Bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate synthesis method

Abstract

The present invention relates to a novel preparation method of a tofacitinib intermediate bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate. According to the preparation method, 3-amino-4-methyl piperidine is adopted as a starting raw material, is subjected to a N-methoxycarbonylation reaction under the sodium hydride effect, and is subjected to a catalytic hydrogenation reaction, a nucleophilic substitution reaction, an amide reduction reaction under the red aluminum effect, and L-di-p-toluyl tartaric acid (L-DTTA) chiral splitting so as to finally prepare the target compound bis-(3R,4R)-1-benzyl-N,4-dimethyl piperidin-3-amine L-di-p-toluyl tartrate. The process of the present invention has characteristics of further existing process improving, simple operation, easy post-treatment, high yield, and low cost.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, in particular to an intermediate bis-(3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine L of a JAK3 kinase inhibitor tofacitinib -The preparation method of di-p-toluoyl tartrate. Background technique [0002] Bis-(3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine L-di-p-methylbenzoyl tartrate is an important intermediate in the synthesis of the JAK3 kinase inhibitor tofacitinib body. Tofacitinib is a class of oral drugs developed by Pfizer (Pfizer) for the treatment of rheumatoid arthritis. It was approved for marketing by the FDA in November 2012 under the trade name Xeljanz. The preparation of this product has been reported in the literature at home and abroad, such as the synthesis method provided in the literature Organic Process Research & Development, 2005, 9, 51-56 and patent WO 200829237: [0003] [0004] In the first step of the method, 3-amino-4-picoline is insoluble in 2-methy...

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Problems solved by technology

[0004] In the first step reaction of this method, 3-amino-4-picoline is insoluble in 2-methyltetrahydrofuran, and the heterogeneous reaction causes the reaction to require a large amount of solvent, and the solvent is expensive and the production cost increases

In the third step reaction, lithium aluminum hydride is used as reducing agent to obtain monomethylated products of primary amines. On the one hand, lithium aluminum hydride is active in nature and is easily decomposed by moisture, which is inconvenient for transportation and storage; on the other hand, lithium aluminum hydride The usage amount should be more than 3 times, the cost of the catalyst itself will increase, and a large amount of industrial wastewater will be generated when excessive lithium aluminum hydride is processed; moreover, the reduction reaction requires THF to reflux for more than 3 hours, the reaction conditions are severe, and the reaction time is long

The whole reaction route is unsatisfactory in terms of safety, cost control and environmental protection

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