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Synthesis method of 4-(difluoromethyl)-2-hydroxypyridine-5-sulfonyl chloride

A synthesis method and hydroxypyridine technology, applied in the direction of organic chemistry and the like, achieve the effects of easy realization, mild reaction conditions, and simple synthesis operation

Active Publication Date: 2020-01-31
埃法姆(常州)生命科学技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In view of this, we propose a synthetic method for the preparation of novel fluorine-containing pyridine intermediates, which has not been reported so far

Method used

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  • Synthesis method of 4-(difluoromethyl)-2-hydroxypyridine-5-sulfonyl chloride
  • Synthesis method of 4-(difluoromethyl)-2-hydroxypyridine-5-sulfonyl chloride
  • Synthesis method of 4-(difluoromethyl)-2-hydroxypyridine-5-sulfonyl chloride

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Experimental program
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Effect test

Embodiment 1

[0026] (1) Synthesis of Compound B

[0027] 5-Bromo-2-methoxypyridine (23g, 120mmol, 1eq.) was dissolved in 250ml of anhydrous tetrahydrofuran and set aside. Diisopropylamine (13.6g, 132mmol, 1.1eq.) was dissolved in 100ml of anhydrous tetrahydrofuran, cooled to -5°C, under nitrogen protection, n-butyl lithium (52.8ml, 132mmol, 1.1eq.) was added dropwise into the above solution. After completion of the dropwise addition, the mixture was stirred for 30 minutes.

[0028] The temperature of the above reaction system was lowered to -78°C, and a tetrahydrofuran solution of 5-bromo-2-methoxypyridine was added dropwise. After completion of the dropwise addition, the mixture was stirred for 1 hour. Then, N,N-dimethylformamide (13.4 g, 180 mmol, 1.5 eq.) was added dropwise to the above reaction system, and reacted for 2 hours.

[0029] After the reaction finished, slowly add 120ml of ammonium chloride solution in the reaction solution. It was extracted with n-hexane, and the organ...

Embodiment 2

[0044] (1) Synthesis of Compound B

[0045] 5-Bromo-2-methoxypyridine (28.8g, 150mmol, 1eq.) was dissolved in 300ml of anhydrous tetrahydrofuran and set aside. Diisopropylamine (17g, 165mmol, 1.1eq.) was dissolved in 150ml of anhydrous tetrahydrofuran, cooled to -5°C, under nitrogen protection, n-butyl lithium (66ml, 165mmol, 1.1eq.) was added dropwise to the above in solution. After completion of the dropwise addition, the mixture was stirred for 30 minutes.

[0046]The temperature of the above reaction system was lowered to -78°C, and a tetrahydrofuran solution of 5-bromo-2-methoxypyridine was added dropwise. After completion of the dropwise addition, the mixture was stirred for 1 hour. Then, N,N-dimethylformamide (16.8 g, 225 mmol, 1.5 eq.) was added dropwise to the above reaction system, and reacted for 2 hours.

[0047] After the reaction finished, slowly add 150ml ammonium chloride solution in the reaction solution. It was extracted with n-hexane, and the organic ph...

Embodiment 3

[0062] (1) Synthesis of Compound B

[0063] 5-Bromo-2-methoxypyridine (17.3g, 90mmol, 1eq.) was dissolved in 200ml of anhydrous tetrahydrofuran and set aside. Diisopropylamine (10.2g, 99mmol, 1.1eq.) was dissolved in 80ml of anhydrous tetrahydrofuran, cooled to -5°C, under nitrogen protection, n-butyl lithium (39.6ml, 99mmol, 1.1eq.) was added dropwise into the above solution. After completion of the dropwise addition, the mixture was stirred for 30 minutes.

[0064] The temperature of the above reaction system was lowered to -78°C, and a tetrahydrofuran solution of 5-bromo-2-methoxypyridine was added dropwise. After completion of the dropwise addition, the mixture was stirred for 1 hour. Then, N,N-dimethylformamide (10.1 g, 135 mmol, 1.5 eq.) was added dropwise to the above reaction system, and reacted for 2 hours.

[0065] After the reaction finished, slowly add 100ml of ammonium chloride solution in the reaction solution. It was extracted with n-hexane, and the organic...

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Abstract

The invention provides a synthetic method of 4-(difluoromethyl)-2-hydroxypyridine-5-sulfonyl chloride, and belongs to the field of organic chemical synthesis. The synthetic method mainly comprises thefollowing steps: reacting a compound B with diethylamino sulfur trifluoride to obtain a compound C; reacting the compound C with sodium iodide and trimethylchlorosilane to obtain a compound D; reacting the compound D with benzyl mercaptan and 4, 5-diphenylphosphine-9, 9-dimethyl xanthene under the action of an alkali and a catalyst to obtain a compound E; and reacting the compound E with N-chlorosuccinimide to obtain a final product compound F. The method is high in selectivity, mild in reaction condition, simple in synthesis operation and easy to implement. In the synthesis process, the compound B is a self-made synthetic material, 5-bromo-2-methoxypyridine is used as a raw material, and nucleophilic substitution reaction is performed to obtain the compound B.

Description

technical field [0001] The invention relates to the field of organic chemical synthesis, in particular to a synthesis method of 4-(difluoromethyl)-2-hydroxypyridine-5-sulfonyl chloride. Background technique [0002] Fluorinated pyridines are important pharmaceutical intermediates. At present, a variety of fluorine-containing compounds have been applied in the fields of pesticides and medicines. For example, fluazinam is a high-efficiency, low-toxic, broad-spectrum fungicide with insecticidal activity, which can kill mosquitoes and flies, and is safe for humans, livestock, poultry, and fish. In terms of medicine, there is talniflumate, and there is also a yellow dye intermediate, and 2,6-difluoro-3-nitropyridine has a bactericidal effect, and it has an anti-caries effect as a chewing gum additive. [0003] Using simple pyridine compounds as raw materials, introduce difluoromethyl groups that regulate lipophilicity in organisms, strong electron-donating hydroxyl groups, or s...

Claims

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Application Information

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IPC IPC(8): C07D213/71
CPCC07D213/71
Inventor 史建云许义波戴红升周超
Owner 埃法姆(常州)生命科学技术有限公司
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