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Preparation method of rupatadine fumarate intermediate 5-methyl-3-hydroxymethylpyridine

A technology of rupatadine fumarate and hydroxymethyl pyridine, which is applied in the field of preparation of pharmaceutical compound intermediates, can solve the problems of complicated operation, flushing of reaction liquid, endangering the life safety of operators and the like, and achieves high product purity. Effect

Active Publication Date: 2021-08-17
BEIJING JIALIN PHARM INC
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] In the patent CN201610181976.2, regarding the preparation process of 5-methyl-3-hydroxymethylpyridine, the operation process is to first add 5-methyl nicotinic acid methyl ester to dissolve in methanol, and then add sodium borohydride solid to 5 -In the methanol solution of methyl nicotinate, then heat up the reaction, because adding sodium borohydride to methanol will make the reaction very violent, and a large amount of sodium borohydride will gather in methanol, which will easily generate a large number of bubbles, which will cause the reaction solution to rush Therefore, the feeding method of sodium borohydride in this patent is to add a large amount of sodium borohydride solids into methanol first. The feeding time is long and the operation is cumbersome. A large amount of sodium borohydride is gathered in methanol. It is dangerous and has great potential safety hazards, so it is not suitable for large-scale industrial production

Method used

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  • Preparation method of rupatadine fumarate intermediate 5-methyl-3-hydroxymethylpyridine

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Embodiment 1

[0036] First add 70mL of tert-butanol into the reaction flask, then add 20g of sodium borohydride, heat to 51°C and stir to mix evenly. Then add the methanol solution of methyl 5-methylnicotinate (25g of methyl 5-methylnicotinate dissolved in 60mL of methanol solution) dropwise into the mixture of tert-butanol and sodium borohydride, and heat up to 70°C to react and reflux 3h. After the reaction, the reaction solution was cooled to room temperature, and 50 mL of purified water was added successively, stirred for 15 minutes, and 160 mL of 6N hydrochloric acid solution, stirred thoroughly. Concentrate under reduced pressure to remove 60%-70% solvent, add 10mol / L sodium hydroxide solution until the pH is about 11, and cool to room temperature. The organic phase was separated by extraction with 100 mL of dichloromethane, concentrated under reduced pressure to dryness of dichloromethane to obtain 18.5 g of yellow oil with a yield of 91%. 99.3% purity.

Embodiment 2

[0038] First add 160mL of tert-butanol into the reaction flask, then add 29.8g of sodium borohydride, heat to 51°C and stir to mix evenly. Then add the methanol solution of 5-methylnicotinate methyl ester (36g of 5-methylnicotinic acid methyl ester dissolved in 80mL methanol solution) dropwise to the above-mentioned mixture of tert-butanol and sodium borohydride, and heat up to 90°C to react and reflux 3h. After the reaction, the reaction liquid was cooled to room temperature, and 70 mL of purified water was added successively, stirred for 15 minutes, and 230 mL of 6N hydrochloric acid solution, stirred thoroughly. Concentrate under reduced pressure to remove 60%-70% solvent, add 10mol / L sodium hydroxide solution until the pH is about 11, and cool to room temperature. The organic phase was separated by extraction with 140 mL of dichloromethane, concentrated under reduced pressure to dry dichloromethane to obtain 25.5 g of yellow oil, with a yield of 86.3%. 98.3% purity.

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Abstract

The present invention relates to a preparation method of rupatadine fumarate intermediate 5-methyl-3-hydroxymethylpyridine , which comprises: 1, sequentially adding tert-butanol and sodium borohydride into a reaction bottle, uniformly stirring and mixing, adding a methanol solution of 5-methyl nicotinate, and carrying out a heating reaction until the raw material disappears; and 2, adding water and an acid solution, fully stirring, concentrating under reduced pressure, adding an alkali solution and an organic solvent, fully stirring and extracting, separating out an organic phase, and concentrating under reduced pressure to obtain the 5-methyl-3-hydroxymethylpyridine.

Description

technical field [0001] The invention relates to a method for preparing a pharmaceutical compound intermediate, in particular to a safe and efficient method for preparing 5-methyl-3-hydroxymethylpyridine, an intermediate of rupatadine fumarate. Background technique [0002] Rupatadine fumarate has the following structural formula: [0003] [0004] As a dual antagonist of histamine and platelet aggregation, rupatadine fumarate is mainly used in the treatment of allergic diseases such as allergic rhinitis and urticaria. Rupatadine fumarate has been listed in many countries around the world since it was first launched in Spain in March 2003. In 2013, my country approved domestic pharmaceutical companies to produce rupatadine fumarate raw materials and preparations. [0005] There are many public reports on the preparation of rupatadine fumarate, and the patent CN201610181976.2 provides a detailed overview of its synthetic routes, most of which involve an important intermedi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/30
CPCC07D213/30Y02P20/55
Inventor 徐贵远
Owner BEIJING JIALIN PHARM INC
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