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Preparation method of high-purity sorafenib tosylate crystal form III

A technology of toluenesulfonic acid and fenib crystal form, which is applied in the field of preparation of high-purity sorafenib toluenesulfonate crystal form III, can solve the problems of high content of toxic impurities, easy residual products, difficult to remove, etc. The effect of impurity content, improving safety and reducing content

Pending Publication Date: 2020-09-25
QILU PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Although the method described in the above-mentioned documents has a high yield and is easy to prepare, there are still certain defects: 1) normal temperature suspension is salified to prepare methanolate, and the removal effect of related substances is poor, so it is necessary to carry out sorafenib free base in advance. Purification treatment; 2) The preparation of methanolate requires the use of second-class solvents, such as N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMF), etc., which are easy to remain in the product and difficult to remove; 3) Sorafil tosylate Genotoxic impurities (methyl p-toluenesulfonate, ethyl p-toluenesulfonate, etc.)
And the preparation method of existing sorafenib tosylate crystal form III still has at least one following defect: need to use the reagent harmful to the environment, product impurity content height, base toxic impurity content height etc., therefore look for better The preparation method is very urgent

Method used

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  • Preparation method of high-purity sorafenib tosylate crystal form III
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  • Preparation method of high-purity sorafenib tosylate crystal form III

Examples

Experimental program
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Effect test

preparation example 1

[0050] Preparation 1: N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-[2-(N-methylcarbamoyl)-4-pyridyloxy]phenyl ] Preparation of urea (compound II):

[0051]

[0052] 10g of 4-chloro-3-trifluoromethylphenyl isocyanate was dissolved in 100ml of dichloromethane to obtain solution 1, and 9.9g of N-methyl-4-(4-amino)phenoxypyridine-2-carboxamide Dissolve in 99ml of dichloromethane to obtain solution 2. Control the temperature at about 0°C, add solution 2 dropwise to solution 1, after the dropwise addition, stir the reaction at room temperature for 70 hours, filter with suction, wash the filter cake with dichloromethane, and dry under reduced pressure to obtain 16.6 g of a light yellow solid, yield 87.5%.

[0053] 1 H-NMR (400MHz, DMSO-d 6 ,δppm): 2.77(d,3H), 7.16(m,3H), 7.37(d,1H), 7.62(m,4H), 8.11(d,1H), 8.49(d,1H), 8.77(dd, 1H), 8.99(s,1H), 9.21(s,1H).

[0054] MS(m / z):M+H + =465.20

preparation example 2

[0055] Preparation 2: N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-[2-(N-methylcarbamoyl)-4-pyridyloxy]phenyl ] Preparation of urea p-toluenesulfonate (compound I) crystal form I

[0056] Add 2g of compound II into 20ml of acetonitrile, stir evenly, add 3.0ml of purified water and 1.2g of p-toluenesulfonic acid, heat to reflux to dissolve, cool down to 20-30°C, filter with suction, and dry in the air to obtain 2.4g of white solid , yield 87.6%. The product obtained is subjected to X-ray powder diffraction, and the result shows that the product is Compound I crystal form I, and the XRPD spectrum is shown in figure 1 shown.

Embodiment 1

[0057] Example 1: N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-[2-(N-methylcarbamoyl)-4-pyridyloxy]phenyl The preparation of urea p-toluenesulfonate (compound I) methanolate

[0058] Add 20 g of compound I crystal form I to 100 ml of methanol, stir evenly, stir at 25 ° C for 2 h, filter with suction, and dry in the air to obtain 21 g of a white solid with a yield of 100%. X-ray powder diffraction is performed on the obtained product, and the results show that This product is the methanolate of compound I, XRPD pattern sees figure 2 shown.

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Abstract

The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of a high-purity sorafenib tosylate crystal form III. According to the method, the content of genotoxic impurities can be effectively reduced by controlling specific reaction conditions, so that the crystal form has a good technical effect.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of high-purity sorafenib tosylate crystal form III. Background technique [0002] Sorafenib (Sorafenib), chemical name: N-[4-chloro-3-(trifluoromethyl)phenyl]-N'-[4-[2-(N-methylcarbamoyl)- 4-pyridyloxy] phenyl] urea tosylate, which has a chemical structure shown in formula I, is a new type of signal transduction inhibitor and multi-target anti-tumor drug, and it is also the first oral multi-kinase inhibitor, It is a multi-target bio-targeted new drug jointly developed by Bayer and Onxy in Germany. Sorafenib has dual anti-tumor effects: it can not only directly inhibit the proliferation of tumor cells by blocking the cell signaling pathway mediated by RAF / MEK / ERK, but also inhibit the formation of new blood vessels and Cut off the nutrient supply of tumor cells to achieve the purpose of curbing tumor growth. [0003] [0004] In ...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81C07B2200/13
Inventor 张进周广强王万远
Owner QILU PHARMA
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