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Synthesis method for sorafenib

A synthesis method and technology for raw materials, applied in the direction of organic chemistry, etc., can solve the problems of complicated post-processing, the yield is only 76%, and the operation is complicated, so as to save the post-processing process, save the nitrogen protection, and shorten the reaction time.

Inactive Publication Date: 2014-04-16
JIANGSU JIXIAN GREEN CHEM TECH RESINST
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Problems solved by technology

[0005] Patent WO2009111061 describes two methods for the preparation of Sorafenib, wherein in the method of synthesizing Sorafenib through CDI (Formula II), a halogenated hydrocarbon solvent is used as a reaction solvent to synthesize the intermediate N-(4-chloro- 3-trifluoromethylphenyl)-1H-imidazole-1-amide (formula III) needs to be reacted for 16 hours, and the post-treatment is cumbersome, and the yield is only 76%. When it is put into industrial production, the efficiency is low and the economy is not high ; The preparation of sorafenib free base from the intermediate N-(4-chloro-3-trifluoromethylphenyl)-1H-imidazole-1-amide (formula III) also needs to react for nearly 18 hours, and the whole process takes a long time , cumbersome operation

Method used

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  • Synthesis method for sorafenib
  • Synthesis method for sorafenib
  • Synthesis method for sorafenib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide

[0024] Add raw material IV (20g, 0.1mol) into the three-neck flask, dissolve it with DMF (50mL), add CDI (16g, 0.1mol), stir and react at 25°C for 2 hours, add raw material V (27g, 0.11mol ), and continue to react for 1 hour. Pour the reaction solution into water (500mL) to form a suspension, adjust the pH to 4 with 6mol / L HCl solution, extract with ethyl acetate (200mL×3), keep the aqueous layer, and adjust it with 30% NaOH solution When the pH reached 8, after the solid was completely precipitated, it was filtered with suction and dried to obtain 45.5 g of a white solid with a yield of 98%, a purity of 99.98%, and m.p.206-208°C.

[0025] 1 H NMR (DMSO, 300MHz) δ2.63(d, 3H, J=4.8Hz); 7.03(m, 1H); 7.09(d, 2H, J=8.9Hz); 7.25(d, 1H, J=2.5Hz ); 7.43(d, 2H, J=8.9Hz); 7.50(m, 1H); 7.64(m, 1H); 8.01(d, 1H, J=2.4Hz); 8.32(d, 1H, J=5.6Hz ); 8.53 (br d, 1...

Embodiment 2

[0027] Preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide

[0028] Add raw material IV (20g, 0.1mol) into the three-neck flask, dissolve it with DMSO (50mL), add CDI (16g, 0.1mol), stir and react at 25°C for 2 hours, add raw material V (27g, 0.11mol ), and continue to react for 1 hour. Pour the reaction solution into water (500mL) to form a suspension, adjust the pH to 4 with 6mol / L HCl solution, extract with ethyl acetate (200mL×3), keep the aqueous layer, and adjust it with 30% NaOH solution When the pH reached 8, the solid was completely precipitated, filtered with suction, and dried to obtain 41.8 g of a white solid, with a yield of 90%, a purity of 99.97%, and m.p.206-208°C.

[0029] 1 H NMR (DMSO, 300MHz) δ2.78(d, 3H, J=4.8Hz); 7.13(m, 1H); 7.16(d, 2H, J=8.9Hz); 7.37(d, 1H, J=2.5Hz ); 7.58(d, 2H, J=8.9Hz); 7.59(m, 1H); 7.64(m, 1H); 8.11(d, 1H, J=2.4Hz); 8.49(d, 1H, J=5.6Hz ); 8.76 (br d, 1H); 8.99 (...

Embodiment 3

[0031] Preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide

[0032] Add raw material IV (20g, 0.1mol) into the three-neck flask, dissolve it with N-methylpyrrolidone (50mL), add CDI (16g, 0.1mol), stir and react at 25°C for 2 hours, add raw material V ( 27g, 0.11mol), the reaction was continued for 1 hour. Pour the reaction solution into water (500mL) to form a suspension, adjust the pH to 4 with 6mol / L HCl solution, extract with ethyl acetate (200mL×3), keep the aqueous layer, and adjust it with 30% NaOH solution When the pH reached 8, after the solid precipitated out completely, it was suction filtered and dried to obtain 42.7 g of a white solid with a yield of 92%, a purity of 99.97%, and m.p.206-208°C.

[0033] 1 H NMR (DMSO, 300MHz) δ2.70(d, 3H, J=4.8Hz); 7.23(m, 1H); 7.14(d, 2H, J=8.9Hz); 7.31(d, 1H, J=2.5Hz ); 7.62(d, 2H, J=8.9Hz); 7.36(m, 1H); 7.58(m, 1H); 8.31(d, 1H, J=2.4Hz); 8.62(d, 1H, J=5.6Hz ...

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Abstract

The invention provides a synthesis method for sorafenib. The synthesis method is characterized by comprising the following steps: (1) dissolving the raw materials of 4-chlorine-3-trifluoromethylaniline and CDI into an organic solvent, reacting for 2 hours under theat a reaction temperature of 15-40 DEG C, and obtaining the intermediate N-(4-chlorine-3-trifluoromethylaniline)-1H-glyoxaline-1-acid amide; (2) adding a raw material of 4-(4-aminophenoxy)-N-methyl picolinamide, continuously reacting for 1 hour under the same condition, and post-processing, so thatso as to obtain the sorafenib is obtained. Compared with the known synthesis process, the synthesis method provided by the invention is simple to operate, the nitrogen protection is eliminated, and the post-processing in the first step is eliminated; by changing the solvent types, the reaction time is shortened greatly, and the yield is increased obviously, so that industrialized production is more facilitated.

Description

technical field [0001] The invention relates to the technical field of pharmacy, in particular to a synthesis technology of Sorafenib. Background technique [0002] Sorafenib (Sorafenib), the chemical name is 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methyl Pyridine-2-carboxamide, the structural formula (Formula I) is as follows: [0003] [0004] Sorafenib was jointly developed by Bayer and Onyx, and its tosylate salt was approved by the FDA in 2005. It is currently a clinically used drug for the treatment of advanced renal cancer. [0005] Patent WO2009111061 describes two methods for the preparation of Sorafenib. In the method of synthesizing Sorafenib through CDI (Formula II), a halogenated hydrocarbon solvent is used as a reaction solvent to synthesize the intermediate N-(4-chloro- 3-trifluoromethylphenyl)-1H-imidazole-1-amide (formula III) needs to be reacted for 16 hours, and the post-treatment is cumbersome, and the yield is onl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 李可庆
Owner JIANGSU JIXIAN GREEN CHEM TECH RESINST
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