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Method for preparing sorafenib tosylate

A technology of toluenesulfonic acid and p-toluenesulfonic acid, which is applied in the field of medicine, can solve the problems of low yield and complicated steps, and achieve the effects of high yield, simple method and simple reaction steps

Active Publication Date: 2016-07-27
JINAN LIMIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are still complicated steps in the preparation process of compound 7 in this method, and the problem of low yield (the yield from compound 2 to compound 7 is only 72%)

Method used

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  • Method for preparing sorafenib tosylate
  • Method for preparing sorafenib tosylate
  • Method for preparing sorafenib tosylate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1: the preparation of compound 7

[0031] (1) 183g (1mol) of 4-bromo-2-cyanopyridine was dissolved in 1L of tetrahydrofuran, and 118g (1.08mol) of p-aminophenol and 50% sodium hydroxide solution (70g of sodium hydroxide+70ml of water) were added; Heat to reflux for 5.5 hours; heat to remove tetrahydrofuran; add 1L of water to the concentrated solution, then add concentrated hydrochloric acid to adjust the pH to 5.5, a brown solid gradually precipitates out, suction filters, and the filter cake is blown-dried to obtain 204.2 g of a brown solid, which is Intermediate 1 (for the next step with a purity of 100%). Mass spectrometry ESI-MS gives the molecular ion peak of intermediate 1 as 231 [M+H] + .

[0032] (2) Add 204.2g of intermediate 1 into 500ml of chloroform, then add 260g (2.18mol) of thionyl chloride, heat and reflux for 1.5 hours, and then directly evaporate to dryness (distilled under reduced pressure at 60°C, if necessary, increase The temperature...

Embodiment 2

[0034] Embodiment 2: the preparation of compound 7

[0035](1) Dissolve 1830g of 4-bromo-2-cyanopyridine in 8L of tetrahydrofuran, add 1150g of p-aminophenol and 50% sodium hydroxide solution (650g of sodium hydroxide + 650ml of water); heat to reflux for 6 hours; heat to evaporate Tetrahydrofuran; add 9L of water to the concentrated solution, then add concentrated hydrochloric acid to adjust the pH5.5, brown solids gradually precipitate out, filter with suction, and after the filter cake is air-dried, 2038g of brown solids are obtained, which is intermediate 1 (carried out according to the purity of 100%) step reaction). Mass spectrometry ESI-MS gave the molecular ion peak of intermediate 1 as 231[M+H]+.

[0036] (2) Add 2038g of intermediate 1 into 4.5L of chloroform, then add 2500g of thionyl chloride, heat and reflux for 1.5 hours, then directly evaporate to dryness (distill under reduced pressure at 60°C, raise the temperature and continue heating if necessary, No resid...

Embodiment 3

[0038] Embodiment 3: the preparation of Sorafenib free base

[0039] 1600 g of compound 7 (Example 2) was dissolved in 6400 mL of ethyl acetate, and stirred evenly at room temperature to obtain a suspension. Dissolve 1604.8g of compound 9 (4-chloro-3-(trifluoromethyl)phenylisocyanate) in 1600mL of ethyl acetate (endothermic); after stabilization, add dropwise to the above-mentioned compound 7 in ethyl acetate solution , temperature control temperature 20 ~ 30 ℃, 30min-60min dripping. During the dropwise addition, the suspension gradually became clear, and then a large amount of precipitate precipitated out. After the drop was completed, it was stirred at room temperature for 4 hours. After suction filtration, the filter cake was washed with ethyl acetate to obtain a light brown powder.

[0040] The light brown powder was recrystallized by adding 21L of absolute ethanol, heated to reflux to dissolve, then lowered to room temperature and stirred for 1-2 hours to crystallize. ...

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Abstract

The invention discloses a method for preparing sorafenib tosylate. The method comprises the following steps: reacting p-aminophenol with 4-bromo-2-cyanopyridine in the presence of sodium hydroxide, and then obtaining 4-(4-aminophenoxy)-2-(formic acid) pyridine after acidification; after carrying out a substitution reaction with thionyl chloride, reacting with methylamine in the presence of potassium carbonate to obtain 4-(4-aminophenoxy)-2-(methyl carbamyl) pyridine; after carrying out direct condensation with a 4-chlorine-3-(trifluoromethyl) phenyl isocyanate compound, salifying with p-toluenesulfonic acid to obtain sorafenib tosylate. The 4-bromo-2-cyanopyridine is used as a starting raw material to prepare the 4-(4-aminophenoxy)-2-(formic acid) pyridine, the steps of subsequent reaction are simplified, the steps of whole reaction are simple, and the yield of product is high.

Description

technical field [0001] The invention relates to a preparation method of sorafenib tosylate, which belongs to the technical field of medicine. Background technique [0002] Sorafenib tosylate is a new type of multi-target anti-tumor drug, successfully developed by Bayer Pharmaceutical Company of Germany (product name: Nexavar), which 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. Extensive antitumor activity has been shown in preclinical animal experiments. [0003] Sorafenib tosylate, chemical name: 4-{4[-3(-4-Chloro-3-trifluoromethylphenyl)ureido]phenoxy}-N2-methylpyridine-2-carboxamidem...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/81
CPCC07B2200/13C07D213/81
Inventor 秦云鹏王翠莲张明铭孙晓博
Owner JINAN LIMIN PHARMA
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