Method for preparing Tofacitinib citrate

A technology of tofacitinib and citric acid, applied in the field of medicine, can solve the problems of forming many by-products, unfavorable to industrialized production, hindering domestic industrialized production of tofacitinib citrate and the like

Active Publication Date: 2018-10-12
科兴生物制药股份有限公司
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Problems solved by technology

[0007] However, the preparation of tofacitinib citrate mainly uses N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H-pyrrole[2,3-d]pyrimidine- 4-amine is used as a raw material, and it is reacted with cyanoacetic acid or its esters in the next step under basic catalytic conditions to prepare tofacitinib. According to literature reports, the yield of this preparation method is lower than 60%, and the reaction time is long, forming by-products More, need column chromatography purification, not conducive to industrial production; more attention should be paid to the use of N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H- The one-step reaction of pyrrolo[2,3-d]pyrimidin-4-amine and cyanoacetate compounds to prepare tofacitinib has been protected by international and domestic patents, which hinders the domestic industrialization of tofacitinib citrate in the future Production
And N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine with a purity of 95% is on the market The price is as high as 3900 yuan / g, which is expensive and difficult to meet the requirements of industrial mass production

Method used

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  • Method for preparing Tofacitinib citrate
  • Method for preparing Tofacitinib citrate

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preparation example Construction

[0029] In order to solve the above problems, the present invention provides a preparation method of tofacitinib citrate, comprising the following steps:

[0030] a. N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine hydrochloride was added to the In a mixed solvent of methyl sulfoxide and purified water, react in the presence of alkali metal hydroxide to obtain N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl] -7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0031] b. N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine with cyanoacetylating reagent in catalyst Under the catalysis of , the reaction is carried out in a solvent, after the reaction is completed, a weakly basic inorganic salt solution is added and stirred for 8 to 12 hours to precipitate, filter and dry to obtain a crude product of tofacitinib; the catalyst is 1-(3-dimethylformaldehyde) A mixture of aminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole and N...

Embodiment 1

[0067] Embodiment 1 provides a kind of preparation method of tofacitinib citrate, comprising the following steps:

[0068] a. Add 10kg of N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidine-4-amine salt to the reactor acid salt, 30kg dimethyl sulfoxide, 20L purified water, 1.5kg sodium hydroxide, heat up to 70°C; after the reaction is completed, stir and crystallize for 2h, suction filtration, and dry to obtain product a; the obtained product a is used for the reaction In the kettle, add 50kg of absolute ethanol, heat to 60°C until the product a is completely dissolved, add 0.5kg of medicinal charcoal for decolorization for 15min; filter while hot, collect the filtrate, cool to 10°C, stir and crystallize for 2h, suction filtration, dry, to obtain the N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0069] b. add N-[(3R,4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine to the reactor, 20L dichlorometha...

Embodiment 2

[0072] Embodiment 2 provides a kind of preparation method of tofacitinib citrate, comprising the following steps:

[0073] a. Add 10kg of N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidine-4-amine salt to the reactor acid salt, 50kg of dimethyl sulfoxide, 30kg of purified water, 2kg of sodium hydroxide, and the temperature was raised to 70 ° C; after the reaction was completed, stirring and crystallization for 2h, suction filtration, and drying to obtain product a; the obtained product a was as the reaction kettle Add 50kg of absolute ethanol, heat to 60°C until the product a is completely dissolved, add 0.5kg of medicinal charcoal for decolorization for 15min; filter while hot, collect the filtrate, cool down to 10°C, stir and crystallize for 2h, suction filtration, and dry to obtain The N-methyl-N-[(3R,4R)-4-methylpiperidin-3-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

[0074] b. add N-[(3R,4R)-4-methylpiperidin-3-yl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-...

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Abstract

The invention provides a method for preparing Tofacitinib citrate. The method comprises the steps of hydrochloric acid removal, amidation reaction, salt forming and the like. According to the method,the cost is low, the operation is simple and convenient, and the obtained product is high in purity, so that the method is applicable to industrial large-scale production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a preparation method of tofacitinib citrate. Background technique [0002] Tofacitinib citrate, chemical name is 3-(3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-1-yl) ) amino)piperidin-1-yl)-3-oxypropionitrile citrate (1:1), molecular formula: C 16 H 20 N 6 O.C 6 H 8 O 7 , molecular weight: 504.5, CAS: 540737-29-9. It is white to off-white crystalline powder, easily soluble in dimethyl sulfoxide, slightly soluble in 0.1mol / L hydrochloric acid, slightly soluble in water and methanol, and almost insoluble in acetonitrile. [0003] Unlike most other current RA therapeutics that mainly act on extracellular targets, tofacitinib citrate targets intracellular signal transduction pathways and acts at the core of the cytokine network. The inhibitory intensity of tofacitinib on JAK3 was 5-100 times that of JAK1 and JAK2. Tofacitinib is the first drug developed for the tre...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/519A61P19/02
CPCA61P19/02A61K31/519C07D487/04
Inventor 崔宁郝志海张允刘海岷郭超任世平王翠翠仇渡先
Owner 科兴生物制药股份有限公司
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