FR2504138A1 - PROCESS FOR THE PREPARATION OF ISOQUINUCLIDINE - Google Patents

Abstract

ACCORDING TO THE INVENTION, A LOWER ALKYL ESTER OF P-AMINOBENZOIC ACID IS HYDROGATED, WHICH GIVES A CISTRANS MIXTURE OF ALKYL ESTERS OF 4-AMINOCYCLOHEXANE-CARBOXYLIC ACID WHICH IS FIRST SUBJECTED TO CYCLIZATION THEN REDUCED AYLATION. IN N-BENZYL-2-AZABICYCLOOCTANE-3-ONE WHICH IS REDUCED TO N-BENZYL-2-AZABICYCLOOCTANE IN WHICH THE BENZYL GROUP IS ELIMINATED.

Description

The present invention relates to a process for preparing

  tion of 2-azabicyclol 2 2 21 octane (isoquinuclidine) corresponding to the structural formula H

NOT

  Isoquinuclidine and its pharmaceutically acceptable salts are known as intermediates in the preparation of certain tertiary amines of general formula R "R C Alk N R '

  in which '"Alk" represents a lower alkylene radical containing

  from 2 to 6 carbon atoms; R is chosen from the class consisting of

  both in lower C 1 -C 6 alkyl, phenyl, halogeno-

  phenyl, tolyl and pyridyl; R 'is selected from the class consisting of C1-C6 lower alkyl, phenyl, halophenyl, tolyl, pyridyl, cyano and hydrogen atoms; R "is selected from the class consisting of lower C 1 -C 6 alkyl, phenyl, halophenyl, tolyl, pyridyl and hydrogen atoms; or alternatively R> and R" may together represent an atom of oxygen linked by a double bond, or, each, an alkoxy group in

  C 1-C 6, or together, an ethylene-dioxy or propylene-dioxy group.

  We know in particular that 2-azabicyclo hydrochloride l 2 2 2 l

  octane is an intermediate product in the preparation of chlorhy-

  2,2-diphenyl-4- (2-azabicyclol 2 2 2 locta-2-yl) -butyronitrile drate.

  The preparation of these tertiary amines is described

  in U.S. Patent 4,086,234 which teaches

  These data are considered to be integrated into the present application. These tertiary amines themselves constitute intermediate products for the preparation of useful compounds described in the patents of

  United States No. 3,772,300, 3,790,581, 3,843,646 and 3,847,923.

  Several methods of pre-

  isoquinuclidine preparation In a known process, p-aminobenzolque acid is hydrogenated to a mixture of cis and trans-4-amino acids.

  nocyclohexane-carboxylic acid cis-4-aminocyclohexane-

  carboxylic acid is then isolated by fractional crystallization, first cyclized to 2-azabicyclol 2 2 2 loctane-3-one (isoquinuclidone)

  by pyrolysis at 250-290 C then reduced to isoquinuclidine.

  For this known process, it was indicated that the yield of cis-4aminocyclohexane-carboxylic acid, by hydrogenation of paminobenzoic acid, was improved and brought to about 29.5%

  when the reaction was carried out on platinum, and the

  isoquinuclidine by reduction of isoquinuclidone on copper chromite was approximately 25 to 30% It is also indicated in previous publications that the reduction of acid

  p-aminobenzoic acid on a mixed metal catalyst (10% rhodium -

  0.1% palladium) gives a cis-trans mixture which is cyclized by

  heating in DOWTHERM A liquid boiling (258 C) in isoqui-

  nuclidone with a yield of 81 to 84% (55 to 60% compared to

  p-aminobenzolque acid) It has also been reported that if the isoqui-

  nuclidone is not reduced by lithium aluminum hydride

  in ether, N-benzylisoquinuclidone prepared from the iso-

  quinuclidone by alkylation using sodium amide and benzyl bromide with a yield of about 74%, was reduced

  by lithium aluminum hydride in ether with a rendering

89%.

  It will be noted that one of the drawbacks of the processes of the prior art lies in the fact that it is not possible to use all of the cistrans mixture of 4-aminocyclohexane-carboxylic acid obtained by hydrogenation of p-aminobenzoic acid. Among the others drawbacks of these processes we will point out the yield

  relatively weak after isolation of cis-4-aminocyclo- acid

  hexane-carboxylic, the high temperature required to cyclize

  this acid and the relatively low yield at the reduction of the iso-

quinuclidone to isoquinuclidine.

  The invention relates to a new synthetic process for the preparation of isoquinuclidine. trans of the 4 aminocyclohexane- carboxylic acid alkyl ester on which

  we proceed first to a reductive benzylation then to a cyclization

  tion to an amide which is finally reduced to isoquinuclidine Against all expectations, it is found that the crude hydrogenation product can be cyclized and that it is therefore not necessary to isolate the isomer

  cis It has also been found that the process according to the invention involves

  due to increased yields under controlled reaction conditions. It is known that the isoquinuclidine salts formed by

  addition with acids are generally more stable than isoqui-

  nuclidine itself These salts can be stored conveniently until the time of use and can then be converted to isoquinuclidine by neutralization using an appropriate basic solution.

  In the practice of the invention, the isoqui-

  nuclidine from a lower alkyl ester of p-amino acid

  benzoic having the general formula t 'C-O-R NH 2

  in which R represents a C1-C4 alkyl group p-amino-

  commercially available ethyl benzoate (benzocaine) from

  from a number of origins is such a suitable compound. The benzocaine is hydrogenated in an ethanol / phosphoric acid mixture over a catalyst at 5% Rh / C The catalyst is then separated by filtration and the phosphoric acid neutralized by addition of the sufficient amount of triethylamine The mixture is then treated with benzaldehyde and acetic acid in it

  letting it sit for a while then hydrogen it on a catalytic converter

  palladium lyser on Ca CO 3 A solution of the esters is obtained

  cis and trans ethyl 4-N-benzylaminocyclohexane-

  carboxylic that we get rid of ethanol after which we alkalize

  the residue with a cold aqueous solution of potassium hydroxide.

  The N-benzylamine esters are isolated by extraction in a hexane / ethyl acetate mixture, 3: 1, and the solvents are removed from the solution. Without prior purification, the mixture of crude esters is treated with sodium tert-butoxide. (obtained from sodium hydride and tert-butyl alcohol) in tetrahydrofuran (THF) and the crude N-benzyl-2-azabicyclooctane-3-one is thus formed, as isolated from reaction mixture, is reduced by bis- (2-methoxyethoxy) aluminum and sodium hydride (which can be obtained under the trademark VITRIDE from the company Hexcel Specialty Chemical Co) into N-benzyl-2azabicyclooctane L ' amine is purified by partitioning between aqueous hydrochloric acid and the acetate mixture of ethydhexane, 4: 1, causing the elimination of neutral impurities (benzyl alcohol, mineral oil obtained from sodium hydride) The amine, such as isolated from aqueous acid, is neutralized by sulfuric acid in ethanol; in the amine sulphate, the benzyl group is eliminated by hydrogen and a palladium catalyst on C. The isoquinuclidine is then obtained in the free amine state by treatment of the amine sulphate using a suitable basic solution, for example an aqueous sodium hydroxide solution. Other salts formed by addition can be prepared by treating the free amine with various acids such as phosphoric, hydrochloric, hydrobromic, sulfamic, citric, lactic acids. , succinic, tartaric, perchloric, acetic, benzoic and the like This process is illustrated by scheme I below.

2 5 O 4 1 3 8

il 'C-oc 2 i 15 il

(-, - OC H 5

il- CH: î N H 2 udder / trans

Na + t Buô-

THF cis / trans ll 1-

1) H 2904

2) H 2 "Pd / C And OH n / a 4 G -J

SCIMIA I

fi CH 1 il 2) H 2 # Pd / Ca Co 3 il

C-OC H

NH 2 H / N J,

0 4 1 3 8

  The example which follows illustrates the invention without however limiting its scope. In this example, the indications of parts

  and percent are by weight unless otherwise stated.

Example

  1 Hydrogenation of benzocatne In a hydrogenation bottle of 2 1 g of benzocaine (0.6054 mole) and 20 g of catalyst at 5% Rh / C are placed in a nitrogen atmosphere A solution of 40 is added to the solid substances , 8 ml of 85% phosphoric acid (0.60 mole) in 1.0 1 of ethanol 3 A (95%), the apparatus is purged with hydrogen and the hydrogenation is carried out under a hydrogen pressure of 4.2 bars at 60-70 C After 8 hours, the absorption of hydrogen has ceased and the mixture is cooled. The catalyst is separated by filtration, and washed with ethanol 3 A to eliminate the

  adhering product (note that the spent catalyst can be pyro-

  phoric and must therefore be handled accordingly) The filtrate

  is brought to a volume of approximately 1 liter by concentration under vacuum.

  The catalyst used in the above hydrogenation has already been used four times before. With fresh catalyst, the hydrogenation is faster and apparently gives a slightly higher yield of the desired ester. The catalyst recovered must be washed with water and then with 3 A ethanol to remove the

  monoammonium phosphate retained by occlusion before reuse.

  Ammonium phosphate comes from the partial hydrogenolysis of

amino group.

  The product obtained in this hydrogenation of benzo-

  calne is a cis-trans mixture of ethyl 4-aminocyclohexane-carboxylate corresponding to formula II

C-OC 2 H 5

NH 2

2 R 54138

  2 Reductive benzvlation of ethyl cis-trans 4-aminocyclohexane carboxylate. To the concentrated hydrogenation filtrate is added 65.4 g (0.647 mole, 89.9 ml) of triethylamine then 46.9 g of glacial acetic acid (0.781 mole, 44.7 ml) A further 60.1 is added g (0.566 mole, 57.6 ml) of benzaldehyde and the mixture is stirred at room temperature for 3 hours The solution is then transferred to a 2 1 hydrogenation bottle containing 10 g of catalyst at 50% Pd / Ca CO and hydrogenated at a pressure of 0.35 bar at 25-30 ° C. The reduction is accompanied by the generation of heat

  appreciable and a certain cooling is necessary at the beginning.

  After 2.5 hours, the absorption of hydrogen has ceased; the catalyst is filtered off The ethanol is distilled from the filtrate under vacuum at a maximum temperature of 60 C. The residue is dissolved in 250 ml of water and a solution of 92 is added slowly, with good cooling and with stirring. 1 g (1.40 mole) 85% potassium hydroxide in 79 ml of water; the temperature is kept below 280 C. An oil separates from the solution The p H of the aqueous layer must be 11.0 (on paper p H), otherwise it is necessary to add a supplement of the hydroxide solution potassium The amount of potassium hydroxide needed to bring p H to 11 is less than the amount calculated from the amounts of phosphoric acid and acid

  acetic originally present in the mixture A certain amount

  phosphoric acid is separated as an ammonium salt with the Rh / C catalyst and acetic acid probably distills with ethanol Potassium carbonate should not be used

  in place of potassium hydroxide.

  The oily product is extracted with three 250 ml portions of ethyl acetate / hexane mixture, 1: 3 The combined extracts are dried over sodium sulfate, the solution is filtered and the solvents are distilled from the filtrate under vacuum (about 25 mm lig to

  the end of the distillation) The residual oil weighs 153.9 g (97.3%).

  The Ref spectrum indicates a ratio of 0.308 between the protons of C 6 H 5-CH 2-0 and the protons of C 6 H 5-CH 2-N- Assuming that all of the benzylamino protons are present in the form of 8 product sought, the ratio found corresponds to relative proportions by weight of 88.7: 11.3 between the N-benzylamine ester and benzyl alcohol (formed by hydrogenation of excess benzaldehyde) A new hydrogenation gives 145.7 g ester crude The product of this reductive benzylation of a 4-aminocyclohexane-carboxylate

  cis-trans ethyl is a cis-trans mixture of N-benzylaminocyclo-

  ethyl hexane-carboxylate with the following formula: O o l

C-OC 2 H 5

H CH

  3 Cyclization of ethyl 4-N-benzvlaminocyclohexane-carboxvlate

  cis / trans to N-benzyl-2-azabicyclooctane-3-one.

  27.93 g (0.67 mole) of a dispersion of 61.7% sodium hydride in mineral oil are introduced into a nitrogen atmosphere into a one-liter flask with three tubes fitted with a condenser

  reflux, an agitator, a dropping funnel and a thermometer.

  79 ml of THF are added and the hydride dispersion is stirred in heating.

  fant at moderate reflux 45.73 g (0.617 mole, 58.7 ml) of tert-butyl alcohol are gradually added over 10 min, the rate of addition being limited by the rate of evolution of hydrogen; we maintain

  then the mixture at reflux for a further 10 min. The N-benzyl ester

  crude amine obtained from 0.6054 mole of benzocaine is dissolved

  in 135 ml of THF; this solution is added slowly to the solution.

  boiling sodium tert-butoxide in about 65 min At the start, the mixture foams slightly When the addition is complete, the mixture is stirred at reflux for a further 5 hours The reaction mixture remains homogeneous except for a small number of

  gelatinous substance which collects in the form of a ring

  above the solution The mixture is cooled to 17 ° C. in a nitrogen atmosphere and 38.2 ml (0.668 mole) of acetic acid are added over 10 min.

  glacial; a gelatinous precipitate of sodium acetate separates.

  This precipitate is redissolved by adding 135 ml of water (the p H of the aqueous layer is 7 to 8) and the THF is distilled from the mixture.

  under the vacuum caused by a vacuum cleaner The oil is extracted

  dual by a portion of 200 ml and two portions of 150 ml of methylene chloride; the combined extracts are washed once per ml of brine and dried over 20 g of anhydrous sodium sulfate. The mixture is filtered and the solvents are filtered off, ending with a vacuum. A soft solid residue weighing 118 is obtained. , 6 g This product is suitable for use

  direct in the reduction with bis- (2-methoxyethoxy> - hydride

  aluminum and sodium It contains 9.9 g of mineral oil; the

  molar ratio of benzyl alcohol to lactam is 1: 3.96 (R} 9 N).

  The product of this cyclization of the cis / trans mixture

  of ethyl 4-N-benzylaminocyclohexane-carboxylate is N-benzyl-

  2-azabicyclooctane-3-one corresponding to the following formula N CH

  4 Reduction of N-benzvl-2-azabicyclooctane-3-one to N-benzvl-

  2-azabicyclooctane. A 1-liter flask with three pipes is used, equipped with a stirrer, a reflux condenser and a dropping funnel. The flask is purged with nitrogen and 293: 0 ml (213: 3 g, -1.055 mole, produced at 70% 7 in toluene) bis- (2-methoxyethoxy) aluminum aluminum hydride 146.5 ml of THF are added with stirring; the temperature rises from 6 to 7 ó The solution is heated to reflux and a solution of 118.0 g of crude bicyclic amide in 96 ml of r THF is added in approximately 50 minutes, the bulb is rinsed with 20 ml of THF The mixture of clear orange color is maintained at reflux (79 C) for 3 hours The reaction mixture is cooled to approximately 40 C and added in min: while cooling, a mixture of 75.5 ml of water and 75.5 ml of THF Immediately after the addition of water there is an appearance

  of a slight precipitate but, in 5 to 10 min, the mixture becomes gelated

  tinous 140.4 ml of 6N hydrochloric acid (70.2 ml of 12 M hydrochloric acid and 70.2 ml of water) are then added over 25 min. The gel rapidly fluidizes and is replaced by a granular precipitate; the temperature is allowed to return to 17 ° C. The mixture is stirred for 10 min and then filtered through Celite; the solid is rinsed by twis port / ons of 150 m 1 of hot THF The combined filtrates are diluted with 250 ml of hexane (commercial product SKELLYSOLVE B) and washed with a solution of 40 g of potassium hydroxide at 85% in 400 ml of water The aqueous layer is discarded, the organic layer is dried over potassium carbonate and the mixture is filtered.

  the solvents of the filtrate, finishing under the vacuum of the vacuum cleaner.

  The residual oil weighs 105.4 g It contains approximately 9.9 g of mineral oil and approximately 12.1 g of benzyl alcohol To remove the mineral oil and most of the benzyl alcohol, l crude amine in a mixture of 368 ml of ethyl acetate

  and 92 ml of hexane (SKELLYSOLVE 3) 80:20 trapport between the solvents).

  This solution is extracted with a portion of 18.5 ml and a portion of 20.7 ml of 3 N hydrochloric acid (51.8 ml of 12 M hydrochloric acid + 155.4 ml of water); during the addition of the acid, due to the heat of neutralization, it is necessary to cool.

  the acid extracts combined cold and they are made alkaline by addi-

  caution with a solution of 81.8 g of potassium hydroxide-

  85% sium (1.24 mole) in 82 ml of water The released amine is extracted

  in three 180 ml portions of ethyl acetate / hexane mixture, 4: 1.

  The combined extracts are dried over sodium sulphate, filtered and the solvent is distilled from the filtrate, ending with a vacuum. The light yellow residual oil weighs 84.7 g This crude amine can be used directly for elimination benzyl group Its purity is 90.9% in gas chromatography Evaporation of the ethyl acetate / hexane layer remaining from the extraction gives a residue weighing 16.9 g The product of this

  reduction of N-benzyl-2-azabicyclooctane-3-one is N-benzyl-

  2-azabicyclooctane corresponding to the following formula

N CHQ

2;) 133

  Elimination of the benzyl group from N-benzyl-2-azabicvclooctane. In a 1 liter flask with three tubes, 240 ml of ethanol (3 A, 95%) are placed and the mixture is cooled with stirring in an ice bath by adding 11.6 ml (0.209 mole) of concentrated sulfuric acid. then little by little, continuously cooling, a solution of 84.2 g (0.418 mole) of crude N-benzylamine in 144 ml of 95% ethanol (3 A) The solution obtained must have a p H from 4.0 to 5.0 (measured using E Merck indicator paper) otherwise sulfuric acid must be added in quantity

sufficient.

  The solution of the amine sulphate is added to 15.4 g of catalyst at 5% Pd over C in a 1 liter hydrogenation bottle purged with nitrogen; 100 ml of 95% ethanol are used for rinsing The hydrogenation is carried out at 50 ° C. under a hydrogen pressure of 3.5 bars; the reduction begins quickly and is completed in 3 hours The mixture is cooled and the catalyst is filtered off The filtrate must have a p H of 5.0 or below, otherwise a little sulfuric acid must be added. ethanol under the vacuum of the vacuum cleaner; a white, pasty solid is obtained which is kept under vacuum for a while in order to remove the residual solvent as completely as possible The solid substance weighs 64.2 g and on drying an analytical sample with the Abderhalden apparatus, it lose about 13% of their weight It is more than likely that weight loss is

  due to the moisture that was in ethanol The product of this eli-

  mination of the benzyl group of N-benzyl-2-azabicyclooctane is a salt of 2azabicyclooctane (isoquinuclidine sulfate) corresponding to the formula

N-H

6 Isolation of the free amine.

  20.0 g of crude isoquinuclidine sulfate, dried under vacuum, are mixed with 35 ml of water and a solution of 9.7 g of sodium hydroxide in 10 ml of water is added. The amine is extracted with

? 504 133

  two 100 ml portions of ethyl ether and the combined extracts are dried over solid potassium carbonate The solution is filtered

  and the filtrate is concentrated by distillation.

  the residue at atmospheric pressure Isoquinuclidine distills at approximately 170-175 ° C. and condenses into a solid crystalline mass;

  about 8.0 g are obtained The compound rapidly absorbs moisture

  carbon dioxide when exposed to the atmosphere.

  The poor yield (53%) is due to the high solubility in water and the high volatility of the compound. The isolated isoquinuclidine corresponds to the following formula N H

2504133 '

R E V E N D I CA T I O N S

  1 Process for the preparation of isoquinuclidine, characterized in that it comprises the following operating stages: a) hydrogenation of a lower alkyl ester of p-aminobenzolque acid with formation of a mixture of the cis and trans isomers a cyclohexylic compound corresponding to the formula COR NH 2 -10 in which R represents an alkyl group containing from 1 to 4 carbon atoms; b) the reductive benzylation of the cyclohexylic compound with the formation of a mixture of the cis and trans isomers of a benzylated compound corresponding to the formula t O C-0-R

NH-CH 2

  c) cyclization of the benzylated compound with formation of N-benzyl-2azabicyclooctane-3-one; d) reduction of N-benzyl-2-azabicyclooctane3-one to N-benzyl-2-azabicyclooctane; and

  e) elimination of the benzyl group from N-benzyl-2-aza-

  bicyclooctane, with the formation of isoquinuclidine.

  2 Method according to claim 1, characterized in

  what R represents the ethyl group -

  3 Method according to claim 1 or 2, character-

  risé in that the operation of stage a) is carried out in a mixture of ethanol and phosphoric acid on a catalyst with rhodium on carbon. 4 Method according to claim 3, characterized in that the catalyst is then removed by filtration and

  phosphoric acid neutralized by adding a sufficient amount

triethylamine health.

  Method according to claim 1 or 2, characterized in that the operation of stage b) is carried out by treating with

  benzaldehyde and acetic acid then by hydrogenating on a catalyst

  palladium lyser on calcium carbonate.

  6 Method according to claim 1 or 2, characterized in that the operation of stage c) is carried out by treating with

  sodium tert-butoxide in tetrahydrofuran.

  7 Method according to claim 1 or 2, characterized in that the operation of stage d) is carried out by treating with

  bis- (2-methoxyethoxy) aluminum and sodium hydride.

  8 Process according to claim 1 or 2, characterized in that, after stage d), the N-benzyl-2-azabicyclooctane is purified by partition, with a view to eliminating the neutral impurities, then

  neutralized by sulfuric acid in ethanol.

  9 Method according to claim 1, characterized in that the operation of stage e) is carried out by treating with an acid and hydrogenating on a catalyst mixed with palladium on carbon, this hydrogenation giving a salt of isoquinuclidine closed with

addition with an acid.

  Method according to claim 9, characterized in

  what acid is sulfuric acid.

  11 Method according to claim 10, characterized in that, after the operation of stage e), the isoquinuclidine is released by neutralization using a base of its salt formed

by addition with an acid.