CA1235128A - Disubstituted proline derivatives, a process for their preparation and their use - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The invention relates to compounds of the formula IV

(IV) in which R1 and R2 are identical or different and represent straight-chain or branched alkyl having 1 to 6 carbon atoms or represent (C6 to C10)-aryl, or together represent one of the chains -(CH2)n- or -(CH2)p-CH=CH-(CH2)q, n, p and q each being an integrer, n being 3-6 and (p+q) being 1-4, and R
represents hydrogen, alkyl having 1 to 10 carbon atoms, aralkyl having 7 to 9 carbon atoms, cycloalkyl having 5 to 10 carbon atoms, alkylcycloalkyl having 6 to 12 carbon atoms or cycloalkylalkyl having 6 to 12 carbon atoms, and to processes for their preparation. Compounds of the formula IV are useful intermediates in the production of inhibitors of the angiotension converting enzyme (ACE).

Description

- ~3~'1f~8 THIS APPLICATION IS A DIVISIONAL OX CANADIAN PATENT
APPLICATION SERIAL NUMBER 444,858, FILED JANUARY 6, 1984.

The invention relates to compounds of the formula I

(I) I ON
CUR
on which R1 and R2 are identical or different and represent straight-chain or branched alkyd having 1 to 6 carbon atoms or represent (C6 to Charlie, preferably phenol, or together represent one of the chains -Sheehan- or ~~CH2)p~CH~C~I~(CH2)q, n, p and q each being an integer, n being 3-6 and pi being 1-4, and R3 denotes straight-chain or branched alkyd having 1 to 5 carbon atoms or (C6 to Charlie, preferably phenol.
It is known that substituted praline derivatives can be prepared by various classical methods of amino acid synthesis. A review of the known work on this topic has been published by AHAB. Mauler and B. Witkop (Chum. Rev.
66, I (1966)). In the processes described on this reference, the compounds usually result as complex mix-lures of isomers. Since certain 4,5-disubstituted is-mews which were required as starting compounds for Z0 further syntheses could only be obtained in poor yield or not at all by known processes with subsequent swooper-lion of isomers, the object was to search for new sync theta routes leading to isomers of this type.

' sluice The praline derivatives of the formula I accord-no to the invention are valuable intermediate products on a synthetic route of thus type. Preferred compounds of the formula I are those in which R1 and R2 together form one of the above mentioned chains and have the trays configuration with respect to one another. If R1 and R2 are not linked together by a chain, these radicals can have the us or trays configuration with respect to one another and to the ON group.
10 The compounds of the formula I can occur in the diastereomeric forms Idea, it being possible to represent the relative configurations of these by the following formulae:

H
I "" 2 R ` Jo ON R Pi ON

CUR CUR

(It) jib) aye form 2.~,4~,5~ form H H

15R2 , 2 R1 ", ON

CUR CUR

tic) (Id) I forum 2~,4~,5~ form The specification "I" means that the substituent on the relevant position is beneath the plane of the f;ve-membered ring and the specification "I" means that ~35128 it us above this plane. If R1 and R2 are connected together, the numbering is modified to accord with the conventions for bicyclic ring systems.
The invention also relates to a process for the preparation of compounds of the formula I in which R1, I and R3 have the abovement;oned meanings, which comprises reacting an organomercury compound of the formula II

R2 Hex (II) R CRY

on which R1, R2 and I have the above mentioned meaning and X denotes halogen, preferably chlorine or bromide, pseudo halogen or acetate, with 2-chloroacrylon;trile and sodium bordered or potassium bordered to give a compound of the formula III

Of R2 C~2~CH \
y (III) on which R1, R2 and R3 have the abovement;oned meaning.
The reaction is carried out on an alcoholic sol-vent, preferably ethanol, with a one to f;fteen-fold, preferably a three to eightfold excess of sheller-20 acrylon;tr;le, at -20C to 60C, preferably at 0C to I, 30C.
1'\

1235~28 The compound of the formula III us then cyclized to give the compound of the formula I by reaction with a suitable base, preferably sodium hydrides in an aprotic bipolar solvent, such as dim ethyl sulfoxide or dim ethyl-formamide, or with potassium carbonate or potassium hydroxide in an aprotic solvent, such as, preferably, acetonitriLe, with the addition of a phase-transfer gala-lust, preferably triethylbenzylammonium chloride, at -20C to 80C, preferably at 0C to 40C.
The invention also relates to compounds of the formula III in which R1, R2 and R3 have the above-mentioned meaning.
Moreover, the invention relates to the use of compounds of the formula I, in which R1, R2 and R3 have the above mentioned meaning, in a process for the prepare-lion of compounds of the formula IV

I (IV) I / COG
'I .

in which R1 and R2 have the above mentioned meanings and R represents hydrogen, alkyd having 1 to 10 carbon atoms, aralkyl having 7 to 9 carbon atoms cycloalkyl having 5 to 10 carbon atoms, alkylcycloalkyl having 6 to 12 carbon atoms or cycloalkylalkyl having 6 to 12 carbon atoms, which comprises subjecting the compounds of the formula I
to solvolysis with compounds of the fornlula ROW in which R has the above meaning.

Hydrolysis is preferred. For this, the compounds .
. . .
:

, 35~28 of the formula I are converted in the presence of a strong acid, preferably a mineral acid such as hydra-caloric acid or hydrobromic acid, in aqueous solution at 20C to 160C, preferably at 70C to 120C, into the amino acids of the formula IV in which R denotes hydrogen.
The resulting mixtures of isomers can be swooper-ted into the isomers at the various stages in the process (compounds of the formulae III, I and IV) by methods of separation known per so, such as, for example, fractional crystallization or column chromatography.
The starting materials for the preparation of compounds of the formula I are known from J. Pratt. Chum.
311, 737 (1969) and from J. Org. Chum. 41, 192 (1976):
they are produce by addition of a mercury salt and a nitrite to the double bond of an olefin of the formula V
in which R1 and R2 have the above mentioned meaning.

R1-CH-CH-R2 (Y) The addition of the two components to the double bond takes place from opposite sides. The result of this is that, starting from cis-disubstituted olefins of the formula Via H H (Via) the trans-disubstituted compounds of the formula Ivy are obtained - 7 _ 123 5~2 I

R1 I' COO (Ivy) since the Stacy in the process according to the invention take place with retention of the configuration at each carbon atom. In analogy, starting from trans-disub-stituted olefins of the formula Vb (Vb) H , R

the cis-disubstituted compounds of the formula Ivy are obtained R2 R COG
. Jo (Ivy) and starting from cycloolefins of the formulae Via and Vim respectively CHIC
CRY: ) (OH Schick (Vim) in which m denotes a number from 1 to 4, bicyctic come pounds of the formulae Viva and VIIb respectively are obtained , .. . ..

- 8- ~35128 COO / (Shop H (Vouch CooR(vIIb) Schick H
the two rungs on these being linked together trans.
The compounds of the formulae I and IVY are value able intermediate products on the preparation of forum-S ceuticals, especially of inhibitors of the ang;otens;nconverting enzyme (ACE). Compounds of thus type are known, for example, from Canadian Patent Application 3~8,336, and Canadian Patent Application 418,453 also relates to them.
Examples of ACE inhibitors of this type are sub-statewide azalea derivatives of the formula VIII
CCH I
COO
Azalea on which m us defined as above and azalea represents, for example, a radical of the formula IX
Y' * `*
-CO-CH-NH-CH-CH2-C-X' (IX) R Corey Z' in which R4 denotes hydrogen, (C1-C6)-alkyl which can optionally be substituted by amino, (C1-C4)-acylamino or benzoy;amino, (C2-C6)-alkenyl, (C5-C9)-cycloalkyl, (C5-C9)-cyclo-5 C7) cycloalkyl-tC1-C4)-alkyl a ..~

. _ 9 _ ~235~28 partially hydrogenated aureole, each of which can be sub-u Ed by ~C1 Cz)-alkyl, (C1-C2~-alkoxy or halogen, aryl-(C,I-C4)-alkyl, the aureole radical of which can be substituted as defined above, a monocyclic or bicycle heterocyclic radical having 5 to 7 or 8 to 10 ring atoms, 1 to 2 of these ring atoms being sulfur or oxygen atoms and/or 1 to 4 of these ring atoms being nitrogen atoms, or a side chain of a naturally occurring am;noac;d, R5 denotes hydrogen (C1-C6)-alkyl, (C2 C6) alkeny or aryl-(C1-C4~-alkyl, Y' denotes hydrogen or hydroxyl, Z' denotes hydrogen or Y' and Z' together denote oxygen, X' denotes (C1 Colloquial (C2-C6)-alkenyl~ (C5 C9 cycloalkyl, aureole which can be moncsubst;tuted, disubst;-tuned or trisubstituted by (C1-C4)-alkyl, (C1-C4) alkoxy, hydroxyl, halogen, Nero amino, (C1-C4)-alkyl3mino, d;-(C1-C4)-alkylamino or methylenedioxy, or 3-;ndolyl, and their physiologically acceptable salts.
Compounds of the formula VIII can be prepared by N-acylation of compounds of the formula IV, on which R1 and R2 have the abovement;oned meaning and R has the above meaning with the exception of that of hydrogen, with compounds of the formula azalea, on which azalea us defined as above, and subsequent hydrogenolyt;c, acid or base el;m;nat;on of the radicals R and, of appropriate, .
~:~ The condensation of the compounds of the formula azalea with the esters of the formula IV preferably :;

: I, . . , - - -- 1235~2~3 takes place by processes known from peptize chemistry.
Those processes which provide adequate protection from racemization, such as, for example, the DCC/HOst method or the alkanephosphonic android method described in German Offenlegungsschrift 2,901,843, are particularly preferred.
The compounds of the general formula VIII have a long-lasting and potent hypotensive effect. They are well absorbed after oral administration and can be employed to control hypertension of various etiologies and can be used alone or combined with other compounds having hypotens;ve, vasodilator or diuretic activity.
Adm;n;strat;on can be intravenous, subcutaneous or oral, oral administration being preferred. The dosage on oral administration is 0.01-10 mg/kg per day, preferably 0.05-1.5 mg/kg per day, especially 0.05-0.5 mg/kg per day.
The dose can also be raised in severe cases, since no toxic properties have hitherto been observed.
It us also possible to decrease the dose and this is particularly appropriate when diuretics are administered concurrently. For intravenous or subcutaneous adrninis-trat;on, the single dose should be between 0.1 and 250 gig per day.
The following examples are untended to Lucy-irate the ;nvent;on.Example 1

2~,3a~,7a~-Octahydro;ndole-2-carboxylic acid a) trans-1-Acetam;do-2-chloromercur;ocyclohexane 20 ml (0.2 mole) of cyclohexene on 50 ml of .

I' ~L235;~ 28 acetonitrile are added drops over the course of pa minutes to a suspension of 65 9 (0.2 mole) of mercurial) nitrate in 150 ml of acetonitrile at 0C. kiter 1 hour at room temperature, the yellow solution is poured into a mixture of 100 ml of saturated sodium chloride solution and S00 ml of water; the precipitated product is filtered off with suction, washed with water and dried in vacua 75 g of colorless crystals of melting point 200-201C are obtained.
b) trueness Acetamido-2-(2-chloro-2-cyanoethyl)cyclohexane 31 9 of trans-1-acetam;do-2-chloromercur;ocyclo-hexane are suspended in 250 ml of 95% strength ethanol:
187 In (4 equivalents) of 2-chloroacrylon;trile are added.
While cooling in ice, a solution of 3 9 of sodium boron hydrides in 50 ml of ethanol us added as rapidly as posy Sibley After warming up to room temperature, the prows-pitted elemental mercury is filtered off with suction over kieselguhr, thoroughly washed with ethanol and the filtrate is evaporated. The residue is taken up in ethylene chloride, washed three times with 1 N sodium hydroxide solution to destroy the boric esters, dried over sodium sulfate and evaporated. 13 9 of the title compound are obtained as a yellow oil.
c) 1-Acetyl-2-cyano-trans-octahydroindole

3.2 9 of trans-1-acetamido-2-~2-chloro-2-cyano-ethyl)cyclohexane are dissolved in 25 ml of dimethylform-aside and added drops, at 0C, to a suspension of 0~7 9 of sodium hydrides (50% in oil, washed three times with hexane) in 10 ml of dimethylformamide. After 1 hour .

- - 12 - ~23S12~
at room temperature, the mixture is poured into water, acidified with 5 N hydrochloric acid and extracted with ethylene chloride. The extract is washed four times with water, dried over sodium sulfate and evaporated.
The crude product contains a mixture of 18.5 parts of the aye isomer and 1 part of the aye isomer.
On trituration with diisopropyl ether; 0.7 g of the I
aye isomer crystallizes out. Chromatography of the mother liquor on silica gel using acetic acid/cyclohexane (2:1) as the mobile phase provides a further 0.2 g of the aye isomer and 45 my of the aye isomer.
Physical data:
awry isomer:
Melting point 110 113C
OH NOR data (270 MHz, DMSO-d6, 100C): = 4.90 do = 5Hz, OH); 3.05 (do, Jo = 5 I Jo = 1.5 It, OH ;
2.60 (d, OH); 2.17 (d, OH); 2.03 (s, OH); 1.95 (broad, d, OH); 1.85-1.6 to, OH); 1.4-1.0 (m, OH) ppm. MS tome 192 (M+, 32%); 150 (M-CH2=C=0, 59%); 149 (18%); 139 ZOO (14%) 107 (100%); 95 (15~); 43 (39%).
aye isomer:

of l OH NOR data (270 MHz, DMSO-d6, 10ûC): = 4.66 (t, J = Shy, OH); 3.10-3~0 (m, OH); 2.75-2.6 (m, OH); 2.08 (s, OH); 2.0-1.4 (m, OH); 1.4-1~2 (m, OH) ppm.
d) 2~,3a~,7a~-octahydroindole-2-carboxylic acid 2.8 9 of aye acetyl-2-cyanooctahydro-dole are bowled under rollicks with 30 ml of 5 N hydra-choleric acid for 4 hours, evaporated to dryness, the - 13 - ~235~28 residue is taken up with water, the pi is adjusted to 4.7 with a weakly basic ion exchanger (Amberlite~ IRA 93, OH form), this is filtered off, the filtrate is evapora-ted, the residue is taken up with ethanol, and acetone is added to precipitate. Filtration with suction and drying provides 1.9 g of the title compound of melting point 2~6-Z88C (decomposition).
OH NOR data (D20, 270 MHz): = 4.15 (d, J = 5Hz, OH); 2~88 (dud, Jo = 12 HO Jo = 3.8 Ho, OH); 2.55 (ma, OH);
Z.3-1.1 (no, 10H) ppm.
Example 2 2l~r3a~,7a~-OrtahydrocyclopentaCb~pyrrole-2-carboxxxylic acid a) trans-1-Acetamido-2-chloromercuriocyclopentane 10 ml of cyclopentene in 3C ml of acetonitrile are added drops to a suspension of 38.3 g of rnercury(II) nitrate in 80 ml of acetonitriLe at 0~. After 1 hour at room temperature, the mixture is poured unto a mixture of 60 ml of saturated sodium chloride solution and 250 ml of water, and the solid is filtered off Thea suction, washed with water and dried. 26 9 of the title compound are obtained as an amorphous powder.
b)trans-1-Acetamido-2-(Z-chloro-2-cyanoethyl)cycloopeentwine 16.1 g of trans-1-acetam;do-2-chloromercurio-cyclopentane are suspended on 200 ml of ethanol. 10.7 ml of 2-chloroacrylon;tr;le are added, followed by 1.7 of sodium bordered on 40 ml of ethanol as rapidly as posy sable whole cooling in ice. After 1 hour at room tempera-lure, the mixture us filtered with suction through cozily-Gore the filtrate is evaporated, the residue is taken up 1235~L2~

with ethylene chloride, this solution is washed twice with 1 N sodium hydroxide solution, and the organic. phase is dried over sodium sulfate and evaporated. Cremate-graph on silica gel (mobile phase ethyl acetate) pro-dupes 2.2 g of crystalline product, melting point 114-117C.
OH NOR data (CDCl3~: = 5.4 (broad s, OH); 4.67 (t, J = 7Hz, OH 3.95 (ma, OH); 2.6-1.0 (m, OH 1.97 (s, OH) ppm MS (Moe: 214 (My, ~%~; 179 (10~; 140 (20,~); 137 (35%);
98 (48%); 6û (78%); 56 (100%); 43 I
c)1-Acetyl-2-cyano-trans-octahydrocyclopenta[b]pyrRoy 0.75 9 of trans-1-acetamido-2-(2-chloro-2-cyano-ethyl)cyclopentane is dissolved in 20 ml of DMF and added to 200 my of sodium hydrides (50% in oil, washed twice with hexane~ and the mixture is stirred a room tempera-lure for 1 hour. It is then poured into 1 N hydrochloric acid, extracted with ethylene chloride, and the organic phase is washed four times with water, dried and evapora-ted. Chromatography on silica gel with ethyl acetate/cyclohexane (2:1~ as the mobile phase provides 0.12 g of the aye isomer as an oil and 0.45 g of the aye aye isomer as colorless crystals of melting point 115-OH NOR data (CDCl3): S = 5.02 (d, J = 7.5 Ho, OH
3.33 (do, Jo = 11Hz, Jo = 6 Ho, OH 2.9~1.0 (m, OH
2.07 (s, OH ppm.
d)2~,3a~,6a~-Octahydrocyclopenta[b~pyrrole-2~carbooxyyolk acid 0.45 9 OX 2~,3ac~6af~-1 acetyl-Z-cyanooctahydro-cyclopenta~b]pyrrole are heated to reflex for 3 hours with 5 ml of S N hydrochloric acid, then evaporated to dryness, the residue is taken up with water, the pi is adjusted to 6 with a weakly basic ion exchanger (Amber-liter IRA 93, OH form), this is filtered off, the lit-irate is evaporated and crystallized with ethanol/ether.
Yield: 0.26 g Melting point: > 250C (decomposition) OH NOR data (D20): = 4.5 (t, OH); 3.6-3.0 (m, OH
2.6-1.0 (m, OH) ppm. MS (m/e): 155 (M+, 1%); 154 (M+7H, 3%); 110 (MCKEE, 100%); 67 (24%).
Example 3 1-Acetyl-2-cyano-4 5-cis-diethylpyrrolidine a) erythro-3-Acetamido-4-chloromercuriohexane 39 9 of murkier) nitrate are suspended in 50 ml of acetonitrile, and 10 9 of transection in 20 ml of acetonitrile are added drops at 0C. After 45 minutes at room temperature, the mixture is poured into 500 ml of saturated sodium chloride solution. The title compound initially separates out as an oil, but crystal-lives completely after a short time. Melting point Yield 41.5 9.
b) 2~Chloro-threo-5-acetam;do-4-ethylheptanonitrile 15 9 of erythro-3-acetamido-4-chloromercur;o-hexane and 9.6 ml of-2-chloroacrylonitrile are dissolved on 250 ml of ethanol. 1.52 9 of sodium bordered is added rapidly while cooling in ice. After 45 minutes, the elemental mercury formed is filtered off with suction ~23~2~3 through kieselguhr, the filtrate is evaporated, the nest-due is waken up with ethylene chloride, and the solution is washed three times with 1 N sodium hydroxide solution, dried over magnesium sulfate and evaporated 6.6 g of a 1:1 mixture of the isomers at the 2 position are obtained.
c) 1-Acetyl-Z-cyano-4,5-cis-diethylpyrrolidine 6.6 9 of 2-chloro-threo-5-acetamido-4-ethylhep-tanonitrile are dissolved in 10û ml of dimethylformamide and added drophise at 0C to 1.7 9 of sodium hydrides (50'~ in oil, washed 2 x with hexane). After 2 hours at room temperature, the mixture is poured into 1 N hydra-caloric acid and this is extracted twice with ethylene chloride. The organic phase is washed four times with water, dried and evaporated. 4.6 9 of a brown oil are obtained, from which the two isomers of the title come pound are isolated by column chromatography on silica gel using ethyl acetate/cyclohexane (2:1) as the mobile phase.
Isomer 1 (1.63 y) 2~,4~,5~ form: Of value (ethyl acetate/cyclohexane 4:1) 0 5 oil; OH NOR data: 5.0-4.4 (m, OH); 4.0-3.3 (m, OH); 2.6-0.7 (m, 13 H); 2.15 + 2.12 (us, OH) ppm.
MS (m/e): 194 (M+, 8%), 165 (MCKEE, 4%); 123 (M -CH3C0-C2H5, 1û0%); 43 (17%).
25 Isomer 2 (1~63 9) 2~,4~,5~ form: Of value (ethyl acetate/cyclohexane 4:1) -0.43, melting point 144-1~t9C: OH NOR data: 5.8-5.4 (m, OH); 4.3-3.9 (m, OH); 3.0-2.5 (m, OH); 2.03 (s, 3!1);
2.2-1.1 (m, OH); 1.08~0.97 (it, 61i) ppm: MS (m/e): YO-YO

~LZ~Z8 (M , I 165 (M -C2H5, 4%), 123 (M -CH3CO-C2H5, 100%); 43 (14%).
Example 4 2~,4~,5~-Diethylproline 1.63 g of 2~,4~,5~-1-acetyl-2-cyano-4,5-diethyl-pyrrolidine (Example 3c, isomer 1) are heated to reflex for 2.5 hours with 20 rnl of 5 N hydrochloric acid. Aster evaporation to dryness, the pi is adjusted to 6 using Amberlite~ IRA 93 (OH form), and the mixture is lit-toned, evaporated, the residue is taken up with ethanol acetone and filtered with suction. Purification is by chromatography on silica gel using ethylene chloride/
methanol/glacial acetic acid/water t10:3:1:1) as the mobile phase. 1.05 9 of the title compound ox melting point 230-235 (decomposition is obtained.
OH NOR data (D20): = 4.1 (t, J = 9 Ho, OH); 3.25 (do, Jo = 7Hz, Jo = 6 Ho, OH); 2~9-1.0 (m, OH); 1.0 (t, J = 7Hz, OH) ppm.
MS (m/e): 171 (M+, I 142 (MCKEE, 100%); 126 2û (MCKEE, 74~); 115 (12%); 96 (30%); 83 (10%); 69 (33%);
55 (19%).
Example 5 2~,4~,5~-Diethylproline 1.63 9 of 2~,4~,5~ acetyl-2-cyano-4,5-diethyl-pyrrolidine (Example 3c, isomer 2) are reacted with 20 ml of 5 N hydrochloric acid in accordance with the process described in Example 4. 0.72 9 of the title compound of melting point 158-162C is obtained.
OH NOR data (D20): I= 4.15 (to J = 8 Ho, OH); 3.68 51~3 to, J = 6Hz, OH); 2.5~ m, OH); 1.0 (t, J = 7Hz~ OH) ppm.
MS (m/e): 171 (My, 1%); 142 (M+-CzH5) 100%);
126 (MCKEE, 96%); 115 (19%); 96 (33%); 83 (11%);
69 t36%); 55 ~22%).
Example 6 1-Acetyl-2-cyano-4,5-cis-dimethylpyrrol;dine Prepared from trans-2-butene in analogy to the procedures described in Example 3 a to c.
Example 7

4,5-cis-Dimethylproline Prepared from 1-acetyl-2-cyano-4,5-cis-dimethyl-pyrrolidine in analogy to the procedure described in Example 4.
Example 8 1-Acetyl-2-cyano-4 5-trans-dimethylpyrrolidine Prepared from cis-2-butene in analogy to the pro-seeders described in Example pa to c.
Example 9 2û 4 5-trans-Dimethylprol;ne Prepared from 1-acetyl-2-cyano-4,5-trans-dimethyl-pyrrol;d;ne on analogy to the procedures described in Example 4.
Example 10 2~,3a~,8a~-DecahydrocycloheptaCb]pyrrole 2-carboxyl;c acid Prepared from cycloheptene on analogy to the pro-seeders described on Example pa to d.

~2~51X8 Example 11 2G,3a~,9ag-Decahydrocycloocta[b]pyrrole-2-carboxylfig acid Prepared from cyclooctene in analogy to the pro-seeders described in Example pa to d.

Claims (12)

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 a compound of the formula IV

(IV) in which R1 and R2 are identical or different and represent straight-chain or branched alkyl having 1 to 6 carbon atoms or represent (C6 to C10)-aryl, or together represent one of the chains -(CH2)n- or -(CH2)p-cH=cH-(cH2)q, n, p and q each being an integrer, n being 3-6 and (p+q) being 1-4, and R
represents hydrogen, alkyl having 1 to 10 carbon atoms, aralkyl having 7 to 9 carbon atoms, cycloalkyl having 5 to 10 carbon atoms, alkylcycloalkyl having 6 to 12 carbon atoms or cycloalkylalkyl having 6 to 12 carbon atoms, by solvolysis of a compound of the formula I

(I) in which R1 and R2 are as defined above and R3 denotes straight-chain or branched alkyl having 1 to 5 carbon atoms or (C6 to C10)-aryl, which may be phenyl, with a compound of the formula ROH in which R has the above meaning.

2. A process for the preparation of a compound of the formula IV

(IV) in which R1 and R2 are identical or different and represent straight-chain or branched alkyl having 1 to 6 carbon atoms or represent (C6 to C10)-aryl, or together represent one of the chains -(CH2)n- or -(CH2)p-cH=cH-(cH2)q, n, p and q each being an integer, n being 3-6 and (p+q) being 1-4, and R1 and R2 have the trans configuration relative to one another, and R represents hydrogen, alkyl having 1 to 10 carbon atoms, aralkyl having 7 to 9 carbon atoms, cycloalkyl having 5 to 10 carbon atoms, alkylcycloalkyl having 6 to 12 carbon atoms or cycloalkylalkyl having 6 to 12 carbon atoms, by solvolysis of a compound of the formula I

(I) in which R1 and R2 are as defined above and R3 denotes straight-chain or branched alkyl having 1 to 5 carbon atoms or (C6 to C10)-aryl, which may be phenyl, with a compound of the formula ROH in which R has the above meaning.

3. The process as claimed in claim 1, wherein R denotes hydrogen.

4. The process as claimed in claim 2, wherein R denotes hydrogen.

5. A compound of the formula IV

(IV) in which R1, R2 and R are as defined in claim 1, whenever obtained according to the process as claimed in claim 1, or by an obvious chemical equivalent thereof.

6. A compound of the formula IV

(IV) in which R1 and R2 are as defined in claim 1 and R denotes hydrogen, whenever obtained according to the process as claimed in claim 3, or by an obvious chemical equivalent thereof.

7. A compound of the formula IV

(IV) in which R1, R2 and R are as defined in claim 2, whenever obtained according to the process as claimed in claim 2, or by an obvious chemical equivalent thereof.

8. A compound of the formula IV

(IV) in which R1 and R2 are as defined in claim 2 and R denotes hydrogen, whenever obtained according to the process as claimed in claim 4, or by an obvious chemical equivalent thereof.

9. The process for preparing a compound of the formula IV

(IV) in which R1 and R2 are identical or different and represent straight-chain or branched alkyl having 1 to 6 carbon atoms or represent (C6 to C10)-aryl, or together represent one of the chains -(CH2)n- or -(CH2)p-CH=CH-(CH2)q, n, p and q each being an integrer, n being 3-6 and (p+q) being 1-4, and R
represents hydrogen, alkyl having 1 to 10 carbon atoms, aralkyl having 7 to 9 carbon atoms, cycloalkyl having 5 to 10 carbon atoms, alkylcycloalkyl having 6 to 12 carbon atoms or cycloalkylalkyl having 6 to 12 carbon atoms which comprises solvolysing a compound of the formula I

(I) in which R1, and R2 are as defined above and wherein R3 denotes straight-chain or branched alkyl having 1 to 5 carbon atoms or (C6 to C10)-aryl, which may be phenyl, with a compound of the formula ROH in which R has the above meaning, with the proviso that a process for preparing 2.beta., 3a.beta., 7a.beta.-octahydroindole-2-carboxylic acid, 2.beta., 3a.beta., 6a.beta.-octahydrocyclopenta?pyrrol-2-carboxylic acid and 2.beta., 3a.beta., 8a.beta.-decahydrocyclohepta?-pyrrol-2-carboxylic acid is excluded.

10. A compound of the formula IV as defined in claim 9 in which R, R, R1 and R2 are as defined in claim 9 whenever prepared by the process of claim 9 or an obvious equivalent thereof.

11. A process for the preparation of trans-octa-hydroindole-2-carboxylic acid or its ester by solvolysis of trans-1- acetyl-2-cyanooctahydroindole with a compound of the formula ROH in which R
represents hydrogen, alkyl having 1 to 10 carbon atoms, aralkyl having 7 to 9 carbon atoms, cycloalkyl having 5 to 10 carbon atoms, alkylcycloalkyl having 6 to 12 carbon atoms or cycloalkylalkyl having 6 to 12 carbon atoms.

12. Trans-octahydroindole-2-carboxylic acid or its ester, wheever prepared by the process of claim 11 or by an obvious chemical equivalent thereof.