CA1267902A - 2-azabicyclo [3.1.0] hexane derivatives and a process for their preparation - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to compounds of the formula IIIa or IIIb.

(IIIa) with mirror image (IIIb) with mirror image wherein W denotes hydrogen or a group esterifying carboxyl, and a process for the preparation of compounds of the formula IIIa or IIIb. The compounds of the formula IIIa or IIIb are intermediates in the process for the preparation of compounds of the formula I:

Description

i7~

2 -KOE ~3/F 119 This is a Divisional of Canadian Patent Application Serial Number 458,205 filed July 5, 1984.

I ~

The invention relates to der;vat;ves of 2-aza~
bicyclo~3.1.0~hexane-3-carboxylic acid of the formula I

02R ~I) I .~ ' * Y
Co-C~3-~H-~H-/CH27n-¢-~t R 1 C2n Z

in which the hydrogen atoms at the br;dgehead carbon atoms have the c;s conf;~uration with respect to one ano~her, and the COOR group on carbon atom 3 ;s oriented exo or endo to the bicyclic ring system, and in which n denotes O or 1, R denotes hydrogen, ~C1-C6) alkyl, ~C2-C6)-aLkenyl or ~C6~C12)~arYi-(c1-c4)-a~ky~
R~ denotes hydrogen or ~C~ ~o C6)-alkyl, uhich can optionally be subst~tuted bY am;no tC~ to C6)-acylam;no or benzoylamino, ~C2 to C6~-alkenyl, ~C5 to C9)-cycloalkyl, ~C5 to C9)-cycloalkenyl, ~C5 to C7)-cycloalkyl-~C1 to C4)-alkyl, ~C6 to C12)-aryL or partially hydrogenated ~C6-C12)~

aryl, each of ~Ihich can be substituted by ~C1 to C4~-alkyl~ (C1 or C2)-alkXY or halogen, ~ 7~

- 3 -(C6-c1Z)-aryl-(c1 to C4)-3lkyl or (C7-C13)-aroyl-(Cl-C2)~alkYl~ both of ~h;ch can be substi-tuted in the aryl radical as defined above~ a monocyclic or bicycLic heterocyclic radical having 5 to ~ or 8 to 10 ring atoms respectively, 1 or 2 of these ring atoms being sulfur or oxy-gen atoms and/or 1 to 4 of these ring atoms being nitrogen a~oms, or an optionally protected side chain of a naturally occurring ~-aminoac;d Rt-CH(NH2)-COOH, R2 denotes hydrogen, (C1-C6)-alkyl~ ~C2-C6)~alkenyl or tC6-C12)-arYl-(~1-c4)-alkyl~ ~
denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen, and X denotes tC1-C6)-alkyl, (C2-C6) alkenyl~ ~Cs 9 cycloalkyl, (C6-C1z)-aryl, preferably phenyl~
~h;ch can be monosubstituted, disubstituted or trisubstituted by ~C1-C4)-alkyl, (C1-C4)-alkoxy~
hydroxyl, halogen, nitro, amino, acyl ~ no,~C1-C4)-aLkyl-amir~o, di- (C1-C4-alkylamino and~or met}~.ylene~
dioxy, or 3-indolyl, and their physiologically acceptable salts.
Those compounds of the formula I in which n is 1, R~ denotes hydrogen, allyl, vinyl or an optionally pro-tected side chain of a naturally occurring ~-aminoacid, and R, RZ, Y, Z and X have the prev;ous mean~ngs, are preferred9

- 4 -in part;cular those compounds of the formula I ;n wh;ch n denotes 1, R denotes hydrogen, R1 deno~es me~hyl~ ~he optionally acylated side chain of lysine or the 0-(C1-C6)-alkyLated side cha;n of tyrosine, R2 denotes hydrogen, methyl, ethyl, benzyl or tert.-butyl, X denotes phenyl or phenyl ~hich is monosubstituted or d;sub-stituted by fluorine and/or chlor;ne, Y denotes hydrogen or hydroxyl, Z denotes hydrogen, or Y and Z together denote oxygen.
Particularly preferred compounds which may be mentioned are:
N-tl-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-aza-bicycloC3.1.0~hexane-endo-3-S-carboxyl;c acid, N-t1-S-carboxy-3-phenylpropyl)-S-alanyl-c;s-2-azobicyclo-C3.1.0]hexane-endo-3-S-carboxylic ac;d~
N-(1-S-carboethoxy-3-phenylpropyl)-S-lysyl-cis-2-azabi-cycloC3.1.~hexane-endo-3-S-carboxYlic acid, N-t1-S-carboxy-3-phenylpropyl)-S-lysyl-cis-2 azabicyclo-~3.1.0~hexane-endo-3-S-carboxylic acid, N-t1-S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-cis-~2-azabicycloC3.1.0~hexane-endo-3-S-carboxylic acid, N-t1-S-carboethoxy-3-phenylpropyl)-0-methyl-S-tyrosYl-cis-2-azabicycloC3.1.0~hexane-endo-3-S-carboxylic ac;d~
N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-azab;-cycloC3.1.0~hexane-exo-3-S-carboxylic acid, N-tl-S-carboxy-3-phenylpropyl)-S-alanyl-cis-2-azabicyclo--- 5 --C3~1.0~hexane-exo~3-S-carboxylic acid, N-(1-S-carboethoxy-3-phenylpropyl)-S lysyl-cis-2-azabi-cycloC3.1.0~hexane-exo-3-S-carboxylic acid, N-~1-S-carboxy-3-phenylpropyl)-S lysyl-c;s-2-azab;cYclo-~3.1.0~he~ane-exo-3-S-carboxylic acid, N-(1-S-carboethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl-cis~
2-azabicyclo;3.1AO~hexane-exo-3~S-carboxylic acid and N-(1-S-carboethoxy-3-phenylpropyl)-0-methyl-S-tyrosyl-c;s~
2-azabicyclo~3.1.0~hexane-exo-3-S-carboxyl;c acid.
Particularly su;table salts are alkali metal and alkaline earth metal salts, salts with physiolo~ically tolerated amines, and salts w;th ;norganic or organ;c ac;ds, such as, for example, HCl, ~IBr, H2S04, maleic acid, fumaric ac;d or tartar;c acid.
In th;s context as in the following, aryl is to be understood to be opt;onally substituted phenyl, naphthyl or b;phenylyl, but particularly phenyl. Alkyl can be straight-chain or branched.Acyl~no is to be ~nderstQod to be in par-ticular (Cl-C6)-a~noyl~no,Bcc-aNno or benzcyl~no.
A monocyclic or bicyclic heterocyclic radical hav-ing S to 7 or 8 to 10 ring atoms respectively, 1 or 2 of these r;ng atoms being sulfur or oxygen atoms and/or 1 ~o 4 of these r;ng atoms being nitrogen atoms, ;s understood to include, for example~ thienyl, benzo~b~thienyl, furyl, pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyr;dyl, pyrimidinyl, pyridazinyl~ indazolyl, isoindolyl, indolyl, purinyl, quinol;z;nyl, isoquinolinyl~ phthala-zinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl.
These radical3 can also be partially or completed hydrogenated.

.

z Naturally occurring ~-aminoac;ds are described in, for example, Houben-~eyl, Volumes XV/1 and XY/2.
. If R1 represents a protected side chain of a naturally occurring ~-aminoac;d, such as, for example, pro-tected Ser, Thr, Asp, Asn~ Glu, Gln, Arg, Lys, Hyl, Cys, Orn, C;t, Tyr, Trp, His or ~yp, ~he preferred pro~ec~ive groups are those customary in peptide chemistry ~cf.
Houben-Weyl, Volumes XV/1 and XV/2~. In the case where R1 denotes the protected side chain of lysine, the known amino protect;ve groups, but particularly ~C1-C6)-alkanoyl, are preferredn In the case where R1 denotes the protected s;de cha;n of tyros;ne, the ether protective group on ~he oxygen, ;n particular ~C1-C6)-alkyl, is preferred; par-t;cularly preferred protect;ve groups are methyl and ethyl.
Compounds of the formula I have ch;ral carbon atoms. The invention relates to both the R and the S con-f;gurations at all centers of asymmetry. Thus the -corn-pounds of the formula I can exist as optical isomers, as diastereomers, as racemates or as mixtures of these. How-ever, those compounds of the formula I ;n wh;ch the carbon atom 3 in the b;cyclic ring system as well as the carbon atoms ;n the side chain labelled with an asterisk t*) have the S configuration are preferred, ~ith the exception tha~
the R configuration of this center is preferred when tNH-GHR~ CO) = Cys.
In addition, the invent;on relates to a process for the preparation of the compounds of the formula I which comprises reacting, by methods of am;de formation known in peptide chemistryO a compound of the formula II, in which `` ~L2~i79@~2 n, R1, R2, X, Y and Z have the previously mentioned meanings, wi~h the exception of that of R2 = hydrogen, with a compound of the-formulae IIIa or IIIb, or the m;rror ;mage or the racemate~ ;r, wh;ch W denotes a group ester;fy;ng carboxyl, suc.h as (C1 C6) alkyl or tC7-C8)-aralkyl, preferably tert.-butyL or benzyl, and subsequently l;beratin~ the com-pounds of type I w;th R = hydrogen by hydrogenation or treatment with ac;d and/or base.
D;astereomers of the formula I can be separated ~rom one another by, for example, crys~allization or chro-matography.

Z R
X~C-~CH2;7n-CH-N~H-CH_Co2H (II) ~N ~ ~IIIa) and m;rror ;mage ~ ' H:

- ~IIIb) and m;rror .mage ~02C ~1 .

Further synthet;c processes for the preparation of the compounds of the formula I in which Y and Z together denote oxygen entail reacting, in a known manner ;n a ~;chael reaction (Organikum, 6th Edit;on, page 492, 1967~, a compound of the formula IV

~d902 CO
~\~ 2 (IV~

, CO-C~ TH2 in ~h;ch R1 has the meaning as in formula I, and ~ has the meaning as in formulae IIIa and b, with a compound of the formula V
R202C-CH=CH-Co-x ~V) in which R2 and X have the meanings as in formula Io and, where appropriate, splitting off the radical W and/or the radical R2 as described above, or reacting, in a known manner in a Mannich reaction ~Bull. Soc. Chim. France 10 1973, page 625), a compound of the abovementioned formula IV uith a compound of the general formula VT, in which R2 has the meaning as in formula I, and with a compound of the general formula VII
OHC-C02R2 ~YI) X-C0-CH3 (VII~
in which X has the meaning as in formula I, and then, where appropriate, splitting off the radical ~ and/or the radical R2 as described above with formation of the free carboxyl groups.
In addition, it ;s also poss;ble to prepare com-pounds of the formula I w;th Y and Z each being hydrogen in a manner such that the compound of the abovementioned formula IY is reacted, in accordance w;th the procedure described ;n J. Amer. Chem. Soc. 93, 2897 t1971), with a compound of the formula VIII

3%

2 ~VIII) ' O = C\

;n which R2 and X have the meanings as ;n formula I, reducing the resulting Sch;ff's bases and then, where appropriate, splitting off the rad;cal W andtor the radical R2 as described above with formation of the free carboxyl groups. The reduction of the Sch;ff's bases can be carried out electrolytically or us;ng reducing agents such as, for example, sodium borohydride or sodium cyano-borohydride.
Compounds of the formula I with Y being hydroxyl and Z be;ng hydrogen can also be obtained by, for example, reducing a compound I, by Y and Z together being oxygen, uhich is obtained w;th the above procedures. This reduc-t;on can be carried out w;th a reducing agent, such as sod;um borohydr;de and other complex boronates or~ for example, borane-am;ne complexes.
Compounds of the formula I in which R represents hydrogen can, where appropriate, be converted by methods known per se into their esters of the formula I in which R
denotes (C1 to C6)-alkyl or (C7 to C9~-aralkyl.
The react;on of a compound of the formula II with a compound of ~he formula $II to prepare a compound of the formula I is carried out ;n accordance w;th a condensation reactinn known in peptide chemistry, the condensing agents added being~ for example, d;cyclohexylcarbod;;mide and 1-~ 10 -hydroxybenzo~r;azole. When subsequently spl;tting off the radical ~ with acid, the acids ~hich are preferably employed are trifluoroacetic acid or hydrogen chloride.
Compounds of the formula II have already been pro-posed. Those w;th X be;ng phenyl, Y be;ng H, Z be;ng H, R1 be;ng CH3 and R2 be;ng CH3 or CzH5 are known tfor example from European Patent 0,037,231) and are accessible by various routes. The benzyl esters tR2 = benzyl) can be preparcd analogously~
The Mannich reaction of acetophenones of the for-mula IXa, in wh;ch X represents aryl ~h;ch is opt;onally subst;tuted as previously, with gLyoxylic esters and ~-aminoscid esters leads to compounds of the formula II in ~hich n denotes 1 and Y and Z together denote oxygen (for-mula IX). In formula IX, W' denotes a radical which can be split off by hydrogenolysis, or by base or acid, preferably benzyl or tert.-butyl, and X, ~here appropriate, represents the meanings defined previously.
However, in the case of the benzyl ester (W' = ben~
zyl), R2 may not be benzyl. On hydrogenolysis of these compounds with Pd, compounds of the formula II in which Y
and Z are hydrogen are produced.

R~
-CO-CH3 + SHO ~ H2N-CH-C02W' C02R2 R1 C02R2 - ~ X-CO-CH2-CH-NH-C~-CO W ' (IXa) (IX) 2 Compounds of the formula II in ~ilich Y and Z to-gether denote oxygen can likewise be obta;ned in high ~ ~ . .

.. .. .

y;elds by M;chael add;~ion of appropr;a~e acylacryl;c esters and ~-aminoac;d esters. Ester cleavage leads to the same products as does the Mann;ch react;onl ~1 (IX) - X-C-C.~-CX-C02~2 ~ NH2-CH-COzW~ ~

The amount of the d;astereomers hav;n~ the pre-ferred S,S conf;gura~;on produced on using es~ers of L-aminoac;ds predominates, and they can be obtained by crystal-~izat;on or chromatographic separation of the esters on silica gel.
The compounds of the abovementioned formula IV used as starting materials for the preparation of the compounds of the formula I are obta;ned from the compounds of the abovementioned ~ormulae IIIa or b or the mirror images by reaction, by kno~n procedures, ~ith an N-protected 2-amino-carboxylic acid of thc formula X

~X) Y - HN - C~ - C02H

in ~hich V is a protective group and R~ has the abovemen-tioned meaning. An example of a suitable protec~ive group ~V, which is spli~ off again after reaction is Gomplete, is tert.-butoxycarbonyl~
The invent;on also relates to compounds of the formulae IlIa and IIIb and their m;rror imagcs in ~hich W
denotes hydrogen or a group esterifying carboxyl, preferably (C1 to C6)-alkyl or ~C7 or C3)-aralkyl, and to a process '' -: ,.

for their preparation which comprises rearranging compounds of the formula XI
Hal (XI) O
H

;n which Hal represents halogen, preferably chlorine or bromine, in the presence of a base~ and, where appropriate, converting~ in a manner known per se, the result-ing com-pounds of the formulae IIIa or IIIb (W = hydrogen) and/or their m;rror images into the abovementioned esters.
Compounds of the general formula XI can be prepared by converting a compound of the formula XII (Limasset et al., 8ull. Soc. Chimn France 1969, 3981) (XII) O, into its oxime, reacting the latter in a aeckmann rearrange-ment, for example ;n analogy to Helv. Ch;m. Acta 46, 1190 ~1963) to give a compound of the formula XIII

<~ ~XIII) H

halogenating the latter to give a compound of the formula XIV

67~32 Hal - ~Hal ~XIV) N~ o in which Hal denotes a halogen atom, preferably chlorine or bromine, and catalytically reducing the latter to give compounds of the formula XI.
S The conversion of the ketone XII ;nto the corres-pond;ng oxime ;s usually carr;ed out ;n an aqueous-alcoholic med;um w;th excess hydroxylamine hydrochloride, the free acid being neutralized with sodium carbonate or sodium acetate. In place of hydroxylamine, ;t is also possible to use sod;um hydroxyla~ine-N,N-disulfonate ~Org. Synth.
3 C1923] 61) or the sod;um salt of hydroxylam;ne-N-mono-sulfonic acid (J. Amer. Chem. Soc~ 46 ~1924~ 12~0).
Reaction of the ketone XII with hydroxylamine-O-sulfonic ac;d ;n a concentrated organ;c ac;dr preferabLy formic acid, has proved to be particularly advantageous, the oxime be;ng formed ;n s;tu and rearranged, without isolation, into the compound XIII~ wh;ch ;s produced to-gether w~th ;ts ;somer of the formula XIIla.

~XIIIa3 ~lH
o Examples of suitable halogenating agents are inor-ganic ac;d haLides, such as PCls~ S02Clz, POCl3, SOCl2 or P~r3~ or halo9ens, such as bromine or chlor;ne. It ;s adv2n-tageous to use PCls or POCl3 combined with S02Cl2 in an ~.~67~

organic solvent. An imide halide is initially formed as an ;ntermed;ate and reacts w;th the halogena~ing agents mentioned and then reacts ~urther by hydrolysis under basic cond;tions, preferably with aqueous alkali metal carbonate, to give a compound of the formula XIV.
The compounds of the formula XIV are subsequently catalyticalLy reduced in a polar protic solvent, such as, for example, an alcohol, preferabty ethanol, or a car-boxylic acid, such as, for example, acet;c acid, ~ith the 1û addition of an acid acceptor, such as, for example, sodium acetate or triethylamine, to give a compound of the for- -mula XI in which Hal has the abovementioned meaningO
ExampLes of suitable catalysts are Raney nickel, or palla-dium or platinum on animal charcoal Compounds of the formuLa XI can also be prepared directly or as mixtures with compounds of the formula XIV by halogenation of the compounds of the formula XIII using smaller amounts of the abovementioned halogenat;ng agents.
Compounds of .he formula XI are reacted in accord-ance with the known Favorskii react;on in the presPnce ofa base to give the compounds of the formulae IIIa or b with W being hydrogen, and the latter are esterified where appropriate~ The abovementioned Favorskii reaction is carried out in an alcoholic solvent such as methanol, ethanol or tert.-butanol or in water or ;n mixtures of these, at temperatures in the range from 20 to 140C, preferably between 60 and 100C~ The bases which are advantageously employed are alkali metal or alkaLine earth metal hydroxides, such as sodium, potassium or barium ~2~

hydroxide or alkal; metal alcoholates, such as, for exam-ple, sodium methylate or potassium tert.-butanolate.
The compounds of the formula IIIa and IlIb or their mirror ;mages ~hich are obtained in accordance with the procedure descr;bed above result as mixtures of stereo-isomers, and these can be separa~ed from one another by, for example, recrys~allization or chromatography. It may be necessary, where appropriate, for the mixtures to bc appro-priately derivatized in order for the stereoisomers then to be separated froln one another by recrystalli~ation or chromatography.
Racemic mixtures of compounds of the formulae IIIa and IIIb can be employed as such in the further syntheses described above. However, if desired, they can also be separated into the enantiomers before further reactions by the known methods of racemate resolution (cf. for example, Quart. Rev. 25 ~1971) 323 ff.).
If the compounds of the formula I result as race-mates, these can also be resolved into their enantiomers or separated by chromatography by the customary methods~
such as, for example, via salt formation with optically active bases or acids.
When R is hydrogen, the compounds of the formula I
according to the invention exist as internal salts. S;nce they are amphoteric compounds, they can form salts wi~h acids or bases. These salts are prepared in a customary manner by reaction with one equivalent of acid or base.
The compounds of the formula I and their salts have a long-lasting and strong hypotensive effect. They ~ i7~
~ 16 -are potent inhibitors of ang;otensin convert;ng enzyme tACE inh;bitors~ and can be employed to control hyperten-sion of a variety of etiologies~ It is also possible to combine them with other compounds having hypotensive, vaso-dilator or d;uretic activity. Typical representatives ofthese classes of active compounds are described in, for example, ~rhardt-Ruschig, Arzneimittel (Drugs), 2nd Edition, Weinhe;m, -1972. They can be administered intravenously, subcutaneously or orally. The dosage on oral adm;r;stra-tion is 1 - 100 mg, preferably 1 - 50, in part;cular 1 - 30 mg, per single dose for an adult of normal weightO
This corresponds to about 13 - 1,300 ~g/kg/day, preferably 13 - 650 ~gJkg/day, in particular 13 - 400 ~g/k/dayO The dose can also be increased in severe cases~ since toxic properties have not hitherto been observed. It ;s also possible to reduce the dose, and this is particularly appro-priate when diuretics are administered concurrently.
The compounds according to the invention can be administered orally or parenterally in appropriate pharma-ceutical formulations. For a form for oral use, the activecompounds are mixed with the addi~ives customary for this purpos~, such as vehicles, stabilizers or inert diluents, and converted by customary methods into suitable forms for àdministration, such as tablets, coated tablets, hard gela-tin capsules, aqueous, alcoholic or oily suspensions oraqueous, alcoholic or oily solutions. Examples o~ ;nert vehicles ~hich can be used are gum arabic, magnesium car-bonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. For this purpose, the preparation ` - ~2~

can be carried out either as dry or as moist granules.
Examples-o-f suitab~e oily vehicles or solvents are vege-table and animal oils, such as sunflower oil or fish liver o; ~.
For subcutaneous or ;ntravenous adm;nistrat;or,, the ac~;ve compounds or t~e;r phys;olog;cally tolerated salts are converted into solutions, suspensions or emulsions ~ith, if desired, the substances customary for th;s pur-pose, such as solub;lizers, emulsif;ers or other auxil;ar;es.
Examples of suitable solvents for the new ac~ive compounds and the corresponding physiologically tolerated salts are:
~ater, physiological sal;nes or alcohols~ for example ethanol, propaned;ol or glycerol, but also sugar solutions, such as glucose or mann;tol solutions~ or a mixture of the various solvents ment;oned.
The examples wh;ch follow are intended to ilLus-trate the procedures according to the invention without restrict;ng the invention to the substances mentioned here as representatives.
The lH NMR data are S vaLues.
Example I
N~ S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-az~bi-cyclo~3.1.03hexane-~-carboxylic acid hydrochloride ~1~ Cis-2-azabicycloC4.1.0]-3-oxoheptane 1 9 of cis-bicycloC3.1.0~-2-oxohexane are dissolved in 10 ml of 97% strength formic acid. While cooling in ice, 1.8 9 of hydroxylamine-0-sulfol1ic acid in 5 ml of 97X
strength form;c ac;d are added, and the mixture is then brought to reflux temperature for 45 minutes. After ;26~ 2 ~ . ~
cooling, the m;xture is poured on to ice, neutralized with sol;d NaHC03 and extracted with ethyl acetate. After drying and evaporating, a residue of 1 9 of oil remains.
~2) Cis-2-azabicycloC4.1.0]-3-oxo-4-dichloroheptane 11 9 of ~he crude product obtained accord;ng to Example I (1) are dissolved in 250 ml of d;chLoroethane.
h'hile cooling in ice~ Z0.8 9 of phosphorus pentachloride are introduced. The mixture ;s st;rred at room temperature for 30 minutes. Then, while cooling ;n ice, 17 ml of sulfuryl chloride are added dropwise, and the mixture is stirred under nitrogen at room temperature for 1 hour and at 60C (bat'h temperature) for 5 hours. After cooling, 2ûO g of ;ce are added, and the mixture ;s neutralized with solid sodium carbonate, the dichloroethane phase is separa-ted off, and the aqueous phase is extracted with methylenechloride. The organic phases are dried, evaporated, and the residue (20 9) is chromatographed on silica gel u'sing methylene chlor;de/ethyL acetate 19:1 as eluting agentO
iield: 4.2 9 Melting po;nt: 174 - 175C
(3) C;s-2-azab;cycloC4.1.0~-3-oxo-4-chloroheptane 3.0 9 of I(2) are dissolved in ethanol, 2.8 ml of tr;ethylam;ne and 2.5 9 of Raney nickel are added and the mixture is hydrogenated for 2û min. The catalys~ is removed by f;ltrat;on with suct;on, the f;ltrate is eva-porated and the res;due ;s chromatographed on s;lica gelus;ng methylene chloride and ethyl acetate 19:1 as the elut;ng agent.
Yield: 1.8 g ~2~i7~32 Analys;s: C8H~NOCl: calculated 49.5 5.5 9.6 24~3 found 49.8 5.Z 9.3 23.9 ~4a) Cis-2-azabicycloC3.1.0]hexane-3-carboxylic acid 1~6 9 of I(3) are suspended in 55 ml of water, and 4.0 9 of ~a(OH)2.8H20 are added. After refluxing for 1 hour, the pH is adjusted to 2.5 ~ith 2 N sulfuric acid, the pre-cip;tate is f;ltered off with suction, and the aqueous solu-tion is adjusted to pH 6~ evaporated to dryness, ethanol and methylene chloride are added, and the precipitate is f;ltered off with suction, the solutivn is concentrated and ethyL acetate is added to the residue. YieLd 1.5 9 of colorless soLid product.
H NMR/60 MHz, D20: 0.4 - 1.2 (m, 2 H);
105 - Z.9 (m, 3 H);
3.1 - 4.4 (m, 2 H~
~4b) Cis-2-azab;cycLo~3.1.0~hexane-endo/exo-3-carboxyl;c acid The product obtained ;n Example I(4a) compr;ses a mixture of cis-endo and cis-exo. After derivatizat;on to giYe the benzyl ester followed by N-acylation wi~h benzyl chloroformate, this product can be separated into the cis-endo and the cis-exo derivat;ves by silica gel chroma-tography. The racem;c cis-endo and c;s-exo aminoacids are ~obtained by subsequent hydrogenat;on w;th Pd/C (10X) as the catalyst.
1H NMR of the c;s-exo-2-azabicycloC3~1.0]hexane-3-.
carboxylic acid ~270 MHz, D20~: 0.8 - 0.93 ~m, 2 H);

1.8 - 1.92 (m, 1 H);

~2~

2 1 - Z.24 tm, 1 H3;
2.45- 2.55 (qu, 1 H);
3029- 3.37 tm, 1 H);
3.78~ 3088 (dd, 1 H)

5 1H NMR of the c;s-exo-2-azabicycloC3.1_0]hexane~3-carboxyl;c ac;d (270 MHz, D20): 0.56 - 0.66 (m, 1 H);
- 1.87 - 0.99 (spl;t qu, 1 H) - 1079 - 1.9 (m, 1 H);
2.32 - 2.41 (m, 1 H);
2.48 - 2~62 (m, 1 H);
3.30 - 3.39 (m, 1 H) 4.26 - 4.35 ~split d, 1 H) The d;astereomerically pure products or the mixture can be employed in the subsequPnt reactions.
(5a) Ben~yl cis-2-azab;cycloC3.1O0~hexane endo/exo-3-carboxylat~
1.22 ml of th;onyl chloride are added dropwise, at -15C, to 30 ml of benzyl alcohol. Then, at -10C, 1.5 9 of the cis-endo/exo-am;noacid mixture prepared in Example I~4a) are introduced. After a reaction time of 24 hours at room temperature, the mixture ;s diluted with e~her ~nd extracted by stirring with wa~er, cooling in ice. The aqueous solution is neutralized with NaHC03 and extracted w;th ether/methylene chloride which, after drying, is evaporated Residue 2.2 9 of oil~
Rf: 0.65 ~silica gel, methylene chlorid0, methanol, ~lacial acetic acid, water Z0:10:2:2, ninhydrin stain) .2~i7~3~2 (Sb) ~enzyl cis-2--azabicycloC3~1.0]hexane-exo-3-carboxylate Th;s compound is obtained by reacting the cis-exo-am;noac;d prepared in Example I(4b) w;th benzyl alcohol and th;onyl chlor;de by the process ind;cated ;n Example I~5a).
Rf 0.62 (sil;ca gel, m~thylene chloride, methanol, glacial acetic acid, water 20:10:2:2, ninhydr;n sta;n) sc? Benzyl c;s-2-azab;cycloC3D1 O~hexane-endo-3-carboxylate This compound is obtained by reacting the cis-endo-aminoacid prepared ;n Example I~4b) with benzyl alcohol and th;onyl chloride by the process ind;cated ;n Example I(5a~.
R 0.69 (sil;ca gel, methylene chloride, methanol, glacial acetic acid, ~ater 20:10:2:2, ninhydr;n stain)

(6) ~enzyl N-~1-S-carboxoethoxy-3-phenylpropyl)-S-alanyl-cis-2-azab;cycloC3.1_.03hexane-exo/endo-3-carboxylate 2.0 9 of the benzyl ester prepared accordin~ to Example I(Sa) are brought to react;on w;th 1.4 g of hy-droxybenzotriazole (HOBt), 1.76 9 of dicyclohexylcarbo-diimide and 2.2 9 of N-(1-S-carboethoxy-3-phenylpropy~)-S-alanine in 28 ml of d;methylformam;de. After st;rring at room temperature for 10 hours, the precipitated dicyclo-hexylurea ;s f;ltered off ~I;th suction, the filtrate ;s concentrated, the res;due ;s taken up ;n methylene chlor;de and th;s solut;on ;5 extracted 2 x with saturated NaHCO~
solut;on. The organic phase is dr;ed, concentrated and 5.4 g of the mixture of c;s-exo and-cis-endo diastereomers are ob~a;ned.

~7) 3enzyl N-t1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-azabicycloC3~1.0]hexane-endo-3-S-carboxylate t;somer 1) The crude product obtained in Example I~6) ;s chro-matographed on silica gel using cyclohexane/ethyl acetatein the ra~io 1.5:1. The isomer which is eluted first is the S,SOS-cis-endo compound.
Rf: 0.24 ~silica gel, cyclohexane/e~hyl acetate 1:1) 1H NMR (CDCl3): 0.6 - 3.0 (m 13 H);
ln 3.2 - 3.9 (m 4 H~;
3.95 - 4~4 (q, 4 H);
4.8 - 5.0 ~doublet of doublets, 1 H) 5.15 (s, 2 H);

7.25 (s, 5 H);
7.35 (s, S H) t8) ~enzyl N~ S-carboethoxy-3-phenylpropyl)-S-alanyl c;s-azab;cyclo~3.1.0~hexane-endo-3-R carboxyLate ~isomer 2) The crude product obtained in Example It6) ;s chro-matographed on a column of silica gel using cyclohexane ethyl acetate in a ratio 1.5:1. The isomer which is eluted fourth is the cis-endo-S,S,R compound.
Rf: 0.09 ~silica gel, cyclohexane/ethyl acetate 1-1) ~ ~9) Benzyl N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-25` c;s-2-azab;cyclo~3.1~û]hexane-exo-3-S-carboxylate ~;somer 3) _ _ The crudc product obtained in ExampLe 1(6) is chro~atographed on a sil;ca gel column using cyclohexane/
ethyl acetate ;n the rat;o 1.5:1. The ; omer wh;ch is ~.2~

eluted second is the cis-exo-S~S S compound.
R~ 0.20 (silica gel~ cyclohexane/ethyl acetate 1:1) t1Q) Benzyl N-(1-S-carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-azabicyclo[3~1.0]-hexane-exo-3 R-carboxylate S (;somer 4) ~ The crude product obtained in Example 1~6) is chromatographed on a silica gel column using cyclohexane/
ethyl acetate in the ratio 1.5:1. The ;somer which is eluted third ;s the cis-exo S S R compound.
R~ : 0.14 (silica gel cycLohexane/ethyL acetate 1:1) ~11) N-(1-S-Carboethoxy-3-pheny~propy~)-S-a~anyl-cis 2-azab;cyclo~3.1.0~hexane-3-carboxylic acid hydro~
chloride 1.0 9 of the benzyl ester prepared in Example I(6) is dissolved as the mixture of d;astereomPrs in 50 ml of ethanol. 100 mg of palladium on charcoal t10%) is added to this and hydrogenation is carried out at room temp-era-ture under atmospheric pressure. After filtering off the catalyst by suct;on the ethanolic solution is evaporated ethanolic hydrochloric acid is added to the remaining oil and the solvent is evaporated off. The residue is vigorously stirred u;th ethyl acetate whereupon a colorless solid mixture of the diastereomeric exo/endo carboxylic acids Chydrochlorides) remains.
Y;eld: 0.7 9 Fxample I~
N-(1-S-Carboethoxy 3-phenylpropyl)-S-alanyl-cis-2-a~ab;-cyclo~3.1.0~hexane-endo-3-S-carboxylic acid hydrochloride (isomer I) ~2~
- 2~ -0.2 9 of ~he benzyl ester prepared in Example I~7) is subjected to catalytic removal of the benzyl group in analogy to Example I(11), and the product ;s converted into the hydrochlorideO
Yield: 0~125 9 H NMR (DMS0-d6): 0.6 - 5.0 (m, 21 H);
7.3 ts, 5 H);
9.~ (very broad s) Example III
N-~1-S-Carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-azabi-cycloC3.1.0]hexane-endo-3-R-carboxylic acid hydrochloride (isomer 2) _ 0.22 g of the benzyl ester prepared in Example I(8) is subjected to catalytic removal of the benzyl group in analogy to Example 1(11), and the product is converted ;nto the hydrochlor;de.
Yield: 0.13 9 H NMR (DMS0-d63: 0.5 - 5.1 tm, 21 H);
7.2 (s, 5 H);
10.1 (very broad s) Example IV
N-(1-S-Carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-azab;-cycloC3.1.0~hexane-exo-3-S-carboxylic acid hydrochloride ~isomer 3~
0.27 9 of the benzyl ester prepared in Example I~9) is subjected to cata~yt;c removal of the benzyl group in ana~ogy to Example I(11), and the product is converted into the hydrochloride.
Yield. 0.23 9 1H NMR ~DMS0-d63: 0.5 - 4u7 ~m 21 H);
7~3 ~s 5 ~);
10.0 (very broad s) Example V
N~ S-Carboethoxy-3-phenylpropyl)-S-alanyl-cis-2-azabi-cyclo~3.1.0~hexane-exo-3-R-carboxylic asid hydrochloride ~;somer 4) , 0.3 9 of the benzyl ester prepared in ~xample I~10) ;s subjected to catalytic removal of the benzyl group in analogy to Example It11)~ and the product is converted into the hydrochloride.
Yield: 0.26 g H NMR tDMS0-d6): D.4 - 4.8 ~m 21 H~;
7.3 ~s 5 H);
9.8 ~very broad s) Example VI
N-~1-S-Carboxy-3-phenylpropyl)-S-alanyl-cis-2-a~abicyclo-~3.1.0~hexane-endo-3-S-carboxylic acid (isomer 1) _ 0.2 9 of the ethyl ester from Example II is dis-solved ;n 5 mL of ~ater~ The solution is basified w;th a4 N aqueou~ solution of potassium hydrox;de. It is left to stand at 0C overn;ght. After react;on has ended~
the pH ;s adjusted to 5 with concentrated hydrochloric acid. The solution ;s appl;ed to 20 ml of strongly acid ;on exchanger ~IR 120~ H~ form)~ wh;ch ;s developed with water and eluted w;th water rontaining 2X of hydrin The fractions containing the above compound are evaporated.
The res;due is treated 2 x ~ith toluene and the toluene is removed under reduced pressure. Ether ;s added to ~he ` - ~L2~9~3Z

resi due.
Yield: 0.13 9 lH NMR (D20) 0.6 - 5.1 ~m, 15 H) 7.3 (s, 5 H) 5 Example VII
N-t1-S-Carboxy-3-phenylpropyl)-S-alanyL-cis-2-azabicyclo-C3.1 0]hexane-exo-3-S-carboxylic acid (isomer 3) 0.2 9 of the ethyl ester from Example IV is hydro-lyzed and ~orked up in anaLogy to Example VI..
1û Yield: 0~12 9 H NMR ~D20): 0.4 - 4.8 (m, 16 H);
7.2 ts, 5 H)

Claims (2)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of compounds of the formula IIIa or IIIb (IIIa) with mirror image (IIIb) with mirror image wherein W denotes hydrogen or (C1-C6) -alkyl or (C7-C8 ) -aralkyl which comprises rearranging a compound of the formula XI

(XI) in which Hal represents halogen, in the presence of a base, and, where appropriate, esterifying the resulting compound of the formula IIIa or IIIb (W=hydrogen).

2. A compound of the formula IIIa or IIIb, as set forth in in claim 1 and the mixture of its stereoisomers.