Propylphosphonic anhydride → Ethyl {7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetate

HRID 1054176Notes

Reaction equation

HRID 1054176 reaction equation
C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:35]=[CH:34][C:23]2[NH:24][CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1.[O:36]=[C:37]1[NH:42][C:41]2[CH:43]=[C:44]([C:47](O)=[O:48])[CH:45]=[CH:46][C:40]=2[O:39][CH2:38]1>CCOC(C)=O>[Br:19][C:20]1[CH:35]=[CH:34][C:23]2[N:24]([C:47]([C:44]3[CH:45]=[CH:46][C:40]4[O:39][CH2:38][C:37](=[O:36])[NH:42][C:41]=4[CH:43]=3)=[O:48])[CH:25]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1

Participants

5

Reactant 3

HCID 111923Propylphosphonic anhydride2×HCID 7061213-Oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acidHCID 118599776Ethyl (7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate2×

Product 1

HCID 131736333Ethyl {7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetateYield 58%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Conditions

Temperature
150 °C

Procedure

TEA (0.737 mL, 5.32 mmol) and T3P (50 wt. % in EtOAc, 2.372 mL, 3.99 mmol) were added to a solution of ethyl (7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-yl)acetate (Intermediate 27, 399 mg, 1.33 mmol) and 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid (308 mg, 1.60 mmol) in EtOAc (7 mL). The reaction mixture was heated in a microwave reactor at 150° C. for 2 h. Additional T3P (50 wt. % in EtOAc, 1.2 mL, 2.02 mmol) and TEA (0.3 mL, 2.16 mmol) was added and the mixture was heated in a microwave reactor at 150° C. for another 2 h. EtOAc (50 mL) was added and the mixture washed with sat. aq. Na2CO3 (2×30 mL), HCl (30 mL, 0.5M) and brine, dried through a phase separator and evaporated. The compound was purified by preparative HPLC (Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 35-75% ACN in H2O/ACN/FA 95/5/0.2 buffer over 20 min with a flow of 100 mL/min, UV detection at 254/280 nm). The title compound (366 mg, 58%) was obtained after removal of solvents in vacuo.

Workup

  1. temperaturethe mixture was heated in a microwave reactor at 150° C. for another 2 h
  2. washthe mixture washed with sat. aq. Na2CO3 (2×30 mL), HCl (30 mL, 0.5M) and brine
  3. customdried through a phase separator
  4. customevaporated
  5. customThe compound was purified by preparative HPLC (Kromasil C8 column (10 μm 250×50 ID mm)
  6. custombuffer over 20 min

Sources & evidence

ORD record
ord-62553ce5482f4aef8fc6dfb2e9a444bb
Source dataset
uspto-grants-2016_07
Patent number
US09394291B2

Reaction notes

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