Note: Descriptions are shown in the official language in which they were submitted.
~;~83X~9
HOE 83iF 016 K
- The resolution of racemates of aminoacids via
crystallization of diastereomeric salts is a widely used
process (~euiew: Boyle, Quart. Rev. 25 (1971) 323)~
Usually, N-acylated aminoacids are employed, the salts
with alkaloid bases are crystallized, and the homogeneous
diastereomeric salts are decomposed by, for example,
extraction of the N-acyl--aminoacids from the acidified
solution (J. Amer. Chem. Soc. 71 (1949) 2541, 3251). It
is also possible to carry out the converse process and to
crystallize aminoac;d es.ers or amides w;th optically
active acids (Chem. Ber. 8~ 53) 1524).
Opt;cally active compounds, such as 10-camphor-
sulfonic acid, abietic acid or tartaric ac;d or their 0
der;vat;ves, for example, are used for this purpose. This
procedure is particularly appropriate when the intention
is to employ optically active aminoacid esters as starting
compounds for further syntheses. In this case, it is not
advantageous init;ally to prepare a N-acyl compound and
then undertake resolution of the racemate via salt forma-
tion with op~ically active bases, split off tne acyl radi-
cal and then ester;fy the free am;noac;d.
A process suitable for bicyclic imino-~-carboxylic
esters has not hitherto been described. It emerged from
experim~ntal tests that all customary acids are unsuitable
.
1~83Z49
-- 3 --
for resolution o~ the racemates~ A process is kno~ln, from
European Patent A 37,231~ for octahydroindole-2-carboxylic
acid, using which the N-benzoyl compound of the racemate
can be resolved v;a the salt w;th opt;calLy act;ve -
phenylethylam;ne. However, for the reasons mentioned,this process is uneconomic when the esters are requ;red as
;ntermediates for further syntheses.
It has now been found, surpr;s;ngly, that N-acyl
der;vat;ves of opt;cally active R- or S-aminoaci~c; which
contaîn a phenyl nucleus, such as, for example, S-phenyl-
alan;ne, tyros;ne or .yros;ne 0-der;vat;ves are suitable
as cl1;ral partners for bicyclic imino-~-carboxyl;~ esters.
Th;s ;s because the (S,S) or (R,R)-salts usually precipi-
tate spontaneously from su;table solvents, wh;le (S,R)-
and (R,S)-salts remain in solut;on. It ;s poss;bler ;n
just a single step, to achieve a greater than 95 per cent
enrichment, and a single recrystallizat;on Leads ~o the
opt;caLly homogeneous salts ;n h;gh y;eld, and these are
- decomposed in a known rnanner.
Thus the inven~ion relates to a process for resolv-
ing racemic m;xtures of bicyclic ;mino a-carhoxyl;c esters
;nto the components of the formulae Ia and Ib
.
C B2
COOR H
t
. .
~L~8;32~
-- 4
in which
R represen~s an aliphatic radical having 1 to 6 carborl atoms,
an alic~clic rad;cal having ~ to 10 carbon atoms,
an aromatic radical having 6 to 12 carbon atoms or
arl araliphatic radical having 7 to 15 carbon atoms,
a~ A and B1 denote hydrogen, and
~2 and C together form a chain of the formula -CCH2]n-,
with n being 3, 4, 5 or 6, or a chain of the
formula ~CCll2~p~CH=CH~CCH2~q-, with ~p+q)
being 1, 2, 3 or 4,
b) C and B2 denote hydrogen, and
A and B1 together form a chain of the formula -~CH2~n-,
with n being 3, 4, 5 or 6, or a chain of the
formula ~[CHz~p-CH=CH~[CH2]q-, with (p-~q)
bein~ 1, 2, 3 or 4, or
c) A and C denote hydrogen, and
B1 ?nd B2 toyether form a chain of the formula -[CH2]m-,
~ith rn being 4, 5, 6 or 7,
by crystallizat;on of diastereomeric salts, which process
compr;ses preparing the salts of the racem;c esters with
opt;cally active N-acylated R or S-aminocarb~xylic acids
which contain a phenyl nucleus, recrystallizing them froM
an aprotic organic solvent or an alcohol having up to 6
carbon atoms, decompos;ng the precipitated, optically
homogeneous diastereomer;c salts in a manner known per se,
and isolatil1g the enantiomers of the formulae Ia and Ib
and, where appropriate, converting the latter into the
free acids by hydrolysis or hydrogenolysis in a manner
known per se.
32419
Resolution of racemates of compounds of the for-
mula Ia and Ib ;n which
a) A and B1 denote hydrogen, and
B2 and C together forrn a cha;n of the formula -~CH~]n-,
with n being 3, 4, 5 or 6, or a chain of the
- formula ~CH2]p~CH=CH~[CH2]q~ with (p~)
being 1, 2. 3 or 4, or
b) C and B2 denote hydrogen, and
A and B1 together form one of the chains defined above
under a)
; s pref erred.
A particularly preferred variant of the process
comprises precip;tating, preferably as crystals, the salts
of racemic bicyclic esters of the formulae Ia and Ib ;n
wh;cil the two br,dgehead hydro~en etoms have the cis con
figuration and the COOR-group is oriented endo with respect
to the bicyclic ring system.
Particularly suitable imino-~-carboxylic esters
are este s with aliphatic, alicyclic or araliphat;c alco-
holsr which can be cleaved by hydrogenolysis or hydrolysis,as are described in, for example, Houben-Weyl, Methoden
der organischer) Chemie (Methods of Organic Chcmistry),
Yolume XV/1, Stuttgart 1974, on pages 314 427, or "Peptide
Synthesis", by Bodanszky et al.~ 2nd edition (1976), John
l~iLey & Sons. Esters of the formula Ia + Ib in which R
represents alkyl having 1 to 6 carbon atoms, cycloalkyl
having Jt to 8 carbon atoms or aralkyl having 7 to 13 car-
bon atoms, which can optionall~ be substituted by N02~ are
preferred, ;li particular alkyl esters having up to 4 alkyl
~'~8~9
carbon atoms alld aralkyl esters, such as benzyl, nitrobenzyl
or benzhydryl esters.
Examples of suitable N-acylated aminocarboxylic
acids containing a phenyl nucleus are derivatives of R- or S-
phenylalanine, -C-phenylglycine, -~-phenyl-a-aminobutyric
acid, -3,4-dihydroxyphenylalanine, -~-phenylserine and
-tyrosine. N-Acyl derivatives of R- or S-phenylalanine, -C-
phenylglycine and -tyrosine are preferred.
The N-acyl protective groups which can be used are
the customary NH2 protective groups described in, for example,
Houben-Weyl, Volume XV/l, pages 46-305 or Bodanszky et al.,
"Peptide Synthesis", 2nd edition (1976), John Niley & Sons.
Alkanoyl having 1 to 6 carbon atoms, in particular formyl,
tert.-butoxycarbonyl, and benzyloxycarbonyl are preferred.
Any free OH groups present can, where appropriate, be O-
alkylated by alkyl having 1 to 6 carbon atoms, in particular
methyl, ethyl or tert.-butyl, by benzyl or by other OH
protective groups customary in peptide chemistry (cf. for
example Houben-Weyl, Volume XV/1 or Bodanszky et al., "Peptide
Synthesis", 2nd edition (1976), John Wiley & Sons).
Suitable and preferred solvents are aprotic organic
solvents, such as, for example, esters, ethyl acetate,
cyclohexane and tetrahydrofuran, but it is also possible to
use alcohols having up to 6 carbon atoms.
Octahydroindole-2-carboxylic acid is known from U.S.
Patent 4,350,704. Canadian Patents 1,187,087, 1,193,607 and
1,197,252 relate to 2-azabicyclo[3.3.0]octane-3-carboxylic
acid, and Canadian Patents 1,223,868 and 1,227,802 relate to
33~g
-- 7 --
2,3,3a,4,5,7a-h~xahydro[lH]indole-2-carboxylic acid. Canadian
Patent 1,198~ relates to octahydroisoindole-l-carboxylic
acid and 3-azabicyclo[3.3.0]octane-4-carboxylic acid.
Racemic bicyclic cis, endo-imino-a-carboxylic acids
of the formulae Ia + Ib, in which C and B2 denote hydrogen, and
A and Bl toge~her denote the abovemen~ioned chain, can be
prepared fxom, for example, enamines of a cycloalkanone and N-
acylated ~-halogeno-a-aminocarboxylic esters of the formula
IV, in which X' represents a nucleofugic group, preferably
chlorine or bromine, Y' represents alkanoyl having 1 to 5
carbon atoms, aroyl having 7 to 9 carbon atoms or other
protective groups which are customary in peptide chemistry and
which can be split off with acid, and R4 represents alkyl
having 1 to 5 carbon atoms or aralkyl having 7 to 9 carbon
atoms,
X'
\CH2
( IV )
CH
Y ' -HN COOR
or with acrylic esters of the formula Y, in which Y' and R4
have the abovementioned meaning,
~ CoOR4
2 \~ ( V )
NH-Y'
3X49
-- 8
by reacting the latter to give compounds of the formula V
in which A, B1, R4 and Y' have the abovementioned meaning,
B / COOR
C~3~ = C \
~ ~H-~' (VI)
A O
cycl;zing the latter using strong ac;ds, with cleavage of
the acrylamide and ester, to give compounds of the formula
VIIa or b,
A ~ COO~I (VII~)
~31
~ ~ ~ Coo,~ ~VI~)
corlvert;ng the latter, by catalytic hydrogenat;on ;n the
presence of transit;on metal catalysts or by reduction w;th
borane-am;ne complexes or complex borohydrides in lower
alcohols, into compounds of the formulae Ta and Ib in
which R represents hydrogen, and esterify;ng the latter to
~ive compounds of the forMulae Ia and Ib ;n which R has the
mean;ng def;ned ahove.
~ acemic bicyclic imino~a-carboxylic acids of the
formuLae Ia and Ib~ in which A and B1 denote hydrogen and
8~
9 _
B2 and C together denote the chain mentioned, can be pre-
pared from, ~or example, compounds of the formula VIII
~32 C
~ ( H
- ~ ~ (VIII)
in which the br;dgehead hydrogen atoms are oriented cis or
trans with respect to one another, and B2 and C have the
abovementioned mean;ng.
Compounds of the formula VIII with n ~ 1 are known
from R. Griot, Helv. Chim. Acta 42, 67 (1959), and those
~ith n = 2 are known from C.M. Rice et al., J. Org. Chem.
Z1, 1687 (195a).
These compounds-of the formula VIII are acylated
in a known mannerr an aliphatic or aromatic acyl radical,
preferably an acetyl or benzoyl radical, being bonded to
the nitrogen atom, and the resulting N-acylated compounds
1S are subjected to anodic oxidation (in analogy to Liebigs
Ann. Chem. 1 _ , page 1719) in an aliphatic alcohol, pre-
ferabLy an aLcohol having 1 to 4 carbon ato~,s, in particular
methanol, in the presence of a conducting salt, pre-ferably
at temperatures in the range from 0 to +40C, ~lith the
formation of a compound of the formula IX in which ~2 and
C have the abovementioned meaning and R5 = C1-C4-alkyl.
83~9
- 10 -
B G
13 7 ~1 (IX)
yl
Thc result;ng compound of the general formula IX
is reacted w;th trimethyls;lyl cyanide by the method of
Tetrahedron Le~ters 1981, page 141, in a hydrocarbon or
halogenated hydrocarbon, in ether or in THF, at tempera-
tures in the range from -60C to +20C~ preferably -40C
to +0C, ;n the presence oF a Lewis acid, such as, for
exaMple, ZnCl2, SnCl2, SnCl4, TiCl4 or BF3-etherate,
preferably BF3-etherate, and the resulting compound of
the formula X
E C
< ~ CN ~X)
Acyl
in which the bridgehead hydrogen atoms are cis or trans
with respect to one another, the Cl~ group being located
cis with respect to the bridgehead hydrogen atom on carbon
atom (4~n~, and in which n, B2 and C have the aLovelnentioned
meanings, ;s, after pur;f;cation and resolution of the
mixture of diastereomers by recrystallization or colurnn
chromatography, hydrolyzed in a known ~anner by the action
of acids or bases to sive a compound of the formulae Ia
and Ib, with R = hydro~ien, and the latter is esterified.
83~3
HCl or ~IBr, in par~icular, is used as the acid for the
acid hydrolysis of the ni~rile group. In this instance
and in those ~hich follow~ the es~erification is carried
out by ~he procedures cus~omary in aminoacid chemistry.
The invention also relates to optically hoMogeneous
compounds of the forrnula Ia or Ib`in which the two bridge-
head hydrogen atoms have the cis configuration, the COOR
group is oriented endo w;th respect to the bicycl;c r;ng
system, the carbon atom a to the COOR group has the R or
S configuration~
P. represents alkyl having 1 to 6 carbon atoms, cycloalkyl
having 4 to 8 carbon atoms or aralkyl having 7 to 13 carbon
atoms, which can optionally be substituted by N02, and A,
B1, B2 and C are defined as above, and to those compounds
of the formulae Ia or Ib in which R denotes hydrogen a~d
a) A and B1 denote hydrogen, and
B2 and C together form a chain of the forMula
-CCH2~n-, with n being 3, 4, 5 or 6, or a
cha;n of the formula
~~CH2]p~CH=CH~CH2]q~~ ~ith (p+q) bring
1, 2, 3 or 4, or
b) C and B2 denote hydrogen, and
A and B1 together form one of the chains defined
abovc a), with n being 3, 5 or ~ and (p~q)
being 1, 2~ 3 or 4, and their salts.
The invention also relates to diastereomeric salts
of a bicyclic cis, endo imino~a~carboxylic ester of the
form(lla Ia or Ib, ;n which A, B1, B2, C and ~ have the
meanings def;ned above as bein~r~ preferred, anrJ an optically
~332~9
- 12 -
active N-acylated R- or S-aminocarbox~lic ac;d which con-
tains a phenyl nucleus and which is protected as defirl~d
above~
The invention aiso relates to.the use of the opti~
S cally pure compounds of the formula Ia or Ib ;n a process
for the preparation of optically pure compounds of the
general formulae IIa or IIb
~1 ~;2 C
COOII
A \ ~
I * # Y
O = C - Cl-l -- N13 ~ C~H -- ~C~2~r
~1 co
B1 ~32 C
A ~ C i ! O ' i
o = c - c.~ - c;~ c.~ c - :~ (rr
R Co2r~ ~,
in which it ;s possible for the carbon atoms !abeled with
an asterisk (*) each, ;nciependently of one ano~her, to
have the R- or the S-configuration,
a~ A and B1 denote hydrogen, and
B2 and ~ together forr,~ a chain of the formula [CH2~n-,
n being 3, 4, 5 or 6, or a chain of the
formula -LCH2ip-Ch=CI~-[CH23~- ,
l'Z8~9
13 -
tp+q) being 1, 2, 3 or 4,
b) C and B2 denote hydrogen, and
A anG s1 together form a chain of the formula -C~H2]n-,
w;th n being 3, 4, 5 or 6, or a chain of the
formula ~CCH2]p~CH-CH~~CHz~q~, with (p+q3
being 1~ 2, 3 or 4~ or
c) A and C denote hydrogen, and
B1 and B2 together form a cl,ain of the
formula -tCHz~n-, with m being 4, S, 6 or 7,
r denotes 0 or 1,
R1 denotes hydrogen, an optionally substituted aliphatic
radical having 1 to 6 carbon atoms, an optionally
substituted alicyclic radical having 3 $o ~ carbon
atoms, an optionally substituted aLicyclic-aliphatic
radical hav;ng 4 to 11 carbon atoms, an optionally
subst;tuted aromatic radical hav;ng 6 to 12 carbon
atoms, ~hich can also be partially hydrogena~ed, an
optionally subst;tuted araliphatic radical having 7
to 15 carbon atoms, an optionally substituted aroyl-
aliphatic radical having 8 to 13 carbon atoms, an
optionally substituted monocyclic or bicyclic hetero-
cycl;c radical having S to 7 or 8 to 10 ring atoms
respectively, 1 or Z of these ring atoms being sulfur
or oxygen atoms and/or 1 to 4 of these rin~ ato,ns
being n;trogen atoms, or a side chain of a naturally
occurring aminoac;d ~Jhich is optionally protected,
R2 denotes hydrogen, an optionally substituted aliphatic
radical havillg 1 to 6 carbon atoms, or an optionally
substituted aralipha~ic radical having 7 to 1S carhor
24~3
- 14 -
atomS r
Y denotes hydrogen or hydro~yl,
Z denotes hydrogen, or
Y and Z together denote oxygen, and
X d~notes an aLiphatic radical having 1 to 6 carbon atoms,
an alicyclic radical having 5 to 9 carbon atoms, an
optionalLy subst;tuted aromatic radical having 6 to 12
carbon atorns, or indolyl~
which process comprises reacting, in the presence of a
condensing agent or, where appropriate, as an active ester,
optically pure compounds of the formulae Ia or Ib, in
which A, 81, B2 and C llave the abovementioned meanings, and
R represents an optionally substituted aliphatic radical
having 1 to 6 carbon atoms, an optionally substituted
alicyclic radical having 4 to 10 carbon atoms, an
optionally substituted aromatic radical having 6 to 12
carbon atoms or an optionally substituted araliphatic
radical having 7 to 15 carbon atoMs, with optically pure
compouncds of the formula III
~ (I I I)
HOOC - J~ N}l - Cll - [ CH~ ] C~ X
C2F~ Z
in which the two carbon atoms labeled with an asterisk
(*) have the (S,R~, ~R,S), (R,R) or~ preferably, (S,S)
configuration, and
R, ~1, R2, X, Y and Z have the abovement;oned meanings,
splitting off the radical R by hyclrogenolysis or hydroly-
s;s~ and, where appropr;ate, converting the optically
~83249
- 15 -
pure compounds of the forrnulae IIa or IIb ;nto physio-
logically tolerated salts~
A preferred embodiment of the process according to
the invent;on compr;ses preparing compounds of the for-
mulae IIa or IIb, in which
r denotes 0 or 1,
R denotes hydrogen, (C1 to C6)-alkyl or araLkyl having
7 to 9 carbon atoms,
R1 denotes hydrogen or (C1 to C6)-a(kyl, which can
opt;onally be substituted by amino, (C1 to C6)~acYl-
amino or benzoylamino, (C2 to C6)-alkenyl, (C5 to C9)-
cycloalkyl, ~C5 to C9)-cycloalkenyl, 5C5 to C7)-cyclo-
alkyl-(C1 to C4)-alkyl, aryl or partially hydrogenated
aryl hav;ng 6 to 12 carbon atoms, each of which can be
substitut~d by (C~l to C4)~alkyl, (C1 or C2)-alkoxy
or halogen, (C6 to C12) aryl-(C1-C4) alkyl or
~c7-c13)-aroyl-(c1~c2)-alkyl~ bo~h of which can be
substituted in the aryl radical as defined above, a
monocyclic or bicyclic heterocycl;c radical having 5
to 7 or 8 to 10 r;ng atoms respectively, 1 or 2 of
these ring atoms being sulfur or oxygen atoms and/or
1 to 4 of these ring atoms be;ng n;trogen atoms, or
an optionally protected side chain of a naturally
occurring aminoacid, `
R2 denotes hydroyen, (C1 to C6)-alkyl, (C2 to C6)-
a~kenyl or (C6 to C12)-ary~(C1 to C4)-al~yl~
Y denotes hydrogen or hydroxyl,
Z denotes hydroger1~ or
Y and Z together denote oxygen~ and
lX~33Z49
- 16 -
X denotcs tC1 to C6)~al~yl, (C2 to C6~-alkenyl~
tC5 to C~-cycloalkyl~ (C6 to C12)-aryl, which can
be monosubstituted, disubstituted or trisubstituted by
(C1 to C4)-alkyl, (C1 to C4)-alkoxy, hydroxyl, halogen,
nitro, amino, ~C1 to C4)~alkylamino, di-(C1 to C~
alkylamino and/or methylenedioxyt or 3 indolyl.
The preparation of the S,S,S-compounds of the
formula Ila is preferred.
In this context as in the following, aryl is to
be understood preferably to include optionally suhstituted
phenyl or naphthyl. Alkyl can be straight-chain or
branched.
Examples of a monocyclic or bicyclic heterocycliç
radical having 5 to 7 or 8 to 10 ring atoms respectively,
;n which the ring atoms have the abovementioned meanings,
inclucle thienyl, benzoCb3thienyl, furyl, pyranyl, benzo-
furyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimi-
dinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl,
~uinolizinyl, isoquinolinyl, phthalazinyl, naphthyridinyl,
quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxa-
zolyl, isoxazolyl, thiazolyl or isothiazolyl. It is also
possible for these rad;cals to be partially or completely
hydrogenated.
Where R1 represents a side chain of a protected
naturally occurring a arninoacid, such as, for example,
protected or optio1lally substituted Ser, Thr, Asp,
Asn, Sluf Gln, Arg, Lys~ Hyl, Cys, Orn, Cit, Tyr, Trp, His
or Hyp, the pre~erred protective groups are those groups
customary in peptide chemistry (cf. Houben~1eyl, Vol.XVi1
'
~;~8~249
- 17 -
and XV~2). In the c~se where R1 denot~s a protected side
chain of a lysine, the known am;no protective groups, but
in particular (C1-C6)-alkanoyl, are preferred. Preferred
0-protective groups for tyrosine are methyl or ethyl.
In the procedures hither~o known for preparing
mixtures of stereo;somers of compounds of the formulae IIa
or IIb, which s~arted from mixtures o, stereoisorners, ;t
was necessary to use elaborate separating procedures to
separate the reaction mixture in order to obtain the
desired op~ically pure stereoisor,lers of the formula IIa or
IIb. By reacting the optically homogeneous imino-a-car-
boxyl;c esters of the formulae Ia or Ib according to the
invent;on with optically homogeneous compounds of the for-
mula III, specific synthesis of opt;cally homGgeneous com
pounds of the formula IIa or IIb has become possible.
The desired compounds of the formulae IIa or IIb are
obtained ;n high yields without using elaborate separating
techniques.
Compounds of the formu~a III are described ;n the
abovement;oned documents or are known from European Patent
A 46,953. The reaction of a compound of the formula III
w;th tert. butyl 1-~2~,3~,7~ octahydro-C1H~-indole-2-
carboxylate followed by el;minat;on of a t&rt.-butylester,
wh~reupon a corresponding octahydro;ndole derivative of
the formula IIb results, is known from Europear, Patent
A 37,231.
llowever, it has been necessary to restrict this
reaction to react;on of a compound of the formula Ia or Ib
with C and e2 each bein3 H and A ~ B1 being (CH2)4, and
~ 2
- 18 -
it has hitherto only been possible to prepare this in a
complicated manner via the N-benzoyl compound, crystallization
of the diastereomeric salts with S-~-phenylethylamine,
liberation of the N-benzoyl compound, elimination of the
benzoyl group and esterification.
It has not hitherto been possible to transfer this
reaction sequence to the intermediates of the formula Ia and
Ib according to the invention. Nor has it been possible to
resolve racemic mixtures of compounds of the formula IIa and
IIb by separating conventional diastereomeric salts with
optically active carboxylic or sulfonic acids. The compounds
of the formula Ia and Ib have been made accessible for
subsequent reactions or the first time by the procedure
described above.
The process according to the invention is
particularly cost-effective, since compounds of the formula
III can be prepared directly in an optically pure form by
straightforward routes from Canadian Patents 1,187,087,
1,193,607 and 1,197,252. However, in this reference, it was
still necessary for these intermediates to be reacted with a
racemic aminoacid and to be converted into an optically pure
compound of the general formulae IIa and IIb by an additional
purification step.
The process ~ccording to the invention, which is
preferably carried out with S,S compounds of the formula III,
thus represents by far the most cost-effective process for the
preparation of the compounds covered since, in all the other
known procedures, great losses have to be accepted due to the
f1 chromatography or crystallization of mixtures
. ~
~832~9
of stereo;somers, some of ~hich are complex.
The condel1sation step is carried out by one of the
conventional processes of peptide syntllesis which involve
little race~mization, such as are described in, for example,
Houben-Weyl, Volume XV, or in "The Pept;des - Analysis,
Synthesis, Biology, Vol.1 Major Methods of Peptide 80nd
Eorlnat;orl, Part A", Gross, Meierhofer, Academic Press N.Y.
~1979). The DCC/HOBt method of Chem. Ber. 103 (1979),
pages 788-798, is particularly advantageous. In this
context, it should be taken into account that reactive
functional groups in the radical R1 must be temporarily pro-
tected by the known methods of peptide chem;stry tfor
exarnple Houben-Weyl, Volume XV, or Bodanszky et al. in
"Peptide Synthesis", 2nd edition (1976), John ~liley & Sons).
The optically homogeneous compounds of the forMula
IIa or IIb are obtained, after eliminat;ng R and, where
appropriate, R2, in high yield in a manner known per se
w;thout using elaborate separating techn;ques.
The compounds of the formula IIa and IIb and their
salts have long-lasting and powerful hypotensive activity.
They are potent inh;b;tors of angiotensin convert;ng
enzyme (ACE) and can be employed to control high bLood
pressure of a variety of etiologies. ACE inhi~itors of
this type are known from, for ex~ampler U.S~ Patent
4,344,949, European Patent A 49,658, European Patent A
46,953, European Patcnt A 50,~00 and European Patent A
79~022.
It is also possible to combine them with other
compounds having hypotensive, vasodilator or diuret;c
. - :
.
.
- ' .
~Z~33~49
~,
act;vity. Typ;cal representat;ves of these classes of
~ctive co~pounds are descrihed in, for example, Erhardt-
Rusch;g~ Arzneir,littel (Drugs), 2nd edit;on, ~e;nhein, 1972.
They can be administered intrave~ously, subcutaneously or
oraLly.
The dosage on oral adm;nistration is generally
1-S00 n~g, preferably 1-100 mg, per single dose for an
adult patient of normal weight. It is also possible to
increase this ;n severe cases, s;nce no tox;c propert;es
have h;therto been observed. It is also poss;ble to reduce
- the dose and this is part;cularly appropr;ate when diure-
tics are adm;nistered concurrently.
The compounds according to the invention can be
administered orally or parenterally in appropr;ate pharma-
~5 ceut;cal formulations. For a form for oral use~ the activecompounds are mixed with ~he add;t;ves customary for this
purpose, such as vehicles, stab;l;zers or inert diluentsr
and converted by customary methods ;nto su;table forms for
adm;n;strat;on, such as tablets, coated tablets, hard
gelat;n capsules, aqueous, alcohol or o;ly suspens;ons or
aqueousr alcollol or oily s~lutions. Examples o-f su;table
inert vehicles which can be used are ~um arabic, ma~nesium
carbonatet potassium phosphate, lactose, glucose or starch,
;n particular corn starch. Th;s can entail formulation
e;ther as dry or as rnoist granules. Examples oF su;table
o;ly vehicles or solvents are vegetable or an;mal oils,
such as sunFlower o;l or fish liver o;l.
For subcutaneous or intravenous administration~
the act;ve compounds or their phys-,ologically tolerated
, ~
lf2~1133~49
salts are converted into a solution, suspension or emulsion,
where appropriate with the substances customary for this
purpose, such as solubilizers, emulsif;ers or other
aux;liaries. Examples of suitable solvents for the new
ac~ive compo~lnds and the corresponding physiologic3lly
tolerated salts are: water, phys;ological saline or alco-
hols, for example ethanol, propanediol or glycerol, but
also sugar solutions, such as glucose or mannitol solutions,
or even a mixture of the various solvents or solutions
mentioned~
The Examples which follow illustrate the process,
but there is no intention to restrict the invention to
these specific ~xamples.
Example 1:
Benzyl (1Sr 3S, 5S)-2-azabicyclo~3.3~0~octane-3-carboxylate
hydrochloride _abbreviated to (S _ Aoc-OBzl-HCl) _ _ _
(A) Mettlyl 2-acetylamino-3-(2-oxocyclopentyl)propionate:
269 g of methyl 3-chloro-2-acetylaminopropionate
and 257 g of cyclopentenopyrrolidine in 1.5 liters of DMF
are kept at room te~perature for 24 hours~ The mixture
is evaporated in vacuo, and the residue is taken up in a
little water~ the pH is adjusted to 2 with concentrated
hydrochloric acid and the solution is extracted twice with
4 liters of ethyl acetate each time. A pale yellow oil
remains on evaporating the organic phase.
Yield: 2~0 9.
1H-NMR:2.02 (s,3H); 3.74 (s,3H~; 4.4-4.8 (m,1H), (CDCl3)
3 ;~ Z4g
- 2~ -
Analysis: C H N
calculated 58.1 7~S4 6.16
found 5~.5 7.2 6.5
(~) c ~endc-2-Azabicyclo[3.3.n]octane-3-carboxylic acid
S hydrochlor_de
270 g of the acetylaminG der;vative prepared under
(~) ;n 1.5 liters of 2 N hydrochloric acid are boiled under
reflux for 45 minutes~ The mixture is evaporated in vacuo,
and the res;due is taken up in glacial acetic acid, 5 y
oF Pt/C (10% Pt) are added and hydrogenation is carried
under S bar. After filtration, the filtrate is evaporated
and the residue is crystall;zed from chloroforrn/diisopropyl
ether.
Melt;ng point: 205-209C,
Yield: 150 g
(C~ Racemic Aoc-OBzl.~lCl
.. . . .
1.2 liters (11.5 mol) of benzyl alcohol are cooled
to -10C. 126 ml (1.73 mol) of thionyl chloride are
added dropw;se, with cooling and stirring, and then 126.5 g
~D.66 mole) of crude Aoc.HCl are added at -10C, with
stirring, and the mixture is then stirred at this tenpera-
ture for 30 minutes. The temperature is then allowed to
r-ise slowly to 20-25C with stirring, the product dissol-
ving within 5 hours. After standing overnight, the brown
solution is run into 4uO liters of diisopropyl ether uith
stirriny. After 1 hour, the precipitated crystals are
filtered off, washed with diisopropyl ether and dried in
- 23 ~ 24'~
vacuo. A further precipitate separates out of the com
bined diisopropyl ether solutions overni~ht~
Yield: 168.5 9 ~O.~X~
~D) (S~-Aoc-ORzl.~-Phc~OH
166.0 9 (0.589 mol) of racemic Aoc-OBzl.HCl are
suspended in 500 ml of methylene chloride and thorouqhly
sha~en with 25 9 (O.ti25 mol) of NaOH in 250 rnl of ~ater.
A solution is proc'uced. After a short time the initially
formed emuls;on has separated. The methylene chloride
phase ;s separated off, washed ~lith 100 mL of 0.1 N NaOI!
and twice with 50 rnl of water each time and the combined
aqueous phases are extracted twice ~lith 100 ml of methylene
chloride each time. The combinetd methylent? chloride phases
are dried over sodium sulfate and evaporated ur~der m;ld
cond;tions w;th waterpump vacuum. The remainins oil is
imrnediately taken up in 100 ml of ethyl acetate, and a
solution of 117.6 9 (0~39 mol) of N-benzyloxycarbonyl-S
phenylalanine (7~Phe~O~J) in 200 ml of ethyL acetate is
added. The flask ;s rinsed with 100 ml of ethyl acetate.
2C 1,600 ml of cyclohexane (- 4 times the amount by volume)
are added, w;th stirring, to the clear solution at rcorn
ternperature. After scratching, crystallization starts,
and th;s is completed by standing overn;gh~ in a cold room.
The crystalline precipitate is filtered off, washed ~ith
250 ml of ethyl acetate/cyclohexane (1+4) and dried.
Yield: 133.6 g of (S) Aoc-OBzl.Z-Phe-OH (50.9%~ corres-
ponding to 102% of theory),
melt-ing point 101-103C; ta~D7: ~5 3 (c = 1, rnethanol).
After recrystallization from ethyl acetate/cyclo-
- 24 ~ 3~49
hexane ~1:1), the follouing data are found for the Z-Phe-OI-I
salt:
melting point: 103-10'~C, Ca]D7: -6.1 (c = 1, in methanol).
(E) ~S)-Aoc-OBzl.HCl
63.0 g (0.142 mole) of the Z-Phe-OH salt obta,ned
according ~o (D) are dissolved in 300 rnl of methylene
chloride and the Solutiol1 is thoroughly shaken with $
(0.15 mole~ of NaOH in about 150 ml of water. Phase
separation takes some time because of a small amount of
1Q insolubles. The methylene chloride phase is separated off,
washed with 50 ml of D.1 ~ NaOH and twice with 50 rill of
water each tirne and dried. The solution is evaporated to
about 100 ~l, diluted with 100 ml of diisopropyl ether and,
~;th stirring, 25 ml of 6 N HCl in ether are added. After
1 hour, the mixture is filtered, and the precipitate is
washed with diisopropyl ether and dried.
Yield: 3Z.5 9 (~1.3%)
Melting point: 185-186C
~a]D -42.5 (c = 1, water)
Methylene chloride is removed from the basic
aqueous phase in vacuo, and it is acidified with toncen
trated HCl. The prec;pitated Z-Phe-OH ;s washed with
water and dried.
The R compound and further Z-Phe-OH are obtained
from the methylene c`hloride mother liquor from Example I(D~
in the manner describecl~
- 2 5 - ~.Z~3324~9
r-- G O
O ~~t
'1 f~~f\l ,_
~ ~~ =r
o.~3 f~ `
rl ~;oL) O~ O~')
~_ f~l c~ ~D
O t~
C~ CO
Cl E~
f`) ~f~ O O O O O O O O O
CJ~~f~ C~ O C~ - CV f~ :r
^ f~l r-- O~ C'~ .-- C~ CJ~ O~ ~D CO
S tf~ :r s s ` rfl f,~l f~ .. 0
~) I I I I 1 1' ~ I I '~'
~0
o~ a
~" r~
0~C~ V OU 0~ OC~ 0;~ OC~
<~ n u~ f~ f
0~ CO C.~ C~ COCOCO Lf~
C~ ,fl I=l I CO r.
E C~ C~ ~ C C Cl~
~ ~ ~_ _ _ _ ,_ ~
.~
- T~ :C o
~ ~ C~ C
C~ O O O
O O O O t-- O O O O ~ ~--
~J ~ CO~J ~ ~ r,~ f? ,f~ r_
O ~O=J' ~'~ O f'~
,~ + ~ I +
a
.~
V V V ;) V V ~ ~J V ~ c
C~ o o o o o o o o o o o
tu ~u~ _r=r o ~ n c~_. ~ co
~ ' tf~ C~C~ t~ t,~ ~C,._ ,_ ,_
~n. I I I I \ I I I I I I
f~ n30 ~c~ t~J n :. -- f
~ _~-- ~-. , _ ,_ ~ _, _,_ ,. ~_ ,_ , ._
s . ~O à) ~ ~ à~ ~d ~ ~ ~
fa a, s^ ~ a) ~ o a~ ~ aJ c: a~ to a~
a, s- a~ aJ f`' 'ILJ~ ~Xa ~J' ~ C ( ) tll N
,c~t S,tl~ CJ n~ CJ ~(D ~,a~ aJ S. fV tO CJ 11~ C)
-~ ~) J O~' -~ O J J OJ OC~ --J -- O --' O
o f-~ S ~-- L ~ r_1 L
aJj~ L~111i~ L~i~ L~ V LLI L~ i~; i ~)
C t iL ~~C ~ 5~
C~C~ IS I I ~ rl f~. C) J, t!?
c~ P.r~_ P~ E-~ ~-- '~i S. S-~. P. t
~3 1 i II I I I rt~ O
~ tii t~ C`l ~ LL, C~ ti t~l
, 1 ,"~ , .~ O ~t '~
tL~ S_ c~ ~ s^S` c c~ ~ S~ t' ;~
L ~? ~ ~li)C; C; CvC?, C~ ;) (li C)
tl_ t~ t~t~ ~tl~ t' . P~ r~ ~ t
G)I X H i H
Jo S_ ~3 -D H H t- I H H H H H H 1-1 t- I
t E ,;~, X ~ X: C X :~ ~C X X
L f~ t~ n ~D t-- co C~ C~
o sv ~ ~ ~
IIJ Q
- ~6 - ~ 9
The Ccis,endo~-imino-~ carboxylic esters in
Tablt-~ 1 are prepared and subjected to racemate resoLution
in an analogGus manner. This Table details their optically
acti~e crystallization par~ners, and the solvents, yields
and properties of the salts and the final products in the
form of the ester hydrochlorides or ester ~osylates.
Explanations of Table 1
.
(XI) - ~ ~
~ N~COOR and mirror image
(XII) H
and mirror image
~ H
10 (XIII)
~\
~ /~ COO~ and mirror image
The free iminocarboxylic acids can be prepared
from the esters by hydrolysis or hyrlro~enolysis.
Exa_ple 13
N-t1S- _rboethoxy 3~phenylpropyl)-S-alanyl-2-cis~endo-
1S azabicycloL3.3.0]octane-7S-carboxyl,c acid
- 27 - ~8~249
(A) Benzyl N-(2S-ca_boethox_-3-phenylpropy()-S-alanyl-
c;s,endo-2-azab;cycloC3.3.0]octane-3S-carboxylate
11~ 9 of the benzyl ester hydrochloride prepared
according to Example 1 E are converted into the free ester
S by extracting by shak;ng the alkal;ne aqueous solution
w;th d;ethyl ether, and~ after dist;ll;ng out the e.her,
are reacted w;th 6.7 9 of Hos~ 13.8 g of N-(1S-carbo-
ethoxy~3-phenylpropyl)-S-alan;ne and 10~Z g of d;cyclo-
hexylcarbod;;mide ;n 200 ml of dimethylformam;de. After
st;rr;ng at room temperature for 3 hours, the precip;tated
d;cyclohexylurea is filtered off, and the filtrate is
evaporated, and the residue is taken up in 1 liter of ethyl
acetate and th;s solut;on is extracted by shaking with
3 x 500 ml of 5 per cent NaHC03 solution. The organic
phase ;s evaporated.
22.4 9 (90X) of product are obtained as an oil.
SHNMR of the S,S,S-compound, characteristic signals:
1.20 td,3H~, 1.27 ~t,2H~, 4.17 (q,3H), 5.13 (s,2H~
7.18 (s,5H~, 7~32 (s,5H) (CDCl3)
Analysis: C H N
C30H3~N20s calculated 71.1 7.56 5.53
found 70.8 7.8 5.7
(B) N-(1S-Carboethoxy-3-pher)ylpropyl)-S-alanyl-c;s,endo-
2-azabicycLoC3.3.0]octane-3S-carboxylic ac;d
8.0 g of the S,S,S-benzyl ester from Example 1 E
are d;ssolved in 100 ml of ethanol, and the benzyl group is
removed by hydrogenolysis under atmospheric pressure with
the addit;on of 0.5 g of 10% PdtC. This reactiol can also
be carried out urder elevated pressure which ;nvolves
2~ 33249
shortenin~ of the reaction time. After the caLculated
amount of hy(lrogen has been taken up, the catalyst is fil-
tered off and the fil~rate is evaporated in vacuo. The
~itterion crystallizes from ether in a virtually quanti-
tative yield:melting point: 110-112C (decomp,osition)
A hydrochloride ~decomposition above 120C) can be
obtained by addit;on of an equ;valent amount of hydrochloric
ac;d.
Analysis: C H N
C23H32Nz05 c~lcu~a~ed 66.3 7.7 6.73
found 66.1 7.8 6.6
The 1H NMR and mass spectra which are obtained are
consistent with the structure indicatedO
~]D = ~-15~6 (c = 1, rnethanol).
Example 1~
N-(1S-Carboethoxy-2-benzoylethyl)-0 ethyl-S-tyrosyl-
c7s,endo-2- zabicyclo~3.3.030ctane-3S-carboxyl;c acid
(A) N-(1S~Carboethoxy-3~ y~e~pyl)-o-ethyl
tyrosine benzyl ester
24 ~ of ethyl benzoylacrylate in 100 ml of ethanol
are reacted w;th 30 g'of 0-ethyl-S-tyros;ne benzyl ester
in the presence of 0.5 ml of triethylamine and~ after
evaporating the solution and diDesting the resitdue with
diethyl ether/petroleum ether (1:1) and drying in vacuo,
42 g of RS,S compound are obtained. Resolut;on of the
diastereomers by chromatography on silica gel using the
system ethyl acetate/cyclohexane (1:3).
Y;eld: 17 9 of the S,S conipour,d.
- 2~ .Z~33~4~
(B) N~ Carboe_hoxy-3-phel1ylpropyl_-0-ethyl-S-tyrosine
17 g of tl1e compound obta;ned accord,ng to (A)
in 800 ml of acetic acid are hydrogenated with 4 9 of Pd/C
(10%) under 1Q0 bar and at roorn temperature. Yield after
chromatography on silica gel using the solvent ethyl ace-
tate/cyclohexane (1:3) and drying the res;due from evapora-
tion: 12 g of title compound wh;ch is virtually homo-
geneous by thin-layer chromatography.
Melt;ng po;nt 205-213C
10 Analys;s: C23H2gNOs (399.5~
calcula ed C 69.15 H 7.31 N 3.50
found C 69.5 H 7.4 N 3.3
(C) N-(1S-Carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-
.
c;s,endo-2-azab;cycLoC3.3.0]octane 3S-carboxyl;c acid
___
In analogy to Exarnple 13 A, ~ g of the free benzyl
ester obta;ned in accordance w;th Example 1 E and extracted
from alkal;ne solut;on by shak;ng with d;ethyl ether are
reacted w;th 8 9 of the cornpound obtained in accordance
w;th Example 14 B us;ng 4.4 g of d;cyclohexylcarbod;;m;de
in the presence of 2.7 g of 1-hydroxybenzotriazole, and
14.3 9 of oily benzyl ester are obta;ned as an ;nterrnediate.
The 1H NMR and mass spectra are cons;stent w;th the
structure ;ndicated.
The benzyl ester in 50 ml of ethanol ;s cataly-
t;cally hydrogenated on Pd/C under atmospheric pressure.
After filtering off the c-atalyst and distill;ng off the
solvent~ there remains a sol;d res;due whicl1 ;s d;gested
with diethyl ether/petroleurn ~ther and ;s dr;ed.
Y;eld: 11.2 g
~ 30 ~ 1Z 8 32
Exarnple 15
N-~15-Carboethoxy 3-phenylpropyl)-0-methyl-S-tyrosyl-
.. . . .
cis,endo-~-azabicyclo~3~3.0~octane-3S-carboxylic acid
_ _ _ , _ _
The procedure is carried out as described in
Example 14~ but in the stage analogous to (A) 0-methyl-S-
tyrosine benzyl ester is used and the title compound is
obtained, the 1H NMR spectrum of which is consistent with
the structure ;ndicated.
1H NMR (CDCl3): 1.2-3.0 (m,15H); 1.27 (t,3~l); 1.4 (t,3H);
3.0-4.3 tm,4H), 3.8-4.2 (rn,4H)~
6~5-7.1 (2d,4H); 7.3 (s,SH)
Example 16
N-(1S-Carboethoxy-3-phenylpropyl)-S-alanyl-2-azaspiro-
. . .
C4.5]decane-3S-carboxylic ac;d
(A~ 1-(D;ethoxyethyl)cycloh =
51.7 ml (0.5 mol) of anhydrous diethylamine are
added dropwise, under protectivc gas at -10C, to 312.5 ml
~0.5 rnol) of a 15X strength solution of n-butyllithium ;n
hexane. The mixture is st;rred for 20 rninutes and then
cooled to -70C. 54.6 g of cyclohexanecarbonitrile are
added dropwise over the course of 30 rninutes and, after a
further 30 minutes, 98.5 g of brorooacetaldehyde diethyl
acetal are added with;n 1 hour and the mixture is left at
low temperature for 24 hours. It is then warmed to room
temperature, 100 g of ice are added, and the mixture is
extracted twice with 500 rml of ethyl acetate, and the
organic phase is dried over sodiurn sulfate, evaporated in
vacuo and the residue is subjected to vacuum distillation.
Yield: 90 g (about 80% of theory), boiling point 7X-7~C at
-
~ ~ :
~ 31 - ~83Z49
S torr t10.7 mbar).
(B) 1~A_inomethyl-1-t_ ethyloxyethyl)cyclGheYane
90 g of d1e~hyloxycyclohexanecarbon;trile are
dissolved in 1 ~iter of ethanol, and 60 g of sodium are
added~ After the metal has d;ssolved, 100 ml of ~later are
added and the solvent is largely removed in vacuo. 300 ml
of ~Jater are added to the residue and the mixture is
extracted 3 x with 200 ml of ether. The ethereal phase
is dr;ed over sod;um sulfate, evaporated and distilled in
vacuo.
Yield: 83 g (about 90% of theory), boiling point 69-72 at
8 torr (10.7 mbar)
(C~ 2 AzaspiroC4.5]decane-3-carbonitrile
80.2 g of aminomethyldiethyloxycyclohexane are
stirred in a mixture of 300 ml of ethanol and 300 ml of
1 N hydrochlor;c acid under a protective gas (N2 or Ar) for
about 1 hour.
After the starting product has been comple~eLy
cleaved, the mixture is cooled to 0C and the solution is
rapidly adjusted to pll 5 by adding 2 N sodium hydroxide
solution. 300 ml of glacial acetic acid are immediately
added (pH about 3), and the mixture is cooled to -10C
and 17.5 9 of sodium cyanide are added. The reaction vessel
is closed and left at room temperature for about 5 hours.
Completion of reaction is checked using tllin-layer chroma-
to~raphy (system ethyl acetate/petroleum ether 2:1)
~Schiff's base Rr = 0.6-0.7; aminoacid nitrile Rf ~ 0~28~ and
the react;on solution ;s evapora.ed to dryness. The crude
aminoacid nitrile is immediately processed further in accor-
- 32 ~ ~X83~9
dance ~ Example 16 D or E.
(D) 2-A_aspiroC$.5~decane-3-carbox ~
25n ml of 4 N hydrochloric acid are added to one
half of- the aminoacid nitrile obtained in Example 16 C, and
the mixture i~ heated under reflux for 4 hours. Traces of
escaping hydrocyan;c acid are made harmless in a suitable
manner (freezing out, absorption in basic iron(II) salt
solution). The solut;on is neutralized, evaporated to
dryness and extracted several times with n-butanol. The
residue from evaporation of the organic phase is
- a) crystallized from chloroform/diisopropyl ether to
obtain the hydrochlor;de and, if necessary, again pre-
cipitated from a mixture w;th ethanol or
b) purif;ed ;n aqueous solut;on by stirring with an ion
exchanger, for example IR 45 (OH form) (Amberlite(R))
and, after remov;ng the water, the zw;tter;on ;s crystal-
l;zed from ethanol/ether.
Yield from a~: 31-32 g ~82%)
Melt;ng po;nt 205C (decompos;tion), hydrochlor;de
(E~ Benzyl 2-azaspiroC4.5~decane-3-carboxylate hydro-
chloride
_ _
Half of the aminoacid nitrile obtained ;n accordance
w;th Example 16 C is taken up ;n 7C ml of benzyl alcohol.
A slow stream o-f HCl gas is passed through the solut;on at
room temperature for 5 minutes, then it is maintained at
room temperature for 2-3 hours~ evaporated to a small
volume ;n vacuo, and aqueous sodium b;carbonate solution
is added until the pH is 8~5 and the benzyl ester is
extracted into ethyl acetate. The organic phase is dried~
_ 33 _ ~28~
an equivalent amount of ethereal hydrochloric acid is
added and the mixture is evaporated. The res;due crystal
lizes ~rom diisopropyl ether aod can be recrystallized
from methy~ene chloride/diisopropyl ether.
Yicld: 43 9 (abou~ 80%)
Melt;ng point 145C (deccmposit;o~
(F~ senzyl 2-azaspiroC4 S~decane-3S-carboxylate hydro
chloride
The racemic hydrochloride obtained in accordance
with Example 16 E is subjected to racemate resolution in
analogy to Examples 1 D and E~
(G) Benzyl N-(1S-carboethoxy-3-phenylpropyL)-S-alanyl-
2-azaspiro~4.5]nonane-3S-carboxylate
__ _ _
15.6 g of benzyl 2 azaspirol4.5~nonane-3S-carboxy-
late hydrochLoride, 6.7 g of 1-hydroxybenzotriazole and
13.8 g of (S,S)-N-(1-carboethoxy-3-phenylpropyl)alanine
are dissolved in 200 ml of DMF and reacted overn;ght with
10.2 9 of dicyclohexylcarbodiimide. Addit;on of tertiary
bases, for example 6.4 ml of N-ethylmorpholine, increases
the yield only inconsiderably. The precipitated DC-
urea is filtered off, the filtrate is evaporated in vacuo,
the residue ;s taken up in ethyl acetate, and the solution
is extracted by sllaking with aqueous sodium bicarbonate
solution~ and the organic phase is dried over solid sodium
sulfate and again evaporated. The 1H NMR spectra tin
CDCl3) confirro the structure.
(H) N-(1S-~Carboethoxy-3-phenylpropyl)-S--alanyl-Z-aza-
spiror4.5]nonane 3S~carboxylic ac;d
The benzyl ester obtained in Example 16 G -i,
. ,
taken up ;n 200 ml of methanol and the benzyl group is
removed by hydrogenolysis with 1 g of Pd/C (10% Pd3~ ~fcer
uptake of hydrogen ;s cornplete, the m;xture is filtered and
the filtrate is evaporated in vacuo. A solid, hygroscopic
foarn of the zwit~erion,c dipep~ide derivative can be
obtained in ~acuo with the addition of pen~cane.
Ca]~1 - 3~.3 (c ~ 1, methanol)
Example 17
N-(1S-CarLoethoxy-3-pheny propyl)-S-alanyl-cis,endo-
2,3,3 _ 4~5,7a-hexahydroC1HJ;ndole-2S-carboxylic acid
(a) Methyl cis-2,3,3a,4,5,7a hexahydroC1H3indole-2S-
carboxylate hydrochloride
Racemic methyl cis-Z,3,3a,4,5~7a~hexahydroC1H~-
;ndole-2-carboxylate hydrochlor;de (obta;nable ;n analogy
to ~he procedure described in German Patent Appl;cation
P 32 10 496~0) ;s subjected to racemate resolution ;n
analogy to Exarnples 1 D and E.
Ca] ~ = +6~ .4 (c = 1, H20)
(B) N-(1S-Carboe.hoxy-3-phenylpropyl)-S-alanyl-c;s,endo-
__ __ _ __ _
2,3,~4,5,7a hexahydro~1_]indole-2S-c _boxylic acid
hydrochlor;de
___
rhe title compound is obtained by a procedure
analogous to that described ;n Exatnples 13 A and B.
1H N~R data 0O9-3~0 (m, 17 H);
.
3.4-4.9 (m, 6 H);
5.2-6.0 (m, 2 H);
7.2 (s, 5 H)
'
.
