Hydrochloric Acid → tert-Butyl 2-oxo-1,2-dihydro-1'H-spiro[3,1-benzoxazine-4,4'-piperidine]-1'-carboxylate

Temperature

-70 °C

N-Boc-aniline (16.12 g, 83.4 mmol) (A1) was dissolved in anhydrous tetrahydrofuran (120 mL) and cooled to −70° C. To this solution was added dropwise, under nitrogen, a 1.7 M solution of tert-butyllithium in pentane (110 mL, 187 mmol) at −70° C. After 30 min at −70° C., the solution was warmed to −20° C. and maintained at that temperature for 2 hours. The solution was again cooled to −70° C. and treated dropwise with a solution of N-Boc-4-piperidone (15.98 g, 80.2 mmol) (A2) in anhydrous tetrahydrofuran (50 mL). The solution was slowly warmed to room temperature, treated with potassium tert-butoxide (25 mg) and stirred at room temperature overnight under nitrogen. The solution was diluted with diethyl ether (300 mL), cooled in an ice water bath and adjusted to pH 7 with 1.0 N HCl (aq). The layers were separated and the aqueous layer extracted once with diethyl ether (100 mL). The pooled organic layers were washed with water and saturated brine, then dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to afford a crude product as a viscous pale yellow oil. The crude product was purified via silica gel flash chromatography (25-50% ethyl acetate in hexanes) to afford tert-butyl 2-oxo-1,2-dihydrospiro[benzo[d][1,3]oxazine-4,4′-piperidine]-1′-carboxylate (A3) as a pale yellow solid. LC/MS m/z 319.0 [M+H]+, retention time 2.72 min (RP-C18, 10-99% CH3CN/0.05% TFA); 1H-NMR (400 MHz, CDCl3) δ 9.06 (br s, 1H), 7.28 (m, 1H), 7.12 (m, 2H), 6.91 (d, J=8.5 Hz, 1H), 4.12 (br d, J=9.9 Hz, 2H), 3.36 (br t, J=12.4 Hz, 2H), 2.13 (br d, J=13.1 Hz, 2H), 1.98 (m, 2H), 1.51 (s, 9H).

1. additionTo this solution was added dropwise, under nitrogen
2. customat −70° C
3. temperaturethe solution was warmed to −20° C.
4. temperaturemaintained at that temperature for 2 hours
5. temperatureThe solution was again cooled to −70° C.
6. temperatureThe solution was slowly warmed to room temperature
7. temperaturecooled in an ice water bath
8. customThe layers were separated
9. extractionthe aqueous layer extracted once with diethyl ether (100 mL)
10. washThe pooled organic layers were washed with water and saturated brine
11. dry with materialdried over Na2SO4
12. filtrationfiltered
13. concentrationThe filtrate was concentrated under reduced pressure
14. customto afford a crude product as a viscous pale yellow oil
15. customThe crude product was purified via silica gel flash chromatography (25-50% ethyl acetate in hexanes)

ORD record

ord-cf985410b8fc4af68a13e0c9711a0689

Source dataset

uspto-grants-2010_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07696201B2