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Synthesis method of 2 - methyl -3 - fluoride - 6 -nitrobenzoic acid

A technology for the synthesis of nitrobenzoic acid and its synthesis method, which is applied in the field of synthesis of important pharmaceutical intermediate 2-methyl-3-fluoro-6-nitrobenzoic acid, and can solve the problems of high synthesis cost, complex post-processing and lack of synthesis methods and other problems, to achieve the effect of fast and convenient raw materials

Active Publication Date: 2010-10-27
SHANGHAI SYNTHEALL PHARM CO LTD
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  • Abstract
  • Description
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Problems solved by technology

[0003] The purpose of the present invention is to provide a novel synthetic method of an important pharmaceutical intermediate 2-methyl-3-fluoro-6-nitrobenzoic acid, which mainly solves the lack of existing synthetic methods and the existing complex post-treatment and difficulty in separation and purification. Technical problems such as low yield, high synthesis cost, and poor applicability

Method used

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  • Synthesis method of 2 - methyl -3 - fluoride - 6 -nitrobenzoic acid
  • Synthesis method of 2 - methyl -3 - fluoride - 6 -nitrobenzoic acid

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Embodiment 1

[0014]

[0015] 1. Synthesis of N-(2-methyl-3-fluoro-6-nitrophenyl)acetamide 2

[0016] 2-Methyl-3-fluoroaniline 1 (600g, 4.8mol) was dissolved in acetic anhydride (3000mL), then the solution was cooled to -10°C, at this temperature 65% by weight of concentrated nitric acid (375mL) was slowly Add dropwise to the reaction solution. After 3 hours, the dropwise addition was completed, and the reaction solution naturally rose to room temperature, and then stirred for 16 hours. The solid precipitated in the reaction solution was filtered to obtain 250 g of the product. The mother liquor was concentrated to dryness again to obtain a crude product, which was recrystallized from ethanol to obtain another 550 g of pure N-(2-methyl-3-fluoro-6-nitrophenyl)acetamide 2. (Yield: 78%).

[0017] H NMR spectrum 1 H-NMR (DMSO, 400MHz), δppm: 9.99 (s, 1H), 7.82 (dd, J 1 =8.8Hz,J 2 =5.6Hz, 1H), 6.50(t, J=8.8Hz, 1H), 2.12(s, 3H), 2.02(s, 3H).

[0018] 2. Synthesis of 2-methyl-3-fluoro-6-...

Embodiment 2

[0031] The second hydrolysis reaction is to dissolve N-(2-methyl-3-fluorophenyl)acetamide 2 in ethanol and concentrated hydrochloric acid, and heat for 15 hours to obtain 2-methyl-3-fluoro-6-nitroaniline 3.

[0032] The third step of the diazotization reaction is that 2-methyl-3-fluoro-6-nitroaniline 3 is dissolved in a 48% hydrobromic acid solution by weight, and an aqueous solution of sodium nitrite is added dropwise at 0°C. React at 0°C for 30 minutes, and add dropwise to the mixed solution of cuprous bromide and water. Reaction at 80°C for 2 hours gave 2-bromo-3-methyl-4-fluoro-nitrobenzene 4.

[0033] The fourth step reaction is to dissolve 2-bromo-3-methyl-4-fluoro-nitrobenzene 4 in N,N-dimethylformamide, add cuprous cyanide, and react at 130°C for 17 hours to obtain 2-Methyl-3-fluoro-6-nitrobenzonitrile 5.

[0034] The fifth step reaction is to dissolve 2-methyl-3-fluoro-6-nitrobenzonitrile 5 in 80% sulfuric acid by weight and react at 90°C for 18 hours, then react f...

Embodiment 3

[0037]The second step of hydrolysis reaction is to dissolve N-(2-methyl-3-fluorophenyl)acetamide 2 in ethanol and concentrated hydrochloric acid, and heat for 18 hours to obtain 2-methyl-3-fluoro-6-nitroaniline 3.

[0038] The third step of the diazotization reaction is that 2-methyl-3-fluoro-6-nitroaniline 3 is dissolved in a 48% hydrobromic acid solution by weight, and an aqueous solution of sodium nitrite is added dropwise at 0°C. React at 0°C for 30 minutes, and add dropwise to the mixed solution of cuprous bromide and water. Reaction at 100°C for 1 hour afforded 2-bromo-3-methyl-4-fluoro-nitrobenzene 4.

[0039] The fourth step reaction is to dissolve 2-bromo-3-methyl-4-fluoro-nitrobenzene 4 in N,N-dimethylformamide, add cuprous cyanide, and react at 110°C for 20 hours to obtain 2-Methyl-3-fluoro-6-nitrobenzonitrile 5.

[0040] The fifth step reaction is to dissolve 2-methyl-3-fluoro-6-nitrobenzonitrile 5 in 60% sulfuric acid by weight and react at 110°C for 12 hours, ...

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Abstract

The invention relates to a synthesis method of important medicine midbody 2 - methyl -3 - fluoride - 6 -nitrobenzoic acid. The invention provides a novel synthesis route, which can rapidly and conveniently prepare an important medicine midbody from the cheap and facile raw materials. The process not only has high yield, but also is applicable to the mass production. The process method is started from 2 - methyl -3-fluoroaniline, crucial midbody N-(2-Methyl -3-- fluoride -6-nitrophenyl) acetamide is selectively generated through the nitration reaction, and the acetyl is hydrolyzed to obtain the 2 - methyl -3-- fluoride -6-nitroaniline; then the amidocyanogen has diazo reaction to generate 2 - bromo -3-- methyl -4-- F - nitrobenzene; bromide generates corresponding cyano compound under the effect of cuprous cyanide; and finally the 2 - methyl -3 - fluoride - 6 -nitrobenzoic acid is obtained under the effect of the sulfuric acid and the sodium nitrite.

Description

Technical field: [0001] The invention relates to a synthesis method of an important pharmaceutical intermediate 2-methyl-3-fluoro-6-nitrobenzoic acid. Background technique: [0002] 2-Methyl-3-fluoro-6-nitrobenzoic acid is an important pharmaceutical intermediate, which can be used to synthesize many small molecule drugs. At present, there is only one Japanese patent (JP04295441) reporting the synthetic route of related analogues. However, its reaction yield is very low, the selectivity is also poor, and it uses expensive and unstable reagents. In addition, two patents (US2008293708A1, WO2006021457A2) reported the use of 2-methyl-3-fluoro-6-nitrobenzoic acid to synthesize anti-tumor drug molecules, but did not indicate the corresponding source. Invention content: [0003] The purpose of the present invention is to provide a novel synthetic method of an important pharmaceutical intermediate 2-methyl-3-fluoro-6-nitrobenzoic acid, which mainly solves the lack of existing sy...

Claims

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Application Information

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IPC IPC(8): C07C205/58C07C201/14
Inventor 张培权肖贻崧马昌友刘世强朱金龙贺海鹰陈曙辉
Owner SHANGHAI SYNTHEALL PHARM CO LTD
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