Methanesulfonic Acid → ethyl 2-chloro-11-fluoro-12,12a-dihydro-6H-pyrido[2',3':5,6][1,3]oxazino[3,4-a]indole-6-carboxylate

HRID 1776850Notes

Reaction equation

[Cl:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[F:17])[NH:9]2)[C:5]([OH:18])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22](=[O:25])[CH:23]=O)[CH3:20].S(O)(C)(=O)=O>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:18][CH:23]([C:22]([O:21][CH2:19][CH3:20])=[O:25])[N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]([F:17])[C:15]=4[CH2:16][CH:8]3[C:6]=2[N:7]=1

Participants

Conditions

Temperature: 50 °C

Procedure

To a solution of 6-chloro-2-(4-fluoroindolin-2-yl)pyridin-3-ol (8.53 g, 32.31 mmol) and Glyoxylic acid ethyl ester (6.59 g, 64.59 mmol) in THF (80 mL), MsOH (0.31 g, 3.23 mmol) was added. The mixture was stirred at 50° C. for 2 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EtOAc=10:1) to provide ethyl 2-chloro-11-fluoro-12,12a-dihydro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indole-6-carboxylate (10.2 g, yield: 90.3%). 1H-NMR (CDCl3, 400 MHz) δ 7.04˜7.13 (m, 3H), 6.63 (d, J=8.0 Hz, 1H), 6.55 (t, J=8.4 Hz, 1H), 6.03 (s, 1H), 5.09 (d, J=8.8 Hz, 1H), 4.22˜4.34 (m, 2H), 3.73 (d, J=16.4 Hz, 1H), 3.44˜3.51 (m, 1H), 1.29 (d, J=7.2 Hz, 3H). MS (M+H)+: 349.

Workup

extractionextracted with EtOAc
washThe organic layer was washed with brine (30 mL)
dry with materialdried over Na2SO4
concentrationconcentrated in vacuo
customThe resulting residue was purified

Sources & evidence

ORD record: ord-33c2ad2fb8324e4c9d479fb4d32c248a
Source dataset: uspto-grants-2016_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09265773B2

Reaction notes

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