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Azilsartan medoxomil preparation method

A technology of azilsartan medoxomil and compounds, applied in the field of hypertension drug synthesis, can solve the problems of long routes, increased consumption, increased production costs, etc.

Inactive Publication Date: 2016-03-16
方晏燕 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This synthesis method route is too long, causes productive rate low; Simultaneously raw material 4 '-bromomethyl-2-cyanobiphenyl is added prematurely, causes its consumption to increase, has increased production cost

Method used

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  • Azilsartan medoxomil preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0014] The preparation of embodiment one 4'-bromomethyl-2-cyanobiphenyl

[0015]

[0016] 206g2-ethoxybenzimidazole-7-carboxylic acid and 195g4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one formula IV are dissolved in 2LN, N - In dimethylformamide, cool the mixture to 0-5°C, add 207g of potassium carbonate, 230g of p-toluenesulfonyl chloride and 35g of 4-dimethylaminopyridine in sequence, and react at 0-5°C for 1 hour after the addition is complete. Raise the temperature to 15°C and continue to stir the reaction for 12 hours. After the reaction was detected by TLC, adjust the pH to 5 with 0.5 mol / L hydrochloric acid, add 2L ethyl acetate and 2L water layer, and wash the ethyl acetate layer with 1L water Wash twice, concentrate the organic phase to obtain a solid that was refluxed with 500 mL of methanol for 4 h, cooled to room temperature and filtered, and the filter cake was further refluxed with 500 mL of methanol for 4 h, cooled to room temperature for filtration, and dried...

Embodiment 2

[0023] The preparation of embodiment two 2-ethoxybenzimidazole-7-carboxylic acid

[0024] References for the preparation of 2-ethoxybenzimidazole-7-carboxylic acid AFacile One-pot Synthesis of Benzimidazoles from 2-Nitroanilines by ReductiveCyclization (Heterocycles, 2008, 8(75): 1907-1911).

Embodiment 3

[0025] The preparation of embodiment three azilsartan medoxomil

[0026] Step 1) Preparation of Compound I

[0027]

[0028] At room temperature, add 250 g of hydroxylamine hydrochloride and 370 g of sodium bicarbonate to 5 LN, N-dimethyl sulfoxide solvent, stir to dissolve it, heat the mixture to 50 ° C, and add 100 g of 4′-bromomethyl- 2-cyanobiphenyl, after the addition, the temperature of the mixture was raised to 90-95°C to continue the reaction for 48 hours, the reaction progress was detected by TLC method, cooled to room temperature, filtered, the filtrate was poured into 10L water, continued to stir for 1 hour, filtered, filtered The cake was washed with 1L of water and dried to obtain 96g of compound I with a yield of 85.6%.

[0029] 1 H-NMR (400MHz, MEOD) δ 4.76 (s, 2H), 7.21-7.87 (m, 8H). LC-MS: m / z = 306.1 (C 14 h 13 BrN 2 O+H + ).

[0030] Step 2) Preparation of Compound II

[0031]

[0032] At room temperature, 150 g of compound I was dissolved in 2...

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Abstract

The present invention relates to an azilsartan medoxomil synthesis method, wherein 4'-bromomethyl-2-biphenylcarbonitrile is adopted as a raw material, a hydroxylamine reaction is performed, cyclization is performed to prepare a compound II, 2-ethoxy benzimidazole-7-carboxylic acid is adopted as a raw material, an esterification reaction is performed to obtain a compound V, and the compound II reacts with the compound V to prepare the azilsartan medoxomil. According to the present invention, the method has characteristics of short synthesis route, easy operation, high yield, 4'-bromomethyl-2-biphenylcarbonitrile consumption reducing, and cost reducing. The compounds I, II and IV are defined in the specification.

Description

technical field [0001] The invention relates to the field of synthesis of hypertension drugs, in particular to a preparation and synthesis method of azilsartan medoxomil. Background technique [0002] Azilsartan medoxomil (Azilsartan medoxomil) is a new generation of selective AT1 subtype angiotensin II receptor antagonists (ARBs) antihypertensive drugs, developed by Takeda Pharmaceutical Co., Ltd., on February 25, 2011 Approved by the FDA for marketing in the United States, the trade name is Edarbi. Compared with other hypertension drugs such as β receptor blockers, calcium channel blockers (CCB), and angiotensin inhibitors (ACEI), azilsartan medoxomil has stable blood pressure reduction, less adverse reactions, and does not cause irritation Due to the advantages of dry cough, it is widely used in the prevention and treatment of clinical hypertensive diseases. The structural formula of Azilsartan medoxomil is as follows: [0003] [0004] At present, the specific synt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D413/14
Inventor 方晏燕杨继斌
Owner 方晏燕
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