Method for preparing irbesartan without solvent

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...

Examples

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...

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...

Examples

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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