Hydrochloric Acid → [(4aR,6R,8aS)-2-amino-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-6-yl]methanol

Participants

Reaction Conditions

Reaction Steps

Concentrated hydrochloric acid (12 M, 17.6 mL) was added to a methanol solution of 9H-fluoren-9-ylmethyl {[(3S,4R,6R)-6-[(benzyloxy)methyl]-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}carbamate (C23) (995 mg, 1.54 mmol), and the reaction mixture was heated to 70° C. for 2 hours. At this point, LCMS analysis indicated that the starting material had been consumed. The methanol was allowed to distill off, and the aqueous residue was heated to 120° C. for 3 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layer was extracted with ethyl acetate. These organic layers were shown by chromatographic separation, followed by 1H NMR and LCMS analysis, to contain cyclized material still retaining the fluorenylmethoxycarbonyl protecting group. The aqueous layer was basified with saturated aqueous sodium bicarbonate solution and extracted three times with ethyl acetate. These extracts were combined, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was triturated with dichloromethane to afford the product as a white solid. The filtrate from the trituration was concentrated in vacuo and triturated with dichloromethane to afford additional product, also as a white solid. Yield: 235 mg, 0.748 mmol, 49%. LCMS m/z 315.3 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.41-1.47 (m, 1H), 1.84-1.96 (m, 1H), 2.61-2.68 (m, 1H), 2.92-3.01 (m, 2H), 3.65 (dd, half of ABX pattern, J=11.7, 6.7 Hz, 1H), 3.70 (dd, half of ABX pattern, J=11.7, 3.2 Hz, 1H), 3.73-3.81 (m, 1H), 3.85 (d, J=11.3 Hz, 1H), 4.11 (dd, J=11.2, 2.2 Hz, 1H), 6.82 (ddd, J=12.4, 8.5, 2.6 Hz, 1H), 6.86-6.92 (m, 1H), 7.34 (ddd, J=9.1, 9.0, 6.7 Hz, 1H).

Provenance & Evidence