| Tofacitinib is an oral JAK(Janus kinase)inhibitor used in the clinical treatment of rheumatoid arthritis by selectively inhibiting JAK1 and JAK3 kinase activity and reducing levels of various cytokines.By comparing the reported synthetic routes for tofacitinib,we choose 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine and(3R,4R)-Nbenzyl-3-methylamino-4-methylpiperidine as the key intermediates.The original route of(3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine has been reported to suffer from multiple hydrogenation reaction,strict operation condition,high production cost and methyl sulfide impurity.In this paper,we have determined the reductive amination route of 3-Amino-4-methylpyridine via 4-methyl-1-(phenylmethyl)-3-piperidone.The reductive amination reaction and chiral splitting were investigated in detail and gave(3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine in 34.4% overall yield which was higher than 30.4%yield reported before.The process route of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine was detected by using ethyl cyanoacetate as the starting material to obtain the target product in a multi-step reaction.The reaction conditions were optimized to avoid the formation of disubstituted impurities in the alkylation reaction and afforded 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine in 53.2% yield.Tofacitinib was synthesized from 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine and(3R,4R)-N-benzyl-3-methylamino-4-methylpiperidine by nucleophilic substitution reaction,debenzylation and amine-ester exchange reaction.By testing the solvent,base and reaction time in the nucleophilic substitution reaction,the production cost was reduced and the yield of the reaction was increased.In addition,the amount of catalyst used for dezincification was screened to determine the optimal reaction conditions.The amount of base in amine-ester exchange reaction was investigated and the most efficient reaction conditions were obtained.This paper provides a simple and economical process for the synthesis of tofacitinib,which has the advantages of inexpensive raw materials,simple operation and high reaction yields. |
