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Preparation method of tofacitinib intermediate

A compound, benzyl technology, applied in the field of preparation of -1-benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride, can solve the problems of high price and increased operation difficulty, and achieve The effect of improving synthesis yield, avoiding the use of dangerous reagents, and shortening process steps

Active Publication Date: 2017-06-13
苏州楚凯药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] This route also uses the expensive reducing agent 5% rhodium carbon catalyst, and uses hydrogen hydrogenation at the same time, which increases the difficulty of operation

Method used

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  • Preparation method of tofacitinib intermediate
  • Preparation method of tofacitinib intermediate
  • Preparation method of tofacitinib intermediate

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Effect test

preparation example Construction

[0029] A preparation method of a drug intermediate I of tofacitinib, the chemical structural formula is as follows:

[0030]

[0031] The preparation method is as follows: using 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine as the starting material, oxidizing alkenes to ketones by one-step method to obtain ketone compound II, and then forming ketone compound II with amines After amine compound III, use asymmetric reduction of imine to form amine, remove the trans isomer by recrystallization to obtain cis structure IV, and finally use chiral resolution to obtain the final product (3R,4R)-1-benzyl-N , 4-dimethylpiperidin-3-amine dihydrochloride I, to obtain;

[0032] The synthetic route is as follows:

[0033]

Embodiment 1

[0034] Example 1: The raw material 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine (187 mg) was dissolved in dichloromethane (10 mL), and trimethyl was added under nitrogen protection at -20°C A dichloromethane solution of silyl trifluorosulfonate (1.1 g) was added, and a catalytic amount of cyclohexanone was added, the reaction was stirred and controlled until the reaction was complete, and compound II was obtained by column chromatography. (Yield 89%).

Embodiment 2

[0035] Example 2: Add compound II (17.6g) and 50ml tetrahydrofuran to a three-necked flask in turn, protect with nitrogen, cool down to 15°C, add methylamine hydrochloride (7g) dropwise, control the temperature at 15-20°C for reaction, and control it until the reaction completely. Jump straight into the next step.

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Abstract

The invention relates to a novel preparation method of a tofacitinib intermediate and in particular to a preparation method of the tofacitinib intermediate (3R,4R)-1-benzyl-N-4-dimethyl piperidine-3-amine dihydrochloride. The preparation method comprises the following steps of: by taking 1-benzyl-4-methyl-1,2,3,6-tetrahydropyridine as an initial raw material, oxidizing olefin to form a ketone II by means of a one-step process; forming imine III with amine; applying asymmetric reduction imine to form amine; removing a trans isomer by recrystallization to obtain a cis-form structure IV; and finally, applying chiral resolution to obtain a final product (3R,4R)-1-benzyl-N-4-dimethyl piperidine-3-amine dihydrochloride I. The preparation method is creative in process, the process steps are shortened, and the synthetic yield of an asymmetric compound is greatly increased, thereby laying a solid foundation for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a tofacitinib intermediate, in particular to a preparation method of (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride. Background technique [0002] JAK / STAT is an important cytokine signaling pathway, which is related to many diseases such as blood system diseases, tumors, rheumatoid arthritis and psoriasis. Tofacitinib, a JAK inhibitor developed by Pfizer, can selectively inhibit JAK3 kinase, and was approved by the US Food and Drug Administration (FDA) for risk assessment on November 6, 2012 and Mitigation Strategies (REMS) for the treatment of adults with moderate to severe rheumatoid arthritis (RA) who are active and unresponsive to methotrexate. [0003] [0004] As an important intermediate of tofacitinib (3R,4R)-1-benzyl-N,4-dimethylpiperidin-3-amine dihydrochloride (I), the development of its synthetic process is worthy of chemical workers Research, the current investigation o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56
CPCC07D211/56
Inventor 刘现军戴益思张中剑余飞飞黄文飞
Owner 苏州楚凯药业有限公司
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