tert-Butyl acetate → methyl 2-(tert-butoxy)-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate

Participants

Reaction Steps

An ice cold solution of methyl 2-hydroxy-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (325 mg, 0.647 mmol) in tert-butyl acetate (8735 μl, 64.7 mmol) was treated with perchloric acid (55.6 μl, 0.647 mmol), and stirred for 20 min. The reaction was then kept in the refrigerator without stirring for 2 days. The reaction was quenched with sat. NaHCO3 at 0° C., extracted with EtOAc 2×, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (219.3 mg, 0.393 mmol, 60.7% yield, racemate) as white solid. The racemate was resolved using a Chiralpak IC column (30×250 mm) with isocratic conditions of 10% EtOH in hexane. The flow rate was 40 mL/min and the baseline was monitored at 280 nm using an Agilent 1100 series prep LC. The third isomer eluting from the column was isolated to afford (S)(M)-methyl 2-(tert-butoxy)-2-(1-(4-methoxybenzyl)-6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (52.9 mg, 0.095 mmol, 14.6% yield) as clear oil: 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.29 (d, J=8.5 Hz, 2H), 6.99-6.91 (m, 2H), 6.85 (d, J=8.5 Hz, 2H), 6.69 (d, J=8.4 Hz, 1H), 5.86 (d, J=14.6 Hz, 1H), 5.71-5.61 (m, 2H), 5.09 (s, 1H), 4.20 (t, J=5.2 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 3.65 (s, 3H), 2.76-2.62 (m, 2H), 2.13-2.04 (m, 2H), 1.91 (s, 3H), 1.11 (s, 9H); LCMS (m/z) ES+=559 (M+1).

Provenance & Evidence