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Preparation method of tofacitinib citrate

A technology of tofacitinib and citric acid, applied in carboxylate preparation, organic chemistry, etc., can solve the problems of low product yield, difficult control of isomers, expensive and rare raw materials, etc.

Pending Publication Date: 2021-04-20
山东天铭医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the raw materials of this route are expensive and rare, and the operating cost is high. The final product needs to be purified from isomers, and the isomers are difficult to control, resulting in low product yields and difficult industrial production.

Method used

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  • Preparation method of tofacitinib citrate
  • Preparation method of tofacitinib citrate
  • Preparation method of tofacitinib citrate

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Embodiment Construction

[0044] The following examples provided by the present invention are only to further illustrate the technical solutions and technical effects of the present invention, rather than to limit the present invention.

[0045] 1) Preparation of Intermediate 3

[0046] Weigh 20.0g of compound 1 (90mmol), 18.3g of compound 2 (90mmol), 0.20g of glacial acetic acid and 200ml of dichloromethane, and incubate at 20-30°C for 2 hours, TLC detects that the reaction is complete, and concentrate under reduced pressure to obtain an oily intermediate 3, directly used in the next reaction;

[0047] 2) Preparation of Intermediate 4

[0048] Add 200ml of acetone and 26.3g of potassium carbonate (90mmol) to the above oil, under nitrogen protection, add 13.4g of methyl iodide (94.5mmol) dropwise at 20-30°C, after the addition is complete, keep warm for 3 hours, filter, and concentrate under reduced pressure to obtain an oil The compound is the intermediate 4, which is directly used in the next step ...

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Abstract

The invention discloses a preparation method of tofacitinib citrate. The method comprises the following steps: by taking 7-tert-butyloxycarbonyl-4-amino-7H-pyrrolo[2, 3-D]pyrimidine and 1-benzyl-4-methyl-piperidine-3-ketone as initial raw materials, carrying out condensation under a weak acidic condition, then carrying out N methylation, selective reduction, debenzylation and Boc removal, and carrying out ester exchange and citric acid salification at a high temperature to obtain the tofacitinib citrate. The method has the advantages of mild reaction conditions, simple post-treatment mode, reduction of the generation amount of hazardous wastes, environmental protection, cost saving, and facilitation of industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis medicine, and in particular relates to a preparation method of tofacitinib citrate. Background technique [0002] Tofacitinib citrate is a tyrosine kinase (JAK) family inhibitor developed by Pfizer in recent years. It is a molecular target drug and was first approved by the US FDA in November 2012. And it was approved for marketing in my country in March 2017. About 40 of the drugs have obtained clinical approval documents, and 15 domestic pharmaceutical companies are in the review and approval status. The market prospect is very broad. The drug is suitable for patients with poor response to methotrexate or active adult patients with moderately to severely active rheumatoid arthritis. The trade name is Shangjie / Xeljanz, and the chemical name is: 3-[(3R,4R)- 4-Methyl-3-[methyl-(7H-pyrrole[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile citrate, structural formula as follow...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07C51/41C07C59/265
Inventor 熊自常刘亚东李松松李晓王显帅
Owner 山东天铭医药科技有限公司
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