Method for preparing key intermediate of Tofacitinib

A technology of tofacitinib and intermediates, which is applied in the field of preparation of key intermediates of tofacitinib, can solve the problems of unqualified substances and difficult removal, and achieve low cost, optimized production process and high yield Effect

Inactive Publication Date: 2019-07-09
SHANDONG XINHUA PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This scheme is easy to produce the perhydrogenated impurity 1 mentioned in the CN104926816A patent, but this impurity is difficult to remove because it is very similar to the structure of compound I
Moreover, this impurity will also participate in the follow-up condensation reaction with ethyl cyanoacetate, and be converted into tofacitinib perhydrocitrate, i.e. impurity 2, thereby causing the related substances of the finished product to be unqualified

Method used

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  • Method for preparing key intermediate of Tofacitinib
  • Method for preparing key intermediate of Tofacitinib
  • Method for preparing key intermediate of Tofacitinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] Embodiment 1, the preparation of compound I

[0013] Add 100g of compound II, 400mL of absolute ethanol, 45g of Pd / C (10%), and 89g of ammonium formate to a 1L reaction flask, and heat in an oil bath to control the temperature of the system at 50°C ± 2°C; TLC detects the reaction progress, After the reaction is complete, cool down to room temperature, filter, and distill the filtrate under reduced pressure to obtain a white flocculent solid. Add 600 ml of dichloromethane to the solid until the solid is completely dissolved. The dichloromethane layer is washed three times with purified water (400 ml), and washed with anhydrous Dry over sodium sulfate and filter. The solvent of the filtrate was concentrated to 1 / 10 of the original volume, and then the concentrated solution was added dropwise to 1000ml of cyclohexane, a white solid was precipitated, and 59.2g of a white solid was obtained by filtration, with a purity of 97.8% and a yield of 81%.

Embodiment 2

[0014] Embodiment 2, the preparation of compound I

[0015] Add 100g of compound II, 600mL of absolute ethanol, 75g of Pd / C (10%), 150g of ammonium formate, and heat in an oil bath to control the temperature of the system at 70°C ± 2°C; After the reaction is complete, cool down to room temperature, filter, and distill the filtrate under reduced pressure to obtain a white flocculent solid. Add 600 ml of dichloromethane to the solid until the solid is completely dissolved. The dichloromethane layer is washed three times with purified water (400 ml), and washed with anhydrous Dry over sodium sulfate and filter. The solvent of the filtrate was concentrated to 1 / 10 of the original volume, and the concentrated solution was added dropwise to 1000 ml of cyclohexane, a white solid was precipitated, and 59.9 g of a white solid was obtained by filtration, with a purity of 98.9% and a yield of 82%.

Embodiment 3

[0016] Embodiment 3, the preparation of compound I

[0017] Add 100g of compound II, 1000mL of absolute ethanol, 150g of Pd / C (10%), ammonium formate 238, and heat in an oil bath to control the temperature of the system at 80°C ± 2°C; TLC detects the reaction progress. After the reaction is complete, cool down to room temperature, filter, and distill the filtrate under reduced pressure to obtain a white flocculent solid. Add 600 ml of dichloromethane to the solid until the solid is completely dissolved. The dichloromethane layer is washed three times with purified water (400 ml), and washed with anhydrous Dry over sodium sulfate and filter. The solvent of the filtrate was concentrated to 1 / 10 of the original volume, and then the concentrated solution was added dropwise to 1000 ml of cyclohexane, a white solid was precipitated, and 60.5 g of a white solid was obtained by filtration, with a purity of 99.1% and a yield of 82.8%.

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Abstract

The invention provides a method for preparing a key intermediate (compound I) of Tofacitinib. The key intermediate of Tofacitinib is prepared through subjecting a compound II, which serves as a starting raw material, with a reaction with ammonium formate in the presence of a catalyst. The method for synthesizing the key intermediate of Tofacitinib-compound I, provided by the invention, has the aimof being applicable to industrial production and high-selectivity preparation. Through changing an experimental method, the generating of superhydrogenated impurities is avoided while operations canbe suitable for industrialization, so that the quality of the compound I can be controllable, and the quality of a finished product is better.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of a key intermediate of tofacitinib. Background technique [0002] Tofacitinib citrate, also known as Tofacitinib citrate, is an orally effective protein tyrosine kinase (JAK) inhibitor developed by Pfizer Corporation of the United States. On November 6, 2012, the FDA approved its tablet listing for adult patients with moderately to severely active rheumatoid arthritis who have insufficient response or intolerance to methotrexate treatment. The trade name is Xeljanz, and the dose is 5 mg twice a day. [0003] Rheumatoid arthritis is an autoimmune disease mainly characterized by chronic inflammation of joint synovium. Highly selective JAK inhibitors have become a hotspot in the development of drugs for the treatment of autoimmune diseases. As the first JAK inhibitor that can be taken orally, tofacitinib may become another new starting point in the devel...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 商艳梅王世营张滨
Owner SHANDONG XINHUA PHARMA CO LTD
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