FI80675B - Azabicycloalkane carboxylic acid derivatives and a process for the preparation thereof - Google Patents

Description

1 80675

Azabicycloalkanecarboxylic acid derivatives and a process for their preparation

Divided separated from application 824 474 5

The invention relates to azabicycloalkanecarboxylic acid derivatives useful as intermediates in the preparation of therapeutically useful compounds and to a process for the preparation of these intermediates.

The azabicycloalkanecarboxylic acid derivatives of the invention have the formula (III ") rf-i

15 I 1 IIlM

N, N-COOW

R 4 R 20 wherein n is an integer from 0 to 2, W is hydrogen, alkyl of 1 to 6 carbon atoms, or benzyl, and R 3, R 4 and R 5 represent hydrogen or R 3 and R 4 or R 4 and R 5 together form a chemical bond, wherein the C atoms 3a and (6 + n) a the attached H atoms are in the cis or trans configuration relative to each other, and in the case of the cis configuration the group -COOW 'attached to the C atom 2 is in the exo position relative to the bicyclic ring system, provided that that when R 3 is hydrogen and R 4 and R 5 together form a chemical bond, then O and W are hydrogen.

Preferred compounds of formula III "are compounds of formula III ':

B

3 a

i I

B

35 4 2 III '2 80675 wherein the H atoms attached to the C atoms 3a and (6 + n) a are in a cis or trans configuration relative to each other, where in the case of the cis configuration the group -CO 2 W attached to the C atom 2? is in the exo position to the bicyclic ring system, and wherein n is 0, 1 or 2 and W is hydrogen or a hydrogenolytically or acid-cleavable group.

The azabicycloalkanecarboxylic acid derivatives III "according to the invention can be used as intermediates in the preparation of therapeutically valuable compounds of formula I.

II

3a____

15 (aI2> n \ N ^ CO2H y I

I * * I

H CO-CH-NH-CH-CHo-C-X

t. ^.

R! CO2R2 Z

wherein the hydrogen atoms at the bridgehead C atoms 3a and (6 + n) a are in the cis or trans position relative to each other, wherein in the cis configuration the carboxy group on the C atom 2 is oriented in the exo position with respect to the bicyclic ring system and has the integer 0- 2, R 1 = hydrogen, (C 1 -C 6) -alkyl, R 2 = hydrogen or (C 2 -C 6) -alkyl, Z = hydrogen or Y and Z together are oxygen and X is phenyl, and in the preparation of their physiologically acceptable salts.

Compounds of formula I prepared from compounds of formula III "have been shown to be preferred over the prior art in the parent application.

Suitable salts of the compounds of the formula I are, in particular, alkali and alkaline earth metal salts, salts with physiologically tolerable amines and salts with inorganic or organic acids such as, for example, HCl, HBr, H2SO4, maleic acid and fumaric acid. .

Il 3 80675

Alkyl can be straight-chain or branched.

In the case of the trans configuration of H atoms in C-3a and C- (6 + n) a, there are two possible configurations of the double ring and then the 2β, 3aa, (6 + n) ap-kon-5 configuration (formula Ib) and the 2β, 3ap, (6 + n) aa configuration, (Formula Ie), whereas in the case of the cis configuration of H atoms, the carboxy group must be oriented in the exo position (= β position).

The exo position (= β-position) of the carboxy group in C-2 is defined so that the carboxy group is oriented in that direction. In the direction of the H atoms, i.e. has turned to the concave side of the double ring, for example corresponding to formula Ia. (For the definition of a and β: η, see Fieser and Fieser, Steroid, p. 2. 1961).

15? H H

£ \ | ^ "U2" in \ I CO2H i I (X) 2H

H H if 20 13 Ic

The compounds of formula I have chiral C atoms at positions C-2, C-3a, C- (6 + n) a, and at the asterisked C-atoms of the side chain. The compounds of formula I may thus exist as optical isomers, diastereomers, racemates or mixtures thereof. Preferred are compounds of formula I in which the C atom 2 is in a double ring system and the C atoms marked with an asterisk in the side chain have the S configuration.

Preferred compounds of formula I are those wherein R 1 is (C 1 -C 3) alkyl and R 2 is hydrogen or (C 1 -C 3) alkyl.

Particularly preferred are compounds of formula I in which R 2 is methyl and those in which R 2 is hydrogen or ethyl.

The compounds of formula I are prepared according to a process variant 4 80675 in such a way that the compound of formula II:

Y

i

HO, C-CH-NH-CH-CH, -C-X II

^ i i i

5 R1 CO2 R2 Z

wherein R 2, R 2, X, Y and Z have the same meaning as in formula I, are reacted with a compound of formula III 'according to known imide formation methods in peptide chemistry.

B

3 a 15 ^ Η2φ6 ^ “2« 'Iir

B

B

wherein the H atoms at the C atoms 3a and (6 + n) a are in a cis or trans configuration relative to each other, wherein in the case of the cis configuration, the group -CO 2 W is located in the exo position relative to the bicyclic ring system and where n = 0.1 or 2 and W * is a hydrogenolytically or acidically cleavable residue, in particular a benzyl or tert-butyl residue, followed by cleavage of the residue W by catalytic hydrogenation or acid treatment and, if appropriate, additional acid or base treatment of the residue R2 to give the free carboxylic acids.

The compounds of formula III "and III 'serve as starting materials in the synthesis of the compounds of formula I and can be prepared according to the invention by the following procedures.

In one synthetic variant, a compound of formula IX is used as a starting material:

II

35 5 «0 ** 75

B

-.3

(6 + n) aj IX

^ ΊΝ, Χ2

5 I

H H

wherein the H atoms on the C atoms 3a and (6 + n) a are in a cis or trans configuration relative to each other and wherein n is the number 10 0, 1 or 2.

Compounds of formula IX wherein n * 0 are known from Booth et al., J. Chem. Soc. 159, pp. 1050; compounds with n = 1 are known from King et al., J. Chem. Soc. 1953, pp. 250, 253 and compounds with 15 = n = 2 are known from Ayerst et al., J. Chem. Soc. 1960, S. 3445.

These compounds of the formula IX are acylated in a known manner in which an aliphatic or aromatic acyl residue, preferably an acetyl or benzoyl residue, is attached to a nitrogen atom and the N-acylated compounds obtained are anodized (analogous: Liebigs Ann. Chem. 1978, p. 1719) in an aliphatic alcohol with 1 to 4 C atoms, especially in methanol, in the presence of a conductivity salt, preferably at temperatures between 0 ° and + 40 ° C, to form a compound of formula X wherein n is 0, 1 or 2 and R is (C 1 -C 4). C4) alkyl.

i ['' "'m

30 I (6 + n) aL

2 n 1 OR

acyl

B

The resulting compound of general formula X is reacted with trimethylsilyl cyanide according to Tetrahedron Letters 1981, p. 141 in an approbated organic solvent such as a hydrocarbon, halogenated hydrocarbon, ether or THF at a temperature between -60 ° C and + 20 ° C. , preferably between -40 ° C and ± 0 ° C in the presence of a Lewis acid such as ZnCl 2, SnCl 2, TiCl 4, BF 3 etherate, preferably BF 3 etherate, and the resulting compound of formula XI:

10 H

3a (6 + n) a.

(CH-J XI

2h CN

H 1 15 acyl in which the H atoms at the C atoms 3a and (6 + n) a are in a cis or trans configuration relative to each other, wherein in the case of the cis configuration the group -CN is in the exo position with respect to the bicyclic ring system and wherein n is as defined above, after purification and separation of the by-products by recrystallization or column chromatography under the action of acids or bases in a known manner, is hydrolyzed to a compound of formula III if W is hydrogen, and the latter is optionally esterified. In the acid hydrolysis of the nitrile group, HCl or HBr in particular is used as the acid. The esterification is carried out here as well as in the amino acid chemistry in the following by standard procedures.

Compounds of general formula III 'may also be prepared by reacting a compound of formula XII:

B

/ Xla_.

[XII '

35 I (6 + n) aJ

"Ch2"

k NOH

7,80675 wherein the H atoms 3a and (6 + n) a are in the cis or trans configuration and n is as defined above, by Beckmann atom transfer in accordance with Helv. Chim. Acta 46 (1963) 1190 to give a compound of formula 5 XIII, wherein n is as defined above, rh 10 1 | w o

H H

and this is halogenated to give a compound of formula XIV: 15

B

\ XIV

'Hai 20

i H

wherein n is as defined above and Hal is a halogen atom, preferably chlorine or bromine. Suitable halogenating agents are inorganic acid halides such as PC15, SO2Cl2, POCl3, SOCl2, PBr3 or halogens such as bromine. It is preferred to use PC15 or POCl3 in combination with SO2 Cl2. As an intermediate, an imide halide is first formed, which further reacts with said halogenating agents and then, by hydrolysis under basic conditions, preferably with aqueous alkali carbonate, to give the compound of formula XIV.

The compounds of formula XIV are then reduced catalytically in a polar protic solvent such as an alcohol, preferably ethanol, or a carboxylic acid such as acetic acid with the addition of an acid acceptor such as sodium acetate or triethylamine to give the compound of formula XV.

B

XV

10

H H

where n and Hai have the same meaning as above. Examples of suitable catalysts are Raney nickel or palladium or platinum carbon.

Compounds of formula XV may also be prepared directly by halogenating compounds of formula XIII with the addition of small amounts of the aforementioned halogenating agents.

The compounds of formula XV are converted according to the known Favorsky-20 reaction in the presence of a base to a compound of formula III 'in which W is hydrogen, and this is optionally esterified. The above-mentioned Favorsky reaction is carried out in an alcoholic solvent such as methanol, ethanol or tert-butanol or water or mixtures thereof at temperatures between 20 and 140 ° C, preferably between 60 and 100 ° C. Alkali or alkaline earth metal hydroxides, such as sodium, potassium or barium hydroxide, or alkali metal alcoholates, such as sodium methylate or potassium tert-butanolate, are preferably used as bases.

Furthermore, compounds of formula III 'in which the H atoms on the C atoms 3a and (6 + n) a are in the cis configuration can be prepared from a compound of formula XVI wherein n is 0, 1 or 2. 80675

XVI

k (CVN \ N / ^ 0

5 H

by reducing this publication to Ann. Chim. 62, 200 (1972) by platinum oxide / acetic acid to give the above-mentioned compound of formula XIII, and this is further reacted according to the procedure described above. Compounds of formula XVI are known from J. Org. Chem. 29, 2780 (1964).

Compounds of formula III 'in which the H atoms at the C atoms 3a and (6 + n) a are in the trans configuration can also be prepared from the compound of formula XVI mentioned above by reducing this in Bull. Soc. Chim. Belg. 85 11 (1976) with sodium formate / formic acid to give a compound of formula XIII and this is further reacted according to the procedures described above.

2-Azabicycloalkane-3-carboxylic acids of the trans configuration of formula III 'wherein n is an integer from 0-10 and W is hydrogen, and their α-25 alkyl and aralkyl esters can be prepared from enamines of formula XVII wherein n is as defined above and X 'is a dialkylamino having 2 to 10 carbon atoms or a residue of formula XVIIa wherein m and 0 are an integer from 1 to 3 (m + o) £ 3 and A is CH 2, NH, O or S (Organicum, 30th ed., P. 370, 1967).

^ X1

-OF

35 '“. (Τ' *>. ^ XVII XVIIa 10 80675 with N-acylated β-halo-α-amino-propionic acid esters of formula XVIII (free amino compound, see Helv. Chim. Acta 40, 1541 ( 1957), wherein X 2 is halogen, preferably chlorine or bromine, Y 1 is alkanoyl having 5 to 5 carbon atoms, aroyl having 7 to 9 carbon atoms or another acid-cleavable protecting group common in peptide chemistry, and R 4 'is alkyl of 1 to 5 carbon atoms or aralkyl of 7 to 9 carbon atoms 10

CH, XVIII

i ch Y1 -HN · "" ^ "O) R4 '15 or with acrylic acid esters of the formula XIX (Chem. Ber. 91 (1968) 2427), where Y1 and R4' have the same meaning as above.

20 CH2 - XIX

NH-Y1 is reacted with compounds of formula XX wherein R4 'and Y1 are as defined above,

c: h2 - CH2 - CH XX

NH-Y1 (CH2) 2 O 30 These 30 are cyclized by means of strong acids to cleave the acylamide and ester to give compounds of formula XXIa, which may also exist in tautomeric form of formula XXIb, of which n is as defined above.

II

il 80675

^ I fji X

5 'CH2fr ^ N' ^ C0 ° H "! '" Νΐ C00H

XXIa H XXIb Compounds of formula XXIa or b, optionally after conversion to their -C 1-8 alkyl or C 7 -C 10 -10 aralkyl esters, are catalytically converted by hydrogenation in the presence of transition metal catalysts or by reduction with borane-amine complexes or complexes with borohydrides. trans configuration and of formula III 'wherein n is as defined above and W is hydrogen, alkyl of 1-18 C atoms or aralkyl of 7-10 C atoms, optionally saponifying the ester of formula III' and this , if W is hydrogen, optionally esterified to compounds of formula III 'wherein n is as defined above and W is aralkyl containing 1-18 C-20 m atoms.

In Am. Soc. 81 (1956) 2596 describes the reaction of 3-bromopropylamine with cyclohexanone enamine.

It is further suggested that a free NH2 group would be required for the initiation of alkylation. Therefore, it is extremely surprising that halopropionic acid derivatives having an acylated amino group, such as the compounds of formula XVIII described above, can also be used for the alkylation of enamines. In this case, the amines of cyclohexanone, cycloheptanone, are preferably used. Suitable amine components are, for example, diethylamine, pyrrolidine, piperidine or morpholine. However, other secondary amines are also suitable. Pyrrolidine cycloalkylenes are preferred.

Formyl, acetyl, propionyl or benzoyl or 12,80675 other acid-cleavable protecting groups such as, e.g., tert-butyloxycarbonyl are particularly suitable groups Y1 of β-bromo or chloro-α-aminocarboxylic acid esters of formula XVIII. Preferably C 1 -C 3 alkyl or benzyl esters are used.

Under basic experimental conditions, the acrylic acid derivatives of formula XIX formed as intermediates from β-halo-α-aminopropionic acid esters are likewise suitable as starting compounds. They are prepared, for example, by treating ha-10 logenaminopropionic acid derivatives or analogous O-tosylserine derivatives with bases. Preferably, tertiary organic bases such as triethylamine are used. It is advantageous to work with the addition of small amounts of polymerization inhibitors, such as hydroquinone in organic solvents. The acrylic acid derivatives of formula XIX can be used instead of the halopropionic acid derivatives under similar reaction conditions.

Suitable solvents for enamine synthesis are not alkylatable organic solvents such as di-methylacetamide, DMSO, THF or toluene. Dimethylformamide is particularly suitable.

It is recommended to use the enamines of formula XVII in excess and thus avoid the N-acyl acrylic ester as an impurity in the final product.

The hydrolysis of the N-acyl group necessary for the cyclization is generally effected together with the cleavage of the ester group with strong aqueous mineral acids such as sulfuric acid or, preferably, hydrochloric acid. In the case of the N-tert-butyloxycarbonyl derivatives of the formula XVII, it is possible, for example, to preserve the ester function, to isolate the esters of dihydrocarboxylic acids XXIa or XXIb when using dioxane / HCl or anhydrous trifluoroacetic acid. These can be changed by hydrogenation in the presence of metal catalysts or by reaction with borane amine complexes 35 or complex borohydrides.

II

i3 to 80675 III '2-azabicyclocarboxylic acid esters having the trans configuration. Precious metal or nickel catalysts suitable for catalytic hydrogenation. The isomer ratio resulting from catalytic hydrogenation depends on the reaction conditions and the type of catalyst used. In addition to Rh / Al 2 O 3, Pt / C is also suitable for reduction, however, some more trans product is obtained. It is possible to shorten the reduction time with a higher hydrogen pressure, however, the temperature should be kept low. Suitable solvents for the catalytic hydrogenation are, for example, ethanol, methanol, ethyl acetate, dioxane, glacial acetic acid or mixtures of these solvents.

Compounds of formula III * b wherein n is an integer from 0-2 and W is hydrogen, 15 (CH III, fa

2; n | COOH

B

20 is also obtainable by reduction of compounds of formulas XXIa or b, wherein n is as defined above, with borane-amine complexes or complex borohydrides in lower alcohols.

As the reducing agent, sodium borohydride in alcohols, especially methanol, ethanol or isopropanol, is preferred. Amine-borane complexes in glacial acetic acid are also useful.

The isolation of pure trans compounds of formula III'b can be carried out, for example, by chromatographic methods or crystallization methods.

The pure trans compound of formula III'b is preferably separated by fractional crystallization from an amine borane complex or borane reduction diastereomer mixture.

14 80675

Formula III 'can in certain cases be converted to Cx8-alkyl or C7-C10-Aralyl esters by methods such as those described, for example, in Houben-Weyl, Volume VIII (1952).

The compounds of formula II used as starting materials for the preparation of the compounds of formula I, in which Y and Z are hydrogen, Rx is methyl and R2 is methyl or ethyl and X is phenyl, are known (European Patent Application No. 37,231). The compounds of formula II can be prepared by a variety of procedures. In one synthetic variant, a ketone of the above formula VII is used, which according to known procedures is reacted in a Mannich reaction with a compound of the above formula VI together with amino acid esters of the formula XXII 15 * *

H, N - CH - CO, W WO, C-CH-NH-CH-CH, -CO-X

2 I 2 2 I I 2

Rx R, CO2R2

20 XXII XXIII

wherein Rx and W are as defined above, are converted to a compound of formula XXIII wherein R1, R2, X and W are as defined above, with the proviso that in the case where W is a hydrogenolytically cleavable residue, in particular benzyl, R2 must not be W. If the residue W is hydrogenolytically cleaved, for example with the aid of palladium, compounds of the formula II in which Y and Z are hydrogen are obtained. Cleavage of the residue W with acids such as trifluoroacetic acid or hydrochloric acid in an inert organic solvent such as dioxane gives compounds of formula II wherein Y and Z together are oxygen.

Compounds of formula XXIII may also be obtained by Michael addition of the compound of formula V mentioned above to the compound

II

is 80675 of the above formula XXII according to known procedures. Preferably, this process is suitable for the preparation of compounds of formula XXIII wherein R 1 is methyl, R 2 is ethyl and X is aryl.

The compounds of formula XXIII are obtained as mixtures of diastereomers. Preferred diastereomers of formula XXIII are those in which the asterisked chiral C atoms have the S configuration. These can be separated by recrystallization or chromatography, for example on silica gel. Subsequent cleavage of the residue W preserves the configurations of the chiral C atoms.

The compounds of formula IV used as starting materials for the preparation of the compounds of formula I are obtained according to known procedures by reacting the compounds of formula III mentioned above with an N-protected 2-aminocarboxylic acid of formula XXIV.

V - HN - CH - CO, H XXIV

k 20 where V is a protecting group and Rx is as defined above. Examples of suitable protecting groups V which are cleaved off at the end of the reaction are, for example, benzyloxycarbonyl or tert-butoxycarbonyl.

The reaction of a compound of formula II with a compound of formula III to prepare a compound of formula I takes place according to a condensation reaction known in peptide chemistry, for example dicyclohexylcarbodiimide and 1-hydroxybenzotriazole are added as condensing agent. Palladium is preferably used as a catalyst in the subsequent hydrogenolytic cleavage of residue W, while in the acidic cleavage of residue W, trifluoroacetic acid or hydrochloric acid is preferably used as acid.

In the reactions described above for the preparation of the compounds of formulas III ', IV 35 and I, the configurations of the intermediates ie 80675 on the bridgehead C atoms 3a and (6 + n) a are retained. In the case of the trans configuration of the C atoms 3a and (6-i-n) a of the H atoms, the the compounds as partially pure diastereomers, partly as mixtures of diastereomers having, as described above, the 2β, 3aa, (6 + η) ββ or 2β, 3ββ, (6 + n) aa configuration. These isomers can be easily separated by recrystallization or chromatography. If the corresponding starting materials having the cis configuration of the H atoms with C-3a and C-6 + n) a are used for the preparation of the compounds of the formulas III ', IV or I, almost exclusively exo- (i.e. β) -isomers are obtained , which can be liberated from small isomeric parts by recrystallization or chromatography.

The compounds of formula III 'obtained according to the procedures described above are obtained as racemic mixtures and can be used as such in the other syntheses described above. However, they can also be used as pure enantiomers as optical enantiomers after resolution of the racemates by conventional methods, for example by salt formation with optically active bases or acids.

If the compounds of the formula I are obtained as racemates, these can also be cleaved into their enantiomers according to customary methods, for example by salt formation with optically active bases or acids.

The compounds of formula I according to the invention exist as internal salts. As amphoteric compounds, they can form salts with acids and bases. These salts are prepared in the usual manner by reacting with 30 equivalents of acid or base.

The compounds of formula I and their salts have a long-lasting, potent antihypertensive effect. They are potent inhibitors of the angiotensin converting enzyme (ACE inhibitors). They can be used to control high blood pressure in different early 35s. Also their

II

17 80675 may be combined with other antihypertensive, vasodilator or diuretic agents. Typical representatives of this class of action are described, for example, in Erhardt-Rusch-5 ing, Arzneimittel, 2nd edition, Weinheim, 1972. The administration can take place intravenously, subcutaneously or orally.

The dosage for oral administration is 1-100 mg, preferably 1-40 mg per single dose in a normal adult 10 adult patient. It can also be increased in severe cases, as no toxic properties have been observed so far. Dose reduction is also possible and is primarily done when concomitant urinary agents are administered.

The compounds of the invention may be administered orally or parenterally as a corresponding pharmaceutical preparation. For oral administration, the active compounds are mixed with customary additives such as carriers, stabilizers or inert diluents and converted into suitable dosage forms, such as tablets, granules, rectal capsules, aqueous, alcoholic or aqueous suspensions by conventional methods. 25 solutions. As inert carriers, for example, gum arabic, magnesium carbonate, potassium phosphate, milk sugar, glucose or starch can be used. In this case, the preparation can equally well take place in the form of dry or wet granules. suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or cod-liver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically tolerable salts are, if desired, brought into solution, suspensions or emulsions with customary substances such as solubilizers, emulsifiers or other excipients. Suitable solvents for these new active compounds and the corresponding physiologically tolerable salts are, for example: water, physiological saline-5 solutions, alcohols, e.g. ethanol, propanediol or Glycerol, as well as sugar solutions such as glucose or mannitol solutions or mixtures of different solvents.

The excellent potency of the compounds of the formula I 10 is demonstrated by analogous numerical values in the following tables:

Intraduodenal administration of an anesthetized rat, 310 ng of angiotensin I to the excited tasoitusreak-State 50 -% in the daily dose of ... = ED50 administration hereinafter-15 footprint:

Table I

(H atoms C-3a and C- (6 + n) a in formula I have the cis configuration) 20 n XYZ R2 R1 ED50 (ug / kg) 0 HH CKa 40 0 HHH CH3 700 25 1 C3 HH c2ns ch3 50 1 ^ 3 HHH CH3 600 30 * OHH C2H5 CH3 230 2 HHH CH3 840 35 r ~ \ 1 <^ = j) - 0 - C2H5 CH3 390 11 19 80675

The symbols n, X, Y, Z, Rx and R2 refer to compounds of formula I.

Table II 5 H atoms C-3a and C- (6 + n) a have the trans configuration; X = phenyl, R2 = methyl n YZ R2 Double ring ED50 (pg / kg) 10 configuration 0 HHH 2S, 3aR, 6aS 700 0 HH C2H5 2S, 3aR, 6aS 40 1 HHH 2S, 3aR, 7aS 800 1 HH C2H5 2S, 3aR , 7aS 55 15 1 HHH 2S, 3aS, 7aR 850 1 HH C2H5 2S, 3aS, 7aR 65 2 HHH 2S, 3aR, 8aS 1080 2 HH C2H5 2S, 3aR, 8aS 110 1 - 0 - C2H5 2S, 3aR, 7aS 180 20

The symbols n, X, Y, Z, R 2 and R 2 refer to compounds of formula I.

The following examples are intended to illustrate the invention without limiting it to the compounds mentioned.

Example 1 2β, 3ap, 7ap-Octahydroindole-2-carboxylic acid a) N-acetyl-3ap, 7a8-octahydroindole

To a solution of 77 g of indole in 700 ml of glacial acetic acid is added 3.5 g of platinum oxide. It is first hydrogenated for 30 to 16 hours at 20 to 25 ° C at 100 atmospheres and then at 20 to 25 ° C under normal pressure until hydrogen uptake is complete. The catalyst is filtered off with suction and the solvent is distilled off under reduced pressure. The residue is taken up in water and basified with saturated potassium carbonate solution. After impregnation with sodium chloride, the aqueous phase is extracted four times with methylene chloride and the organic phase is dried and evaporated to dryness.

The residue is taken up in 250 ml of pyridine, 93 ml of acetic anhydride are added and the mixture is allowed to react for 5 to 12 hours at 20 to 25 ° C. After distilling off the pyridine, water is added to the residue and basified with concentrated aqueous sodium hydroxide. The aqueous phase is extracted with methylene chloride, the organic phase 2n obtained is washed with hydrochloric acid and then with water. After drying and evaporation of the solvent, the residue is distilled.

Yield: 85 g; kp .; 91-95 ° C / 0.2 mm Hg b) N-acetyl-2-methoxy-3ap, 7ap-octahydroindole 54 g of N-acetyl-3ap, 7ap-octahydroindole are oxidized anodically in methanol with the addition of tetramethylammonium tetrafluoroborate according to the instructions presented in Liebigs. Ann. Chem. 1978, page 1719. The solvent is distilled off and the residue is filtered through 500 g of silica gel with ethyl acetate. After evaporation, 53.6 g of the above product are obtained from the ethyl acetate solution. Rf value (thin layer chromatography): 0.33 (silica gel, ethyl acetate).

c) N-Acetyl-2β, 3α, 7α8-octahydrolindole-2-carboxylic acid nitrile To a solution of 49.8 g of N-acetyl-2-methoxy-3ββ, 7α-octahydroindole in 250 ml of methylene chloride is added dropwise -40 ° C. in 25 g of trimethylsilyl cyanide in 50 ml of methylene chloride. 35.9 g of boron trifluoride etherate are then added dropwise so that the temperature of the reaction mixture does not rise above -25 ° C. After a reaction time of 2 hours at -20 ° C, the temperature is slowly raised to 0 ° C, stirred overnight at 0 ° C and then for a further 1 hour at 20-25 ° C. Add water and stir for 10 minutes. The aqueous phase is extracted three times with methylene chloride-35a. The combined organic extracts are dried and evaporated

II

2i 80675 to dryness and the residue is triturated with diisopropyl ether. Yield: 47 g; mp: 128-130 ° C.

d) 2β, 3ap, 7ap-Octahydroindole-2-carboxylic acid 10 g of N-acetyl-2β, 3ap, 7ap-octahydroindole-2-carb-5-carboxylic acid nitrile are boiled in 30 ml of concentrated hydrogen bromide for 2 hours. After distilling off the hydrogen bromide, the residue is taken up in a small amount of acetone and filtered off with suction.

The aqueous solution of the product is adjusted to pH 6.0 with a weakly 10 basic ion exchanger. After filtration, the solution is evaporated and the residue is filtered through silica gel with a mixture of methylene chloride, methanol, glacial acetic acid and water in a ratio of 20: 10: 0.5: 0.5. The eluate is evaporated and the residue is triturated with diisopropyl-15 ether.

Yield: 7.6 g 1 H-NMR spectrum *: 1.0-2.5 (m, 11H); 3.4-3.9 (m. 1H); 4.0-4.5 (1 H); 7.5-8.3 (s-broad, interchangeable Dj 0: 11a) 20 If the procedure is described in accordance with the procedure described in Example 1, the following compounds are obtained in Example 2 and Example 3:

Example 2 2P, 3aP, 6ap-Octahydrocyclopenta [b] pyrrole-2-carboxylic acid 25 a) N-Acetyl-cis-octahydrocyclopenta [b] pyrrole 1 H-NMR values: 1.0-2.3 (m, 9H ); 2.0 (d. 3H); 3.3-4.2 (m, 3H) b) N-Acetyl-2-methoxy-cis-octahydrocyclopenta [p] pyrrole 30 * 1 H-NMR values were determined here as in the following CDCl 3 and given here as in the following ppm (in parts per million).

1 H-NMR values: 0.9-2.6 (m, 9H); 2.1 (s. 3H); 22 80 675 3.3 (s. 3H); 3.8 - 4.3 (m, 1 H); 4.7 - 5.5 (m, 1 H).

c) N-acetyl-2-cyano-cis-octahydrocyclopenta [p] pyrrole 1 H-NMR values: 1.0-3.0 (m, 9H); 2.1 (d. 3H); 3.5 - 4.1 (m, 1 H); 4.4 - 4.7 (m, 1 H).

d) 2β, 3ββ, 6aβ-octahydrocyclopenta [p] pyrrole-2-carboxylic acid 1 H-NMR values: 1.0-2.3 (m, 9H); 3.5 - 3.9 (m, 1 H); 4.0 - 4.6 (m, 1 H); 7.7 - 8.4 (s-wide, interchangeable 15 D2 0: 11a)

Example 3 2β, 3ββ, 8aβ-Decahydrocyclopenta [b] pyrrole-2-carboxylic acid a) N-Acetyl-cis-decahydrocyclohepta [b] pyrrole 0.9-2.5 (m, 13H); 2.1 (s. 3H); 3.1 - 4.1 (m. 3H).

b) N-acetyl-2-methoxy-cis-decahydrocyclohepta [b] pyrrole 1 H-NMR values: 0.9-2.7 (m, 13H)? 2.1 (s. 3H); 3.2 (s. 3H); 3.7 - 4.2 (m, 1 H); 4.7-5.3 (m, 1H) c) N-acetyl-2-cyano-1S-decahydrocyclohepta [b] pyrrole 1 H-NMR values: 0.9-3.1 (m, 13H); 2.1 (s. 3H); 3.5-4.1 (m, 1H) δ 4.3-4.7 (m, 1H) d) 2β, 3a8,8a8-Decahydrocyclohepta [b3pyrrole-2-carboxylic acid 35]. 23 8 0 6 7 5 1 H-NMR values: 0.8-2.4 (m, 13H); 3.5 - 3.9 (m, 1 H); 4.1 - 4.6 (m, 1 H); 7.6 to 8.3 (s-wide, interchangeable with 5 D20).

Example 4 2β, 3aP, 7ap-Octahydrolindole-2-carboxylic acid a) 3,4,5,6,7,8-Hexahydro-1H-quinolin-2-one 10 392 g of cyclohexanone and 216 g of acrylonitrile are heated together to 20 g. with cyclohexylamine, with 4 g of glacial acetic acid and with 0.4 g of hydroquinone at reflux for 4 hours to a final temperature of 200 ° C. After distillation at 100-150 ° C / 0.5 mm Hg, the remaining residue containing the desired product is recrystallized from n-hexane.

The distillate is heated for 2 days with 10 ml of 10% acetic acid at 200 ° C. After cooling, more product is obtained which crystallizes from methanol / water.

A total of 460 g of the title compound is obtained, m.p. 143-144 ° C.

b) Cis-octahydro-1H-quinolin-2-one

To a solution of 80 g of 3,4,5,6,7,8-hexahydro-1H-quinolin-2-one is added 1 g of platinum (IV) oxide and hydrogenated at 20-25 ° C under normal pressure. . After filtration of the reaction solution, this is evaporated to dryness and the residue is fractionally crystallized from n-hexane. 35 g of cis-octahydro-1H-quinolin-2-one are obtained, m.p. is 123-126 ° C.

c) 3,3, -Dichloro-cis-octahydro-1H-quinolin-2-one To a solution of 23 g of cis-octahydro-1H-quinolin-2-one in 350 ml of anhydrous chloroform is added 28.8 g of phosphorus pentachloride. To this is added dropwise 43.1 g of sulfuryl chloride in 45 ml of anhydrous chloroform over 30 minutes at 20-30 ° C, and the reaction mixture is stirred for 5 hours to 35 hours at reflux temperature. After standing overnight, the mixture is neutralized with aqueous potassium carbonate cooled to 0 ° C. The aqueous phase is extracted twice with methylene chloride. The combined organic phases are dried over sodium sulfate and evaporated. The residue is recrystallized from ethanol with the addition of activated carbon. 32 g of pale yellow crystals are obtained, m.p. is 176-177 ° C.

d) 3-Chloro-cis-octahydro-1H-quinolin-2-one 15.9 g of 3,3, -dichloro-cis-octahydro-1H-quinolin-2-one are hydrogenated in 1 l of ethanol with the addition of 10 ml of triethyl 10 amines and Raney nickel at 20-25 ° C under normal pressure until 1 molar equivalent of hydrogen is received. After filtration, the solution is evaporated, the residue is taken up in ethyl acetate, the solution is extracted twice with water and dried over sodium sulfate. After removal of the solvent, the product is triturated with diisopropyl ether and filtered off with suction. Colorless crystals are obtained, m.p. is 185®C.

e) 2β, 3a8,7a8-Octahydroindole-2-carboxylic acid 3.75 g of 3-chloro-cis-octahydro-1H-quinolin-2-one are added to a boiling solution of 6.63 g of barium hydroxide-20 cidooctahydrate in 120 ml. of water. After refluxing for 3.5 hours, 0.9 ml of concentrated sulfuric acid is added to the reaction mixture, boiled for a further hour and then allowed to stand overnight.

The precipitate formed is filtered off with suction and the filtrate, adjusted to pH 6.5 with 1N sodium hydroxide, is evaporated to dryness. The residue is extracted with boiling ethanol, evaporated and crystallized.

Yield: 3.1 g.

In a uniform manner as described in Example 4, the compounds 28-cis-octahydro-cyclopenta [b] pyrrole-2-carboxylic acid (corresponding to the compound of Example 2d) and 2β, 3ap, 8aβ-decahydrocyclohepta [b] pyrrole can also be prepared. -2-carboxylic acid (corresponding to the compound of Example 3d d).

35 25 80675

Example 5 2β, 3ββ, 7a8-Octahydroindole-2-carboxylic acid benzyl ester hydrochloride 3 ml of thionyl chloride are added dropwise to 25 ml of 5 benzyl alcohol. To this is added 3 g of 2β, 33β, 73β- € Λΐβϊιγά-roindole-2-carboxylic acid hydrochloride. The reaction mixture is allowed to stand for 2 days at 5 ° C, after which a clear solution is formed. After evaporation, diisopropyl ether is added to the residue obtained and filtered off with suction. 3.8 g of the title compound are obtained, m.p. is 150 ° C (decomposes).

In a uniform manner, as described in Example 5, the following ester compounds of Examples 6 and 7 can be prepared:

Example 6 2β, 3a8, 6a8-Octahydrocyclopenta [b] pyrrole-2-carboxylic acid benzyl ester hydrochloride 1 H-NMR values: 1.0-2.3 (m, 9H); 3.4 - 3.9 (m, 1 H); 4.1 - 4.6 (m, 1 H); Δ 5.1 (s, 2 H); 7.2 (s. 5H).

Example 7 2β, 3a8, 8a8-Decahydrocyclohepta [b] pyrrole-2-carboxylic acid benzyl ester hydrochloride 1 H-NMR values: 0.9-2.3 (m, 13H); 3.5 - 3.9 (m, 1 H); 4.2 - 4.7 (m, 1 H); 5.2 (s. 2H); 7.2 (s. 5H).

Example 8 2β, 3a8,7a8-Octahydroindole-2-carboxylic acid tert. -butyy-ethyl ester hydrochloride

To a solution of 10 g of 2β, 3aβ, 7aβ-octahydroindole-2-carboxylic acid in 100 ml of dioxane, cooled to -10 ° C, are added 10 ml of concentrated sulfuric acid 26 80675 and 50 g of isobutylene. The reaction mixture is slowly heated in an autoclave to 20-25 ° C and stirred at this temperature for 20 hours.

The mixture is added to ice-cold 50% aqueous sodium hydroxide and extracted with methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate and evaporated to dryness. The residue is taken up in ether and adjusted to pH 2.0-3.0 with ethereal hydrogen chloride. Evaporate to dryness and triturate the product with diisopropyl ether. After suction filtration, 7.3 g of the title compound are obtained.

1 H-NMR values: 1.0-2.5 (m, 11H); 1.3 (s. 9H); 3.4 - 3.9 (m, 1 H); 4.0 - 4.5 (m, 1 H).

The following ester compounds of Examples 9 and 10 can be prepared in accordance with the procedure described in Example 8:

Example 9 2β, 3a8, 6a8-Octahydrocyclopenta [b3pyrrole-2-carboxylic acid tert-butyl ester hydrochloride 1 H-NMR values: 1.0-2.7 (m, 9H); 1.3 (s. 9H); 3.4 - 3.9 (m, 1 H); 4.0 - 4.5 (m, 1 H).

Example 10 2β, 3a8, 8a8-Decahydrocyclohepta [b] pyrrole-3-carboxylic acid polytert-butyl ester hydrochloride 1 H-NMR values: 0.8-2.9 (m, 13H); Δ 1.3 (s, 9 H); 3.4 - 3.9 (m, 1 H); 4.0 - 4.5 (m, 1 H)

Example 11 ΡΙ.-2β, 3a8,7aa-Octahydroindole-2-carboxylic acid benzyl-35 ester hydrochloride 11 27 80675

To a solution prepared at -5 to 0 ° C and containing 1.4 ml of thioenyl chloride in 14 ml of benzyl alcohol is added, at -10 to 0 ° C, 1.4 g of DL-2β, 3ββ, 7aa-octahydride. roindoli-2-carboxylic acid. Stir for 1 hour at 0 ° C and allow to stand overnight at 20-25 ° C. The benzyl alcohol is distilled off under high vacuum at 50 ° C and the residue is treated with diisopropyl ether. 2.5 g of colorless crystals are obtained, m.p. is 154 ° C.

Example 12 2β, 3aP, 7aa-Octahydrolindole carboxylic acid a) 3-Chloro-N-acetyl-alanine methyl ester 181 g of 3-chloro-alanine methyl ester hydrochloride are heated with 163.9 g of acetyl chloride in 1.5 liters of anhydrous toluene at reflux for about 5 hours, 15 until a clear solution is formed. Evaporate to dryness and the residue is crystallized from ethyl acetate / petroleum ether. 170 g of product are obtained, m.p. is 104 ° C.

b) 3- (2-Oxo-cyclohexyl) -N-acetyl-alanine methyl ester 160 g of 3-chloro-N-acetyl-alanine methyl ester and 171.9 g of 1-pyrrolidinecyclohexene are dissolved in 1.2 l. absolute DMF and the mixture is allowed to stand for 3 days at 20-25 ° C.

The solution is evaporated under high vacuum, the residue obtained is taken up in 600 ml of water and adjusted to pH 2.0 with concentrated hydrochloric acid. The aqueous solution is extracted with ethyl acetate, the organic phase is dried over sodium sulfate and evaporated. The product is obtained as a yellow oil.

c) 3,3a, 4,5,6,7-2H-Hexahydroindole-2-carboxylic acid hydrochloride 220 g of the compound obtained in b) are refluxed for 2 hours with 1 liter of 2N hydrochloric acid. The reaction mixture is extracted with ethyl acetate and the aqueous phase is evaporated. Residual water is removed by evaporation three times in vacuo with the addition of toluene. 210 g of product are obtained in the form of a yellow oil which crystallizes on standing, d) 2β, 3a3,7aa-octahydrolindole-2-carboxylic acid 128 g of 3,3a, 5,6,7-2H-hexahydroindole-2-carboxylic acid hydrochloride are hydrogenated In 700 ml of glacial acetic acid, 5 4 g of platinum / carbon (10%) are added under normal pressure at room temperature.

The catalyst is filtered off and the filtrate is evaporated to dryness. The residue is dissolved in 500 ml of hot ethanol and cooled to -20 ° C. This precipitates the 2β, 3ap, 7a3 isomer of the title compound 10. The product is obtained from the solution by evaporation and addition of isopropanol in the form of colorless crystals of m.p. is 280 ° C.

Example 13 2β, 3aP, 8aa-Decahydro-cyclohepta [b] pyrrole-2-carboxylic acid This compound is prepared starting from pyrrolidine cycloheptene according to methods b) to d) of Example 12.

Example 14 2β, 3a3, 6ag-Octahydro-cyclopenta [b] pyrrole-2-carboxylic acid This compound is prepared starting from pyrrolidine cyclopentene in accordance with procedures b) to d) of Example 12.

Example 15 2β, 3aa, 7a3-Octahydroindole-2-carboxylic acid a) 3,4,5,6,7,8-Octahydro-1H-quinolin-2-one 392 g of cyclohexanone and 212 g of acrylonitrile are refluxed together for 20 g: with 30 cyclohexylamine and 4 g with glacial acetic acid and 9.4 g with hydroquinone for 4 hours to a final temperature of 200 ° C. The distillate obtained after distillation at 100-150 ° C / 0.5 mm Hg is heated for 2 days with 10 ml of 50% acetic acid at 200 ° C. After cooling, the reaction mixture is recrystallized from methanol / water. Together with the distillation residue n 29 8 0 6 7 5 obtained above, which is recrystallized from n-hexane, 460 g of product are obtained, m.p. is 143-144 ° C.

b) Trans-octahydro-1H-quinolin-2-one 5 A mixture of 25 g of the product obtained in a) and 70 g of sodium formate in 120 ml of formic acid is refluxed for 18 hours. The reaction solution is made alkaline with 20% aqueous sodium hydroxide and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. The residue is recrystallized from cyclohexane to give the product, m.p. is 152 ° C.

c) 3,3, -Dichloro-trans-octahydro-1H-quinolin-2-one

To a solution of 19.4 g of the compound obtained in b) and 24.3 g of phosphorus pentachloride in 300 ml of anhydrous chloroform is added dropwise a solution of 36.4 g of sulfuryl chloride in 40 ml of chloroform at 20-30 ° C: within 30 minutes. The mixture is boiled for 6 hours and allowed to stand overnight at 20-25 ° C.

Neutralize with ice-cold saturated aqueous potassium carbonate, extract the mixture with methylene chloride, dry the organic phase over sodium sulfate and evaporate. After recrystallization of the residue from ethanol and addition of activated carbon, 25 g of product are obtained, m.p. is 195-198'C.

d) 3-Chloro-trans-octahydro-1H-quinolin-2-one 15.6 g of the compound obtained in c) are hydrogenated in 1 liter of ethanol and 9.7 ml of triethylamine with the addition of Raney nickel at 20-25 ° C under normal pressure until 1 molar equivalent of hydrogen 30 is received.

After filtering off the catalyst, the filtrate is evaporated to dryness and the residue is taken up in ethyl acetate.

. . The organic phase is washed twice with water, dried over sodium sulfate and evaporated. The residue is triturated with di-35 isopropyl ether, filtered off with suction and dried. 80675 g of product are obtained in the form of pale yellow crystals, m.p. is 115-120 ° C.

e) 2β, 3ββ, 7ap-Octahydrolindole-2-carboxylic acid 3.75 g of the compound obtained in d) are added to a boiling solution of 6.63 g of barium hydroxide octahydrate in 120 ml of water. After refluxing for 4 hours, 0.9 ml of concentrated hydrochloric acid are added, the mixture is refluxed for a further 1 hour, the reaction solution is filtered and the filtrate is adjusted to pH 6.5 with 1N sodium hydroxide. After evaporation of the solution, the residue is heated in ethanol, filtered again and the filtrate is evaporated to a small volume. On cooling, a crystalline 1: 1 mixture of the title compound with the compound of Example 12, m.p. is 275-276 ° C.

Example 16 2β, 3a8, 6aa-Octahydrocyclopenta [b] pyrrole-2-carboxylic acid E a) 1,2,3,4,6,7-Hexahydro-5H-1-pyridin-2-one

A mixture of 1 mole of cyclopentanone, 1 mole of 20 acrylonitrile, 0.05 moles of ammonium acetate and 3 ml of 30% ammonia is heated in a pressure vessel for 3 hours at 229 ° C. The mixture is filtered on silica gel using ethyl acetate / cyclohexane (1: 1) and the residue obtained after evaporation of the filtrate is recrystallized from cyclo-hexane. The product melts at 118-120 ° C.

1 H-NMR values: 9.4 (s-broad, 1H); 3.2 - 2.0 (m. 12H).

b) O-octahydro-trans-5H-1-pyridin-2-one This compound is prepared according to the procedure described in Example 15 b).

1 H-NMR values: 7.8 (s-broad, 1H); 2.9 (s broad, 1H); 2.6 - 2.2 (m. 2H); 2.1 - 1.0 (m, 8 H).

c) 3,3-Dichloro-octahydro-trans-5H-1-pyrid-2-one This compound is prepared in a uniform manner according to

II

3i 80675 with the procedure described in paragraph 15 (c).

1 H-NMR values: 7.9 (s-broad, 1H); 3.8 (s-broad, 1H); 3.2 - 2.0 (m. 2H); Δ 2.1-1.0 (m. 6H).

d) 3-Chloro-octahydro-trans-5H-1-pyrid-2-one This compound is prepared in accordance with the procedure described in Example 15 (d).

1 H-NMR values: 7.8 (s-broad, 1H); 4.6 - 4.3 (m, 1 H); 3.3 - 3.0 (m, 1 H); 2.1 (d, J = 6Hz, 2H); 1.8 - 1.1 (m, 6 H).

e) 2β, 3ag, 6aa-Octahydrocyclopenta [b] pyrrole-2-carboxylic acid This compound is prepared according to the procedure described in Example 15 e). 1 H-NMR values: 4.7-4.4 (m, 1H); 3.0-0.9 (m. 10H).

Example 17 2β, 3a8,8aa-Decahydrocyclohepta [b] pyrrole-2-carboxylic acid 22 a) 1,2,3,4,5,6,7,8-Octahydrocyclohepta [b] pyrld-2-one This compound is prepared in accordance with the procedure described in Example 15 (a) starting from 25 cycloheptanone.

1 H-NMR values: 9.4 (s-broad, 1H); 3.2-2.0 (m. 14H).

b) Trans-decahydrocyclohepta [b] pyrid-2-one This compound is prepared according to the procedure described in Example 15 (b) starting from the compound mentioned in 30 (a) above.

1 H-NMR values: 7.9 (s-broad, 1H); 2.9 (s broad, 1H); 2.6-2.2 (m. 2H); 2.1-1.0 (m. 12H).

35 32 80675 c) 3,3, -Dichloro-trans-decahydrocyclohepta [b] pyrid-2-one This compound is prepared in accordance with the procedure described in Example 15 c). 1 H-NMR values: 7.9 (s-broad, 1H); Δ 3.8 (s-broad, 1H); 3.2 - 2.0 (m. 2H); 2.1 - 1.0 (m, 10 H); d) 3-Chloro-trans-decahydro-cyclohepta [b] pyrrolidin-2-one This compound is prepared according to the procedure described in Example 10 (d).

1 H-NMR values: 7.8 (s-broad, 1H); 4.6 - 4.3 (m, 1 H); 3.3 - 3.0 (m, 1 H); 2.1 (d, J = 6 Hz, 2 H); 1.8 - 1.1 (m, 10 H).

e) 2β, 3a8,8aa-Decahydrocyclohepta [b] pyrrole-2-carboxylic acid This compound is prepared according to the procedure described in Example 15 e).

1 H-NMR values: 4.7-4.4 (m, 1H); 3.2 - 1.1 (m, 1 H).

Example 18 2β, 3aα, 7α8-Octahydroindole-2-carboxylic acid tert-butyl ester hydrochloride This compound was prepared from 2β, 3aα, 7α-octahydroin-25-diol-2-carboxylic acid according to the procedure described in Example 8.

1 H-NMR values: 4.7-4.4 (m, 1H); 3.2 - 1.1 (m. 12H); 1.2 (p. 9H).

The compounds of the following Examples 18-22 were prepared in accordance with the procedure described in Example 8.

Example 19 2β, 3a8,7aa-Octahydroindole-2-carboxylic acid tert. -butyl-35 ester hydrochloride I! 33 8 0 6 7 5 1 H-NMR values; 4.7 - 4.3 (m, 1 H); 3.4 - 1.1 (m, 12 H); 1.2 (s, 9Η).

Example 20 2β, 3aA, 6ap-Octahydrocyclopenta [b] pyrrole-2-carboxylic acid tert-butyl ester 1-hydrochloride 1 H-NMR values; 4.8 - 4.4 (m, 1 H); 3.4 - 1.2 (m. 10H); 1.2 (s. 9H).

Example 21 2β, 3ββ, 6α-Octahydrocyclopenta [b] pyrrole-2-carboxylic acid polytert-butyl ester hydrochloride 1 H-NMR values: 4.8-4.4 (m, 1H); 3.5 - 1.2 (m. 10H); 1.2 (s. 9H).

Example 22 2β, 3aα, 8α8-Decahydrocyclohepta [b] pyrrole-2-carboxylic acid polytert-butyl ester hydrochloride 1 H-NMR values; 4.7 - 4.4 (m, 1 H); 3.3 - 1.0 (m, 14 H); 1.2 (s. 9H).

Example 23 2β, 3a8,8ag-Decahydrocyclohepta [b] pyrrole-2-carboxylic acid po-tert-butyl ester hydrochloride 1 H-NMR values; 4.7 - 4.3 (m, 1 H); 3.2 - 0.8 (m. 14H); 1.2 (s. 9H).

Example 24 2β, 3ηβ, 7g8-Octahydrolindole-2-carboxylic acid 290 g of the acylamino derivative obtained according to Example 1 are heated as described in Example 2 with 2N hydrochloric acid. Evaporate in vacuo, take up to 1 liter of isopropanol and reduce with about 35 g of NaBH4, which is added portionwise over 30 minutes. The reaction temperature should be 40-50 ° C. After reacting for about 4 hours, 3480675 t are evaporated in vacuo, adjusted to pH 6.5 with dilute hydrochloric acid, saturated with solid sodium chloride and the amino acids are extracted several times with n-butanol. After evaporation of the organic phase, the remaining residue is fractionally crystallized from chloroform / diisopropyl ether as described in Example 2. Yields: 40-60 g of 2β, 3αβ, 7o ^ product 20 g of mixed fraction 100-130 g of trans product.

In the same manner, trans-2-azabicyclo (5.3.0) decane-3-carboxylic acid and 2β, 3αβ, 7αβ-2-azabicyclo- (6.3.0) undecane-3-carboxylic acid can be prepared.

Claims (15)

H n is a halogen atom, and the compound XIV is reduced to give a compound of formula XV s 1 I XV (ch 2 Hai is as defined above, and finally the compound XV is converted with a base to a compound of formula III ', wherein W is hydrogen, and that the thus obtained compound is esterified, if necessary, or c) to produce a compound having formula III ', where the H atoms bonded at C atoms 3a and (6 + n) are in the cis configuration, a compound of formula XVI is reduced: "PO lc% \ A, o xvi H where n has as defined above, under metal catalysis in a protic medium to a compound of formula XIII specified in point b), and this compound is further reacted in the manner specified in point b), or d) to produce a compound of formula III ' , where the H atoms bonded at C atoms 3a and (6 + n) a are in the trans configuration, reducing is added to a compound having the formula XVI specified in paragraph (c), with sodium formate and formic acid to a compound having the formula XIII specified in paragraph (b), and this compound is further converted to & 1 paragraph b) the method as specified, or e) for the preparation of a compound of formula III ', where n is an integer 0-2 and W is hydrogen, an enamine of formula XVI1 is converted to X1 CH XVI1 where n is as defined above and X1 is dialkylamino or the group of formula XVIIIa -NA XVIIa where m and o are an integer of 1-3, (m + o) s 3 and A are CH 2, NH, 0 or S, with an N-acylated β-halogen-α -amino-propionic acid ester of formula XVIII X2 \ 25 CH XVIII Y1 -NH / COOR4 »wherein X2 is chlorine or bromine, Y 'is alkanoyl having 1-5 C atoms, aryl having 7-9 C atoms or another at peptide chemistry customary by an acid cleavable protecting group and R 4 'is alkyl of 1-5 C atoms or aralkyl of an acrylic acid ester of formula XIX 35 II 47 80675 C NH4oorooroor ch2222IXIXIX NH NH NH NH NH NH NH--------NH--NH-NH-NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH-Y xx (CB2 + where R4 'and Y1 are as defined above, and this compound is cyclized with a strong acid under acylamide or ester decomposition to a compound of formula XXIa or xxib 20 n, which formula n is as defined above, and that the thus obtained compound of formula XXIa or XXlb, after being optionally converted to a Cx-C6 alkyl ester or benzyl ester, is converted by catalytic hydrogenation in the presence of a catalyst of a transition metal or by reducing with a borane-amine complex or a complex borohydride to a compound of formula IIi and W is hydrogen, alkyl of 1-6 C atoms or benzyl, the optionally obtained ester of formula III ' is hydrolyzed and that, if W is hydrogen, then the obtained compound is esterified into a compound of formula III ', wherein n is as defined above and W is alkyl of 1-6 carbon atoms or benzyl. 1. Azabicycloalkanecarboxylic acid derivative of the general formula III "5 ^ 5 ^ η 2): \ νΛ 111" 2r \ N COOW R, I 10. R 3 where n is an integer 0-2, W Sr is hydrogen, alkyl of 1-6 carbon atoms or benzyl and R3, R4 and represents hydrogen or R3 and R4 or R4 and R5 together form a chemical bond, wherein H atoms which are Sr bonded to the C atoms 3a and (6 + n) a, Sr with respect to each other in the cis or trans configuration, the dS substituents in each case denote vSte, and in the case of the cis- the configuration is the group -COOW 'bound to the C atom 2 in the exosystem with respect to the bicyclic ring system with the proviso that when R3 Sr and R4 and Rj together form a chemical bond, where Sr n 0 and W Sr vSte. Compounds according to claim 1, which have the formula III 'H 3a 2 Nch 1111 1CH 2 30. IH wherein the C atoms 3a and (6 + n) a are bonded with respect to each other in the cis or trans configuration, where in the case of the cis configuration it is at the C atom 2 is attached to the -CO 2 W group in the exo position with respect to the bicyclic ring system, and wherein n is 0, 1 or 2 and W is hydrogen or a group which is decomposable hydrogenolytically or by the action of an acid. A process for the preparation of compounds of formula III 'and as defined in claim 2, characterized in that a) a compound of formula IX H) n) a] IX f 2 HH being those at the C atoms 3a and the (6 + n) a bonded H atoms are with respect to each other in the cis or trans configuration and n is 0, 1 or 2, then acylated and then oxidized anodically with an alcohol in the presence of a conductivity. compound salt to give a compound of formula X 20 H Hr, OR 25 * cyl H wherein n is as defined above and R is) -alkyl, then compound X is reacted with trimethylsilyl cyanide in the presence of a Lewis acid to give a compound of formula XI fT-i «S + n) aL OK k XI 35 (CH 2k | y CN H 1 acyl) 80675 where the C atoms 3a and (6 + n) a are bonded with respect to each other in the cis or trans configuration, wherein in the fail of the cis configuration, the group -CN is in the exo position with respect to the bis. Cyclic ring system, and wherein n is as defined above, and that compound XI is hydrolyzed with acids or bases to a compound of formula III ', wherein W is hydrogen, and that the thus obtained compound is esterified, if needed. b) a compound of formula XII H 3a. (6 + n) aJ XI1 A NOH where the C atoms 3a and (6 + n) a atoms are in the cis or trans configuration and n is as defined above are converted by Beckmann rearrangement to a compound of formula XIII H X XII Sch2) / \ ν / Λ o HH wherein n is as defined above, whereupon compound 30 XIII is halogenized to give a compound of formula XIV H 35. f Hai XIV 4. A process according to claim 3, characterized in that the compound of formula XXIa or XXIb is converted by catalytic hydrogenation in the presence of a catalyst of a transition metal to a compound of formula III 'wherein W is hydrogen and which has a predominantly the endo-cis isomer of the formula III'a 10> TTT 'a (CH 2) ^ COOH λ n | H 15 5. A process according to claim 3, characterized in that the compound of formula XXIa or XXIb is converted by reduction with borane-amine complex or complex borohydrides dissolved in lower alcohols to a compound of formula III 'in which W is hydrogen and which contains over 50% of the trans isomer of formula III'b 25 "CH