Preparation method of irbesartan isomer and irbesartan intermediate

A technology of irbesartan and isomers, which is applied in the field of preparation of irbesartan isomers and their intermediates, can solve the problems of reporting impurities of irbesartan isomers and preparation methods of their intermediates, etc. Achieve environmental friendliness, low energy consumption and cost, and simple operation

Inactive Publication Date: 2016-11-09
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Irbesartan isomers are important potential process impurities produced during the preparation of irbesar...

Method used

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  • Preparation method of irbesartan isomer and irbesartan intermediate
  • Preparation method of irbesartan isomer and irbesartan intermediate
  • Preparation method of irbesartan isomer and irbesartan intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Add 70.0g irbesartan cyclic compound hydrochloride, 82.0g biphenyl bromide, 2.0g tetrabutylammonium bromide and 300mL cyclohexane into a 500mL three-necked flask, and add 240g 30% sodium hydroxide solution at 5°C . Raise the temperature of the material solution to 30° C. and stir for 10 hours to react, and the reaction of the material is complete. The reaction solution was filtered, and the filter cake was separated by column chromatography (using ethyl acetate as eluent) to obtain 40.9 g of irbesartan condensate isomers, with a yield of 35% and a purity of 99.1% by HPLC;

[0030] Add 20g of irbesartan condensate isomers, 14.2g of triethylamine hydrochloride, 6.9g of sodium azide and 125mL of xylene into a 250mL three-neck flask, raise the temperature to 125°C and react for 20-25 hours, and the raw materials are completely reacted . Add 45g of 30% sodium hydroxide solution and 35mL of ethyl acetate to the reaction solution, stir, let stand, and separate the organic la...

Embodiment 2

[0032] Add 70.0g irbesartan cyclic compound hydrochloride, 78.5g biphenyl bromide, 2.0g tetrabutylammonium bromide and 300mL cyclohexane into a 500mL three-necked flask, and add 180g 30% sodium hydroxide solution at 5°C . Raise the temperature of the material solution to 30° C. and stir for 10 hours to react, and the reaction of the material is complete. The reaction solution was filtered, and the filter cake was separated by column chromatography (using ethyl acetate as the eluent) to obtain 37.4 g of irbesartan condensate isomers, with a yield of 32% and a HPLC purity of 99.3%;

[0033] Add 20g of irbesartan condensate isomers, 14.2g of triethylamine hydrochloride, 6.9g of sodium azide and 100mL of xylene into a 250mL three-neck flask, raise the temperature to 125°C and react for 20-25 hours, and the raw materials are completely reacted . Add 45g of 30% sodium hydroxide solution and 35mL of ethyl acetate to the reaction solution, stir, let stand, and separate the organic l...

Embodiment 3

[0035] Add 70.0g irbesartan cyclic compound hydrochloride, 82.0g biphenyl bromide, 2.0g tetrabutylammonium bromide, 100mL tert-butyl acetate and 100mL n-hexane into a 500mL three-necked flask, add 135g 30 % sodium hydroxide solution. Raise the temperature of the feed liquid to 30° C. and stir for 8 hours to react, and the raw materials are completely reacted. The reaction solution was filtered, and the filter cake was separated by column chromatography (using ethyl acetate as the eluent) to obtain 27.2 g of irbesartan condensate isomers, with a yield of 23.2% and a purity of 99.4% by HPLC;

[0036] Add 20g of irbesartan condensate isomers, 14.2g of triethylamine hydrochloride, 6.9g of sodium azide and 125mL of xylene into a 250mL three-neck flask, raise the temperature to 125°C and react for 20-25 hours, and the raw materials are completely reacted . Add 45g of 30% sodium hydroxide solution and 35mL of ethyl acetate to the reaction solution, stir, let stand, and separate the...

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Abstract

The invention relates to a preparation method of an irbesartan isomer and an irbesartan condensation compound isomer as an irbesartan intermediate. The method comprises the following steps: 1) a phase transfer catalyst and an organic solvent are added to an irbesartan ring compound hydrochloride and biphenyl bromide, a sodium hydroxide solution is added, a reaction liquid is filtered after sufficient reaction of the raw materials, a filter cake is subjected to column chromatographic separation, and the irbesartan condensation compound isomer is obtained; 2) triethylamine hydrochloride, sodium azide and an organic solvent A are added to the irbesartan condensation compound isomer, the materials are heated to 100-130 DEG C and reacted, the sodium hydroxide solution and an organic solvent B are added, the mixture is stirred, left to stand and subjected to organic layer removal, hydrochloric acid is added to an aqueous-layer solution to regulate pH to 3.5-6.0, the solution is stirred and filtered, a filter cake is subjected to recrystallization with an organic solvent C or subjected to column chromatographic separation, and the irbesartan isomer is obtained. The irbesartan isomer impurity and the irbesartan intermediate prepared with the method have higher purity and lower energy consumption and cost. Meanwhile, the preparation method is simple to operate and environment-friendly and has important value in irbesartan production and research.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a method for preparing irbesartan isomers and intermediates thereof. technical background [0002] Irbesartan is an angiotensin II (AT1) receptor competitive antagonist developed by the French company Sanofi, which lowers blood pressure by blocking type I angiotensin II (AT-II) receptors. Irbesartan was first launched in the UK in 1997 and is clinically used for the treatment of hypertension. [0003] [0004] The chemical name of irbesartan is: 3-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2-butyl -1,3-diazaspiro[4,4]non-1-en-4-one. [0005] The chemical name of the isomer of irbesartan is: 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-2 -Butyl-1,3-diazaspiro[4,4]non-1-en-4-one. [0006] [0007] The chemical name of the irbesartan condensate is 2-cyano-4'-((2-butyl-4-keto-1,3-diazaspiro[4.4]non-1-en-3-yl) Methyl)-1,1'-biphenyl. [0008...

Claims

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Application Information

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IPC IPC(8): C07D403/10C07D235/02
CPCC07D235/02C07D403/10
Inventor 王松青陈旺炜董鹏包有超黄风菱
Owner ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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