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Synthesis method for preparing intermediates of tofacitinib

A technology of tofacitinib and intermediates, applied in the field of synthesis of organic compounds, can solve problems such as danger and difficulty in scale-up production

Inactive Publication Date: 2018-10-23
甘肃皓天医药科技有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The synthetic route shown in the following formula II is reported by US6627754, and very dangerous reagent LiAlH is also used in this route 4 , it is difficult to scale up the production

Method used

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  • Synthesis method for preparing intermediates of tofacitinib
  • Synthesis method for preparing intermediates of tofacitinib
  • Synthesis method for preparing intermediates of tofacitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment one: X is a chlorine atom, X 1 is a bromine atom.

[0040]

[0041] Take 10 moles of the compound 3-bromo-4-methylpyridine and dissolve it in an aqueous solution of methylamine containing 40 moles of methylamine, then add 0.01 moles of copper powder to it, and then heat it to 150-160 degrees to react. After the raw materials disappear, stop heating , cooled to room temperature, the reaction liquid was extracted with dichloromethane, and then the organic phase was concentrated to obtain product 4 (9.5 moles), and the reaction yield was 95%.

[0042] The obtained compound 4 was dissolved in 10 times the volume of methyl tert-butyl ether, and then 19 moles of benzyl chloride was added thereto, and stirred until the reaction was complete to obtain a suspension of compound 5. Slowly add the suspension to a solution of 10 times the volume of ethanol containing 38 moles of sodium borohydride between 60 and 70 degrees. After the addition is complete, continue to ...

Embodiment 2

[0044] Embodiment two: X is a bromine atom, X 1 for the chlorine atom.

[0045]

[0046] Take 30 moles of the compound 3-chloro-4-methylpyridine and dissolve it in an aqueous solution containing 1.2 times the molar amount of methylamine, then add 0.2 moles of cuprous chloride to it, and then heat it to 140-150 degrees to react. After the raw materials disappear , stop heating, cool to room temperature, extract the reaction liquid with dichloromethane, then concentrate the organic phase to obtain product 4, and the reaction yield is 65%.

[0047] The obtained compound 4 was dissolved in 5 times the volume of dichloromethane, and then 21 moles of benzyl bromide was added dropwise thereto, and stirred until the reaction was complete to obtain a suspension of compound 5. Slowly add the suspension into an ethanol solution containing 2 times the molar amount of sodium borohydride and 10 times the volume of ethanol solution between 60-70 degrees. The reaction was quenched, the r...

Embodiment 3

[0049] Embodiment three: X is a chlorine atom, X 1 is a bromine atom.

[0050]

[0051] Take 20 moles of the compound 3-bromo-4-methylpyridine and dissolve it in an aqueous solution containing 2.0 times the molar amount of methylamine, then add 0.1 moles of copper powder to it, then heat the reaction (between 90-100 degrees), and the reaction is completed Afterwards, heating was stopped, cooled to room temperature, and the reaction solution was directly filtered to remove solids, then concentrated under reduced pressure and evaporated to dryness to obtain product 4, with a reaction yield of 70%.

[0052] Dissolve the obtained compound 4 in 2 volumes of acetone, then dropwise add 17 moles of benzyl chloride therein, stir until the reaction is complete, solid precipitates, cool and filter to obtain compound 5; then the solid compound 5 obtained above is redissolved in ethanol , the resulting solution is slowly added dropwise to an aqueous ethanol solution containing 40 moles...

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Abstract

The invention provides a novel method for synthesizing primary ring cis-4-methyl-3-methylamino-1-benzylpiperidine bis-hydrochloride of tofacitinib. The primary ring cis-4-methyl-3-methylamino-1-benzylpiperidine bis-hydrochloride is made from 3-halogenation-picoline. The novel method includes steps of catalytic Ullman coupling, 3-halogenation-picoline and benzyl halide salifying, hydroboration reagent reduction, salifying and the like to obtain target compounds. The method has the advantages of simple conditions, easily available reagents and operational safety.

Description

technical field [0001] The present invention relates to a synthetic method of an organic compound, specifically to design a method called tofacitinib [0002] The synthetic method of the intermediate of anti-rheumatoid arthritis drug, the structure of the compound and tofacitinib is shown as compound 1 and compound 2 shown in formula 1. Background technique [0003] Tofacitinib is a new anti-rheumatoid arthritis drug launched by Pfizer on August 24, 2012. Rheumatoid arthritis is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue, causing inflammation in the joints and surrounding tissue. According to the U.S. Centers for Disease Control and Prevention, approximately 1.5 million people in the U.S. suffer from rheumatoid arthritis. Badrul Chowdhury, MD, director of the Division of Pulmonary, Allergy and Rheumatology Products in the FDA's Center for Drug Evaluation and Research, said: "Tofacitinib provides a new treatment option for pa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D211/56
CPCC07D211/56C07B2200/07
Inventor 薛吉军杨博李学海王世娇其他发明人请求不公开姓名
Owner 甘肃皓天医药科技有限责任公司
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