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Method for preparing candesartan cilexetil

A technology for candesartan cilexetil and esterification, which is applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of long reaction route, drug residues, low total yield of toxic substances, etc. Yield, reducing effect of sodium azide

Active Publication Date: 2013-07-10
QINGDAO HUANGHAI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The invention provides a method for preparing candesartan cilexetil, which can solve the problems in the prior art that the reaction route is long, toxic substances are easy to remain in the medicine, and the total yield is low

Method used

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  • Method for preparing candesartan cilexetil
  • Method for preparing candesartan cilexetil
  • Method for preparing candesartan cilexetil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Wherein in embodiment 1: (R=methyl, X=Br)

[0044] 1, 2-amino-3-nitrobenzoic acid;

[0045] II. Methyl 3-nitro-2-aminobenzoate;

[0046] III, N-(triphenylmethyl)-5-(4'-bromomethylbiphenyl-2-yl)tetrazolium;

[0047] IV, 2-N-[[(2'-(N'-trityl)-tetrazol-5-yl](1,1'-biphenyl)-4-yl]methyl]amino)- Methyl 3-nitrobenzoate;

[0048]V, 2-N-[[(2'-(N'-trityl)-tetrazol-5-yl](1,1'-biphenyl)-4-yl]methyl]amino)- Methyl 3-aminobenzoate;

[0049] VI, 2-ethoxy-1-[[2'-(N'-trityl)-tetrazol-5-yl](1,1'-biphenyl)-4-yl]methyl] -1-H-benzimidazole-7-carboxylic acid methyl ester;

[0050] VII, 2-ethoxy-1-[[2'-(N'-trityl)-tetrazol-5-yl](1,1'-biphenyl)-4-yl]methyl] -1-H-benzimidazole-7-carboxylic acid;

[0051] VIII, 2-ethoxy-1-[[2'-(N'-trityl)-tetrazol-5-yl](1,1'-biphenyl)-4-yl]methyl] -1-(cyclohexyloxycarbonyloxy)ethyl 1-H-benzimidazole-7-carboxylate;

[0052] (1), the synthesis of methyl 3-nitro-2-aminobenzoate (II)

[0053] Add 18.2g (0.1mol) of 3-nitro-2-aminobenzoic acid into the reac...

Embodiment 2

[0068] Embodiment 2 wherein: (R=ethyl, X=Br)

[0069] 1, 2-amino-3-nitrobenzoic acid;

[0070] II. Ethyl 3-nitro-2-aminobenzoate;

[0071] III, N-(triphenylmethyl)-5-(4'-bromomethylbiphenyl-2-yl)tetrazolium;

[0072] IV, 2-N-[[(2'-(N'-trityl)-tetrazol-5-yl](1,1'-biphenyl)-4-yl]methyl]amino)- Ethyl 3-nitrobenzoate;

[0073] V, 2-N-[[(2'-(N'-trityl)-tetrazol-5-yl](1,1'-biphenyl)-4-yl]methyl]amino)- Ethyl 3-aminobenzoate;

[0074] VI, 2-ethoxy-1-[[2'-(N'-trityl)-tetrazol-5-yl](1,1'-biphenyl)-4-yl]methyl] - ethyl 1-H-benzimidazole-7-carboxylate;

[0075] VII, 2-ethoxy-1-[[2'-(N'-trityl)-tetrazol-5-yl](1,1'-biphenyl)-4-yl]methyl] -1-H-benzimidazole-7-carboxylic acid;

[0076] VIII, 2-ethoxy-1-[[2'-(N'-trityl)-tetrazol-5-yl](1,1'-biphenyl)-4-yl]methyl] -1-(cyclohexyloxycarbonyloxy)ethyl 1-H-benzimidazole-7-carboxylate;

[0077] (1), the synthesis of ethyl 3-nitro-2-aminobenzoate (II)

[0078] Add 18.2g (0.1mol) of 3-nitro-2-aminobenzoic acid into the reaction flask, suspe...

Embodiment 3

[0093] The intermediate 2-ethoxy-1-[[2'-(N'-trityl)-tetrazol-5-yl](1,1'-biphenyl)-4- Base]methyl]-1-H-benzimidazole-7-carboxylic acid 1-(cyclohexylcarbonyloxy)ethyl ester (VIII) can be obtained according to the above-mentioned Example 1 or Example 2.

[0094] Preparation of candesartan cilexetil

[0095] Add 60ml of 1N hydrochloric acid, 240ml of methanol and 50ml of chloroform to 50g of the compound VIII produced above, stir at room temperature for 3 hours, concentrate in vacuo at room temperature, extract with dichloromethane, wash with water, dry over anhydrous magnesium sulfate, concentrate in vacuo to dryness, and wash with 300ml of methanol 23.89 g of candesartan cilexetil was obtained by recrystallization, with a yield of 68% and a purity of 91%.

[0096] The average total yield of candesartan cilexetil obtained by the method is 37.78%.

[0097] Of course, in the above embodiment, Br in compound III can also be replaced by other elements in halogen, such as Cl, I, etc...

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Abstract

The invention provides a method for preparing candesartan cilexetil, which can solve the problems of longer reaction route, easy remaining of toxic substances in medicines and lower total yield existing in the prior art. In the method, the candesartan cilexetil is finally prepared by using 2-amino-3-nitrobenzoic acid as an initial raw material through esterification reaction, N-alkylation reaction, nitro reduction reaction, cyclization reaction, hydrolysis reaction, esterification reaction and tetrazole protecting group deprotection reaction. The synthetic method has simple steps and high yield, greatly reduces the participation and generation of toxic products in the reaction process, reduces the release of waste and is beneficial to clean production.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a method for preparing candesartan cilexetil, a sartan type hypertension drug. Background technique [0002] Candesartan cilexetil, the chemical name is (±)-2-ethoxy-1-[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl] methyl]-1H-benzimidazole-7-carboxylic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester. Candesartan cilexetil is the prodrug of candesartan, which can be completely converted into highly active candesartan during the absorption process in the gastrointestinal tract. The latter avoids the side effects of calcium antagonists and increases the concentration in the circulation system and tissues. The specificity and selectivity of blocking the level of angiotensin II receptor has the characteristics of stable blood pressure reduction, good curative effect, high safety, few side effects and good patient compliance. It is a non-peptide angioten...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/10
CPCY02P20/55
Inventor 祝少良赵明媚于华芝隋宇纪存朋李永刚
Owner QINGDAO HUANGHAI PHARM CO LTD
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