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Synthetic method of irbesartan

A synthetic method and methyl technology, applied in the field of pharmaceutical preparation, can solve the problems of life-threatening operators, difficulty in removing isomers, affecting the purity of the final product, etc., and achieve low-cost raw materials, convenient post-processing, and low equipment requirements. Effect

Active Publication Date: 2018-07-13
山东大医精诚药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0015] The synthetic method of irbesartan in the prior art is to use cyclopentanone as a starting material, which inevitably uses highly toxic, inflammable and explosive sodium cyanide or potassium cyanide, which is not only extremely harmful to the environment, but also And it also poses a potential threat to the life of the operator, and while synthesizing 2-butyl-1,3-diazaspiro[4,4]nonan-1-en-4-one, it is inevitable It will produce isomer 2-butyl-1,3-diazaspiro[4,4]nonane-1-en-8-one, which will also participate in the next reaction, and the generated iso The conformation is difficult to get out, thereby affecting the purity of the final product; and at least six steps of reaction are required to obtain the final product, and the route is also slightly longer

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0044] A synthetic method of irbesartan, comprising the following steps:

[0045] (1) Add glycine methyl ester hydrochloride (25.11g, 200mmol) and 200mL of dichloromethane in a 500mL single-necked bottle, cool to 0°C in a low-temperature bath, add triethylamine (34.7mL, 750mmol), and The reaction was stirred at °C for 0.5 h, then n-valeryl chloride (25.1 mL, 210 mmol) was slowly added dropwise, and reacted at 0 °C for 6 h. After the reaction, the reaction system was filtered, the filtrate was washed three times with saturated NaCl solution, the organic phase was dried with anhydrous sodium sulfate, filtered with suction, and the filtrate was evaporated to dryness to obtain 32.16 g of light yellow oily liquid N-n-pentanoyl glycine methyl ester, the yield 93.36%. The proton nuclear magnetic resonance spectrum of N-n-pentanoylglycine methyl ester is as attached figure 2 shown. 1HNMR (400MHz, Chloroform-d) δ6.02(s, 1H), 4.07(d, J=5.1Hz, 2H), 3.78(s, 2H), 2.27(t, J=7.6Hz, 2H), ...

Embodiment 2

[0051] A synthetic method of irbesartan, comprising the following steps:

[0052] (1) Add glycine methyl ester hydrochloride (25.11g, 200mmol) and 200mL of dichloromethane in a 500mL single-necked bottle, cool to -10°C in a low-temperature bath, add pyridine (31.64mL, 400mmol), and The reaction was stirred under low temperature for 0.5h, then n-valeryl chloride (23.9mL, 200mmol) was slowly added dropwise, and reacted at -10°C for 8h. After the reaction, the reaction system was filtered, the filtrate was washed three times with saturated NaCl solution, the organic phase was dried with anhydrous sodium sulfate, filtered with suction, and the filtrate was evaporated to dryness to obtain 30.34 g of light yellow oily liquid with a yield of 88.08%.

[0053] (2) Add 4'-aminomethyl-2-cyanobiphenyl (20.83g, 100mmol), N-n-pentanoyl glycine methyl ester (17.325g, 100mmol) and catalyst sodium ethylate (10.2 g, 150mmol), heated to reflux for 20h, after the reaction was over, most of the s...

Embodiment 3

[0058] A synthetic method of irbesartan, comprising the following steps:

[0059](1) Add glycine methyl ester hydrochloride (25.11g, 200mmol) and 200mL of dichloromethane in a 500mL single-necked bottle, cool to 0°C in a low-temperature bath, add triethylamine (70mL, 800mmol), and The reaction was stirred under low temperature for 0.5h, then n-valeryl chloride (28.7mL, 240mmol) was slowly added dropwise, and reacted at 20°C for 3h. After the reaction, the reaction system was filtered, the filtrate was washed three times with saturated NaCl solution, the organic phase was dried with anhydrous sodium sulfate, filtered with suction, and the filtrate was evaporated to dryness to obtain 33.21 g of a light yellow oily liquid with a yield of 96.41%.

[0060] (2) Add 4'-aminomethyl-2-cyanobiphenyl (20.83g, 100mmol), N-n-pentanoyl glycine methyl ester (27.72g, 160mmol) and catalyst potassium acetate (34.3 g, 350mmol), heated to reflux for 24h, after the reaction was over, most of the ...

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Abstract

The invention discloses a synthetic method of irbesartan. The method comprises the following steps: by using glycine methyl ester hydrochloride as an initial raw material, performing the acylation reaction on the glycine methyl ester hydrochloride and valeryl chloride to obtain N-pentanoyl glycine methyl ester, performing the aminolysis reaction of ester on the N-pentanoyl glycine methyl ester and4-aminomethyl-2'-cyanobiphenyl, thus obtaining a bisamide intermediate, condensing the bisamide intermediateunder the catalysis of acid to establish a five-membered ring, reacting with 1,4-dihalogenated butane in the presence of alkali to obtain irbesartan hydrocarbon, and finally performing the cyclization reaction with sodium azide to obtain irbesartan. According to the synthetic method of theirbesartan, the glycine methyl ester hydrochloride is first used as the initial raw material, so that the use of sodium cyanide or potassium cyanide in an existing production process is avoided, and the production operation is safer and more convenient. The novel synthetic method has the advantages that the raw materials are low in price and easy to obtain, no toxic cyanide is used, the environment friendliness is achieved, the cost is low and the like, and is suitable for the industrialized application.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a synthesis method of irbesartan. Background technique [0002] The chemical name of irbesartan is 2-butyl-3-[[2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl]methyl]-1 ,3-diazaspiro[4.4]non-1-en-4-one, the chemical structure is as follows: [0003] [0004] Irbesartan is a long-acting angiotensin II receptor antagonist with a half-life of 11 to 15 hours. It was first launched in the UK in 1997 for the treatment of hypertension. Both imported and domestic drugs have been listed in my country. This product has good safety and tolerance, few adverse reactions, no first-pass and postural hypotension effects, and no rebound phenomenon after drug withdrawal. Irbesartan has a strong affinity for AT2 and is suitable for various degrees of essential hypertension. As a new class of antihypertensive drugs, it has attracted widespread attention in recent years. With...

Claims

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Application Information

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IPC IPC(8): C07D403/10
CPCC07D403/10
Inventor 乔仁忠李建明王金鑫李超
Owner 山东大医精诚药业有限公司
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