Process for the preparation of alectinib

Abstract

The present invention relates to a process for preparing alectinib, or a pharmaceutically acceptable salt thereof, and to related intermediates.

1 . A process for preparing alectinib of formula I, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, the process comprising:
 a) reacting a compound of formula IV 
 
       
         
           
           
               
               
           
         
       
       with trimethylsilylacetylene in the presence of a fit base, and a catalyst optionally comprising a ligand;
 b) treating the resulting intermediate compound of formula III 
 
       
         
           
           
               
               
           
         
       
       with a second base; and
 c) converting the resulting intermediate compound of formula II: 
 
       
         
           
           
               
               
           
         
       
       into alectinib, or a pharmaceutically acceptable salt thereof, by reduction of the ethynyl group. 
     
     
         2 . The process according to  claim 1 , wherein
 the first base is an organic base;   and the second base is an inorganic base.   
     
     
         3 . The process according to  claim 1 , wherein the catalyst comprises a palladium (II) or palladium (0) catalyst, and the optional ligand comprises triphenylphosphine (PPh 3 ), 1,1′-bis(diphenylphosphino)ferrocene (dppf), 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,4-bis(diphenylphosphino)butane (dppb), tricyclohexylphosphine (PCy 3 ), 2-(dicyclohexylphosphino)biphenyl, tri-tert-butylphosphine (tBu 3 P), tBu 3 PH.BF 4 , 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, or 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos). 
     
     
         4 . The process according to  claim 2 , wherein the inorganic base comprises KOH, NaOH, Na 2 CO 3 , Cs 2 CO 3 , or K 2 CO 3 , and the base is provided in an alcohol solvent comprising methanol, ethanol, or isopropanol. 
     
     
         5 . The process according to  claim 2 , wherein the organic base comprises trimethylamine (TEA), diisopropylethylamine (DIEA), pyrrolidine, piperidine, N-methylmorpholine, tetramethylguanidine (TMG), 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), or N,N,N′,N′-tetramethylethylenediamine. 
     
     
         6 . The process according to  claim 2 , wherein the organic base is provided in a solvent comprising 1-octyl-2-pyrrolidone, 1-cyclohexyl-2-pyrrolidone, 1-(2-hydroxyethyl)-2-pyrrolidone, 1-benzyl-2-pyrrolidinone and N-methylpyrrolidone, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethylformamide selected from the group consisting of 1-octyl-2-pyrrolidone, 1-cyclohexyl-2-pyrrolidone, 1-(2-hydroxyethyl)-2-pyrrolidone, 1-benzyl-2-pyrrolidinone, or N-methylpyrrolidone, N,N-dimethylacetamide, N,N-diethylacetamide. 
     
     
         7 . The process according to  claim 3 , wherein the catalyst comprises Pd(OAc) 2 , PdCl 2 , PdCl(PhCN) 2 , PdCl 2 (MeCN) 2 , PdCl 2 (PCy 3 ) 2 , Pd(tBu 3 P) 2 , Pd(PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , PdCl 2 (dppf), PdCl 2 (dppe), PdCl 2 (dppp), PdCl 2 /XPhos, or a combination thereof. 
     
     
         8 . The process according to  claim 1 , wherein step a) is performed at a temperature of 50-100° C. 
     
     
         9 . The process according to  claim 1 , wherein the reduction is performed in a solvent comprising tetrahydrofuran. 
     
     
         10 . The process according to  claim 1 , wherein the steps a), b) and c) are performed as a one-pot process. 
     
     
         11 . The process according to  claim 2 , wherein the organic base comprises triethylamine, the palladium catalyst comprises PdCl 2 (PPh 3 ) 2 , the inorganic base comprises K 2 CO 3  provided in an alcohol solvent comprising methanol, and the reduction is performed by treatment with hydrogen in the presence of Pd/C in a solvent comprising tetrahydrofuran. 
     
     
         12 . A process for preparing alectinib of formula I, 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, the process comprising: 
         a) reacting a compound of formula IV 
       
       
         
           
           
               
               
           
         
       
       with trimethylsilylacetylene in the presence of an organic base, and a palladium catalyst optionally comprising a ligand;
 b) treating the crude product from step a) with an inorganic base; and 
 c) treating the crude product from step b) with hydrogen after addition of Pd/C. 
 
     
     
         13 . The process according to  claim 12 , wherein, in step a), the base comprises triethylamine, the palladium catalyst comprises PdCl 2 (PPh 3 ) 2 , PdCl 2 (dppf), PdCl 2 /XPhos, or a combination thereof, and the temperature is 70-90° C., and in step b), the base comprises K 2 CO 3  and the reaction is performed in the presence of an alcohol solvent. 
     
     
         14 - 16 . (canceled) 
     
     
         17 . Alectinib or a pharmaceutically acceptable salt thereof prepared by the process according to  claim 1 . 
     
     
         18 . Alectinib or a pharmaceutically acceptable salt thereof prepared by the process according to  claim 12 . 
     
     
         19 . A process for preparing alectinib hydrochloride, the process comprising contacting the alectinib according to  claim 17  with a solvent to form a solution or a suspension, adding hydrochloric acid to the solution or the suspension, and isolating the alectinib hydrochloride. 
     
     
         20 . A process for preparing alectinib hydrochloride, the process comprising contacting the alectinib according to  claim 18  with a solvent to form a solution or a suspension, adding hydrochloric acid to the solution or the suspension, and isolating the alectinib hydrochloride. 
     
     
         21 . Alectinib hydrochloride prepared by the process according to  claim 19 . 
     
     
         22 . Alectinib hydrochloride prepared by the process according to  claim 20 .