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Sorafenib alpha-amino butyrate and preparation method thereof

A technology of aminobutyrate and sorafenib, applied in the directions of organic chemistry, organic chemistry, antitumor drugs, etc., can solve the problems of unfavorable industrial method production, large molecular weight of toluenesulfonic acid, unfavorable long-term administration, etc. Facilitate industrial production, improve medicinal safety, and have good fluidity

Active Publication Date: 2017-05-24
TIANJIN UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Research shows that sorafenib p-toluenesulfonate crystal form I is transformed from metastable crystal form II, and the operation of forming crystal form I is very cumbersome and harsh, which is not conducive to industrial production; in addition, for Toluenesulfonic acid contains a benzene ring, which itself has certain toxicity, and the molecular weight of p-toluenesulfonic acid itself is relatively large, which is not conducive to long-term administration. Some studies have also reported that some sulfonates have certain genotoxicity

Method used

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  • Sorafenib alpha-amino butyrate and preparation method thereof
  • Sorafenib alpha-amino butyrate and preparation method thereof
  • Sorafenib alpha-amino butyrate and preparation method thereof

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Effect test

Embodiment 1

[0038] Mix 200g of crystal form sorafenib, 70g of α-aminobutyric acid, 2L of ethanol, and 1L of water in a reaction flask, heat to 80°C, and carry out reaction crystallization for 0.5 hours; then cool to 10°C at a rate of 3°C / min, The obtained product was filtered and fully dried to obtain 235g of Sorafenib α-aminobutyrate, with a yield of 96.3% and a purity of 99.9%. The powder X-ray diffraction pattern of the product and figure 1 In agreement, the DSC spectrum is consistent with figure 2 Consistent, the product microscope photos are attached image 3 , the main particle size is 15μm.

Embodiment 2

[0040] Add 200g of amorphous sorafenib, 44g of α-aminobutyric acid, 1.5L of n-butanol, and 0.5L of water into the reaction flask, heat to 75°C, and fully react for 3 hours. Cool to 20 DEG C with the rate of 1 DEG C / min then, the product obtained is filtered, washed, obtains 237g Sorafenib α-aminobutyrate after fully drying, yield 97.0%, purity 99.9%. The powder X-ray diffraction pattern of the product has characteristic peaks at 3.7, 5.5, 7.4, 11.2, 12.4, 14.4, 14.9, 18.4, 21.3, 22.5, 24.5, 25.0, 30.1 degrees, and the DSC spectrum has an endothermic peak at 202 ° C.

Embodiment 3

[0042] Add 200g of sorafenib in crystal form, 89g of α-aminobutyric acid, 2L of ethanol, 2.7L of n-propanol, and 230mL of water into the reaction flask, heat to 70°C, and fully react for 1.5 hours. Cool to 15 DEG C with the rate of 1.5 DEG C / min then, the product obtained is filtered, washed, obtains 233g Sorafenib α-aminobutyrate after fully drying, yield 95.3%, purity 99.9%. The powder X-ray diffraction pattern of the product has characteristic peaks at 3.7, 5.5, 7.4, 11.2, 12.4, 14.4, 14.9, 18.4, 21.3, 22.5, 24.5, 25.0, 30.1 degrees, and the DSC spectrum has an endothermic peak at 202 ° C.

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Abstract

The invention relates to a sorafenib alpha-amino butyrate and a preparation method thereof. The crystal of sorafenib alpha-amino butyrate has a characteristic peak when the diffraction angle 2theta value is 3.7+ / -0.1 degrees, 5.5+ / -0.1 degrees, 7.4+ / -0.1 degrees, 11.2+ / -0.1 degrees, 12.4+ / -0.1 degrees, 14.4+ / -0.1 degrees, 14.9+ / -0.1 degrees, 18.4+ / -0.1 degrees, 21.3+ / -0.1 degrees, 22.5+ / -0.1 degrees, 24.6+ / -0.1 degrees, 25.0+ / -0.1 degrees, and 30.1+ / -0.1 degrees. According to the invention, sorafenib, alpha-aminobutyric acid and mixed solvent of alcohol and water are mixed and heated, sorafenib and alpha-aminobutyric acid react to generate sorafenib alpha-amino butyrate, and sorafenib alpha-amino butyrate is crystallized. The purity of the product reaches more than 99%, the process yield is more than 95%, the particle size is uniform, compared with sorafenib p-toluenesulfonate, the sorafenib alpha-amino butyrate has better water solubility, so that the bioavailability of the medicine is improved. The method is simple and convenient to operate.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical crystallization, and in particular relates to a sorafenib α-aminobutyrate and a preparation method thereof. Background technique [0002] Sorafenib (Sorafenib, formula I), also known as Sorafenib free base, the chemical name is 4-{4-[3-(4-chloro-3-trifluoromethylphenyl)ureide]phenoxy Base} pyridine-2-carboxamide, the molecular formula is C 21 h 16 CIF 3 N 4 o 3 , with a molecular weight of 464.8, is a white powdery solid. It is a multi-target anti-tumor compound jointly developed by Bayer of Germany and Onyx Pharmaceuticals of the United States. It can directly inhibit the proliferation of tumor cells by inhibiting the cell signal transduction pathway induced by VEGF and platelet-derived growth factor (PDGF) receptors to block the formation of tumor neovascularization and indirectly inhibit the growth of tumor cells. In addition, because sorafenib has a broad spectrum of zymoids, it a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81A61P35/00
CPCC07B2200/13C07D213/81
Inventor 龚俊波秦宇佳游伟王静康杨鹏尹秋响侯宝红李晶
Owner TIANJIN UNIV
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