反应详情

A scintillation vial was charged with bicyclo-[3.2.1]octan-3-one (iia) (31 mg, 0.25 mmol), spiro[4H-3,1-benzoxazine-4,4′-piperidin]-2(1H)-one (A4) (44 mg, 0.20 mmol), and anhydrous dimethoxyethane:dichloromethane (1.0 mL, 1:1 v/v). The mixture was treated with titanium tetraisopropoxide (171 mg, 0.60 mmol). The vial was flushed with nitrogen and stirred at room temperature for 60 hours. The reaction was then cooled in an ice water bath, quenched with methanol (1.0 mL) and treated with sodium borohydride (15 mg, 0.40 mmol). The reaction mixture was slowly warmed to room temperature, stirred for 1 hour, treated with 1.0 N NaOH (1.0 mL), diluted with methanol (2.0 mL), and stirred at room temperature for 15 min. The suspension obtained was centrifuged (3K rpm, 10 min), and the supernatant was filtered (Whatman 0.2 μm PTFE). The filtrate was concentrated under reduced pressure and the residue obtained dissolved in DMSO:methanol (1.5 mL, 1:1 v/v), filtered and subjected to reverse-phase HPLC purification [2-99% CH3CN gradient over 13 min with 0.1% TFA (aq), 35 mL/min, 1.0 mL injected] to provide 1′-(bicyclo[3.2.1]octan-3-yl)spiro[benzo[d][1,3]oxazine-4,4′-piperidin]-2(1H)-one (compound no. 67) as a TFA salt. LC/MS m/z 327.2 [M+H]+, retention time 1.80 min (RP-C18, 10-99% CH3CN/0.05% TFA).

1. customThe vial was flushed with nitrogen
2. temperatureThe reaction was then cooled in an ice water bath
3. customquenched with methanol (1.0 mL)
4. temperatureThe reaction mixture was slowly warmed to room temperature
5. stirringstirred for 1 hour
6. stirringstirred at room temperature for 15 min
7. customThe suspension obtained
8. filtrationthe supernatant was filtered (Whatman 0.2 μm PTFE)
9. concentrationThe filtrate was concentrated under reduced pressure
10. customthe residue obtained
11. filtrationmethanol (1.5 mL, 1:1 v/v), filtered
12. customsubjected to reverse-phase HPLC purification [2-99% CH3CN gradient over 13 min with 0.1% TFA (aq), 35 mL/min, 1.0 mL injected]