Preparation method of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-cyano

A technology of isothiocyanate and trifluoromethyl is applied in the field of preparation of 5-isothiocyanate-3-pyridine-2-cyano, which can solve the problems of low total yield, long reaction steps, and low yield. problem, to achieve the effect of high yield, low cost and easy industrialization

Inactive Publication Date: 2019-09-13
南京焕然生物科技有限公司
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Problems solved by technology

[0004] 1. US2014309262A1 publicly reported that using 3-trifluoromethylpyridine as a raw material, the target compound was synthesized in five steps through nitrogen oxidation reaction, cyanation reaction, nitration reaction, reduction reaction, and isothiocyanation reaction, as shown in the attached figure 2 As shown, the problem that this method exists is that trimethylsilyl cyanide and thiophosgene are used in the reaction process, and these two compounds are not only expensive, but also highly toxic, and have potential safety hazards; nitro reduction is reduced with iron powder, A lot of iron sludge will be produced, and the yield is not high
as attached image 3 As shown, the problem of this route is that the reaction steps are long, the total yield is low, and there are many wastes; among them, highly toxic potassium cyanide, cuprous cyanide and thiophosgene are used, and the safety risks are relatively high.

Method used

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  • Preparation method of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-cyano
  • Preparation method of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-cyano
  • Preparation method of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-cyano

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Embodiment 1

[0032] A preparation method of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-cyano group, is characterized in that, comprises the following steps:

[0033] Step 1: Add 106g sodium carbonate, 0.1g palladium acetate, and 1.5L DMF to the reaction flask, stir, add 0.2gdppf (1,1-diphenylphosphinoferrocene), after reflux, add 271g 2-bromo- 3-trifluoromethyl-5-nitropyridine, add 100g potassium ferrocyanide, nitrogen protection, reflux reaction for 20 hours, after the reaction, quench with water, extract with n-hexane, wash with brine, dry, and distill under reduced pressure Solvent, to obtain 206g of intermediate 1, yield: 95%.

[0034] Step 2: add 200g of intermediate 1 to the autoclave, then add Raney nickel, 650mL of ethanol, and feed hydrogen to 2 atm. After the reaction is completed, cool, replace with nitrogen, filter, wash, and concentrate the filtrate to obtain 155g of intermediate 2. Yield: 90%.

[0035] Step 3: Add 150g of intermediate 2 to the reaction flask, then add 7...

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Abstract

The invention relates to a novel synthesis route of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-cyano. The route comprises the steps: adopting 2-halo-5-nitro-3-(trifluoromethyl)pyridine as a raw material, cyanation reaction, and performing three steps including a cyanation reaction, a reduction reaction and an isothiocyanate reaction so as to synthesize 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-cyano of high yield. The preparation method of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-cyano is a preparation method which has high yield, low cost, environmental protection and easy operation, and is suitable for industrialization.

Description

technical field [0001] The invention relates to the field of medicines, in particular to a preparation method of 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-cyano. Background technique [0002] On February 15, 2018, the U.S. FDA approved Erleada (apalutamide), funded by Jensen Pharmaceuticals, for the treatment of castration-resistant, non-metastatic prostate cancer. This is the first drug approved by the FDA for the treatment of castration-resistant, non-metastatic prostate cancer. [0003] 5-isothiocyanato-3-(trifluoromethyl)pyridine-2-cyano is used as the key intermediate of apalutamide, and there are two main synthetic methods at present: [0004] 1. US2014309262A1 publicly reported that using 3-trifluoromethylpyridine as a raw material, the target compound was synthesized in five steps through nitrogen oxidation reaction, cyanation reaction, nitration reaction, reduction reaction, and isothiocyanation reaction, as shown in the attached figure 2 As shown, the proble...

Claims

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Application Information

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IPC IPC(8): C07D213/84
CPCC07D213/84
Inventor 王坤鹏韩月林
Owner 南京焕然生物科技有限公司
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