Diisopropylamine → 7,8-Dihydro-7-hydroxy-6-methyl-7-(2'-methylphenyl)-1,6-naphthyridine-5(6H)-one

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Reaction Steps

109 ml. of 1.6 M. n-butyl lithium in hexane (174.4 mmol.) were added to a solution of 24.4 ml. of diisopropylamine in 200 ml. of dry tetrahydrofuran stirred at -10°--30° C. under nitrogen. To the resulting solution of lithium diisopropylamide, 13.1 g. (87.3 mmol.) of 2-methylnicotinic acid N-methylamide (Compound XII), dissolved in 110 ml. of dry tetrahydrofuran, were added slowly at -30°--20° C. with stirring under nitrogen. Stirring under nitrogen was continued for 2 hours at -30°--20° C. Then 14.3 g. (87.2 mmol.) of freshly distilled ethyl 2-methylbenzoate dissolved in 60 ml. of dry tetrahydrofuran were slowly added at the same temperature and stirring under nitrogen was continued for a further 2 hours at the same temperature. The reaction mixture was then quenched with 150 ml. of concentrated sodium chloride solution and the reaction mixture was extracted three times with ethyl acetate. The ethyl acetate extracts were combined, washed six times with water, once with concentrated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated at reduced pressure to obtain a crude material (20.4 g.). The crude material was dissolved in ethyl acetate and filtered through silica gel. Evaporation at reduced pressure yielded 16.3 g. of material which was separated into neutral and basic components by dissolving in toluene and cold 2 N. hydrochloric acid and extracting the toluene phase twice with cold 2 N. hydrochloric acid. The three aqueous phases were combined, made basic with sodium hydroxide solution and extracted twice with methylene chloride. The methylene chloride extracts were combined, dried over anhydrous sodium sulfate and evaporated at reduced pressure to obtain the basic component (8.7 g.), i.e., the crude hydroxylactam of Formula XV.

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