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A kind of sorafenib tosylate crystal form and preparation method thereof

A technology for sorafenib toluenesulfonate crystal and sorafenib p-toluenesulfonate, which is applied in the field of sorafenib toluenesulfonate crystal form and preparation thereof, and can solve the problem that the crystallinity of the crystal form is not high and it is difficult to meet the requirements of industrialization. Mass production, residues, etc.

Active Publication Date: 2022-07-29
SICHUAN KELUN PHARMA RES INST CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Among the literature patents of above-mentioned sorafenib p-toluenesulfonate, CN 101065360 B relates to polymorphic form I, polymorphic form III of sorafenib p-toluenesulfonate, methanol solvate, ethanol solvate, all need high temperature or The polymorph II was prepared by stirring for a long time, and the crystallinity of the obtained crystal form was not high; WO2009 / 106825A obtained an amorphous solid product of sorafenib p-toluenesulfonate by grinding; CN104761492A required high-temperature heating to remove solvent to obtain polymorph crystal form; the above-mentioned preparation methods are difficult to meet the requirements of large-scale industrial production
Polymorph A of WO2009 / 092070A is obtained by floating crystallization of polymorph III in water, recrystallization after salt formation reaction, wherein the latter requires the use of isopropanol (or propanol or acetone), 1-butyl methyl ether Solvent, will cause a large organic solvent residue

Method used

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  • A kind of sorafenib tosylate crystal form and preparation method thereof
  • A kind of sorafenib tosylate crystal form and preparation method thereof
  • A kind of sorafenib tosylate crystal form and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0047] Add 10 g of sorafenib free base product to 100 g of ethanol to suspend, and the stirring speed is 300 r / min; the temperature is raised to 65 ° C at a heating rate of 3 ° C / min, and the temperature is kept constant; 3.58 g of p-toluenesulfonic acid monohydrate is dissolved in In the mixed solvent of 71.6g of ethanol-water, wherein the mass ratio of ethanol and water is 2:1; then the above-mentioned p-toluenesulfonic acid solution is added to the sorafenib free base suspension at a rate of 1ml / min, and after the reaction is complete. , cooled to 20°C at a cooling rate of 0.5°C / min, kept at a constant temperature for 1.5h, suction-filtered the obtained crystal slurry, and dried the obtained wet crystal product at 20°C and a vacuum of 0.1Mpa for 20 hours. The purity of sorafenib tosylate crystal form was 99.6%, and the process yield was 90.0%. The specific characteristics of the powder diffraction pattern of its X-ray powder diffraction pattern are shown in the 2θ value sho...

Embodiment 2

[0052] 10 g of sorafenib free base product was added to 50 g of ethanol to suspend, and the stirring speed was 200 r / min; the temperature was raised to 70 ° C at a heating rate of 5 ° C / min, and the temperature was kept constant; 3.58 g of p-toluenesulfonic acid monohydrate was dissolved in In the mixed solvent of 35.8g of ethanol water, wherein the mass ratio of ethanol and water is 4:1; then the above-mentioned p-toluenesulfonic acid solution is added to the sorafenib free base suspension at a rate of 0.4ml / min, and the reaction is complete After that, the temperature was lowered to 0°C at a cooling rate of 0.5°C / min, kept at a constant temperature for 0.5h, the obtained crystal slurry was suction filtered, and the obtained wet crystal product was dried at 20°C and a vacuum of 0.1Mpa for 20h. The purity of sorafenib tosylate crystal form was 99.6%, and the process yield was 93.0%. Its X-ray powder diffraction pattern, TGA pattern, DSC pattern and crystal appearance are basic...

Embodiment 3

[0054] 10 g of sorafenib free base product was added to 200 g of ethanol to suspend, and the stirring speed was 500 r / min; the temperature was raised to 30 ° C at a heating rate of 2 ° C / min, and the temperature was kept constant; 3.58 g of p-toluenesulfonic acid monohydrate was dissolved in In the mixed solvent of 107g of ethanol water, wherein the mass ratio of ethanol and water is 1:1; then the above-mentioned p-toluenesulfonic acid solution is added to the sorafenib free base suspension at a rate of 2.2ml / min, and after the reaction is complete , cooled to 20°C at a cooling rate of 0.5°C / min, kept at a constant temperature for 2 hours, suction filtered the obtained crystal slurry, and dried the obtained wet crystal product at 65°C and a vacuum degree of 0.8 Mpa for 2 hours, the obtained p-toluenesulfonic acid The purity of sorafenib acid crystal form was 99.6%, and the process yield was 91.5%. Its X-ray powder diffraction pattern, TGA pattern and crystal appearance are bas...

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Abstract

The present application discloses a crystal form of sorafenib p-toluenesulfonate and a preparation method thereof. The X-ray powder diffraction pattern of the crystal form is at diffraction angles 2θ=10.6±0.2, 17.9±0.2, and 27.9±0.2 degrees. There are characteristic peaks. The crystal form has good stability and good solubility.

Description

technical field [0001] The present application relates to a new crystal form of sorafenib p-toluenesulfonate and a preparation method thereof. Background technique [0002] Sorafenib Tosylate, its chemical name is 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy} - p-toluenesulfonate of N-methylpyridine-2-carboxamide. Its structure is shown in the following figure: [0003] [0004] Sorafenib p-toluenesulfonate was first produced and marketed by Bayer under the trade name of Nexavar tablets. As an enzyme Raf kinase inhibitor, the compound can directly inhibit the proliferation and growth of tumor cells by blocking the RAF / MEK / ERK-mediated cell signaling pathway; at the same time, sorafenib p-toluenesulfonate can also inhibit VEGF And platelet growth factor receptor, thereby blocking the formation of tumor blood vessels, indirectly inhibiting the growth of tumor cells, and treating diseases mediated by VEGF signal transduction pathway. That is, ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/81A61K31/44A61P35/00
Inventor 王天明张娇吴转杨阳李宏名张勇王利春王晶翼
Owner SICHUAN KELUN PHARMA RES INST CO LTD