Processes and intermediates for preparing a btk inhibitor

Abstract

which intermediate and processes are useful in the preparation of a BTK inhibitor, such as ibrutinib.

1 . A process for preparing a compound of formula (I) 
       
         
           
           
               
               
           
         
         in an enantioenriched form, 
         wherein 
         R 1  represents hydrogen or an acyl group; 
         R 2  represents hydrogen or an amino-protecting group; 
         * represents a chiral centre of an (S) configuration; 
         which comprises enzymatic kinetic resolution of a compound of formula (II) 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents hydrogen and R 2  is as defined above, 
         and the process is performed in the presence of an acyl donor. 
       
     
     
         2 . A process as claimed in  claim 1 , where acyl donor is a compound of the following formula R x —R 1 , in which:
 R 1  represents —C(O)—C 1-8  alkyl (in which the alkyl moiety is optionally substituted by one or more substituents selected from e.g. halo (e.g. fluoro), —OC 1-6  alkyl (e.g. methoxy; 
 itself optionally substituted by one or more fluoro atoms) and phenyl (itself optionally substituted by one or more substituents selected from halo and C 1-3  alkyl)) or —C(O)phenyl (in which phenyl is optionally substituted by one or more substituents selected from e.g. halo and C 1-3  alkyl); and 
 R x  represents —O—C 1-8  alkyl (optionally substituted by one or more substituents selected from fluoro and —OC 1-6  alkyl; the latter alkyl moiety optionally substituted by one or more fluoro atoms) or —O-phenyl (optionally substituted by one or more substituents selected from halo (e.g. chloro, fluoro, bromo), —NO 2 , C 1-6  alkyl and —OC 1-6  alkyl; in which the latter two alkyl moieties are themselves optionally substituted by one or more fluoro atom). 
 
     
     
         3 . A process as claimed in  claim 1 , wherein R 1  represents —C(O)—C 1-6  alkyl (in which the alkyl moiety is optionally substituted by one or more substituents selected from e.g. halo (e.g. fluoro) and —OC 1-6  alkyl (e.g. methoxy; itself optionally substituted by one or more fluoro atoms). 
     
     
         4 . A process as claimed in  claim 3 , wherein R 1  represents a —C(O)CH 2 —OCH 3  moiety or a —C(O)CH 2 CH 2 CH 3  moiety. 
     
     
         5 . A process as claimed in  claim 1 , wherein the acyl donor is iso-propenyl acetate, trifluoroethyl acetate, vinyl butyrate, isopropyl butyrate, phenyl butyrate (e.g. 3-fluoro-phenyl butyrate or 4-fluorophenyl butyrate), o-cresol 2-methoxy acetate or 2,2,2-trifluoroethyl butyrate. 
     
     
         6 . A process as claimed in  claim 5 , wherein the acyl donor is 2,2,2-trifluoro ethyl butyrate or 4-fluorophenyl butyrate. 
     
     
         7 . A process as claimed in  claim 1 , wherein at least one at least one acyl donor equivalent is employed compared to the compound of formula (II). 
     
     
         8 . A process as claimed in  claim 7 , where about two equivalents of acyl donor are employed (compared to the compound of formula (II)). 
     
     
         9 . A process as claimed in  claim 1 , wherein the enzyme is a protease or lipase. 
     
     
         10 . A process as claimed in  claim 9 , where in the enzyme is selected from Savinase,  Candida Rugosa  Lipase B,  Candida Rugosa  Lipase A, Lipase from  Carica Papaya , alkaline Protease B, and Subtilisin. 
     
     
         11 . A process as claimed in  claim 1 , wherein the process is performed in the presence of an inorganic base. 
     
     
         12 . A process as claimed in  claim 1 , wherein the process is performed in the presence of a suitable solvent (e.g. toluene or methyl-THF). 
     
     
         13 . A process as claimed  claim 1 , wherein the process is performed at a temperature of between about 25 and 40° C. (e.g. between about 25 and 35° C.), such as at about 30° C. 
     
     
         14 . A process as claimed in  claim 1 , wherein the resolution is a dynamic kinetic resolution, performed in the presence of a racemisation catalyst. 
     
     
         15 . A process as claimed in  claim 14 , wherein the racemisation catalysts are one or more catalysts selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A process as claimed in  claim 1  comprising further conversion steps including the following:
 separation/isolation of the compound of formula (I) 
 conversion of the compound of formula (I) obtained in a process as claimed in any one of the previous claims or as further separated/isolated as described above, to ibrutinib. 
 
     
     
         17 . A process as claimed in  claim 16 , wherein the following conversion steps to ibrutinib are employed: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . A pharmaceutical composition comprising ibrutinib (or a salt thereof) as obtained by the process of  claim 16 . 
     
     
         19 . A process for preparing a pharmaceutical composition of  claim 18 , which comprises a process for preparing ibrutinib, or a salt thereof, as claimed by  Claims 16 ,. followed by contacting it with a pharmaceutically acceptable carrier, diluent and/or excipient. 
     
     
         20 . A process for preparing a pharmaceutical composition of  Claim 18 . which comprises a process for preparing ibrutinib. or a salt thereof, as claimed by  Claim 17 . followed by contacting it with a pharmaceutically acceptable carrier, diluent and or excipient.