Water → HCID 86727386, compound

HRID 519026Notes

Reaction equation

HRID 519026 reaction equation
[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH2:20]C)([N:7]1[C:12]2[CH:13]=[C:14]([OH:18])[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:19])C)[CH3:2].[CH:23]([N:36]1[CH2:39][C:38](OS(C)(=O)=O)([CH3:40])[CH2:37]1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:18][C:38]3([CH3:40])[CH2:39][N:36]([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:37]3)[C:15]([F:17])=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:19])[CH3:20])[CH3:2]

Participants

6

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 100652951-Benzhydryl-3-methylazetidin-3-yl methanesulfonateHCID 86727387HCID 86727387, compound

Product 1

HCID 86727386HCID 86727386, compoundYield 76.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of ethyl 2-(7-fluoro-6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (0.200 g, 0.706 mmol), methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (Preparation #3, Step B, 0.257 g, 0.777 mmol) and Cs2CO3 (0.460 g, 1.412 mmol) in DMF (8 mL) was stirred at 90° C. for 3 h. The reaction mixture was cooled to ambient temperature and poured into water (150 mL). The aqueous mixture was extracted with EtOAc (3×20 mL) and the combined organic phase was washed with brine (3×20 mL), dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether) to give 2-[7-fluoro-6-(1-benzhydryl-3-methyl-azetidin-3-yloxy)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propionic acid ethyl ester as a white solid (0.280 g, 76%). 1H NMR (CDCl3, 400 MHz): δ 7.44 (m, 4H), 7.31 (m, 2H), 7.29 (m, 2H), 7.27 (m, 2H), 6.87 (d, J=10.4 Hz, 1H), 6.22 (d, J=7.6 Hz, 1H), 5.45 (q, J=7.2 Hz, 1H), 4.55 (d, J=15.2 Hz, 2H), 4.41 (s, 1H), 3.98 (q, J=7.2 Hz, 2H), 3.34 (d, J=7.6 Hz, 2H), 3.19 (d, J=7.6 Hz, 2H), 1.59 (s, 3H), 1.56 (d, J=7.2 Hz, 3H), 1.16 (t, J=7.2 Hz, 3H).

Workup

  1. temperatureThe reaction mixture was cooled to ambient temperature
  2. extractionThe aqueous mixture was extracted with EtOAc (3×20 mL)
  3. washthe combined organic phase was washed with brine (3×20 mL)
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. customevaporated in vacuo
  7. customThe residue was purified by column chromatography on silica gel (eluting with 5-10% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-dce6a0bd4a75481c9218ef130b723505
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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