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

Temperature

0 °C

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).

1. customdid not exceed 5° C
2. waitThe resulting bright orange solution was left
3. temperatureto warm up to room temperature
4. waitwas left
5. stirringstirring for another 30 minutes
6. temperatureThe reaction mixture was cooled down to 0° C.
7. additionOnce the addition
8. stirringthe resulting solution was stirred at 0° C. for 30 minutes
9. customThe reaction mixture was quenched by addition of a saturated aqueous solution of sodium bicarbonate (100 mL)
10. extractionThe mixture was extracted with ethyl acetate (3×150 mL)
11. washThe combined organics were then washed with brine (100 mL)
12. dry with materialdried over sodium sulfate
13. filtrationfiltered
14. concentrationconcentrated
15. customPurification via silica gel chromatography (Gradient: 0% to 50% ethyl acetate in heptane)

ORD record

ord-dd09231c18194eab92ae1d8ce37f3386

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09198917B2