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Crystalline 1-(cyclohexyloxycarbonyloxy) ethyl 1-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1h-benzo[d]imidazole-7-carboxylate and a process for its preparation

A technology of oxycarbonyloxy and cyanobiphenyl, which is applied in the field of useful intermediates for the preparation of candesartan cilexetil, and can solve problems such as difficult purification and handling

Inactive Publication Date: 2010-03-24
KRKA D D NOVO MESTO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] The disadvantage of the existing method is that the isolated 1-((2′-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid 1-(Cyclohexyloxycarbonyloxy)ethyl ester is a viscous, resinous form that is difficult to purify and handle when it is used in the preparation of candesartan cilexetil

Method used

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  • Crystalline 1-(cyclohexyloxycarbonyloxy) ethyl 1-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1h-benzo[d]imidazole-7-carboxylate and a process for its preparation
  • Crystalline 1-(cyclohexyloxycarbonyloxy) ethyl 1-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1h-benzo[d]imidazole-7-carboxylate and a process for its preparation
  • Crystalline 1-(cyclohexyloxycarbonyloxy) ethyl 1-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1h-benzo[d]imidazole-7-carboxylate and a process for its preparation

Examples

Experimental program
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Effect test

Embodiment 1

[0153] 1-((2′-cyanobiphenyl-4-yl)methyl-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid 1-(cyclohexyloxy Preparation and Crystallization of Carbonyloxy)ethyl Ester

[0154] 2.16g (4mmol) 1-(4-bromobenzyl)-2-ethoxyl-1H-benzimidazole-7-carboxylic acid 1-[[(cyclohexyloxy)carbonyl]oxyl]ethyl ester, Add 1.2g (5.74mmol) (2-cyanophenyl)-potassium trifluoroborate, 20mg (0.09mmol) palladium acetate, 40mg (0.13mmol) tris-o-tolylphosphine to a dry flask equipped with a reflux condenser middle. The flask was capped with a septum and filled with nitrogen three times. 24 mL of ethanol and 1.2 mL of diisopropylethylamine were added to the flask via syringe. The reaction mixture was heated at reflux for 5 hours. The seal was then broken, the reaction mixture was exposed to air, cooled, filtered and the solvent was evaporated under vacuum. To the residue were added 80 ml of isopropyl acetate and 80 ml of 1% HCl. Stir, then separate the mixture. The organic phase was washed twice with...

Embodiment 2

[0158] 1-((2′-cyanobiphenyl-4-yl)methyl-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid 1-(cyclohexyloxy Preparation and Crystallization of Carbonyloxy)ethyl Ester

[0159] a) 2-ethoxy-1-[(2'-cyanobiphenyl-4-yl)-methyl]-1H-benzimidazole-7-carboxylic acid

[0160] A mixture of ethyl 2-ethoxy-1-[(2'-cyanobiphenyl-4-yl)-methyl]-1H-benzimidazole-7-carboxylate, 150 ml methanol and 37.5 ml 1M NaOH Heated at reflux for 3-4 hours. The reaction mixture was then cooled and the solvent was evaporated under vacuum. 150 ml of water were added to the residue. 1M HCl (42ml) was added to acidify the mixture. The precipitated product was collected by filtration, washed and dried under reduced pressure for 2 h (11.8 g, 98%).

[0161] b) 1-((2′-cyanobiphenyl-4-yl)methyl-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy base) ethyl ester

[0162] 11.8g (29.7mmol) 2-ethoxy-1-[(2'-cyanobiphenyl-4-yl)-methyl]-1H-benzimidazole-7-carboxylic acid, 30ml dimethyl ethyl...

Embodiment 3

[0166] 1-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid 1-(Cyclohexyloxycarbonyloxy)ethyl ester (candesartan cilexetil)

[0167] Step 1 - Suzuki Reaction

[0168] The glassware was dried in an air dryer at 130° C., the flask was vented with argon, and 1-(4-bromobenzyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid 1-( Cyclohexyloxycarbonyloxy)ethyl ester (16.4g, 30mmol), potassium 2-cyanophenyltrifluoroborate (7.22g, 34.5mmol), palladium acetate (0.00225g), triphenylphosphine (0.078g ), diisopropylethylamine (9ml) and ethanol (180ml). The reaction mixture was heated at reflux temperature for 18.5 h. The mixture was cooled to room temperature, and the precipitate was filtered off. To the filtrate was added 300ml of isopropyl acetate and washed with 1% HCl (240ml). Then the organic phase was washed with saturated NaHCO 3 (240ml) and water (240ml) wash, Na 2 SO 4 (30 g) dried. The solvent was removed under reduced pressu...

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Abstract

The present invention relates to 1-(cyclohexyloxycarbonyloxy)ethyl 1-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate in crystalline form and a process for its preparation,which is useful intermediate in the preparation of candesartan cilexetil. The present invention also relates to the preparation of candesartan cilexetil and pharmaceutical composition comprising candesartan cilexetil.

Description

technical field [0001] The present invention relates to 1-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-1H-benzo[d]imidazole-7-carboxylic acid 1-(cyclo Hexyloxycarbonyloxy)ethyl ester and a process for its preparation, the compound being a useful intermediate for the preparation of candesartan cilexetil. The present invention also relates to the preparation of candesartan cilexetil and the pharmaceutical composition containing candesartan cilexetil. Background technique [0002] Chinese Patent Application CN 1361101 A Example 8-10 has disclosed the preparation of 1-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxyl-1H-benzo[d]imidazole - the method for 7-carboxylic acid 1-(cyclohexyloxycarbonyloxy) ethyl ester, the structural formula (I) of this compound is as follows: [0003] [0004] Under alkaline conditions, 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid and cyclohexyl 1-iodocarbonic acid Ethyl esters were reacted in DMF. A viscous, resinous comp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D235/26A61K31/4184A61P9/00
CPCC07D235/26A61P9/00
Inventor 西尔沃·祖普契奇玛泰伊·斯姆尔科尔伊雷娜塔·奥索尔尼克米哈·弗尔宾克
Owner KRKA D D NOVO MESTO
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