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Synthesis method of 2-fluoro-3-hydroxypyridine-4-carboxylic acid

A synthetic method, the technology of hydroxypyridine, applied in the direction of organic chemistry, etc., can solve the problems of no literature reports, etc., and achieve the effects of easy realization, short process route, and convenient reaction operation

Active Publication Date: 2020-01-10
阿里生物新材料(常州)有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] In view of this, we proposed a synthetic method for the preparation of new fluorine-containing pyridine intermediates from fluorine-containing pyridines containing strong electron-donating hydroxyl groups, which has not been reported in the literature so far.

Method used

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  • Synthesis method of 2-fluoro-3-hydroxypyridine-4-carboxylic acid
  • Synthesis method of 2-fluoro-3-hydroxypyridine-4-carboxylic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Dissolve 2-fluoro-3-hydroxypyridine (23.08g, 200mmol, 1eq.) and N,N-diisopropylethylamine (50ml, 300mmol, 1.5eq.) in 200ml dichloromethane. After cooling, dropwise Add 2-(trimethylsilyl)ethoxymethyl chloride (42.5ml, 240mmol, 1.2eq.), and react at 25°C for 20 hours.

[0022] After the reaction of the raw materials is completed, add saturated sodium bicarbonate solution and separate the layers. After the organic layer is concentrated, 45.26g of pale yellow oily 2-fluoro-3-(trimethylsilyl)ethoxymethylpyridine is obtained. The yield is 93%.

[0023] Dissolve 2-fluoro-3-(trimethylsilyl)ethoxymethylpyridine (45.26g, 186mmol, 1eq.) in tetrahydrofuran and put it in the dropping funnel for later use. Add diisopropylamine (31.6ml, 223.2mmol, 1.2eq.) and 300ml of tetrahydrofuran to the reactor, cool to -78°C under nitrogen protection, and add n-butyllithium (82ml, 204.6mmol, 1.1eq.) dropwise, After raising to 25°C and stirring for 1 hour, it was cooled to -78°C again, and the standb...

Embodiment 2

[0027] Dissolve 2-fluoro-3-hydroxypyridine (18.46g, 160mmol, 1eq.) and N,N-diisopropylethylamine (40ml, 240mmol, 1.5eq.) in 150ml of dichloromethane. After cooling, dropwise Add 2-(trimethylsilyl)ethoxymethyl chloride (34ml, 192mmol, 1.2eq.), and react at 25°C for 8 hours.

[0028] After the raw materials have been reacted, saturated sodium bicarbonate solution is added to separate the layers. After the organic layer is concentrated, 27.64 g of pale yellow oily 2-fluoro-3-(trimethylsilyl)ethoxymethylpyridine is obtained. The yield is 71%.

[0029] Dissolve 2-fluoro-3-(trimethylsilyl)ethoxymethylpyridine (27.64g, 113.6mmol, 1eq.) in tetrahydrofuran and put it in the dropping funnel for later use. Add diisopropylamine (19.3ml, 136.3mmol, 1.2eq.) and 200ml of tetrahydrofuran to the reactor, cool to -78°C under the protection of nitrogen, and add n-butyllithium (50ml, 125mmol, 1.1eq.) dropwise. After stirring for 1 hour at 25°C, it was cooled to -78°C again, and the standby 2-fluoro-...

Embodiment 3

[0033] Dissolve 2-fluoro-3-hydroxypyridine (28.85g, 250mmol, 1eq.) and N,N-diisopropylethylamine (62ml, 375mmol, 1.5eq.) in 200ml of dichloromethane. After cooling, dropwise Add 2-(trimethylsilyl)ethoxymethyl chloride (53.1ml, 300mmol, 1.2eq.), and react at 25°C for 36 hours.

[0034] After the raw materials have been reacted, saturated sodium bicarbonate solution is added to separate the layers. After the organic layer is concentrated, 51.1 g of pale yellow oily 2-fluoro-3-(trimethylsilyl)ethoxymethylpyridine is obtained. The yield is 84%.

[0035] Dissolve 2-fluoro-3-(trimethylsilyl)ethoxymethylpyridine (51.1g, 210mmol, 1eq.) in tetrahydrofuran and put it in the dropping funnel for later use. Add diisopropylamine (35.7ml, 252mmol, 1.2eq.) and 400ml of tetrahydrofuran to the reactor, cool to -78°C under the protection of nitrogen, and add n-butyllithium (92.5ml, 231mmol, 1.1eq.) dropwise. After stirring for 1 hour at 25°C, it was cooled to -78°C again, and the standby 2-fluoro-3...

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Abstract

The invention provides a synthesis method of 2-fluoro-3-hydroxypyridine-4-carboxylic acid, and belongs to the field of organic chemical synthesis. The target product 2-fluoro-3-hydroxypyridine-4-carboxylic acid is prepared from 2-fluoro-3-hydroxypyridine used as a raw material through a two-step reaction of carbon dioxide addition under hydroxyl protection and deprotection under the action N,N-diisopropylethylamine, 2-(trimethylsilyl)ethoxymethyl chloride, diisopropylamine, n-butyllithium and carbon dioxide. The method has the advantages of short reaction steps, simplicity in synthesis operation and easiness in realization.

Description

Technical field [0001] The invention relates to the field of organic chemistry synthesis, in particular to a method for synthesizing 2-fluoro-3-hydroxypyridine-4-carboxylic acid. Background technique [0002] Fluorine-containing pyridine compounds are an important class of fine chemical intermediates. Due to their low dosage, low toxicity, and high efficacy, they account for an increasing proportion of new medicines and pesticides. It is also one of the main directions of research and development of domestic fluorine-containing intermediates. Using some simple pyridine compounds and organic reagents as raw materials, by introducing some specific groups, more competitive new fluorine-containing pyridine fine intermediate products can be obtained. Therefore, it is of great significance to develop synthetic processes for fluorine-containing pyridine compounds. [0003] In view of this, we have proposed a synthetic method for preparing novel fluorine-containing pyridine intermediates...

Claims

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Application Information

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IPC IPC(8): C07D213/79C07D213/803
CPCC07D213/79C07D213/803
Inventor 史建云刘超许义波戴红升江云青
Owner 阿里生物新材料(常州)有限公司