N-Hydroxysuccinimide → 1-[[3-Chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione

Participants

Reaction Conditions

Reaction Steps

A 3-neck 1 L round-bottom flask equipped with a magnetic stirrer, ice cooling bath, thermometer and an argon inlet tube was set up and charged with 3-chloro-4-(methoxycarbonyl)benzoic acid (Example 72; 21.5 g, 0.1 mol) in tetrahydrofuran (250 mL). The solution was cooled to 10° C. under argon and was treated in succession with N-hydroxysuccinimide (12.66 g, 0.11 mol) and N,N-dicyclohexylcarbodiimide (21.66 g, 0.105 mol). These reagents were washed into the reaction flask with additional tetrahydrofuran (100 mL). A precipitate started to form immediately. The cooling bath was removed and the reaction mixture was stirred at ambient temperature overnight, then was diluted with diethyl ether (400 mL) and stirred for another 30 min. The precipitate was collected by filtration and the filter cake was washed with diethyl ether (3×50 mL). The dried solids (N,N-dicyclohexylurea) weighed 22.2 g (>99% of theory). The combined filtrates were diluted with hexane (100 mL) then were transferred to a 2 L separatory funnel and were washed in turn with cold saturated sodium bicarbonate solution (150 mL) and brine (150 mL). Each aqueous layer was back-extracted in turn with diethyl ether (200 mL), then the combined organic extracts were dried (MgSO4) and evaporated to give crude 2-chloro-4-[[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl]benzoic acid methyl ester (˜35 g) as a colorless solid. This material was used directly in the next step without purification.

Provenance & Evidence