反应详情

温度

65 °C

An inerted 6 L reactor is charged with THF (242.5 mL), magnesium (54.47 g, 2240 mmol) and 5% of the total amount of 4-chlorotetrahydropyran (12.28 mL, 112 mmol). Then, a small amount of methyl iodide (0.5 mL) and one iodine crystal is added. The reaction mixture is stirred and heated up to 64-66° C. After initiation, the remaining 4-chlorotetrahydropyran (233.22 mL, 2127 mmol) diluted in THF (890 mL) is slowly added over 135 mins. The mixture is heated up for 30 additional minutes before being cooled to 0° C. Then, the Weinreb amide 2b (370 g, 1400 mmol) diluted in THF (2777 mL) is added over 180 mins between 0-4° C. and the mixture is stirred for a further 60 mins. Then, acetic acid (48 mL, 0.83 mmol) is added to the mixture followed by a 55/45:v/v:saturated NH4Cl/H2O mixture (2590 mL) keeping the temperature below 9° C. The organic layer is washed with a 60/40:v/v:saturated NH4Cl/H2O mixture (500 mL) and, after separation, toluene (1800 mL) and water (1800 mL) is added to the organic solution. Then after extraction, water (1100 mL) is added to the toluene mixture which is basified with 3.68 M Na2CO3aq (148 mL). The organic layer is dried over MgSO4, filtered and concentrated under reduced pressure to dryness to yield compound 8b as the free base (400.8 g, 98.6% yield).

1. additionis slowly added over 135 mins
2. temperatureThe mixture is heated up for 30 additional minutes
3. temperaturebefore being cooled to 0° C
4. additionis added over 180 mins between 0-4° C.
5. stirringthe mixture is stirred for a further 60 mins
6. customthe temperature below 9° C
7. washThe organic layer is washed with a 60/40
8. customv/v:saturated NH4Cl/H2O mixture (500 mL) and, after separation, toluene (1800 mL) and water (1800 mL)
9. additionis added to the organic solution
10. extractionThen after extraction, water (1100 mL)
11. additionis added to the toluene mixture which
12. dry with materialThe organic layer is dried over MgSO4
13. filtrationfiltered
14. concentrationconcentrated under reduced pressure to dryness