Synthesis of temozolomide and analogs

Abstract

This invention relates to a novel process for the synthesis of Temozolomide, an antitumor compound, and analogs, and to intermediates useful in this novel process.

1 . A process for the preparation of a compound of the formula:  
       
         
           
           
               
               
           
         
         wherein R is an alkyl group having from 1 to 6 carbon atoms, which comprises:  
         (a) diazotizing a compound of the formula:  
         
           
             
             
                 
                 
             
           
         
          wherein R is as defined above;  
          and Pg″ is a divalent protecting group that is readily removable by hydrolysis or hydrogenolysis; or two monovalent protecting groups Pg that are readily removable by hydrolysis or hydrogenolysis; or a bulky monovalent protecting group Pg that is readily removable by hydrolysis or hydrogenolysis, together with a hydrogen atom;  
          and thereafter  
         (b) hydrolyzing the resulting compound of the formula:  
         
           
             
             
                 
                 
             
           
         
       
     
     
         2 . A process as claimed in  claim 1  wherein R is a straight-chain alkyl group having from 1 to 4 carbon atoms.  
     
     
         3 . A process as claimed in  claim 1  wherein R is a methyl group.  
     
     
         4 . A process as claimed in  claim 3  wherein Pg″ is a monovalent protecting group together with a hydrogen atom.  
     
     
         5 . A process as claimed in  claim 4  wherein the monovalent protecting group is a 1,1-dimethylethyl group.  
     
     
         6 . A process as claimed in  claim 5  wherein step (a) is carried out in solution in an aqueous organic acid with a source of nitrous acid.  
     
     
         7 . A process as claimed in  claim 6  wherein the organic acid is acetic acid and the source of nitrous acid is inorganic.  
     
     
         8 . A process as claimed in  claim 7  wherein the source of nitrous acid is sodium nitrite.  
     
     
         9 . A process as claimed in  claim 8  wherein the reaction is carried out in the presence of LiCl.  
     
     
         10 . A process as claimed in  claim 5  wherein step (b) is carried out by hydrolysis with a mineral acid.  
     
     
         11 . A process as claimed in  claim 10  wherein the mineral acid is concentrated sulfuric acid.  
     
     
         12 . A process as claimed in  claim 1  for the preparation of Temozolomide having the formula:  
       
         
           
           
               
               
           
         
       
       which comprises 
 (a) diazotizing a compound of the formula:  
                     
  wherein Pg″ is a divalent protecting group that is readily removable by hydrolysis or hydrogenolysis; or two monovalent protecting groups Pg that are readily removable by hydrolysis or hydrogenolysis; or a bulky monovalent protecting group Pg that is readily removable by hydrolysis or hydrogenolysis, together with a hydrogen atom;  
  and thereafter  
 (b) subjecting the resulting compound of the formula:  
                     
  wherein Pg″ is as defined above, to hydrolysis or hydrogenolysis.  
 
     
     
         13 . A process as claimed in  claim 12  wherein the protecting group Pg″ is a 1,1-dimethylethyl group together with a hydrogen atom, the diazotization is effected in solution in acetic acid with sodium nitrite and in the presence of LiCl;  
       and step (b) is carried out by hydrolysis with concentrated sulfuric acid.  
     
     
         14 . A process as claimed in  claim 1  wherein the compound of the formula II is prepared by reaction of a compound of the formula Pg″N.CO.CH(NH 2 ).CN (V) (wherein Pg″ is a protecting group as defined in  claim 1)  with methyl[[[(methyl-amino)carbonyl]amino]methylene]urea or with N-methylurea and an orthoformate in an inert organic solvent.  
     
     
         15 . A process as claimed in  claim 14  wherein the compound of the formula V is prepared by hydrolysis of a compound of the formula Pg″N.CO.CH(N:Ar).CN (VI) (wherein Pg is as defined in  claim 14  and Ar is an arylmethylene group) with mild acid.  
     
     
         16 . A process as claimed in  claim 15  wherein Pg is a 1,1-dimethylethyl group together with a hydrogen atom, and Ar is a diphenylmethylene group.  
     
     
         17 . A process as claimed in  claim 15  wherein the compound of the formula VI wherein Pg is a 1,1-dimethylethyl group together with a hydrogen atom and Ar is a diphenylmethylene group is prepared by condensation of [(diphenylmethylene)amino]acetonitrile with 1,1-dimethylethylisocyanate.  
     
     
         18 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein Pg″ is a protecting group that is readily removable by hydrolysis as defined in  claim 1 , Ar is an arylmethylene group, and R is an alkyl group having from 1 to 6 carbon atoms;  
       together with the salts thereof.  
     
     
         19 . A compound as claimed in  claim 18  wherein Pg is a 1,1-dimethylethyl group together with a hydrogen atom, Ar is a diphenylmethylene group, and R is an alkyl group having from 1 to 4 carbon atoms.  
     
     
         20 . A compound as claimed in  claim 18  having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         21 . A process for the preparation of a compound having the formula III set forth in  claim 1 , which comprises diazotizing a compound of the formula II set forth in  claim 1 .  
     
     
         22 . A process for the preparation of a compound having the formula II set forth in  claim 1 , which comprises reacting a compound of the formula Pg″N.CO.CH(NH 2 ).CN (V) with a compound of the formula R.NH.CO.NH.CH:N.CO.NH.R or with an N-R-urea and an orthoformate in an inert organic solvent (wherein Pg″ is a protecting group as defined in  claim 1  and R is as defined in  claim 1) .  
     
     
         23 . A process as claimed in  claim 22 , which comprises reacting a compound of the formula t-BuNH.CO.CH(NH 2 ).CN with methyl[[[(methylamino)carbonyl]-amino]methylene]urea or with N-methylurea and an orthoformate in an inert organic solvent.  
     
     
         24 . A process for the preparation of a compound having the formula Pg″N.CO.CH(NH 2 ).CN (V), which comprises hydrolyzing a compound of the formula Pg″N.CO.CH(N:Ar).CN (VI) (wherein Pg″ is a protecting group that is readily removable by hydrolysis as defined in  claim 1 , and Ar is an arylmethylene group) with mild acid.  
     
     
         25 . A process for the preparation of a compound having the formula VI set forth in  claim 18  wherein Pg is a 1,1-dimethylethyl group and Ar is a diphenylmethylene group, which comprises the condensation of [(diphenylmethylene)amino]acetonitrile with 1,1-dimethylethylisocyanate.  
     
     
         26 . The acid addition salts of the compounds of the formulae 4, 5, 6, 8, and 17 defined in  claim 20 .  
     
     
         27 . The salts with bases of the compound of the formula 13 defined in  claim 20 .  
     
     
         28 . A process for the preparation of the compound of the formula  
       
         
           
           
               
               
           
         
         or an acid addition salt thereof,  
          which comprises hydrolyzing, or hydrogenolyzing and hydrolyzing, a compound of the formula  
         
           
             
             
                 
                 
             
           
         
          (wherein Pg″ and R are as defined in  claim 1) , and isolating the resulting compound of the formula  
         
           
             
             
                 
                 
             
           
         
          or an acid addition salt thereof.  
       
     
     
         29 . A process for the preparation of a compound of the formula  
       
         
           
           
               
               
           
         
         or an acid addition salt thereof,  
          which comprises condensing a compound of the formula H 2 N.CO.CH(NH 2 ).CN with a compound of the formula R.NH.CO.NH.CH:N.CO.NH.R or with an N-R-urea and an orthoformate in an inert organic solvent (wherein R is as defined in  claim 1) , hydrolyzing the resulting compound of the formula  
         
           
             
             
                 
                 
             
           
         
          (wherein R is as defined in  claim 1) , and isolating the resulting compound of the formula  
         
           
             
             
                 
                 
             
           
         
          or an acid addition salt thereof.  
       
     
     
         30 . A process for the preparation of a compound of the formula  
       
         
           
           
               
               
           
         
         wherein R is as defined in  claim 1 ,  
          which comprises condensing a compound of the formula H 2 N.CO.CH(NH 2 ).CN with a compound of the formula R.NH.CO.NH.CH:N.CO.NH.R or with an N-R-urea and an orthoformate in an inert organic solvent (wherein R is as defined in claim  1 ).