Process for making sugammadex

Abstract

The invention relates to a process for making the pharmaceutical product Sugammadex. The process comprises reacting a 6-per-deoxy-6-per-halo-γ-cyclodextrin with 3-mercaptopropionic acid in the presence of a sodium base and DMSO to form Sugammadex.

1 . A process to synthesize Sugammadex comprising the steps of:
 a) substituting the primary hydroxy groups of the γ-cyclodextrin by chlorine to give the corresponding 6-per-deoxy-6-per-chloro-γ-cyclodextrin compound of formula (3),   
       
         
           
           
               
               
           
         
          wherein X is Cl; and 
         b) reacting the compound of formula (3) with 3-mercaptopropionic acid in the presence of a sodium base and DMSO. 
       
     
     
         2 . The process according to  claim 1 , wherein the sodium base is aqueous sodium hydroxide. 
     
     
         3 . The process according to  claim 2 , wherein aqueous sodium hydroxide is used in a concentration from 3 to 7 Molar. 
     
     
         4 . The process of  claim 1 , wherein 8 to 15 equivalents of 3-mercaptopropionic acid are used. 
     
     
         5 . The process of  claim 1 , wherein from 25 to 35 equivalents of sodium base are used. 
     
     
         6 . The process according to  claim 1 , wherein the base of step b) is added over a period of at least 8 min. 
     
     
         7 . The process according to  claim 1 , wherein the sodium base of step b) is added to the 3-mercaptopropionic acid, and to the resulting solution the 6-per-deoxy-6-per-halo-γ-cyclodextrin in DMSO is added. 
     
     
         8 . The process according. to  claim 1 , wherein 6-per-deoxy-6-per-halo-γ-cyclodextrin is dissolved in DMSO, 3-mercaptopropionic acid is added followed by addition of the base of step b). 
     
     
         9 . The process according to  claim 1 , wherein the reaction temperature of step b) is from 30 to 70° C. 
     
     
         10 . The process according to  claim 1 , wherein Sugammadex is precipitated by adding subsequently methanol and ethanol. 
     
     
         12 . The process according to  claim 1 , wherein Sugammadex is isolated by
 i) adding water till complete dissolution followed by addition of one or more organic solvents, wherein one of the organic solvents is water miscible; and   ii) decreasing the temperature of the mixture to 0-10° C. to obtain Sugammadex solid.   
     
     
         13 . The process according to  claim 12  where the organic solvent is DMSO. 
     
     
         14 . The process according to  claim 1  wherein the compound of formula (3) has been synthesized reacting γ-cyclodextrin with PPh 3 , X 2  and DMF, wherein X is Cl.