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Synthesis method of 2-fluoro-3-nitrobenzoic acid intermediate raw material

A technology of nitrobenzoic acid and a synthesis method, which is applied in the field of synthesis of 2-fluoro-3-nitrobenzoic acid intermediate raw materials, can solve the problems of reduced nitration reaction rate, harsh reaction conditions, unfavorable industrialized production, etc. The effect of raw material cost, improved yield and low price

Inactive Publication Date: 2021-06-25
HUNAN INSTITUTE OF ENGINEERING
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The advantage of this method is that only two products can be obtained during nitration, and the separation operation will be simpler, but the nitration reaction rate will decrease, because fluorine atoms and nitro groups are passivation groups, and the reaction conditions are more harsh, which is not conducive to industrial production.

Method used

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  • Synthesis method of 2-fluoro-3-nitrobenzoic acid intermediate raw material
  • Synthesis method of 2-fluoro-3-nitrobenzoic acid intermediate raw material
  • Synthesis method of 2-fluoro-3-nitrobenzoic acid intermediate raw material

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] 1.1 Synthesis of intermediate 2-methyl-6-nitrophenol

[0026]

[0027] Weigh 10.8g o-cresol (100mmol), 18.3g Co(NO 3 ) 2 (100mmol), 0.21g TsOH (1.2mol%) in a 250mL reaction flask, add 100mL acetone (analytical grade, ≥97%), and react under reflux for 8 minutes. After the reaction was completed, it was cooled to room temperature, and the acetone was removed under reduced pressure; simply washed with water to obtain 14.84 g of pale yellow crystals with a yield of 97% and a chromatographic purity of ≥98%. 1 H NMR (400MHz, CDCl 3 ) δ7.83(s, 1H), 7.28(s, 1H), 6.96(s, 1H), 5.0(s, 1H), 2.35(s, 3H).

[0028] 1.2 Synthesis of intermediate 2-chloro-3-nitrotoluene

[0029]

[0030] 14.84g (97mmol) of 2-methyl-6-nitrophenol obtained in step 1, 6.44g C 6 H 5 POCl 2 (33mmol), 66.56g PCl 5 (320 mmol) was all put into a 250 mL round-bottomed flask, slowly heated to 160 ° C, stirred for 5 hours, followed by TLC until the reaction was completed, and the POCl was removed by ...

Embodiment 2

[0039] 1.1 Synthesis of intermediate 2-methyl-6-nitrophenol

[0040]

[0041] Weigh 10.8g o-cresol (100mmol), 18.3g Ni(NO 3 ) 2 (100 mmol) and 0.21 g of TsOH (1.2 mol%) in a 250 mL reaction flask, add 100 mL of acetone (analytical grade, ≥97%), and react under reflux for 5-10 minutes. After the reaction was completed, it was cooled to room temperature, and the acetone was removed under reduced pressure; simply washed with water to obtain 14.84 g of pale yellow crystals with a yield of 97% and a chromatographic purity of ≥98%.

[0042] 1.2 Synthesis of intermediate 2-chloro-3-nitrotoluene

[0043]

[0044] 14.84g (97mmol) of 2-methyl-6-nitrophenol obtained in step 1, 6.44g C 6 H 5 POCl 2 (33mmol), 66.56g PCl 5 (320 mmol) was all put into a 250 mL round-bottomed flask, slowly heated to 160 ° C, stirred for 5 hours, followed by TLC until the reaction was completed, and the POCl was removed by vacuum evaporation 3 . The reaction solution was poured into an ice-water ...

Embodiment 3

[0053] 1.1 Synthesis of intermediate 2-methyl-6-nitrophenol

[0054]

[0055] Weigh 10.8g o-cresol (100mmol), 24.2g Fe(NO 3 ) 3 (100mmol), 0.17g TsOH (1.0mol%) in a 250mL reaction flask, add 100mL acetone (analytical grade, ≥97%), and react under reflux for 5-10 minutes. After the reaction, it was cooled to room temperature, and the acetone was removed under reduced pressure; simply washed with water to obtain 14.68 g of pale yellow crystals with a yield of 96% and a chromatographic purity of ≥98%.

[0056] 1.2 Synthesis of intermediate 2-chloro-3-nitrotoluene

[0057]

[0058] 14.68g (96mmol) of 2-methyl-6-nitrophenol obtained in step 1 and 8.95g C 6 H 5 PCl 2 (50mmol) was added to a 250mL round bottom flask, slowly heated to 160°C, 34.08g Cl 2 (480mmol) was passed into the reaction solution, stirred for 5 hours, followed by TLC until the reaction was completed, and the POCl was removed by vacuum evaporation 3 . The reaction solution was poured into an ice-water...

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Abstract

The invention discloses a synthesis method of a 2-fluoro-3-nitrobenzoic acid intermediate raw material. The invention provides a novel synthesis route, and an important medical intermediate can be rapidly and conveniently prepared from cheap and easily available raw materials. The process method comprises the following steps: starting from o-methylphenol, carrying out nitration reaction to selectively generate a key intermediate 2-methyl-6-nitrophenol, carrying out hydroxyl chlorination to generate 2-chloro-3-nitrotoluene, then carrying out fluorination reaction to generate 2-fluoro-3-nitrotoluene, and finally oxidizing methyl under the action of an oxidant to generate 2-fluoro-3-nitrobenzoic acid. The method is not only high in yield, but also suitable for large-scale production.

Description

technical field [0001] The invention relates to the synthesis of 2-fluoro-3-nitrobenzoic acid, in particular to a method for synthesizing an intermediate raw material of 2-fluoro-3-nitrobenzoic acid. Background technique [0002] 2-Fluoro-3-nitrobenzoic acid, light yellow solid, slightly soluble in water, is a common intermediate raw material, widely used in the synthesis of benzenesulfonamide thiazoles, quinolone derivatives, active biological enzymes and other drugs (ZL 201010264912.1; ZL 200910078771.1; WO2009137391; ACS Med. Chem. Lett., 2013, 4, 1059-1063). At present, the domestic and foreign reports on the synthesis process of 2-fluoro-3-nitrobenzoic acid mainly use 2-fluorotoluene as the raw material (ZL200610147128.6, Tetrahedron Letters, 2006, 47, 4933-4935). This method mainly adopts the following synthetic route (as shown in 1), takes 2-fluorotoluene as raw material, directly nitrifies under the condition of sulfuric acid / nitric acid, obtains 2-fluoro-3-nitrotol...

Claims

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Application Information

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IPC IPC(8): C07C201/12C07C205/12C07C205/58C07C201/08C07C205/22
CPCC07C201/12C07C201/08C07C205/22C07C205/12C07C205/58
Inventor 阳海易年年谢艳军易兵庞怀林
Owner HUNAN INSTITUTE OF ENGINEERING
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