Preparation of losartan

A technology of reaction solution and hydroxymethyl, which is applied in the field of preparation of losartan, a high blood pressure drug, can solve problems such as difficult recovery of solvents, environmental impact, and impact on product yield, and achieve the goals of small amount of solvent, small damage, and cost reduction Effect

Active Publication Date: 2012-05-30
ZHEJIANG MENOVO PHARMA
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Problems solved by technology

[0008] PCT patent WO2007020654A1 discloses 2-butyl-4-chloro-5-(hydroxymethyl)-1-[(2'-cyano)-biphenyl-4-methyl]imidazole represented by formula (II) Reaction with triethylamine hydrochloride and sodium azide in the presence of a polar protic solvent, wherein the polar protic solvent is dimethylformamide (DMF), dimethylacetamide (DMA), dimethylmethylene Sulfone (DMSO), N-methylpyrrolidone (NMP), 1,3-dimethyl-2-imidazolinone (DMI), because the polar protic solvent here has a high boiling point, the solvent is not easy to recycle, and must be added during post-treatment Diluted with a large amount of water, it is easy to affect the environment and affect the yield of the final product

Method used

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Examples

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Embodiment 1

[0028] Example 1: Preparation of Losartan

[0029] To 2-butyl-4-chloro-5-(hydroxymethyl)-1-{[(2'-cyano)biphenyl-4-yl]methyl}imidazole (200g, 0.53mol), azide Add 400ml of toluene to sodium (100g, 1.54mol) and triethylamine hydrochloride (215g, 1.54mol), react at 100°C for 40 hours, cool to 20-30°C, adjust the pH of the reaction solution with alkaline water 9-10, separate the toluene layer, add sodium metabisulfite (50g, 0.26mol) to the resulting reaction solution, stir for 30 minutes, add 200ml ethyl acetate, adjust the pH of the reaction solution to 3.5 with dilute hydrochloric acid, and stir for 6 hours to obtain a solid wet The wet product was dissolved in 400ml isopropanol, heated under reflux and cooled to 10-20°C, filtered and dried to obtain Losartan (201g, molar yield 90%).

Embodiment 2

[0030] Example 2: Preparation of Losartan

[0031] To 2-butyl-4-chloro-5-(hydroxymethyl)-1-{[(2'-cyano)biphenyl-4-yl]methyl}imidazole (200g, 0.53mol), azide Add 400ml of toluene to sodium (100g, 1.54mol) and triethylamine hydrochloride (215g, 1.54mol), react at 100°C for 40 hours, cool to 20-30°C, adjust the pH of the reaction solution with alkaline water 9-10, divided into three layers, add sodium metabisulfite (50g, 0.26mol) to the middle layer, stir for 30 minutes, add 200ml ethyl acetate, adjust the pH of the reaction solution to 3.5 with dilute hydrochloric acid, and stir for 6 hours to obtain a solid wet product. The wet product was dissolved in 400ml of isopropanol, heated under reflux and cooled to 10-20°C, filtered and dried to obtain Losartan (203g, molar yield 91%).

Embodiment 3

[0032] Example 3: Preparation of Losartan

[0033] To 2-butyl-4-chloro-5-(hydroxymethyl)-1-{[(2'-cyano)biphenyl-4-yl]methyl}imidazole (200g, 0.53mol), azide Add 400ml of toluene to sodium (100g, 1.54mol), triethylamine hydrochloride (215g, 1.54mol), react at 120°C for 40 hours, cool to 20-30°C, adjust the pH of the reaction solution to 9 with alkaline water ~10, separate the toluene layer, add sodium nitrite (36.6g, 0.53mol) to the resulting reaction solution, stir for 30 minutes, add 200ml ethyl acetate, adjust the pH of the reaction solution to 3.0 with dilute hydrochloric acid, stir for 8 hours, filter and dry Losartan (215 g, 96% molar yield) was obtained.

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Abstract

The invention provides a method for preparing losartan shown in a formula (I). The method comprises the following steps: reacting 2-butyl-4-chlorine-5-(hydroxymethyl)-1-{[(2'- cyano-group) xenyl-4-group]methyl} imidazole and natrium azide and triethylamine hydrochloride shown in a formula (II) in toluol; regulating the obtained reaction liquid by alkali to separate organic layers; adding a reducing agent into the collected liquid; regulating the obtained reaction liquid by acid to obtain losartan solid; and if required, refining the losartan solid by isopropyl alcohol. The method has the advantages of high yield, high purity of the losartan, low cost, little environmental pollution and suitability for industrialized production.

Description

(1) Technical field [0001] The invention relates to a preparation method of the hypertension drug Losartan. (2) Background technology [0002] Losartan Potassium (Losartan Potassium) was developed by the United States DuPont and Merck. It is the first non-peptide angiotensin II receptor antagonist to be marketed. [0003] The chemical name of Losartan is: 2-butyl-4-chloro-5-(hydroxymethyl)-1-{[(2'(1H-tetrazole-5-)biphenyl-4-yl] Methyl}imidazole, the structural formula is shown in the following formula I: [0004] [0005] There are many synthetic methods for preparing Losartan. At present, four patent documents have disclosed the 2-butyl-4-chloride represented by formula (II) [0006] 5-(hydroxymethyl)-1-{[(2'-cyano)biphenyl-4-yl]methyl}imidazole tetrazole to prepare Losartan. [0007] [0008] PCT patent WO2007020654A1 discloses 2-butyl-4-chloro-5-(hydroxymethyl)-1-[(2'-cyano)-biphenyl-4-methyl]imidazole represented by formula (II) It reacts with triethylamine hydrochloride and sod...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/10A61P43/00
Inventor 龚道新焦华石建祥
Owner ZHEJIANG MENOVO PHARMA
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