Process for the preparation of (1r,2r)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol

Abstract

The present invention relates to a process for the preparation of (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol.

What is claimed is: 
     
         1 . A process for preparing (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof, comprising the steps of:
 (a) reacting a compound of general formula (I),   
       
         
           
           
               
               
           
         
         wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, —C 1-3 -alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C 1-6 -alkyl, 
         with ethyl magnesium halide in an inert reaction medium under Grignard conditions, 
         (b) converting the thus obtained compound of general formula (II), 
       
       
         
           
           
               
               
           
         
         wherein R has the above defined meaning, 
         to a compound of general formula (III), 
       
       
         
           
           
               
               
           
         
         wherein R has the above defined meaning, 
         optionally in the form of an acid addition salt, 
         (c) deprotecting the thus obtained compound of general formula (III) to obtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of the formula (IV), 
       
       
         
           
           
               
               
           
         
       
       and
 (d) optionally converting the thus obtained (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol into an acid addition salt; 
 wherein the compound of formula (I) has not been prepared by a process comprising: 
 (a′) reacting a compound corresponding to formula (V): 
 
       
         
           
           
               
               
           
         
         wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, —C 1-3 -alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C 1-6 -alkyl, 
         with dimethylamine hydrochloride and paraformaldehyde in an inert reaction medium under Mannich conditions to yield a compound of formula (VI), 
       
       
         
           
           
               
               
           
         
         wherein R has the above defined meaning, and 
         (a″) subsequently resolving the compound of formula (VI), wherein the resolution is carried out by: 
         (i) reacting the compound of formula (VI) with a chiral acid selected from the group consisting of L-(−)-dibenzoyl tartaric acid and L-(−)-dibenzoyl tartaric acid.H 2 O to yield a salt, 
         (ii) separating the salt, and 
         (iii) liberating the corresponding compound of formula (I) in the free base to yield a compound of formula (I). 
       
     
     
         2 . A process according to  claim 1 , wherein R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, —C(═O)—CH 3 , —C(═O)—C 2 H 5 , —C(═O)—CH(CH 3 ) 2  or —C(═O)—C(CH 3 ) 3 . 
     
     
         3 . A process according to  claim 2 , wherein R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH 3 . 
     
     
         4 . A process according to  claim 3 , wherein R represents methyl, benzyl or tetrahydropyranyl. 
     
     
         5 . A process according to  claim 1 , wherein the ethyl magnesium halide used in step (a) is the chloride or bromide. 
     
     
         6 . A process according to  claim 1 , wherein the inert reaction medium is selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl-methylether, diisopropylether or any mixture thereof. 
     
     
         7 . A process according to  claim 1 , wherein a compound of general formula (I) was obtained by (a′) reacting a compound of general formula (V), 
       
         
           
           
               
               
           
         
         wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, —C 1-3 -alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C 1-6 -alkyl, 
         with dimethylamine hydrochloride and paraformaldehyde in an inert reaction medium under Mannich conditions and 
         (a″) subsequent resolution of the thus obtained compound of general formula 
       
       
         
           
           
               
               
           
         
         wherein R has the above defined meaning, 
         with D-(−)-tartaric acid, subsequent separation of the thus obtained salt and liberation of the corresponding compound of general formula (I) in the form of the free base. 
       
     
     
         8 . A process according to  claim 7 , wherein R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, —C(═O)—CH 3 , —C(═O)—C 2 H 5 , —C(═O)—CH(CH 3 ) 2  or —C(═O)—C(CH 3 ) 3 . 
     
     
         9 . A process according to  claim 8 , wherein R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH 3 . 
     
     
         10 . A process according to  claim 9 , wherein R represents methyl, benzyl or tetrahydropyranyl. 
     
     
         11 . A process according to  claim 7 , wherein the resolution is performed in an alcoholic reaction medium selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol and any mixture thereof. 
     
     
         12 . A process according to  claim 1 , wherein the converting according to step (b) is performed by (b′) subjecting the compound of general formula (II) to dehydration and (b″) hydrogenation of the thus obtained compound of general formula (VII), 
       
         
           
           
               
               
           
         
         wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, —C 1-3 -alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C 1-6 -alkyl, 
         using a suitable catalyst in an inert reaction medium in the presence of hydrogen. 
       
     
     
         13 . A process according to  claim 12 , wherein R represents methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzyl, phenethyl, tetrahydropyranyl, —C(═O)—CH 3 , —C(═O)—C 2 H 5 , —C(═O)—CH(CH 3 ) 2  or —C(═O)—C(CH 3 ) 3 . 
     
     
         14 . A process according to  claim 13 , wherein R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH 3 . 
     
     
         15 . A process according to  claim 14 , wherein R represents methyl, benzyl or tetrahydropyranyl. 
     
     
         16 . A process according to  claim 12 , wherein after the dehydration step (b′) the hydrogenation in step (b″) is effected via homogeneous catalysis. 
     
     
         17 . A process according to  claim 12 , wherein the dehydration step (b′) is acid-catalysed. 
     
     
         18 . A process according to  claim 17 , wherein the acid is selected from the group consisting of formic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrobromic acid or any mixture thereof. 
     
     
         19 . A process according to  claim 12 , wherein the hydrogenation of step (b″) is effected via heterogeneous catalysis. 
     
     
         20 . A process according to  claim 19 , wherein the catalyst used for hydrogenation is selected from the group consisting of Raney nickel, palladium, palladium on carbon, platinum, platinum on carbon, ruthenium on carbon or rhodium on carbon. 
     
     
         21 . A process according to  claim 12 , wherein the reaction medium is selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl-methylether, diisopropylether or any mixtures thereof. 
     
     
         22 . A process according to 1, wherein step b) is a direct replacement reaction of the OH group by H. 
     
     
         23 . A process according to  claim 22 , wherein said direct replacement reaction is a one-pot reaction. 
     
     
         24 . A process according to  claim 1 , wherein the converting according to step (b) is not performed by (b′) subjecting the compound of general formula (II) to dehydration and (b″) hydrogenation of the thus obtained compound of general formula (VII), 
       
         
           
           
               
               
           
         
         wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, —C 1-3 -alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C 1-6 -alkyl, using a suitable catalyst in an inert reaction medium in the presence of hydrogen. 
       
     
     
         25 . A process for preparing (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof, comprising the steps of:
 (a) reacting a compound of general formula (I),   
       
         
           
           
               
               
           
         
         wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, —C 1-3 -alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C 1-6 -alkyl, 
         with ethyl magnesium halide in an inert reaction medium under Grignard conditions, 
         (b) converting the thus obtained compound of general formula (II), 
       
       
         
           
           
               
               
           
         
         wherein R has the above defined meaning, 
         to a compound of general formula (III), 
       
       
         
           
           
               
               
           
         
         wherein R has the above defined meaning, 
         optionally in the form of an acid addition salt, 
         (c) deprotecting the thus obtained compound of general formula (III) to obtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of the formula (IV), 
       
       
         
           
           
               
               
           
         
       
       and
 (d) optionally converting the thus obtained (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol into an acid addition salt; 
 wherein the compound of formula (I) has not been prepared by a process comprising: 
 (a′) reacting a compound corresponding to formula (V): 
 
       
         
           
           
               
               
           
         
         wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, —C 1-3 -alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C 1-6 -alkyl, 
         with dimethylamine hydrochloride and paraformaldehyde in an inert reaction medium under Mannich conditions to yield a compound of formula (VI), 
       
       
         
           
           
               
               
           
         
         wherein R has the above defined meaning, and 
         (a″) subsequently resolving the compound of formula (VI). 
       
     
     
         26 . A process according to  claim 25 , wherein the converting according to step (b) is not performed by (b′) subjecting the compound of general formula (II) to dehydration and (b″) hydrogenation of the thus obtained compound of general formula (VII), 
       
         
           
           
               
               
           
         
         wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C 1-6 -alkyl, 
         using a suitable catalyst in an inert reaction medium in the presence of hydrogen. 
       
     
     
         27 . A process for preparing (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof, comprising the steps of:
 (a) reacting a compound of general formula (I),   
       
         
           
           
               
               
           
         
         wherein R represents —C 1-6 -alkyl, —C 3-8 -cycloalkyl, —C 1-3 -alkylene-phenyl, —C 1-3 -alkylene-naphthyl, tetrahydropyranyl or —C(═O)—C 1-6 -alkyl, 
         with ethyl magnesium halide in an inert reaction medium under Grignard conditions, 
         (b) converting the thus obtained compound of general formula (II), 
       
       
         
           
           
               
               
           
         
         wherein R has the above defined meaning, 
         to a compound of general formula (III), 
       
       
         
           
           
               
               
           
         
         wherein R has the above defined meaning, 
         optionally in the form of an acid addition salt, 
         (c) deprotecting the thus obtained compound of general formula (III) to obtain (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol of the formula (IV), 
       
       
         
           
           
               
               
           
         
       
       and
 (d) optionally converting the thus obtained (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol into an acid addition salt.