Method for synthesizing 2, 4-dimethyl pyrimidine-5-alcohol serving as intermediate of Leibolifera

A technology of dimethyl pyrimidine and synthesis method, which is applied in the field of organic chemistry, can solve the problems of low EHS risk, achieve the effects of low cost, solve health problems, and high production efficiency

Active Publication Date: 2021-08-06
广西天铭药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method uses benzoic acid, which is widely present in nature, as the main raw material, which solves the health problems caused in production. The raw material is non-toxic, and has the advantages of "low EHS risk, low cost, and high production efficiency"

Method used

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  • Method for synthesizing 2, 4-dimethyl pyrimidine-5-alcohol serving as intermediate of Leibolifera
  • Method for synthesizing 2, 4-dimethyl pyrimidine-5-alcohol serving as intermediate of Leibolifera
  • Method for synthesizing 2, 4-dimethyl pyrimidine-5-alcohol serving as intermediate of Leibolifera

Examples

Experimental program
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Effect test

Embodiment 1

[0037] 1) Preparation of benzoic acid-2-oxypropyl ester

[0038] Stir the mixture of 20g benzoic acid, 15.9g chloroacetone and 100ml tetrahydrofuran at room temperature, add 45.27g potassium carbonate and 0.2g potassium iodide catalyst to the reaction mixture under temperature control below 40°C, and then stir the resulting mixture at 40°C for reaction 16 hours.

[0039] After the reaction was completed, the reaction mixture was cooled in an ice bath, and then 40 ml of purified water was added dropwise to the reaction mixture. The aqueous phase was separated and washed with 10% aqueous sodium chloride solution. After washing, the organic phase was concentrated until there was no distillate, and 100 ml of n-heptane was added to lower the temperature at 5° C. for crystallization for 0.5 hours, and then the turbid system was filtered. The obtained solid was washed with n-heptane and dried under reduced pressure to obtain 27.1 g of the target compound with a molar yield of 93% an...

Embodiment 2

[0045] 1) Preparation of benzoic acid-2-oxypropyl ester

[0046] Stir the mixture of 100g benzoic acid, 79.5g chloroacetone and 500ml tetrahydrofuran at room temperature, add 226g potassium carbonate and 1g potassium iodide catalyst to the following reaction mixture under temperature control below 40°C, then stir the resulting mixture at 40°C for 16 hours . The reaction mixture was cooled in an ice bath, and then 200 ml of purified water was added dropwise to the reaction mixture. The water phase was separated, and then washed with 10% aqueous sodium chloride solution. After washing, the organic phase was concentrated until there was no distillate, and then 500 ml of n-heptane was added to cool down at 5° C. for crystallization for 0.5 hours, and then the cloudy system was filtered. The obtained solid was washed with n-heptane and dried under reduced pressure to obtain 138.4 g of the target compound with a molar yield of 95% and a purity of 99.5%.

[0047] 2) Preparation of ...

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Abstract

The invention discloses a method for synthesizing 2, 4-dimethyl pyrimidine-5-alcohol serving as an intermediate of Lemborexant , and aims to solve the problems of safety risk and heavy environmental pollution of the 2, 4-dimethyl pyrimidine-5-alcohol in industrial production of the 2, 4-dimethyl pyrimidine-5-alcohol. The preparation method comprises the following steps: firstly, carrying out esterification reaction on benzoic acid serving as an initial raw material and chloroacetone; then, carrying out alkylation reaction and ring closing reaction with N, N-dimethylformamide dimethyl acetal and acetamidine hydrochloride; and finally, carrying out hydrolysis reaction to remove benzoic acid to obtain the 2, 4-dimethyl pyrimidine-5-alcohol. According to the method, benzoic acid widely existing in nature serves as a main raw material, the health problem caused in production is solved, the raw materials are non-toxic, and the method has the advantages that the EHS risk is low, the cost is low, the production efficiency is high, the yield is larger than or equal to 60%, and the purity is larger than or equal to 99.0%.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a method for synthesizing the key intermediate 2,4-dimethylpyrimidin-5-ol, which is an orexin receptor antagonist, Dayvigo. Background technique [0002] The orexin receptor antagonist leborexan (Dayvigo) is indicated for the treatment of insomnia in adults, characterized by disturbances in initiating and / or maintaining sleep. Dayvigo is a small molecule compound developed by Eisai, as a dual orexin receptor antagonist, which inhibits appetite by competitively binding to two orexin receptors (OX1R and OX2R). Neurotransmitter, regulating sleep-wake rhythm. Blocking the binding of the wake-promoting neuropeptide orexin to the receptors OX1R and OX2R is considered to inhibit the drive of wakefulness. The drug binds to the orexin receptors OX1R and OX2R and acts as a competitive antagonist, which has a stronger inhibitory effect on OX2R. It can inhibit REM and...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/36
CPCC07D239/36
Inventor 高志国刘鹏李松松宁尚恩邹琪琪秦建丽
Owner 广西天铭药业有限公司
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