Methyl chloroformate → HCID 67578602, compound

Participants

Reaction Conditions

Reaction Steps

A mixture of 5-chloro-2,3-dihydro-1-(4-fluorophenyl)-3-1H-indolone (5) (1.1 g, 5.7 mmol), (S)-N-Ethoxycarbonylalaninol (2.9 g, 17 mmol), p-toluenesulfonic acid (0.8 g) and toluene (50 mL) was refluxed for 18 h. Evaporation of the solvents and purification by column chromatography (eluted with ethyl acetate/heptane 1:2) afforded the crude (S)-N-methyl-2-[5-chloro-1-(4-fluorophenyl)-3-1H-indolyloxy]-N-ethoxycarbonyl-1-methylethylamine as an oil (1.1 g). The crude carbamate was dissolved in dry diethyl ether (50 mL) and added to a suspension of lithium aluminum hydride (0.5 g, 13 mmol) in dry diethyl ether (50 mL). After reflux for 2 h the reaction mixture was cooled to 0° C. and carefully treated with water (1 mL) and 4N aqueous NaOH (1 mL). The precipitate was filtered off and extracted with dichloromethane (3×50 mL). The combined organic phases were dried (Na2SO4) and the solvents were evaporated affording the crude N-methyl compound as an oil (0.6 g). A solution of methyl chloroformate (0.20 g, 2.1 mmol) in dichloromethane (20 mL) was added to a mixture of the crude N-methyl compound, K2 CO3 (0.3 g) and dichloromethane (20 mL). After reaction for 3.5 h the reaction mixture was filtered and the solvents were evaporated. The remaining oil was suspended in dry diethyl ether (20 mL) and added to a suspension of lithium aluminum hydride in dry diethyl ether (20 mL). The resulting mixture was refluxed for 2 h and subsequently cooled to 0° C. The reaction mixture was treated with water (0.5 mL) and 4N aqueous NaOH (0.5 mL). The precipitate was filtered off and extracted with dichloromethane (3×50 mL). The combined organic phases were dried (Na2SO4) and the solvents were evaporated affording an oil. The product was purified by column chromatography (eluted with ethanol/ethyl acetate 6:1 containing 4% triethylamine) giving the title compound 6a (0.30 g, 23%) as an oil which was precipitated as its oxalate in acetone: mp 161°-163° C.; [α]22D +11.4° (c 1.0; CH3OH); 1H NMR (DMSO-d6) δ 1.35 (d, 3 H), 2.80 (s, 6 H), 3.80 (sex, 1 H), 4.30 (m, 2 H), 7.20 (broad d, 1 H), 7.40 (t, 2 H), 7.50 (d, 1 H), 7.55 (s, 1 H), 7.60 (dd, 2 H), 7.75 (broad s, 1 H). MS (m/z) 347 (MH+), 260 (3), 86 (100); Anal. (C19H20 ClFN2O.C2H2O4) C, H, N.

Provenance & Evidence