Formic Acid → HCID 136163957, compound

HRID 390348Notes

Reaction equation

HRID 390348 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]1[NH:23][C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[C:25](Cl)[N:26]=1)C1C=CC=CC=1.C(O)=O.[Cl-]>CO.[Pd]>[F:35][C:32]1[CH:33]=[CH:34][C:29]([CH2:28][C:24]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:26][CH:25]=2)=[CH:30][CH:31]=1

Participants

6

Reactant 3

HCID 284Formic AcidHCID 312Chloride2×HCID 58458901HCID 58458901, compound

Product 1

HCID 136163957HCID 136163957, compoundYield 36%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 887MethanolSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of 3-(benzyloxy)-2-(4-chloro-5-(4-fluorobenzyl)-1H-imidazol-2-yl)-9,9-dimethyl-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (0.03 g, 0.061 mmol, 1.0 equiv) in MeOH (3 mL) under a nitrogen atmosphere, was added formic acid (0.1 mL, 2.61 mmol, 43 equiv) and 10% Pd/C (0.065 g, 0.061 mmol, 1.0 equiv). The reaction was stirred for 5 h after which LCMS analysis indicated complete benzyl hydrogenolysis but no chloride reduction. The reaction was warmed to 40° C. (oil bath) and stirred 2 h. LCMS analysis now indicated complete chloride reduction. The reaction was cooled to ambient temperature and stirred a further 16 h. The reaction was then filtered through celite and concentrated in vacuo. The residue was added to saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×5). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was purified by silica gel chromatography (7% MeOH/CH2Cl2) to provide the title compound (0.008 g, 36% yield) as a tan solid. 1H NMR (400 MHz, d7-DMF) δ ppm (major imidazole tautomer) 13.14 (s, 1H), 7.48-7.58 (m, 2H), 7.39 (s, 1H), 7.29 (t, J=8.56 Hz, 2H), 4.21-4.25 (m, 2H), 4.15 (s, 2H), 4.08 (t, J=5.16 Hz, 2H), 1.74 (s, 6H); LCMS (ES+, (M+H)+) m/z 371.17.

Workup

  1. stirringstirred 2 h
  2. temperatureThe reaction was cooled to ambient temperature
  3. stirringstirred a further 16 h
  4. filtrationThe reaction was then filtered through celite and
  5. concentrationconcentrated in vacuo
  6. additionThe residue was added to saturated aqueous solution of NaHCO3
  7. extractionextracted with CH2Cl2 (×5)
  8. dry with materialThe combined CH2Cl2 extracts were dried (Na2SO4)
  9. concentrationconcentrated in vacuo
  10. customThe crude product was purified by silica gel chromatography (7% MeOH/CH2Cl2)

Sources & evidence

ORD record
ord-b6f063852e0846a28d4f91a7148a279a
Source dataset
uspto-grants-2013_02
Patent number
US08383639B2

Reaction notes

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