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Method for synthesizing sorafenib through solid ball milling

A ball-milling, solid-state technology, applied in the direction of organic chemistry, can solve the problem of no reports, and achieve the effects of easy operation, shortening the reaction time, and speeding up the reaction rate.

Active Publication Date: 2018-11-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The method for the synthesis of Sorafenib by solid state ball milling has not been reported so far

Method used

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  • Method for synthesizing sorafenib through solid ball milling
  • Method for synthesizing sorafenib through solid ball milling
  • Method for synthesizing sorafenib through solid ball milling

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide

[0027] In a 100mL polytetrafluoroethylene ball mill jar equipped with about 100g of zirconia grinding balls, add 0.50g (2.06mmol) of 4-(4-aminophenoxy)-N-methylpyridine-2-carboxamide, 4 - 0.46 g (2.06 mmol) of chloro-3-trifluoromethylphenyl isocyanate and 240 µl of acetonitrile (0.25 µl / mg solid compound). The rotating speed of the ball mill was set at 400r / min, and the reaction was stopped after 4h in a closed state of the tank. After the reaction was completed, the methanol-dissolved product was added into a ball mill, and evaporated to dryness by rotary evaporation, and purified to obtain 0.92 g of brown powder (yield 96%) with a purity of 99% (HPLC method). 1H NMR (600MHz, DMSO-d6) δ: 2.79(d, J=4.9Hz, 3H), 7.18(m, 3H), 7.38(d, J=2.6Hz, 1H), 7.62(m, 4H), 8.13 (d, J=2.5Hz, 1H), 8.51(d, J=5.6Hz, 1H), 8.78(q, J=4.8Hz, 1H), 9.02(s, 1H), 9.24(s, 1H)....

Embodiment 2

[0029] Preparation of N-(4-chloro-3-trifluoromethylphenyl)-1H-imidazol-1-amide

[0030] In a 100mL polytetrafluoroethylene ball mill jar equipped with about 100g of zirconia grinding balls, add 1g (5.113mmol) of 4-chloro-3-trifluoromethylaniline, 0.83g (5.118mmol) of N,N'-carbonyldiimidazole mmol) and 460 μl of acetonitrile (0.25 μl / mg solid compound). The rotational speed of the ball mill was set at 400r / min, followed by TLC until the reaction was complete, and the reaction was stopped after 5h in a closed state of the tank. After completion, the reaction mixture was vigorously stirred with water, filtered with suction, the filtrate was discarded, and dried overnight to obtain 1.18 g of white powder (yield 80%).

Embodiment 3

[0032] Preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide

[0033] In a 100mL polytetrafluoroethylene ball mill jar equipped with about 100g of zirconia grinding balls, add 0.12g (0.49mmol) of 4-(4-aminophenoxy)-N-methylpyridine-2-carboxamide, N -(4-chloro-3-trifluoromethylphenyl)-1H-imidazole-1-amide 0.14g (0.48mmol), potassium carbonate 0.14g (1.01mmol) and dichloromethane 65μl (0.25μl / mg solid compound ). The rotating speed of the ball mill was set at 400r / min, and the reaction was stopped for 8 hours in a closed state of the tank. Add methanol lysate in the ball mill jar after reaction finishes, and liquid is transferred in the pear-shaped bottle, and heating makes dissolving completely, and rotary evaporation is to dryness, purifies brown powder 0.17g (yield 72%), and purity 99% (HPLC Law). 1H NMR (500MHz, DMSO-d6): δ2.81(d, J=4.9Hz, 3H), 7.18(m, 3H), 7.40(d, J=2.6Hz, 1H), 7.66(m, 4H), 8.14 (d, J = 2...

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Abstract

The invention relates to a method for synthesizing sorafenib through solid ball milling. The method comprises the following steps: taking a compound 4-(4-aminophenoxy)-N-methylpyridine-2-formamide anda compound 4-chlorine-3-trifluoromethyl isocyanate as raw materials, or taking a compound 4-chlorine-3-trifluoromethyl phenylamine, a compound N,N'-carbonyl diimidazole and a compound 4-(4-aminophenoxy)-N-methylpyridine-2-formamide as raw materials, and performing solid ball milling on the raw materials in a ball mill under the catalysis of a small amount of liquid (and alkali), so as to synthesize the sorafenib. The method has the main innovation points that the sorafenib is firstly synthesized in the ball mill through solid ball milling, and compared with the conventional method of synthesizing sorafenib in a liquid solvent, the method has the advantages of high reaction speed, not overflowed dust, good reaction controllability, high simpleness in operation, high reaction yield, small pollution and high feasibility.

Description

technical field [0001] The invention relates to the technical field of preparation of sorafenib, in particular to a method for synthesizing sorafenib by solid state ball milling. Background technique [0002] Sorafenib is a novel diaryluret with the chemical name 4-{4-[({[4chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy }-N-methylpyridine-2-carboxamide, the molecular formula is C 21 h 16 CIF 3 N 4 o 3 , the molecular weight is 464.83, and the structural formula is formula I. [0003] [0004] Sorafenib is a multi-target targeted therapy drug with dual anti-tumor effects: it can block RAF / MEK / ERK by inhibiting the serine / threonine kinase activity of RAF-1 and B-RAF Signal transduction pathway, inhibiting the proliferation of tumor cells, and inhibiting the tyrosine kinase activity of vascular endothelial growth factor receptors VEGFR and PDGFR, thereby blocking the formation of tumor new blood vessels and cutting off the nutrient supply of tumor cells to...

Claims

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Application Information

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IPC IPC(8): C07D213/81
CPCC07D213/81
Inventor 栾立标赵敏
Owner CHINA PHARM UNIV
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