Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-YL)methyl]-4H-carbazol-4-one

Abstract

A process for preparing ondansetron by transamination of an ondansetron structural analog that can be readily prepared conveniently by a Mannich reaction is provided. The process represents an improvement upon known procedures for making ondansetron by transamination because of its rapid rate, selectivity and the ease with which the product can be isolated from the reaction mixture.

1 - 16 . (canceled)  
   
   
       17 . 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one prepared by a process comprising: 
 a) contacting 3-[(dialkylamino)methyl]-1,2,3,9 tetrahydro-9-methyl-4H-carbazol-4-one of formula (II)                          or salt thereof and 2-methylimidazole in a solvent system comprising water and N,N-dimethylformamide, wherein substituents R 1  and R 2  are independently selected from C 1 -C 6  linear, branched and cyclic alkyl groups, to form 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one.    b) separating the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one from the solvent system.    c) forming a solution of the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one in an alcohol;    d) contacting the solution with an adsorbent;    e) separating the adsorbent from the solution; and    f) crystallizing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one from the solution.    
   
   
       18 . A drug product comprising the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one of  claim 17 .  
   
   
       19 . The drug product of  claim 18  that is an orally disintegrating tablet.  
   
   
       20 . 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one prepared by a process comprising contacting 3-[(dialkylamino)methyl]-1,2,3,9 tetrahydro-9-methyl-4H-carbazol-4-one of formula (II)  
     
       
         
         
             
             
         
       
     
     or salt thereof and 2-methylimidazole in a solvent system comprising water and N,N-dimethylformamide, wherein substituents R 1  and R 2  are independently selected from C 1 -C 6  linear, branched and cyclic alkyl groups.  
   
   
       21 . A drug product comprising the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one of  claim 20 .  
   
   
       22 . The drug product of  claim 21  that is an orally disintegrating tablet.  
   
   
       23 - 25 . (canceled)  
   
   
       26 . 1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate prepared by a process comprising: 
 a) contacting 3-[(dialkylamino)methyl]-1,2,3,9 tetrahydro-9-methyl-4H-carbazol-4-one of formula (II)                          or salt thereof and 2-methylimidazole in a solvent system comprising water and N,N-dimethylformamide, wherein substituents R 1  and R 2  are independently selected from C 1 -C 6  linear, branched and cyclic alkyl groups, to form 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one; and    b) converting the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one into 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate.    
   
   
       27 . A drug product comprising the 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one hydrochloride dihydrate of  claim 26 .  
   
   
       28 . The drug product of  claim 27  that is a compressed tablet comprising 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one in a vehicle comprising at least one excipient or adjuvant.  
   
   
       29 . The drug product of  claim 27  that is an oral solution of 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one in an aqueous vehicle.  
   
   
       30 - 31 . (canceled)  
   
   
       32 . 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one essentially free of 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one.  
   
   
       33 . The 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one of  claim 32  containing about 1% or less 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one as determined by comparison of the integrated areas under the curve in chromatogram obtained by high performance liquid chromatography with UV detection at 216 nm.  
   
   
       34 . The 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one of  claim 33  containing about 0.25% or less 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one.  
   
   
       35 . The 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one of  claim 34  containing about 0.25% or less 9-methyl-3-methylene-1,2,3,9-tetrahydro-4H-carbazol-4-one.