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Candesartan Cilexetil and its precursor compound preparation method

The technology of a precursor compound, candesartan cilexetil, is applied in the direction of organic chemistry, which can solve the problems of difficult preparation, unsatisfactory yield and complex structure.

Active Publication Date: 2007-05-30
CHONGQING SHENGHUAXI PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since the 2-ethoxy-1-(p-halophenyl)methyl-1H-benzimidazole-7-carboxylic acid 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester as a raw material The structure is relatively complex, and there are multiple sensitive parts in the structure, so there are many restrictions on the control of reactivity and reaction conditions, the preparation is difficult, and the yield of the product is not ideal

Method used

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  • Candesartan Cilexetil and its precursor compound preparation method
  • Candesartan Cilexetil and its precursor compound preparation method
  • Candesartan Cilexetil and its precursor compound preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] 2-Ethoxy-1-[[2′-(trityltetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-benzimidazole- Preparation of 1-(cyclohexyloxycarbonyloxy)ethyl 7-carboxylate (III)

[0027] Put 80 parts of the mixed solvent of DME / THF at 1 / 1 (volume) into the reactor, pour in nitrogen to drive out the air in the system, and put in 1 part of triphenylphosphine (Ph3P) and Pd(OAc)2 0.2 After stirring for 30 minutes at room temperature, 10 parts of 2-(1-trityl-1H-tetrazol-5-yl)phenylboronic acid (II) were added, and stirring was continued for 10 minutes at room temperature. Join K in turn 2 CO 3 6 parts of fine powder, 2-ethoxy-1-(4'-bromophenyl)methyl-1H-benzimidazole-7-carboxylic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethane 12 parts of ester (I), heated to about 75° C. and refluxed for 15 hours (thin layer chromatography monitoring: Hex / EtOAc 2:1).

[0028] After cooling to normal temperature and suction filtration, the filtrate can be distilled under reduced pressure to remove most of the solvent. 80 ml...

Embodiment 2

[0030] 2-Ethoxy-1-[[2′-(trityltetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1H-benzimidazole- Preparation of 1-(cyclohexyloxycarbonyloxy)ethyl 7-carboxylate (III)

[0031] Put 80 parts of dioxane into the reactor, blow in nitrogen to remove the air in the system, put in 0.2 parts of triphenylphosphine (Ph3P) and 0.5 parts of Pb[Ph3]4 in turn, stir at room temperature for 30 minutes, and then add 2 -(1-Trityl-1H-tetrazol-5-yl) phenylboronic acid ethyl ester (II) 10 parts, and continue to stir at room temperature for 10 minutes. Sequentially add 6 parts of K2CO3 fine powder, 2-ethoxy-1-(4'-bromophenyl)methyl-1H-benzimidazole-7-carboxylic acid-1-[[(cyclohexyloxy)carbonyl] 12 parts of oxy]ethyl ester (I) were heated to 90° C. and the reaction was incubated for 6 hours (thin layer chromatography monitoring: Hex / EtOAc=2 / 1).

[0032] Cool to room temperature and filter with suction. The filtrate can be distilled under reduced pressure to remove most of the solvent. Add 80ml of toluene and 8...

Embodiment 3

[0034] Preparation of candesartan cilexetil (IV)

[0035] The 2-ethoxy-1-[[2'-(trityltetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]- 10g of 1H-benzimidazole-7-carboxylic acid 1-(cyclohexyloxycarbonyloxy)ethyl (III), dissolved in 80ml of acetone, adjusted to pH 2 with 5% hydrochloric acid at room temperature, and stirred for 5-10 hours , Monitoring the progress of the reaction by means of thin layer chromatography (thin layer chromatography monitoring: chloroform: petroleum ether: methanol = 4:3:1) or high performance liquid chromatography.

[0036] Then, 5% NaOH aqueous solution was slowly added dropwise to the reactant until it became neutral, most of the acetone was removed by distillation under reduced pressure, 50 ml of ethyl acetate was added, and the mixture was cooled and crystallized, and the mixture was stirred for 30 minutes and then filtered. The filter cake was washed with an appropriate amount of ice ethyl acetate, purified in DMF / water, or purified by silica gel column c...

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Abstract

The invention discloses a ridge-ground shatan ester and making method of prosoma compound, wherein the prosoma compound is 2-ethoxy-1-[[2'-(1-R-tetrazole-5-base) [1, 1'-biphenyl]-4-base] methyl]-1H-benzimidazole-7- carboxyl acid1-(cyclohexaoxy carbonyloxygen) carbethoxy (III), which is reacted by 2-ethoxy-1-(4'-halogenated phenyl) methyl-1H-benzimidazole-7-carboxyl acid1-[[(cyclohexaoxy) carbonyl] oxygen] carbethoxy (I) and 2-(1-R-1H-tetrazoline-5-base) borophenylic acid or 2-(1-R-1H-tetrazoline-5-base) borophenylic acid ester (II) in the organic dielectric and catalyst allowed by Suzuki reaction under soluble alkaline compound condition; hydrolyzing the prosoma compound under acid condition to obtain the medical product.

Description

Technical field [0001] The present invention relates to the preparation of ester compounds of benzimidazole, in particular to a method for preparing p-candesartan cilexetil and its precursor compounds. Background technique [0002] Candesartan cilexetil, chemical name: (±)-2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H- Benzimidazole-7-carboxylic acid 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester, a benzimidazole compound, is a kind of compound that has been put into use and has ideal antihypertensive and AngII-1 Medicinal drugs with receptor antagonistic activity. Its different preparation routes and methods have been reported in a variety of literature. Among them, in the Chinese patent document with the publication number CN 1207287C, the applicant proposed a method consisting of 2-ethoxy-1-(p-halophenyl)methyl-1H-benzimidazole-7-carboxylic acid The preparation principle and method of 1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester and protected 5-(2'-halophenyl)-2(1H)te...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/10
Inventor 姜维平贾春荣王宗玉
Owner CHONGQING SHENGHUAXI PHARMA CO LTD
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