反应详情

温度

50 °C

To a suspension of Intermediate 3b (27.4 g, 102.9 mmol) and pyridine (25 mL, 309.1 mmol) in toluene (250 mL) at 50° C. was added POCl3 (11.0 mL, 118 mmol) in 3 portions at 30 s intervals. (CARE: exotherm to 70° C.). The brown suspension was stirred at 50° C. for 1 h, then cooled to RT. Water (100 mL) and sat. aqueous NaHCO3 solution (100 mL) were added (CARE: gas evolution) and the mixture stirred at RT for 30 min. The aqueous was extracted with EtOAc (2×250 mL), then the combined organics washed with brine (250 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a brown oil (26.3 g, overweight). The oil was redissolved in MeOH (150 mL) then charcoal (6 g) was added and the mixture swirled for 30 min. The suspension was filtered through Celite and the filtercake washed with MeOH (25 mL). The filtrate was concentrated in vacuo to leave a red oil. this was azeotroped with pentane (25 mL) (24.0 g). The solid was slurried in diethyl ether/pentane (1:1, 40 mL), filtered and dried in vacuo to leave Intermediate 3c (20.6 g, 81%). The mother liquor was concentrated in vacuo, the residue dissolved in hot cyclohexane (50° C., 30 mL), then cooled to RT and allowed to stand for over the weekend. The mixture was filtered, the solid washed with cyclohexane (5 mL) then dried in vacuo at 45° C. to leave additional Intermediate 3c (1.8 g, 6%). LCMS: Rt 3.30 min, m/z 249 [MH+]. 1H NMR (300 MHz, CDCl3): 0.68 (6H, d, J=6.2 Hz), 1.36-1.49 (2H, m), 1.52-1.68 (1H, m), 1.75-1.90 (3H, m), 3.29-3.40 (2H, m), 7.16 (1H, ddd, J=10.0, 7.6, 2.3 Hz), 7.67 (1H, dd, J=10.0, 4.7 Hz), 8.03 (1H, t, J=2.7 Hz).

1. custom(CARE: exotherm to 70° C.)
2. temperaturecooled to RT
3. stirringthe mixture stirred at RT for 30 min
4. extractionThe aqueous was extracted with EtOAc (2×250 mL)
5. washthe combined organics washed with brine (250 mL)
6. dry with materialdried (Na2SO4)
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. customto leave a brown oil (26.3 g, overweight)
10. waitthe mixture swirled for 30 min
11. filtrationThe suspension was filtered through Celite
12. washthe filtercake washed with MeOH (25 mL)
13. concentrationThe filtrate was concentrated in vacuo
14. customto leave a red oil
15. customthis was azeotroped with pentane (25 mL) (24.0 g)
16. filtrationfiltered
17. customdried in vacuo