Methylamine → 2-{7-Bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}-N-methylacetamide

HRID 1054191Notes

Reaction equation

HRID 1054191 reaction equation
C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[Br:19][C:20]1[CH:46]=[CH:45][C:23]2[N:24]([C:32]([C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=4[CH:44]=3)=[O:33])[CH:25]([CH2:28][C:29](O)=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1.[CH3:47][NH2:48].C1COCC1>CCOC(C)=O>[Br:19][C:20]1[CH:46]=[CH:45][C:23]2[N:24]([C:32]([C:34]3[CH:35]=[CH:36][C:37]4[O:42][CH2:41][C:40](=[O:43])[NH:39][C:38]=4[CH:44]=3)=[O:33])[CH:25]([CH2:28][C:29]([NH:48][CH3:47])=[O:30])[CH2:26][O:27][C:22]=2[CH:21]=1

Participants

6

Reactant 4

HCID 6329MethylamineHCID 8028TetrahydrofuranHCID 111923Propylphosphonic anhydrideHCID 118599755{7-Bromo-4-[3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid2×

Product 1

HCID 1185997632-{7-Bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}-N-methylacetamideYield 56%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent2×

Procedure

TEA (0.461 mL, 3.33 mmol) and T3P (50 wt. % in EtOAc, 0.989 mL, 1.66 mmol) were added to a solution of {7-bromo-4-[(3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl)carbonyl]-3,4-dihydro-2H-1,4-benzoxazin-3-yl}acetic acid (Intermediate 29, 372 mg, 0.83 mmol) in EtOAc (5 mL). The mixture was stirred for 5 min. Methanamine in THF (1.248 mL, 2.50 mmol) was added and the mixture was stirred at rt for 2 h. EtOAc (50 mL) was added and the mixture washed with Na2CO3 (40 mL), HCl (1 M, 30 mL) and brine (30 mL), 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 15-55% 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) to give the title compound (215 mg, 56%) as a white solid.

Workup

  1. stirringthe mixture was stirred at rt for 2 h
  2. washthe mixture washed with Na2CO3 (40 mL), HCl (1 M, 30 mL) and brine (30 mL)
  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-6b50627c631e4d17a334572350f108bd
Source dataset
uspto-grants-2016_07
Patent number
US09394291B2

Reaction notes

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