Diisopropylethylamine → Ethyl 2-[(3S)-7-bromo-4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetate

HRID 1054177Notes

Reaction equation

HRID 1054177 reaction equation
[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C@@H:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1.[O:18]=[C:19]1[CH2:24][O:23][C:22]2[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:21]=2[NH:20]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCCCC)(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:29]([C:27]3[CH:26]=[CH:25][C:22]4[O:23][CH2:24][C:19](=[O:18])[NH:20][C:21]=4[CH:28]=3)=[O:30])[C@@H:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][O:9][C:4]=2[CH:3]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 7061213-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acidHCID 131736334HCID 131736334, compound2×

Product 1

HCID 118599611Ethyl 2-[(3S)-7-bromo-4-(3-oxo-4H-1,4-benzoxazine-6-carbonyl)-2,3-dihydro-1,4-benzoxazin-3-yl]acetateYield 63.6%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 31272Butyl AcetateSolvent

Conditions

Temperature
117 °C

Procedure

In a 250 mL 3-necked flask, ethyl [(3S)-7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-yl]acetate (Intermediate 27a, 4.2 g, 14.0 mmol) and 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (2.73 g, 14.1 mmol) were suspended in butyl acetate (40 mL). DIPEA (7.31 mL, 42.0 mmol) was added followed by T3P (50% in BuOAc) (17.8 g, 28.0 mmol). The reaction was heated in an alumina block for 7 h at 117° C. (internal reaction temp. the heating block was set to 135° C.). The reaction was allowed to cool to r.t over night. The crude reaction was diluted with EtOAc (150 mL) and washed with sat. aq. NaHCO3 (100+30 mL), 1 M citric acid aq. (50 mL), 1 M HCl (50 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford crude product as a red and foamy oil. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient from 30% to 75% of EtOAc in heptane over 5 CV was used as mobile phase. The product was collected using the wavelengths 254/280 nm. The title compound (4.23 g, 63.6%) was obtained as a foamy solid.

Workup

  1. customwas set to 135° C.
  2. temperatureto cool
  3. waitto r.t over night
  4. customThe crude reaction
  5. washwashed with sat. aq. NaHCO3 (100+30 mL), 1 M citric acid aq. (50 mL), 1 M HCl (50 mL) and brine (100 mL)
  6. dry with materialdried over anhydrous Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto afford crude product as a red and foamy oil
  10. customThe residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column
  11. customThe product was collected

Sources & evidence

ORD record
ord-ecd07949220247a993eccf229f4d9728
Source dataset
uspto-grants-2016_07
Patent number
US09394291B2

Reaction notes

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