反应详情

温度

0 °C

To a stirred solution of Intermediate 58 (352 mg) in anhydrous N,N-dimethylformamide (15 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (55 mg) as a 60% by weight suspension on mineral oil in one charge. The reaction was stirred at 0° C. for 30 min. To the reaction was added neat tert-butyl bromoacetate (0.18 mL) in one charge the reaction was stirred at 0° C. for a further 30 min before allowing to warm to ambient temperature over 1 hr. The reaction was stirred at ambient temperature for 3 hr. Sodium hydride (55 mg) as a 60% wt suspension on oil was added and the reaction stirred for 30 min. To the reaction was added tert-butyl bromoacetate (0.18 mL) in one charge. The reaction was quenched with water (75 mL) and extracted with ethyl acetate (75 mL). The extract was dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-25% methanol-dichloromethane gradient. Separation poor all product containing fractions were combined and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and concentrated in vacuo to give the title compound (130 mg). LC/MS MH+ 419, 421, Rt 1.00 min (2 min run). Chiral separation of this material using a chiralpak AD column eluting with 5% ethanol in heptane to provide the two enantiomers in order of elution:

1. additioncharge
2. additioncharge the reaction
3. stirringwas stirred at 0° C. for a further 30 min
4. temperatureto warm to ambient temperature over 1 hr
5. stirringThe reaction was stirred at ambient temperature for 3 hr
6. stirringthe reaction stirred for 30 min
7. additioncharge
8. customThe reaction was quenched with water (75 mL)
9. extractionextracted with ethyl acetate (75 mL)
10. customThe extract was dried (hydrophobic frit)
11. concentrationconcentrated in vacuo
12. custompurified on silica using a 0-25% methanol-dichloromethane gradient
13. customSeparation poor all product
14. additioncontaining fractions
15. concentrationconcentrated in vacuo
16. custompurified on silica using a 0-100% ethyl acetate-cyclohexane gradient
17. concentrationconcentrated in vacuo