New method for preparing citric acid tofacitinib medicinal crystal form

A technology of tofacitinib and citric acid, applied in the field of medicine, can solve the problems of unreproducible operation, unsatisfactory purification effect, undisclosed and other problems

Inactive Publication Date: 2018-03-20
JIANGSU ALICORN PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] (1) The amount of solvent (acetone) used is very large, and the solubility of tofacitinib free base in acetone is not very good, especially for free base with higher purity (purity ≥ 95%), 100v / w acetone is used (v: the volume of acetone used; w: the quality of tofacitinib free base) could be completely dissolved free base;
[0008] (2) Although tofacitinib free base with low purity has slightly better solubility in acetone, it still cannot reach the effect of removing impurities after becoming citrate;
[0009] (3) During the preparation process, citric acid is added in solid form, resulting in low purity of the crystal form obtained
The actual operation found that the operation in the example cannot be reproduced, especially the amount of solvent that actually dissolves tofacitinib free base is far greater than the amount of solvent reported in the patent, and the purification effect after salt formation is not satisfactory
[0011] Chinese patent CN103073552A reports the preparation method of amorphous tofacitinib citrate, which has poor reproducibility and the finished product cannot be dissolved in methanol
[0012] Chinese patent CN104530053A reports a preparation method of pharmaceutical crystalline form tofacitinib citrate, but this report is only a crystallization and purification method for tofacitinib citrate, and does not disclose how to make salt

Method used

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  • New method for preparing citric acid tofacitinib medicinal crystal form
  • New method for preparing citric acid tofacitinib medicinal crystal form
  • New method for preparing citric acid tofacitinib medicinal crystal form

Examples

Experimental program
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Effect test

Embodiment 1

[0027] (3R,4R)-4-methyl-3-(methyl-7H-pyrrole[2,3-d]pyrimidin-4-ylamino) with a purity of 94% (normalized method) detected by HPLC -β-carbonyl-1-piperidinepropionitrile (10.00g, 32.01mmol) was dissolved in 100ml of acetone / water mixed solvent (acetone / water=9 / 1, v / v), heated to 50-60°C, and stirred until Dissolve completely. To the clear liquid was added dropwise a solution of citric acid monohydrate (7.40 g, 35.21 mmol) in water (20 ml). The resulting mixture was kept at 50-60° C. and stirred for 30 minutes, then cooled to room temperature and stirred for another 2 hours. After filtering, the filter cake was washed with acetone and dried under vacuum at 40° C. to obtain 15.00 g of white crystalline powder with a yield of 93% and a purity of 99% by HPLC (normalization method).

Embodiment 2

[0029] (3R,4R)-4-methyl-3-(methyl-7H-pyrrole[2,3-d]pyrimidin-4-ylamino) with a purity of 96% (normalized method) detected by HPLC -β-carbonyl-1-piperidinepropionitrile (5.00g, 16.01mmol) was dissolved in 30ml of ethanol / water mixed solvent (ethanol / water=9 / 1, v / v), heated to 50-60°C, stirred until Dissolve completely. To the clear solution was added dropwise a solution of citric acid monohydrate (3.70 g, 17.61 mmol) in water (10 ml). The resulting mixture was kept at 50-60° C. and stirred for 30 minutes, then cooled to room temperature and stirred for another 2 hours. After filtering, the filter cake was washed with ethanol and dried under vacuum at 40° C. to obtain 7.60 g of white crystalline powder with a yield of 94% and a purity of 99% by HPLC (normalization method).

Embodiment 3

[0031] (3R,4R)-4-methyl-3-(methyl-7H-pyrrole[2,3-d]pyrimidin-4-ylamino) with a purity of 95% (normalized method) detected by HPLC -β-carbonyl-1-piperidinepropionitrile (5.00g, 16.01mmol) was dissolved in 30ml of methanol / water mixed solvent (methanol / water=9 / 1, v / v), heated to 50-60°C, stirred until Dissolve completely. To the clear solution was added dropwise a solution of citric acid monohydrate (3.70 g, 17.61 mmol) in water (10 ml). The resulting mixture was kept at 50-60° C. and stirred for 30 minutes, then cooled to room temperature and stirred for another 2 hours. After filtering, the filter cake was washed with methanol and dried under vacuum at 40° C. to obtain 7.09 g of white crystalline powder with a yield of 88%, and the purity detected by HPLC was 99% (normalized method).

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Abstract

The invention belongs to the field of medicine and particularly relates to a new method for preparing a citric acid tofacitinib medicinal crystal form. The method has the advantages of being simple inoperation, good in reproducibility, high in yield, good in purifying effect for API related substances, high in crystal form purity, suitable for industrialized mass production and the like, and overcomes the problems of complicated operation, low reproducibility, low yield, poor purifying effect for API related substances, low crystal form purify, unsuitability for industrialized production andthe like.

Description

technical field [0001] The invention belongs to the field of medicine, and in particular relates to a preparation method of pharmaceutical crystal form tofacitinib citrate. Background technique [0002] Tofacitinib citrate, the structure is shown in formula I, the chemical name is: (3R,4R)-4-methyl-3-(methyl-7H-pyrrole[2,3-d] Pyrimidin-4-ylamino)-β-carbonyl-1-piperidinepropionitrile-2-hydroxy-1,2,3-propane tricarboxylate (1:1). [0003] [0004] Tofacitinib citrate was developed by Pfizer and was approved by the U.S. Food and Drug Administration (FDA) on November 6, 2012, and then approved by Japan Pharmaceuticals on March 25, 2013. Approved by the General Device Agency (PMDA), it is marketed by Pfizer in the United States and Japan under the trade name [0005] Tofacitinib citrate is a Janus kinase (JAK) inhibitor that affects the DNA transcription process by interfering with the JAK-STAT signaling pathway. This medicine is used to treat moderately to severely activ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
Inventor 陈磊刘玉先张伟伟陆平波
Owner JIANGSU ALICORN PHARMATECH CO LTD
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