Ester compounds of bezimidazole and their preparations and uses in preparation of medicinal compound

A technology for ester compounds and benzimidazoles, applied in the field of preparing medicinal compounds candesartan medoxomil, can solve the problems of long synthetic route, complicated operation, adding auxiliary steps of adding protective group and deprotecting group, etc. Simple operation, great flexibility and applicability, cost-reducing effect

Inactive Publication Date: 2004-07-07
CHONGQING SHENGHUAXI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its synthetic route is relatively long, and because the tetrazolyl group with higher activity is introduced earlier in the reaction process, th

Method used

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  • Ester compounds of bezimidazole and their preparations and uses in preparation of medicinal compound
  • Ester compounds of bezimidazole and their preparations and uses in preparation of medicinal compound
  • Ester compounds of bezimidazole and their preparations and uses in preparation of medicinal compound

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0030] Example 1:

[0031] One of the preparation methods of 1-(p-bromophenyl)methyl-2-ethoxybenzimidazole-7-carboxylic acid ethyl ester (VI)

[0032] a) Preparation of ethyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (II)

[0033] 24 g (0.1 mol) of ethyl 2-carboxy-3-nitrobenzoate, 20 ml of thionyl chloride and 100 ml of toluene were sequentially added to the reaction flask, and heated and refluxed for reaction for 3 hours. The reaction mixture was concentrated to dryness. The obtained acid chloride was dissolved in 100 ml of chloroform, and a solution of 10 g (0.15 mol) of sodium azide and 50 ml of DMF was added dropwise with stirring. After the addition, the reaction was continued for 3 hours. Add 500 ml of water to the reaction mixture, place it in a separatory funnel, separate the organic layer, extract the aqueous layer with chloroform, wash the organic layer with water, dry, and distill to recover the solvent. The residue was dissolved in tert-butanol, and the solution was g...

Example Embodiment

[0040] Example 2

[0041] The second preparation method of 1-(p-bromophenyl)methyl-2-ethoxybenzimidazole-7-carboxylic acid ethyl ester (VI)

[0042] a) Preparation of 2-ethoxybenzene-1H-imidazole-7-carboxylic acid ethyl ester (VIII) (ie [1-1])

[0043] 36 g (0.1 mol) of ethyl 2,3-diaminobenzoate, 60 g of ethyl orthocarbonate, and 5 g of acetic acid were sequentially added to the reaction flask, and the reaction was stirred at 80° C. for 5 hours. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate, and washed successively with aqueous sodium bicarbonate solution and water. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-benzene to obtain 16 g of yellow solid, with a yield of 70%, mp. 125-130°C

[0044] b) Preparation of 1-(p-bromophenyl)methyl-2-ethoxybenzimidazole-7-carboxylic acid ethyl ester (VI)

[0045] 200 ml of acetonitrile was added to 23.4 g (0.1 mol) of the intermediate 2-ethoxybenzene-1H-imidazole...

Example Embodiment

[0046] Example 3

[0047] Preparation of 1-(p-bromophenyl)methyl-2-ethoxybenzimidazole-7-carboxylic acid (VII)

[0048] Add 40 g of 1-(p-bromophenyl)methyl-2-ethoxybenzimidazole-7-carboxylic acid ethyl ester (VI) obtained in the above manner to 150ml of 1N NaOH and 100ml of ethanol, and reflux and stir for reaction 6 After hours, concentrate, add 200ml of water to the concentrate, extract with ethyl acetate, adjust the water layer with 1N HCl to pH 3-4 to precipitate crystals, and recrystallize it from ethyl acetate-ethanol to obtain 16g of colorless crystal product (VII). The calculated yield is 42%, mp. (melting point) 175-180°C.

[0049] Element composition Theoretical value% Measured value (%)

[0050] C 17 H 15 BrN 2 O 3 C54.41 54.28

[0051] 375.217 H4.03 4.15

[0052] N7.46 7.47

[0053] Br21.32 21.06

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Abstract

A benzimidazole ester compound, 2-ethoxy-1-(p-halophenyl) methyl-1H-benzimidazole-7-carboxylate-1-[[(cyclohexoxy)carbonyl] oxy] ethylester, its preparing process, and its application in preparing medicinal compound candesartan ester are disclosed.

Description

technical field [0001] The invention relates to a benzimidazole ester compound, a preparation method of the compound, and a method for preparing the medicinal compound candesartan cilexetil by using the compound as a raw material. Background technique [0002] Candesartan cilexetil is an AngII-1 receptor antagonist drug that has been put into use. It belongs to a kind of benzimidazole compound, and its chemical name is: (±)-2-ethoxy-1-[[ 2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester. [0003] The preparation method of the pharmaceutical compound is provided in the Chinese patent literature with the notification number CN1048486C, including benzimidazole compounds in different substitution forms (such as the formula II and formula V' compounds in the literature) or substituted ortho Phenylenediamine compounds (such as the compound of formula IV in this document) are used as starting materials and pr...

Claims

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Application Information

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IPC IPC(8): C07D235/26C07D403/06
Inventor 贾春荣姜维平王宗玉
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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