2-Dimethylaminopyridine → N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide

HRID 348177Notes

Reaction equation

HRID 348177 reaction equation
[CH2:1]([O:8][C:9]1[C:19](=[O:20])[N:18]2[C:12]([C:13]([CH3:22])([CH3:21])[O:14][CH2:15][CH2:16][CH2:17]2)=[N:11][C:10]=1[C:23](O)=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.FC(F)(F)C(O)=O.[NH2:57][CH2:58][C:59]1[CH:68]=[CH:67][C:66]([F:69])=[CH:65][C:60]=1[C:61]([NH:63][CH3:64])=[O:62].CN(C1C=CC=CN=1)C>CN(C)C=O>[F:69][C:66]1[CH:67]=[CH:68][C:59]([CH2:58][NH:57][C:23]([C:10]2[N:11]=[C:12]3[N:18]([C:19](=[O:20])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:22])=[O:24])=[C:60]([C:61](=[O:62])[NH:63][CH3:64])[CH:65]=1

Participants

6

Reactant 4

HCID 218852-DimethylaminopyridineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 210698142-(Aminomethyl)-5-fluoro-n-methylbenzamide trifluoroacetate saltHCID 210698553-(Benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylic acid

Product 1

HCID 21070020N-(4-Fluoro-2-(methylcarbamoyl)benzyl)-3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxamide

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of intermediate 35, 3-(benzyloxy)-10,10-dimethyl-4-oxo-6,7,8,10-tetrahydro-4H-pyrimido[2,1-c][1,4]oxazepine-2-carboxylic acid in anhydrous dimethylformamide (4 mL) was treated with HATU (0.278 g, 0.70 mmol) and stirred for 10 minutes. The reaction mixture was treated with 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetic acid salt (0.24 g, 0.8 mmol), followed by dimethylaminopyridine (0.121 g, 0.97 mmol), then stirred for 4 hours at 60° C. Following this, the solvent was removed in vacuo and the remaining residue dissolved in ethyl acetate (15 mL) and washed with 1.0 N HCl (15 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated to dryness. The crude product was purified by flash column chromatography (SiO2), eluting with ethyl acetate. Fractions containing the product were pooled, concentrated to dryness and triturated with ether to provide 0.366 g of the title compound as a white glassy solid. 1H NMR (500 MHz, d6-acetone) δ ppm: 8.71–8.82 (1H, m), 7.84–7.95 (1H, br), 7.47–7.62 (4H, m), 7.27–7.40 (5H, m), 7.20 (1H, dt, J=8.5, 2.7 Hz), 5.15–5.21 (2H, 4.48–4.60 (4H, m), 2.96 (2H, s), 2.94 (2H, s), 1.62–1.64 (6H, s).

Workup

  1. stirringstirred for 4 hours at 60° C
  2. customwas removed in vacuo
  3. dissolutionthe remaining residue dissolved in ethyl acetate (15 mL)
  4. washwashed with 1.0 N HCl (15 mL)
  5. dry with materialThe organic layer was dried (sodium sulfate)
  6. filtrationfiltered
  7. concentrationconcentrated to dryness
  8. customThe crude product was purified by flash column chromatography (SiO2)
  9. washeluting with ethyl acetate
  10. additionFractions containing the product
  11. concentrationconcentrated to dryness
  12. customtriturated with ether

Sources & evidence

ORD record
ord-87cd8a5013c941219bb5aa499cb35ede
Source dataset
uspto-grants-2007_02
Patent number
US07176196B2

Reaction notes

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