A kind of preparation method of amorphous tofacitinib citrate

A technology of tofacitinib and citric acid, which is applied in the field of pharmacy, can solve the problems of cumbersome operation, many impurities in the product, and reduced product purity and quality, and achieve the effects of simple preparation method, good stability, and low cost

Inactive Publication Date: 2015-08-12
BEIJING PHARMA GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The preparation method is relatively cumbersome to operate, and there are many impurities in the obtained product, including impurities such as tofacitinib acetate, which reduces the purity and quality of the product

Method used

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  • A kind of preparation method of amorphous tofacitinib citrate
  • A kind of preparation method of amorphous tofacitinib citrate
  • A kind of preparation method of amorphous tofacitinib citrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: Preparation of amorphous tofacitinib citrate (ethanol-water system) by precipitation method

[0028] Add 5g of tofacitinib citrate into the reaction flask, add 20mL of ethanol, heat to 30-35°C to completely dissolve the solid, add the solution to 20mL of 15-25°C water, and stir at 15-25°C The suspension was filtered for about 16 hours, the obtained solid was washed with ethanol / water (volume ratio 1:1), and air-dried at 60°C to constant weight to obtain 4.5 g of amorphous tofacitinib citrate with a yield of 95 %, HPLC analysis purity is 99.6%.

Embodiment 2

[0029] Example 2: Preparation of amorphous tofacitinib citrate (methanol-ethyl acetate system) by precipitation method

[0030] Add 50g of tofacitinib citrate into the reaction flask, add 100mL of methanol, heat to 30-35°C to completely dissolve the solid, add the solution to 50mL of ethyl acetate at 25-30°C, and heat at 25-30°C The resulting suspension was stirred at low temperature for about 20 hours, filtered, the obtained solid was washed with methanol / ethyl acetate (volume ratio 2:1), and air-dried at 60°C to constant weight to obtain 45.8 g of amorphous tofacitinib citrate , the yield was 91.6%, and the HPLC analysis purity was 99.7%.

Embodiment 3

[0031] Embodiment 3: Preparation of amorphous tofacitinib citrate by spray drying method

[0032] 50 g of tofacitinib citrate was dissolved in 100 mL of methanol at about 30-35° C., and the solution was spray-dried at a flow rate of about 2.5 ml / min at 30° C. to 35° C. in a nitrogen flow of 600 Nl / h. The substance was recovered from the receiver, and the obtained solid was air-dried at 60°C to constant weight to obtain 46.8 g of amorphous tofacitinib citrate, with a yield of 93.6% and a purity of 99.5% by HPLC analysis.

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Abstract

The invention provides a preparation method for amorphous tofacitinib citrate. The preparation method is simple, can easily obtain high-purity amorphous tofacitinib citrate, and is suitable for industrial application. The preparation method includes the following steps: under the temperature range between 30 DEG C and 50 DEG C, organic solvent is used for dissolving tofacitinib citrate, so that solution is produced, water which is 15 DEG C to 25 DEG C is added into the solution, so that precipitate is produced, the precipitate is put in the environment of 15 DEG C to 25 DEG C for 4 to 24 hours, and the amorphous tofacitinib citrate is then recovered.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a preparation method of amorphous tofacitinib citrate. Background technique [0002] The chemical formula of tofacitinib citrate is 3-{(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piper Pyridin-1-yl}-3-oxopropionitrile citrate, whose structural formula is shown in formula I, is a Janus kinase (JAKs) inhibitor developed by Pfizer. On November 6, 2012, the U.S. Food and Drug Administration (FDA) approved the listing of tofacitinib citrate (Xeljanz) for moderately to severely active rheumatoid joints that have insufficient response or intolerance to methotrexate treatment Treatment of adult patients with RA. [0003] [0004] Formula I [0005] Patent WO2012135338 discloses a method for preparing amorphous tofacitinib citrate, which mainly involves first salting tofacitinib free base and acetic acid to obtain tofacitinib acetate, and then tofacitinib Dissolve acetate...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04
Inventor 李日东陈国东杨琰
Owner BEIJING PHARMA GRP CO LTD
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