Hydrochloric Acid → 6-chloro-5-(6-(dimethylamino)-2-methoxypyridin-3-yl)-1H-indole-3-carboxylic acid

Participants

Reaction Steps

To a solution of Intermediate 6-chloro-5-(6-dimethylamino-2-methoxy-pyridin-3-yl)-1H-indole-3-carboxylic acid methyl ester (45.0 g, 130 mmol) in 1:1 tetrahydrofuran:methanol (1250 mL) at 50° C. was added 2 N NaOH (1250 mL). After 60 h, the reaction was cooled to <5° C. and with stirring, 6 N HCl (417 mL) was added dropwise until pH 6-7. The solution was divided in half and each was diluted with ethyl acetate (1.5 L) and the layers separated. The aqueous layers were back extracted with ethyl acetate (2×600 mL). All organics were combined and washed with sat. aq. NH4Cl (1 L) and brine (1 L), and dried over MgSO4, filtered and concentrated in vacuo to give crude material. Several batches of crude material were combined (117 g) and acetone (3.5 L) was added. This was refluxed to dissolve all solids and then partially concentrated to ˜1.5 L and slowly cooled to lead to solids crashing out. These solids were suspended in heptanes (˜500 mL) and stirred at 80° C. for 48 h. Solids were collected by filtration and suction dried for 15 h to afford desired product (80.0 g) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ=12.03 (br. s., 1 H) 11.86 (br. s., 1 H) 8.04 (d, J=2.73 Hz, 1 H) 7.83 (s, 1 H) 7.55 (s, 1 H) 7.32 (d, J=8.20 Hz, 1 H) 6.21 (d, J=8.20 Hz, 1 H) 3.76 (s, 3 H) 3.07 (s, 6 H); MS (ES+) 346.1 (M+H)+.

Provenance & Evidence