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Sorafenib crystal form and preparation method thereof

A fenib crystal form and crystal form technology are applied in the field of new crystal form and its preparation, anticancer drug Sorafenib, can solve the problems of high requirements for crystallization conditions, complicated preparation method, etc., achieve good safety, The effect of reducing the temperature of crystallization and purification and reducing the energy consumption of production

Inactive Publication Date: 2019-03-05
GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The preparation method is relatively complicated, and the conditions for crystallization are relatively high.

Method used

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  • Sorafenib crystal form and preparation method thereof
  • Sorafenib crystal form and preparation method thereof
  • Sorafenib crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Preparation of Sorafenib Crystal Form B

[0036] The crude product of Sorafenib is prepared by the method disclosed in patent WO2006 / 034796.

[0037] Add 10g of crude Sorafenib and 20ml of N,N-dimethylformamide into the three-necked flask, stir at 29°C to dissolve, add 200ml of anhydrous methanol quickly during stirring, stir and crystallize for 1.6 hours after adding, filter, and use a small amount of the product Washed with anhydrous methanol, sucked dry, and vacuum-dried the product at 55° C. for 4 hours to obtain 6.5 g of the product with a molar yield of 65%. Melting point: 193-196°C.

[0038] Gained crystals are subjected to X-ray powder diffraction, and the results are shown in figure 1 According to X-ray powder diffraction analysis, the characteristic absorption peak 2θ values ​​are located at 11.3±0.2゜, 12.5±0.2゜, 14.5±0.2゜, 15.1±0.2゜, 18.0±0.2゜, 18.6±0.2゜.7±0.2 ゜, 22.4±0.2゜, 22.9±0.2゜, 23.5±0.2゜, 24.3±0.2゜, 24.7±0.2゜, 25.2±0.2゜, 25.6±0.2゜, 29.5±0.2゜.

[00...

Embodiment 2

[0048] Preparation of Sorafenib Crystal Form B

[0049] The crude sorafenib was prepared by the method on page 781 of the document reported by Donald Bankston et al. (Organic Process Research & Development 2002, 6, 777 781).

[0050] Add 10g of crude Sorafenib and 20ml of dimethyl sulfoxide into the three-necked flask, stir at 20°C to dissolve, add 400ml of absolute ethanol quickly during stirring, stir and crystallize for 2 hours after adding, filter, and wash the product with a small amount of anhydrous methanol , drained, and vacuum-dried the product at 55° C. for 4 hours to obtain 6.35 g of the product with a molar yield of 64%. Melting point: 193-196°C.

[0051] The obtained crystals were analyzed by X-ray powder diffraction pattern, and the characteristic absorption peak 2θ values ​​were located at 11.3±0.2゜, 12.5±0.2゜, 14.5±0.2゜, 15.1±0.2゜, 18.0±0.2゜, 18.6±0.2゜.7± 0.2°, 22.4±0.2°, 22.9±0.2°, 23.5±0.2°, 24.3±0.2°, 24.7±0.2°, 25.2±0.2°, 25.6±0.2°, 29.5±0.2°. and figu...

Embodiment 3

[0054] Preparation of Sorafenib Crystal Form B

[0055] The crude sorafenib was prepared by the method on page 781 of the document reported by Donald Bankston et al. (Organic Process Research & Development 2002, 6, 777 781).

[0056] Add 10g of crude Sorafenib and 40ml of N,N-dimethylformamide into the three-necked flask, stir at 10°C to dissolve, add 100ml of isopropanol quickly during stirring, stir and crystallize for 2 hours after adding, filter, and use a small amount of Washed with anhydrous methanol, sucked dry, and vacuum-dried the product at 55° C. for 5 hours to obtain 6.99 g of the product with a molar yield of 70%. Melting point: 193-196°C.

[0057] The obtained crystals were analyzed by X-ray powder diffraction pattern, and the characteristic absorption peak 2θ values ​​were located at 11.3±0.2゜, 12.5±0.2゜, 14.5±0.2゜, 15.1±0.2゜, 18.0±0.2゜, 18.6±0.2゜.7± 0.2°, 22.4±0.2°, 22.9±0.2°, 23.5±0.2°, 24.3±0.2°, 24.7±0.2°, 25.2±0.2°, 25.6±0.2°, 29.5±0.2°. and figure 1 T...

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Abstract

The invention belongs to the fields of pharmaceutical and chemical industry, and in particular relates to a sorafenib crystal form B with anti-tumor activity and a preparation method thereof. A new crystal form of sorafenib is obtained by dissolving 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureide]phenoxy}pyridine-2-formamide, i.e. a sorafenib crude product, with N,N-dimethylformamide or dimethylsulfoxide, and adding an alcoholic solvent to crystallize. The method has the advantages of cheap and readily available reagents, environmental friendliness, simple preparation method, mild crystallization conditions and easy crystal separation. The X-ray powder diffraction spectrum analysis shows that the crystal has characteristic absorption peaks 2[theta] of 11.3+ / -0.2 degrees, 12.5+ / -0.2 degrees, 14.5+ / -0.2 degrees, 15.1+ / -0.2 degrees, 18.0+ / -0.2 degrees, 18.6+ / -0.2 degrees, 19.7+ / -0.2 degrees, 22.4+ / -0.2 degrees, 22.9+ / -0.2 degrees, 23.5+ / -0.2 degrees, 24.3+ / -0.2 degrees, 24.7+ / -0.2 degrees, 25.2+ / -0.2 degrees, 25.6+ / -0.2 degrees, and 29.5+ / -0.2 degrees. The obtained crystal has high yield, high crystal form purity, high chemical purity and good crystal form chemical stability.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a new crystal form of an anticancer drug sorafenib and a preparation method thereof. Background technique [0002] Sorafenib (sorafenib, formula 1), the chemical name is 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureide]phenoxy}pyridine-2-carboxamide, Developed by Bayer Company of Germany, it was approved by the US FDA in 2005. This product is the first oral multi-kinase inhibitor that targets tumor cells as well as serine / threonine kinase receptors and tyrosine kinase receptors in tumor blood vessels. Sorafenib has dual anti-tumor effects, which can directly inhibit tumor growth by inhibiting Raf / MEK / ERK signaling channels, and can also inhibit the activity of VEGF tyrosine kinase receptors related to angiogenesis and tumor growth, Block tumor angiogenesis and indirectly inhibit tumor cell growth. It is clinically used to treat advanced renal cell carcinoma, unres...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81C07B2200/13
Inventor 黄小光朱少璇王健松陈红英史雷杨放钱日彬张桂生鲍颖霞陈溪
Owner GUANGZHOU BAIYUNSHAN PHARMA HLDG CO LTD BAIYUNSHAN PHARMA GENERAL FACTORY
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