Preparation and application of methyl 2-(tert-butoxy-2-carboxamide)-3-nitrobenzoate_Industrial additives

Background and overview^[1]

Methyl 2-(tert-butoxy-2-carboxamide)-3-nitrobenzoate is a pharmaceutical intermediate that can be used in the synthesis of candesartan. Candesartan and candesartan cilexetil are a new type of non-peptide angiotensin II (ATII) receptor antagonist, which is clinically used for the treatment of hypertension. The drug was first launched in Sweden in 1997.

Preparation^[2]

Methyl 2-(tert-butoxy-2-carboxamide)-3-nitrobenzoate is prepared as follows: In a 1000mL four-neck bottle equipped with a thermometer, reflux condenser tube, drying tube, and mechanical stirring, Add 225g of methyl 2-carboxy-3-nitrobenzoate, thionyl chloride (120mL), and 600mL of dry toluene in sequence, stir and reflux for 3.5h, and concentrate under reduced pressure. The residue was dissolved in 200 mL of methylene chloride, and this solution was slowly dropped into a solution of 96 g of sodium azide in DMF (200 mL) while stirring, and the reaction was stirred for 30 min. After the reaction, the reaction solution was poured into a mixture of diethyl ether-n-hexane (3:1, 1L) and water (1L); the organic phase was separated, washed with deionized water, concentrated under reduced pressure to half the volume, and added 600mL of tert-butanol, slowly heated to reflux while stirring, react for 2 hours and then evaporate the solvent under reduced pressure to obtain 2-(tert-butoxy-2-carboxamide)-3-nitrobenzoic acid methyl ester as a yellow paste Material, weight 290g, yield 94%, HPLC purity 92%.

Apply^[1]

Used to prepare methyl 2-[[(2’-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate. This intermediate can be used to synthesize candesartan. The method is as follows: under alkaline conditions, DMF is used as the solvent, 2-(tert-butoxy-2-carboxamide)-3-nitrobenzoic acid methyl ester and 4-bromomethyl-2′-cyanobiphenyl Nucleophilic substitution occurs, and then removal of tert-butoxycarbonyl gives 2-[[2-cyanobiphenyl)-4-yl]methyl]amino-3-nitrobenzoic acid methyl ester.

Main reference materials

[1] CN201010229921.7 One-pot method for preparing methyl 2-(substituted phenyl)methylamino-3-nitrobenzoate

[2] CN200510131970.6 A method of preparing candesartan