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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, thus in the whole synthetic route, corresponding auxiliary steps of protecting and deprotecting groups have to be added, complicate the operation

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
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Effect test

example 1

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

[0032] a) Preparation of 2-tert-butoxycarbonylamino-3-nitrobenzoic acid ethyl ester (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 into the reaction flask, and heated under reflux 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 (0.15 mol) and 50 ml of DMF was added dropwise with stirring. After the addition was complete, the reaction was continued for 3 hours. Add 500ml of water to the reaction mixture, place in a separatory funnel, separate the organic layer, extract the water layer with chloroform, wash the organic layer with water, dry, and recover the solvent by distillation. The residue was dissolved in tert-butanol, the solution was gradual...

example 2

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

[0042] a) Preparation of ethyl 2-ethoxybenzene-1H imidazole-7-carboxylate (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 into the reaction flask, and stirred and reacted at 80° C. for 5 hours. The reaction mixture was concentrated, and the concentrate was dissolved in ethyl acetate, washed successively with aqueous sodium bicarbonate and water. The solvent was distilled off, and the residue was recrystallized from ethyl acetate-benzene to obtain 16 g of a yellow solid, yield 70%, mp.125-130°C

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

[0045] Add 200 ml of acetonitrile to 23.4 g (0.1 mol) of the intermediate 2-ethoxybenzene-1H-imidazole-7-carboxylic acid ethyl ester (VIII) prepared above, ...

example 3

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

[0048] Add 40 g of ethyl 1-(p-bromophenyl)methyl-2-ethoxybenzimidazole-7-carboxylate (VI) obtained in the above-mentioned manner to 150 ml of 1N NaOH and 100 ml of ethanol, and stir at reflux for reaction 6 Hours, concentrated, 200ml of water was added to the concentrate, extracted with ethyl acetate, the aqueous layer was adjusted to pH 3-4 with 1N HCl to precipitate crystals, which were recrystallized in ethyl acetate-ethanol to obtain 16g of colorless crystal product (VII), The calculated yield was 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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