Application of methyl 2-(tert-butoxy-2-carboxamide)-3-nitrobenzoate_Kain Industrial Additive

Background and overview^[1]

Methyl 2-(tert-butoxy-2-carboxamide)-3-nitrobenzoate can be used as a pharmaceutical synthesis intermediate, such as the preparation of candesartan intermediates. If methyl 2-(tert-butoxy-2-carboxamide)-3-nitrobenzoate is inhaled, move the patient to fresh air; if skin contact occurs, remove contaminated clothing and wash with soap and water. Rinse the skin thoroughly and seek medical attention if you feel any discomfort. If contact occurs with the eyes, separate the eyelids, rinse with running water or saline, and seek medical attention immediately. If ingested, rinse mouth immediately. Do not induce vomiting and seek medical attention immediately.

Structure

Preparation^[1]

The preparation of methyl 2-(tert-butoxy-2-carboxamide)-3-nitrobenzoate is as follows: in a 1000mL four-neck bottle equipped with a thermometer, reflux condenser tube, drying tube, and mechanical stirring , add 2-carboxy-3-nitrobenzoic acid methyl ester (2225g, 1.0mol), sulfoxide chloride (120mL), and dry toluene 600mL 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-butyl alcohol was slowly heated to reflux with stirring. After reacting for 2 hours, the solvent was evaporated under reduced pressure to obtain 2-tert-butoxycarbonylamino-3-nitrobenzoic acid ethyl ester as a yellow paste, weighing 300g, collected The yield was 94%, and the HPLC purity was 92%.

Apply^[1]

Methyl 2-(tert-butoxy-2-carboxamide)-3-nitrobenzoate can be used as a pharmaceutical synthesis intermediate. For example, it can be used to prepare 2-[N-[(2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl)methyl]amino]-3-nitrobenzene Methyl formate (IV, R = methyl), the specific steps are: in a 1000mL four-neck bottle equipped with a thermometer, reflux condenser tube, drying tube, and mechanical stirring, add 2-(tert-butoxy-2-methyl Amide)-3-nitrobenzoic acid methyl ester 47.7g (purity 93%, 0.15mol) and acetonitrile 500ml, add 32g potassium carbonate (0.23mol) under stirring. After the mixture was stirred for 30 minutes, 89g of N-(triphenylmethyl)-5-(4′-bromomethylbiphenyl-2-yl)tetrazole (II) (content 95%, 0.15mol) was added. The reaction was stirred and refluxed for 14 hours. Cool and filter, concentrate under reduced pressure to recover acetonitrile. Add 150 ml of ethyl acetate to the residue to dissolve, wash with water, dry the organic layer over anhydrous sodium sulfate, and filter. Add 600 ml of methanol to the filtrate, heat to reflux for 24 hours, and concentrate. The residue was crystallized with dichloromethane and petroleum ether, filtered, and the filter cake was washed with a little petroleum ether, drained, and dried under vacuum to obtain 54.8g of solid, which is 2-[N-[(2′-(1H-tetrazole- Methyl 5-yl)[1,1′-biphenyl]-4-yl)methyl]amino]-3-nitrobenzoate. Based on methyl 2-(tert-butoxy-2-carboxamide)-3-nitrobenzoate, the yield was 85.5%.