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Preparation method of candesartan cilexetil

A technology of candesartan cilexetil and tetraethyl orthocarbonate, which is applied in the field of preparation of candesartan cilexetil, can solve problems such as difficulties in the industrial production of candesartan cilexetil, achieve high industrialization development prospects, simple process steps, The effect of easy purification of the product

Inactive Publication Date: 2016-01-27
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The deprotection of this route is carried out under reflux in trifluoroacetic acid or in a mixed solvent containing methanol, and it has been found in experiments that the trityl group will migrate to the amino group during the above deprotection process, which brings certain benefits to the industrial production of candesartan cilexetil. Difficulties

Method used

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  • Preparation method of candesartan cilexetil
  • Preparation method of candesartan cilexetil
  • Preparation method of candesartan cilexetil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] The preparation method of the candesartan cilexetil of the present embodiment comprises the following steps:

[0029] (1) Alcoholyzing compound IV to obtain compound III: in a 1000mL four-neck flask equipped with a thermometer and mechanical stirring, add 0.1 moL of compound IV, namely 2-(tert-butoxycarbonyl ((2-(1-triphenyl Methyl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)amino)-3-nitrobenzoic acid-1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester and 250mL methanol, reacted at 40-45°C for 3 hours, TCL detected that the reaction was complete, then lowered to room temperature, stirred at room temperature for 6-8 hours, filtered, and the filter cake was washed with 100mL glacial methyl tert-butyl ether, sucked dry, and vacuumed Dry to obtain 61.7 g of light yellow solid, which is compound III, 2-(tert-butoxycarbonyl((2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)amino )-1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester of 3-nitrobenzoate, the yield is 90%, and the melting point is 105~106°C...

Embodiment 2

[0033] (1) Alcoholyze compound IV to obtain compound III: in a 1000mL four-neck flask equipped with a thermometer and mechanical stirring, add 0.1moL of 2-(tert-butoxycarbonyl ((2-(1-trityl- 1H-tetrazol-5-yl)biphenyl-4-yl)methyl)amino)-3-nitrobenzoic acid-1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester, 50mL ethanol , 300mL ethyl acetate, add 1mL concentrated hydrochloric acid, stir at room temperature for 6-8 hours, after TCl detects that the reaction is complete, add 200mL of water, stir for 10 minutes, let stand to separate layers, concentrate the organic layer under reduced pressure to 100mL, cool to 0~ Stir at 5°C for 4-6 hours, filter, drain, and vacuum-dry to obtain 58.3 g of a light yellow solid, which is compound III, namely 2-(tert-butoxycarbonyl ((2-(1H-tetrazole -5-yl)biphenyl-4-yl)methyl)amino)-3-nitrobenzoic acid-1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester, the yield was 85%.

[0034](2) Add 68.6 g of 2-(tert-butoxycarbonyl ((2-(1H-tetrazol-5-yl)biphenyl-4-yl)methan...

Embodiment 3

[0037] (1) Alcoholyze compound IV to obtain compound III: in a 1000mL four-neck flask equipped with a thermometer and mechanical stirring, add 0.1moL of 2-(tert-butoxycarbonyl ((2-(1-trityl- 1H-tetrazol-5-yl)biphenyl-4-yl)methyl)amino)-3-nitrobenzoic acid-1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester, 50mL ethanol , 300mL ethyl acetate, add 1mL concentrated hydrochloric acid, stir at room temperature for 6-8 hours, after TCl detects that the reaction is complete, add 200mL of water, stir for 10 minutes, let stand to separate layers, concentrate the organic layer under reduced pressure to 100mL, cool to 0~ Stir at 5°C for 4-6 hours, filter, drain, and vacuum-dry to obtain 58.3 g of a light yellow solid, which is compound III, namely 2-(tert-butoxycarbonyl ((2-(1H-tetrazole -5-yl)biphenyl-4-yl)methyl)amino)-3-nitrobenzoic acid-1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester, yield 85%;

[0038] (2) Add 2-(tert-butoxycarbonyl((2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)amino to a 1000mL...

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Abstract

The invention relates to a preparation method of candesartan cilexetil. 2-(tert-butoxycarbonyl((2-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl)methyl)amino)-3-nitrobenzoic acid-1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester is used as an initial reactant, a tetrazole protecting group has a deprotection reaction through alcoholysis, 2-(tert-butoxycarbonyl((2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)amino)-3-nitrobenzoic acid-1-(((cyclohexyloxy)carbonyl)oxy)ethyl ester is obtained, a tetrazole ring is directly introduced, raw materials which are expensive and have dangerous toxic properties, such as trialkyl tin azide or trialkyl tin chloride, organic zinc or organic palladium are avoided in the follow-up process, reaction conditions are mild, and the safety of the preparation process is improved; meanwhile, the preparation method has simple technological steps, products are easy to purify, the candesartan cilexetil can be synthesized on a large scale, and the industrial development prospect is brighter.

Description

technical field [0001] The present invention relates to a preparation method of candesartan cilexetil, specifically (±)-2-ethoxy-1-[2'-(1H-tetrazol-5-yl)[l,l'-biphenyl Base] -4-base] methyl] -1H-benzimidazole-7-carboxylic acid -l-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester. Background technique [0002] The chemical name of candesartan cilexetil is (±)-2-ethoxy-1-[2'-(1H-tetrazol-5-yl)[l,l'-biphenyl]-4-yl] Methyl]-1H-benzimidazole-7-carboxylic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester, the structural formula is as follows: [0003] [0004] Candesartan is a long-acting antagonist of angiotensin II subtype I receptor (AT1), which is a non-peptide drug molecule. Candesartan cilexetil is a prodrug of candesartan. Candesartan cilexetil can be completely converted into highly active candesartan during the absorption process in the gastrointestinal tract. Candesartan avoids the side effects of calcium antagonists and increases the level of angiotensin II receptors in th...

Claims

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Application Information

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IPC IPC(8): C07D403/10
CPCY02P20/55C07D403/10
Inventor 刘雄
Owner ZHEJIANG MENOVO PHARMA
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