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Preparation method of tofacitinib citrate

A technology of tofacitinib and citric acid, applied in the field of chemical substances, can solve the problems of many side reactions, low yield, high cost of raw materials, etc., and achieve the effect of easy operation, high yield and low cost

Inactive Publication Date: 2018-08-03
南京法恩化学有限公司
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  • Abstract
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  • Application Information

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Problems solved by technology

[0004] The literature reports the synthesis methods of tofacitinib citrate and its key intermediates, but these methods have some problems such as high cost of raw materials, long reaction time, low yield, many side reactions, and potential safety hazards.

Method used

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  • Preparation method of tofacitinib citrate

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Embodiment Construction

[0025] The technical solutions in the present invention are clearly and completely described below in conjunction with the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

[0026] The present embodiment provides a kind of preparation method of tofacitinib citrate, such as figure 1 As shown, it specifically includes the following steps:

[0027] Step 1: Add 100ml of dichloromethane to the reaction flask, then add 10g of 4-chloro-7-pyrrolo[2,3-d]pyrimidine, then add 10g of triethylamine, then dropwise add 15g of (BOC) 2 O, stirred at room temperature, controlled reaction, after the reaction, concentrated the reaction solution, crystallized, filtered, washed with water, dried to obtain 18g of intermediate 1, the yield was 95%;

[0028] Step 2: Add 15g of intermediate 1 to 100ml DMF, add 25g of potassium c...

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Abstract

The invention relates to a preparation method of tofacitinib citrate, in particular to high-yield synthesis of tofacitinib citrate. The tofacitinib citrate is synthesized from raw materials including4-chloro-7-pyrrolo[2,3-d]pyrimidine, (BOC)2O, (3R,4R)-(1-benzyl-4-methylpiperidine-3-yl)methylamine-L-di-p-toluoyl tartrate, Pd / C, cyanoacetic acid and citric acid through six steps including an aminoprotection reaction, an amination reaction, a debenzylation reaction, a condensation reaction, a deprotection reaction and a salt forming reaction. The synthesis route provides the preparation methodof tofacitinib citrate, and the preparation method is high in yield, low in cost, easy to operate and suitable for industrialization.

Description

technical field [0001] The invention relates to the field of chemical substances, in particular to a preparation method of tofacitinib citrate. Background technique [0002] Tofacitinib citrate, the Chinese chemical name is 3-[(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidine- 4-yl)amino]piperidin-1-yl]-3-oxopropionitrile citrate is a new type of oral Janus kinase (JAK) inhibitor developed by Pfizer, and its inhibitory strength to JAK3 is the same as that of 2 to 5 times that of JAK1 and JAK2. The drug was approved by the U.S. FDA in November 2012 through Risk Evaluation and Mitigation Strategy (REMS). It is used for adults with moderate to severe rheumatoid arthritis (RA) who are active and have poor response to methotrexate. The trade name is For Xeljanz. Tofacitinib is different from other rheumatoid arthritis drugs that act on extracellular targets. It targets intracellular signal transduction pathways and acts on the core part of the cytokine network. In addit...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 王坤鹏陈晨张有成
Owner 南京法恩化学有限公司
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