Ethyl 2-methylacetoacetate → HCID 10754932, compound

Participants

Reaction Conditions

Reaction Steps

A stirred solution of 4-[2-(dimethylamino)ethoxy]aniline [R Paul et al, J. Med. Chem. 36, 1993, 2716-2725](3.61 g, 20 mmol) in water (34 mL) and concentrated HCl (10 mL) was diazotized at 0° C. with a solution of NaNO2 (1.52 g, 22 mmol) in water (4 mL). The cold solution was added in one portion to a vigorously stirred ice-cold mixture of ethyl 2-methylacetoacetate (3.03 g, 21 mmol), anhydrous NaOAc (17 g), EtOH (25 mL), and freshly added ice (20 g). After stirring at 20° C. for 1 h, the mixture was cooled to 0° C., basified by the slow addition of solid Na2CO3, and extracted immediately with CH2Cl2 (×2). The combined organic layers were washed with water, dried (Na2SO4), and evaporated. The residue was extracted with hot petroleum ether (bp 60-65° C.) in the presence of decolorizing charcoal, and the clarified solution was evaporated. The remaining oil (4.55 g) was dissolved in absolute EtOH (6 mL) and HCl-saturated EtOH (10 mL) was added. After heating at reflux for 25 min, the solution was concentrated and the residue was partitioned between dilute Na2CO3 and CH2Cl2. The organic layer was washed with water and NaCl solution, dried, and evaporated. The residue was triturated with iPr2O/hexanes and the resulting solid was recrystallized from iPr2O/hexanes to give ethyl 5-[2-(dimethylamino)ethoxy]indole-2-carboxylate (1.32 g, 24% overall yield) as needles, mp 110° C. 1H NMR [(CD3)2SO] δ 11.72 (s, 1 H, NH), 7.34 (d, J=9.0 Hz, 1 H, H-7), 712 (d, J=2.4 Hz, 1 H, H-4), 7.03 (d, J=1.6 Hz, 1 H, H-3), 6.91 (dd, J=9.0, 2.4 Hz, 1 H, H-6), 4.32 (q, J=7.1 Hz, 2 H, CH2CH3), 4.03 (t, J=5.9 Hz, 2 H, OCH2), 2.63 (t, J=5.9 Hz, 2 H, OCH2CH2), 2.22 (s, 6 H, N(CH3)2), 1.33 (t, J=7.1 Hz, 3 H, CH2CH3).

Provenance & Evidence