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New method for preparing tofacitinib citrate crystal-form A

A technology of citric acid and new method, applied in the field of medicine, can solve the problems of low yield, poor reproducibility, unsuitable for industrialized production and the like

Inactive Publication Date: 2015-07-15
JIANGSU CAREFREE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The object of the present invention is to provide a kind of tovatinib citrate crystal form A in order to overcome the problems of poor reproducibility, low yield and unsuitability for industrialized production of the existing method for preparing tovatinib citrate crystal form. new preparation method

Method used

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  • New method for preparing tofacitinib citrate crystal-form A
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  • New method for preparing tofacitinib citrate crystal-form A

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Example 1: 3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3- Oxo-propionitrile monocitrate

[0022]

[0023] 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- Propionitrile (5.0g / 16.0mmol) was dissolved in 75ml of acetone and heated to 60°C. To this solution was added dropwise a solution of citric acid (3.4 g / 16.2 mmol) in acetone (25 ml). The resulting mixture was cooled to room temperature and stirred for an additional 2 hours. The solid was collected by filtration, washed with acetone and dried under vacuum at 35°C to afford 5.6 g (69%) of a white crystalline powder. As determined by X-ray powder diffraction, it was shown that the generated crystal form was the target crystal form A.

Embodiment 2

[0024] Example 2: 3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3- Oxo-propionitrile monocitrate

[0025] 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- Propionitrile (5.0g / 16.0mmol) was dissolved in 25ml of tetrahydrofuran and heated to 60°C. To this solution was added dropwise a solution of citric acid (3.4 g / 16.2 mmol) in tetrahydrofuran (25 ml). The resulting mixture was cooled to room temperature and stirred for an additional 2 hours. The solid was collected by filtration, washed with tetrahydrofuran and dried under vacuum at 50°C to afford 4.3 g (53%) of a white crystalline powder. As determined by X-ray powder diffraction, it was shown that the generated crystal form was the target crystal form A.

Embodiment 3

[0026] Example 3: 3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3- Oxo-propionitrile monocitrate

[0027] 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- Propionitrile (5.0 g / 16.0 mmol) was dissolved in 40 ml of methanol and heated to 50°C. To this solution was added dropwise a solution of citric acid (3.4 g / 16.2 mmol) in methanol (25 ml). The resulting mixture was stirred at 50°C for 0.5 hours and then at room temperature for an additional 2 hours. The solid was collected by filtration, washed with methanol and dried under vacuum at 40°C to afford 6.8 g (84%) of a white crystalline powder. As determined by X-ray powder diffraction, it was shown that the generated crystal form was the target crystal form A.

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Abstract

The invention belongs to the field of medicine, and in particular, relates to a new method for preparing a tofacitinib citrate crystal-form A. The method has the advantages of being simple to operate, good in reproducibility, high in yield, suitable for industrialized mass production and the like, and overcomes the problems that a conventional method for preparing a tofacitinib citrate crystal form is poor in reproducibility, low in yield, not suitable for industrialized production and the like.

Description

field of invention [0001] The invention belongs to the field of medicine, and in particular relates to a new method for preparing crystal form A of tovatinib citrate. Background of the invention [0002] Tofacitinib citrate, the chemical name is 3-{4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino] -Piperidin-1-yl}-3-oxo-propionitrile monocitrate, the chemical structural formula is as shown in [I]. The trade name is Xel janz. [0003] [0004] Tofacitinib citrate (Tofacitinib citrate) was developed by Pfizer Pharmaceuticals of the United States and launched in the United States in November 2012. It is used for moderately to severely active rheumatoid arthritis with insufficient response or intolerance to methotrexate treatment (RA) adult patients. [0005] 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propane Nitriles and their corresponding citrates are useful as inhibitors of protein kinases such as Janus kinase 3 (her...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C59/265C07C51/41
Inventor 秦引林吕勇
Owner JIANGSU CAREFREE PHARM CO LTD
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