The Synthesis And Optimization Of Rolapitant And Betrixaban

Rolapitant is the first long-acting NK-1 receptor antagonist,with good treatment and market prospects.In September 2015 Rolapitant was reviewed and approved for listing by FDA.In this paper,the research work of synthesis Rolapitant is mainly carried out in three aspects:We get the Rolapitant by 23-step reaction and optimization of the process.Two key chiral intermediates were synthesized by phenylglycine and 3,5-bistrifluoromethylacetophenone as starting materials,respectively.The Synthesis of Rolapitant was synthesized by wittig reaction,hydrogenation reaction,Grignard reaction,olefin metathesis reaction.And the reaction conditions were optimized for each step reaction,the yield was increased and the reaction cost was reduced.The synthesis of the three chiral centers of loratadine was controlled and the optical purity was determined.In this study,the natural chiral products L-phenylglycine,(S)-CBS-H chiral catalysts,(R)-tBuSONH2 were used to control three chiral centers.And geting high yields optical purity products by means of recrystallization.We designed and synthesized the key intermediate 3-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]-5-oxo-3-oxazo lidinecarboxylic acid(2R,4S)-biphenyl-phenylmethyl ester by modifying the two docking intermediates.Thus the docking mode was changed.The reaction system of the ultra-low temperature reaction replaced by room temperature,improving the feasibility of the reaction.Betrxiaban is an oral Xa factor inhibitor,the advantages of metabolic through bile and rapid onset aroused the attention.The drug is under the phase III clinical,the market outlook is optimistic.In this study,the following research work is carried out in the synthesis of Betrixaban:Through the synthetic route of Betrixaban.and optimized the each reaction.Through the use of Raney nickel instead of platinum carbon to complete the key intermediate nitro reduction,significantly reduce costs and increase yield.The synthesis of dimethylamine formamidine structure,which is the key group of drugs,is discussed in depth,which avoids the use of high-risk reagent n-hexyl lithium and explores the high efficiency synthesis of amidine-containing intermediates,effectiveness.In this paper,the synthesis of some reaction impurities is predicted and synthesized by analyzing the reaction mechanism,and the impurities and contents in the reaction are identified and analyzed.