Methanol → Methyl 5-nitronaphthalene-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

1 cm3 of 97% sulphuric acid is added to a suspension of 4.7 g of 5-nitro-1-naphthoic acid in 50 cm3 of methanol and the reaction mixture is then brought to reflux for 12 hours. The solution is cooled to a temperature in the region of 20° C. and the precipitate formed is filtered off by centrifuge and washed twice with 5 cm3 of ice-cold methanol and then dried to constant weight. 4.56 g of methyl 5-nitro-1-naphthoate are obtained, melting at 105° C. 21.5 g of tin(II) chloride dihydrate are added to a solution of 4.45 g of methyl 5-nitro-1-naphthoate in a mixture of 150 cm3 of ethyl acetate and 35 cm3 of ethanol. The solution is heated to a temperature in the region of 70° C. for 30 minutes and then cooled to a temperature in the region of 20° C. The reaction mixture is poured onto 200 cm3 of ice and the pH of the solution is progressively brought to 7-8 by addition of a 5% (w/v) sodium hydrogen carbonate solution. The mixture obtained is filtered on a sintered glass covered with Celite, the organic phase is separated by settling and the aqueous phase is extracted twice with 150 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. 4.5 g of methyl 5-amino-1-naphthoate are obtained in the form of an oil which are used in the following stage without other purification. 14.75 g of S-triphenylmethyl-N-(tert-butoxycarbonyl)cysteinal, 0.14 cm3 of concentrated acetic acid, molecular sieves (3Å) and then 4.15 g of sodium cyanoborohydride are added to a solution of 4.5 g of methyl 5-amino-1-naphthoate in 30 cm3 of methanol. The reaction mixture is stirred for 2 days at a temperature in the region of 20° C. and then filtered on sintered glass covered with Celite. The sintered glass is washed with methanol. The filtrate is concentrated under reduced pressure, redissolved in 150 cm3 of ethyl acetate and washed with 100 cm3 of a 10% (w/v) aqueous sodium hydrogen carbonate solution, with 100 cm3 of a 10% (w/v) aqueous citric acid solution, with 100 cm3 of distilled water, with 100 cm3 of a 10% (w/v) aqueous sodium hydrogen carbonate solution and finally with 100 cm3 of a saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure. The product is purified by chromatography on silica [eluent: cyclohexane/ethyl acetate (85/15 by volume)]. 3.5 g of methyl 5-(2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)-propylamino)-1-naphthoate are obtained in the form of a beige foam which are used in the following stage without other purification.

Provenance & Evidence