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Preparation method of 2-chloro-5-hydroxypyrimidine

A technology of hydroxypyrimidine and methoxypyrimidine, which is applied in the field of preparation of 2-chloro-5-hydroxypyrimidine, can solve the problems of expensive reagents, high cost, large consumption, etc., and achieves improved purity and reaction yield and reduced cost , the effect of reducing the impurity content

Inactive Publication Date: 2019-07-23
HAIMEN RUIYI MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the method for the synthesis of 2-chloro-5-hydroxypyrimidine reported in the literature is to use 2-chloro-5-methoxypyrimidine as raw material, and carry out demethylation reaction with boron tribromide. This route has the advantages of low reaction temperature, Reagents are expensive and used in large quantities, high cost, low yield, and boron tribromide is easy to decompose and not easy to store for a long time.
As for another route using 5-amino-2-chloropyrimidine to add sulfuric acid, the yield of the resulting product is between 25% and 33%, and the yield is very low

Method used

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  • Preparation method of 2-chloro-5-hydroxypyrimidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Prepare a 1L four-neck flask with a stirring device and a thermometer, add 100g of 2-chloro-5-methoxypyrimidine, add 300mL of acetic acid into the reaction flask, stir well, then add 800g of 48% hydrobromic acid and 1g of methionine, and heat up to Reflux reaction for 5 hours, sample HPLC control until the end of the reaction, product content 80%, dihydroxy by-product 15%; down to room temperature, add 300mL water to the reaction solution, extract three times with 300mL dichloromethane, combine the organic phase, use saturated washed with sodium bicarbonate solution, then dried with anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain a crude product; ethanol was added to the crude product for recrystallization to obtain 64 g of a light yellow solid with a yield of 70% and a purity of 98%.

Embodiment 2

[0021] Prepare a 1L four-neck flask with a stirring device and a thermometer, add 100g of 2-chloro-5-methoxypyrimidine, add 300mL of acetic acid into the reaction flask, stir well, then add 300g of 48% hydrobromic acid and 1g of methionine, and heat up to Reflux reaction for 5 hours, sample HPLC control until the end of the reaction, product content 92%, dihydroxy by-product 5%; down to room temperature, add 300mL water to the reaction solution, extract three times with 300mL dichloromethane, combine the organic phase, use saturated washed with sodium bicarbonate solution, then dried with anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain a crude product; ethanol was added to the crude product for recrystallization to obtain 74 g of a pale yellow solid, with a yield of 80% and a purity of 98%.

Embodiment 3

[0023] Prepare a 1L four-necked flask with a stirring device and a thermometer, add 100g of 2-chloro-5-methoxypyrimidine, add 300mL of acetic acid into the reaction flask, stir well, then add 153g of 48% hydrobromic acid and 1g of methionine, and heat up to Reflux reaction for 5 hours, sample HPLC control until the end of the reaction, product content 96%, dihydroxy by-product 0.5%; cool down to room temperature, add 300mL water to the reaction solution, extract three times with 300mL dichloromethane, combine organic phases, use saturated washed with sodium bicarbonate solution, then dried with anhydrous sodium sulfate, filtered, and the organic phase was concentrated under reduced pressure to obtain a crude product; ethanol was added to the crude product for recrystallization to obtain 82 g of a light yellow solid, with a yield of 91% and a purity of 98%.

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Abstract

The invention relates to a preparation method of 2-chloro-5-hydroxypyrimidine. The preparation method is characterized by comprising the following steps: step a, adding 2-chloro-5-methoxypyrimidine and an organic acid solvent in a reaction vessel, stirring uniformly, adding hydrobromic acid and methionine, and stirring and heating for carrying out reflux reaction for 3-8 hours; step b, cooling toroom temperature after the reaction, adding water, carrying out solvent extraction several times, and merging organic phases; step c, washing and drying the organic phases, and then concentrating andpurifying to obtain a pale yellow solid target product. The preparation method has the beneficial effects that the ratio of raw materials is optimized, so that the impurity content of the product is significantly reduced; a hydrobromic acid-methionine system replaces boron tribromide for performing demethylation reaction, so that the cost of the raw materials is effectively reduced, and the product purity and the reaction yield are greatly improved.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of 2-chloro-5-hydroxypyrimidine. Background technique [0002] Pyrimidine compounds are an important class of nitrogen-containing heterocyclic compounds. Due to their special structure, pyrimidine compounds have high biological activity. These compounds have the functions of antifungal and promoting plant growth regulation. In recent years, pyrimidine compounds as pesticides emerge in an endless stream, including insecticides, herbicides and fungicides. 2-Chloro-5-hydroxypyrimidine is an important raw material for the synthesis of 2-(substituted phenoxy)-5-hydroxypyrimidine compounds, which are widely used in the fields of organic chemistry and medicinal chemistry such as antifungal. At present, the method for the synthesis of 2-chloro-5-hydroxypyrimidine reported in the literature is to use 2-chloro-5-methoxypyrimidine as raw materia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/34
CPCC07D239/34
Inventor 薛嵩周文俊
Owner HAIMEN RUIYI MEDICAL TECH
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