Method for preparing 3-fluor-4-trifluoromethylbenzonitrile

Abstract

The invention relates to a method for preparing a medical intermediate that is 3-fluoro-4-trifluoromethyl benzonitrile and is the key intermediate of medical active species of p-cyano group ortho-benzotrifluorides. By taking ortho-fluoro benzotrifluoride as material, the method comprises five steps that are nitration, reduction, bromination, diazotization amine-removing reaction, and substitution reaction. Firstly, ortho-fluoro benzotrifluoride is utilized to prepare 3-trifluoromethyl-4-fluoroaniline through the nitration and the reduction reaction; then, 3-fluoro-4-trifluoromethyl bromobenzene is prepared through bromination of bromine and the diazotization amine-removing reaction; finally, cyano-groups are used for replacing the bromine to prepare 3-fluoro-4-trifluoromethyl benzonitrile. The method has simple technology, the reaction condition is mild, the operation is safe and convenient, the material can be easily obtained, the yield and the purity quotient of the product are high, and the method is suitable for industrialized production.

Description

(1) Technical field

[0001] The present invention relates to a kind of preparation method of 3-fluoro-4-trifluoromethylbenzonitrile (2) Background technology

[0002] 3-Fluoro-4-trifluoromethylbenzonitrile is a very important pharmaceutical and chemical intermediate, especially a key intermediate of p-nitrile-o-trifluorotoluene pharmaceutical active substances (eg WO2005 / 044784 A1).

[0003] So far, there has been no document publicly reporting the preparation method of 3-fluoro-4-trifluoromethylbenzonitrile. In recent years, many pharmaceutical companies in the world have synthesized 3-fluoro-4-trifluoromethylbenzonitrile in their own companies in order to research and develop pharmaceutical active substances containing p-cyanotrifluorotoluene, and the technology is not disclosed; or, Some companies simply commission the synthesis of 3-fluoro-4-trifluoromethylbenzonitrile. In order to meet the needs of the market, our company researches and develops a preparation method of...

Examples

Embodiment 1

[0014] Example 1: 3-trifluoromethyl-4-fluoronitrobenzene

[0015] A mechanical stirrer, a thermometer and a dropping funnel were installed on a two-liter three-neck reaction flask, and then 540mL of 98% sulfuric acid and 500.0g (3.049mol) of o-fluorobenzotrifluoride were added, and the temperature of the system did not change significantly. Use a beaker to prepare 144mL 98% nitric acid (3.354mol) and 180mL 98% sulfuric acid to make a uniform mixed acid, and then transfer it to the dropping funnel. Under stirring, slowly add the mixed acid dropwise into the reaction mixture, the temperature rises significantly during the dropwise addition, and the temperature of the reaction system is controlled between 10-20°C, and it takes about 3 hours to complete the dropwise. Stirring was continued for 0.5 hours after dropping. After the system was left to stand for stratification, the water layer was separated and extracted once with dichloromethane. The dichloromethane solution was mixe...

Embodiment 2

[0016] Example 2: 3-trifluoromethyl-4-fluoroaniline

[0017] Mechanical stirring, reflux condenser, thermometer and dropping funnel are installed on the four-necked reaction flask of two liters, then add 1087 milliliters of water, 333.7g iron powder (5.958mol) and 42.8g ammonium chloride (0.793mol), heat Warm to reflux. Heating was stopped after reflux, and 425 g (2.03 mol) of 3-trifluoromethyl-4-fluoronitrobenzene was slowly added dropwise to the system, and the system was kept under reflux slowly, and the dropwise addition was completed after 2.0 hours. Reflux was continued for 3.5 hours. The reflux device was changed to a steam distillation device, and the organic layer was separated from the water to obtain 421.3 g of colorless liquid 3-trifluoromethyl-4-fluoroaniline, with a yield of more than 100% and a purity of 99.12% (GC).

Embodiment 3

[0018] Example 3: 2-Bromo-4-fluoro-5-trifluoromethylaniline

[0019] Install a mechanical stirrer, a thermometer and a dropping funnel on a 5-liter three-neck reaction flask, then add 2450 mL of acetic acid and 490.0 g (2.737 mol) of 3-trifluoromethyl-4-fluoroaniline into the reaction flask. Under stirring, 481.0 g (3.0 mol) of bromine was added dropwise through the dropping funnel, and the temperature of the system was controlled at 10-20°C. After the dropwise addition was complete (about 2 hours), stirring was continued at room temperature for 2 hours. Pour the system into 5L of water, brown oil can be seen, adjust the pH of the system to about 7 with saturated sodium carbonate aqueous solution, a solid appears, filter with suction to obtain a brownish yellow solid 2-bromo-4-fluoro-5-trifluoromethane Aniline 600g, yield 85%, purity 93.35% (GC).

(1) Technical field

[0001] The present invention relates to a kind of preparation method of 3-fluoro-4-trifluoromethylbenzonitrile (2) Background technology

[0002] 3-Fluoro-4-trifluoromethylbenzonitrile is a very important pharmaceutical and chemical intermediate, especially a key intermediate of p-nitrile-o-trifluorotoluene pharmaceutical active substances (eg WO2005 / 044784 A1).

[0003] So far, there has been no document publicly reporting the preparation method of 3-fluoro-4-trifluoromethylbenzonitrile. In recent years, many pharmaceutical companies in the world have synthesized 3-fluoro-4-trifluoromethylbenzonitrile in their own companies in order to research and develop pharmaceutical active substances containing p-cyanotrifluorotoluene, and the technology is not disclosed; or, Some companies simply commission the synthesis of 3-fluoro-4-trifluoromethylbenzonitrile. In order to meet the needs of the market, our company researches and develops a preparation method of...

Examples

Embodiment 1

[0014] Example 1: 3-trifluoromethyl-4-fluoronitrobenzene

[0015] A mechanical stirrer, a thermometer and a dropping funnel were installed on a two-liter three-neck reaction flask, and then 540mL of 98% sulfuric acid and 500.0g (3.049mol) of o-fluorobenzotrifluoride were added, and the temperature of the system did not change significantly. Use a beaker to prepare 144mL 98% nitric acid (3.354mol) and 180mL 98% sulfuric acid to make a uniform mixed acid, and then transfer it to the dropping funnel. Under stirring, slowly add the mixed acid dropwise into the reaction mixture, the temperature rises significantly during the dropwise addition, and the temperature of the reaction system is controlled between 10-20°C, and it takes about 3 hours to complete the dropwise. Stirring was continued for 0.5 hours after dropping. After the system was left to stand for stratification, the water layer was separated and extracted once with dichloromethane. The dichloromethane solution was mixe...

Embodiment 2

[0016] Example 2: 3-trifluoromethyl-4-fluoroaniline

[0017] Mechanical stirring, reflux condenser, thermometer and dropping funnel are installed on the four-necked reaction flask of two liters, then add 1087 milliliters of water, 333.7g iron powder (5.958mol) and 42.8g ammonium chloride (0.793mol), heat Warm to reflux. Heating was stopped after reflux, and 425 g (2.03 mol) of 3-trifluoromethyl-4-fluoronitrobenzene was slowly added dropwise to the system, and the system was kept under reflux slowly, and the dropwise addition was completed after 2.0 hours. Reflux was continued for 3.5 hours. The reflux device was changed to a steam distillation device, and the organic layer was separated from the water to obtain 421.3 g of colorless liquid 3-trifluoromethyl-4-fluoroaniline, with a yield of more than 100% and a purity of 99.12% (GC).

Embodiment 3

[0018] Example 3: 2-Bromo-4-fluoro-5-trifluoromethylaniline

[0019] Install a mechanical stirrer, a thermometer and a dropping funnel on a 5-liter three-neck reaction flask, then add 2450 mL of acetic acid and 490.0 g (2.737 mol) of 3-trifluoromethyl-4-fluoroaniline into the reaction flask. Under stirring, 481.0 g (3.0 mol) of bromine was added dropwise through the dropping funnel, and the temperature of the system was controlled at 10-20°C. After the dropwise addition was complete (about 2 hours), stirring was continued at room temperature for 2 hours. Pour the system into 5L of water, brown oil can be seen, adjust the pH of the system to about 7 with saturated sodium carbonate aqueous solution, a solid appears, filter with suction to obtain a brownish yellow solid 2-bromo-4-fluoro-5-trifluoromethane Aniline 600g, yield 85%, purity 93.35% (GC).

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