Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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