A kind of preparation method of tofacitinib citrate

Abstract

The invention belongs to the field of medicine and chemical engineering and particularly relates to a preparation method of tofacitinib citrate. The method comprises steps as follows: 1-benzyl-4-methyl-2,6-dihydro-3-piperidone taken as a starting material is subjected to an asymmetric reduction reaction, 1-benzyl-4-methyl-3-piperidone is obtained, and (3R,4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochloride is produced under the action of a chiral catalyst; (3R,4R)-cis-1-benzyl-4-methyl-3-methylamino-piperidine dihydrochlorid and a paratoluensulfonyl chloride protection product 4-chloro-7-(methyl-4-benzenesulfonyl) pyrrolo[2,3-d]pyrimidine of 4-chloropyrrolo[2,3-d]pyrimidine are subjected to a condensation reaction, [(3R,4R)]-1-benzyl-4-methyl-piperidine-3-yl]-methyl-(7H-pyrrolo[2,3-d]pyrimidine-4-yl)-amine is obtained through deprotection, and tofacitinib citrate is obtained through debenzylation protection, an acylation reaction and citric acid salifying. The process route is short, the process cycle is short, chiral synthesis is performed by means of a catalyst, the product purity is improved, the cost is reduced, the yield is high, and the operation is simple and convenient.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of tofacitinib citrate. Background technique [0002] Tofacitinib Citrate (Tofacitinib Citrate) was developed by Pfizer of the United States and was approved by the FDA for marketing in the United States in November 2012. The product name is The preparation is a tablet with a specification of 5 mg (calculated as tofacitinib). Indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It can be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). [0003] The target molecules of the existing immunosuppressants are widely distributed in tissues, so the selectivity is poor, and pleiotropic toxic adverse reactions are likely to occur. In order to solve th...

AI Technical Summary

Problems solved by technology

[0018] Cis-(1-benzyl-4-methylpyridin-3-yl)methanamine dihydrochloride was resolved by L-di-p-toluenesulfonyl tartaric acid (L-DTTA) to obtain (3R, 4R)-(1- Benzyl-4-methylpyridin-3-yl)methanamine-L-di-p-toluenesulfonyl tartaric acid, the problem of this step reaction is that cis-(1-benzyl-4-methyl has been synthesized by 4-step reaction in the early stage Pyridin-3-yl) methylamine dihydrochloride, long steps, low yield, the product obtained is resolved through L-di-p-toluenesulfonyl tartaric acid (L-DTTA), and the resolution yield is lower, with As for the lower overall yield of chiral side chains, it is difficult to control the complete resolution of chiral isomers through resolution, resulting in low chiral purity

[0021] The route is a 5-step reaction, the route is long, the yield is low, and the use of tert-butyllithium is unstable and not suitable for scale-up production

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