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Preparation method of 4-amino-3-fluorobenzoic acid

A technology of fluorobenzoic acid and aminobenzonitrile, which is applied in the field of compound preparation, can solve the problems of high raw material prices, large environmental pollution, and large safety hazards, and achieve the effects of low cost, small environmental pollution, and easy industrial production

Active Publication Date: 2019-04-26
KINGCHEM LIAONING CHEMICAL CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The technical problem solved by the present invention is: in the above-mentioned prior art, the first method produces two kinds of isomers, the selectivity to the target product is lower than 20%, causes the price of the raw material to be higher, and the nitration step and the oxidation step belong to strong Exothermic reaction, great potential safety hazard, and produces a large amount of acidic wastewater and wastewater containing manganese or chromium, causing great environmental pollution

Method used

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  • Preparation method of 4-amino-3-fluorobenzoic acid
  • Preparation method of 4-amino-3-fluorobenzoic acid
  • Preparation method of 4-amino-3-fluorobenzoic acid

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preparation example Construction

[0049] In a preferred embodiment, the present invention provides a kind of preparation method of 4-amino-3-fluorobenzoic acid, and synthetic route is as shown in following reaction formula, mainly comprises the following steps:

[0050]

[0051] (1) Ammonification: react 3,4-difluorobenzonitrile and ammonia in an autoclave to obtain the intermediate 3-fluoro-4-aminobenzonitrile;

[0052] (2) Hydrolysis: The intermediate 3-fluoro-4-aminobenzonitrile obtained in step (1) undergoes a hydrolysis reaction under alkaline conditions to generate 4-amino-3-fluorobenzoic acid.

[0053] Preferably, the amination reaction described in step (1) is: first add 3,4-difluorobenzonitrile and solvent (or no solvent) into the autoclave, then feed ammonia gas, and heat up to 60-150°C Reaction, take the reaction material liquid chromatography (LC) and control the reaction to complete. When the solvent exists, reduce the temperature to 10-30°C and release the pressure. According to the type of s...

Embodiment 1

[0073] Step 1: Add 3,4-difluorobenzonitrile (30 g, 0.22 mol) into a 500 mL autoclave, and feed 7.5 g (0.44 mol) of ammonia gas. Then the temperature was raised to 90° C. to react for 24 hours (the maximum pressure during the reaction was 4.0 Mpa), and samples were taken, and the reaction was monitored by liquid chromatography until the normalized content of raw materials was ≤0.5%. After cooling down to room temperature and releasing the pressure, add methyl tert-butyl ether (90mL) to dissolve the material; wash with water (150mL×3) to remove the ammonium fluoride generated by the reaction, separate the organic phase, and concentrate under reduced pressure until it does not flow to obtain a crude product . Recrystallize with toluene (120mL), cool down to 0°C and filter, rinse the filter cake with cold toluene (0-5°C) once, and dry under vacuum at 40°C to obtain 8.8g of 3-fluoro-4-aminobenzonitrile (yield: 30%; purity>99%; off-white solid, melting point 70-72°C).

[0074] Whe...

Embodiment 2

[0088] Step 1: Add 3,4-difluorobenzonitrile (30g, 0.22mol) into a 500mL autoclave, and feed 15g (0.88mol) of ammonia gas. Then the temperature was raised to 90° C. to react for 24 hours (the maximum pressure during the reaction was 4.0 Mpa), and samples were taken, and the reaction was monitored by liquid chromatography until the normalized content of raw materials was ≤0.5%. After cooling down to room temperature and releasing the pressure, add ethyl acetate (90 mL) to dissolve the material; wash with water (150 mL x 3) to remove the ammonium fluoride generated by the reaction, separate the organic phase, and concentrate under reduced pressure until it stops flowing to obtain a crude product. Recrystallize with toluene (120mL), cool down to 0°C and filter, rinse the filter cake once with cold toluene (0-5°C), and dry under vacuum at 40°C to obtain 27.9g of 3-fluoro-4-aminobenzonitrile (yield: 95%; purity>99%; off-white solid, melting point 70-72°C), the intermediate was detec...

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Abstract

The invention relates to a preparation method of 4-amino-3-fluorobenzoic acid, which is characterized in that 4-amino-3-fluorobenzoic acid is prepared by taking 3,4-difluorobenzonitrile as a raw material, and perferably, the preparation method comprises the following steps: (1) allowing 3,4-difluorobenzonitrile to react with ammonia to form an intermediate, 3-fluorine-4-aminobenzonitrile, and (2)allowing the intermediate, 3-fluorine-4-aminobenzonitrile, to give a hydrolysis reaction under an alkaline condition to form 4-amino-3-fluorobenzoic acid. The preparation method takes cheap 3,4-difluorobenzonitrile as a main raw material, synthesizes 4-amino-3-fluorobenzoic acid with high yield and high purity through steps of ammoniation and hydrolysis, has the advantages of convenience in operation, low price and low environmental pollution, and can achieve large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of compound preparation, in particular to a preparation method of 4-amino-3-fluorobenzoic acid. Background technique [0002] The existing methods for synthesizing 4-amino-3-fluorobenzoic acid include the following three methods: 1) from 4-nitro-3-fluorotoluene as raw material, through a strong oxidant such as potassium permanganate (US20080139619; US20090270372), Potassium dichromate (J.Med.Chem.2005,48(6),729; PCT2009130481) or sodium dichromate (Bio.Med.Chem.Lett.2007,17(4),1043; Bio.Med.Chem .Lett.2009,19(5),1386) oxidation to prepare 4-nitro-3-fluorobenzoic acid, followed by Pd / C catalyzed hydrogenation nitro reduction (Bio.Med.Chem.2016,24(12),2697 ; PCT2000016769) to prepare 4-amino-3-fluorobenzoic acid. The raw material 4-nitro-3-fluorotoluene is prepared by nitration of 3-fluorotoluene (Dye and Dyeing. 2004, 41(5), 271; Journal of Shangrao Normal University. 2006, 26(3), 49). 2) Also use 4-nitro-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/26C07C229/60C07C227/40
CPCC07C227/26C07C227/40C07C253/30C07C255/58C07C229/60
Inventor 杨小格王永灿王秀英姜志鹏张金鑫宋桐集
Owner KINGCHEM LIAONING CHEMICAL CO LTD
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