Note: Descriptions are shown in the official language in which they were submitted.
- 2 - HOE 82/F 065
The present invention relates to new derivatives of
bicyclic aminoacids of the formula I
[Cl~
\~ /
H,' ~ H
(7~n) \
1>~)2E~
-N'
* * l
CO - f~I - N~ - CH - ÇH2 - C - X ( I )
CO2~ Z
;n ~hich the hydrogen atoms at the bridgehead carbon atoms 4
and (7+n~ are in a cis or trans configuration relative to
each other, and the carboxyl group on carbon atom 1 can be
in a cis or trans configuration relative to the hydrogen atom
on carbon atom (7+n)~ and in which
n = 1, 2 or 3,
R1 = hydrogen, (C~-C6)-alkyl ~hich can be optionally
substituted by amino or (C1 C4~acylamino~ prefer~
ably (c1-c4)-alkanoyla~ino or benzoylam;no~ (C27C6)
alkenyl, (cs-Cg)-cYcloalkylp (C5-C9~-cycloalkenyl~
tC5-C7)-cycloalkYl~(c1 C4)-alkyl, (C6-C10)-aryl
or partly hydrogenated (C~ C10)-arYl, either of w~ich
,~
can be substituted by (C1-C2)-alkyl, (C1-C2)-alkoxy
or halogen~ (Cs-C10)-aryl-(C1-C4)-alkyl~ the aryl
radical of which can be substituted as defined above,
a monocyclic or bicycl;c heterocyclic radicaL hav;ng
S to 7 or 8 to 10 r;ng atoms, of which 1 or 2 r;ng
atoms represen. sulfur or oxygen atoms and/or of
wh;ch 1 to 4 ring atoms represent nitrogen atoms~ or
a s;de cha;n of a naturally occurr;ng am;noac;d,
R2 = hydrogen, (C~-C6)-alkyl, tC2-C6)-alkenyl or
(C6-C~o)-aryl~(C1-C~-alkyl,
Y = hydrogen or hydroxyl,
Z = hydrogen or
Y and Z ~ogether = oxygen,
X = ~c1-CO)-alkY~, (C2'~C6)-alkenylO ~C5-C9)~cyclo
alkyl, tC6-C10)-aryl which can be monosubstituted,
disubstituted or tr;subst;tuted by (C1 C4)-alkyl,
(C1-C4)-alkoxy, hydroxyl, halogen~ n;tro, am;no~ (C
C4)-alkylamino, d;-~C1-C4)-alkylamino or methylene-
d;oxy, or ;ndol-3-yl,
and to the;r physiologically acceptable saltsr
Sui~able salts are in particular alkali metal and
alkal;ne earth metal salts, salts ~;th phys;ologically acc~pt-
able am;nes~ and salts w;th ;norganic or organic acids,
such as, for example, ~Cl, HBr, H2S04, maleic acid or fumaric
acid.
Aryl is preferablY understood as mean;ng, here and
below~ phenyl or naphthyl~ Alkyl can be stra;ght-cha;n or
branched.
Compounds of the formula I have chiral carbon atoms
,.
in the pos;tions carbon 1, carbon 4~ and carbon (7+n) and
in the carbon atoms of the s;de cha;n ~hich are marked ~ith
a star. The ;nven~ion relates to the R as well as the S
configurations at all centers~ Compounds of the formula
I can therefore be ;n the form of op~ical isomers, d;astereo-
;somers, racemates or m;xtures thereof. Those compounds
of the formula I are preferable in wh;ch the carbon atQm
1 ;n the b;cycl;c ring system and the carbon atoms of the
s;de chain wh;ch are marked w;th a star have the S configur-
10 at;on.
Preferable compounds of the formula I are those ;n
~h;ch
R1 = hydrogen~ (C1-C3)-alkyl, ~C2-C3~-alkenyl,
benzyl, 4-aminobutyl, 4-methoxybenzyl or 4-ethoxy-
benzyl~
R2 - hydrogen, (C1-C~)-alkyl or benzyl, and
X - phenyl wh;ch can be monosubstituted or disubst;-
tuted by (C1-C2)-alkyl, ~C1-C2)-alkoxy, hydroxyl,
fluor;ne, chlorine~ bromine, amino, (C1-C4)-alkylam;no,
di-~C1-C4~-alkylamino9 nitro or methylened;oxy or tri~
subst;tuted by methoxy.
Those compounds of the formula I are particularly
preferred in which n = 1 or 2~ R = methyl, 4-methoxybenzyl
or 4-ethoxybenzyl, and X ~ phenyl~ of which those in which
R2 = hydrogen or ethyl are specifically mentionedD
The invent;on also relates to a process for preparing
compounds of the formula I. One vers;on of the process com~
pr;ses react;ng a compound of the formula II
-- 5
H~2C ~ ~ H - NH - CH - CH2 - C - X
R~ C02R2 Z ~ I I )
in ~hich R1, R2, X~ Y and Z are defined as in the formula
I, w;th a compound of the formula III
<(C~23~
) H
I I I )
C02W
N/
H
in wh;ch the configuration of the bicyclic ring system and
of the s~bst;tuent on carbon 1 ;s the same as in the formula
I and ;n ~hich
n = 1, 2 or 3 and
W = a radical which can be elim;nated by hydrogenoly-
s;s or under acid;c cond;t;ons, ;n particular a benzyl
or a terta~butyl rad;cal,
accord;ng to known amide forming methods of pept;de chem;stry,
and then us;ng catalyt;c hydrogenation or a treatment ~;th
ac;d to el;minate the radical W and, ;f necessary, ~he rad;cal
R2 by add;t;onal treatment ~ith ac;d or base~ to obta;n
;n either case the free carboxylic acids.
Further methods of synthes;z;ng compounds of the
formula I in wh;ch Y and Z together denote oxygen compr;se
reacting a compound of the formula IV
` ,!
( CH 2 ) r~
H ~ ~ H
~\N ~--C02W
co - fH -- NH2 . (IY)
Rl
;n ~hich the confi~uration of the bicyclic ring system and
of the subst;tuent on carbon 1 is the same as ;n the formula
I and in which n and R1 are defined as in the formula I,
and W is defined 2s in the formula III, with a compound of
the formula Y
R202C - CH = CH - CO - X (V)
in which R2 and X are defined as in the formula I~ ;n a
known manner in a Michael reaction ~Organikum CPractical
Organic Chem;stry]O 6th EditionO page 492, 1967)9 and el;m;-
nating the radical W and, if necessary, the radical R2 as
described above, or reacting a compound of the abovementioned
formula IV with a csmpound of the ger,eral formula VI in which
R2 is defined as ;n the formula I and with a compound of
the general formula VII
OHC-C02R2 X-C~-C~3
(VI) (VII)
in which X is defined as in the formula I, in a known manner
in a Mannich reaction (see Bull. Socu Chim. France 1973,
page 625), and then eliminat;ng the radical W and, if neces
sary~ the radical R2 as described above to give the free
carboxyl groupsS
It is aLso poss;ble to prepare compounds of the
formula I in which Y and Z = hydrogen by reacting a compound
of the abovementioned formula IV as described ;n ~ Amer.
Chem~ Soc. 93, 2,897 (1971) w;th a compound of the formula
5 VIII
~C02~2
O = C
C~ CH2--X ~YIII)
in which R2 and X are defined as in the formula I, reducing
the Schiff's bases obtainsd, and then eliminating the radi-
cal W and, ;f necessary, the radical R2 as described above
1D to give the free carboxyl groups~ or by reducing a compound
of the formula I in ~hich Y and Z together denote oxygen,
obtained by one of the above methods. Catalytic hydrogenation
is preferred. The Schiff 9S bases can be reduced catalytic-
ally, electrolytically or by means of reducing agen~s~ such
15 as, for example, complex boronates, preferabLy sodium boro-
hydride or sodium cyanoborohydride.
Compounds of the formula I in ~hich Y = hydroxyl
and Z = hydrogen can also be obtained, for example, by
reducing a compound I in ~hich Y and Z together ~ oxygen
2~ and which has been obtained by one of the above methods~
This reduction can be effected catalytically with hydrogen
or ~;th any other reducing agent~ such as, for example,
complex boronates, preferably sodium borohydride.
The invention aLso r~lates to compounds of the
formula III '
<(CH2 ) n~
4 ~7Tny
C02W ( I I I ' )
in which the carbon atoms 1, 4 and (7~n~ have the same con-
f;gurations as ;n the formula III, n = 1~ 2 or 3, and W'
has the meaning of W in the formula III and additionally
denotes hydrogen. The invention uses these compounds as
starting materials in the synthesis of compounds of the for
mula I, and, according to the invention~ they can be prepared
by the following methods.
In one version of the synthesis, the starting mater;al
is a compound of the formula IX
/ICH2 ~ n\
H )4 t7+n ~ -I
\ N / ~IX)
H
in which the hydrogen atoms on the carbon atoms 4 and (7~n)
are in a c;s or trans conf;gurat;on relat;ve to each other,
and n denotes the number 1, 2 or 3.
Compounds of the formula IX ;n wh;ch n - 1 are known
from R. Griot, Helv7 Chim. Acta 42~ 67 (1959), and those
in ~hich n = 2 are known from C.M. Rice et al.~ J. Org. Chem.
21, 10687 (1955).
These compounds of the formula IX are acylated in
a known manner wherebY an aliphat;c or aromatic acyl radi-
cal~ preferably an acetyl or benzoyl radicaL, is bonded to
'~:
- 9 -
the nitrogen atom, and the N-acylated compounds obtained
are anodically oxidized in an aliphatic alcohol, preferably
an alkanol having 1 to 4 carbon atoms, ;n particular meth-
anol, ;n the presence of a conduct;ng salt preferably at
temperatures wi~hin the range 0 to +40C to give a compound
of the formula X
~(CH2 ) n~
N OR ~X)
Acyl
in ~hich n = 1, 2 or 3 and R3 = (C1-C4)-alkyl (s;m;lar to
L;eb;gs Ann. Chem. 1978, page 1,719).
The result;ng compound of the general formula X ;s
reacted ~ith trimethylsilyl cyanide by the method of Tetra-
hedron Letters 1981, page 141 ;n an aprotic organ;c solven~
such as, for example~ in a hydrocarbon~ halogenohydrocarbon,
ether or THF, at temperatures ~ithin the range -60~C to ~20C,
preferably -40C to +0C, in the presence of a Lewis ac;d,
such as, for example, ZnCl2, SnCl2, SnCl4~ TiCl4 or BF3
etherate, preferably ~F3 etherate, and the resulting compound
of the formula XI
<~( 2 ) n~
H > < H
~N--CN
tXI)
~c~i
in ~hich the hydrogen atoms on the carbon atoms 4 and 7~n
are in a cis or trans conf;guration relative to each otherO
~he CN grvup is in ~he cis position relative to the hydro-
gen atom on Lhe carbon atom (7~n), and n has the above
~entioned meaning, is purified and separa~ed -Frnm by-products
by means o-f recrystallization or column chroma~oyraphy and
then hydrclyYed under the ac~;on of ac;ds or bases ;n a known
manner to g;ve a compouncl of the formula III in ~Ihich W'
= hydrogen, ancl the la~er compound is esteri-fied if des;red~
The ac1d used in the acid hydrolys;s of the n;trile group
is irl particular lICl or HBr~ The estcrification ;s carr;ed
out here~ and belowr by using a conventional me~hod of amino-
ac;d chemistry.
Compounds o-f t'ne general formula III' can also he
prepared by convert;n~ a compouncd of the formula XII
r7~
( C ~! 2 ) n f G~
\~ (YII3
in ~Ihich the hydrogen atoms on the carbon atoms /~ and (7-~n)
are ;n a c;s or trans conf;gurat;on, and n has the above-
mentioned mean;rIg~ in a BeckInann rearran~ement by react;ng
it ~;th a mine,al acicl, such asr for example, sulfuric ac;d
or polyphosphoric acid, or l~ith ben~.enesulFonyl chloride
7~ or p~toluenesulFonyl chloride and a base such as trietnyl-
amine into a compound .o-F the -Formula X~II
(C~l~) n
l~l-J
( Y I 1 I ~
in which n has the abovementioned Mean1ng, and halcgenatirlg
thls compound to give a compound of the formula XIV
~J~l Hal
\/
/ ,/\~/
~Cil2) n
. ~1 `
in ~Jhich n has the aboverner,tioned meaning and Hal deno-tes
a halogen atomf pre-ferably chlorine or bromine Examples
of suitable halogenat;n~ agents are inorgan;c ac;d halides,
such as PCl5, S02Cl2, POCl3, SOCl~ or PBr3, or haloclens
sucll as bromine~ It ;s advantageous to use PCl5 or POCl3
combined w;th SO~Cl2~ First an imidc halide forms as the
intermedi~te, and reacts ~ith the halogenating agents men-
tioned to give a compourld which is then hydrolyzed under
bas;c ccnditions~ pre-ferably by using an aqueous alkali rnetal
carbonater to give a compound of the rormula )IV~
rl-e compounds of the -formula XIV ar~ then catalytic~
ally reduced in a polar procic solvent, such asr for example~
an alcohol, preFerably ethanol, or a carboxylic acicl~ such
as, for examp!e~ acetic acid. in tne presel-lce of an acicl
acceptol~ such as~ for exarnplef sod7um acetate or triethyl~-
am;ne~ ~o a compouncl o-f the forllulc! XV
- 12
~3 )!~l
,~ "."~
(C112 ~
X V >
in which n and Hal have the abovementionea meaningsO A
suital)le catalyst is~ for example, Paney nickel or pallad;um
or pla.inum on an;mal charcoal.
Compounas of tht- formula Y`l can also be preparet~
directly hy halosenatin~ compounds of the forrnula XIXI by
us;n9 smaller amounts of the abovement;oned halogenac;ng
agents~
Compounos o-f the formula XV are con~erttd by means
of the weLl-kno~ln Favorsk;i reac~ion ;n tht presence o-f a
base ;nto a compoul1d o, the -formula III' in which I~J' - hydro-
gen~ and .his ;s esterif;ed i-f des;redO The abovemel1tioned
Favorsk-i; reaction is carried out in an alcoholic sol~ent,
such as metl1arlol, etharlc!l or tert~~butanol~ or in ~later or
in mixtures thereo-f, at temperacures w;thin the rangc 2C)C
to 140C, preferably bet~een 60C and 100('C. The bases used
are advanta~eollsly alkali metal or alkal;ne earth metal
hydrox;des, such as sod;um hydrox;cle, potassium hydrox;de
or barium hytlrox;de, or alkal; metal alcoholates, such as,
for example~ sodium methylate or potass;um tert. butanolate
The intermed;ates of tht formula XIII can also be
preparecD accordin~ to Can. '~ Chem~ ~8~ 557 (1C~60), irom
unsaturatecl n;tr;les o-~ the forllula XVI
~ 13 ~
Cl~
tCE12)~ (XVI )
in which n has the abovernenticned mean;l-R~ by reacting the
n;tr1les \lith malonates in a Michael add;c;on, followec1 by
a reducing cyclizàtion, hydrolysis and decarboxylation.
Tl1e compounds of the forrnula IX in ~Ihich Y and Z
~ hydrogen, R1 ~ metilyl and R2 = rr.ethyl or ethyl~ and X =
phenyl, which are used as startiny materi~ls in preparing
compounds of the formula I~ are known (European Patent Appli-
cation No. 37,231). The compounds of the formula XI can
be prcpared ;n various ways~ One version of their synchesis
starts frorn 3 ketone of the abovernentioned folmula VII~ ~Ihich
is reacteo in a known manner in a rlannic.h reaction with a
compc,und of the abovementioned formula VI togetller with nmino
carboxylates of the formula XVII
* *
H 2 N - CEl - C 2~ ~10 2C ~ C H -~ NEl - Cl i I C 2
R1 R C02R
15 (XVIX) (XVI;I)
in which R1 ancl l~l have the abovementioned meanin~s~ to
aive a compound of ~.he formula YVIII in uhich R2, R2~ y~ and i~l
have the abovernentior)ed meanin~s~ with the proviso that i f W
denotes a hydro~el1oly-t cally detachable radical~ in particular
ben2yl~ R2 must not have ~he meani!~g of l~v Xf the rad;cal ~J
is hydrogenolytically elirnint-ted ~ h the aid of ~ for example~
9~
palladium, ~hose co Inpoun ds of the for mula II are ob.a;ned
in ~hich Y and Z - hydro~en. If the radical W is eliminated
by neans of acids, such as, for example, trifluoroacetic
ac;d or hyclrochlor;c ac;d, in an inert or~an-ic solvent~ such
as, for exarnple~ dioxane~ those compounds of the forrnula
II are obtained in which Y and Z together - oxygenD
Compourds of the Forlllula X~ L can also he obtained
by kno~ln methods~ namely by reacting a compoul1d of the above-
mentioned formula V in a M;chael addit-ion ~lith a compound
of the abovernentioned formula XVII. This rne~hod is particu-
Larly suitable for preparin~ those compounds oF the formula
XVIII in ~lhich R1 = methylf R2 - ethyl and X = aryl.
Compounds of th~ formula XVIII are obtained as mixed
diastereoisomers. ~hose diasterroisomers of the forlnula
15 X~III are preferred in which the chiral carbon atoms which
are marked ~ith a star each have the S configuratiorl. These
can be separated off by means oF recrystallization or chroma~
tography~ for example over silica gel. The configwrations
of the chiral carbon a~oms are preserved ;n the subsequent
elimination of the radical WO
Compounds o-F the abovementioned Formula IV, which
are used as starting rnaterials in the preparation cF compounds
of the formula I~ are obtained in a kr1ol~l rnanner From com
pounds of the abovernentioned formula III by reactin~ them
~ith an N protected 2~aminocarbo~yl;c acid oF the formula
XIX
V - IIN -- C~l - CO H
~1
X I X
~ 15 ~
in whicil V is a protective group anc~ has the ahovementionecl
meaning. Examples of ~roups ~h;ch can be useo' as the pro-
tect;ve ~our~ V~ which is set free again after completeci
reac~ion, are benzyloxycarbonyl and tertO~butoxycarhorlylO
The startil1g materials of the -forrnula YII are obtainecd
in a customary manner frorn tl1e kncl~n ketones of the formula
XX
(CH2)~ 0
(XX)
in which the hydro~en atorns on the br;dgehead carbon atoms
can be in the cis or trans configuration and n has the above~
r~entioned meanings. Compounds o-f the formulcl XX in which
n = 1 are know;7 from S. Devt J. Indian Chem. Soc. 30, 815
t1953), those in which n = 2 from Ar Kand1ah, Ju ChemO Soc~
922 (1~313, and those in which n = 3 from A.Mu Islam~ R~AD
15 Raphaelr J~ Chelnu Soc. 315 (1955).
The reaction o-f a compound o-f the formula II with
a compound of thP formula III to prepare a compourld of tl1e
formula I is effected by means of a condensat1Orl reaction
whicl1 is known ln peptide chemistry and to ~Ihich dicyclo-
2n hexylcarbodiimide or 'i-hydroxybenzotriazole, for example~
are added as condens;n~ a~entsO The subsequent hydlo~eno-
lytic elimirlation of the rad;cal ~.J pre-ferably uses pallad1um
as catalyst, while the ac;cls prefel-?bly used in the elimi-~
nation of the radica'L W nder acid,c conc~ ions are lri-
-fluoroacetic acid alld hydlo~en chloride.
Each of the c7bove reac~ions for pleparil1g tompc,urlds
- ~6 -
of the formulae III'~ IV and I preserves the configurations
of the intermediates at the bridgehead atoms 4 and (7+n).
The starting mater;als of the formulae IX, XII and XIII are
formed in the synthesis e;ther as pure diastereoisomers or
as m;xtures of the poss;ble d;astereo;somers wh;ch can be
separated from one another by chromato3raphy or crystal-
l;zat;on.
Compounds of the forrnula IIIe which are prepared
by the above methods are obta;ned as racemic m;xtures, and
can be used as such in the further syntheses described above.
However, they can also be used in the form of pure enantio
mers after the racemates have been separated ;nto the optical
ant;podes by customary methodsD for example by a salt form-
at;on w;th opt;cally act;ve bases or ac;ds.
If compounds of the formula I are obta;ned as race-
mates~ these can l;kew;se be separated ;nto the;r enant;omers
by means of customary method~, such as~ for example~ v;a
salt formation ~;th opt;cally act;ve bases or ac;ds.
The novel compounds of the formula I are in the form
of their inner salts. Since they are amphoteric compounds,
they can form salts with acids as well as bases. These salts
are prepared in a customary manner by reacting the compounds
with one equ;valent of acid or base.
Compounds of the formula I, and the;r salts, have
a prolonged, powerful hypotensive act;on. They are power-
ful inhibitors of the ang;otensin converting enzyme (ACE
inhibitors~ They can be used to control hypertension of
various etiologies. They can also be combined with other
hypotens;~e, vasodilating or diuretically active compounds.
- 17 ~
Typical represen;~t;ves of tl-is class of active cornpour1d
are desc ibed ;n~ for example, Erhardt~Ruschig~ ArzneiMittel
[~rugs~, 2nd Edition, ~leinheim, 1972. 1hey can be adminis~
tered intravenously, subcutaneously or orally~
On oral adm;nistration the dose ;s 1-100 mg, prefer-
ably 1-40 mg, per s;ngle dose for adult patients o-f norm3l
weig,-t, ~Ihich corresponds to about OoQ13~1~3 mg/l;g/day~ pre~
ferably 0~013~0~53 mg/kg/dayO In severe cases the close can
be ;ncreased, sincè toxic properties have not so far been
observed~ lt is also possible to reduce ihe dose~ ~Jhicl
reduction is apprcpriate in particular when diuretics ar
administered at the same time~
Compounds according to the ir~vent;on can be admin;~
stered Grally or parenterally ;n the appropriate pharrna~
ceut;cal forrnulation. For an oral form of administr.ltior1~
the active compounds are mixed ~lith the add;~ives customary
for this purpose, such as excip;ents~ stabil;zers or inert
d;luentc, and are adrninistered by customary methods in suit-
able administration forms, such as tablecs, coated tabletsf
hard gelatine capsules aqueous~ alcoholic or oily suspensions
or aqueous~ alcol1olic or o;ly solutions. Examples of materials
hich can be used as inert excipients are ~um araibic, magnesium
carbonaie~ potass;um phosphate~ lactoseO glucose and starch,
;n part;cular corn starch~ and they can be formulated not
X5 only as dry but also as moist granules~ Examples of suitable
oily exc;p;ents or solvents are ve~etahle and animal oilsr
such as sul-,flol:er o;l or cod liver oilO
To administer theln suhcutaneously or in~ravenously
the active cornpounds or their physiologically acceptal-)le
- 18 ~
salts are dissolved, suspr-nded or emulsified, if desired
together with the substarlces customary for this purpose,
such as solub;lizels, emulsifiers or further auxiliaries.
Exarnples of materials which are suitable for use as solv~nts
for the new active compounds ancl the corresponding physio-
logically acceptable saLts are h~ater, physiological sodiurn
chloride solu~ions and alcohols, for example ethanol, pro-
panediol or glycerol, and also sugar solutions, such as
glucose or mannitol solutions, or even a mixture of the
various solvents mentiol1ed.
The reMarkably po~erful activity of the compounds
of the formula I is supported by the pharmacoLog-ical data
of the table below:
intraduodenal (i.d.) or intravenous (i~v.) adrlini-
stration to anesthetized rats; 50~ inhibitlon o-f the
pressor reaction triggered by 310 mg of angiotrlnsirl I 30
minutes after administration in the dose .... = ED50:
Tabl~
All thé compounds listed haveX = phenyl and R1 =
methyl.
n Y ~ R2 Configurationofthe ED (mg/kg)
bicyclicr~-~iety 50
1 H ~ C2H5 1S~ 4S, 8S 0.8 (i.d.)
1 H H H 1S, 45, 8S 0.2 (i.v.)
2 H H C2H5 1S, 4S, 9S 0.6 (;.d.)
ll ll C2H5 1S, 4S, 10S 1.8 (i.d.)
I H H C2 5 1S, 4R, 8S 1.0 (i.d.
2 H H H 1S, 4R, 9S 0.3 (i.v.)
2 H 2 5 1S, 4R, 9S 1.2 (i.d.)
3 H H C2ll5 1S, 4R, 10S 2.1 (i.d.)
3 H H H 1 S, 4S, 1 O`S 0 . 5 ( i . V . )
3 1I H H 1S, 4R, 10S 0.6 (i.v.)
1 - 0 -- C H 1S, 4S, 8S 1.1 (i.d.)
2 - 0 - C2H5 1S, 4S, 9S 1.4 (i.d.)
The symbols n, X~ Y~ Z, R1 and RZ relate to compourlds
of the formula I.
The examples ~Ihich -follow serve to illustrate the
;nvention ~I;thout restricting it to the compourlds merltioned
as representatives.
Exarnple 1
t~)-(1S,~tS,~S)~OctahydrocyclopentaCc]pyrrole~1~carboxylic
acid
a) N-Acetyl cis-octahyclrocyclopenla~c~pyrrole
201 ml of acetyl chloride are added drop~Jise at 0C
to a solut;on of 3 g of octahydrocyclopenta~c~pyrrole and
4~2 ml of triethylamine in 30 ml of dry te~rahydrofuranD
When the mixture has been stirred at 0C for 15 m;nutes,
it is diluted ~ith 150 ml of ~Jater, acidi-fied ~Jith 1 N hydro-
chloric acid~ and extracted with methylene chlorideL The
organic phase is dried and concentrated. The crude product
is distilled under a high vacuum~
Yield: 2.~i 9; boiling point 71CtO.2 mmO
b) N~Rcetyl-2-methoxy-cis-octahydrocyclopenta'.c~pyrrole
2.~ g of N-acetyl cis-octahydrocyclopentaCc~pyrrole
are anodically oxidi~ed in methanol in the presence of tetra-
methylamMonium tetrafluoroborate in accordance with the
information in Liebigs Annu Chemu 197~~ page 1,719. The
solvent is removed, the residue is taken up ;n ether~ the
mixture is filtered, and the -filtrate is concentratedu
ll-NI~ data: 3~33 ~ 3.27 ~2s, OC~13)
201Z ~ 2.06 (2s, COCH~)
~ 20 -
c> t~) ~15,4Sf8S)~ Acetyl~octahydrocyclopen~2~c:1pyrrol.e-
1-carbonitrile
1.31 g of -crime~llylsilyl cyanide in 3 ml of methylene
chloride are added at ~ 0C to a solution of 2u~ 9 of N~
S acetyl-2-methoxy-cis-octahydrocyclopentatc~pyrrole in 15 ml
of rnethylene chloride~ 9 of boron trifluoride etherate
are then added dropwise, and the termperature rises to -~0C~
After 2 hours a. -20C and 2 hours a-f 0C wa~er ;s added, and
the mixLure ;s extracted three times w;th methylel)e chlorideO
The organic phase is washed Witll sodium bicarbonate solution
and water as well as with saturated sodium chloride, and
dr;ed, and the filtrate is concentrated~ This gives 202 g
of the title compound in the form of a colorless oil.
d) (_)-(lS,~S,~S)-OctahydrocyclopentaCc~pyrrole-1~carboxylic
acid
2.2 cJ of (_)-(1S~Sr8S)-N~acetyl~octahydrocyclopenta~
[c~ carbonitrile are heated at tlle boil for 2 hours in
ml of concentrated hydrogen bromicleO Tt7e hydrogen brom;de
is distilled of-F, the residue is stirred with a small amount
of acetone~ and the solids are filtered off with suction.
An aqueous soLution of the product is adjusted to pH c;~n
with a weal~ly basic ion exchange material. The ion exchange
rnaterial is filtered off, the solution is evaporated, and
the residue is filtereo' througll silica gel with a mixl:ure
of methylene chloridef methanol, ~cllacic7l acetic acid and
water in a racio of 20 ~ 10 : ODS 0~5~ The el.uate is con~
centrated~ and the residue is triturated with diisopropyl
etherD
Yield: 1.~ g; rnelting point 1')0 - 1~50Co
- 21 -
If the procedures described under Example 1 are
folLowed, the compounds mentioned below under Example 2 and
Example 3 are obta;ned:
Example 2
(+)-(1S,4S,8S)-Octahydro-2H-cyclohexaCc~pyrrole~1~carboxyliC
a _
a) N-Acetyl-cis-octahydro-ZH~isoindole
1H NMR data (CDCl3): 1.0 to 2.3 (m, 10H~
2.0 (2s9 3l~)
3.3 to 4.2 (m~ 4H)
b) N-Acetyl-1-methoxy-cis-octahydro-2H-isoindole
1H NMR data tCDCl3): n.s - 2.6 (m, 10H)
2c1 ts, 3H)
3.3 (s, 3H~
3.5 - 4.0 (m~ 2H3
4.7 - 5.5 (m, 1H)
c) N-Acetyl-1-cyano-cis-octahydro-2H-iso;r,dole
H NMR data (CDCl3): 1.0 - 3.0 (m~ 10H)
2.0 (2S, 3H)
3~3 - 3.9 (m, 2H)
4.4 - 4.7 (m, 1H)
d) tt)-(lS,4S,9S)-Octahydro-2H-cyclohexaCc~pyrrole-1-
carboxyl;c acid
1H NMR data (D20): 1.0 - 3.5 tm, 12H)
3.8 ~ 4.3 tm, 1H~
Example 3
t~)-t1S,4S,10S)-DecahydrocYclohePtaCc]pyrrole-1-carboxylic
a _
a) N-Acetyl-cis-decahYdrOcycloheptacc]pyrrole
i . i
.
- 22 -
1H NMR data (CDCl3)- 1.0 - 2~4 (m~ 12H~
?.0 (2s, 3H)
3.3 - 4.2 ~m, 4H)
b) N-AcetyL 1-methoxy-cis-decahydrocyclohepta~c]pyrrole
1H NMR data (CDCl3): 0.9 - 2.5 (mO 12H)
2.1 (s, 3H~
3.3 (s~ 3H)
305 - 4.0 (m, 2H)
4.7 - 5.5 (m, lH)
c) N-Acetyl-1-cyano-cis decahydrocyclohepta~c]pyrrole
1H NMR data (CDCl3). 1.0 - 3.0 (m, 12H)
Z.O (2s, 3H~
303 ~ 3.9 (m, 2H)
4~4 - 4~7 (m, lH)
d) (t)-(1S,4S,10S)-DecahydrocycloheptaCc~pyrrole-1-carboxyl;c
ac;d
1H NMR data (D20~: 0.8 - 3.4 (m, 14H~
3.8 - 4.3 (m, 1H)
Example 4
ZO (~)-(lS~4S,9S~-Octahydro-2H-cyclohexaCc~pyrrole-1-carboxylic
acid
a) Cis-octahydro-2H-isoquinol;n-3-one
41 9 (0.24 mole) of benzenesulfonyl chloride are
added to a mixture of 33.6 9 ~0~22 mole~ of cis hexahydroindan-
2-oneoxime and 300 ml of 5 N sodium hydroxide solution, the
temperature be;ng kept below 50Cu One hour after the
addit;on has ended, the m;xture is extracted ~ith methylene
chloride, and dried, the filtrate is concentrated, and the
residue is sublimed at 100-110C/20 mm7
~ 23 --
Y i e l a': 2 0 9; In e l t 1 n 9 p o; n t 1 4 9 ~ 1 5 1 C .
bj 4r4-D;chloro-cis octahydro-2H~-isoqu;nol.;n-3 one
28.8 g of phosphorus pentachloride are added at room
ternpera~ure to a solut;on of 23 9 of c;s oclahydro--2~iso-
qu;nolin~3-one ;n 350 ml of anhydrous chloroform. 43.1 g
of sulfuryl c~lor;de in ~5 ml of anhydrous chlorofor~l are
added dropwise at 20 to 30C ;n the course of 30 minutesO
and the reaction mixture ;s stirred at the bo;l for 5 hours~
The m;xture is left to stand overn;ght, and then neutral;~ed
with aqueous potassium chloride wh;ch has been cooled to
0C. The aqueous phase is extracced ~w;ce w;th methylene
chloride~ The combined organic phases are dr;ed over sodium
sulfate~ and concentrated. The residue is recrystallized
from ethanol ;n the presence of active charcoal~ ~his gives
32 9 of pale yellow crystals.
c) 4-Chloro-cis-octahydro~211-isoqu;nol;n~3~one
15.9 9 of ~,4-d;chloro cis-octahydro--2H-isoqu;nolin
3 one are hydrogenated at 20 to 25C in 1 liter of ethanol
in the presence of 10 ml of triethylamine and Raney n;ckel
under atmospheric pressure unt;l 1 mole equivalent of hydro-
~en has been absorbedc The catalyst ;s f;ltered off, the
filtrate is evaporated, the res;due is taken up in ethyl
acetate, and the solution is extractecl twice wlth water and
dried over sodiuM sul-rate~ The solvent is removed, and tl-e
product is triturated with d;;sopropyl e~cher~ and f;ltered
with suct;on~ This gives colorless crystals of the t;tle
compouncl~
d~ (~)D(1S,~4~9S)~Octahydro 211-cyclohexaCc~pyrrole-1-
carboxylic acid
3.75 (~ of 4-chloro~c;s-octahydro-211-;soquinolin~-
one are added to a boilin~ solution OT 6a63 9 of bariurn
hydroxide octahydrate in 120 ml of waterO 'The reaction
mixture is rei'luxed For 3.5 hours~ 0~9 ml of concentrated
sulfuric acid are added, and the r',ix.ure is heated at the
boil for a further houl, and then lef~ to stand overni~ht
to induce coagula~ion.
The pr~c;pitate which is fGrmed is filtered ofF ~ith
suction, and the filtrate is adjusted to pH 605 and then
evaporated to dryness. The residue is extracted ~ h boilin~
ethanol, concentrated~ and made to crystalli~e.
Yield: 3.1 9 (identical to the coMpouncJ describe(l in Example
2d~).
E~ample 5
~ (1S,4R,~S)-Octahydro 2H-cyclollexa[c:lpyrrole~1-carboxyl;c
acid
a) trans-Octahydro-2h-isoquir\olin-3-olle
14.1 9 of trans-hexahydroindall~2-oneoxime are reacted
with 17.2 ~ of ben7encsul-fonyl chloride in a manner similar
to Example 4a) to ~ive 8 ~ of the title sompound;
melt;ng point: 165 167C.
h) 4,4-~Dicllloro-trans octahydro 2H~isoquinol1n~3-one
7.1 9 of trans-oc-tahydro~2H isoquinolin-3 one are
reacted w;th 8~9 9 of phosphorus pentachloride and 14 ml
of sulfuryl chloride in a manner sim1lar to Ex~ample 4b~ to
give 11 ~ of the title compo~lnd. pale yelloll crystals~
melting point: 133 13'7~'C.
~ 25 -
c) 4~Chloro-tralls~octallydro 2H-isoqulnolin 3-one
8 9 of 4~4 dichloro-tralls-octahydro-~2il isoquinolin~
3~one are hydrogenated ;n a manner s;rnilar to Example 4c)
to ~ive 5 g of the t;tle compound~
5 d) (~)-(1Sr4R~9C.j-Octahydro 2H~cyclohe~a[c~pyrrole-1-
carboxylic acid
4.2 ~ of 4-chloro~trans-octahydroY2H~isoqu;nol;n-
3-one are converted in a manner similar to Example 4d) into
3.4 g of the title compound in the form of a colorless,
10 amorphous po~lder.
1H r~lilR data (D~n) 0 ~ - 3.~ (m, 12H)
3.6 4~3 (m, 1H)
The aminoacids which follow can be prepared ;n a
manner similar to the procedure described in Exarnple 4a)
to d).
Example 6
(_)-(1S~4S~8,S~-Oc~ahyclrocyclopentaCc3pyrrole~1-carboxylic
acid
Colorless crystals, rneltin~ poin~c 190 - 195C (identi~
cal with the cornpouncl describecl in Exarnple 1d)).
Example 7
~ (1S,4Rr~3S)-Octahydrocyclopen~aCc~pyrrole~1 carboxylic
ac;d
Colorless, amorphous powder.
1H r~lMR data (D20): 009 3~2 (rn, 10H)
3~5 ~ 404 (m~ 111)
- 26 -
Example 8
~ 1S,4S~1~5)-Dec~hydrocycloheptaCc]pyrrole 1 carboxyl-ic
acid
Colorless~ arnorphous pouder.
1H N~llR data (D20?: 1.0 - 3e4 (rn; 14H)
3~ 4~4 tmf 1H)
Exarnple ~
(~ (1S~'tR~10S)-DecahydrocycloheptaCc~pyrrole 1-carboxylic
ac;d
10 Color.essf amorptlous powderO
H NMR data (D20~: 1uO - 3.6 (In~ H)
3.7 4.1 (rn, 1H)
Example 10
Benzyl t~)~(1S,4S~S)-octahydrocyclopentarc~pyrrole~1
carboxylate hydrochloride
0~7 cg of (~)-(1S,';S,~S)-octahydrocyclopentaCc]pyrl-ole-
1-carboxyl;c acid is added ac -5C to a solution, prepared at
-~tOC, of 0.7 ml of thionyL chloride in 7 rnl of benzyl alcoholL
The mixture is reacted at room teMperature for 20 hours, the
benzyl alcohol is rernoved~ and the residue is triturated
with diisopropyl ether~ This ~ives 0~84 9 of the title
compound in the forrn of colorless crystals ~hicll n~elc at
120 -~ 122C.
1H NM~ daca (DMS0--d6)~ 2~3 (mf ~H)
3~2 3~7 (m, 2H)
3~8 ~ 4O2 (m~ 1H)
5~1 (s, 2Hj
lhe follo~ing benzyl ester deriva~ives of Examples
-- 27 -
11 to 15 can be prepared ;n a manner s;m;lar to the procedure
described in Exarnple 10:
Exampl.e 11
Benzyl ~:t)~-(1S~4S,9S)~oc~ahYdrocYclohexaCc~PYrrole~1
carbo~ylate hydrochloride
1~1 r~Mr~ data ~D~lS0-d6) 1.1 - 2,4 (m, 10H~
3.2 - 3.7 (m~ 2H)
3.8 - 4L3 tlll, 11~)
501 (s, 2H~
7.2 (s~ 5H)
Example 12
Benzyl (~)-(15~4S,1QS) decahydrocyclohep~a~c]-1~carboxylate
hydrochloride
1H N~lR data (DMSO-d6) 0~9 2.4 ~m, 12H)
3.2 - 3.7 (m, 2H)
3.8 - /~.4 (m, 1H)
5.1 (s, 2H)
7.2 (s, 5~1)
Example 1-.
2n Benzyl (t)-(1sr~Rr8s)~octahydrocyclopentaic:lpyrrole~1
carboxylate hydrochlor1de
1~1 NP~R data (DMSo-d6) 10~ - 2D2 (m, 8H)
3.0 ~ 307 (M, 21~)
3.8 ~ 4~4 (m, 111)
. 5.2 (s, ~
7.2 (sr 5~-1)
-- 2
Exarnple 1~.
Benzyl (~ 4R~9S)-octahydrocyelohexarc~pyrrole-1-
carboxylate hydrochlor;cle
~ MR data (DMSO-d6) 1~1 - Z~2 (In~ 1C~I!)
3.0~6 (Ill~ 2~)
,,6 (alO 1~)
5.1(s, 2H)
7~2(s~. 5
Example 15
Benzyl (t)-t1S,4R~10S)-decahydrocyclohepcaCc~pyrlole-1-
carboxylate hydrochlor;de
1H NMR data (DMS0-d~): 1O0 - 2.4 (m~ 12H)
3uO o 306 (m~ 211)
3~7 - 4O4 (m~ 1H)
5.1 (sr 2l-1)
7u~ (s, 5l~)
Exan~ple 16
TertO-butyl (t)-(1S,,4S,8S)-oGtahydrocyclopentaCc:lpyrrole~
1-carboxylate hydrocllloride
2n 10 ml of concentrated sulfuric acid and S0 ~ of
;sobutylene are added to a solution of 10 g of (t)~(1S,4S,SS)
octahyclrocyclnpentaCc3pyrrole 1-carboxylic acid in 100 ml
of dioxane and vhich has been cooled down to -10C. Tl)e
react1On mixture is graduall~ warmed in an autoclave to 20
to 25C, and stirred at th;s temperature for 20 hoursr
The m;xture is added to ice cold 50% strength aqueous
sodiunl hyc~roxicle, and the resultin~ mixture is ex'cracted
with me'chylene chlorideG l'he combined organic phases are
washed with uater~ dried with sod;um sulfate~ and concentrated~
- 29 -
The residue i~ taker, up in ether~ and the solut;on is adjusted
to pH Z~0 to 3~0 by means of ethereal hydroJen chLoride.
The rnixture is evaporated ~o dryness, and the product is
tritllrated wi~n diisopropyl ether~ Filteriny wlth suctiGn
then gives 7.3 9 o-f the ti-tle compouncl.
1H N~lR data (DMS0~d6) 1.0 - 2.4 tm, ~H)
1.3 (s, 91-i)
3 ~2 ~ 3 n O ~m~
3~8 - 4.4 (m, 111)
The ter~ butyl esters of Cxanlplex 17 to 19~ wh1ch
follo~, can be prepared in a sirrlilar manner.
Example 17
Tert.~butyl (~)-(1S~4S,9S)~octahydrocyclonexa~c:lpyrrole~
carboxylate hydrochloride
~H N~lR data (DMS0-d6~: 1.1 2r7 (m, 10H)
1.3 (s, 9H)
3.2 - 3.7 (m, 21-1)
3.8 - 4.5 (rn~ 1H)
Example 1~
Tert. butyl (~-) (1S,4R~8S)-octahydrocyclopenta~c]pyrrole--
1-carboxylate hydrochloride
lR data (D~`lSo-d6' 1.1 - 2~8 (mr ~H)
~ (s~ 91-1)
3.2 ~ 3.6 (m, 2H)
3.7 - 4.5 (m~ 1H)
Exarnple 1~
Tert.^b~tyl ( )-(1S~4R~S)~oc~ahydrocyclol,exa~c]pyrrole 1-
carboxylate hydrochloride
H tJ~lR data ~DMSO~d6) 1.1 3~0 (m~ 10H)
- 30
1~3 (s~ 9H)
3n1 ~ 3~5 (m~ 2~1~
3.7 ~ 4.5 (rn~ 11-l)
Exanlplr.! 20
~enzyl r~l ~1S~carbethoxy~3-pherlylpropyl)~S-alanyl 1s~4Sr~S~
octahydrocyclopentaCc]pyrrole 1~-carboxylate (~~ cl;astereo-
1sor,ler A 20) and ben~yl N~(1S~-carbethoxy 3 phenylpropyl)
S alanyl~1R"~R,~R-octahydrocycl~pentaCc:lpyrrole~1-carboxyl~
ates (= diastereo1somer B 20)
0~82 g of N-(1S~carbethoxy-3~pllenylpropyl)-S~alar,ine~
0.39 g of 1~hydroxybenzotria~ole, 0.~,2 g of benzyl (~ 1S,~S,SS)
octahydrocyclopenta~c~pyrrole 1-carboxylate hydrochlor;de~
0.5 ml of N--ethylmorphol;ne and 0.59 g of dicyclohexyl carbo
diirn;de are added at 20C to 4 ml of dimethyl-formalnide~
15 The mixture is stirred for 3 hours~ diluted ~Jith 50 ml o'r
ethyl acetate, extracted tw;ce ~ith water~ drled over sodiurn
sulfate, and concentrated~
~ his gives a mixture of the abovemen~.loned diastereo-
isonlers A 20 and B 20~ which are separated over silica ~el
witll a mixture of cyclohexane/ethyl acetate (Z~
R~ value for cdiastereo;somer A 20~ 0O22
R~ value For diastereo;sorner B 20 0~20
The compounds of Exarnples Z1 to 29~ which foli.o~,
are prepared in a manner similar to that describec! in Example
~t~
- 31 -
Example 21
Benzyl N~ S-carbethoxy-3-phenylpropyl)-S-alanyl-1S,4R~8S-
octahydrocycLopentaCc~pyrrole-1-carboxylate (= diastereo
isomer A 21)
5 1H NMR data (CDCl3): 1.25 (d+t 6H)
1.3 - 2~4 (m, 10H3
2.3 3.4 (m~ 6H)
4~1 (9, 2H)
4.6 (d~ 1H)
10 5.Z ~s, ZH)
7~2 (59 5H)
7.4 (s, 5H)
Example 22
~n~yl N-(1-S-carbethoxy 3-phenylpropyl)-S-alanyl-1S,4S~9S-
octahydrocyclohexaCc]pyrroLe-1-carboxylate (= d;astereo
;somer A 22)
1H NMR data (CDCl3): 1.1 (d~ 3H~
1.3 (t, 3H)
1.4 - 2~5 (m, 1ZH)
2~3 - 3.4 (m, 6H)
4.2 (q~ 2~13
4.5 (d, 1H)
S.1 (s, 2H)
~.2 ~s~ 5H)
25 7.35 (s~ 5H)
- 32 -
Example 23
8enzyl N~ S-carbethoxy-3-phenylpropyl)~S-alanyl-1S,4R,95-
octahydrocyclohexaCc~pyrrole-1-carboxylate (= d;astereo-
isomer A 23)
5 1H NMR data (CDCl3): 1~2 (d~t, 6H)
1~3 - 205 (m, 12H)
2~3 - 3~4 tm~ 6H3
401 (q, 2H)
4.5 td~ 1H3
5.2 (s~ 2H)
7.2 (s, 5H)
7.35 (s, 5~)
Example 24
Benzyl N-t1-S-carbethoxy-3-phenylpropyl)-S-alanyl-1S04S~10S
decahydrDcyclohepta~c]pyrrole-1-carboxylate (= diastereo-
;somer A 24)
1H NMR data tCDCl3): 1 n2 td~t~ 6H)
1~3 2.6 ~mO 14H)
2.3 - 3u4 ~m, 6H)
4.1 tq~ 2H)
4.6 (d, 1H)
5~2 ts~ 2H)
7~2 (s~ 5H)
7.4 (s, 5H)
25 Example 25
~enzyl N-(1-S-carbethoxy 3-phenylpropyl)-S~alanyL-1S,4R~10S-
dehydroeyclohepta~c]pyrrole 1~carboxylate t= diastereo~
isomer A 25)
1H NMR data (CDCl3): 1.25 (d~t, 6H)
~rl
. ~ .
1,3 Z.5 (m, 1411)
2.3 - 3.4 (mO 6H)
4~5 (d, 1H)
5~2 (s~ 2H)
7.2 ts~ 5i~)
7.4 (s, 5H)
Example 2b
TertO~butyl N~ S-carbethoxy-3-phenylpropyl)-S-alan~l-
1S~S,~S octahydrocyçlopenta~c~pyrrole~1-carboxylate
(= çdiastereoisomer A Z6)
1H N'MR data (CDCl3): 1.25 (d~t, bH)
1.3 (s~ 9H)
1~3 2,6 (.m; 1nH~
2~3 - 3.4 (m, 6h')
. 1 ( q ,, ~
~1.6 td, 1H)
7.2 (s~ S~l)
Example 27
20 Tert.-butyl N-(1~S~carbethoxy-3-phenylpropyl)-~S alarlyl~
1S~4S,~iS-octahydrocyclohexa~c:lpyrrole~1-carboxylate
(= d;astereo;somer A 27)
1H NMR data (CDCl3): 1.25 (d-~t, 6H)
1~3 (s~ 9H)
1.3 2.4 (In~ 12H)
2 r 4 3 ~ 5 (m~
4.1 tq, 2H)
4.6 tcl, 1il)
7~2 (s~ S~l)
- 3~ -
Example 2B
Tert. bu~yl N~ S-carbe~hoxy-3-phenylpropyl)~S~alanyl~
1S,~R,8S-octahydrocyclopentatc]pyrrole-1-~arboxylate
(= diastereo;somer A 28)
H NMR data (CDCl3) 1.25 (d~t~ 6H~
1.3 (s, 9H)
1~3 - 3~5 (m, 10H)
2.5 - 3.5 (m~ 6H)
4.1 (q, ~H)
4.55 (d, 1H)
7.2 (s~ 5H)
Example 29
TertO-butyl N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl-
1S,4R,9S-octahydrocyclohexa~c~pyrrole-1-carboxylate
t- diastereoisomer A 29~
1H NMR data tCDCl3): 1.25 td+t, 6H)
1.3 (s, 9H)
1.3 - 2.6 (m, 12H)
2~ - 3.~ (m, 6H)
4.1 (q, 2H)
4.5 (d, 1H)
7.2 (s, 5H)
Example 30
N-t1-S-Carbethoxy 3-phenylpropyl)-5-alanyl-15,45,8S-octa
hydropenta~c~pyrrole-1-carboxylic acid hydrochloride
Method A:
0.7 g of diastereoisomer A 20, of Example 20, is
hydrogenated at 2D to 25C under atmospher;c pressure in
25 ml of e~hanol ~ith 100 mg of pall.ad;um an;mal charcoal
- ~5 -
(10/~)~ The ca~alyst is separated of;~ and O.S n ethanolic
hydrogen chloride is added to the s,lution un~il it reacts
acidicO The solution is concentrated in vacuo, and the
residue is tr-iturated with di;sopropyl ether~ This gives
400 rng of the title cornpound in the form oF an amorpl-lous
powder.
1H NMR data (DMS0 d6~ 1.25 (d~t~ 6H)
1.3 - 2.~ (m~ 101-l)
2.~ - 3O7 (mr 6H)
~1 tq~ 2i1)
4u4 (d, 1H)
7.2 (s~ 5~)
Method B:
A solution o-f 0.8 9 of diastereoisomer A 26~ of
Example 26, in 5 ml of methylene chloride is saturated uith
dry hydrogen chloride ~as, and then le-ft to stand at 20 to
25C for 16 hoursO The solution is concentrated in vacuo;
the residue is triturated with diisopropyl etherO and fil-
~tered with suction.
Yield: 550 mg.
Example 31
N~ S Carbethoxy~3~-phenylpropyl) S alanyl-1R,4R~8R oc~a
hydrocyclopenta[c~pyrrole-1~carboxyl1c acid hydrochloride
This compound is obtained frorn the diastereoisorner
B 20 of Example 20 in a manner similar to that oF method
of Exarnple 30. Colorless crystals of melting point 185
1 ~8C
- 36
Example 32
N--(1 S-^Carbethoxy-3 phenylpropyl)-S~alanyl~1S~4R~S-octa-
hydrocyclopentaCc~pyrrole~ carhoxylic acid hydrochl.orîde
This compound is obtained from the diastereo;sonler
A 21 of Example 21 ;n a manner similar to that of metilod
A of Example 30.
1H NMI data (CDCl3): 1.2 (d-~, 611)
1~3 ~ 2r4 (m, 1nl~)
2.4 3.7 (m~ 6~)
4.1 tq, 2H~
~ .b (dr 1 H)
7~2 (S~r 51
Example 33
t~i~(1 S~Carbethox>~3 phenylpropyl)-S~alanyl--1$~S~9S~octa~
hydrocyclohexai~c]pyrrole 1-carboxylic acid hydrochloride
This coMpound is obta;ned f-rom the diastereo,somer
A 22 of Exa~ple 22 ;n a manner similar to method A of i--xclmple
30.
1l~ N~lR data (D~1S0 d6) 1.3 td ~ 611)
Z0 1.3 - 2.4 (m~ 12H)
2~4 - 3.7 tm~ 6il)
4.1 (q~ 21-i)
b~4 (d, 1l~)
7.2 (s, 5H)
25 Example 34
N~ S~Carbethoxy-3-pllellylpropyl)-S-alanyl 1S~4Rf9S-octa
c~c~O
hydrc~lexaCc]pyrrole-1 carboxylic acid hydrochloride
~his compound ;s obta;ned from tile d;as-cereoisomer
A 23 o~ E ample 23 in a manner similar to method A o-. Exampl.e
3~
- 3~
1H NM~ data ~PMsO~d6) 1.3 (d:t, 61~?
103 - 2.f~ (In~ 12H)
2.4 3.7 (m, 6H)
4.1 (q, 2H)
~.45 (d, 1l-l~
7.~ ~s, 51~)
The compounds of ExaMples 32 to 34 can likewise be
prepared from the diastereoisomers A 26 to A 2~ by the rnethod
B described in Example 30r
Example 35
N-(1 S-Carbethoxy-3-phenylpropyl)-S-alanyl-1Sr4Sr10S-deca-
hydrocyclohepta[c~pyrrole 1-carboxyl;c acid hydrochloride
This compound is obta;ned from the d;astereoisomer
A 24 of Example 24 in a manner sirnilar to methoa' A of Example
30.
H NMR data (D~lSO~d6): 103 (dlt, 6H)
1Y3 - 204 tm, 14H)
204 - 3Y7 (m~ 6~1)
4.1 (q, 2l-1)
~.6 (d, 1h')
7.2 (s, 5H~
Example 36
N~ S-Carbethoxy-3-phen~lpropyl)-S~alanyl-1S~4R~.10S-deca-
hydrocyclohepta~c pyrrole~1-ca.boxylic acid hydrochloride
25 This compownd is obtained from the diastereoisomer
A 25 of Example 25 in a manner s;milar to method A of Example
3~0
1l~ NrlR data (DMS0 d6) 1.3 (d~t~ 6H)
1.3 - 2~5 ~m~ 1~iH)
38
2uS ~ 3.7 (m, 6H)
4.1 (q. 2H)
4.4 (d~ 1H)
7.2 (s, 5H)
Example 37
S--Carboxy~3-phenylpropyl)-S~alanyl~1Sr4S,8S-oc-tahydro-
cyclopenta~c~pyrrole 1-carboxylic acid
Two ec~uivalellts of potassium hydrox;de and a 10X
strength excess oF 4n potassium hydroxid~e solution are added
to a solution of 1 9 of N~ S-carbethoxy~3~phenylpropyl)-
S-alanyl~15~4$~8S-octahydrocyclopenta~c~pyrrole~1 carboxylic
acid hydrochloride in 10 ml of watern The reac~ion solutior,
is stirred at 20 to 25C for 8 hours, then adjusted to pl-l b ~n
w;tll 2 N hydrochloric acid~ and concentra~ed in vacuou The
residue ;s taken up in ethyl acetate; precipitc\ted salt
;s filtered off~ The ethyl acetate solutic,n is concentrated~
and the res;clue i~ triturated ~ith diisopropyl ether and
filtered off w;th suct;on.
Yield: 0.6 gO
2n 1 H NMR data (CDCl3) 1.2 (d, ~H)
1~2 3~8 (m~ 16H)
4~0 ~ 406 ~mr 1H)
7~2 ts, S~
Example 3
N (1-S-Carboxy 3~phenylpropyl)-S-alanyl-1S~4R~S-octahyclro~
cyclopenta~c~pyrrole~1 carboxylic acid
Th;s cornpound ;s prepared Frorn the compound of
Example 32 in a method similar to that described in Example
~8~
39 ~
1H NMR data (CI~Cl3): 1.25 (d~ 311)
1.3 - 3uq (m 16H)
~nO 4~6 (rn~ 1H~
7~2 ts~ 51~)
S ExaMple 39
N~(1-S Carboxy-3-phenylpropyl)-S-alanyl~1S~4S~S~octahydro-
cyclohexa~c~pyrrole~1~carboxyl;c ac;d
This compound ;s prepared from the compound of
Example 33 ;n a method s;milar that descr;bed ;n Example
37.
1H NMR data (CDCl3)~ 1~25 (d~ 3H~
1~3 ~ 4rO (m~ 18H)
4-0 4Y~ (m~ 11-1)
7~2 (s, 511)
5 Example 40
oc~y~c~
N~ S-Carboxy 3 phenylpropyl~-S~alanyl 1S 4R~9$~cyclohexa-
Cc~pyrrole-1~carboxyl;c acid
This compound is prepared from the compound of
Example 34 ;n a method similar to that describecl in Example
20 37~
1H Ni~R daLa (CDCl3): 1.3 (d~ 3H)
1.3 - 4.0 (m 1~H)
4.0 ~ ~6 (m~ 1H)
7.2 (s 5il)
Example 41
N-(1 S~Carboxy~3-phenylpropyl) S~alanyl--1S~4S 10S~(iecahydro-~
cycloheptaCc~pyrrole~1-calboxylic acid
This compound is prepared flom the compound o
Example 35 in a methoc similar to that described in Example
37.
-- 40 -
~H NMR data (C~Cl3~: 1.2 (d, 3H)
1.3 ~ 4.0 (m, 20H)
l~.0 - 4.5 (m, 1H)
7~2 ~s~ SH)
Example 42
N-(1~S-Carboxy-3 pl-enylpropyl)~S-alc7nyl-1S,4R,,lOS decahydro-
cyclohepta[c~pyrrole~1~carboxylic acid
Thls compound is prepared from the cornpound o-F
Example 36 ;n a method similar to that described in ~xample
37.
1H NMR data (CDCl3): 1.2 (d~ 311)
103 4~0 (m, 20H)
4.0 - 4.5 (m~ 1H)
7.2 (s, 5H)
Example 43
Benzyl N-(1-S-carbctho~y-3 phellyl-3-oxo~propyl) S~alanyl-
1S~4S,8S-octahydrocycloperlta~cipyrrole-1-carboxylate
2.5 g of N~ S-carbethoxy~3~phenyl-3-oxo-propyl)-
S-alaniner 1.2 g of 1-hydroxybenzotria20le, 2 5 g of benzyl
(~)-1S,4S,8S-octahydrocyclopentai~c]pyrrole-1~carboxylate
hydrochloride, 1.25 ml of N-~thylmorpholine and 2 g of di-
cyclohexylcarbodi;m;de are added to 20 ml of dimethylform-
am;de. The mixture is stirred at 0C for 1 hour and then
at 20 to 25C for 12 hours.
The reaction solution is diluted Witil 25 ml of ethy~
acetate; precipitated urea is filtered off witll suctionO
The filtrate ;s concenJr~ted ln vacuo~ the resldue is taken
up in eth~r, the ethereal solut;on is ~lashed ~;th saturated
a~ueous sodiu?l bicarbonate and ll;th ~later, dried~ and
~ 41 ~
concentrated. This gives 3 g of the t;~le compound ;n the
fornl of a d;astereoisomeric mixture~
1H NMR data (CDCl3) 1.2~ (d~t, 61t)
1.0 ~ 2.8 (m~ 14H)
3.~ 5~1 tm, 6H)
7.2 - S~2 (m, 1~ll)
The m;xt~lre of d;astereo;somers can be separated
in.o the optically pure compounds over silica gel by using
cyclohexane/ethyl acetate as an eluanta
Examples b~4 to S0
The following compo~nds, of Examples 44 to 50, can
be prepared from the corresponding bicycl;c carboxylate com~
pounds ;n a manner s;m;lar to that of Example 43.
Example 44
Ben~yl N-(1 S~carbcthoxy~3-phenyl~3-oxo-propyl)~S-alanyl-~
1S~4R~8S~octahydrocyclopenta[c~pyrrole-1 carboxylate
1H NMR data (CDCl~): 1.25 (d+t, 6H)
1~3 r~ z~4 (m, 6H)
2.4 - 3 ~ (m, 8H)
~.2 (~, 2H)
4~3 - 4n8 (mr 1H)
5.2 (s, 2H)
7.2 (s, SH)
7.4 - ~.1 (m, SH)
Example 45
~enzyl N (1 S-carbethoxy~3-phenyl 3~oxo~propyl)-S-alanyl~
1Sr45~9S~octal-ydrocyclohexa~cIpyrrole-1-carboxylate
1H NMR data (CDCl3): 1 o2 (d, 3H)
1.3 (t, 3H)
1.3 - 2.4 (m, 8H)
ZO4 - 3u8 (m, 8H)
4.1 tq, 2H)
4O3 4.8 (m, 1H)
5.2 (s, 2H)
7.2 - 8~2 (m~ 10H)
Example 46
Benzyl N-~1-S-carbethoxy-3-phenyl-3-oxc--propyl)-S-alanyl-
. Oc~hyc1~r~7
1S,4R~9S-~yclohexaCc]pyrrole 1~carboxylate
10 H N~lR data (CDCl~): 1.25 (d~ 6H)
1.3 - 2..4 (m, 8H)
2.4 - ~æ (m~ 8
4.1 (q~ 2H~
4.3 - 4.8 (m~ 2H)
5.Z (s, 2~1~
7~1 - 8.2 (m~ 10H)
Example 47
Tert.-butyl N-(1-S-carbethoxy-3-phenyl-3 oxo~propyl)~S
c~c~ h~
alanyl-1S,4Sf8S-lcyGlopelltaCcIpyrrole-1~carboxyla~e
20 1H NMR data (CDCl3): 1~25 (d+t, 6H)
1u3 (s, 9H~
1.3 ~ 2~4 ~m~ 6H)
2.4 - 30æ (nl~ 8~1)
4.1 (q~ ZH)
4.3 - 4.8 (m, 1H)
7.2 - s~n (m,~ Sl-l)
~L~9~
43 ~
Example 4
Terto~butyl 1~ S-carbe~:hoxy-3~-phenyl-3-oxo-propyl~-S~
alanyl-1S,4R~8S~octahydrocyclopentaCc~pyrrole-1~carboxylate
1H NMR da~a (CDCl3): 1~3 (d~t, 6H)
1.35 (s, 9H)
1~4 ~ 2~5 (m~ bH)
2~5 ~ 3~8 (m~ 8H)
4n15 (q~ 21-l)
4 ~ n 8 t M, 1 ~1 )
7.2 - 800 ~m, 5H)
Example 49
Tert.-butyl N-(1~S-carbechoxy~3-phenyl~3-oxo~propyl.)~S-
alanyl--1S,4SfSS octallyclrocyclohexa[c]pyrrole-1-carboxylace
1H NMR data (CDCl~): 1.3 ~d~c, 6H)
1 4 (s, 9H)
1~4 ~ 2n5 (m~ 8H)
2~5 3~ (m, 8H)
4~2 ~q~ 2~)
4 n3 4 ~8 (m, 1H)
7.3 8.1 (m, SH)
Example 50
Bucyl r~-(1 S carbethoxy-3-phenyl-3-oxo-propyl)-S alanyl~
1S,4R,9S-octahydrocyclohexaCc]pyrlole-1~carboxylate
1H NMR data (CDC l3)~ 1o2 (d~t, 6H)
1~3 (s,,. 9H~
104 - 2~6 (rnO ~H)
2~6 ~ 3~9 ~m~ n~l)
4=2 ~q~ 2H)
4.3 - 4~ tm~ 1H)
7~13 ~ 8n1 (m~ 5H)
4~ -
~xample 51
N-(1 S Carbethoxy-3~pllenyl-3-oxo propyl)-S-alanyl-1S,4S~S~
octahydrocyclopentatc]pyrrole-1~carboxylic acid
0.9 t1 of the compound ~f Example 47 are st;rred at
20C for 2 hours in 6 ml of tri-fluoroacet;c acid. The solution
is concentrated in vacuo~ and the residue is tritura~ed ~ h
diisopropyl ether and filtered of~ ~ith suct1on.
Yield: 0.4 9~
11l NMR data (CDCl3). 1.2 (d-tt, 6H)
1.3 - 3.6 (m, 12H)
4.2 (q, ~)
4.1 - 4.6 (m, 4H)
7~3 - 8~1 (m~ 511)
The compounds of Examples 52 to 54, which -follou~
can be prepared in a manner similar to that described in
~Example 51:
Example 5~
N~ S-Carbethoxy~3-phenyl-3~oxo-propyl)-S~alanyl-1Sr4~,8S-
octahydrocyclopentarc]pyrrol.e-1-carboxylic acid
20 1H NrlR data (CDCl3): 1.25 (d-~t, 61-l)
1.3 - 306 tmr 12H)
4.2 t~ ?H)
4o1 ~ 406 (mr 4H)
7~3 - 8.1 (rn~ 5H)
Example 53
N-(1-S-Carhethoxy~3-phenyl~3~oxo-propyl)~S-alanyl~1Sr4S,95-
octahyclrocyclohexaCc]pyrrole-1^ca.rboxyl;c acicl
1H NM~ data (CDC l3) 1~3 td~t~ 6H)
1~3 - 3~6 (m, 14H)
4.2 (q, 211)
4 ~ o 6 ( m ~
7=3 - ~1 (m~ 511)
Example 54
N~ S-Carbetl)oxy~3~phenyl-3-oxo-propyl)-S~al.anyl 1S,~tR,9S-
octahydrocyclohexaCc]pyrrole 1-carboxylic acid
1H NM~ da~a (CPCl3)~ 1.3 (d~tf 6H)
1~ - 3~6 (m, l4H)
~.2 (q~ 2~)
4.1 - 4.6 (r,l, 4H)
7~3 ~ 8 1 ~m, 5~l)
Example 55
N-(1-S-Carbethoxy-3~phenyl~3~oY.o-propyl)-S~alanyl~1S~4Sr8S-
oc~ahydrocyclopenta[c]pyrrole-l-carboxylic acid
15 This compound is prepared by reacting 0~5 g of N~
S-carbe'choxy 3-phenyl~oxo-propyl)-S-alanyl-lS,4Sr8S-
octahydrocyclopenta~c~pyrrole-1~carboxyl.ic acid with potassiuln
hydroxide ;n a rnanner similar to that described in Example
37:
20 1ll NM~ data (CDCl3) 1.2 (d~ 3H)
1.2 3O8 (m, 14H)
4.0 - 4u6 (m, 1H)
7O2 - 7=9 (m, SH)
Example 56
25 N-~1-S-Carbethoxy-3~phetlyl~3~hydroxypropyl)~S~alanyl-1S,~tSr8S-
octahydlocyclopentaCc~pyrrole~1-carboxylic ac;d
1 g of N-(1-s-carbe1:hoxy-3-phenyl 3voxo~propyl)-S~
alanyl-1S~4S~8S-octahydrocyclopentaCc~pyrrcle~ carboxylic
acia is dissolved in 50 ml o-F anhydrcus e-thanolr and
ll9B3L:l~
~ ~6
hydrogenated a~ 20 to 25C under atmospheric pressure ~ith
1 mole equivaler,~ o-f hydrogen usin~ SO rng of palladium/char
coal. The catalyst ;s f;ltered oFF, the solut;on is evapor~
ated to dryness, and the residue is triturated with diiso
propyl ether and filtered oFf ~ith suction.
~'ield: 0.7 9.
1H NM~ data (CDCl3)o i n3 (d~t, 6H~
1~3 - 3.6 ~m, 12~')
4~2 (q, 2~1)
4u1 - 406 (m~ 4H)
4.8 (d, 1H)
7.0 ~ 7.5 (m, 5H)
Example 57
Benzyl S-alanyl~1S~S~8S~oc~ahydrocyclopeniaic~pyrrole-1-
carboxylate
a) Ben~yl N-tertc-butoxycarbonyl-S~alanyl~1S,~S,8S-octahydro-
cycloDenta[c~pyrrole~1 carboxylate
13 ml of N-etllylmolpilvline, 13~5 g of 1-hydroxyben~o-
triazole and 29.6 g of benzyl 1S~4S,SS--octahydrocyclopenta
~c]pyrrole-1-carboxylate hydrochloride are added to a sol-
ut;on of 19 9 of BOC-Ala-OII in 100 rnl oF D~lF~ The mixture
;s cooled in an ice bath, and 21 g of dicyclohexylcarbodi~
imide are added to it. The resultincJ mixture is st1rred
at 20 to 25C for 15 hours. The precipitated urea is f;l~
tered off ~ith suction, the Filtrate is concentrated in
vacuo~ and the residue is taken up in ethyl acetate~ The
organic phase is extracted 3 times each ~ith aqueous potas~
sium hydro~e~sulFate, potaC;sium hydr~encarborlate and sodium
chloride~ dried~ alld evaporated to dryr,ess~ The residue is
- 47 -
is chromatographecI over s;l;ca ~el ~;th ethyl acetate/cyclo~
hexane ~1:3)~ TI1e first fract;on conta;ns the des;red product.
Yield: 21 ~.
1H NMP~ data (CDCl3): 1.3 (d, 3H)
1045 ts~ 91~)
1.1 - Zu4 (m~ 8H)
3.2 - 3~9 (m, 4H)
5 a 3 ( s ~ 2 ~1 )
7~ ~s~ 5~
10 b) Benzyl S~alanyl-1S~4S,~S oc~ahydrocyclopeI-taCc~-
pyrrole~1-carboxyl3te
20~5 9 o-f benzyl N-te,t~-butoxycarbonyl S-hlanyl
1S,4S,~S-octahydrocyclopenta~c]py,-role-1-carboxylate are
dissolved in 50 ml of tr1fluoroacetic acid~ The solution
is reacted fGr 10 minutes and then concentrated in vacuo,
and the residue is triturated several t;mes with diisopropyl
ether, and dried in vacuo.
Yield: 12~5 ~
Examples 58 to 62
These compounds are prepared in ways simiLar to
those described in Exarnple 57 under a3 and b):
Example 58
Benz~l S-alanyl-1S,~R,8S octahydrocyclopenta~c~pyrrole-1
carboxylate
25 1II N,lR data (C~5l3): 1.3 ~d, 3H)
1.1 - 2~4 tm~ 8~I3
302 ~ 3~9 (m~ 4H)
5.3 (s, 2~1)
7~4 ~s~ 5H)
~3~
,~ ~
Example 59
Benzyl S--alar.yl~1S,~S~9S-octahydrocyclohexa~c~pyrrole-1
carboxylate
1H NMR data tCDCl3): 1.3 (d~ 311)
1.3 - 2.6 (m, 10H)
3.2 - 3~9 tm~ l.H)
5~3 (5r 2H)
7O~ (s~ 5~I)
Example oO
Benzyl ~-alanyl-1S~4Rj~S-octahydrocyclohexa~c:lpyrrole~1
carboxylate
1H NMP~ data tCDC l3) 1~3 (d, 3H)
1.3 - 2.5 (m, 1~H)
3.1 - 3.9 (m~ 4H~
5.2 (s, 2H)
7.4 (sO 5H)
Example 61
Benzyl S~alanyl 1S,4S,10S~decahydrocyclohep~aCc~pyrrole~1
carboxylate
1It NMR da~a tCDCl3): 1.3 td~ 3H)
1.3 2~7 ~m, 1211)
3.1 3.9 (rn, ~H)
5.2 (s, 2H~
7.4 (s~ 5H)
Example 62
Ben.~yl S~alar,yl 1S~.Rr10S-decahydrocycloheptaCc]pyrrole-1
carboxylate
1H NMR data (CDCl3~ 3 (d~ 3H~
1rr3 ~~ 2~8 fmr 1ZH)
3.1 3.9 (m, I~H)
5.2 (s, 2H)
7~4 (s~ 5~1)
Example 63
N~ S-Carbethoxy~3~phenylpropyl)~S~alanyl~1S~tSs.8S-octa-
hydrocyclopentaCc3pyrrolP-1-carboxylic acid
a) ~en~yl ~-(1 S~carhe-thoxy~3-phenylpropyl)-~S--alanyl-1S~4S~aS-
octahydrQcyclopenta~c:lpyrrole-1~carboxyla~ie
10 rnrnoles o-f benzyl S--alanyl 1S~-'tS~8S~octahydro-
cyclopentaLc~pyrrole 1-carboxyla~e are dissolved in 30 rnl
of anhydrous ethanol~ The solution is adjusted to pl~ 7.0
by means of ethanolic potass;um hydroxider and 1 ~ of- pulver
ized molecular sieve (4R) and then 10 mrnoles o-F ethyl 2~keto-
4-pllenylb~ltyrate are added. A solution of 1 ~ of sodium
cyanoborohydride in 10 ml of anhydrous cthanol are slowly
added dropwis2. The react;on solution is reacted at 20 to
25C for 2~ hours and then f-iltered~ and the solvent is
distilled o~f~ The residue is talen up in ethyl accta~e/
~ater~ The ethyl acetate phase is evaporatedr and ihe resi
due is chromatographed over silica gel with ethyl acetate~
cyclohexane (1:~). The ~H NMR data agree with the data
of the compound of Exanlple 20~
b) Ihe coMpound obtained above ;s converted as described
;n rnethod A of Example 30 into the desired compound~
Example 64
~en7.yl rl-~1-S carbethc,xy~3 phenyl-3~oxo~propyl)~S-alanyl-
15,,llS,,,.9S~oc_ah~/drocyclc)hexal~c'll)yrrole-1 carhoxylate
10 nlrnoles of benzyl S--alanyl~1 S~4Sr9S octahyclrocyclo~
penta[c~pyrrole~ carboryla~e~ 10 rnmoles of 3 ethyl ben~oyl
- 50 -
acrylate and 10 mmoles of triethylamine are dissolved in
100 ml o-f anhydrous ethanol~ and the mixtule is stirred at
20 to 25C for 2C~ hours. It is neutralized w;th 1 N hydro-
chloric acid, and evaporated t~ dryness~ and the residue
is taken up in ethyl acetate/waterO ~he ethyl acetate phase
;s dried and evaporated to dryness,. and the residue is chroma-
to~raphed over s;lica gel~
Example 65
Benzyl N~ S-carbethoxy-3-oxo~3-phenyl-propyl)-
1S~I~S~10S~-decatlydrocycloi1e~taCc~pYrrole-1-carboxylate
10 mmoles of acetophenone. 10 mmoles o-f ethyl ~lyoxyl~
ate and 10 mmoles of benzyl S alanyl~1S,~S,10S-decahydrocyclo-
hepta[c~pyrrole-1-carboxylate are heated at 45C in ~0 ml of
glacial acetic acid for 3O hours. The mixture is concentr~ted
in vacuo, renoered alkaline with aqueous so~ium bicarbonateg
and extracted ~ith e-thyl acetate. The ethyl acetate phase
;s evaporated to dryness, and the residue is chromatographed
over silica gel.
Example 66
2n N~ S-Carbetlloxy~3 pherlylpropyl)-O ethyl-S-tyros~Jl~ 1Sr/~S,~gS-
octahydrocyclopenta~c~pyrrole-1 çarboxylic acid
a) Benzyl N-~1 R~S-carbethoxy-3-phenylpropyl)~0 ethyl-S-
tyrosyl ester
24 9 of ethyl benzoylacrylate are reacted in 1C0 ml
of ethanol h~ith 30 g of benzyl 0-ethyl S-tyrosine ester in
the presence of O~S ml of triethylamine~ the mixturc is con-
centrated to dryness, and the residue ;s taken up ~ith dieth>l
etl1er/petroleum ethe~ 1) and dried in vacuo, to g;ve
~2 g of the title compound~
b~ N~ R~S Carbethoxy-3-phcrlylpropyL)-n~etllyl~S~tyros;ne
~ 0 g of the comF)ound obta1ned in Example 66a are
hydrogenated at room temperature and under 100 bar in 800 ml
of glacial acet;c ac;d us;ng 4 ~ of Pd/C (10%)~ Chromato-
graphy over silica gel using ethyl aceta.e/cyclohexane (1:3)as eluant and drying of the residue of evaporation give 25 9
of the title compound in a form ~/hich is alrnost pure by
thin layer chromatography and has a melting point of 205-
213C
C22H29N05(39~5) Calculated C 6~.15 ll 7~31 N 3~50
Found C 69uS H 7n~ N 3~3
c) N~ S~Carbethoxy 3~phenylpropyl~ 0 ethyl~S tyrosyl-
1S~4S 8S octahydlocyclopentaCc~pyrrole~1-carboxylic acid
1.5 g of the benzyl ester described in Example 10
are reacted in a manner similar to that descr;bed in Example
20 ~lith 2.5 9 of N (1 R S-carbethoxy 3~phenylpropyl)-3 ethyl-
S~tyrosine 1.3 9 of dicyclohexylcarbodi;lll;de and 0~ g of
1-hydroxybenzotriazole. Chromatography of the crude product
over s;lica gel using cyclohexane/ethyl acetate (1:1) as
eluan~ gi~es 1 9 of the title compound in the form of a col-
orless oil.
The 1H NMR data and the mass spectrum are in accord
ith the ind;cated structure~
The benzyl ester is hydrogenolyzed in a manner similar
to that described ;n Example 30. This ~ives 006 9 of the
title compolnd in the forrn of a colorles amorphous powder;
H NMR data. 7.3 ~s 5H)~
7~1 6 5 (2d~ llH)d
4~4 ~ 'tuC (m~ 4H);
~~ 52
3~9 3nU (m, 4~
2~9 ~ 1~2 (m, 15H);
1.4 (t, 3H);
1~25 (t, 3H)o5 Example 67
N-(1-S~Carhethoxy-3-phenylpropyl)-0 methyl-S tyrosyl-1S~4S~8S-
octahydrocyclopentaCc~pyrrole-1 carboxylic acid
The title compound is obtained in a manner similar
to that described ;n Example 66 by using benzyl O-me-thyl
1n tyrosine ester in place o, benzyl O-ethyltyros;nc ester in
the stage analogous to 56a, L
1H NMR data: 7L2(S~ 5H);
7.16.5 (2d, 4H)~
~n O ( m, 31~)~
~3~0 (rn, 3li);
~5(s, 31~);
2.9 - 1.2 (m, 15H);
1.3 (t, 3H)~
Examp~e 6~
20 N~ S-Carbethoxy-3 phenylpropyl?~O ethyl-S-tyrosyl 1S,LSr9S-
octahydro;soindole-1~carboxylic acid
Prepared in a manner similar to that described in
Example 66 from the aminoacid described in Example 2r The
1l-l NMR data agree with the indicated structure~
Example 69
N~ S Carbethoxy~3~phenylprop)~ 0-methyl~ tyrosyl~1S~4S~9S~
octahydro;soindole-2~carboxylic acid
Prepared in a manner similar to that o'escribed in
~xaMple 6~ frorn the aminoacid described in Example 2. The
- 53
H NMR data agree with the indicated structure~
Example 70
N~ S-Carbethoxy-3-phenylpropyL)-0-ethyl-S tyrosyl-1S~4S,8R-
octahydrocyclopenta[c]pyrrole-l-carboxylic acid
Prepared in a manner sim;lar to that described in
Example 6~ from the aminoacid described in Example 7.
1H NMR data: 7.3 (s, 5H);
7.2 - 6~6 ~2d, 4H);
4.4 - 3.9 (m, 4H)~
3~9 3.0 (m, 4H~;
2 ~9 ~ 1 r2 (m, 15H~;
1.35 (t, 3H)9
1925 (t, 3H~.
Example 71
15 N-(1-S-Carbethoxy 3-phenylpropyl)-0 methyl-S-tyrosyl-1S94S,8R
octahydrocyclopentaCc]pyrrole-1 carboxyLic acid
Prepared ;n a manner s;m;lar to that described in
Example 67 from the aminoacid descr;bed in Example 7. The
1H NMR data agree w;th the indicated structureD
ExampLe 72
N~ S-Carbethoxy-3-phenylpropyl)-D-ethyl-S-tyrosyl~1S~45,9R-
octahydrocyclohexaCc~pyrrole-1-carboxy~;c acid
Prepared in a manner similar to that described ;n
Example 66. The analyt;cal data agree w;th the indicated
structure.
Example 73
N-~1-S-Carbethoxy-3-phenylpropyl)-O~methyl-S-tyrosyl-1S,4S,9R-
vctahydrocyclohexaCc~pyrrole~1~carboxyl;c ac;d
Prepared in a manner similar to that described in
.~
L8
-- 54 --
Example 67. The analytical cla~a a~ree wi~h l:l~e inclical:ed
~trucl:ure~
