Process Development For The Synthesis Of Vismodegib

Vismodegib was jointly developed by Genentech and Curis,approved by the FDA in January 2012 for the treatment of laBCC or mBCC for which surgery or radiation cannot be utilized.This is the first drug ever approved for the treatment of BCC,and its process development is of great significance.This paper summed up a total of 12 synthetic routes,analyzed the steps,reaction condition,workup procedure,cost,and yield of each route detailly.The key structure of the synthesis of Vismodegib is 2-phenylpyridine,which is mostly prepared using a coupling reaction in the reported routes.However,anhydrous and oxygen-free conditions,palladium metal reagents are required in coupling reaction,limiting its industrial application.Therefore,we intend to use other methods to construct 2-phenylpyridine.It is found that the study of cyclization of acetophenone constructing 2-phenylpyridine has made great progress in recent years.Based on the above,we design a novel synthetic route by starting with condensation reaction of 2-chloro-4-(methylsulfonyl)benzoic acid with m-aminoacetophenone.Followed by cyclization reaction and chlorination affording the final product.This route was completed and key parameters(solvent,temperature,the amount of 1,3-propanediamine,copper catalyst type,and acid species)in the route were optimized,and the optimum process parameters were determined.Due to the poor solubility of intermediate ? in most common solvents,the optimized solvent is NMP.NMP is a high-boiling point solvent and workup procedure is not easy.In addition,2-chloro-4-(methylsulfonyl)benzoic acid is the largest portion of raw material cost,and the cyclization have lower yield compared with the other steps.Thus,we continue to adjust the route.With m-aminoacetophenone as the starting material,the first cyclization with 1,3-propanediamine,and then condensed,chlorinated to give the final product.The key parameters(solvent,the amount of 1,3-propanediamine,and the amount of copper catalyst)in the cyclization were optimized,and the optimum process parameters were determined.In the course of the project,the original research company published a new route.The 2-phenyl pyridine structure in the route is also prepared by cyclization of the acetophenones.This reaction has a high yield and the post-treatment is simple.We draw on the advantages of using a pyrimidine chloride salt for the cyclization of intermediate III.The key parameters(the amount of pyrimidine chloride salt and solvent,temperature)in the cyclization were optimized,and the optimum process parameters were determined.The purity of final product was more than 99%determined by HPLC and a preliminary impurity analysis was completed.Through the above studies,we designed and completed two new Vismodegib process routes.The key step in the first route is cyclization reaction with acetophenones and 1,3-propanediamine.The route is relatively novel and the relevant patent has been applied.Compared with the reported routes,the second route have the advantages of low cost,mild reaction conditions and not using palladium reagent,which have the potential of industrial application and the patent is drafting.