Dimethylformamide → 2-[5-[(4-Fluorophenyl)methyl]-4-methyl-1,2,4-triazol-3-yl]-3-hydroxy-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4-one

HRID 390353Notes

Reaction equation

HRID 390353 reaction equation
C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](=S)[NH:23][CH3:24])C1C=CC=CC=1.CI.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH:38][NH2:39])=O)=[CH:31][CH:30]=1.CN(C=O)C>C(#N)C>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][C:36]2[N:23]([CH3:24])[C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:20])[CH3:21])=[N:39][N:38]=2)=[CH:33][CH:34]=1

Participants

6

Reactant 4

HCID 6228DimethylformamideHCID 6328Methyl iodideHCID 37716122-(4-Fluorophenyl)acetohydrazideHCID 584589123-(Benzyloxy)-N,9,9-trimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide

Product 1

HCID 1361639602-[5-[(4-Fluorophenyl)methyl]-4-methyl-1,2,4-triazol-3-yl]-3-hydroxy-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4-oneYield 22.4%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of 3-(benzyloxy)-N,9,9-trimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.1 g, 0.278 mmol, 1.0 equiv) in acetonitrile (0.9 mL) under a nitrogen atmosphere, was added MeI (0.070 mL, 1.11 mmol, 4 equiv). The reaction was heated at 50° C. (oil bath) for 45 min. The reaction was then cooled to ambient temperature and concentrated in vacuo. 2-(4-Fluorophenyl)acetohydrazide (0.14 g, 0.84 mmol, 3 equiv) was then added to the residue followed by DMF (2 mL) and the slurry was heated at 140° C. (oil bath). After stirring 16 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The residue was added to a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was treated with DMF (˜1.5 mL). After trying to dissolve material, the insoluble portion was filtered and washed with methanol to provide the title compound (0.024 g, 22% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.21 (dd, J=8.81, 5.29 Hz, 2H), 7.03 (t, J=8.69 Hz, 2H), 4.24 (s, 2H), 4.04 (q, J=2.77 Hz, 4H), 3.93 (s, 3H), 1.57 (s, 6H); LCMS (ES+, (M+H)+) m/z 386.22.

Workup

  1. temperatureThe reaction was then cooled to ambient temperature
  2. concentrationconcentrated in vacuo
  3. temperaturethe slurry was heated at 140° C. (oil bath)
  4. temperaturethe reaction was cooled to ambient temperature
  5. concentrationconcentrated in vacuo
  6. additionThe residue was added to a saturated aqueous solution of NaHCO3
  7. extractionextracted with CH2Cl2 (×3)
  8. dry with materialThe combined CH2Cl2 extracts were dried (Na2SO4)
  9. concentrationconcentrated in vacuo
  10. additionThe crude product was treated with DMF (˜1.5 mL)
  11. dissolutionto dissolve material
  12. filtrationthe insoluble portion was filtered
  13. washwashed with methanol

Sources & evidence

ORD record
ord-9cb1be685e28446895eda5b47be84002
Source dataset
uspto-grants-2013_02
Patent number
US08383639B2

Reaction notes

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