Preparation method of anti-hypertensive drug

A compound, inert solvent technology, applied in the field of chemical pharmacy, can solve the problems of less by-products, high raw material price, danger, etc.

Inactive Publication Date: 2015-01-28
SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The amidation of these two synthetic routes all uses highly toxic ethyl chloroformate as raw material; and the raw materials of 2-cyano-4'-methylbiphenyl and 2-cyano-4'-bromomethylbiphenyl are relatively expensive , not easy to obtain and other disadvantages
[0013] The third route is the synthesis route of azilsartan introduced in the literature [Chinese Journal of Pharmaceutical Industry, 2010, 41(12), 881-883] and WO2006015134. The total yield of the process is low, which is 14.2%; and the reaction uses relatively dangerous chemical raw materials sodium azide and highly toxic ethyl chloroformate as reaction raw materials, which is not conducive to the safety of industrial production and environmental protection
[0014] In summary, there is still a lack of a method for the preparation of azilsartan with short reaction route, simple operation, few by-products and high total yield in this area.

Method used

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  • Preparation method of anti-hypertensive drug
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  • Preparation method of anti-hypertensive drug

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preparation example Construction

[0099] The preparation method of described formula (IV) compound comprises steps:

[0100] (2) In an inert solvent, the compound of formula (III) is reacted with a halogenating reagent to obtain a compound of formula A;

[0101]

[0102] In the formula, X is a halogen.

[0103] Preferably, in the step (2), the halogenation reagent is selected from the group consisting of chlorine, NCS, thionyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, trichloroisocyanate Uric acid, or combinations thereof; preferably NCS, trichloroisocyanuric acid, or combinations thereof.

[0104] In the step (2), the inert solvent is not particularly limited, and the preferred inert solvent includes (but not limited to) a solvent selected from the following group: dichloromethane, tetrahydrofuran, toluene, xylene, di Hexane, n-heptane, n-hexane, or combinations thereof; preferably dichloromethane.

[0105] Preferably, in the step (2), the reaction temperature i...

Embodiment 1

[0179] (1) Preparation of compound (III):

[0180] Add hydroxylamine hydrochloride solution (10.63g, 152.87mmol, water 50ml) into 20% aqueous sodium hydroxide solution (25mL) at room temperature, and stir at this temperature for 15min, then add 2-formyl-4'-methyl Biphenyl (II) (20.0g, 101.92mmol), and continued to react at this temperature for 2h, and TLC detected that the reaction was complete. After suction filtration, the filter cake was washed three times with water, and dried to obtain 21.1 g of compound (III), with a yield of 98%.

[0181] (2) Preparation of compound (IV):

[0182]Add compound (III) (21.0g, 99.41mmol), DMF (10mL) and DCM (500mL) to a 1L round bottom flask, cool to 0°C, slowly add NCS (14.6g, 109.35mmol), after the addition is complete, place at room temperature After stirring for 2 h, TLC detected that the reaction was complete. Pour the reaction solution into water (300mL), stir for 15min, take the organic phase, wash with water (200mL) and saturated...

Embodiment 2

[0193] (1) Preparation of compound (III):

[0194] Add hydroxylamine hydrochloride solution (10.63g, 152.87mmol, water 50ml) into 20% aqueous sodium hydroxide solution (25mL) at room temperature, and stir at this temperature for 15min, then add 2-formyl-4'-methyl Biphenyl (II) (20.0g, 101.92mmol), and continued to react at this temperature for 2h, and TLC detected that the reaction was complete. After suction filtration, the filter cake was washed three times with water, and dried to obtain 20.9 g of compound (III), with a yield of 97%.

[0195] (2) Preparation of compound (IV):

[0196] Add compound (III) (20.5g, 97.04mmol), DMF (10mL) and DCM (500mL) to a 1L round bottom flask, cool to 0°C, slowly add NCS (14.25g, 106.74mmol), after the addition is complete, place at room temperature After stirring for 2 h, TLC detected that the reaction was complete. Pour the reaction solution into water (300mL), stir for 15min, take the organic phase, wash with water (200mL) and saturat...

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Abstract

The invention provides a preparation method of an anti-hypertensive drug. Specifically the invention provides a novel intermediate: 2-ethoxy-1-{[2'-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-yl)biphenyl-4-yl]methyl}-1H-benzoimidazole-7-carboxylic acid (Azilsartan). The intermediate is represented by the formula A, wherein in the formula the X represents an H atom or a halogen atom. The Azilsartan can be rapidly and conveniently prepared through the prepared intermediate represented by the formula A. Moreover, the preparation method has the advantages of short reaction route, less by products, high total yield, and mild conditions, and is suitable for industrial production of Azilsartan.

Description

technical field [0001] The invention relates to the technical field of chemical pharmacy, in particular to an antihypertensive drug 2-ethoxy-1-{[2'-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole -3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (I) synthesis method. Background technique [0002] Azilsartan is a drug for the treatment of hypertension, which can reduce blood pressure by blocking the activity of angiotensin Ⅱ receptors. As an angiotensin Ⅱ receptor antagonist, it can be used alone Use or use with other blood pressure lowering drugs. The drug has the advantages of good effect, good curative effect and high bioavailability, and may also reduce the risk of cardiovascular disease and diabetes through various mechanisms. Azilsartan was first launched in Japan by Takeda Pharmaceutical in January 2012. [0003] Its chemical structure is as follows: [0004] [0005] According to existing literature, the synthetic route of preparing Azilsartan has as foll...

Claims

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Application Information

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IPC IPC(8): C07C259/02C07D413/10C07D271/07
Inventor 李新涓子李健之马西来池王胄刘海胡旭华郑肖利翟志军李建勋
Owner SHANGHAI TIANCI BIOLOGICAL VALLEY BIOLOGICAL ENG
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