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Preparation method of tofacitinib hydrolysis impurity

A technology for tofacitinib and impurities, which is applied in the field of drug synthesis, can solve the problems of complicated operation, difficult separation of two hydrolyzed impurities, low yield and the like, and achieves the effects of simple operation steps, short route and high reaction yield.

Pending Publication Date: 2021-03-30
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method is cumbersome to operate, and it is difficult to separate the two hydrolyzed impurities, and the yield is low, only 31.7%.

Method used

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  • Preparation method of tofacitinib hydrolysis impurity
  • Preparation method of tofacitinib hydrolysis impurity
  • Preparation method of tofacitinib hydrolysis impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Dissolve cyclo(ethylene)isopropyl malonate (17.28g, 0.12mol) in 50ml of acetonitrile, add N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl) -7H-Pyrrolo[2,3-d]pyrimidin-4-amine (24.53g, 0.10mol), stirred at room temperature until the reaction solution dropped to 0°C after the reaction was completed, and crystallized by adding 20ml of methyl tert-butyl ether to obtain Tofacitinib hydrolyzed the impurities, the yield was 87.7%, and the HPLC purity was 99.95%.

Embodiment 2

[0032] Dissolve cyclo(ethylene)isopropyl malonate (17.28g, 0.12mol) in 50ml DMF, add N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)- 7H-Pyrrolo[2,3-d]pyrimidin-4-amine (24.53g, 0.10mol), stirred at room temperature until the reaction solution dropped to 5°C after the reaction, added 30ml of acetone for crystallization to obtain tofacitinib hydrolyzed impurities , the yield was 85.5%, and the pure HPLC degree was 99.92%.

Embodiment 3

[0034] Dissolve cyclo(ethylene)isopropyl malonate (17.28g, 0.12mol) in 50ml toluene, add N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl) -7H-Pyrrolo[2,3-d]pyrimidin-4-amine (24.53g, 0.10mol), stirred at room temperature until the reaction solution dropped to 8°C after the end of the reaction, added 25ml isopropyl ether for crystallization to obtain tofacitinib The impurities were hydrolyzed, the yield was 84.1%, and the HPLC purity was 99.81%.

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a tofacitinib hydrolysis impurity. The method comprises the following steps: dissolving isopropyl malonate in an organic solvent, adding N-methyl-N-((3R,4R)-4-methylpiperidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine, conducting stirring at room temperature until the reaction is finished, and recrystallizing the reaction solution to obtain the tofacitinib hydrolysis impurity. The synthesis method provided by the invention is simple, the tofacitinib hydrolysis impurity obtainedby the method is recrystallized for separation, the purity is high, the yield is high, and the impurity compound can be used as an impurity reference substance in tofacitinib finished product detection standards.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of tofacitinib hydrolyzed impurities. Background technique [0002] Tofacitinib citrate, the chemical name is (3R,4R)-4-methyl-3-(methyl-7H-pyrrole[2,3-d]pyrimidin-4-ylamino)- β-Carbonyl-1-piperidinepropionitrile-2-hydroxy-1,2,3-propane tricarboxylate (1:1). Tofacitinib citrate is a new type of oral JAK inhibitor developed by Pfizer of the United States. It was approved by the FDA in November 2012. The trade name is Xeljanz. For the treatment of adult patients with to severely active rheumatoid arthritis, the formula is as follows: [0003] [0004] In the preparation process of tofacitinib, the N-nitrile acetylation reaction on the piperidine ring is an essential step. Considering the efficiency and cost control in actual production, the intermediate ((3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidine- 4-yl) amino] piperidin...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04Y02P20/55
Inventor 刘忠翟立海李振郑家芳
Owner LUNAN PHARMA GROUP CORPORATION
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