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Preparation method for 2-chlorine-4-trifluoromethyl-3-cyanopyridine

A technology of trifluoromethyl and cyanopyridine, which is applied in the chemical field, can solve the problems of complex operation, low product yield, and high cost, and achieve the effects of low reaction cost, high yield, and simple operation

Active Publication Date: 2014-03-12
贵州威顿晶磷电子材料股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The process for the synthesis of 2-chloro-4-trifluoromethyl-3-cyanopyridine uses 4-trifluoromethyl-3-cyanopyridine as a raw material, and its finished products are less, which need to be synthesized by other ways, and the operation is comparatively difficult. Complex and high cost; the used trifluoroacetic anhydride has tear gas and corrosiveness, which will cause environmental pollution, and the product yield is low, which is not conducive to actual production

Method used

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  • Preparation method for 2-chlorine-4-trifluoromethyl-3-cyanopyridine
  • Preparation method for 2-chlorine-4-trifluoromethyl-3-cyanopyridine

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Embodiment 1

[0030] A preparation method of 2-chloro-4-trifluoromethyl-3-cyanopyridine, comprising the steps of:

[0031] (1) Synthesis of 4,6-dihydroxy-4-trifluoromethyl-3-cyanopyridine (Ⅲ)

[0032] Add 80g of ethyl trifluoroacetoacetate to the reactor, then add 36.5g of cyanoacetamide, then dissolve it in 400g of 1,4-dioxane, add 44g of triethylamine, heat to 75°C and reflux for 15 hours, It was detected by thin-layer chromatography that the reaction was complete, spin-dried, added 30 g of ether, stirred for 15 minutes, a white solid precipitated, filtered, and the filter cake was dried to obtain a white solid 4,6-dihydroxy-4-trifluoromethyl-3-cyanide Base pyridine 77.6g, productive rate is 87.5%.

[0033] (2) Synthesis of 2,6-dichloro-4-trifluoromethyl-3-cyanopyridine (Ⅱ)

[0034] Add 90 g of the obtained 4,6-dihydroxy-4-trifluoromethyl-3-cyanopyridine into the reactor, add 48.3 g of tetramethylammonium chloride, 600 g of phosphorus oxychloride, and raise the temperature to 100 ° C. ...

Embodiment 2

[0041] (1) Synthesis of 4,6-dihydroxy-4-trifluoromethyl-3-cyanopyridine (Ⅲ)

[0042] Add 80g of ethyl trifluoroacetoacetate to the reactor, then add 65.8g of cyanoacetamide, then dissolve in 400g of ethanol, then add 80g of triethylamine, heat to 90°C and reflux for 12 hours, and the reaction is complete by thin layer chromatography , spin dry, add ether 50g, stir for 20 minutes, a white solid precipitates out, filter, and dry the filter cake to obtain 79.02g of white solid 4,6-dihydroxy-4-trifluoromethyl-3-cyanopyridine, the yield It was 89.1%.

[0043] (2) Synthesis of 2,6-dichloro-4-trifluoromethyl-3-cyanopyridine (Ⅱ)

[0044] Add 90 g of the obtained 4,6-dihydroxy-4-trifluoromethyl-3-cyanopyridine into the reactor, add 62.4 g of tetramethylammonium chloride and 800 g of phosphorus oxychloride, and raise the temperature to 80°C. React for 120 minutes, the reaction is complete by thin-layer chromatography, cool to room temperature, spin dry phosphorus oxychloride with a dr...

Embodiment 3

[0051] (1) Synthesis of 4,6-dihydroxy-4-trifluoromethyl-3-cyanopyridine (Ⅲ)

[0052] Add 80g of ethyl trifluoroacetoacetate to the reactor, then add 91.3g of cyanoacetamide, then dissolve it in 500g of isopropanol, then add 110g of triethylamine, heat to 80°C and reflux for 13 hours, and detect by thin layer chromatography After the reaction was complete, spin dry, add 50 g of diethyl ether, stir for 20 minutes, a white solid precipitated, filtered, and dried the filter cake to obtain 80.18 g of white solid 4,6-dihydroxy-4-trifluoromethyl-3-cyanopyridine, The yield was 90.4%.

[0053] (2) Synthesis of 2,6-dichloro-4-trifluoromethyl-3-cyanopyridine (Ⅱ)

[0054] Add 90 g of the obtained 4,6-dihydroxy-4-trifluoromethyl-3-cyanopyridine into the reactor, add 96.7 g of tetramethylammonium chloride and 900 g of phosphorus oxychloride, and raise the temperature to 50 ° C. Reacted for 150 minutes, the reaction was complete as detected by thin layer chromatography, cooled to room temp...

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Abstract

The invention discloses a preparation method for 2-chlorine-4-trifluoromethyl-3-cyanopyridine. The method comprises the following steps: 4, 6-dyhydroxy-4-trifluoromethyl-3-cyanopyridine is obtained through the condensation and amidation between ethyl trifluoro acetoacetate and cyanoacetamide, triethylamine is used as an alkali of the reaction, and ethyl alcohol, isopropanol and 1, 4-dioxane are used as reaction solvents; 2, 6-dichloro-4-trifluoromethyl-3-cyanopyridine is obtained in the way that the 4, 6-dyhydroxy-4-trifluoromethyl-3-cyanopyridine as a reaction intermediate is subjected to chlorination reaction, the reaction temperature is 50-100 DEG C, and phosphorus oxychloride is used as a solvent for the reaction; the 2-chlorine-4-trifluoromethyl-3-cyanopyridine is obtained in the way that the 2, 6-dichloro-4-trifluoromethyl-3-cyanopyridine (II) is subjected to reduction reaction under the catalysis of palladium carbon, the reaction conditions are normal temperature and normal pressure, the reaction solvent is methyl alcohol or ethyl alcohol. The preparation method is high in product yield, simple and convenient to operate, and low in reaction cost.

Description

technical field [0001] The invention belongs to the technical field of chemistry and relates to a preparation method of 2-chloro-4-trifluoromethyl-3-cyanopyridine. [0002] Background technique [0003] 2-Chloro-4-trifluoromethyl-3-cyanopyridine is an important intermediate in drug synthesis, which can be applied to drug synthesis for the treatment of acute and chronic neuropathic pain and acute and chronic inflammatory pain (Chinese Patent Publication No. CN101128470A in A "new compound" was disclosed on February 20, 2008) and the synthesis of thienopyrimidine amide derivatives (see patent PCT Int.Appl., 2006068618). There are very few literature reports on the synthetic route of 2-chloro-4-trifluoromethyl-3-cyanopyridine, in which: [0004] PCT Int. Appl., 2006068618, Griffin (Griffin), Andrew (Andrew) et al. A process for preparing 2-chloro-4-trifluoromethyl-3-cyanopyridine disclosed on June 29, 2006 The route looks like this: [0005] [0006] The process for the ...

Claims

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Application Information

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IPC IPC(8): C07D213/85
CPCC07D213/85
Inventor 赵春深蒋飚王天喜张虎程吴省付周银宋吾燕吴昌云
Owner 贵州威顿晶磷电子材料股份有限公司
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