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-dimethylamino-1-ethyl-2-methyl-propyl)-phenol.

1 . A process for preparing (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol, or an acid addition salt thereof, comprising the step 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) transferring 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 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 formula (IV), 
       
       
         
           
           
               
               
           
         
         (d) optionally converting the thus obtained (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol into an acid addition salt. 
       
     
     
         2 . A process according to  claim 1 , characterized in that 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 1  or  2 , characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH 3 . 
     
     
         4 . A process according to any of  claims 1  to  3 , characterized in that R represents methyl, benzyl or tetrahydropyranyl. 
     
     
         5 . A process according to any of  claims 1  to  4 , characterized in that the ethyl magnesium halide used in step (a) is the chloride or bromide. 
     
     
         6 . A process according to any one of  claims 1  to  5 , characterized in that 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 any one of  claims 1  to  6 , characterized in that 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 (VI), 
       
       
         
           
           
               
               
           
         
         wherein R has the above defined meaning. 
       
     
     
         8 . A process according to  claim 7 , characterized in that 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 7  or  8 , characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH 3 . 
     
     
         10 . A process according to any of  claims 7  to  9 , characterized in that R represents methyl, benzyl or tetrahydropyranyl. 
     
     
         11 . A process according to any of  claims 7  to  10 , characterized in that the resolution in step (a″) is performed by reacting a compound of general formula (VI) with a chiral acid selected from the group consisting of L-(−)-dibenzoyl tartaric acid, L-(−)-dibenzoyl tartaric acid.H 2 O and D-(−)-tartaric acid, subsequent separation of the thus obtained salt and liberation of the corresponding compound of general formula (I) in form of the free base. 
     
     
         12 . A process according to  claim 11 , characterized in that 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. 
     
     
         13 . A process according to any of  claims 1  to  12 , characterized in that the transfer 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. 
       
     
     
         14 . A process according to  claim 13 , characterized in that 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 . 
     
     
         15 . A process according to  claim 13  or  14 , characterized in that R represents methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, phenethyl, tetrahydropyranyl or —C(═O)—CH 3 . 
     
     
         16 . A process according to any of  claims 13  to  15 , characterized in that R represents methyl, benzyl or tetrahydropyranyl. 
     
     
         17 . A process according to any of  claims 13  to  16 , characterized in that after the dehydration step (b′) the hydrogenation in step (b″) is effected via homogeneous catalysis. 
     
     
         18 . A process according to any of  claims 13  to  17 , characterized in that the dehydration step (b′) is acid-catalysed. 
     
     
         19 . A process according to  claim 18 , characterized in that the acid is selected from the group consisting of formic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, hydrobromic acid or any mixture thereof. 
     
     
         20 . A process according to any of  claims 13  to  16 , characterized in that the hydrogenation of step (b″) is effected via heterogeneous catalysis. 
     
     
         21 . A process according to  claim 20 , characterized in that 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. 
     
     
         22 . A process according to any of  claims 13  to  21 , characterized in that the reaction medium is selected from the group consisting of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl-methylether, diisopropylether or any mixtures thereof. 
     
     
         23 . A process according to any of  claims 1  to  12  characterized in that step b) is a direct replacement reaction of the OH group by H, preferably carried out in a one-pot reaction.