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Preparation method of telmisartan impurity B

A technology for telmisartan and impurities, applied in the field of preparation of telmisartan impurity B, can solve the problems such as no public information reporting impurity B synthesis method, no sales, etc.

Active Publication Date: 2011-10-19
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] There are 7 impurities in the European Pharmacopoeia 2008 7.0 edition telmisartan quality standard, wherein impurity B (formula I) compound is not sold on the market, and there is no public information to report the synthetic method of impurity B

Method used

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  • Preparation method of telmisartan impurity B
  • Preparation method of telmisartan impurity B
  • Preparation method of telmisartan impurity B

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Step 1: Preparation of 4-[N-(2'-cyanobiphenyl-4-methylene)butyramide]-3-methyl-5-nitro-benzoic acid methyl ester

[0044] At room temperature, add 14.0 g of 4-butyrylamino-3-methyl-5-nitro-benzoic acid methyl ester, 13.8 g of potassium carbonate and 70 mL of dimethylformamide solvent into a 250 mL four-necked flask, and stir for 0.5 h. Then add 14.00 g of 4'-bromomethyl-biphenyl-2-carbonitrile in one go, continue to stir at room temperature for 1 h, and monitor the reaction by thin-layer chromatography (dichloromethane:methanol=20:1), the results show that the raw materials are completely consumed , generating a strong UV spot with a slightly smaller polarity.

[0045] The solvent was distilled off under reduced pressure (60°C), and a large amount of white solid was precipitated. Add 70mL of water, stir for 0.5h, filter, wash the filter cake twice with water (about 30mL each time), and dry to obtain 23.5g of white product.

[0046] The preparation of the second step 1-...

Embodiment 2

[0065] Step 1: Preparation of 4-[N-(2'-cyanobiphenyl-4-methylene)butyramide]-3-methyl-5-nitro-benzoic acid methyl ester

[0066] At room temperature, add 14.0 g of 4-butyrylamino-3-methyl-5-nitro-benzoic acid methyl ester, 16.8 g of sodium bicarbonate and 80 mL of tetrahydrofuran solvent into a 250 mL four-neck flask, stir for 1 hour, and then add 14.0 g (0.052 mol) of 4'-bromomethyl-biphenyl-2-carbonitrile was stirred at room temperature for 1 h.

[0067] The solvent was distilled off under reduced pressure (60°C), and a large amount of white solid was precipitated. Add 70mL of water, stir for 0.5h, filter, wash the filter cake twice with water (30mL×2), and dry to obtain 22.5g of white product.

[0068] Preparation of the second step 1-(2'-cyanobiphenyl-4-methylene)-7-methyl-2-n-propyl-1H-benzimidazole-5-formic acid methyl ester

[0069] At room temperature, add 4-[N-(4'-cyanobiphenyl-2-methylene)butyrylamide]-3-methyl-5-nitro-benzoic acid methyl ester 23.6 g, 120mL of gla...

Embodiment 3

[0086] Example 3 Preparation of 1-(2'-cyanobiphenyl-4-methylene)-7-methyl-2-n-propyl-1H-benzimidazole-5-methyl carboxylate

[0087] At room temperature, add 4-[N-(4'-cyanobiphenyl-2-methylene)butyrylamide]-3-methyl-5-nitro-benzoic acid methyl ester 23.6 g, 120mL of glacial acetic acid solvent and 5.6g of aluminum powder, stirred, and slowly raised the temperature to 80°C to reduce the ring closure for 1h.

[0088] Cool to about 80°C, filter hot, rinse the aluminum sludge with 100mL dichloromethane (dichloromethane), extract the dichloromethane filtrate for later use, add 250mL water after the acetic acid filtrate spins dry, extract 3 times with dichloromethane (100mL×3 ), combined organic phases, washed once with 50mL of 10% aqueous sodium bicarbonate solution, washed once with 50mL of water, dried over anhydrous sodium sulfate, filtered, and evaporated the solvent to obtain 21.6g of light yellow oil.

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Abstract

The invention relates to a preparation method of an impurity B in telmisartan bulk drugs which are antihypertensive drugs. Seven impurities appear in the quality standards of telmisartan in European Pharmacopoeia, 7th Edition, 2008, impurity B is out of the market service, and synthetic methods of the impurity B are not reported by public data. The invention provides the preparation method of the telmisartan impurity B and provides qualified reference substances for controlling the quality of telmisartan.

Description

technical field [0001] The invention relates to a preparation method of telmisartan impurity B. Background technique [0002] Telmisartan is a new antihypertensive drug and a specific angiotensin II receptor (AT1 type) antagonist. The compound can replace the angiotensin II receptor and bind with high affinity to the AT1 receptor subtype (the known action site of angiotensin II), and the binding effect is long-lasting. The drug is developed and manufactured by Boehringer Ingelheim, Germany. [0003] There are 7 impurities in the European Pharmacopoeia 2008 7.0 edition telmisartan quality standard, wherein impurity B (formula I) compound is not sold on the market, and there is no public information to report the synthetic method of impurity B. Quality analysis of telmisartan must have a qualified compound of formula I as a reference substance. [0004] [0005] Formula I Contents of the invention [0006] The technical problem to be solved in the present invention is...

Claims

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Application Information

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IPC IPC(8): C07D235/18
Inventor 刘桂峰刘菲姜琪夏海建李宗文
Owner 迪嘉药业集团股份有限公司
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