Method of preparation of metaxalone

Abstract

The present invention relates to a method of preparation of metaxalone comprising reaction of triglycidyl isocyanurate (TGIC) with m-xylenol, characterized in that said reaction is carried out in a solvent mixture comprising an aprotic polar solvent with dielectric constant greater than or equal to 30 and at least one other solvent selected from the group comprising apolar solvents and aprotic polar solvents with dielectric constant below 30 said solvent mixture comprising from 5 to 40 wt. % of said first solvent and from 95 to 60 wt. % of said second solvent, adding the TGIC at a temperature between 30° C. and 50° C., and after adding the TGIC, raising the temperature of the reaction solution to a value between 80° C. and 180° C. in a time between 120 and 180 minutes at a rate of increase not greater that 1.25° C. per minute. The invention also relates to a metaxalone with a reduced content of impurities derived from incomplete reactions and/or side reactions of the method of production.

1 . A method for preparing a metaxalone of formula (I): 
       
         
           
           
               
               
           
         
       
       the method comprising reacting a triglycidyl isocyanurate (TGIC) of formula (III): 
       
         
           
           
               
               
           
         
       
       with an m-xylenol of formula (V): 
       
         
           
           
               
               
           
         
       
       to form the metaxalone of formula (I),
 wherein: 
 the reacting occurs in a solvent mixture comprising
 a first solvent which is an aprotic polar solvent having a dielectric constant greater than or equal to 30, and 
 a second solvent having a dielectric constant below 30 selected from the group consisting of an apolar solvent and an aprotic solvent; 
 
 the solvent mixture comprises from 5 to 40 wt. % of the first solvent and from 95 to 60 wt. % of the second solvent; 
 the TGIC is added to a reaction solution at a temperature between 30° C. and 50° C.; and 
 after the TGIC is added, the temperature of the reaction solution is increased to between 80° C. and 180° C. over a time between 120 and 180 minutes such that a rate of increase in temperature not greater that 1.25° C. per minute. 
 
     
     
         2 . The method according to  claim 1 , wherein the aprotic polar solvent having a dielectric constant greater than or equal to 30 is selected from the group consisting of N-methylpyrrolidone, dimethylformamide, dimethylsulphoxide, hexamethylphosphoramide, dimethylacetamide and acetonitrile, preferably N-methylpyrrolidone and dimethylformamide. 
     
     
         3 . The method according to  claim 1 , wherein the second solvent comprises an apolar solvent selected from the group consisting of cyclohexane, heptane, benzene, toluene, xylene, mesitylene, naphthalene, chlorobenzene, chloroxylene, chloroform, propyl ether, isopropyl ether, butyl ether, pentyl ether, benzylethyl ether, tetrahydrofuran (THF) and 2-methyl tetrahydrofuran, preferably toluene and xylene. 
     
     
         4 . The method according to  claim 1 , wherein the second solvent comprises an aprotic polar solvent having dielectric constant below 30 which is selected from the group consisting of acetone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone, 2-pentanone, cyclopentanone and 2-heptanone, preferably methyl isobutyl ketone. 
     
     
         5 . The method according to  claim 1 , wherein the solvent mixture comprises from 10 to 30 wt. %, of the first solvent and from 90 to 70 wt. %, of the second solvent. 
     
     
         6 . The method according to  claim 1 , wherein the reaction solution further comprises an organic or inorganic base. 
     
     
         7 . The method according to  claim 6 , wherein the reaction solution comprises between 3 and 10 mol. % of the organic or inorganic base, relative to an molar amount of TGIC in the reaction solution. 
     
     
         8 . The method according to  claim 6 , wherein the reaction solution comprises between 0.5 and 5 mol. % of the phase transfer catalyst, relative to an amount of TGIC in the reaction solution. 
     
     
         9 . The method according to  claim 6 , wherein the reaction solution, which comprises m-xylenol, the base and the phase transfer catalyst dissolved in the solvent mixture, is heated to a temperature between 35° C. and 45° C., before adding the TGIC. 
     
     
         10 . The method according to  claim 1 , wherein, after adding TGIC, the reaction solution is heated to a temperature between 80° C. and 180° C. over a time between 120 and 180 minutes. 
     
     
         11 . The method according to  claim 10 , wherein the reaction solution is heated at a rate of increase not greater than 1.00° C. per minute. 
     
     
         12 . The method according to  claim 11 , further comprising, after the raising of the temperature, adding between 3 and 10 mol. % of a base, relative to a molar amount of TGIC present in a starting reaction solution. 
     
     
         13 . A metaxalone, comprising less than 1 ppm of genotoxic impurities comprising epoxides represented by formulas (III), (VII) and (VIII): 
       
         
           
           
               
               
           
         
       
     
     
         14 . The metaxalone according to  claim 13 , comprising less than 0.5 ppm of the genotoxic impurities comprising epoxides. 
     
     
         15 . A metaxalone, comprising less than 500 ppm of an impurity represented by formula (IX): 
       
         
           
           
               
               
           
         
       
     
     
         16 . The metaxalone according to  claim 15 , comprising less than 300 ppm of the impurity. 
     
     
         17 . A pharmaceutical composition, comprising the metaxalone according to  claim 13  and at least one pharmaceutically acceptable excipient. 
     
     
         18 . A pharmaceutical composition, comprising the metaxalone according to  claim 14  and at least one pharmaceutically acceptable excipient. 
     
     
         19 . A pharmaceutical composition, comprising the metaxalone according to  claim 15  and at least one pharmaceutically acceptable excipient. 
     
     
         20 . A pharmaceutical composition, comprising the metaxalone according to  claim 16  and at least one pharmaceutically acceptable excipient.