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

HRID 390352Notes

Reaction equation

HRID 390352 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:38]=[CH:37][C:31]([CH2:32][N:33]([CH:35]=O)[NH2:34])=[CH:30][CH:29]=1.C([O-])(O)=O.[Na+]>C(#N)C.CN(C=O)C>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH:35]=[N: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([CH3:20])[CH3:21])=[N:34]2)=[CH:37][CH:38]=1

Participants

7

Reactant 4

HCID 6328Methyl iodideHCID 516892Sodium BicarbonateHCID 58458904N-(4-Fluorobenzyl)formohydrazideHCID 584589233-(Benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide

Product 1

HCID 1361639592-[1-[(4-Fluorophenyl)methyl]-1,2,4-triazol-3-yl]-3-hydroxy-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4-oneYield 53%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.042 g, 0.122 mmol, 1.0 equiv) in acetonitrile (1.2 mL) under a nitrogen atmosphere, was added MeI (0.038 mL, 0.61 mmol, 5 equiv). The reaction was heated at 40° C. (oil bath) for 1 h. The reaction was then cooled to ambient temperature and concentrated in vacuo. N-(4-Fluorobenzyl)formohydrazide (0.045 g, 0.268 mmol, 2.2 equiv) was then added to the residue followed by DMF (1.5 mL) and the solution was heated at 140° C. (oil bath). After stirring 1 h, the reaction was cooled to ambient temperature stirred 17 h. The reaction 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 purified by reverse phase preparatory HPLC and trituration from ether to provide the title compound (0.024 g, 53% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.10 (s, 1H), 7.29-7.35 (m, 2H), 7.07-7.14 (m, 2H), 5.44 (s, 2H), 4.02-4.10 (m, 4H), 1.68 (s, 6H); LCMS (ES+, (M+H)+) m/z 372.20.

Workup

  1. temperatureThe reaction was then cooled to ambient temperature
  2. concentrationconcentrated in vacuo
  3. temperaturethe solution was heated at 140° C. (oil bath)
  4. temperaturethe reaction was cooled to ambient temperature
  5. stirringstirred 17 h
  6. extractionextracted with CH2Cl2 (×3)
  7. dry with materialThe combined CH2Cl2 extracts were dried (Na2SO4)
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by reverse phase preparatory HPLC and trituration from ether

Sources & evidence

ORD record
ord-d638aa9ed2aa42b5bf42c595701e025c
Source dataset
uspto-grants-2013_02
Patent number
US08383639B2

Reaction notes

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