Ethyl Acetate → AZD9977

HRID 1054184Notes

Reaction equation

HRID 1054184 reaction equation
[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[O:4][CH2:3]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(OCC)(=O)C.CCN(C(C)C)C(C)C.[F:48][C:49]1[CH:63]=[CH:62][C:52]2[NH:53][C@@H:54]([CH2:57][C:58]([NH:60][CH3:61])=[O:59])[CH2:55][O:56][C:51]=2[CH:50]=1>C(OCCCC)(=O)C.O>[F:48][C:49]1[CH:63]=[CH:62][C:52]2[N:53]([C:12]([C:9]3[CH:10]=[CH:11][C:5]4[O:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)=[O:14])[C@@H:54]([CH2:57][C:58]([NH:60][CH3:61])=[O:59])[CH2:55][O:56][C:51]=2[CH:50]=1

Participants

8

Reactant 5

HCID 8857Ethyl AcetateHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 7061213-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acidHCID 1185997752-[(3S)-7-Fluoro-3,4-dihydro-2H-1,4-benzoxazin-3-yl]-N-methyl-acetamide2×

Product 1

HCID 118599727AZD9977Yield 50.9%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 31272Butyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

3-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (9.58 g, 48.0 mmol) was suspended with stirring in n-butyl acetate (48 mL). T3P in ethyl acetate (52.5 mL, 87.5 mmol, 50.0% w/w) was added followed by DIPEA (3.82 mL, 21.9 mmol). The resulting suspension was heated at 80° C. over night. 2-[(3S)-7-fluoro-3,4-dihydro-2H-1,4-benzoxazin-3-yl]-N-methylacetamide (Intermediate 13, 10.0 g, 43.7 mmol) was added portion wise over approximately 90 min and then held at 80° C. over night. Water (100 mL) was added and the mixture stirred at 40° C. The organic phase was collected and washed with aqueous sodium hydrogen carbonate (100 mL, 5.25% w/w) at 40° C. The organic phase was cooled to 10° C. and stirred over night. Isopropanol (100 mL) was added and the solid collected by filtration and dried under vacuum at 40° C. The title compound was obtained as an off-white solid (9.29 g, 22.3 mmol, 95.7% w/w, ee 98.4%, 50.9% yield).

Workup

  1. waitheld at 80° C. over night
  2. customThe organic phase was collected
  3. washwashed with aqueous sodium hydrogen carbonate (100 mL, 5.25% w/w) at 40° C
  4. temperatureThe organic phase was cooled to 10° C.
  5. stirringstirred over night
  6. additionIsopropanol (100 mL) was added
  7. filtrationthe solid collected by filtration
  8. customdried under vacuum at 40° C

Sources & evidence

ORD record
ord-4d5f5eca125648468878a259a2a5dc42
Source dataset
uspto-grants-2016_07
Patent number
US09394291B2

Reaction notes

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