GB2560903A — New synthetic path to pharmaceutically acceptable vismodegib

USPTO Abstract

A process for the preparation of Vismodegib (2-chloro-N-(4-chloro-3-(pyridine-2-yl)-4-(methylsulfonyl)-benzamide) (5) characterised in that the process at least comprises the steps of preparing 2-(2-chloro-5-nitrophenyl)-pyridine (5) via nitration of 2-(2-chlorophenyl)-pyridine (1) in the presence of nitric acid; reducing Compound (2) to give 4-chloro-3-(pyridine-2-yl)-aniline (3); reacting (3) with 2-chloro-4-(methylsulfonyl)benzoyl chloride (4) to give Compound (5). The process preferably further comprises various synthetic processes of preparing Compound 1 from Compound (9) via Compounds (6)-(8); or Compound (16) via Compound (15); or the combination of Compounds (13) and (14). The preparation of (7) from (6) is preferably performed in the presence of dimethylformamide (DMF), dichloromethane (DCM), TiCl4 and triethylamine (Et3N). The preparation of (1) from (9) is preferably performed in the presence of a polar aprotic solvent and a base. The preparation of (9) from (8) is preferably performed in the presence of 4 molar equivalents of N-Chlorosuccinamide. The preparation of (1) from (13) and (14) is preferably conducted in boiling acetic acid anhydride ((Ac)2O.) Pharmaceutical compositions comprising Vismodegib are also disclosed, including use of the compositions as oral dosage forms and/or in the treatment of basal-cell carcinomas.