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Method for synthesizing irbesartan and intermediate thereof

A technology for intermediates and compounds, applied in the field of pharmaceutical preparation, can solve the problems of safety risks, high cost, complicated preparation process, etc., and achieve the effects of ensuring safety, saving raw material costs, and convenient synthesis methods.

Active Publication Date: 2012-05-02
ZHEJIANG TIANYU PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The purpose of the present invention is to provide a new method for synthesizing irbesartan in order to solve the problems of safety risks, cumbersome preparation process and high cost in the current method for preparing irbesartan

Method used

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  • Method for synthesizing irbesartan and intermediate thereof
  • Method for synthesizing irbesartan and intermediate thereof
  • Method for synthesizing irbesartan and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] Example 1: Preparation of formula 3 compound: 1-aminocyclopentanitrile oxalate

[0054] 20g (0.41mol) of sodium cyanide was dissolved in 40mL of water, 60mL of aqueous solution of 23g (0.43mol) of ammonium chloride was added, 35mL of 20% ammonia water and 40mL of methanol solution of 30g (0.36mol) of cyclopentanone were stirred at room temperature for 1.5 hours, and the temperature was raised Stir at 60°C for another 45 minutes, stop heating, and continue stirring for 45 minutes. Cool down to room temperature, extract with 80mL×6 dichloromethane, dry the organic phase with anhydrous magnesium sulfate, filter, concentrate the filtrate, dissolve 41g of the remaining oil in 100mL of acetone, add 25g (0.28mol) of oxalic acid in 200mL of acetone solution while stirring, The solid was precipitated, filtered, the filter cake was rinsed with acetone, and dried to obtain 50.0 g of white solid, yield 70.0%, Mp 220°C.

Embodiment 2

[0055] Example 2: Preparation of formula 4 compound: 1-aminocyclopentamide

[0056] 50.0g (0.25mol) of compound (3) was slowly added to 75mL of concentrated sulfuric acid, stirred, bubbles were generated, and the temperature rose to 90°C. After adding, heat and stir for 1 hour, cool down to 35°C, pour into ice water containing 300mL concentrated ammonia water, extract 6 times with chloroform containing 10% methanol, combine organic phases, dry over anhydrous magnesium sulfate, filter, and evaporate the filtrate under reduced pressure solvent to obtain 35.0 g of white solid, Mp 94-95°C.

Embodiment 3

[0057] Example 3: Preparation of compound of formula 5: 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one hydrochloride 30.0g (0.23mol) compound (4), 33mL (0.24mol) Add triethylamine to 500mL tetrahydrofuran, add dropwise 50mL of a tetrahydrofuran solution of 30g (0.25mol) valeryl chloride, stir for 0.5 hours, add 70mL water, 150mL methanol and 70g potassium hydroxide, reflux for 5 hours, and add 90g chloride Ammonium, stirred for 0.5 hours, concentrated under reduced pressure, added 40 mL of water to the residue, extracted with 100 mL of ethyl acetate x 3, combined the organic layers, added anhydrous magnesium sulfate to dry and filtered, added 20 mL of methanol to the filtrate, cooled to below 20 °C, HCI gas was introduced to pH=1-2, cooled to 0-5°C, stirred for 1 hour, and filtered to obtain 40.2 g of white powdery solid, yield 88.4%, Mp 259-261°C.

[0058] IR (KBr, cm -1 ): 2962.1, 2787.6, 2631.8, 1777.9 (C=O), 1641.4, 1517.4, 1061.2. 1 H-NMR (DMSO-d 6 , 400MHz) δ: 13.648 (br...

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Abstract

The invention discloses a method for synthesizing irbesartan and an intermediate thereof, and belongs to the technical field of preparation methods for medicines. The method comprises the following steps of: protecting 5-(4'-methylbiphenyl-2-yl)-2-(1-methyl-1-phenylethyl)tetrazole by using alpha-methyl styrene under the catalysis of organic acid through the novel convenient reaction process, brominating a benzyl group, condensing a solid phase and a liquid phase under phase transfer to obtain irbesartan protected by 1-methyl-1-phenylethyl, performing acid hydrolysis on the protection to obtain the irbesartan and 2-phenyl-2-propanol, and recovering the 2-phenyl-2-propanol to obtain the alpha-methyl styrene. The invention has the advantages that: the synthetic process is suitable for industrial production, economic value can be produced, the synthetic process is safe, the cost for raw materials is saved, the subsequent product can be easily treated, the reaction raw material is single, and the synthetic method is convenient.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation methods, in particular to a method for synthesizing irbesartan and its intermediates. Background technique [0002] Irbesartan (1) is a non-peptide angiotensin II receptor antagonist with good antihypertensive effect. The structure is as follows: [0003] [0004] In the previous literature, most of the synthesis of irbesartan was through the combination of 2-butyl-1,3-diazaspiro[4,4]non-1-en-4-one and 2'-cyano-4- After bromomethylbiphenyl is condensed, it is prepared by cyclizing the cyano group with an azide derivative to form a tetrazole (for example, CN101006064A, EP454511, WO2005051943, WO9906398), and the use of azide compounds for production will have safety risks. The reaction formula is as follows: [0005] [0006] The second synthesis process is to prepare irbesartan by SUZUKI coupling method, which has little economic value in industrial production due to the use ...

Claims

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Application Information

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IPC IPC(8): C07D257/04C07D403/10
Inventor 屠勇军张毅徐贤光章波
Owner ZHEJIANG TIANYU PHARMA
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