Method for synthesizing irbesartan and intermediate thereof

A technology of intermediates and compounds, which is applied in the field of drug preparation, can solve the problems of high cost, cumbersome preparation process, and safety risks, and achieve the effects of saving raw material costs, convenient synthesis methods, and ensuring safety

Active Publication Date: 2014-04-09
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 compound of formula 3: 1-aminocyclovaleronitrile oxalate

[0054] 20g (0.41mol) sodium cyanide dissolved in 40mL water, add 23g (0.43mol) ammonium chloride aqueous solution 60mL, 20% ammonia water 35mL and 30g (0.36mol) cyclopentanone methanol solution 40mL, stir at room temperature for 1.5 hours, warm up Stir for another 45 minutes at 60°C, stop heating, and continue stirring for 45 minutes. Reduce to room temperature, extract with 80mL×6 methylene chloride, dry the organic phase with anhydrous magnesium sulfate, filter, and concentrate the filtrate. The remaining oily substance 41g is dissolved in 100mL acetone, and 25g (0.28mol) oxalic acid in acetone solution 200mL is added with stirring. The solid was separated out, 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 the compound of formula 4: 1-aminocyclopentaneamide

[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, keep stirring for 1 hour, cool to 35℃, pour into ice water containing 300mL concentrated ammonia, extract 6 times with chloroform containing 10% methanol, combine the organic phases, dry with anhydrous magnesium sulfate and filter, and distill the filtrate under reduced pressure Solvent, white solid 35.0g, Mp 94~95℃.

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 500mL of tetrahydrofuran to triethylamine, dropwise add 50mL of 30g (0.25mol) valeryl chloride solution in tetrahydrofuran, stir for 0.5 hour, add 70mL of water, 150mL of methanol and 70g of potassium hydroxide, reflux for 5 hours, and add 90g of chlorinated to room temperature Ammonium, stirred for 0.5 hours, concentrated under reduced pressure, added 40 mL of water to the residue, extracted with ethyl acetate 100 mL×3, combined the organic layers, added anhydrous magnesium sulfate, dried and filtered, added 20 mL of methanol to the filtrate, and cooled to below 20°C. Pass HCI gas to PH=1~2, cool to 0~5℃, stir for 1 hour, and filter to obtain 40.2g of white powdery solid, yield 88.4%, Mp 259~261℃.

[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...

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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 pharmaceutical preparation methods, and specifically relates to a method for synthesizing irbesartan and its intermediates. Background technique [0002] Irbesartan (1) is a non-peptide angiotensin II receptor antagonist, which has a good hypotensive effect. The structure is as follows: [0003] [0004] In the previous literature, most of the synthesis of irbesartan is through 2-butyl-1,3-diazaspirocyclo[4,4]non-1-en-4-one and 2'-cyano-4- After condensing bromomethyl biphenyl, it is prepared by cyclizing the cyano group with an azide derivative to generate a tetrazole (for example, CN101006064A, EP454511, WO2005051943, WO9906398). The use of azide compounds in production will have safety risks. The reaction formula is as follows: [0005] [0006] The second synthesis process is to prepare irbesartan by the SUZUKI coupling method. Because of the zero-valent palladium catalysis, it has little economic value in ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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