.
2. A compound of the formula II,
<IMG>
(II)
in which
n = 2
R denotes (C1 to C6)-alkyl, (C2 to C6)-alkenyl,
(C3 to C9)-cycloalkyl, (C2-C5)-acylamino-(C1-
C4)-alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl,
(C1-C4)-alkoxycarbonylamino-(C1-C4)-alkyl, (C6-
C12)-aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4)-
alkyl, (C6 to C12)-aryl which can be monosubstituted,
disubstituted or trisubstituted by one or more of (C1 to C4)-alkyl,
(C1 to C4)-alkoxyhydroxy, halogen, nitro, amino,
(C1 to C4)-alkylamino, di-(C1 to C4)-alkylamino and
methylenedioxy, or 3-indolyl, and

R2 denotes hydrogen, (C1 to C6)-alkyl, (C2 to
C6)-alkenyl or (C6 to C12)-aryl, (C1 to C4)-
alkyl.
3. A compound of the formula III,
<IMG>
(III)
in which
R1 denotes hydrogen or (C2 to C6)-alkyl, which can
be optionally substituted by amino, (C1 to C6)-acyl-
amino or benzoylamino, (C2 to C6)-alkenyl, (C3 to
C9)-cycloalkyl, (C5 to C9)-cycloalkenyl, (C3 to
C7)-cycloalkyl-(C1 to C4)-alkyl, (C6 to C12)-
aryl or partially hydrogenated aryl, either of
which can be substituted by (C1 to C4)-alkyl, (C1
or C2)-alkoxy or halogen, (C6 to C12)-aryl-(C2 to
C4)-alkyl or (C7-C13)-aroyl-(C1-C2)-alkyl,
either of which can be substituted in the aryl
radical as defined above, a monocyclic or bicyclic
heterocyclic radical having 5 to 7 of 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 which can
be thienyl, benzo-[b]thienyl, furyl, pyranyl,
benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl,
purinyl, quinolizinyl, isoquinolinyl, phthalazinyl,
36

naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl,
pteridinyl, oxazolyl, isoxazolyl, thiazolyl or
isothiazolyl, or a side chain of a naturally
occurring protected .alpha.-amino acid, and
R3 represents hydrogen, (C1 to C6)-alkyl, (C2 to
(C6)-alkenyl or (C6-C12)-aryl-(C1 to C4)-alkyl
4. A compound of the formula II, as defined in claim 2,
wherein
R denotes ethyl, tert.-butoxycarbonylamino-(C1-C4)-
alkyl, benzyloxycarbonylamino-(C1-C4)-alkyl, cyclo-
hexyl or phenyl which can be monosubstituted or
disubstituted by one or more of phenyl, (C1 or C2)-
alkyl, (C1 or C2)-alkoxy, hydroxyl, fluorine,
chlorine, bromine, amino, (C1 to C4)-alkylamino,
di-(C1 to C4)-alkylamino, nitro and methylenedioxy or,
is trisubstituted by methoxy, and
R2 denotes hydrogen, (C1 to C4)-alkyl or benzyl,
5. A compound of the formula III, as defined in claim 3,
wherein
R1 denotes hydrogen, (C2 or C3)-alkyl, (C2 or
C3)-alkenyl, benzyloxycarbonyl, t.-butyloxycarbonyl or
(C1-C6)-alkanoyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl,
4-aminobutyl or benzoylmethyl and R3 denotes hydrogen,
(C1 to C4 )-alkyl or benzyl.
37

6. A compound of the formula II, as defined in claim 2 ,
wherein
R denotes one or more of phenyl or fluorine- and
chlorine-monosubstituted or -disubstituted phenyl and
R denotes hydrogen, methyl, ethyl, tert.-butyl or
benzyl.
7, A compound of the formula III, as defined in claim 3,
wherein
R1 denotes the acylated side chain of lysine or the
O-(C1-C6)-alkylated side chain of tyrosine and
R3 denotes hydrogen, methyl, ethyl, tert.-butyl or benzyl.
8. A compound of the formula II, as defined in claim 2,
in which n = 2, R denotes phenyl and R2 denotes ethyl,
9. A process for preparing compounds of the formulae
II or III
<IMG>
(II)
in which
n = 2,
38

R denotes (C1 to C6)-alkyl, (C2 to C6)-alkenyl,
(C3 to C9)-cycloalkyl, (C2-C5)-acylamino-(C1-
C4)-alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl,
(C1-C4,)-alkoxycarbonylamino-(C1-C4)-alkyl, (C6-
C12)-aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4)-
alkyl, (C6 to C12)-aryl which can be monosubstituted,
disubstituted or tristituted by one or more of (C1 to C4)-alky1,
(C1 to C4)-alkoxyhydroxy, halogen, nitro, amino,
(C1 to C4)-alkylamino, di-(C1 to C4)-alkylamino and
methylenedioxy, or 3-indolyl, and
R2 denotes hydrogen, (C1 to C6)-alkyl, (C2 to
C6)-alkenyl or (C6 to C12)-aryl, (C1 to C4)-
alkyl,
<IMG>
(III)
39

in which
R1 denotes hydrogen or (C2 to C6)-alkyl, which can
be optionally substituted by amino, (C1 to C6)-acyl-
amino or benzoylamino, (C2 to C6)-alkenyl, (C3 to
C9)-cycloalkyl, (C5 to C9)-cycloalkenyl, (C3 to
C7)-cycloalkyl-(C1 to C4)-alkyl, (C6 to C12)-
aryl or partially hydrogenated aryl, either of
which can be substituted by (C1 to C4)-alkyl, (C1
or C2)-alkoxy or halogen, (C6 to C12)-aryl-(C2 to
C4)-alkyl or (C7-C13)-aroyl-(C1-C2)-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 which can
be thienyl, benzo-[b]thienyl, furyl, pyranyl,
benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,
pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl,
purinyl, quinolizinyl, isoquinolinyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl,
pteridinyl, oxazolyl, isoxazolyl, thiazolyl or
isothiazolyl, or a side chain of a naturally
occurring protected .alpha.-amino acid, and
R3 represents hydrogen, (C1 to C6)-alkyl, (C2 to
(C6)-alkenyl or (C6-Cl2)-aryl-(C1 to C4)-alkyl

which comprises reacting .alpha.-hydroxycarboxylic acid
derivatives of the formulae VI or VII
(VI)
<IMG>
(VII)
<IMG>
in which n, R, R1, R2 and R3 have the abovementioned mean
ings, with a trifluoromethanesulfonating agent in the
presence or absence of a base.
10. The process as claimed in claim 9, wherein
R denotes ethyl, tert.-butoxycarbonylamino-(C1-C4)-
alkyl, benzyloxycarbonylamino-(C1-C4)-alkyl, cyclo-
hexyl or phenyl which can be monosubstituted or
disubstituted by one or more of phenyl, (C1 or C2)-
alkyl; (C1 or C2)-alkoxy, hydroxyl, fluorine,
chlorine, bromine, amino, (C1 to C4)-alkylamino,
di-(C1 to C4)-alkylamino, nitro and methylenedioxy or,
is trisubstituted by methoxy, and
R2 denotes hydrogen, (C1 to C4)-alkyl or benzyl.
41

11. The process as claimed in claim 9, wherein
R1 denotes hydrogen, (C2 or C3)-alkyl, (C2 or
C3)-alkenyl, benzyloxycarbonyl, t.-butyloxycarbonyl or
(C1-C6)-alkanoyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl,
4-aminobutyl or benzoylmethyl and
R3 denotes hydrogen, (C1 to C4)-alkyl or benzyl.
12. The process as claimed in claim 9, wherein
R denotes one or more of phenyl or fluorine- and
chlorine-monosubstituted or -disubstituted phenyl and
R2 denotes hydrogen, methyl, ethyl, tert.-butyl or
benzyl.
13. The process as claimed in claim 9, wherein
R1 denotes the acylated side chain of lysine or the
O-(C1-C6)-alkylated side chain of tyrosine and
R3 denotes hydrogen, methyl, ethyl, tert.-butyl or
benzyl.
14. The process as claimed in claim 9, wherein a compound
of the formula II, as defined in claim 9, is prepared in
which n = 2, R denotes phenyl and R2 denotes ethyl which
comprises reacting a compound of the formula VI as defined
in claim 9 in which n, R and R2 have the above-mentioned
meanings, with a trifluoromethanesulfonating agent in the
presence or absence of a base.
42

Description

This Application is a Divisional of Canadi~n Patent
Application Serial Number 446,562, Filed February 1, 1984
The invention relates to a process for preparing
compounds of the formula I
R3o-c-c~ H- I H-/CH2~n~R
O ~ C=O
in ~hich oR2
S n = 1 or 2,
R denotes hydrogen,
an optionally subst;tuted aliphatic radical hav.ir7g
2-8 carbon atoms~
an optionally subst;tuted cycloaliphat;c rad;cal
hav;ng 3-9 carbon atoms, an opt;onally subst;tuted
aromatic radicaL having 6-12 carbon atoms,
an oR4 or SR4 radical ;n which
R4 represents an opt;onally subst;tuted aliphatic
rad;cal hav;ng 1-4 carbon atoms, an opt;onally
substituted aromatic rad;cal having 6-12 carbon
atoms or an optionally substituted heteroaromatic
r~ad;cal hav;ng 5-10 r;ng atoms, or
an opt;onally substituted heteroaromatic radical
hav;ng 5-10 ring atorns,
20 R1 denotes hydrogen,
an optionally substituted aliphatic radical having
1-6 carbon atoms,
an optionally substituted cycloal;phatic radical
having 3-? carbon atoms,
an opt;onally subst;tuted cycloaliphatic-aliphatic

33
-- 3 --
radical having 4-13 carbon atoms,
an opt;onally substituted aromat;c radical having
6-12 carbon atoms,
an opt;onally substituted araliphatic radical
having 7-16 carbon atoms,
an opt;onally substituted heteroaromatic radical
hav;ng 5-10 ring atoms or
the side chain of an optionally protected naturally
occurring a-amino acid,
10 R2 and R3 are identical or different and denote
hydrogen,
an optionally substituted aliphatic radical having
1-6 carbon atoms,
an opt;onally substituted cycloaliphatic radical
hav;ng 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
* O-S02CF3 * O~S02-CF
R-~CH27n CH ~ C-OR2 ~1 c~ ~ 3
O
(II) (III)
.

~,
;n ~rh;ch n, R, R1~ R~ and R3 have the abovement;oned mean-
ings, with compounds of the forrnulae IV or V
R3o-c-cH-NH2 ~ ~C~12`~n ~ R
(IV) ~V)
in ~hich R, R1, R2, R3 and n have the abovementioned mean-
;ngs, ;f desired el;rriinating es~er groups by hydrolysisor hydrogenolysis or, if des;red, esterifying free carboxyl
groups in a manner known per se.
The literature (for example U.S. Patent 4,350,704
and European Patents A 49,605 and 46~953) discloses pro-
cesses for preparing compounds of the formula I by react-
ing a-halogenocarboxylates or the corresponding tosyloxy
or mesyloxy compounds w;th amino esters. The reaction
requires an elevated react;on temperature. The yields
are low because of the drastic reaction conditions, bhich
lead to side reactionsc In many cases it is necessary
to catalyze the reaction w;th silver ions~ as, for example,
~hen a-halogeno compounds are reacted, and the catalys;s
can ;mprove the yield, but is more expensive~ What is more,
racemic products are obtained ~hen opt;cally active ~-
halcgenocarboxylates are used.
In a further process, to which~ inter alia, CanadianPatent Application 414,858 relates, ~-keto esters
are reacted with amino esters and the resultin~ imino
compounds are reduced with var;ous reducing agents~ If
sod;um cyanoborohydride is used, the working-up becomes
technically complicated because of thc formation of hydro-

~6~
-- 5 --cyanic acid. Even if optically pure amino esters are
used 3S start;ng materials, this process only produces
d;astereoisomer;c mixtures which are, if desired, separ-
ated in~o tlleir components in a technically complicated
~ay.
The process o~ the invention is free of the dis~
advantages listed.
In a preferred embodiment the compounds prepared
have the formula I ;n which
ln 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 monosubstituted, disubstituted or tri-
substituted by (C1-C4)-alkyl, (C1-C~)-alkoxy,
hydroxyl, halogen, nitro, amino, aminomethyl,
(C1-C4~-alkylamino, di-(C1-C4)-alkylamino,.
2û (C1-C4)-acylamino, preferably (C1-C4)-alkanoyl-
amino, methylenedioxy, carboxyl, cyano and/or
sulfamoyl,
alkoxy having 1-4 carbon atoms,
aryloxy ~hich has 6-12 carbon atoms
and ~hich can be substituted as described above for
aryl,
monocyclic or bicyclic heteroaryloxy ~hich has 5-
7 or 8~10 ring atoms respectively of which 1 cr 2
ring atoms represent sulfur or oxygen atoms anci/or

~2~
1 to 4 r;ng atoms represent n;trogen
and which can be subst;tuted as descr;bed above
for aryl~
amino-tC1-C4)-alkyl,
tC1 C4) alkanoylamino-(C1-C4)~alkYl,
- tC7~C13~~arYlamin~(C1~C4)-aLkyl"
(c1-c4)-alkoxycarbonylamino-(c1-c4)-alkyl~
t~-C12)-aryl-(C1-C4)-alkoxycarbonylamino~
(c1-c4)-alkYl
(c6-c12)-aryl-(c1-c4)-alkylamino-(c1-c4)
alkyl,
(C1-C4)-alkylamino-(C1-C4)-alkyl,
di~(Cl~C4)~aLkYlaminO~tc1~c4)-alkyl"
guanidino-(C1-C4)-alkyl"
inlidazolyl, indolyl,
~C1-C4)-alkylthio,
(C1-C4)-alkylthio-(C1-C4)-alkyl,
6 C12)-aryLthio-(c1-c4)-alkyl
~hich can be substituted in the aryl moiety as
described above for aryl,
(C6 C12)-aryl-(c1-c4)-alkylthio
which can be substituted in the aryl moiety as
described above for aryl,
carboxy-(C1-C4)-alkyl,
carboxyl~ carbamoyl,
carbamoyl-(C1 C4)-alkyl,
(C1-C~,)-alkoxycarbonyl-(C1-C4)-alkyl,
(C1-C~ alkoxycarbollyl)
(C1-C12) arylo.xy-(C1 C4)-alkyl
which can be substituted ;n the aryl mGiety as

-- 7 --
described above for aryl or
tC6~C12)~arYl~(Cl~C~)-alkoxy
~hich can be substituted in the aryl moiety as
described above for aryl,
5 R1 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,
tC3-C9)-cycloalkyl-~C1-C4)-alkyl,
~C5-C9)-cycloalkenyl-~C1-C4)-alkyl,
optionally partially hydrogenated aryl which has
6-12 carbon atoms and can be substituted as des-
t5 cribed above for R~
6-C12)-arYl~c1 c4)-alkyl or (C7-C13)-aroyl-
(C1 or Cz)-alkyl
either of ~hich can be substituted like aryl
above,
. monocyclic or bicyclic optionally partially hydro-
genated heteroaryl which has 5-7 or 8-10 ring atoms
respectively, of which 1 or 2 ring atoms rep-
resent sulfur or oxygen atoms and/or 1 to 4 ring
atoms represent nitrogen atoms,
and which can be substituted like aryl above, or
the side chain of an optionally protected naturally
occurring ~-amino acid of the formula Rl CH(~IHz)-
COOH,
R2 and R3 are identical or different and denote

-- 8
hydrogen,
aLkyl hav;ng 1-6 carbon atoms,
alkenyl having 2-6 carbon atoms,
di (C1-C4)-alkylamino-(C1-C4)-alkyl,
(C1~C5)-alkanoyloxy-~C1-C~)-alkyl,
(c1-c6)-alkoxycarbonyloxy-(c1-c4)-alkyl~
(C7-C13)-aroyloxy-(C1-C4)~alkyl,
(c6-c12)-aryloxycarbonyloxy-(c1-c/~) alkyl,
aryl having 6-12 carbon atoms,
(C6~C12)~arYl-(c1-c4)-alkyl~
(C3-C9)-cycloalkyl or
(C3-C9-cycloalkyl-(C1-C4)-alkyl.
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 C6)-alkyl, (C2 to C6)-alkenyl,
(C3 to C9)-cycloalkyl, am;nc-(C1-C4)-alkyl, (C2-
Cs)-acylam;no-(c1-c4)~alkyl~ (C7-C13)-arYlan
(C1-C4)-alkyl, (C1-C4~-alkoxycarbonylam;no-
~C1-C4)-alkyl~ (C6 to C12)-aryl-(C1 C4) alkoxy
carbonylamino-(c1-c4)-alkyl~ (C6 to C12) ary
which can be monosubstituted, disubstituted or
trisubstituted by-(C1 to C4)-alkyl, (C1 to C4)-
alkoxy, hydroxyl, halogen, n;tro, am;no, (C1 to
C4)-alkylam;no, d;-(C1-C4)-alkylamino and/or rneth~l-
ened;oxy, or 3-;ndolyl, in part;cul~r ethy!,
cyclohexyl, tert.-butoxycarbonylam;no-(C1-C4)-alkyl~
benzoyloxycarbonylam;no-(C1-C4)-alkyl or phenyl

- ~2~ 3
_ 9 _
which can be monosubs~;tu~ed or disubstituted by
phenyl (C1 to C2)-alkyl, (C1 or C2)-alkoxy, hydroxy,
fluorine, chlor;ne, brom;ne, am;no, (C1 to C4)-
alkylamino, di-~C1 to C4)-alkylaminoO nitro and/or meth~l-
enedioxy or, in the case of methoxy, trisubsti-
tuted,
R1 denotes hydrogen or (C1 to C6)~-alkyl which
can be optionally substituted by amino, tC1 to C6)-
acylamino or benzoylamino, (C2 to C6)-alkenyl,
1n tC3 to C9)-cycloalkyl, (C5 to C9)-cycloalkenyl,
(C3 to C7)-cycloalkyl-(C1 to C4)-alkyl, (C6 to
C12)-aryl or partially hydrogenated aryl, either
of which can be substituted by (C1 to C4)-alkyl,
(C1 or C2)-alkoxy or halogen, (C6-C12)-aryl-(C1 to
c4)-alkyl or (C7-C13)-arYl-(c1 C2) alkyl~ b
of which can be substituted in the aryl radiczl
as defined above~ a monocyclic or bicyclic hetero-
cyclic radical having 5 to 7 or 8 to 10 ring atoms
respectively, of wh;ch 1 or 2 ring atoms rep-
resent sulfur or oxygen atoms and/or 1 to 4 ring
atorns represent nitrogen atoms, or a side chain
of a naturally occurring optionally protected
a -amino acid, but in particular hydrogen, (C1 ~o
C3)-alkyl, ~C2 or C3)-alkenyl, the optionally
protected side chain of lysine, benzyl, 4-methoxy-
benzyl, 4-ethoxybenzyl, phenethyl, 4-am;nobutyl
or benzoylmethyl, and
R2 and R3 denote identical or different radicals fronl among
hydrogen, ~C1 to C6) alkyl,(C2 to C6)-alkenyl and ~C6 to

- 10 -
C12)-aryl~(C1 to C4)-alkyl, but in particular
hydrogen, ~C1 to C4)-alkyl or benzylO
Here, and below, aryl is preferably to be under-
stood as mean;ng opt;onally substituted phenyL, biphenylyl
or naphthyl. This also applies to radicals derived from
aryl, such as aryloxy or arylthio. Aroyl is to be under-
stood as meaning in particular benzoyl. Aliphatic radi-
cals can be straight-chain or branched.
A monocyclic or bicyclic heterocyclic radical
ha~ing 5 to 7 or 8 to 1û ring atoms respectively, of which
1 or 2 ring atoms represent sulfur or oxygen atoms and/or
o~ which 1 to 4 r;ng atoms represent nitrogen atoms, is
to be understood as meaning, for example, thienyl, benzo-
~b]th;enyl; furyl, pyranyl, ben_ofuryl, pyrrolyl, imidaz-
olyl, pyrazolyl, pyridyl, pyrimid,nyl, pyridazinyl, inda-
~olyl, isoindolyl, indolyl, purinyl, quinolizinyl, iso-
quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,
quinazolyl~ c;nnolinyl, pteridinyl, oxazolyl, isoxâzolyl,
thiazolyl or isothiazolyl. These radicals can also have
been partially or completely hydrogenated.
Naturally occurring a-amino acids are described,
for example, in Houben-Weyl, Methoden der Organischen
Chemie CMethods of Organic Chemistry~, Volumes X~'~1 and
XY/2.
If R1 represents a side chain of a protected nat-
urally occurring ~-amino acid, such as, for example, pro-
tected ser, thr, asp, asn, glu, gln~ arg, lys, hyl, cys~
orn, cit, tyr, trp, his or hyp, the protective groups
are preferably those customary in peptide chemistry (cf.

~Z~7~3
Houben-Weylr Volumes XV/1 and XV/2). In the case ~ihere
R1 denotes the protected lys;ne s;de cha;n, the kn~in
amino-protective groups, but in particular Z, BoC or (C1-
C6)-alkanoyl. The O-protective groups for tyrosine can
preferably be ~C1-C6)-alkyl, but in particular methyl or
ethyl.
The process of the invention~ depending on ~ihich
ch;ral starting compounds have been used, can produce
compounds of the formula I in wh;ch the chirality center
formed in this SN2 react;on is ;n the S- or R-conf;gur-
ation or racemic.
The react;on ~hich takes place in the process of
the invent;on proceeds stereochem;cally unamb;guously.
This fact is also conf;rmed by studies of the stereochemi
cal course of the reaction of a-trifluorome~hanesulfonyl-
oxycarboxylates w;th opt;cally act;ve am;nes (Effenberoer
ee al., Angew. Chem. 95 ~1983) 50).
The follo~i;ng chart illustrates the stereochem;-
cal course of the react;on ;n the process of the ;nvent;on:
a b
Start;ns compounds R302C-c~H-NH-cH-~c2H2 n
.
(R)-IY ~ (R)-II ~ ( a~ b)
( X ) - I V + ( S ) ~ ( a ~ b )
(S)-IY + tR)-II ~ (Sa ~ Sb) - I
(S)-IV + (S)-II ~ (Sa ~ Rb)
(R)~ (R)-V ~ (Sa, Rb) - I
(R)-III + (S)-V > ( a ' b)
(S)-III + (R~-V --~ ( a ~ b)
(S)~ f (S) -V --~> (Ra ~ Sb) - I

- 12 -
The followin~ compounds can be obtained particu-
larly advantageously by the process of the invention.
Benzyl N-(1-S-carbethoxy-3-phenylpropyl)L-S-a!anine,
benzyl N-(1-R-carbethoxy-3-phenylpropyl)-S-alanine,
benzyl N~ S~carbethoxy-3-phenyLpropyl)-R-alanine,
benzyl N-~1-R-carbethoxy-3-phenylpropyl)-~-alanine,
benzyl N-~1-R,S-carbethoxy-3-phenylpropyl)-S-alanine,
- . benzyl N~ R,S-carbethoxy-3-phenylpropyl)-R-alanine,
benzyl N-(1-S-carbethoxy-3-phenylpropyl)-R,S-alanine,
benzyl N-~1-R-carbethoxy-3-phenylpropyl)-R,S-alanine~
benzyl N-(1-R,S-carbethoxy-3-phenylpropyl)-R,S-alanine,
tert.-butyl Na -(1~S-carbethoxy-3-phenylpropyl)-N -benz~l-
oxycarbonyl-S-lys;ne,
benzyl Na -t1-S-carbethoxy-3 phenylpropyl)-N -tert.-
butoxycarbonyl-S-lys;ne,
benzyl N-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-
tyros;ne,
benzyl N-(1-S-carbethoxy-3-phenylpropyl)-0-methyl-S-
tyros;ne,
benzyl N~ S-carbethoxy-3-phenylpropyl)-S-tyrosine,
benzyl N-~1-S-carbethoxy-3-C4-fluorophenyl]-propyl)~S-
alan;ne,
benzyl N-~1-S-carbethoxy-3-C4-methoxypher,yl]-propyl)-S-
alan;ne,
2S benzyl N-~1-S-carbethoxy-3-~4-chlorophenyl~-propyl)-S-
alanine,
benzyl N-(1-S-carbethoxy-3-C2-methylphenyl] propyl)-S-
alanine,
benzyl h (1-S-carbethoxy 3-C3,4-dimethoxyphenyl] propyl)~

~26~3
- 13 -
S-alanine,
benzyl N-(1-S-carbethoxybutyl)-S-alanine,
benzyl N-~1-S-carbethoxy-3-Ccyclohexyl]-propyl)-S-alanine,
benzyl N-~1-S-carbethoxy-3-C4-phenylphenyl]-propyl)-S-
alan;ne,benzyl N-t1-S-carbethoxy-3-C4-fluorophenyl]-propyl)-0
methyl-S-tyrosine~
benzyl N-(1-S-carbethoxy-C4-~luorophenyl]-propyl)-0-ethyl-
S-tyrosine,
benzyl N-t1-S-carbethoxy-3-C4-methoxyphenyl]-propyl) O-
ethyl-S-tyrosine,
benzyl N-(1-S-carbethoxy-3-C4 chlorophenyl]-prcpyl)-O-
ethyl-S-tyros;ne,
benzyl N-(~-S-carbethoxy-3-C2-methylphenyl]-propyl)-0-
ethyl-S-tyrosine,
benzyl N-(1-S-carbethoxy-3-C3,4-dimethoxyphenyl]-propyl)-
O-ethyl-S-tyrosine,
benzyl N-(1-S-carbethoxybutyl)-O-ethyl-S-tyrosine,
benzyl N-(1-S-carbethoxy-3-cyclohexylpropyl)-0-ethyl-S-
tyrosine,benzyl N-(1-S-carbethoxy-3-C4-methoxyphenyl]-propyl)-0-
methyl~S-tyrosine,
benzyl N-(1-S-carbethoxy-3-C4-chlorophenyl]-propyl)-0-
~ methyl-S-tyrosine,
benzyl N-~1-S-carbethoxy-3-C~-methylphenyl]-propyl~-O-
methyl-S-tyrosine,
benzyl N-(1-S-carbethoxy-3-C3,4-dimethoxyphenyl]-propyl)-
O-methyl-S-tyros;ne,
benzyl N-(1-S-carbethoxybutyl)-O-methyl-S-tyrosine,

s~
- 14 -
benzyl N~ S-carbethoxy-3-Ccyclohexyl]-propyl)-0-methyl-
S-tyros;ne,
tert.~butyl N a-(1-S-carbethoxy-3-C4-~luorophenyl]-propyl)-
N -benzyloxycarbonyl-S-lysine,
S tertO^butyl Na o(1-S-carbethoxy-3-C4-methoxyphenyl]-propyl)~
N E -benzyloxycarbonyl-S-lysine,
tert.-butyl N ~(1-S carbethoxy-3-C4-chlorophenyl]-propyl)-
N E -berlzyloxycarbonyl-S-lys;ne,
tert.-butyl N a -(1-S-carbethoxy-3-C4-methylphenyl]-propyl)-
N~ -benzyloxycarbonyl S-lysine,
N a ~1-S-carbethoxy-3-C3,4-dimethoxyphenyl]-propyl,
tert.-butyl N E benzyloxycarbonyl-S-lys;ne~
ethyl N a -(1-S-carbobenzyloxyethyl)-N~ -tert.-butoxycar-
bonyl~S-lys,ne,
ethyl N a -(1-S-carbo-tert.-butoxyethyl)-N~ -benzyloxycar-
bonyl-S-lys;ne~
tert.-butyl Na -(1-S-carbethoxybutyl)-N -ben~yloxycar-
bonyl-S-lys;ne,
tert.-butyl Na ~ S-carbethoxy-3-Ccyclohexyl]-propyl)-
2û N F -benzyloxycarbonyl-S-lys;ne,
ethyl Na -(1-S-carbo-tert.-butoxy-2-C4-ethoxyphenyl~-
ethyl)-N E -benzyloxycarbonyl-S-lysine,
ethyl N -(1-S-carbo-tert.-butoxy-2--C4-methoxyphenyl]-
ethyl)-NE.-benzyloxycarbonyl-S-lysine~
The invention also relates to compounds o~ the
formulae II and III in which
n ~ 2,
R denotes tC1 to C6)-alkyl, (C2 to C6)-alkenyl,
(C3 to C9~-cycloalkyl, amino(C1-C4)-alkyl~

- 15 -
(C2-C5)-acylamino-(C1-C4) alkyl, (C7-C1g~-
aroylamino-(C1-Cb~-alkyl, (C1-C4)-alkoxycarbonyl
amino tC1 c4~-alkYl~ (C6~c12)-arY~-(c1-c~)-
alkoxycarbonylam;no (C1-C4~-alkyl~ ~Cb to C12)-aryl
~hich can be monosubstituted, disubstituted or
tr;substituted by (C1 to C4)~alkyl, (C1 to C~)-
alkoxy~ hydroxyl, halogen, nitro~ am;no, (C1 to
C~-alkylamino, di-(C1 to C4)-alkylamino and/or
methylenedioxy, or 3-;ndoLyl,
10 R1 denotes hydrogen or (C2 to C6)-alkyl, ~hich
can be optionally substituted by amino~ (C1 to C6)-
acylamino or benzoyl3mino, tC2 to C6)-alkenyl, (C3
to Cg)-cycloalkyl, (C5 to C9)-cycloalkenyl, (C3 to
C7)-cycloalkyl-(C1 to C4)-alkyl, (C6 to C12)-
aryl or partially hydrogenated aryl, either of
which can be substituted by (C1 to C4)~alkyl, (C1 or
C2)-alkoxy or halogen, (C6 to C12)-aryl-(C2 to
C4)-alkyl or (C7 to C13)-arYl-tC1 C2) alkYl~
either of ~hich can be substituted in the ary(
radical as defined above, a monocyclic or bicyclic
heterocyclic radical having 5 to 7 or ~ to 10 ring
atoms respectively, of which 1 or 2 ring atoms
represent sulfur or oxygen atoms andlor 1 to 4
ring atoms represent nitrogen atoms, or a side
chain of a naturally occurring, protected a-amino
acid and
R2 and R3 denote hydrogen (C1 to C6)-alkyl, (C2-to
C6)-alkenyl or (C6-C12)-arYl-(c1 to C4) aL y
Those compounds of the formula II and III are
'

- 16 -
preferred ;n which
n = 2,
R denotes methyl, cyclohexyl, tert~-butoxycarbonyl-
amino-(C1 C4)-alkyl, benzyloxycarbonylamino-(C1-C~,)-
alkyl or phenyl ~Jhich can be monosubstituted or
disubstituted by phenyl, (C1 or C2)-alkyl, (C1 or
C2)-alkoxy, hydroxyl, fluor;ne, chlor;ne~ bromine,
am;no, (C1 to C4)-alkylamino, di-tC1 to C4~-
alkylamino, nitro and/or me~ylenedioxv or, in the
case of methoxy, trisubstituted,
R1 denotes hydrogen, (C2 or C3) alkyl, (C2 or
C3)-alkenyl, the protected side chain of lysine~
4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-
aminobutyl or benzoylmethyl,
15 R2 and R3 d~note hydrogen, (C1 to C4)-alkyl or
benzyl,
but in particular compounds of the formulae II and III in
~hich
n 2,
20 R denotes methyl, tert.-butoxycarbonylaminoethyl,
benzyloxycarbonylaminoethyl, phenyl or fluorine-
and~or chlorine-monosubstituted or -disubstituted
phenyl,
R1 denotes ethyl, phenyl, the acylated side chain
of lysine or the 0-tC1-C6)-alkylated side chain
of tyrosine, and
R2 and R3 denote hydrogen, methyl, ethyl, tert.-
bu~yl or benzyl.
The trifluoromethanesulfonates of the forrl~ulae II
,

and III are obtained by reacting ~-hydroxycarboxylic
acid derivatives of the formulae VI or VII
R ~ ~CH2/n ~ CH \ OH 2 (VI)
COR
R1 _ C~'./
C-oR3 (V I I )
o
in wh;ch n~ R, R1, R2 and R3 have the abovementioned mean-
ings, with a trifluoromethanesulfonating 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 re-
action, it is advantageous to carry out the reaction inthe presence of a base. Suitable for this purpose are
inorganic salts, such as carbonates (for example K2C03,
Na2C03 or NaHC03)~ Na2S04 or organic bases, such as, for
example, triethylamine or pyridine~ The base can be used
in a sto;chiometr;c amount or in excess.
Suitable solvents are those which cannot react
with the trifluoromethanesulfonating agent and the tri
fluoromethanesulfonic acid derivatives~ Examples of such
solvents are methylene chlor;de, chloroform, carbon tetra~
chloride, other halogenated hydrocarbons and even hydro-
carbons, such as, for example, hexane. The react;on can
be carried out within the t~mperature range from -80C to
~80C. The reaction is particularly advantageous in

- 18 -
methylene chloride, chloroform or carbon tetrachloride,
and trifluorome~hanesulfon;c anhydride is reacted ~ith
the -hydroxycarboxylic acid derivative at temperatures
bet~een -80C and room temperature in the presence of
pyridine. Trifluoromethanesulfon;c anhydr;de can also be
used ;n excess.
If optically active compounds of the formulae VI
or VII are used, the configuration on the chiral carbon
atom is preserved on convers;on ;nto compounds of the
formulae II or III.
The trifluoromethanesulfon;c acid derivatives of
the formulae II or III react smoothly w;th am;no esters
of the formulae IV or V respectively to give compounds
of the formula I. To trap the result;ng tr;fluoromethane-
sulfon;c ac;d, the react;on is preferably carried out ;nthe presence of one equivalent of a base wh;ch cannot re-
act w;th compounds of the formulae II or III. Tert;ary
amines`, such as tr;ethylam;ne or pyr;dine, have been founcl
to be advantageous. ~ven the amino acid der;vatives ther,1-
selves can serve as ac;d acceptors. Also su;table areinGrganic salts, such as, for example, NazCO3, K2C03,
NaHC03 or NazSO4.
The react;on ;s carried out in an aprot;c polar
~ solvent or non-polar solvent. Examples of su;table sol-
vents are me.hylene chlor;de, chloroform, carbon tetra-
chloride, dimethylformamide, ethyl acetate, d;methoxy-
ethane, hexane, ether and tetrahydrofuran~
The reaction temperature is w;thin the range be-
tween -80 and +150C. The range from -20 to +80GC has

- 19 -
been found to be particularly advantageous.
The working-up ;s very simple. The solvent is
uashed ~;th water to remove the salts formed. The organ;c
solution is dried and then concen~rated, ;n the course
of ~hich the compounds of the formula I are obtained in
a pure form and can, if required, be highly purified by
general purification methods, such as~ for example, inter
alia, f;ltration or chromatography over s;l;ca gel.
If opt;cally pure compounds of the formulae II
1~ or III are used ;n ~he reaction, the subst;tut;on of the
tr;fluoromethanesulfon;c ac;d ester by the am;no acid
derivat;ve of the formula IV or V ;s accompanied by in~ -
vers;on of conf;gurationr Optically pure start;ng mat-
erials, w;thout racemization, g;ve optically pure end
prooucts. A d;astereoiso0er;c m;xture ;s obta;ned by,
for example, react;ng racem;c compounds of the formula
II or III w;th opt;cally pure am;no acid der;vat;ves, or
v;ce versa, or reacting racem;c compounds of the formula
II or III w;th racem;c am;no ac;d der;vat;ves. The re-
sulting d;astereo;somers can be separated by generallycustomary separat;ng methods, such as, for example, ;nter
alia~ fractional crystallization of the salts or column
chromatography over silica gel. Even if one of the start-
~ ing components is racemic, the process of the invention,
by virtue of the h;gh y;elds and pur;ty, offers great
advantages over existing processes.
The compounds of the formulae I, II and III are
valuable intermediates in preparing compounds oF the for-
mula VIII

33
-- -- 20 --
R4
C ~ CH - Nl~ - CH ~ ~CH~7n - 8
~ tVIII)
O R CO
OR
in ~h;ch n, R, R1 and R~ have the abovementioned meanings
and R4 represents the radical of a monocyclic, bicyclic
or tricyclic imino-a-carboxylic acid bonded to ~he rest
of the molecule via the imino nitrogen atom. Compounds
of the formula VIII are known, for example, from U.S. Patents
4,350,704;4,344,949; 4,374,847; European Patent A 50,800, European
Patent A 31,741, European Patent A 51,0Z0~ European Pat-
ent A 49,658, European Patent A 49,605, European Patent
A 29,488, European Patent A 46,953 and European Patent
A 52,870. They are also the subject-matter of Canadian
Patent Applications 414,858, 418,453, 424,127, 424,488,
424,770, 432,274, 441,040, 443,407 and 443,559.
The compounds of the formula VIII are inhib;tors
of th~ angiotensin converting enzyme (ACE) and can be
used for controlL;ng hypertension of d;fferent etiolog,es.
Compounds of the formula VIII are obtained by
reacting the corresponding a-iminocarboxylic ac;ds R4-H
or derivatives thereof with compounds of the formula I by
kno\~n amide formation methods of peptide che~istry.
The follow;ng examples will illustrate the process
of the invention without l;miting the invent;on to ~he
substances mentioned as representative therein.
,

- 21 ~
Example I:
aenzyl N-~1-S-carbethoxy-3-phenylpropyl)-S-alan;ne
a) E~hyl 2-R,S-trifluoromethanesulfonyloxy-4 phenyl-
butyrate
S A solution of 2.37 9 (30 mmoles) of dry pyridine
and 9.73 9 (34.5 mmoles) of trif!uoromethanesulfonic an-
hydride in 8 ml of dry methylene chloride is added drop-
wise with stirring at ûC in the course of one hour to
a solution of 6.24 9 (30 mmoles) of ethyl 2-R,S hydroxy-
4-phenylbutyrate in 30 ml of dry methylene chloride.
When the dropwise addition is complete, the mixture is
stirred at 0C for a further 15 minutes. The precipil_ -
ate is then filtered off with suction, and the methylene
chloride solution is washed twice ~ith water, is dried
over ~gS04 and is concentrated.
Yield: 8.6 9 = 84.3% of theory.
Rf: 0.37 (SiO2; cyclohexane/ethyl acetate (4:1); molyb-
datophosphoric acid 15% in methanol).
b) Benzyl N~ S-carbethoxy-3-phenylpropyl)-S-alanine
4.4 9 (24.6~ mmoles) of benzyl S-alanine and 2.5 9
(24.7 mmoles) of triethylamine are dissolved in 20 ml of
dry methylene chloride. 8.4 9 of ethyl 2-R,S-trifluoro-
methanesulfonyloxy-4-phenylbutyrate of Example 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 Na2S04, and is concentraied in vacuo.
Yield: ~.0 9 (99~ of theory) of benzyl N~ R,S-carbe~hoxy-

- 22 -
3-phenylpropyl)-S alan;ne mixed diastereoisomers
Rf of diastereoisomer l: 0.12
Rf of diastereoisomer II: 0.07
(SiO2; cyclohexane/ethyl acetate (9:1), molybdatophos-
S phoric acid 15~ in methanol).
The t~o diastereoisomers can be easily separated
from each other over silica gel by means of the eluent
mixture of cyclohexane/ethyl acetate (9 1)o
The slow ;somer has the S,S-configurationO
Exampl~
Benzyl N-(1-S-carbethoxy-3-phenylpropyl~-S-alanine
a) Ethyl 2-~-tr;fluoromethanesulfonyloxy-4-phenyl-
butyrate
The compound is obtained fro~ etllyl 2-R-hydroxy-
4-phenylbutyrate and trifluoromethanesulfonic anhydride
analogously to the preparation method of Example Ia. The
ethyl ester is prepared analogously to siquard's me~hod
in Annales de Chimie 20, 147 (1933), from 2-R-hydroxy-4-
phenylbutyric acid tBiquard, Annales de Chimie 20, p3ge
145 (1933)) and absolute ethanol by passing dry hydrogen
chloride gas into the solution heated up on the waterba~ll.
Rf: 0.11 (SiO~; cyclohexane/ethyl acetate (9:1)).
Yield: 90% of theory.
b) Benzyl N-(1-S-carbethoxy-3-phenylpropyl)-S-alanine
- Ethyl 2-R-trifluoromethanesulfonyloxy-4-phenyl-
bu~yrate is reacted with benzyl S-alanine analo~ously to
Example Ib. The configuration in the butyric acid mciety
inverts to give the desired S~S-compound in a 92,. yield.
Rf: 0.07 (SiO2, cyclohexane/ethyl acetate (9:i~).

The configuration was determined as follo~s. If
the compounds obtained ;n Example Ib (diastereo;somer II)
and Example IIb are hydrogenated ;n ethanol by means of
10X palladium on carbon, this gives in each case N~ S-
carbethoxy-3-phenylpropyl)-S-alanine having an angle of
optical rotation of //22D = +28 (c = 1, CH30H). This
value is in good agreement Jith the literature value
(European Patent A 37,231, page 30) of ~31 (c = 1, ~H~OH~o
The 270-MH~ 1H-NMR shows no contamination by the R,S-dia-
stereoisomer.Example III:
Benzyl N-(1-R,S-carbethoxy-3-phenylpropyl)-0-ethyl-S-
tyrosine
6 1 g of ethyl 2-R,S-trifluoromethanesulfonyloxy-
4-phenylb~tyra~e of Example Ia are reacted analogously
to Example Ib ~ith 5.4 9 of benzyl 0-ethyl-S-tyrosine and
1.8 9 of triethylamine in methylene chloride.
Yield: 95X of theory of a 1:1 diastereoisomeric mixture
of S,S and R,S-compounds.
Rf of diastereoisomer I: 0.46 (SiO~; cyclohexane/diiso-
propyl ether (1:1))
Rf of diastereoisomer II: Q.39 (SiO2; cyclohexane/diiso-
propyl ether tl: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-
configuration.

~'$~33
- 24 -
Example IV
Benzyl N (1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosine
The compound is obta;ned by reacting ethyl 2-R~
trifluoromethanesulfonyloxy-4-phenylbutyrate of Example
IIa, benzyl 0-ethyl-S-tyrosine and triethylamine ;n dry
methylene chloride analogously to Example Ib.
Y;eld- 95% of theory.
Rf: 0.39 (SiO2; cyclohexane/diisopropyl ether (1:1)).
Example V
8enzyl N-tl-R,S-carbethoxy-3-phenylpropyl)-0-methyl-S-
tyrosine
The diastereoisomeric mixture is obtained by re-
acting ethyl 2~R,S-trifluoromethanesulfonyloxy 4-phenyl-
butyrate of Example Ia with benzyl 0-methyl~S-tyrosine
and triethylamine in methylene chloride analogously to
Example Ib.
Yield: 92% of theory of diastereoisomeric mixture
Rf of d;astereoisomer I: 0.23 (SiO2; cyclohexane/ethyl
acetate (9:1)).
Rf of diastereoisomer II: 0.19 (SiO2; cyclohexane/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-configuration.
Example VI
Benzyl N-(1-S-carbethoxy-3 phenylpropyl)-0-methyl-S-
tyrosine
The compoulid is obtained by reacting ethyl 2-R-
trifluoromethanesulfonyloxy-4-phenylbutyrate of Example

~2~
- Z5 -
IIa ~rith benzyl O~methyl-S-tyrosine and triethy~amine in
methylene chloride analogously to Example Ib.
Yield: 94~ of theory
Rf: 0.19 (SiO2; cyclohexane/ethyl acetate (9:1)).
Exam~le VII
Tert.-butyl Na ~ R,S-carbethoxy-3-phenylpropyl)-N -
benzyloxycarbonyl-S-lysine
The diastereoisomeric mixture is obtained by re-
acting ethyl 2-R,S-trifluoromethanesulfonyloxy-4-phenyl-
butyrate of Example Ia ~ith tert.-butyl NE -benzyloxy-
carbonyl-S-lysine and triethylamine in me~hylene chloride
analogously to Example Ib.
Yield: 95% of theory
m/e: 526
Exa~ple VI~I
Tert~-butyl N ~ S-carbethoxy-3-phenylpropyl)-N -
benzyloxycarbonyl~S-lysine
The compound is obtained by reacting ethyl Z-R-
trifluoromethanesulfonyloxy-4-phenylbutyrate of Example
IIa with tert.-butyl NE -benzyloxycarbonyl-S-lysine ard
triethylamirle in methylene chloride analogously to Example
Ib.
Yield: 82% of theory
m/e: 520
25 Example IX
Benzyl N-(1 R,S-carbethoxy-3-phenylpropyl)-S-alanine
a) Benzyl 2-R-trifluoromethanesulfonyloxyprop;onate
The compound is obtained by reacting benzyl D~
` lactate wi~h trifluoromethanesulfonic anhydride and pyricline

~2~7~
- 26 -
in methylene cHloride analogously to Exam?le Ia.
Yield: 95% of theory.
b~ Benzyl N-(1-R,S-carbethoxy-3-phenylpropyL~-S-
alanine
The diastereoisoMeric mixture is obtained by re-
acting benzyl 2-R-trifluoromethanesulfonyloxypropionate
~ith ethyl R,S-homophenylalanine and triethylamine in
methylene chloride analogously to Example Ib.
Yield: 90~ of theory
R~ of diastereoisomer I: û.12 (SiO2; cyclohexane/ethyl
acetate (~
Rf of diastereoisomer II: 0.07 (SiO2; cyclohexane/ethyl
acetate (9:1)).
The physical data agree with those of the dias-
1~ tereoisomers OT Example Ib.Example X
Benzyl N-t1-S~carbethoxy-3-phenylpropyl)-S alanine
The compound is obtained by reacting benzyl 2-R-
trifluoromethanesulfonyloxypropionate ~ith ethyl S-homo-
phenylalanine and triethylamine in carbon tetrachlorideanalogously to Example Ib~
Yield: 98% of theory
Rf: 0.07 (SiO2; cyclohexane/ethyl acetate (9:1))~
The physical data agree with those of the compound
of Example IIb.
Example XI
Ethyl Na -(1-S-carbobenzyloxyethyl)-N~ -tert.-butoxycar-
bonyl-S-lysinP
The compound is obtained by reacting benzyl 2-R-

- 27 ~
trifluoromethanesulfonyloxypropionate of Example Ixa with
ethyl N -tert.-butoxycarbonyl-S-lys;ne and trlethylam;ne
;n methylene chloride analogously to Example Ib.
Y;eld: 82% of theory
m/e: 436
Example XII
Benzyl N~t1 R,S-carbethoxy-3-phenylpropyl) 2-alanine
The diastereoisomeric mixture is obtained by re-
acting benzyl 2-R,S-trifluoromethanesulfonylcxybutyrate
~;th benzyl R-alan;ne and triethylamine in methylene chlor-
;de analogously to Example Ib and by reacting benzyl 2-
S-trifluoromethanesulfonyloxylactate and ethyl R,S-homo-
phenylalanine analogously to Example Ib.
Yield: 92~, of theory
Rf of diastereoisomer I: 0.13 (SiO2; cyclohexane/ethyl
acetate (9:1))
Rf of diastereoisomer II: 0.07 (SiO2; cyclohexane/ethyl
acetate (9:1)).
Example XII
Benzyl N-~1-S-carbethoxy-3-phenylpropyl)-R-alanine
The compound is obtained by reacting benzyl 2-S-
tr;fluoromethanesulfonyloxypropionate~ 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 Ib.
Yield: 95~ oi theory
Rf: 0.0~ (SiO2; cyclohexal1e/ethyl acetate t9:1)).

28 -
Example XIV
EthyL Na -~1-S-carboxy-tert.-butoxyethyl~-NE -benzyloxy-
carbonyl-S-lysine
The compound is obtained by reacting tert.-butyl
S 2-R-tr;fluoromethanesulfonyloxypropionate and ethyl N
benzyloxycarbonyl-S-lysine and tr;ethylamine in methylene
chlor;de anaLo~ously to Example ~b.
The follow;ng tr;flates are prepared by the above-
ment;oned methods from the correspond;ng ~-hydroxycarboxyl-
ates which are used in the R or S or R,S-form (preferably
the R and R~S-forms):
ethyl 2-R,S-trifluoromethanesulfonyloxy-4-(4-fluorophenyl)-
butyrate,
ethyl 2-R-trifluoromethanesulfonyloxy-4-(4-fluorophenyl)-
butyrate,ethyl 2-R,S-tr;fluoromethanesulfonyloxy-4-(4-methoxyphenyl)-
butyrate,
ethyl 2-R-trifluoromethanesulfonyloxy-4-(4-me~hoxyphenyl)-
butyrate,
ethyl 2-R~S-trifluoromethanesulfonyloxy-4-(4-chlorophenyl)-
butyrate,
ethyl 2-R-trifluoromethanesulfonyloxy-4-(4-chlorophenyl)-
butyrate,
ethyl 2-R,S-tr;fluoromethanesulfonyloxy-4-(3,4-dichloro-
phenyl)-butyrate,
ethyl 2-R-tr;fluoromethanesulfonyloxy-4-~3,4-d;chloro-
phenyl)-butyrate,
ethyl 2-R,S-trifluoromethanesulfonyloxy-4-~2-methylphenyi)-
butyrate,

~'~d~
- 29 -
ethyl 2-R-trifluoromethanesulfonyloxy-4-(2-methylphenyl)-
butyrate,
ethyl 2-R,S-tr;fluoromethanesulfonyloxy-4-(3,~-dimethoxy-
phenyl)-butyrate,
ethyl 2-R-trifluoromethanesulfonyloxy-4-(3,4-dimethoxy-
phenyl)-butyrate,
ethyl 2-R~S-trifluoromethanesulfonyloxy-4-~4-phenylphenyl)-
butyrate,
ethyl 2-R-tr;fluoromethanesulfonyloxy-4-(4-phenylphenyl)-
butyra~e,ethyl 2~R,S-tr;fluoromethanesulfonyloxybutyrate,
ethyl 2-R-trifluoromethanesulfonyloxybutyrate,
ethyl 2-R,S-trifluoromethanesulfonyloxy-4-cyclohexyl-
butyrate,
ethyl 2~R-trifluoromethanesulfonyloxy-4-cyclohexyL-
butyrate,
ethyl 2-R,S-tr;fluoromei-hanesulfonyloxy~3-(;ndol-3-yl)-
propionate,
ethyl 2-R-tr;fluoromethanesulfonyloxy-3-(;ndol-3-yl)-
prop;onate,
ethyl 2-R,S-trifluoromethanesulfonyloxy-3-(N-trifluoro-
methanesul,onylindol-3~yl)-propionate,
ethyl 2-R-trifluoromethanesulfonyloxy-3-tN-trifluoro-
. methanesulfonylindol-3-yl)-propionate.
The 2-R,S-hydroxycarboxylates required for pre-
par;ng the triflates are obtained by reducing the corres-
ponding a-keto esters with Raney nickel and hydrogen in
ethanol~ In a further method of preparation used, the
corresponding cyanohydrins are acid-hydrolyzed and the

- 30 -
resulting 2-hydroxycarboxyl;c acids are converted into
the ethyl esters by conventional esteri~ication methods.
The racemic 2-hydroxycarboxylic acids are racemic-
ally resolved either via diastereoisomeric salt ~ormation
~ith optically active amines or amino esters and fractional
crystallizatian or by ester;~;cation ~i~h opt;cally act;ve
alcohols, such as, for example, menthol, and separat;ng
the esters by column chromatography or by ~ract;onal crys-
tall;zation. The esterification to the optically active
2-hydroxycarboxylates is effected by the conventional
esterification methods.
The 2-tri~luoromethanesulfonyloxycarboxylates des-
cribed abo~e are reacted with the corresponding amino
esters analogously to the method given in Example Ib or
15 IIb to give the ~ollow;ng compounds:
benzyl N-(1~S-carbethoxy-3-C4-~luorophenyl~-propyl)-S-
alan;ne,
benzyl N-t1-S-carbethoxy-3-C4-methoxyphenyl]-propyl)-S-
alanine,
benzyl N-(1-S-carbethoxy-3-C4-chlorophenyl~-propyl)-S-
alanine,
ben~yl N-(1-S-carbethoxy-3-C2-methylphenyl~-propyL)-S-
alanine,
~ benzyl N-~1-S-carbethoxy-3-C3,4-dimethoxyphenyl~-propyl)-
S-alanine,
benzyl N-t1-S-carbethoxybutyl)-S-alanine,
benzyl N (1-S-carbethoxy-3-cyclohexylpropyl)-S-alanine,
Denzyl N-(l S-carbethoxy-3-C4-phenylphenyl]-propyl)-S
alanine,

- 31 -
benzyl N-(1 S-carbethoxy-3-C4-fluorophenyl~-propyl)-0-
methyl-S-tyrosine,
benzyl N-t1-S-carbethoxy-3-C4-fluorophenyl]-propyl)-0-
ethyl-S-tyrosine,
benzyl N~ S-carbethoxy-3-C4-methoxyphenyl~-propyl)-0-
ethyl-S-tyros;ne,
benzyl N-(1-S-carbethoxy-3-C4-methoxyphenyl]-propyl)-0-
methyl-S-tyrosine,
benzyl N-(1-S-carbethoxy-3-C2,6-d;chlorophenyl]-propyl)-
0-ethyl-S-tyrosine,
benzyL N-tl-S-carbethoxy-3-C2,6-dichlorophenyl]-propyl)-
0-methyL-S-tyrosine,
benzyl N-t1-S-carbe~hoxy-3-C2,6-dichlorophenyl~-propyl)-
S-alanine,
benzyl N-~1-S-carbethoxy-3-C4-chlorophenyl]-propyl)-0-
ethyl-S-tyrosine,
benzyl N~tl-S-carbethoxy-3-C'-chlorophenyl]-propyl)-0-
methyl-S-tyrosine,
benzyl N-(1-carbethoxy-3-C2-methylphenyl]-propyl)-0-ethyl~
S-tyrosine,
benzy`l N-(1-S-carbethoxy-3-C2-methylphenyl]-propyl)-0-
methyl-S-tyrosine,
benzyl N-~1-S-carbethoxy-3-C3,4-dimethoxyphenyl]-propyl)-
0-ethyl-S-tyros;ne,
benzyl N-(1-S-carbethoxy-3-C3,4-dimethoxyphenyl]-propyl)-
0-methyl-S-tyrosine,
benzyl N-(1-S-carbethoxybutyl)-0-ethyl-S-tyrosine,
benzyl N (1-S-carbethoxybutyl)~O~methyl-S-tyrosine,
banzyl N-(1-S-carbethoxy-3-cyclohexylpropyl)-0-eth~l-S~

~7
- 32 -
tyrosine,
benzyl N~ S-carbethoxy-3-cyclohexylpropyl)-0-methyl-
S-tyrosine,
benzyl Na~(1-S~carbethoxy-3-C4-methoxyphenyl]-propyl)~
N-tert.-bu~oxycarbonyl-S-lysine,
tert.-butyl N -(1-S-carbethoxy-3-[4-chlorophenyl]-propyl)-
N -benzyloxycarbonyl-S-lysine,
benzyl Na-(1-S-carbethoxy-3-C4~chlorophenyl]-propyl)-
N-tert~-butoxycarbonyl-S-lysine,
tO benzyl Na-(1-s-carbethoxy-3-~2~6-dichlorophenyl]-propyl)
N~-tert~-butoxycarbonyl-S-lysine,
tert.-butyl N -(1-S-carbethoxy-3-~2,6-dichlorophenyli-
propyl)-N-benzyloxycarbonyl-S-lysine,
tert.-butyl N -(1-S-carbethoxy-3-CZ-methylphenyl]-propyl)
N-benzyloxycarbonyl-S-lysine,
benzyl Na-(1-S-carbethoxy-3-C2-methylphenyl]-propyl)-
N-tert.-butoxycarbonyl-S-lysine,
benzyl N -(1-S-carbethoxy-3-C3,4-dimethoxyphenyli-propyl)-
N-tert.-butoxycarbonyl-S-lysine,
tert.-butyl ~ -(1-S-carbethoxy-3-C3,4-dimethoxyphenyl]-
propyl)-N~-benzyloxycarbonyl-S-lysine,
tert.-butyl N -(1~S-carbethoxybutyl)-Ni-benzyloxycarbonyl-
S-lysine,
benzyl N -(l-S-carbethoxybutyl) N-tert.-butoxycarbonyl-
S-lys;ne,
benzyl Na-(1-S-carbethpxy-3-cyclohexylpropylj-N~-tert.-
butoxycarbonyl-S-lys;ne,
tert.-butyl N -(1-S-carbe~hoxy-3-cyclohexylpropyl)-N
benzyloxycarbonyl-S-lysine~

ethyl Na-(1-S-carbobenzyloxyethyl)-N-tert.-butoxycarbonyl~
S-lys;ne,
ethyl N -(1-S-carbo-tert.-butoxy 2-C4-ethoxyphenyl~-ethyl)-
N-benzyloxycarbonyl-S-lysine,
S ethyl Na t1~S~carbo-tert.-butoxy-2-C4-methoxyphenyl~-
ethyl)-N-benzyloxycarbonyl-S-lysine.
If the corresponding tert.-butyl S-amino acid
éster educts are used, the tert.-butyl ester end products
are obtained in place of the benzyl ester products.
If the racemic triflate educts are used, the cor-
responding S-amino acid esters with the R,S-configuration
in the N-alkyl moiety are obtainedu