Methoxymethyl-triphenylphosphonium chloride → N-{(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-[(E)-2-methoxyethenyl]-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl}benzamide

Participants

Reaction Conditions

Reaction Steps

A suspension of oven-dried (methoxymethyl)triphenylphosphonium chloride (2.56 g, 7.46 mmol) in tetrahydrofuran (41 mL) was cooled to 0° C. To this solution was added potassium tert-butoxide (1.0 M in tetrahydrofuran, 6.41 mL, 6.41 mmol) at a very slow rate such that the internal temperature did not exceed 5° C. The resulting bright orange solution was left stirring at the same temperature for 5 minutes. It was then allowed to warm up to room temperature and was left stirring for another 30 minutes. The reaction mixture was cooled down to 0° C. and a solution of N-[(4aR,6R,8aS)-8a-(5-bromo-2-fluorophenyl)-6-formyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C42) (1.00 g, 2.10 mmol) in tetrahydrofuran (18 mL) was then added slowly. Once the addition was completed, the resulting solution was stirred at 0° C. for 30 minutes. The reaction mixture was quenched by addition of a saturated aqueous solution of sodium bicarbonate (100 mL). The mixture was extracted with ethyl acetate (3×150 mL). The combined organics were then washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. Purification via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane) afforded the product as a white solid. Yield: 540 mg, 51%. 1H NMR (400 MHz, CD3OD) characteristic peaks: δ 8.13 (br d, J=7.4 Hz, 2H), 7.44-7.57 (m, 4H), 7.13 (dd, J=12.1, 8.6 Hz, 1H), 6.05 (dd, J=6.3, 1.0 Hz, 1H), 4.58-4.63 (m, 1H), 4.48 (dd, J=7.9, 6.4 Hz, 1H), 4.12-4.15 (m, 1H), 3.85 (d, J=11.9 Hz, 1H), 3.63 (s, 3H), 3.20 (br s, 1H), 2.93 (dd, J=13.1, 4.1 Hz, 1H), 2.72 (J=13.2, 2.8 Hz, 1H), 1.84-1.90 (m, 1H), 1.71-1.75 (m, 1H).

Provenance & Evidence