反应详情

温度

2.5 °C

Into an oven dried 2 L 4-neck round bottom flask was charged 9-fluorenylmethanol (50.0 g, 255 mmol) and anhydrous DCM (382 mL) at room temperature. The resulting slurry was cooled in an ice-bath to about 0-5° C. A solution of chlorosulfonyl isocyanate (CSI, 23.0 mL, 264 mmol) in anhydrous DCM (127 mL) was added dropwise to the slurry through an addition funnel over 22 minutes, maintaining the reaction mixture temperature at <5° C. The resulting mixture was stirred at 0-5° C. for 1.75 h, producing a thick white slurry. A solution of aminoacetaldehyde dimethyl acetal (27.9 mL, 255 mmol) in anhydrous DCM (382 mL) and 4-methylmorpholine (84.0 mL, 764 mmol) were added to the mixture at about 0-5° C. over 71 minutes. The resulting reaction mixture was then stirred in the ice bath for 1.5 hours. When HPLC showed the reaction was complete, the reaction mixture was acidified by the dropwise addition of a 1.0 M phosphoric acid (H3PO4, aq., 640 mL) over 22 minutes to pH 1-2. Water (300 mL), EtOAc (2150 mL) and heptane (250 mL) were then added and the resulting mixture was stirred for 10 minutes. The two phases were separated and the organic phase was washed sequentially with water (500 mL), heptane (300 mL) and water (2×500 mL) and dried over MgSO4. The filtrate was concentrated under vacuum to dryness. The resulting solids were redissolved in EtOAc (600 mL) at 65° C. and the warm solution was filtered into a clean 3 L round bottom flask. The filtrate was cooled to room temperature and stirred for 2.5 h before heptane (1200 mL) was then added via an addition funnel over 80 min. After stirring overnight at room temperature, the mixture was then cooled in an ice bath for 1 h. The resulting solids were collected by filtration, washed with 25% EtOAc/heptane (250 mL), and dried overnight at about 40-45° C. under vacuum to afford 9H-fluoren-9-ylmethyl {[(2,2-dimethoxyethyl)amino]sulfonyl}carbamate (91.3 g, 88% yield) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.98-7.85 (m, 3H), 7.76 (d, J=7.5 Hz, 2H), 7.43 (t, J=7.2 Hz, 2H), 7.33 (td, J=7.4, 1.1 Hz, 2H), 4.44-4.33 (m, 3H), 4.33-4.22 (m, 1H), 3.23 (s, 6H), 2.99 (t, J=5.8 Hz, 2H) ppm.

1. customInto an oven dried 2 L 4-neck round bottom flask
2. temperaturemaintaining the reaction mixture temperature at <5° C
3. customproducing a thick white slurry
4. customThe resulting reaction mixture
5. stirringthe resulting mixture was stirred for 10 minutes
6. customThe two phases were separated
7. washthe organic phase was washed sequentially with water (500 mL), heptane (300 mL) and water (2×500 mL)
8. dry with materialdried over MgSO4
9. concentrationThe filtrate was concentrated under vacuum to dryness
10. dissolutionThe resulting solids were redissolved in EtOAc (600 mL) at 65° C.
11. filtrationthe warm solution was filtered into a clean 3 L round bottom flask
12. temperatureThe filtrate was cooled to room temperature
13. stirringstirred for 2.5 h before heptane (1200 mL)
14. additionwas then added via an addition funnel over 80 min
15. stirringAfter stirring overnight at room temperature
16. temperaturethe mixture was then cooled in an ice bath for 1 h
17. filtrationThe resulting solids were collected by filtration
18. washwashed with 25% EtOAc/heptane (250 mL)
19. customdried overnight at about 40-45° C. under vacuum