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Synthesis method of olmesartan intermediate

A synthetic method and intermediate technology, applied in the field of pharmaceutical intermediate synthesis, can solve the problems of many by-products in the oxidation ring-opening reaction, difficult to control, and high ring-closing temperature, and achieve easy control of the overall steps, low production costs, and side reactions. little effect

Active Publication Date: 2020-05-19
ZHEJIANG RUIQING PHARM C0 LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The main disadvantage of this route is that the first step of cyclization temperature is high, which is difficult to control, and the second step of oxidative ring-opening reaction has more by-products

Method used

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  • Synthesis method of olmesartan intermediate
  • Synthesis method of olmesartan intermediate
  • Synthesis method of olmesartan intermediate

Examples

Experimental program
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Embodiment 1

[0061] A kind of synthetic method of olmesartan intermediate, take tartaric acid as raw material, make through cyclization reaction, esterification reaction and methylation reaction, wherein,

[0062] The chemical reaction equation for the cyclization reaction is:

[0063]

[0064] The chemical reaction equation of the esterification reaction is:

[0065]

[0066] The chemical reaction equation for the methylation reaction is:

[0067]

[0068] The cyclization reaction includes the following steps:

[0069] Step 1, put dehydrating agent into the ring-closure reaction kettle, cool down to 0°C; add fuming nitric acid dropwise, control the temperature in the kettle to drop at 3°C-6°C, add dropwise in 4 hours, and keep warm at 5°C for 1-2 Hours; then add tartaric acid in batches, 25 parts per batch, feed once every 30 minutes, and keep warm for 10-12 hours between 5-10°C; When it exceeds 5°C, add alkaline solution dropwise to adjust to PH7-7.5, the temperature does not...

Embodiment 2

[0087] The reaction steps and the amount of each substance added in this example are almost the same as those in Example 1, the difference being that the dehydrating agent in the cyclization reaction of this example is concentrated sulfuric acid. The alkaline solution used for the cyclization reaction in this embodiment is 5% sodium hydroxide solution. The acidic solution in the cyclization reaction of this embodiment is dilute sulfuric acid. The catalyst in the esterification reaction of this embodiment is oxalyl chloride, and the alkaline solution in the esterification reaction of this embodiment is 5% sodium hydroxide solution. The monohalomethane in the methylation reaction of this embodiment is methyl bromide; the first organic solvent in the methylation reaction of this embodiment is 2-methyltetrahydrofuran; the second organic solvent in the methylation reaction of this embodiment The solvent is ethanol.

Embodiment 3

[0089] The reaction steps and the amount of each substance added in this embodiment are almost the same as those in Example 1, the difference being that the dehydrating agent in the cyclization reaction of this embodiment is polyphosphoric acid. The alkaline solution used for the cyclization reaction in this embodiment is 10% sodium carbonate solution. The acidic solution in the cyclization reaction of this embodiment is acetic acid. The catalyst in the esterification reaction of this embodiment is concentrated sulfuric acid, and the alkaline solution in the esterification reaction of this embodiment is 10% sodium carbonate solution. The monohalomethane in the methylation reaction of this embodiment is methyl bromide; the first organic solvent ether in the methylation reaction of this embodiment; the second organic solvent in the methylation reaction of this embodiment is acetone.

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Abstract

The invention relates to the field of drug intermediate synthesis, in particular to a synthesis method of an olmesartan intermediate, which is characterized in that tartaric acid is used as a raw material, and the olmesartan intermediate is prepared by cyclization reaction, esterification reaction and methylation reaction. According to the synthesis method of the olmesartan intermediate, the totalyield can reach 60% or above, the yield is high, and economic benefits are high; the synthesis route is simple, basic raw materials are cheaper, side reactions are few, and purification is easy; andthe whole steps are easy to control, the method is more suitable for industrial application from raw materials to production, selection of ingredients and determination of the addition amount, and theproduction cost is low.

Description

technical field [0001] The invention relates to the field of synthesizing pharmaceutical intermediates, more specifically, it relates to a method for synthesizing olmesartan intermediates. Background technique [0002] Olmesartan (Olmesartan) chemical name: 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(tetrazol-5-yl)phenyl]phenyl]methanol Kimidazole-5-carboxylic acid is a new type of angiotensin II receptor inhibitor successfully developed by Japan Sankyo Co., Ltd. Its structural formula is as follows: [0003] [0004] 4-(1-hydroxyl-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (imidazole monoester for short) is a key intermediate for the preparation of olmesartan, its chemical structural formula as follows: [0005] [0006] Yanagisawa H. (J.Med.Chem.1996,39(1):323-338) etc. reported that 2,3-diaminobutenedinitrile and trimethyl orthobutyrate were used as raw materials, through cyclization and hydrolysis Obtain imidazole dicarboxylic acid, and f...

Claims

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Application Information

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IPC IPC(8): C07D233/90
CPCC07D233/90
Inventor 王雷徐委岭王坚坚
Owner ZHEJIANG RUIQING PHARM C0 LTD
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