Refining method for tolfirinib citrate compound

A technology of tofacitinib and refining method, which is applied in the field of refining tofacitinib citrate compound, can solve the problems of reducing product purity and quality, low yield, etc., and achieves reduced losses, good product purity and excellent reaction conditions mild effect

Active Publication Date: 2018-12-14
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method reduces the purity and quality of the product, and the yield is not high

Method used

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  • Refining method for tolfirinib citrate compound
  • Refining method for tolfirinib citrate compound
  • Refining method for tolfirinib citrate compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Preparation of Tofacitinib Citrate Crude Product

[0022] Add 31.2g of tofacitinib crude product (purchased from Estel (Chengdu) Biopharmaceutical Co., Ltd.) into a 250mL reaction bottle and dissolve in 90mL of acetone / n-propanol mixed solvent (acetone / n-propanol=1.5 / 1, v / In v), heat to 75-80°C, stir to dissolve, dissolve 22.1g of citric acid monohydrate and 10mL of mixed solvent, then slowly add it dropwise into the reaction bottle, keep warm and stir for 2h, cool down to 15-20°C, Continue to stir for 1-2 hours, filter, wash the filter cake with a solvent, and dry it under vacuum at 40°C for 8 hours to obtain 47.6g, with a yield of 94.3%, a purity of 94.89% (detected by HPLC), a maximum of 1.71%, and a total of 4.35%. .

Embodiment 2

[0024] Preparation of Tofacitinib Citrate Crude Product

[0025] In a 250mL reaction bottle, 31.2g of tofacitinib crude product (purchased from Nanjing Elsa Biotechnology Co., Ltd.) was dissolved in 90mL of acetonitrile / acetone mixed solvent (acetonitrile / acetone=1 / 1, v / v), heated to 75-80°C, stir to dissolve, dissolve 31.5g citric acid monohydrate and 10mL mixed solvent, then slowly add dropwise to the reaction bottle, keep stirring for 2 hours, cool down to 15-20°C, continue stirring for 1-2 hours, After filtering, the filter cake was washed with a solvent, and dried under vacuum at 50°C for 10 h to obtain 47.2 g, with a yield of 93.7%, a purity of 94.11% (HPLC detection), a maximum single impurity of 1.92%, and a total impurity of 3.95%.

Embodiment 3

[0027] Preparation of Tofacitinib Citrate Crude Product

[0028] Add 31.2g of tofacitinib crude product (purchased from Estel (Chengdu) Biopharmaceutical Co., Ltd.) into a 250mL reaction bottle and dissolve in 90mL n-propanol / acetonitrile mixed solvent (n-propanol / acetonitrile=1 / 1, v / In v), heat to 75-80°C, stir to dissolve, dissolve 25.2g of citric acid monohydrate and 10mL of mixed solvent, then slowly add it dropwise into the reaction bottle, keep warm and stir for 1h, cool down to 15-20°C, Stirring was continued for 2 h, filtered, the filter cake was washed with a solvent, and dried under vacuum at 50° C. for 8 h to obtain 47.4 g, with a yield of 94.1%, a purity of 95.19% (by HPLC detection), a maximum single impurity of 1.63%, and a total impurity of 3.53%.

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Abstract

The invention provides a refining method for a tofartinib citrate compound. The method comprises the following steps: preparing a tofartinib citrate crude product by a tofartinib crude product and citric acid monohydrate; adding a prepared mixed solvent, heating and stirring the mixture to be completely dissolved to obtain a clear solution, adding activated carbon, performing keeping warm and stirring, performing filtering, cooling a filtrate and performing recrystallization, performing filtering, washing a filter cake, and performing vacuum drying to obtain a tofatinib citrate refined product. The refining method has simple operation and high yield, the purity of tofartinib citrate reaches 99.93% or more, the maximum single impurity content is controlled to be 0.06% or less, and the totalimpurity content is controlled to be within 0.08%.

Description

technical field [0001] The invention belongs to the technical field of medicine purification, and relates to a method for refining tofacitinib citrate compound. Background technique [0002] Tofacitinib citrate, the 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, on November 6, 2012, the U.S. Food and Drug Administration (FDA) and Pfizer jointly announced that Torfa citrate Tofacitinib is approved for adult patients with moderately to severely active rheumatoid arthritis (RA) who have insufficient response or intolerance to methotrexate treatment. Tofacitinib is the first drug developed for the treatment of rheumatoid arthritis, with the trade name Xeljanz. [0003] Rheumatoid arthritis (rheumatoid arthritis) is a chronic disease with an extremely long course and extremely painful, which has caused great harm to the physical and mental health of patients. Systemic disease, characterized by ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C59/265C07C51/41
CPCC07D487/04
Inventor 董雪菊尹欣秦丽丽
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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