反应详情

温度

-16 °C

To a jacketed round bottom 1L flask was added 27.5 g (1 eq) of the product of Example 2-1, 300 mL of dimethylacetamide and 30 mL of isopropyl alcohol. The reaction solution was cooled to about −16° C. and treated with 33 mL (10 eq) of methanesulfonic acid slowly (The reaction was exothermal, temperature raised to 9° C.). The mixture was cooled to about −16° C., treated with 54.1 g (5 equivalents) of sodium triacetoxylborohydride. Mixed at −16° C. for about 2 hrs and 30 min, HPLC showed the first reduction was completed. 67.9 mL (10 equivalents) of triethanolamine was then added slowly (exothermal). The mixture was stirred at about −16° C. for 1 hr. 7.7 g of sodium borohydride was added in 7 portions. The reaction mixture was stirred at −16° C. until the reduction was completed as indicated by HPLC (Column: YMC QDS-AQ 15 cm, flow 1 ml/1 min, Gradient system: 0-15 min, 80% 0.03M HK2PO4/20% CH3CN/to 20% 0.03M HK2PO4/80% CH3CN, 15-20 hold at 20% 0.03M HK2PO4/80% CH3CN, 20-21 min, 20% 0.03M HK2PO4/80% CH3CN to 80% 0.03M HK2PO4/20% CH3CN, 21-23 min, hold at 80% 0.03M HK2PO4/20% CH3CN), treated with 100 mL of water, stirred at room temperature overnight and diluted with 300 mL of dichloromethane to the reaction mixture. The isolated dichloromethane layer (Assay: 23 g, yield: 83.5%. ds: 95% as measured by HPLC (Column: YMC QDS-AQ 15 cm, flow 1 ml/1 min, Gradient system: 0-15 min, 80% 0.03M HK2PO4/20% CH3CN/ to 20% 0.03M HK2PO4/80% CH3CN, 15-20 hold at 20% 0.03M HK2PO4/80% CH3CN, 20-21 min, 20% 0.03M HK2PO4/80% CH3CN to 80% 0.03M HK2PO4/20% CH3CN, 21-23 min, hold at 80% 0.03M HK2PO4/20% CH3CN) was extracted with 0.3% H3PO4 solution (3×200 mL). The pH of the isolated aqueous layer was adjusted to 6-7 with sodium carbonate. The resulting solution was extracted with dichloromethane (2×300 ml). The combined isolated dichloromethane layers were washed with 200 mL of 5% aqueous KH2PO4, dried (Na2SO4) and concentrated. The resulting residue was dissolved in 100 mL of isopropyl acetate and washed sequentially with 100 mL of 5% KH2PO4 and brine. The isopropyl acetate solution was concentrated and 21.2 g of the title compound was obtained as a yellow foam.

1. temperaturetemperature raised to 9° C.)
2. temperatureThe mixture was cooled to about −16° C.
3. additionMixed at −16° C. for about 2 hrs and 30 min
4. stirringThe reaction mixture was stirred at −16° C. until the reduction
5. stirringstirred at room temperature overnight
6. extractionwas extracted with 0.3% H3PO4 solution (3×200 mL)
7. extractionThe resulting solution was extracted with dichloromethane (2×300 ml)
8. customThe combined isolated dichloromethane layers
9. washwere washed with 200 mL of 5% aqueous KH2PO4
10. dry with materialdried (Na2SO4)
11. concentrationconcentrated
12. dissolutionThe resulting residue was dissolved in 100 mL of isopropyl acetate
13. washwashed sequentially with 100 mL of 5% KH2PO4 and brine
14. concentrationThe isopropyl acetate solution was concentrated