CS247193B2 - Process for preparing cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid and its esters - Google Patents

Abstract

A process for the production of cis,endo-2-azabicyclo[3,3,oj - octane-3-carboxylic acid, as well as esters of this acid of the general formula III, in which the hydrogen atoms on the carbon atoms at the bridgehead in positions 1 and 5 are in the cis-configuration with respect to each other and the WO2C- group on the carbon atom in position 3 is oriented towards the bicyclic ring system in the endo-position, and in which W represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms or a phenylalkyl group with 1 to 2 carbon atoms in the alkyl moiety, and salts of these compounds, characterized in that the compounds of the formula Xla or Xlb are converted by catalytic hydrogenation in the presence of transition metal catalysts or by reduction with borane and amine complexes or complex borohydrides in lower alcohols to compounds of the general formula III, in which W represents a hydrogen atom, after which these compounds are optionally converted to compounds of the general formula III, in which W represents an alkyl group with 1 to 6 carbon atoms or a phenylalkyl group with 1 to 2 carbon atoms in the alkyl part, and the obtained compounds of general formula III are then optionally converted into addition salts with acids or bases. The compounds produced by the process according to the invention are used as starting materials for the production of pharmacologically active compounds.

Description

(54) A method for producing cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid and its esters

A process for the preparation of cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid as well as esters thereof having the general formula (III) in which the hydrogen atoms on the carbon atoms of the bridgeheads in the 1 and 5 positions are the cis configuration and the WO2C- group on the carbon atom at the 3-position is oriented towards the bicyclic ring system at the endo-position, and wherein W represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 2 phenylalkyl group an alkyl moiety, and salts thereof, characterized in that the compounds of formula XIa or XIb are converted by catalytic hydrogenation in the presence of transition metal catalysts or by reduction of borane-amine complexes or complex borohydrides in lower alcohols to compounds of formula III wherein W is hydrogen, whereupon these compounds are optionally converted to compounds of formula III wherein W is C 1 -C 6 alkyl or a phenylalkyl group having 1 to 2 carbon atoms in the alkyl moiety, and the compounds of formula III obtained are then optionally converted into acid or base addition salts.

The compounds of the present invention are used as starting materials for the production of pharmacologically active compounds.

The present invention relates to a process for the preparation of cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid as well as esters of this acid of formula III below. These compounds of formula III serve as intermediates in the preparation of novel cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid derivatives having valuable pharmacological properties and which can be used as medicaments.

The present invention provides a process for the preparation of cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid as well as esters of this acid of formula III

HN

WOOC

H (III) wherein the hydrogen atoms on the carbon atoms on the bridgehead at the 1 and 5 positions are in the cis configuration with each other and the WO 4 C group on the carbon at the 3-position is oriented towards the bicyclic ring system in the endo-position;

W represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenylalkyl group having 1 or 2 carbon atoms in the alkyl moiety, and a salt of these compounds, characterized in that the compounds of formula XIa or XIb

(X1a) (X1b) are converted by catalytic hydrogenation in the presence of transition metal catalysts or by reduction of borane-amine complexes or complex borohydrides in lower alcohols to compounds of formula III in which W is hydrogen, and optionally converted to compounds of formula of formula III in which W represents a C 1 -C 6 alkyl group or a C 1 -C 2 phenylalkyl group in the alkyl moiety, and the compounds of formula III obtained are then optionally converted into acid or base addition salts.

The process according to the invention advantageously produces compounds of formula III in which W represents a hydrogen atom, a tert-butyl group or a benzyl group.

The compounds of formula XIa and XIb which are used as starting materials for the process of the invention can be obtained from the cyclopentanone enamines of formula VI

X ¹ -C (VI)

LJ in which "1 represents a C 2 -C 10 dialkylamino group or a radical of formula VII" [CH "

1 ^ch 2]

2J o

24719 where m and o represent an integer from 1 to 3, and (m + o) >> 3 a

A is NH, O or S, and the N-acylated N-halo-1 H -aminocarboxylic acid esters of formula VIII

(VIII) in which:

X is a nucleofugic group, preferably chloro or bromo,

Y ^ represents a Can-C alkoy alkanoyl group, a C až až-Croy a aroyl group or other peptide chemistry which is normally cleavable under acidic conditions, and

R represents a C 1 -C 5 alkyl group or a C 1 -C 3 phenylalkyl group in the alkyl moiety, or using esters of acrylic acid of formula IX, COOR ² (IX).

Y and R have the above meanings by reacting these compounds to form compounds of formula X

z-NH2 (X)

1,,

R and Y are as defined above, and these compounds cyclize to compounds of formula XIa or XIb by treatment with strong acids to cleave the acylamide group and ester.

COOK (Xla)

COOH

The bicyclic amino acid derivatives of formula III have the cis, endo-configuration, i.e. the -CO ₂ -W group has the same direction as the cyclopentane ring. This is expressed by the general formulas IIIa or IIIb

HN

AND

WO ₂ C (lila)

H wo ₂ c

Η

(IIIb) wherein it is as defined above.

Preferred enamines are, for example, pyrrolidinocyclopentene and morpholinocyclopentene. The cyclization of the alkylation products of formula X is preferably carried out by treatment with aqueous hydrochloric acid. Compounds of formula III (with W = H) can be esterified by methods conventional to amino acids (cf., for example, Houben-Weyl, Methoden der organischen Chemie, Vol. VIII (1952)), for example with a mixture of thionyl chloride and benzyl alcohol or isobutylene and sulfuric acid. Appropriate treatment leads to compounds of formula III in free base or salt form.

The following examples illustrate the process of the invention in more detail without restricting it in any way.

Example 1

Cis, Endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester (1) 2-Acetylamino-3- (2-oxocyclopentyl) -propionic acid methyl ester

269 g of 3-chloro-2-acetylaminopropionic acid methyl ester and 257 g of cyclopentenopyrrolidine are kept in 1.5 l of dimethylformamide for 24 hours at room temperature. The reaction mixture is concentrated in vacuo, the residue is taken up with a small amount of water, adjusted to pH 2 with concentrated hydrochloric acid and extracted twice with 4 liters of ethyl acetate each time. Concentration of the organic phase gave a pale yellow oil. Yield 290 g.

NMR Spectrum (CDCl 3): 2.02 (s, 3H), 3.74 (s, 3H), 4.4-4.8 (m, 1H). Analysis:

C, 58.1; H, 7.54; N, 6.16.

Found: C, 58.5; H, 7.2; N, 6.5.

(2) cis, endo-2-azabicyclo [3.3.3] octane-3-carboxylic acid hydrochloride

270 g of the acetylamino derivative produced in (1) are refluxed in 1.5 L of 2N hydrochloric acid for 45 minutes. The reaction mixture is concentrated in vacuo, the residue is taken up in glacial acetic acid, 5 g of platinum on carbon (10% platinum) are added and hydrogenation is carried out under a hydrogen pressure of 0.5 MPa. After filtration, the filtrate is concentrated and the residue is crystallized from a mixture of chloroform and diisopropyl ether. Melting point

205 DEG-209 DEG. Yield 150 g.

(3) cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester hydrochloride g of the carboxylic acid produced according to (2) is added to an ice-cooled mixture of 390 g of benzyl alcohol and 65 g of thionyl chloride and reaction mixture. is left at room temperature for 24 hours. After concentration in vacuo, 47 g of the benzyl ester crystallized from a mixture of chloroform and isopropanol. Melting point of hydrochloride 175 ° C.

Example 2

Cis, endo-2-azabieyclop, 3, O] octane-3-carboxylic acid tert-butyl ester g Azabicyclo [3.3.0] octocanecarboxylic acid hydrochloride of Example 1, paragraph (2), is reacted in 250 ml dioxane with 250 ml isobutylene and 25 ml of concentrated sulfuric acid. After 14 hours at room temperature, the reaction mixture was basified with sodium hydroxide, concentrated in vacuo, water (100 ml) was added, and extraction was performed to obtain the ester.

Evaporation of ether gave 15 g of a colorless oil.

Claims (2)

SUBJECT OF THE INVENTION CLAIMS 1. A process for the preparation of cis, endo-2-azabicyclo [3.3.0] octane-3-carboxylic acid as well as esters of the acid of formula III in which the hydrogen atoms on the carbon atoms of the bridgeheads in the 1 and 5 positions are each other in the cis-configuration and the WO-C-group on the carbon atom at the 3-position is oriented towards the bicyclic ring system at the endo-position and wherein W represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a phenylalkyl group having 1 or 2 carbon atoms in the alkyl moiety, and a salt thereof, characterized in that the compounds of formula XIa or XIb Q COOH (Xl) (Xlb) COOHs convert catalytic hydrogenation of transition metal catalysts or reduction of borane-amine complexes or complex borohydrides in lower alcohols to compounds of formula III wherein W is hydrogen, optionally esterified to compounds of formula 111 wherein W is alkyl C 1 -C 6 or phenylalkyl. The compounds of formula (III) are then optionally converted into acid or base addition salts. 2. The process of claim 1, of the general formula: corresponds to the general formula Ii ^T. wherein W group. characterized in that compounds which use reducing and esterifying agents are used as starting materials to give compounds: a hydrogen atom, a tert-butyl group or a benzyl group