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Method for preparing irbesartan without solvent

A solvent-free and solution-free technology, applied in organic chemistry, bulk chemical production, etc., can solve the problems of increased difficulty in product drying and desolvation, increased difficulty in three wastes treatment, increased post-treatment procedures, etc., to achieve safe and reliable reaction conditions, improve Purity and quality stability, the effect of reducing the production process

Pending Publication Date: 2022-08-02
ZHEJIANG KINGLYUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the introduction of high-boiling-point solvents makes the product solvent residues, resulting in an increase in the post-treatment process, a decrease in the yield, an increase in the difficulty of product drying and desolvation, and an increase in the difficulty of the three wastes treatment, resulting in higher production costs.

Method used

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  • Method for preparing irbesartan without solvent
  • Method for preparing irbesartan without solvent
  • Method for preparing irbesartan without solvent

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] 1) Preparation process: in a 2000mL four-necked reaction flask, add irbesartan hydrocarbyl compound, namely 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]nonane-1) -Alken-3-yl)methyl]biphenyl-2-carbonitrile 300g (0.778mol), triethylamine hydrochloride 107.0g (0.778mol), heated to 80 ℃, the solid material began to melt, when the raw material was completely When melted into a liquid state, start stirring, add sodium azide in 3 times, add 17.2g each time, and add 51.6g (0.778mol) in total at an interval of 1h, then continue to stir and heat up to 100 ° C, keep the reaction 24h, the reaction solution was obtained.

[0040] 2) Post-treatment: prepare 10% liquid caustic soda (sodium hydroxide 77.8 g+water 700 mL), add the liquid caustic soda to the reaction solution in the reaction flask, stir for 30 min to dissolve the feed liquid, then transfer to a separatory funnel, and stand for stratification 1h, the feed liquid is divided into upper and lower layers, the lower alkaline salt-c...

Embodiment 2

[0043] 1) preparation process: in 2000mL four-necked reaction flask, add irbesartan hydrocarbyl compound 300g (0.778mol), triethylamine hydrochloride 160.0g (1.167mol), be heated to be warming up to 100 ℃ to raw material and melt into liquid state completely, Then start stirring, continue to stir and heat up to 110 ° C, and add 75.9 g (1.167 mol) of sodium azide in 5 times, adding 15.18 g each time, each time interval is 1 h, and keep reacting for 20 h to obtain a reaction solution.

[0044] 2) Post-processing: prepare 15% liquid caustic soda (sodium hydroxide 120 g+water 680 mL), add the liquid caustic soda to the reaction solution in the reaction flask, stir for 30 min to dissolve the feed liquid; transfer to a separatory funnel, and let stand for stratification for 1 hour , the feed liquid is divided into upper and lower layers, and the lower alkaline salt-containing phase is discarded; the organic phase of the upper product layer (mainly composed of triethylamine and the pr...

Embodiment 3

[0047] 1) preparation process: in 2000mL four-hole reaction flask, add irbesartan hydrocarbyl compound 300g (0.778mol), triethylamine hydrochloride 214.0g (1.556mol), be heated to be warming up to 100 ℃ to raw material and melt into liquid state completely, Then start stirring, continue to stir and heat up to 110 ° C, and add 101.2 g (1.556 mol) of sodium azide in 3 times, adding 33.73 g each time, each time interval is 1 h, and keep reacting for 18 h to obtain a reaction solution.

[0048] 2) Post-treatment: prepare 20% liquid caustic soda (sodium hydroxide 160 g+water 640 mL), add the liquid caustic soda to the reaction solution in the reaction flask, and stir for 30 min to dissolve the feed solution. Transfer to a separatory funnel, let stand for stratification for 1 hour, the feed liquid is divided into upper and lower layers, discard the lower alkaline brine-containing phase; the upper product layer organic phase (mainly composed of triethylamine and product) is transferre...

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Abstract

The invention relates to a method for preparing irbesartan in a solvent-free manner, which comprises the following steps: heating 4 '-[(2-butyl-4-oxo-1, 3-diazaspiro [4.4] nonyl-1-ene-3-yl) methyl] biphenyl-2-formonitrile and triethylamine hydrochloride until the 4'-[(2-butyl-4-oxo-1, 3-diazaspiro [4.4] nonyl-1-ene-3-yl) methyl] biphenyl-2-formonitrile and triethylamine hydrochloride are molten into a liquid state, then adding sodium azide into a reaction system, and carrying out an addition reaction to generate irbesartan, and after the reaction is finished, adding an alkaline aqueous solution into a reaction solution for extraction, separating to remove an alkaline aqueous layer, adding an inorganic acid solution into a product layer for acidification crystallization, filtering to obtain a crude product, and recrystallizing and drying the crude product to obtain irbesartan. According to the invention, a high-boiling-point solvent is not used in the synthesis process of the tetrazole structure, but solvation treatment is carried out by adopting a reaction substrate, so that no high-boiling-point solvent is left in the obtained product, the production procedures are reduced, and the difficulty of drying and desolvation of the product is greatly reduced; by adopting the technical method provided by the invention, the production cost can be greatly reduced, and meanwhile, the purity and quality stability of the product are improved.

Description

technical field [0001] The present application relates to the technical field of organic synthesis, in particular to a solvent-free method for preparing irbesartan. Background technique [0002] Irbesartan is a non-peptide angiotensin II (AT1) receptor competitive antagonist antihypertensive drug, which has a unique effect on cardiovascular disease. It was developed by the French company sanofi and was first listed in the United Kingdom in 1997. . The chemical structural formula is as follows: [0003] [0004] The main characteristic structures of irbesartan are diazaspiro ring, biphenyl moiety and tetrazolium structure, and important intermediates are: 2-butyl-1,3-diazaspiro[4,4]nonane- 1-En-4-one, N-(triphenylmethyl)-5-(4'-bromomethylbiphenyl-2-yl)tetrazolium, 2-cyano-4'-bromomethylbiphenyl Benzene, 4'-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]biphenyl-2-carbonitrile, etc. There are many synthetic routes, and there are two mature synthetic routes cent...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10
CPCC07D403/10Y02P20/55
Inventor 陈小红盛凯蔓唐雄峰赵斌锋马帅
Owner ZHEJIANG KINGLYUAN PHARMA
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