Preparation method of 2-trifluoromethyl-4-aminobenzonitrile

A technology of trifluoromethyl fluorobenzene and trifluoromethyl, which is applied in the field of preparation of 2-trifluoromethyl-4-aminobenzonitrile, can solve the problems of many by-products, the discharge of three wastes affecting environmental protection, and the destruction of waste water.

Active Publication Date: 2010-06-30
SHANGHAI CHEMSPEC CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] From the perspective of the two synthetic routes, the first route uses diazotization reaction, which is cumbersome to operate, has many by-products, and the yield is only about 60%. In the reduction reaction of iron powder, the product is mixed with iron powder and must be extracted repeatedly. The operation is cumbersome, and CuCN is used, which is dangerous. The whole synthesis yield is only about 30%, the cost is obviously high, and a large amount of sewage is produced at the same time, which is not suitable for pro

Method used

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  • Preparation method of 2-trifluoromethyl-4-aminobenzonitrile
  • Preparation method of 2-trifluoromethyl-4-aminobenzonitrile

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preparation example Construction

[0073] The inventor also provides a preferred specific embodiment, the preparation method of 2-trifluoromethyl-4-aminobenzonitrile includes using m-trifluoromethyl fluorobenzene as the main raw material, through bromination, grignardization and formylation , cyanide, amino substitution four-step synthesis, the preparation steps are as follows;

[0074] (1) Bromination: react m-trifluoromethylfluorobenzene with brominating agent in acid to generate 2-bromo-5-fluorobenzotrifluoride;

[0075] (2) Grignardization and formylation: under the reaction of magnesium chips and organic solvents, the Grignard reagent is obtained, and then reacted with N,N-dimethylformamide (DMF) through continuous reaction to obtain 2-trifluoro Methyl-4-fluorobenzaldehyde;

[0076] (3) Cyanide: 2-trifluoromethyl-4-fluorobenzaldehyde is reacted with hydroxylamine hydrochloride and Lewis acid to generate 2-trifluoromethyl-4-fluorobenzonitrile;

[0077] (4) Amination: react 2-trifluoromethyl-4-fluorobenzon...

Embodiment 1

[0088] The first step of positioning bromination: add 300g m-trifluoromethylfluorobenzene (1.83mol), 550g concentrated sulfuric acid (5.61mol), and 110g glacial acetic acid (1.83mol) into the reaction kettle, stir and heat up to 20°C, and add in batches 366 g (1.28 mol) of dibromohydantoin was reacted at heat preservation, deiced, and washed with water to obtain 380 g (1.56 mol) of 2-bromo-5-fluoro-trifluorotoluene with a content of more than 95%.

[0089] The second step of Grignard and formylation: add 39g magnesium chips (1.625mol) and 1200mlTHF into the reaction kettle, stir and heat up to 20°C, add dropwise 300g of 2-bromo-5-fluoro-trifluorotoluene (1.23mol) and keep it warm DMF 117g was added dropwise, and hydrochloric acid was added to destroy the reaction after 2 hours, THF was evaporated, and 218g (1.14mol) of 2-trifluoromethyl-4-fluorobenzaldehyde was obtained by layering, with a content of more than 98%.

[0090] The third step cyanation reaction: 200g2-trifluoromet...

Embodiment 2～5

[0093] Proceed in the same manner as in Example 1, except that the type of brominating agent in the first step of positioning bromination, the molar ratio of m-trifluoromethylfluorobenzene: brominating agent, and the reaction temperature are as shown in Table 1. Table 1 also shows the yield and purity of 2-bromo-5-fluoro-benzotrifluoride.

[0094] Table 1

[0095]

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Abstract

The invention relates to a preparation method of 2-trifluoromethyl-4-aminobenzonitrile, comprising the following steps of: (a) providing m-trifluoromethyl benzene; (b) carrying out bromination reaction on the m-trifluoromethyl benzene in the presence of an acid and a bromating agent so as to obtain 2-bromine-5-fluorine-benzotrifluoride; (c) carrying out Grignard reaction on the 2-bromine-5-fluorine-benzotrifluoride to prepare a Grignard reagent, and carrying out formylation reaction in the presence of a formylation reagent so as to obtain 2-trifluoromethyl-4-fluorobenzaldehyde; (d) carrying out cyaniding reaction on the 2-trifluoromethyl-4-fluorobenzaldehyde so as to obtain 2-trifluoromethyl-4-fluorobenzonitrile; and (e) reacting the 2-trifluoromethyl-4-fluorobenzonitrile with an ammoniation reagent so as to obtain the 2-trifluoromethyl-4-aminobenzonitrile.

Description

technical field [0001] The invention relates to a reaction scheme design of organic synthesis, in particular to a preparation method of 2-trifluoromethyl-4-aminobenzonitrile. Background technique [0002] 2-Trifluoromethyl-4-aminobenzonitrile is a key intermediate in the synthesis of drug bicalutamide. Bicalutamide is an anti-androgen non-corticosteroid, widely used in the prevention and treatment of prostate cancer, pancreatic cancer, breast cancer and other chronic diseases. Because bicalutamide is well tolerated, has no steroidal effect after taking it, and has no obvious side effects on blood vessels and metabolism, so the demand for its intermediate 2-trifluoromethyl-4-aminobenzonitrile increase rapidly. [0003] There are currently two synthetic routes for this intermediate. [0004] The first route: using o-trifluoromethylaniline as the starting material, it is synthesized through four steps of diazotization, nitration, cyano substitution, and iron powder reduction...

Claims

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Application Information

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IPC IPC(8): C07C255/58C07C253/30
Inventor 李功勇金云舟
Owner SHANGHAI CHEMSPEC CORP
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