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Method for industrial production of sorafenib tosylate polymorphic form I

A technology of polymorphic form and toluenesulfonic acid of fenib, which is applied in the field of industrial production of polymorphic form I of sorafenib tosylate, can solve problems such as unfavorable scale-up production, cumbersome conversion operations, etc., and achieves low pollution and short process route. , the effect of high product purity

Inactive Publication Date: 2014-12-03
TAIZHOU EOC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, polymorph I is transformed from polymorph II, and the conversion operation is very cumbersome, such as: (1) Polymorph II is heated to 200°C at a certain rate, and then cooled to room temperature at a certain rate to obtain polymorph I; (2) Polymorph II uses one or two mixed solvents of toluene, methanol, ethanol, water, and crystallization at room temperature for one week to obtain polymorph I, which is not conducive to industrial scale-up production

Method used

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  • Method for industrial production of sorafenib tosylate polymorphic form I
  • Method for industrial production of sorafenib tosylate polymorphic form I
  • Method for industrial production of sorafenib tosylate polymorphic form I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Synthesis of Embodiment 1 Sorafenib Tosylate Polymorph I

[0033] ①Synthesis of Compound 1

[0034] In a 50L reaction kettle, add 12L of nitrogen, nitrogen-dimethylformamide, and add 1.92kg (17.58mol) of p-aminophenol and 960g of sodium hydroxide into the reaction flask. Then, under nitrogen protection, 300 g of anhydrous sodium carbonate was added, 3.0 kg (17.58 mol) of N-methyl-4-chloro-pyridineformyl was added into 12 L of DMF to dissolve, and N-methyl-4-chloro-pyridineformyl Acyl DMF solution was added dropwise into the reaction system. After the dropwise addition was completed, stir at room temperature for 30 min. The reaction solution was heated to 90°C, stirred for 4 hours, and the reaction of the raw materials was complete. After the reaction, 16L of water was added to the system, extracted with ethyl acetate, the organic layer was concentrated and dried, beated with petroleum ether for 1 hour, then suction filtered, the filter cake was washed with petroleum ...

Embodiment 2

[0040] Synthesis of Embodiment 2 Sorafenib Tosylate Polymorph I

[0041] ①Synthesis of Compound 1

[0042]In a 50L reactor, add 12L of nitrogen, nitrogen-dimethylformamide, 3.84kg (35.16mol) of p-aminophenol and 960g of sodium hydroxide into the reaction flask. Then, under the protection of nitrogen, 3.0kg (17.58mol) of N-methyl-4-chloro-pyridinecarboxamide was added to 12L of DMF to dissolve, and the DMF solution of N-methyl-4-chloro-pyridinecarboxamide was added dropwise to in the reaction system. After the dropwise addition was completed, stir at room temperature for 30 min. The reaction solution was heated to 100°C and stirred for 4 hours. After the reaction, 16L of water was added to the system, extracted with ethyl acetate, the organic layer was concentrated and dried, beated with petroleum ether for 1 hour, then suction filtered, the filter cake was washed with petroleum ether, and dried by blasting to obtain tan solid compound 1, 2.2kg, collected rate of 63%.

[0...

Embodiment 3

[0048] Synthesis of Embodiment 3 Sorafenib Tosylate Polymorph I

[0049] ①Synthesis of Compound 1

[0050] In a 50L reactor, add 12L nitrogen, nitrogen-dimethylformamide, add 4.80kg (43.95mol) of p-aminophenol, and 960g of sodium hydroxide into the reaction flask. Then, under nitrogen protection, 300 g of anhydrous sodium carbonate was added, 3.0 kg (17.58 mol) of N-methyl-4-chloro-pyridinecarboxamide was added to dissolve in 12 L of DMF, and N-methyl-4-chloro- The DMF solution of picolilyl was added dropwise into the reaction system. After the dropwise addition was completed, stir at room temperature for 30 min. The reaction solution was heated to 110°C and stirred for 4 hours. After the reaction, 16L of water was added to the system, extracted with ethyl acetate, the organic layer was concentrated and dried, beated with petroleum ether for 1 hour, then suction filtered, the filter cake was washed with petroleum ether, and dried by blast to obtain tan solid compound 1, 2.8...

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Abstract

The invention discloses a method for industrial production of a sorafenib tosylate polymorphic substance I. The method comprises the following steps: by adopting N-methyl-4-chloro-pyridine carboxamide and p-aminophenol as raw materials, adding a proper amount of alkali to obtain an intermediate 4-(4-aminophenoxy)-N-methyl-2-pyridine carboxamide by virtue of nucleophilic substitution reaction in an organic solvent, performing condensation on 4-(4-aminophenoxy)-N-methyl-2-pyridine carboxamide and 4-chloro-3-benzenyl trifluoride isocyanate to obtain free alkali of sorafenib, finally performing back-flow and salification with p-toluenesulfonic acid in a mixed solvent of acetone and acetonitrile, and cooling and crystallizing to obtain sorafenib tosylate of the polymorphic substance I. Compared with the prior art, the scheme of the method disclosed by the invention is simple and safe to operate, is mild in reaction condition, and does not need crystal form transformation steps; an obtained product is single and stable in crystal form and high in purity, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of pharmaceutical production, and in particular relates to a method for industrialized production of polymorph I of sorafenib tosylate. Background technique [0002] 4-{4-[3-(4-Chloro-3-trifluoromethylphenyl)ureide]phenoxy}pyridine-2-carboxamide tosylate (Sorafenib Tosylate, Sorafenib Toyslate , trade name: Nexavar, Nexavar) was developed by German Bayer company, can act on tumor cells and tumor blood vessels at the same time. It 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 proliferation of tumor cells by inhibiting VEGF and platelet-derived growth factor (PDGF) receptors. Block the formation of tumor angiogenesis and indirectly inhibit the growth of tumor cells. In December 2005, it was approved by the US Food and Drug Administration (FDA) as a first-line drug for the treatment of adv...

Claims

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Application Information

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IPC IPC(8): C07D213/81C07C303/44C07C309/30
CPCC07D213/81
Inventor 李合亭王德强邵宪伟冀学芳
Owner TAIZHOU EOC PHARMA CO LTD
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