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Synthesis method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile

A technology of trifluoromethyl and isothiocyanate, applied in the field of drug synthesis, can solve the problems of environmental hazards, cumbersome operations, and low yields, and achieve the effects of mild reaction conditions, simple synthetic routes, and high product yields

Pending Publication Date: 2021-06-01
SHANDONG BOYUAN PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method adopts carbon disulfide to replace thiophosgene, and the follow-up process uses lead nitrate aqueous solution to desulfurize, generating a large amount of lead sulfide precipitates, which is cumbersome to operate, low in yield (about 65%), and harmful to the environment

Method used

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  • Synthesis method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile
  • Synthesis method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile
  • Synthesis method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile

Examples

Experimental program
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Effect test

Embodiment 1

[0027] 1) Synthesis of 4-isocyanate-2-(trifluoromethyl)benzonitrile

[0028] Add 20 g of 3-trifluoromethyl-4-cyanobenzoic acid and 28.14 g of diphenylphosphoryl azide into 80 ml of toluene, raise the temperature to 45 ° C, stir for 3.5 h, and TLC detects that the reaction is complete (TLC, ethyl acetate : n-hexane=1:1), the reaction solution is down to room temperature for stand-by, to obtain 4-isocyanic acid-2-(trifluoromethyl)benzonitrile toluene solution;

[0029] 2) Synthesis of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile

[0030] Add 41.36 g of Lawson's reagent to the 4-isocyanic acid-2-(trifluoromethyl)benzonitrile toluene solution, raise the temperature to 35°C and keep it warm for 4.5h, and TLC detects that the reaction is complete (TLC, ethyl acetate: di Chloromethane=1:1), add 50ml of saturated sodium bicarbonate to wash, wash with water, evaporate the solvent to dryness, add 150ml of n-heptane, beat and stir for 0.5 hours, filter, wash the filter cake with n-h...

Embodiment 2

[0032] 1) Synthesis of 4-isocyanate-2-(trifluoromethyl)benzonitrile

[0033] Add 20 g of 3-trifluoromethyl-4-cyanobenzoic acid and 28.10 g of diphenylphosphoryl azide into 80 ml of toluene, heat up to 50°C, stir for 3 hours, and TLC detects that the reaction is complete (TLC, ethyl acetate: n-Hexane=1:1). The reaction solution was lowered to room temperature for use to obtain 4-isocyanic acid-2-(trifluoromethyl)benzonitrile toluene solution.

[0034] 2) Synthesis of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile

[0035] Add 41.30 g of Lawson's reagent to the 4-isocyanic acid-2-(trifluoromethyl)benzonitrile toluene solution, raise the temperature to 40°C and keep it warm for 4 hours, and TLC detects that the reaction is complete (TLC, ethyl acetate: dichloro Methane=1:1), add 50ml of saturated sodium bicarbonate to wash, wash with water, evaporate the solvent to dryness, add 150ml of n-heptane, beat and stir for 0.5 hours, filter, wash the filter cake with n-heptane, and d...

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Abstract

The invention discloses a synthesis method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. The synthesis method comprises the following steps: with 3-trifluoromethyl-4-cyanobenzoic acid as an initial raw material, firstly, subjecting 3-trifluoromethyl-4-cyanobenzoic acid to reacting with diphenyl azidophosphate under an anhydrous condition to generate 4-isocyanato-2-(trifluoromethyl)benzonitrile, and then subjecting 4-isocyanato-2-(trifluoromethyl)benzonitrile to reacting with a Lawson reagent to obtain the compound 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. The method has the advantages of simple synthetic route, one-pot reaction, mild reaction conditions, simple post-treatment, high product yield (wherein total yield is greater than or equal to 83.9%), and easy industrial production.

Description

technical field [0001] The invention relates to a synthesis method of 4-isothiocyano-2-(trifluoromethyl)benzonitrile, which belongs to the technical field of medicine synthesis. Background technique [0002] Enzalutamide (enzalutamide) is an androgen receptor inhibitor jointly developed by Astellas and Medivation. The drug was initially approved by the FDA in August 2012 for the treatment of advanced castration-resistant prostate cancer. for Xtandi. 4-isothiocyanato-2-(trifluoromethyl)benzonitrile is a starting material for the synthesis of enzalutamide (see WO2015154730, CN106164052A), molecular formula C 9 h 3 N 2 f 3 S, molecular weight: 228.19, structural formula as shown below. [0003] [0004] WO2011106570 introduces a synthetic method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile, the synthetic route is as follows, the method uses 3-trifluoromethyl-4 cyanoaniline and sulfur Phosgene reacts to obtain the target product. The thiophosgene used in the met...

Claims

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Application Information

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IPC IPC(8): C07C331/28
CPCC07C253/30C07C263/12C07C331/28C07C255/57C07C265/12
Inventor 张杰朱义胜杨铎吴玉停吕红超赵希伟
Owner SHANDONG BOYUAN PHARM CO LTD
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