Optical resolution of 3-carbamoylmethyl-5-methylhexanoic acid

Abstract

The invention relates to pure (R)—CMH and to the optical resolution of CMH-racemate, a key intermediate in the synthesis of (S)-Pregabalin. The invention also relates to the process for optically purifying (R)—CMH and to the process for isolating (S)—CMH from the mother liquor.

1 . (R)—CMH containing less than about 0.2% area by HPLC of (S)—CMH.  
   
   
       2 . The (R)—CMH of  claim 1 , containing less than about 0.1% area by HPLC of (S)—CMH.  
   
   
       3 . A process for the optical resolution of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (CMH-racemate),  
     
       
         
         
             
             
         
       
     
     comprising: 
 a) combining CMH-racemate, a solvent selected from the group consisting of: ketone, ester, nitrile, C 1-4  alcohol, water, or mixtures thereof, a chiral resolving reagent of amino alcohol and salts thereof to obtain a precipitate;  
 b) isolating the precipitate; and  
 c) adding a solvent selected from the group consisting of: ketone, C 1-8  alcohol, water or mixtures thereof, and a strong mineral acid.  
 
   
   
       4 . The process of  claim 3 , wherein the precipitate of (R)—CMH contains less than about 7% area by HPLC of (S)—CMH.  
   
   
       5 . The process of  claim 4 , wherein the precipitate of (R)—CMH contains less than about 4% area by HPLC of (S)—CMH.  
   
   
       6 . The process of  claim 5 , wherein the precipitate of (R)—CMH contains less than about 0.2% area by HPLC of (S)—CMH.  
   
   
       7 . The process of  claim 6 , wherein the precipitate of (R)—CMH contains less than about 0.1% area by HPLC of (S)—CMH.  
   
   
       8 . The process of  claim 3 , wherein the chiral resolving reagent of amino alcohol and salts thereof is selected from the group consisting of: ephedrine, ephedrine salt, norephedrine and norephedrine salt.  
   
   
       9 . The process of  claim 8 , wherein the salt is a hydrochloride, nitrate or sulfate.  
   
   
       10 . The process of  claim 9 , wherein the salt is a hydrochloride.  
   
   
       11 . The process of  claim 8 , wherein the chiral resolving reagent of amino alcohol and salts thereof is ephedrine or ephedrine salt.  
   
   
       12 . The process of  claim 11 , wherein the chiral resolving reagent of amino alcohol and salts thereof is 1R, 2S-(−)-ephedrine.  
   
   
       13 . The process of  claim 8 , wherein the chiral resolving reagent of amino alcohol and salts thereof is a salt of ephedrine or of norephedrine.  
   
   
       14 . The process of  claim 13 , wherein a base is added.  
   
   
       15 . The process of  claim 14 , wherein the base is either an organic base or an inorganic base.  
   
   
       16 . The process of  claim 15 , wherein the organic base is an amine.  
   
   
       17 . The process of  claim 16 , wherein the amine is tertiary or secondary amine.  
   
   
       18 . The process of  claim 17 , wherein the tertiary amine is triethylamine or tributylamine.  
   
   
       19 . The process of  claim 18 , wherein the tertiary amine is triethylamine.  
   
   
       20 . The process of  claim 17 , wherein the secondary amine is diisopropylamine or n-dipropylamine.  
   
   
       21 . The process of  claim 15 , wherein the inorganic base is alkali metal hydrogen carbonates, alkali hydroxide or alkali carbonate.  
   
   
       22 . The process of  claim 21 , wherein the alkali hydroxide is either NaOH or KOH.  
   
   
       23 . The process of  claim 22 , wherein the alkali hydroxide is NaOH.  
   
   
       24 . The process of  claim 21 , wherein the alkali carbonate is either K 2 CO 3  or Na 2 CO 3 .  
   
   
       25 . The process of  claim 3 , wherein the ketone is a C 2  to C 6  ketone.  
   
   
       26 . The process of  claim 25 , wherein the ketone is C 2  to C 5  ketone.  
   
   
       27 . The process of  claim 3 , wherein the ketone is either acetone or methyl isobutyl ketone.  
   
   
       28 . The process of  claim 27 , wherein the ketone is acetone.  
   
   
       29 . The process of  claim 3 , wherein the C 1-4  alcohol is selected from the group consisting of: methanol, ethanol, isopropanol, or isobutanol.  
   
   
       30 . The process of  claim 29 , wherein the C 1-4  alcohol is methanol.  
   
   
       31 . The process of  claim 3 , wherein the ester is a C 3  to C 8 .  
   
   
       32 . The process of  claim 31 , wherein the ester is a C 4  to C 6  ester.  
   
   
       33 . The process of  claim 31 , wherein the ester is ethyl-acetate, butylacetate or isopropylacetate.  
   
   
       34 . The process of  claim 33 , wherein the ester is ethylacetate.  
   
   
       35 . The process of  claim 3 , wherein the nitrile is acetonitrile.  
   
   
       36 . The process of  claim 3 , wherein the solvent is acetone or a mixture of acetone and water.  
   
   
       37 . The process of  claim 3 , wherein the strong mineral acid is HCl, HBr, H 2 SO 4  or H 3 PO 4 .  
   
   
       38 . The process of  claim 36 , wherein the strong mineral acid is HCl.  
   
   
       39 . The process of  claim 3 , wherein after the addition of the acid, a pH of about 0 to about 4 is obtained.  
   
   
       40 . The process of  claim 39 , wherein after the addition of the acid, a pH of about 1 to about 3 is obtained.  
   
   
       41 . The process of  claim 3 , wherein the ketone, which is added with the strong mineral acid, is acetone.  
   
   
       42 . The process of  claim 3 , wherein the C 1-8  alcohol, which is added with the strong mineral acid, is methanol.  
   
   
       43 . The process of  claim 3 , wherein the solvent, which is added with the strong mineral acid, is a mixture of water and ketone or water and C 1-8  alcohol.  
   
   
       44 . A process for the optical resolution of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (CMH-racemate),  
     
       
         
         
             
             
         
       
     
     comprising: 
 a) combining CMH-racemate, a solvent selected from the group consisting of: ketone, ester, nitrile, C 1-4  alcohol, water, or mixtures thereof, a chiral resolving reagent selected from: ephedrine, ephedrine salt, norephedrine and norephedrine salt to obtain a precipitate, wherein the precipitate is of (R)—CMH-ephedrine salt of the following structure:  
                     
  or of (R)—CMH-norephedrine salt of the following structure:  
                     
 b) isolating the precipiatate; and  
 c) combining the precipitate with a solvent selected from the group consisting of: ketone, C 1-8  alcohol, water or mixtures thereof, and with a strong mineral acid to obtain a precipitate of (R)—CMH of the following structure  
                     
 
   
   
       45 . A process for the optical resolution of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (CMH-racemate),  
     
       
         
         
             
             
         
       
     
     comprising: 
 b) combining CMH-racemate, a solvent selected from ketone, ester, nitrile, C 1-4  alcohol, water, or mixtures thereof, and 1R, 2S-(−)-ephedrine to obtain a a reaction mixture;  
 c) heating the reaction mixture to a temperature of about 50° C. to about 140° C.;  
 d) cooling the reaction mixture to a temperature of about 20° C. to about −20° C. to obtain a precipitate, wherein the precipitate is of (R)—CMH-ephedrine salt of the following structure:  
                     
  or of (R)—CMH-norephedrine salt of the following structure:  
                     
 e) isolating the precipitate;  
 f) combining the precipitate with a solvent selected from ketone, C 1-8  alcohol, water or mixtures thereof, and a strong mineral acid, to obtain a slurry; and  
 g) cooling the slurry to a temperature of about 10° C. to about 2° C. to obtain a precipitate of (R)—CMH of the following structure  
                     
 
   
   
       46 . The process of  claim 44 , wherein the chiral resolving reagent is ephedrine salt or norephedrine salt.  
   
   
       47 . The process of  claim 46 , wherein the chiral resolving reagent is combined with a base.  
   
   
       48 . The process of  claim 44 , wherein the reaction mixture of step b) is heated to a temperature of about 50° C. to about 100° C.  
   
   
       49 . The process of  claim 48 , wherein the reaction mixture is maintained for about 0.5 hour to about 5 hours.  
   
   
       50 . The process of  claim 44 , wherein the reaction mixture obtained in step b) is a solution.  
   
   
       51 . The process of  claim 45 , wherein prior to step d), the solution is maintained for about an hour to about 24 hours.  
   
   
       52 . The process of  claim 45 , wherein the slurry is cooled to a temperature of about 2° C.  
   
   
       53 . The process of  claim 45 , wherein the slurry is maintained at a temperature of about 2° C. to about ambient temperature.  
   
   
       54 . The process of  claim 53 , wherein the slurry is maintained at a temperature of about 2° C. to about 10° C.  
   
   
       55 . The process of  claim 53 , wherein the slurry is maintained for about 0.5 hours to about 24 hours.  
   
   
       56 . The process of  claim 44 , wherein the precipitate of (R)—CMH is recovered.  
   
   
       57 . (R)—CMH-Ephedrine salt.  
   
   
       58 . A process for optically purifying (R)—CMH comprising combining (R)—CMH with water.  
   
   
       59 . The process of  claim 58 , wherein the water is in an amount of 8-15 vol.  
   
   
       60 . The process of  claim 58 , wherein the (R)—CMH has a specific optical purity as measured by HPLC.  
   
   
       61 . The process of  claim 58 , wherein the (R)—CMH has a purity of about 90% to about 99% area by HPLC.  
   
   
       62 . The process of  claim 61 , wherein the (R)—CMH has a purity of about 96.5% to about 99% area by HPLC.  
   
   
       63 . The process of  claim 58 , wherein the combination of (R)—CMH and water results in a slurry.  
   
   
       64 . The process of  claim 63 , wherein the slurry is stirred to obtain a precipitate of (R)—CMH.  
   
   
       65 . The process of  claim 64 , wherein the obtained slurry is stirred at a temperature of about 2° C. to about 30° C. for about one hour to about 24 hours.  
   
   
       66 . The process of  claim 65 , wherein the obtained slurry is stirred at a temperature of about 15° C. to about 20° C. for about 0.5 hour to about 24 hours.  
   
   
       67 . The process of  claim 66 , wherein the obtained slurry is stirred for about one hour to about 2 hours.  
   
   
       68 . The process of  claim 58 , wherein the (R)—CMH obtained by the above process contains less than about 1% area by HPLC of (S)—CMH.  
   
   
       69 . The process of  claim 68 , wherein the (R)—CMH obtained by the above process contains less than about 0.2% area by HPLC of (S)—CMH.  
   
   
       70 . The process of  claim 69 , wherein the (R)—CMH obtained by the above process contains less than about 0.1% area by HPLC of (S)—CMH.  
   
   
       71 . The process of  claim 64 , wherein the precipitate is recovered.  
   
   
       72 . A process for isolating (S)—CMH from the remaining mother liquor comprising: 
 a) combining the mother liquor obtained after the flirtation of (R)—CMH with water;    b) heating to obtain a solution;    c) cooling the solution;    d) combining the solution with an acid to obtain a precipitate of CMH containing about a specific amount of (S)—CMH;    e) filtering the precipitate;    f) combining the precipitate with acetone and 1R, 2S-(−)-ephedrine, to obtain a second precipitate in a mother liquor;    g) removing the precipitate from the mother liquor;    h) evaporating the mother liquor to obtain a residue;    i) combining the residue with a solvent selected from ketone, C 1-8  alcohol, water or mixtures thereof, and with a strong mineral acid to obtain a slurry; and    j) recovering the (S)—CMH.    
   
   
       73 . The process of  claim 72 , wherein step f) further comprises adding a base.  
   
   
       74 . A process for preparing (S)-Pregabalin comprising preparing (R)—CMH by the process of  claim 3 , and converting it to (S)-Pregabalin.  
   
   
       75 . The process of  claim 74 , wherein the conversion comprises: reacting (R)—CMH with bromine in a Hoffman reaction under basic conditions at a temperature of about 60° C. to about 85° C., to obtain a basic mixture, followed by an addition of a strong mineral acid, to obtain an acidic mixture containing a (S)-Pregabalin salt.  
   
   
       76 . The process of  claim 74 , wherein (S)-Pregabalin contains less than about 0.2% area by HPLC of (R)-Pregabalin.  
   
   
       77 . The process of  claim 76 , wherein (S)-Pregabalin contains less than about 0.1% area by HPLC of (R)-Pregabalin.  
   
   
       78 . A-pharmaceutical composition comprising (S)-Pregabalin made by the process of  claim 74  and at least one pharmaceutically acceptable excipient.  
   
   
       79 . A process for preparing a pharmaceutical formulation comprising combining (S)-Pregabalin made by the process of  claim 74 , with at least one pharmaceutically acceptable excipient.