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

HRID 390351Notes

Reaction equation

HRID 390351 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)[NH2:23])C1C=CC=CC=1.CI.[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]([NH:37][NH2:38])=O)=[CH:30][CH:29]=1.CO>C(#N)C>[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][C:35]2[NH:23][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([CH3:21])[CH3:20])=[N:38][N:37]=2)=[CH:30][CH:29]=1

Participants

6

Reactant 4

HCID 887MethanolHCID 6328Methyl iodideHCID 37716122-(4-Fluorophenyl)acetohydrazideHCID 584589233-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide

Product 1

HCID 1784316042-[5-[(4-fluorophenyl)methyl]-4H-1,2,4-triazol-3-yl]-3-hydroxy-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4-oneYield 49%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

To a slurry of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.04 g, 0.116 mmol, 1.0 equiv) in acetonitrile (1.2 mL) under a nitrogen atmosphere, was added MeI (0.011 mL, 0.174 mmol, 1.5 equiv). The reaction was heated at 50° C. (oil bath) for 1 h. The reaction was then cooled to ambient temperature and concentrated in vacuo. 2-(4-Fluorophenyl)acetohydrazide (0.058 g, 0.35 mmol, 3 equiv) was then added to the residue followed by methanol (1 mL) and the slurry was heated at 70° C. (oil bath). After stirring 1 h, the reaction was cooled to ambient temperature and concentrated in vacuo. DMF (1 mL) was added to the residue and the solution was heated at 150° C. (oil bath) for 3.5 h. The reaction was then cooled to ambient temperature and stirred 3 d. The reaction was heated at 140° C. (oil bath) for 2 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 (×2). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by reverse phase preparatory HPLC to provide the title compound (0.021 g, 49% yield) as a gray solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.99 (s, 2H), 7.21-7.39 (m, 2H), 7.00 (t, J=8.69 Hz, 2H), 4.17 (s, 2H), 4.05 (s, 4H), 1.62 (s, 6H); LCMS (ES+, (M+H)+) m/z 372.16.

Workup

  1. temperatureThe reaction was then cooled to ambient temperature
  2. concentrationconcentrated in vacuo
  3. temperaturethe slurry was heated at 70° C. (oil bath)
  4. temperaturethe reaction was cooled to ambient temperature
  5. concentrationconcentrated in vacuo
  6. additionDMF (1 mL) was added to the residue
  7. temperaturethe solution was heated at 150° C. (oil bath) for 3.5 h
  8. temperatureThe reaction was then cooled to ambient temperature
  9. stirringstirred 3 d
  10. temperatureThe reaction was heated at 140° C. (oil bath) for 2 h
  11. temperatureThe reaction was cooled to ambient temperature
  12. concentrationconcentrated in vacuo
  13. additionThe residue was added to a saturated aqueous solution of NaHCO3
  14. extractionextracted with CH2Cl2 (×2)
  15. dry with materialThe combined CH2Cl2 extracts were dried (Na2SO4)
  16. concentrationconcentrated in vacuo
  17. customThe crude product was purified by reverse phase preparatory HPLC

Sources & evidence

ORD record
ord-b5fba06d87d6410c86373aa899c09f23
Source dataset
uspto-grants-2013_02
Patent number
US08383639B2

Reaction notes

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