Water → 2-[6-(1-Benzhydryl-3-methyl-azetidin-3-yloxy)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propionic acid ethyl ester

HRID 519000Notes

Reaction equation

HRID 519000 reaction equation
[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH2:19]C)([N:7]1[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])C)[CH3:2].[CH:22]([N:35]1[CH2:38][C:37](OS(C)(=O)=O)([CH3:39])[CH2:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([O:17][C:37]3([CH3:39])[CH2:38][N:35]([CH:22]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:36]3)[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[O:18])[CH3:19])[CH3:2]

Participants

6

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 100652951-Benzhydryl-3-methylazetidin-3-yl methanesulfonateHCID 86727346Ethyl 2-(6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester

Product 1

HCID 867273552-[6-(1-Benzhydryl-3-methyl-azetidin-3-yloxy)-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propionic acid ethyl esterYield 79.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of ethyl 2-(6-hydroxy-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (Example #65, Step C, 0.200 g, 0.754 mmol), methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (0.275 g, 0.829 mmol) and Cs2CO3 (0.491 g, 1.508 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% to 10% EtOAc in petroleum ether) to give 2-[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 (0.300 g, 79%). 1H NMR (CDCl3, 400 MHz): δ 7.44 (m, 4H), 7.30 (m, 3H), 7.29 (m, 1H), 7.28 (m, 2H), 6.87 (d, J=8.8 Hz, 1H), 6.28 (d, J=8.8 Hz, 1H), 6.22 (s, 1H), 5.32 (q, J=7.2 Hz, 1H), 4.55 (d, J=17.6 Hz, 2H), 4.42 (s, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.38 (m, 2H), 3.19 (m, 2H), 1.59 (m, 6H), 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% to 10% EtOAc in petroleum ether)

Sources & evidence

ORD record
ord-517845cd41fd4628b712c31a0fedab36
Source dataset
uspto-grants-2015_08
Patent number
US09115151B2

Reaction notes

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