Processes and intermediates for preparing a medicament

Abstract

Disclosed is a process for the preparation of the following compounds: where R 1 , R 1a and R 2a have the definitions in the description, as well as a process to prepare other intermediates that may be useful to synthesise downstream products, especially compounds that are useful as medicaments, for instance Bruton's tyrosine kinase (Btk) inhibitors such as ibrutinib. Also disclosed are other processes, other intermediates and compounds per se.

1 . A process for the preparation of a compound of formula I, 
       
         
           
           
               
               
           
         
         or a derivative thereof, wherein 
         R 1  represents a nitrogen protecting group; 
         R 1a  represents —CN, —C(O)OR 1b  or —C(O)N(R 1c )(R 1d ); 
         R 1b , R 1c  and R 1d  each independently represent C 1-6  alkyl, aryl or heteroaryl; 
         R 2a  represents:
 (i) phenyl substituted at the 4-position with halo or —O—R 2b ; or 
 (ii) hydrogen; 
 
         R 2b  represents hydrogen or phenyl; 
         which process comprises reaction of a compound of formula II, 
       
       
         
           
           
               
               
           
         
         or a derivative thereof, wherein 
         R 1a  and R 2a  are as defined above; 
         X 1  represents a suitable leaving group, 
         with a compound of formula III, 
       
       
         
           
           
               
               
           
         
         or a derivative thereof, wherein R 1  is as defined above. 
       
     
     
         2 . A process for the preparation of a compound of formula I as claimed in  claim 1  wherein the process comprises preparation of the following compound of formula (I): 
       
         
           
           
               
               
           
         
         or a derivative thereof, wherein R 1  is as defined in  claim 1 , which process comprises reaction of the following compound of formula (II), 
       
       
         
           
           
               
               
           
         
         or a derivative thereof, with the following compound of formula III, 
       
       
         
           
           
               
               
           
         
         or a derivative thereof. 
       
     
     
         3 . A process for the preparation of a compound of formula (IVA), which process comprises conversion of a compound of formula (I) as defined in  claim 1  to a compound of formula (IVA) (and, in particular, comprises a process for the preparation of a compound of formula (I) as defined in  claim 1  followed by conversion to a compound of formula (IVA), 
       
         
           
           
               
               
           
         
         or a derivative (including isomer), wherein X 2  represent —OH or —NH 2 , and R 1  and R 2a  are as defined in  claim 1 . 
       
     
     
         4 . A process for the preparation of a compound of formula (IV), 
       
         
           
           
               
               
           
         
         or a derivative thereof, wherein R 1  is as hereinbefore defined, which process comprises conversion of a compound of formula (I) as defined in  claim 2  by (and, in particular, comprises a process for the preparation of a compound of formula (I) as claimed in  claim 1  followed by) reaction with either:
 (i) formamide (HCONH 2 ); 
 (ii) formamidine or a formamidine salt H—C(═NH)—NH 3   + X − , wherein X −  represents a suitable counterion, such as a halide (e.g. Cl − ) or an oxy anion (e.g. acyl-O − ), so forming for example formamidine HCl or formamidine acetate or the like; 
 (iii) alkyl (e.g. ethyl) formimidate, or a salt thereof, such as ethyl formimidate HCl; 
 (iv) ethylorthoformate followed by ammonium acetate. 
 
       
     
     
         5 . A process as claimed in  claim 3 , wherein the reaction is with (ii) a formamidine salt in which the counterion is a halide or oxygen-based anion. 
     
     
         6 . A process as claimed in any one of  claim 5 , wherein the reaction is performed at a temperature of below 160° C., for instance between 100° C. and 140° C. 
     
     
         7 . A compound of formula (III), characterised in that it has an ee of greater than 50%. 
     
     
         8 . A compound of formula (I), (II) or (IVA) (or derivatives thereof) as defined in  claim 1 . 
     
     
         9 . A process for the preparation of ibrutinib: 
       
         
           
           
               
               
           
         
         which process comprises either:
 a process for the preparation of a compound of formula (I) as defined in  claim 1  or  claim 2 , followed by conversion to ibrutinib; 
 a process for the preparation of a compound of formula (IVA) or (IV) as defined in any one of  claims 2  to  6 , followed by conversion to ibrutinib, for example by deprotection (i.e. removal of the R 1  group) followed by acylation with acryl chloride; and/or 
 a resolution process for the preparation of a compound of formula (III) as defined in  claim 1 , followed by conversion to ibrutinib. 
 
       
     
     
         10 . A use of a compound of formula (I), (IVA), (IV) and/or (III) (or derivatives thereof) as defined in  claim 1  as intermediates in the preparation of ibrutinib. 
     
     
         11 . A process for the preparation of a pharmaceutical formulation comprising ibrutinib, which process comprises bringing into association ibrutinib (or a pharmaceutically acceptable salt thereof), which is prepared as claimed in  claim 9 , with (a) pharmaceutically acceptable excipient(s), adjuvant(s), diluents(s) and/or carrier(s). 
     
     
         12 . A compound of formula I, 
       
         
           
           
               
               
           
         
         or a derivative thereof, wherein 
         R 1  represents a nitrogen protecting group; 
         R 1a  represents —CN, —C(O)OR 1b  or —C(O)N(R 1c )(R 1d ); 
         R 1b , R 1c  and R 1d  each independently represent C 1-6  alkyl, aryl or heteroaryl; 
         R 2a  represents:
 (iii) phenyl substituted at the 4-position with halo or —O—R 2b ; or 
 (iv) hydrogen; 
 
         R 2b  represents hydrogen or phenyl. 
       
     
     
         13 . A compound as claimed in  claim 12  which is represented by the following compound of formula (I): 
       
         
           
           
               
               
           
         
         or a derivative thereof. 
       
     
     
         14 . A compound as claimed in  claim 13  where R 1  represents Boc, Bn or CBz. 
     
     
         15 . A compound as claimed in  claim 14  where R 1  represents Bn (i.e. “benzyl”). 
     
     
         16 . A compound of formula III, 
       
         
           
           
               
               
           
         
         or a derivative thereof, characterised in that it has an ee of greater than 50%; 
         and wherein R 1  represents a nitrogen protecting group. 
       
     
     
         17 . A compound as claimed in  claim 16  wherein R 1  represents Boc, Bn or Cbz. 
     
     
         18 . A compound as claimed in  claim 17  wherein R 1  represents Bn (i.e. “benzyl”).