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Novel preparation method of tofacitinib citrate

A technology of tofacitinib and citric acid, which is applied in the field of medicine, can solve the problems of low yield, high cost, and many impurities in by-products, and achieve the effect of good fluidity and uniform particle size

Pending Publication Date: 2018-09-04
科兴生物制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] In the existing process, use N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidin-4-amine as Raw materials, react with cyanoacetate compounds under alkaline conditions to prepare tofacitinib, such as the preparation method reported in the patent document WO2007012953A2, the yield is low (about 60%), the by-product impurities are more, and the refining and purification process is complicated , the cost of obtaining high-purity refined tofacitinib citrate is relatively high

Method used

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  • Novel preparation method of tofacitinib citrate

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preparation example Construction

[0035] The invention provides a kind of preparation method of tofacitinib citrate, described method comprises steps:

[0036] (1) Add the crude product of tofacitinib intermediate into the solvent and dissolve it completely at a higher temperature (such as about 65°C), add medicinal activated carbon and activated alumina and stir for adsorption for 0-10min, then cool down to a lower temperature (such as about 30°C) ~40°C), stir and adsorb at a lower temperature for 20-50 minutes, then raise the temperature to a higher temperature (such as about 65°C), and continue to stir and adsorb for 10-40 minutes;

[0037] (2) Remove medicinal activated carbon and activated alumina by filtration, add pre-cooled alkaline aqueous solution to the filtrate, cool to 0-5°C to crystallize, wash and dry to obtain the refined product of tofacitinib intermediate;

[0038] (3) Citric acid monohydrate (C 6 h 8 o 7 ·H 2 O) Dissolve in ethanol aqueous solution, then add the refined tofacitinib inter...

Embodiment 1

[0045] Add 2.0kg of the crude product of tofacitinib intermediate (HPLC purity is about 92%) into 20L ethanol, heat to 65°C and dissolve completely, then add 200g of medicinal activated carbon and 100g of activated alumina and stir for 10min, then continue to stir and cool down to 10 ~15°C, maintain for 30min, then raise the temperature to 65°C, continue stirring for 30min, then filter while hot. Add 50L of sodium bicarbonate solution (mass fraction 0.5%) to the filtrate, cool to 0-5°C, filter after crystallization for 6 hours, wash with cold water and dry to obtain the refined product of tofacitinib intermediate, with a yield of 89.4%, HPLC purity is 99.61%.

[0046] Citric acid monohydrate (C 6 h 8 o 7 ·H 2 O) 7.4g is dissolved in 150ml ethanol aqueous solution (the volume ratio of ethanol and water is 3:2), then add 10g of tofacitinib intermediate refined product, heat and reflux until completely dissolved, cool to 35°C, and transfer the solution to ultrasonic In the p...

Embodiment 2

[0052] Add 1.0kg of the crude product of tofacitinib intermediate (HPLC purity is about 92%) into 15L ethanol, heat to 65°C and dissolve completely, then add 150g of medicinal activated carbon and 100g of activated alumina and stir for 10min, then continue to stir and cool down to 10 ~15°C, maintain for 30min, then raise the temperature to 65°C, continue stirring for 35min, then filter while hot. Add 40L of sodium bicarbonate solution (mass fraction 0.5%) to the filtrate, cool to 0-5°C, filter after crystallization for 6 hours, wash with cold water and dry to obtain the refined product of tofacitinib intermediate, with a yield of 86.3%, HPLC purity is 99.81%.

[0053] Citric acid monohydrate (C 6 h 8 o 7 ·H 2 O) 7.4g was dissolved in 200ml ethanol aqueous solution (the volume ratio of ethanol and water was 3:2), then added 10g of tofacitinib intermediate refined product, heated to reflux until completely dissolved, cooled to 35°C, and the solution was transferred to ultras...

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Abstract

The invention discloses a novel preparation method of tofacitinib citrate, and particularly provides a preparation method of tofacitinib citrate. The preparation method comprises the following steps:adding a tofacitinib intermediate crude product in a solvent, completely dissolving at a relatively high temperature, and adding medicinal activated carbon and activated aluminum oxide for stirring and adsorption; filtering to remove the medicinal activated carbon and the activated aluminum oxide, adding a pre-cooled alkaline aqueous solution in a filtrate, reducing the temperature to 0-5 DEG C for crystallization, washing and then drying to obtain a tofacitinib intermediate refined product; dissolving citric acid monohydrate in an ethanol aqueous solution, then adding the tofacitinib intermediate refined product and crystallizing to obtain the tofacitinib citrate. The novel preparation method disclosed by the invention has the benefits that hard-to-remove pigments and impurities in the tofacitinib intermediate crude product can be significantly reduced, and further, the high-purity tofacitinib intermediate refined product is obtained.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a novel preparation method of tofacitinib citrate. Background technique [0002] Tofacitinib citrate is a Janus kinase inhibitor developed by Pfizer, and its chemical name is 3-{(3R,4R)-4-methyl-3-[formazan Base-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-1-yl]-3-oxo-propionitrile citrate, the structural formula is as follows: [0003] [0004] The drug was approved by the U.S. Food and Drug Administration (FDA) in 2012 for the treatment of moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate therapy. [0005] In the existing process, use N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7-H-pyrrole[2,3-d]pyrimidin-4-amine as Raw materials, react with cyanoacetate compounds under alkaline conditions to prepare tofacitinib, such as the preparation method reported in the patent document WO2007012953A2, the yield is low (ab...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P19/02
CPCA61P19/02C07B2200/13C07D487/04
Inventor 郝志海崔宁张允王翠翠仇渡先宋先显
Owner 科兴生物制药股份有限公司
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