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Crystal form A of Sorafenib and preparation method thereof

A fennel, crystal form technology, applied in the field of medicine and chemical industry, can solve the problems of long reaction cycle and unsuitability for industrial production, and achieve the effect of not easy to decompose, good stability and high purity

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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, people have carried out more research on the crystal form of sorafenib tosylate and its preparation method, but there are not many studies on the polymorphic form of sorafenib as the active ingredient of medicine; although WO0041698 and WO0042012 disclose The preparation method of Sorafenib, but its reaction cycle is very long, and the reaction cannot be carried out completely for more than 10 hours; the resulting product contains more raw materials, and is also easy to decompose in post-reaction treatment, so this method is not suitable for industrial production

Method used

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  • Crystal form A of Sorafenib and preparation method thereof
  • Crystal form A of Sorafenib and preparation method thereof
  • Crystal form A of Sorafenib and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14-

[0040] Example 14- Preparation of [4-[3-(4-chloro-3-trifluoromethylphenyl)ureide]phenoxy]-pyridine-2-carboxamide (crude sorafenib)

[0041]

[0042] 52.3 g of 4-(4-aminophenoxy)-N-methylpyridine-2-carboxamide were suspended in 146 g of ethyl acetate, and the suspension was heated to about 40°C. Then 50 g of 4-chloro-3-trifluoromethylphenyl isocyanate dissolved in 53 g of ethyl acetate was added at a controlled rate to keep the reaction temperature below 60°C. Cool to 20°C over 1 hour, then the mixture is stirred for a further 30 minutes and the product is filtered off. Washed with 30 g of ethyl acetate, and then dried under vacuum at 50°C to obtain 93 g of sorafenib with a yield of 93% and a purity of 57.8% by HPLC. MS(m / z):[M-H]465.15

Embodiment 24-

[0043] Example 24- Preparation of crystalline form A of [4-[3-(4-chloro-3-trifluoromethyl-phenyl)ureide]phenoxy]-pyridine-2-carboxamide (Sorafenib)

[0044]1g of the obtained Sorafenib in Example 1 was added to a mixed solvent of 20ml of dichloromethane and 3.3ml of methanol, heated to reflux for 10min, stopped heating, and after naturally cooling to room temperature, continued stirring and crystallization for 2 hours, suction filtration, washing, Vacuum drying gave 0.92 g of off-white solid with a yield of 92%, HPLC: 99.7%.

[0045] The obtained crystal form is determined by X-ray powder diffraction pattern, and its X-ray powder diffraction represented by 2θ angle is at 6.6±0.2°, 9.9°±0.2°, 11.4±0.2°, 12.6±0.2°, 13.2±0.2°, 13.5±0.2°, 14.6±0.2°, 15.1±0.2°, 15.6±0.2°, 18.1±0.2°, 18.6±0.2°, 19.8±0.2°, 21.8±0.2°, 22.5±0.2°, 22.9±0.2°, There are characteristic peaks at 23.5±0.2°, 24.8±0.2°, 25.2±0.2°, 29.7±0.2°, 30.4±0.2°, 31.6±0.2°, 32.7±0.2°, 36.5±0.2°.

[0046] In differentia...

Embodiment 34-

[0047] Example 34-[4-[3-(4-Chloro-3-trifluoromethyl-phenyl)ureide]phenoxy]-pyridine-2-carboxamide (Sorafenib) Preparation of Form A

[0048] 1g of Sorafenib obtained in Example 1 was added to a mixed organic solvent of 10ml of dichloromethane and 15ml of ethanol, heated to reflux for 20min, cooled to -5°C, continued to stir and crystallize for 1 hour, washed with suction and dried to obtain 0.86 g off-white solid, yield 86%, HPLC: 99.2%.

[0049] According to the XRPD data, the obtained crystal form is the crystal form A of sorafenib described in the present invention.

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a crystal form A of 4-[4-[3-(4-chloro-3-trifluoromethyl phenyl) ureide) phenoxy]-pyridine-2-formamide (sorafenib) with antitumor activity and a preparation method thereof. The purity of a crystal form A of Sorafenib prepared according to the invention is high, and is over 99.0%, an X-ray powder diffraction of the crystal form expressed by a 2theta angle has characteristic peaks at angles of 11.2-11.6 degrees, 11.4-11.8 degrees, 18.4-18.8 degrees, 22.3-22.7 degrees, 24.6-25.0 degrees and 29.5-29.9 degrees, and the crystal form is uneasy to decompose at a temperature of 25-50 DEG C, so that the crystal form shows good stability.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and specifically relates to a 4-[4-[3-(4-chloro-3-trifluoromethylphenyl)ureide]phenoxy]-pyridine-2- The crystal form A of formamide (sorafenib) and its preparation method, the crystal form A has better stability and purity. Background technique [0002] Sorafenib (Sorafenib), the chemical name is: 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureide]phenoxy}-pyridine-2-carboxamide, with Chemical structure shown in formula I: [0003] [0004] Formula I [0005] Sorafenib is a new type of signal transduction inhibitor and multi-target anti-tumor drug, and it is also the first oral multi-kinase inhibitor, jointly developed by Bayer and Onxy in Germany. Sorafenib has dual anti-tumor effects: it can directly inhibit the proliferation of tumor cells by blocking the cell signaling pathway mediated by Raf / MEK / ERK, and it can also inhibit the formation and cutting of new blood vessels by a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 林栋张进王丙忠
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