Preparation method of tofacitinib citrate starting material

Abstract

The invention discloses a synthesis method of a tofacitinib citrate starting material N-((3R, 4R)-4-methyl-1-benzyl-3-piperidyl)-N-methyl-7-tolylsulfonyl-7H-pyrrolo[2,3-D]pyrimidine-4-amine(I). The method comprises the specific steps that 4-methylpyridine is adopted as the starting material to be subjected to nucleophilic substitution with benzyl chloride to obtain 4-methyl-1-benzyl-pyridinium chloride, a reduction reaction is performed under the effect of sodium borohydride, a hydroboration-oxidation reaction is performed, hydroxyl oxidation is performed, two chiral centers are introduced in a reductive amination stereoselectivity mode, splitting is performed through cheap chiral acid (L-DTTA) easy to obtain to obtain an optically pure intermediate body (3R, 4R)-(1-benzyl-4-methyl-piperidine-3-yl)-methyl amine, and finally, the intermediate body and 4-chloropyr are condensed to obtain the tofacitinib citrate starting material. The whole method is easy to implement and low in cost, raw materials are easy to obtain, and aftertreatment is easy. The formula is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a starting material N-((3R,4R)-4-methyl-1-benzyl-3- The preparation method of piperidinyl)-N-methyl-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidin-4-amine. Background technique [0002] Tofacitinib is a drug for the treatment of rheumatoid arthritis developed by Pfizer. The trade name is Xeljanz, which belongs to a Janus kinase inhibitor and is used for moderate to severe active rheumatoid arthritis who have insufficient response or intolerance to methotrexate treatment Arthritis in adults. N-((3R,4R)-4-Methyl-1-benzyl-3-piperidinyl)-N-methyl-7-p-toluenesulfonyl-7H-pyrrolo[2,3-D]pyrimidine -4-amine is the key starting material for the synthesis of tofacitinib citrate. [0003] Pfizer announced a preparation route in patent WO2007012953 (see route 1). The preparation method is to use (4-methylpyridin-3-yl) methyl carbamate (1) as the starting material, re...

AI Technical Summary

Problems solved by technology

Use a large amount of 2-methyltetrahydrofuran in the first step reaction of this route, this solvent is expensive, and production cost increases

In the second step of catalytic hydrogenation, expensive chiral catalyst rhodium is used, which makes it difficult to realize industrial production

Lithium aluminum hydride is used as a reducing agent in the third step of the reaction. This reagent is easily decomposed by moisture, which is inconvenient for transportation and storage. It will also cause a large amount of industrial wastewater and increase the pressure on environmental protection.

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