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 1054178Notes

Reaction equation

HRID 1054178 reaction equation
CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:26]=[CH:25][C:14]2[NH:15][C@@H:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][O:18][C:13]=2[CH:12]=1.[O:27]=[C:28]1[CH2:33][O:32][C:31]2[CH:34]=[CH:35][C:36]([C:38](O)=[O:39])=[CH:37][C:30]=2[NH:29]1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>C(OCCCC)(=O)C.CCOC(C)=O>[Br:10][C:11]1[CH:26]=[CH:25][C:14]2[N:15]([C:38]([C:36]3[CH:35]=[CH:34][C:31]4[O:32][CH2:33][C:28](=[O:27])[NH:29][C:30]=4[CH:37]=3)=[O:39])[C@@H:16]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:17][O:18][C:13]=2[CH:12]=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 58%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 31272Butyl AcetateSolvent

Conditions

Temperature
140 °C

Procedure

DIPEA (46.4 g, 360 mmol) was added to ethyl [(3S)-7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-yl]acetate (Intermediate 27a, 36 g, 120 mmol), 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (28 g, 144 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% solution in EtOAc) (152.6 g, 240 mmol) in butyl acetate (100 mL) at rt. The resulting suspension was stirred at 140° C. for 2 hours. The reaction mixture was diluted with EtOAc (700 mL) and washed with saturated NaHCO3 (500 mL), 1 M HCl (500 mL) and brine (500 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to afford crude product. The residue was purified by a silica chromatography, eluent gradient from 5% to 20% of EtOAc in PE. The pure fraction was evaporated to dryness to afford title compound (33 g, 58%) as an off-white solid.

Workup

  1. washwashed with saturated NaHCO3 (500 mL), 1 M HCl (500 mL) and brine (500 mL)
  2. dry with materialThe organic layer was dried over anhydrous Na2SO4
  3. filtrationfiltered
  4. customevaporated
  5. customto afford crude product
  6. customThe residue was purified by a silica chromatography, eluent gradient from 5% to 20% of EtOAc in PE
  7. customThe pure fraction was evaporated to dryness

Sources & evidence

ORD record
ord-1a0f9657e967423c82e28fcb3ad5641b
Source dataset
uspto-grants-2016_07
Patent number
US09394291B2

Reaction notes

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