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Preparation method for tofacitinib citrate

A technology of tofacitinib and citric acid, applied in the field of drug synthesis, can solve the problems of complicated post-processing, high cost, unstable product purity and the like, and achieves the effects of high reaction yield, simple post-processing and few by-products

Inactive Publication Date: 2019-05-21
BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] For the above 4 routes, only the materials recorded in the original research patent CN1325498C are available in the market, and the rest of the materials cannot be obtained or the acquisition cost is extremely high. Obvious Disadvantages

Method used

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  • Preparation method for tofacitinib citrate
  • Preparation method for tofacitinib citrate
  • Preparation method for tofacitinib citrate

Examples

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Embodiment 1

[0045] At room temperature, 12.0Kg (35.8mol) ((3R,4R)-1-benzyl-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-D] Pyrimidin-4-yl)-amine and 1mol / L hydrochloric acid aqueous solution were added to the hydrogenation kettle, and 1.2Kg of palladium carbon with a water content of 50% was added, and hydrogenation was carried out at room temperature under 0.2-0.4MPa hydrogen pressure for 4-6 hours. After the reaction was completed, Palladium carbon was filtered off, concentrated to remove water and dried to obtain ((3R,4R)-4-methyl-piperidin-3-yl)-methyl-(7H-pyrrolo[2,3-D]pyrimidine-4 -base)-amine salt 11.1Kg, yield 97.5%.

[0046] Add the above-mentioned amine salt and 19.9Kg (130.7mol) DBU into ethanol, stir and heat up to 35°C, add 7.9Kg (69.8mol) of ethyl cyanoacetate dropwise and react for 4-8 hours. After the reaction is completed, add aqueous sodium carbonate solution to quench extinguished, stirred and cooled to crystallize, obtained tofacitinib 10.0Kg after suction filtrati...

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Abstract

The invention relates to the field of medicinal chemistry, and provides a preparation method for tofacitinib. ((3R,4R)-1-benzyl-4-methyl-piperidine-3-radical)-methyl-(7H-pyrrolo [2, 3-D] pyrimidine-4-radical)-amine is taken as a starting material, after the hydrogenation debenzylation reaction and amidation, tofacitinib is prepared, and after the tofacitinib and citric acid are salified, the tofacitinib citrate is obtained. According to the developed technology, the product quality is quite high, the purity is 99.9% or above, the content of any individual impurity is less than 0.1%, and the quality standard of tofacitinib citrate medicine as a registered active pharmaceutical ingredient is met. The hydrogenation reaction utilizes an aqueous hydrochloric acid solution as a solvent, and thehydrogenation reaction is quite safe, green and environmentally friendly.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of tofacitinib citrate. Background technique [0002] The original research company of Tofacitinib Citrate is Pfizer, and its chemical name is: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl Amino)-β-oxo-1-piperidine propionitrile citrate (1:1), trade name: XELJANZ. Tofacitinib is mainly used for adult patients with moderately to severely active rheumatoid arthritis (RA) who have insufficient efficacy or intolerance to methotrexate, and can be combined with methotrexate or other non-biological disease-modifying anti-rheumatic drug (DMARD) in combination. 2012.11.06 listed in the United States, 2013.05 in Japan, 2017.03 in China. [0003] Tofacitinib citrate has a three-dimensional structure with R, R configuration, specifically the following structure: [0004] [0005] The original research patent CN1325498C is based on ((3R,4R)-1...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 白明龙胡卫东王辉
Owner BEIJING XINLINGXIAN MEDICAL TECH DEV CO LTD
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