Study On The Synthesis Of Tofacitinib

Tofacitinib is the first inhibitor of Janus kinase approved by the US Food and Drug Administration(FDA)for use in moderate to severe rheumatoid joints that are not adequately or intolerant to methotrexate treatment inflammation.Tofaticinib is composed of 4-chloro-7H-pyrrole-[2,3-d]pyrimidine and(3R,4R)-1-benzyl-3-methylamino-4-methylpiperidine structural units.In this thesis,the synthesis of the two key intermediates has been studied:The key intermediate 4-chloro-7H-pyrrole-[2,3-d]pyrimidine was synthesized via alkylation,cyclization,chlorination,olefins double bond oxidation,SN2 nucleophilic substitution,and intramolecular cyclization reactions starting from cheap and easily available reagent dimethyl malonate.The reaction conditions and post-processing of each step are mild and easy operated.The overall yield can reach 43%.The synthesis of(3R,4R)-1-benzyl-3-methylamino-4-methyl-Piperidine is difficult due to the two chiral centers.In this thesis,1-benzyl-3-oxo-4-methyl piperidine and methylamine were used to get racemic compounds by reductive amination,then single configuration products can be obtained by chemical resolution.Two routes about the synthesis of 1-benzyl-3-oxo-4-methylpiperidine were invegested.The proposed synthesis process consists of a series of steps:starting from 3-amino-4-methylpyridine as the starting material,through acetyl protection,pyridine salt activation,boron hydride reduction,hydrolysis to get the target compound.The construction of tofacitinib from the above mentioned two structural units were investigated.Through the screening and optimization of reaction conditions,the yield and purity of the target compound were significantly higher than the reported method.