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Method for preparing candesartan ring compound

A technology of candesartan and cyclic compound, which is applied in the field of preparation of candesartan cyclic compound, can solve the problems of high consumption and high final cost of candesartan cyclic compound, and achieve low cost The effect of minimization and consumption minimization

Inactive Publication Date: 2011-10-05
ZHANGJIAGANG XINYI CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The cost of the candesartan cyclic compound mainly depends on the consumption cost of cyanobromobiphenyl and tetraethyl orthocarbonate. The above three process routes, due to the premature use of cyanobromobiphenyl and tetraethyl orthocarbonate, Makes their consumption high, resulting in high final cost of candesartan cyclic compound

Method used

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  • Method for preparing candesartan ring compound
  • Method for preparing candesartan ring compound
  • Method for preparing candesartan ring compound

Examples

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Embodiment 1

[0048] Step 1) the preparation of ethyl 3-nitro-2-ethoxycarboxamidobenzoate: 1. monoesterification: get dehydrated alcohol 400g, 3-nitrophthalic acid 90g and the vitriol oil 90g mix, control Temperature 70°C, heat and reflux for 12 hours, distill off ethanol under reduced pressure, add 1000g of chloroform, stir, extract and separate layers to obtain a monoesterified chloroform solution; To complete, then add 4g DMF and 45g thionyl chloride, control the temperature at 60°C, reflux for 5 hours, distill off 500g of chloroform to obtain a chloroform solution of acid chloride; ③ azidation: add 50g of DMF to the chloroform solution of acid chloride , 30g of sodium azide, react at room temperature 25°C for 3 hours, add 500g of chloroform, 500g of water, extract and separate layers, and obtain the chloroform solution of acyl azide; Add 200g of Yuanming powder for drying and dehydration, filter, add 300g of absolute ethanol to the filtrate, slowly heat to reflux, control the temperatur...

Embodiment 2

[0053] Step 1) the preparation of 3-nitro-2-ethoxycarboxamidoethyl benzoate: 1. monoesterification: get dehydrated alcohol 1800g, 3-nitrophthalic acid 450g and the concentrated sulfuric acid 485g mix, control Temperature 70°C, heat and reflux for 17 hours, distill off ethanol under reduced pressure, add 4500g of chloroform, stir, extract and separate layers to obtain a monoesterified chloroform solution; To complete, then add 20g DMF and 250g thionyl chloride, control the temperature at 60°C, reflux for 5 hours, distill off 2600g of chloroform to obtain a chloroform solution of acid chloride; ③ azidation: add 260g of DMF to the chloroform solution of acid chloride , 150g of sodium azide, react at room temperature 25°C for 3 hours, add 2500g of chloroform, 2600g of water, extract and separate layers, and obtain the chloroform solution of acyl azide; Add 1000g of Yuanming powder for drying and dehydration, filter, add 1500g of absolute ethanol to the filtrate, slowly heat to ref...

Embodiment 3

[0058] Step 1) Preparation of 3-nitro-2-ethoxycarboxamidoethyl benzoate: 1. monoesterification: dehydrated alcohol 40Kg, 3-nitrophthalic acid 9Kg, concentrated sulfuric acid 9Kg, heat reflux reaction 18 Hours, evaporate ethanol under reduced pressure, add 100Kg of chloroform, stir, extract, and separate layers to obtain a monoesterified chloroform solution; 4.5Kg of thionyl chloride, reflux reaction for 5 hours, distilled off 50Kg of chloroform to obtain a chloroform solution of acid chloride; ③Azidation: Add 5.4Kg of DMF and 3Kg of sodium azide to the chloroform solution of acid chloride, and react at room temperature for 3 4 hours, add 50Kg of chloroform, 50Kg of water, extract and separate layers to obtain the chloroform solution of acyl azide; ④ rearrangement esterification: add 20Kg of chloroform solution of acyl azide, dry and dehydrate, filter, add the filtrate 30Kg of absolute ethanol, slowly heated to reflux, reflux for 8 hours, distilled off chloroform and ethanol, a...

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Abstract

The invention relates to a method for preparing a candesartan ring compound, which comprises the following steps: 1) preparing 3-animo-2-ethyl ethoxy formacyl amino benzoate; 2) preparing 2-ethyoxylbenzimidazole-4-ethyl indole carboxylate; and 3) preparing candesartan ring compound, namely 2-ethyoxyl-1-1[[(2-cyanobiphenyl-4-yl) mthyl] benzimidazole]-7-carboxylate. In the invention, a benzimidazole ring is constructed, tetraethyl orthocarbonate is avoided, and intramolecular dehydration construction is realized; and finally alkylation is accomplished, canobromobiphenyl is introduced; and thus, the minimum consumption of canobromobiphenyl is realized and the cost of the candesartan ring compound is minimized.

Description

technical field [0001] The invention relates to a preparation method of an important intermediate of the antihypertensive drug candesartan cilexetil which has significant curative effect, and more specifically relates to a preparation method of the candesartan cyclic compound. Background technique [0002] Candesartan cilexetil is a non-peptide angiotensin II (Ang II) receptor antagonist drug, which has the best curative effect and the safest among the marketed drugs. The synthesis of the drug, no matter what route, involves the synthesis and preparation of the candesartan ring compound. [0003] Candesartan cyclic compound, chemical name: 2-ethoxy-1-1[[(2-cyanobiphenyl-4-substituted)methyl]benzimidazole]-7-carboxylate (methyl ester or ethyl ester). [0004] The structural formula is as follows: [0005] [0006] At present, the synthesis of candesartan ring compound, common methods can be summarized into three types: A, B, and C: [0007] One is based on 3-nitrophtha...

Claims

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Application Information

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IPC IPC(8): C07D235/26
Inventor 楼新灿陈立坤
Owner ZHANGJIAGANG XINYI CHEM
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