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Method for preparing 2-(substituted phenyl) methylamino-3-nitrobenzene methyl formate by one-pot method

A technology of methyl tert-butoxycarbonylaminobenzoate and methyl nitrobenzoate, applied in the fields of chemical industry and chemical medicine, can solve the problems of high solvent consumption, large waste water pollution, low yield and the like, and achieves improved operating environment, The effect of reducing labor intensity

Active Publication Date: 2010-11-10
ZHEJIANG MENOVO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] This process also has cumbersome operation steps, a large amount of solvent, low yield, and large waste water pollution

Method used

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  • Method for preparing 2-(substituted phenyl) methylamino-3-nitrobenzene methyl formate by one-pot method
  • Method for preparing 2-(substituted phenyl) methylamino-3-nitrobenzene methyl formate by one-pot method
  • Method for preparing 2-(substituted phenyl) methylamino-3-nitrobenzene methyl formate by one-pot method

Examples

Experimental program
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Effect test

example 1

[0042] Example 1. Preparation of methyl 2-[[(2'-cyanobiphenyl)-4-yl]methyl]amino-3-nitrobenzoate

[0043] Add 90g of methyl 3-nitro-2-carboxybenzoate and 150ml of dimethylformamide (DMF) into a 1000ml three-necked flask, add 70g of thionyl chloride dropwise in a water bath, stir at room temperature for 3 hours after dropping, add 250ml of chloroform, Tetrabutylammonium bromide 4g, stir to dissolve. t3 20% NaOH solution was added dropwise to neutrality, and when t<20°C, the layers were separated, and the aqueous layer was extracted with 50 ml of chloroform. Add 100ml of tert-butanol to the organic layer, slowly raise the temperature, reflux at 65-70°C for 2h, cool to t<30°C, add 400ml of water to wash, stand to separate the layers, extract the aqueous layer with 100ml of chloroform, and combine the organic layers. Add 76.2g of 4-bromomethyl-2′-cyanobiphenyl and 4g of tetrabutylammonium bromide to the organic layer, stir to dissolve, add 60g of 30% NaOH dropwise at t<10°C, stir...

example 2

[0044] Example 2. Preparation of methyl 2-[[(2'-cyanobiphenyl)-4-yl]methyl]amino-3-nitrobenzoate

[0045]Add 90g of methyl 3-nitro-2-carboxybenzoate and 150ml of dimethylformamide (DMF) into a 1000ml three-necked flask, add 70g of thionyl chloride dropwise in a water bath, stir at room temperature for 3 hours after dropping, add 250ml of chloroform, 4g 15-crown (ether)-5, stirred to dissolve. t3 20% NaOH solution was added dropwise to neutrality, and when t<20°C, the layers were separated, and the aqueous layer was extracted with 50 ml of chloroform. Add 100ml of tert-butanol to the organic layer, slowly raise the temperature, reflux at 65-70°C for 2h, cool to t<30°C, add 400ml of water to wash, stand to separate the layers, extract the aqueous layer with 100ml of chloroform, and combine the organic layers. Add 76.2g of 4-bromomethyl-2′-cyanobiphenyl and 4g of tetrabutylammonium bromide to the organic layer, stir to dissolve, add 60g of 30% NaOH dropwise at t<10°C, stir at 25...

example 3

[0046] Example 3. Preparation of methyl 2-(4'-bromophenyl)methylamino-3-nitrobenzoate

[0047] Add 90g of methyl 3-nitro-2-carboxybenzoate and 150ml of DMF to a 1000ml three-necked flask, add 70g of thionyl chloride dropwise in a water bath, stir at room temperature for 3h after dropping, add 250ml of chloroform, 4g of tetrabutylammonium bromide , stir to dissolve. t3 20% NaOH solution was added dropwise to neutral, the layers were separated at <20°C, and the aqueous layer was extracted with 50ml of chloroform. The organic layer was washed once more with 400ml of water (t<20°C). The organic layer was dried with anhydrous magnesium sulfate, the desiccant was filtered off, 100ml of tert-butanol was added, the temperature was raised slowly, and the mixture was refluxed at 65-70°C for 2h. Cool to t<30°C, add 400ml of water to wash, let stand to separate the layers, extract the aqueous layer with 100ml of chloroform, and combine the organic layers. Add 70g of p-bromobenzyl bromi...

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Abstract

The invention provides a method for preparing candesartan cilexetil intermediate products of 2-(substituted phenyl) methylamino-3-nitrobenzene methyl formate by a one-pot method. The candesartan cilexetil intermediate products are 2-(4-bromophenyl) methylamino-3-nitrobenzene methyl formate and 2-[[(2'-cyano xenyl-4-pyridyl) methyl] amino]-3-nitrobenzene methyl formate. The process comprises the step of using 3-nitryl-2-carboxyphenyl methyl formate as raw materials to obtain target products through continuous reaction process. The extraction and the purification are not needed, the work intensity is reduced, the operation environment is improved, the environment pollution is reduced, the raw material and product loss is reduced, the industrial production cost is greatly reduced, and the yield is improved.

Description

technical field [0001] The invention relates to a preparation method of methyl 2-(substituted phenyl)methylamino-3-nitrobenzoate, an important intermediate of candesartan cilexetil, belonging to the fields of chemical industry and chemical medicine. Background technique [0002] Candesartan, the English name is Candesartan, and the chemical name of candesartan cilexetil is 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)[1,1'-linked Phenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester, its structural formula is as follows: [0003] [0004] Candesartan cilexetil is a new type of non-peptide angiotensin II (ATII) receptor antagonist, clinically used for the treatment of hypertension, the drug was first listed in Sweden in 1997. [0005] Methyl 2-(substituted phenyl)methylamino-3-nitrobenzoate is an important intermediate in the synthesis of candesartan cilexetil, which specifically refers to 2-(4-bromophenyl)methylamino-3-nitro Methyl ben...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/56C07C227/20C07C255/58C07C253/30
Inventor 刘雄冯玲肖映春
Owner ZHEJIANG MENOVO PHARMA
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