Dimethyl Sulfoxide → Methyl {(7 R)-7-[[(4-fluorophenyl)sulfonyl](methyl)amino]-6,7-dihydro pyrido[1,2-alpha]indol-10-yl}acetate

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Reaction Steps

A solution of CH2Cl2, oxalyl chloride (0.54 M, 1.2 equiv.) was cooled to −76° C. DMSO (2.5 equiv.) was then added dropwise such that T<−60 ° C. The mixture was stirred for 30 min, upon which methyl (1-{(2R)-2-[[(4-fluorophenyl)sulfonyl](methyl)amino]-4-hydroxy-butyl}-1H-indol-3-yl)acetate from Step 6 was added as a solution in CH2Cl2 (0.3 M). The reaction was stirred an additional 30 min. Triethylamine (4 equiv.) was then added dropwise, and the reaction warmed to rt and stirred for 2 h. The reaction was quenched by the addition of saturated NaHCO3. The layers were separated, and the aqueous back-extracted with CH2Cl2 (2×). The combined organic phases were washed with brine, dried over Na2SO4, filtered through a plug of SiO2 and concentrated to give a yellow foam. This crude aldehyde was dissolved in toluene (0.25 M) and charged in a three necked round bottom flask fitted with a temperature probe, nitrogen inlet, reflux condenser, and mechanical stirrer. Pyridinium p-toluenesulfonate (0.2 equiv.) was added, and the reaction heated to 60° C. for 16 h (protected from light with aluminum foil). The reaction was diluted with water and extracted with EtOAc. The layers were separated, and the aqueous back extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated and the residue was purified by column chromatography on silica gel using automatized gradiant pump system CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hex (20:80 to 40:60) to give a light yellow foam. This light yellow foam was then swished by dissolving in EtOAc (2 mL/g), slow addition of MTBE (5 mL/g), then slow addition of Heptanes (7 mL/g) to give the title compound (73%) as an off white solid . The mother liquor was concentrated and purified by flash again to more (7%) of the desired compound.

Provenance & Evidence