Process for the preparation of tiotropium bromide

Abstract

The invention is directed to improved processes for preparing Tiotropium bromide.

1 . A scopine salt of formula II-s  
     
       
         
         
             
             
         
       
     
     comprising a salt content of about 0.5% to about 40% by weight; wherein X is selected from the group consisting of Br, Cl, SO4, MeCOO, PO4, MeSO3, tartrate, fumarate, citrate, maleate, succinate, p-toluene sulphonate and amidosulphonate.  
   
   
       2 . The scopine salt of  claim 1 , wherein X is Br.  
   
   
       3 . The scopine salt of  claim 1 , wherein said salt content is about 0.5% to about 20% by weight.  
   
   
       4 . The scopine salt of  claim 1 , wherein said scopine salt is selected from the group consisting of an HBr, HCl, H 2 SO4, CH 3 COOH, H 3 PO 4 , MeSO 3 H, tartrate, fumarate, citrate, maleate, succinate, maliate, p-toluenesulphonate, borate and amidosulphonate scopine salt.  
   
   
       5 . A process of preparing said scopine salt of  claim 1 , comprising: 
 a. filtering a reaction mixture containing said scopine salt to produce a filtrate,    b. adding water to said filtrate to precipitate insoluble salts;    c. filtering said insoluble salts from said filtrate;    d. adding an acid to said filtrate to precipitate said scopine salt; and    e. collecting said precipitated scopine salt.    
   
   
       6 . The process of  claim 5 , wherein said acid is HBr.  
   
   
       7 . The process of  claim 5 , further comprising washing said precipitated scopine salts with a polar organic solvent.  
   
   
       8 . The process of  claim 7 , wherein said polar organic solvent is selected from the group consisting of a C 1-6  alcohol, a C 4-8  ether, a C 3-10  ketone, a C 2-4  nitrile, and mixtures thereof.  
   
   
       9 . The process of  claim 8 , wherein said polar organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, 1,4-dioxane, acetone, acetonitrile, and mixtures thereof.  
   
   
       10 . A process for preparing Tiotropium bromide comprising preparing a scopine salt of formula II-s containing about 0.5% to about 40% by weight of salts by the process of  claim 5 , and converting it to Tiotropium bromide.  
   
   
       11 . A process for the preparation of N-demethyl-tiotropium of formula III,  
     
       
         
         
             
             
         
       
     
     comprising reacting methyl-di-(2-thienyl)-glycolate of formula I,  
     
       
         
         
             
             
         
       
     
     with a scopine salt as defined in  claim 1 .  
   
   
       12 . The process of  claim 11 , wherein said methyl-di-(2-thienyl)-glycolate of formula I,  
     
       
         
         
             
             
         
       
     
     is combined with a weak inorganic base, a polar organic solvent, and a scopine salt of formula II-s containing about 0.5% to about 40% by weight of salts to obtain a mixture, and heating said mixture.  
   
   
       13 . The process of  claim 12 , wherein said scopine salt is suspended in a polar organic solvent prior to said combination.  
   
   
       14 . The process of  claim 13 , wherein said weak inorganic base is added to said suspension providing a new suspension.  
   
   
       15 . The process of  claim 14 , wherein said weak inorganic base is anhydrous.  
   
   
       16 . The process of  claim 15 , wherein said weak inorganic base has a pKa of about 8 to about 12.  
   
   
       17 . The process of  claim 16 , wherein said weak inorganic base is selected from the group consisting of K 2 CO 3 , NaHCO 3 , Li 2 CO 3 , CS 2 CO 3 , t-ButOK, and t-ButOLi.  
   
   
       18 . The process of  claim 17 , wherein said weak inorganic base is K 2 CO 3 .  
   
   
       19 . The process of  claim 14 , wherein after said addition of said weak inorganic base, a mixture of said methyl-di-(2-thienyl)-glycolate and another portion of said weak inorganic base are added to said new suspension to provide a mixture.  
   
   
       20 . The process of  claim 12 , wherein said methyl-di-(2-thienyl)-glycolate is added in solution in a polar organic solvent.  
   
   
       21 . The process of  claim 12 , wherein said polar organic solvent is selected from a group consisting of C 1 -C 4  amides, C 2 -C 4  sulfoxides, C 2 -C 4  sulfones, C 7 -C 8  aromatic hydrocarbons, and C 2 -C 4  nitrites.  
   
   
       22 . The process of  claim 21 , wherein said polar organic solvent is dimethylformamide.  
   
   
       23 . The process of  claim 12 , wherein an amount of said weak inorganic base is about 0.45 to about 2.5 moles per mole equivalent of said scopine salt.  
   
   
       24 . The process of  claim 14 , wherein said addition of said weak inorganic base is performed at a temperature of about 25° C. to about 65° C.  
   
   
       25 . The process of  claim 24 , wherein said mixture is heated to a temperature of less than about 70° C.  
   
   
       26 . The process of  12 , further comprising recovering said N-demethyl-tiotropium.  
   
   
       27 . A process for the preparation of N-demethyl-tiotropium of formula III,  
     
       
         
         
             
             
         
       
     
     comprising reacting methyl-di-(2-thienyl)-glycolate of formula I,  
     
       
         
         
             
             
         
       
     
     with a scopine base.  
   
   
       28 . The process of  claim 27 , wherein said methyl-di-(2-thienyl)-glycolate is combined with a scopine base, about 1 to about 1.5 mole equivalents of a weak inorganic base per mole equivalent of said scopine base, and a polar organic solvent to obtain a mixture, and heating said mixture.  
   
   
       29 . A process for the preparation of Tiotropium bromide comprising the steps of: 
 a. preparing N-demethyl-tiotropium by a process as defined in  claim 11;  and    b. reacting said N-demethyl-tiotropium with methylbromide in an organic solvent to form Tiotropium bromide.    
   
   
       30 . The process of  claim 29 , wherein said organic solvent is selected from the group consisting of a C 2-4  nitrile, a C 4-8  linear or cyclic ether, a mixture of a C 2-4  nitrile and a C 4-8  linear or cyclic ether, a mixture of a C 7-8  aromatic hydrocarbon and a C 2-4  nitrile, and a mixture of a C 2-4  nitrile and a C 3-10  ketone.  
   
   
       31 . The process of  claim 30 , wherein said organic solvent is selected from the group consisting of acetonitrile, tetrahydrofuran, a mixture of acetonitrile and tetrahydrofuran, a mixture of toluene and acetonitrile, and a mixture of acetone and acetonitrile.  
   
   
       32 . The process of  claim 31 , wherein said organic solvent is acetonitrile.  
   
   
       33 . Use of a scopine salt as defined in any of  claims 1  to  5  in a process for the manufacture of N-demethyl tiotropium of Formula III or Tiotropium bromide.