Process for production of glycopyrronium tosylate

Abstract

Provided herein are methods for the production of glycopyrronium tosylate and glycopyrronium tosylate compositions. Also provided herein are compositions useful in the production of glycopyrronium tosylate. Additionally provided herein are glycopyrronium tosylate compositions. Glycopyrronium tosylate is useful for the treatment of, among other conditions, hyperhidrosis.

1 .- 30 . (canceled) 
     
     
         31 . A glycopyrronium tosylate composition produced by a method comprising:
 purifying glycopyrronium tosylate by one or more crystallizations in an aqueous solvent to obtain a purified glycopyrronium tosylate, wherein the aqueous solvent consists essentially of water;   the composition comprises threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, wherein the threo-glycopyrronium tosylate is at least 98% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 2% of the total glycopyrronium tosylate content of the composition.   
     
     
         32 . The glycopyrronium tosylate composition of  claim 31 , wherein the threo-glycopyrronium tosylate is at least 99% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 1% of the total glycopyrronium tosylate content of the composition. 
     
     
         33 . The glycopyrronium tosylate composition of  claim 31 , wherein the threo-glycopyrronium tosylate is at least 99.5% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 0.5% of the total glycopyrronium tosylate content of the composition. 
     
     
         34 . The glycopyrronium tosylate composition of  claim 31 , wherein the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate content of the composition. 
     
     
         35 . A glycopyrronium tosylate composition comprising threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, wherein the threo-glycopyrronium tosylate is at least 98% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 2% of the total glycopyrronium tosylate content of the composition. 
     
     
         36 . The glycopyrronium tosylate composition of  claim 35 , wherein the threo-glycopyrronium tosylate is at least 99% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 1% of the total glycopyrronium tosylate content of the composition. 
     
     
         37 . The glycopyrronium tosylate composition of  claim 35 , wherein the threo-glycopyrronium tosylate is at least 99.5% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 0.5% of the total glycopyrronium tosylate content of the composition. 
     
     
         38 . The glycopyrronium tosylate composition of  claim 35 , wherein the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate content of the composition and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate content of the composition. 
     
     
         39 . The glycopyrronium tosylate composition of  claim 31 , wherein the aqueous solvent consists of water. 
     
     
         40 . The glycopyrronium tosylate composition of  claim 31 , wherein in the method the glycopyrronium tosylate is purified by at least two crystallizations in the aqueous solvent. 
     
     
         41 . The glycopyrronium tosylate composition of  claim 31 , wherein the method further comprising producing glycopyrronium tosylate by
 contacting glycopyrrolate base with methyl tosylate to produce glycopyrronium tosylate:   
       
         
           
           
               
               
           
         
       
       wherein the glycopyrrolate base is contacted with a water-miscible organic solvent. 
     
     
         42 . The glycopyrronium tosylate composition of  claim 41 , wherein the water-miscible organic solvent is a water-miscible aldehyde, organic acid, ketone, nitrile, diol, alcohol, aminoalcohol, glycol, sulfoxide, ether, cyclic ether, cyclic diether, amine, polyol, or cyclic amine comprising from 1 to 6 carbon atoms. 
     
     
         43 . The glycopyrronium tosylate composition of  claim 41 , wherein the water-miscible organic solvent is acetone. 
     
     
         44 . The glycopyrronium tosylate composition of  claim 41 , wherein the reaction is conducted at a temperature selected over the range of 20° C. to 26° C. 
     
     
         45 . The glycopyrronium tosylate composition of  claim 41 , wherein the glycopyrronium tosylate is produced as a mixture of threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, and the threo-glycopyrronium tosylate is at least 95% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 5% of the total glycopyrronium tosylate in the mixture. 
     
     
         46 . The glycopyrronium tosylate composition of  claim 45 , wherein the threo-glycopyrronium tosylate is at least 96% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 4% of the total glycopyrronium tosylate in the mixture. 
     
     
         47 . The glycopyrronium tosylate composition of  claim 45 , wherein the threo-glycopyrronium tosylate is at least 97% of the total glycopyrronium tosylate in the mixture and erythro-glycopyrronium tosylate is less than 3% of the total glycopyrronium tosylate in the mixture. 
     
     
         48 . The glycopyrronium tosylate composition of  claim 41 , wherein the method further comprising producing glycopyrrolate base by contacting a glycopyrrolate base, 5-nitroisophthalate salt with an inorganic base to form the glycopyrrolate base: 
       
         
           
           
               
               
           
         
       
     
     
         49 . The glycopyrronium tosylate composition of  claim 48 , wherein the inorganic base is aqueous sodium hydroxide. 
     
     
         50 . The glycopyrronium tosylate composition of  claim 48 , wherein the glycopyrrolate base, 5-nitroisophthalate salt, and inorganic base are contacted with a water-immiscible organic solvent. 
     
     
         51 . The glycopyrronium tosylate composition of  claim 50 , wherein the water-immiscible organic solvent is selected from the group consisting of benzene, n-butanol, carbon tetrachloride, chloroform, cyclohexane, ethylene chloride, heptane, hexane, pentane, toluene, trichloroethylene, and xylene. 
     
     
         52 . The glycopyrronium tosylate composition of  claim 50 , wherein the water-immiscible organic solvent is toluene. 
     
     
         53 . The glycopyrronium tosylate composition of  claim 48 , wherein the glycopyrrolate base is produced as a mixture of threo-glycopyrrolate base and erythro-glycopyrrolate base, and the threo-glycopyrrolate base is at least 95% of the total glycopyrrolate base produced and the erythro-glycopyrrolate base is less than 5% of the total glycopyrrolate base produced. 
     
     
         54 . The glycopyrronium tosylate composition of  claim 53 , wherein the threo-glycopyrrolate base is at least 96% of the total glycopyrrolate base produced and the erythro-glycopyrrolate base is less than 4% of the total glycopyrrolate base produced. 
     
     
         55 . The glycopyrronium tosylate composition of  claim 53 , wherein the threo-glycopyrrolate base is at least 97% of the total glycopyrrolate base produced and the erythro-glycopyrrolate base is less than 3% of the total glycopyrrolate base produced. 
     
     
         56 . The glycopyrronium tosylate composition of  claim 48 , wherein the method further comprising producing glycopyrrolate base, 5-nitroisophthalate salt by contacting a glycopyrrolate base with 5-nitroisophthalic acid to form the glycopyrrolate base, 5-nitroisophthalate salt: 
       
         
           
           
               
               
           
         
       
     
     
         57 . The glycopyrronium tosylate composition of  claim 56 , wherein the glycopyrrolate base and 5-nitroisophthalic acid are contacted with methanol. 
     
     
         58 . The glycopyrronium tosylate composition of  claim 56 , wherein the contacting of a glycopyrrolate base with 5-nitroisophthalic acid is conducted at a temperature selected over the range of 20° C. to 26° C. 
     
     
         59 . The glycopyrronium tosylate composition of  claim 56 , wherein the method further comprising producing glycopyrrolate base by contacting cyclopentylmandelic acid with 1-methylpyrrolidin-3-ol to form the glycopyrrolate base: 
       
         
           
           
               
               
           
         
       
     
     
         60 . A glycopyrronium tosylate composition produced by a method comprising:
 (i) contacting cyclopentylmandelic acid with 1-methylpyrrolidin-3-ol to form glycopyrrolate base:   
       
         
           
           
               
               
           
         
         (ii) contacting the glycopyrrolate base with 5-nitroisophthalic acid to form glycopyrrolate base, 5-nitroisophthalate salt: 
       
       
         
           
           
               
               
           
         
         (iii) contacting the glycopyrrolate base, 5-nitroisophthalate salt with an inorganic base to form glycopyrrolate base: 
       
       
         
           
           
               
               
           
         
         (iv) contacting the glycopyrrolate base with methyl tosylate to produce glycopyrronium tosylate: 
       
       
         
           
           
               
               
           
         
       
       wherein the glycopyrrolate base is contacted with a water-miscible organic solvent; and
 (v) purifying the glycopyrronium tosylate obtained in step (iv) by one or more crystallizations in an aqueous solvent to obtain a purified glycopyrronium tosylate; wherein the aqueous solvent consists essentially of water. 
 
     
     
         61 . The glycopyrronium tosylate composition of  claim 60 , wherein the purified glycopyrronium tosylate of step (v) is a mixture of threo-glycopyrronium tosylate and erythro-glycopyrronium tosylate, and the threo-glycopyrronium tosylate is at least 99% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 1% of the total glycopyrronium tosylate in the mixture. 
     
     
         62 . The glycopyrronium tosylate composition of  claim 61 , wherein the threo-glycopyrronium tosylate is at least 99.5% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.5% of the total glycopyrronium tosylate in the mixture. 
     
     
         63 . The glycopyrronium tosylate composition of  claim 61 , wherein the threo-glycopyrronium tosylate is at least 99.6% of the total glycopyrronium tosylate in the mixture and the erythro-glycopyrronium tosylate is less than 0.4% of the total glycopyrronium tosylate in the mixture. 
     
     
         64 . The glycopyrronium tosylate composition of  claim 60 , wherein the step (v) is purifying the glycopyrronium tosylate obtained in step (iv) by at least two crystallizations in the aqueous solvent. 
     
     
         65 . The glycopyrronium tosylate composition of  claim 60 , wherein in step (v) the aqueous solvent consists of water. 
     
     
         66 . The glycopyrronium tosylate composition of  claim 60 , wherein in step (iv) the water-miscible organic solvent is acetone. 
     
     
         67 . The glycopyrronium tosylate composition of  claim 60 , wherein in step (iii) the glycopyrrolate base, 5-nitroisophthalate salt is dissolved in water and contacted with toluene, and the inorganic base is aqueous sodium hydroxide. 
     
     
         68 . The glycopyrronium tosylate composition of  claim 60 , wherein in step (ii) the glycopyrrolate base is contacted with 5-nitroisophthalic acid in methanol.