N-((5-Oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl)cyclobutanecarboxamide → 7-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

HRID 1878860Notes

Reaction equation

HRID 1878860 reaction equation
[O:1]=[C:2]1[C:7]([CH2:8][NH:9][C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)=O)=[N:6][N:5]=[CH:4][NH:3]1>P(Cl)(Cl)(Cl)=O>[CH:12]1([C:10]2[N:6]3[C:7]([C:2](=[O:1])[NH:3][CH:4]=[N:5]3)=[CH:8][N:9]=2)[CH2:15][CH2:14][CH2:13]1

Participants

3

Reactant 1

HCID 135993273N-((5-Oxo-4,5-dihydro-1,2,4-triazin-6-yl)methyl)cyclobutanecarboxamide

Product 1

HCID 1359932727-cyclobutyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one

Reagents, catalysts & solvents 1

HCID 24813Phosphorus oxychlorideSolvent

Conditions

Temperature
0 °C

Procedure

A crude solution of cyclobutanecarboxylic acid (5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)amide (1.33 g, 6.39 mmol) in phosphorus oxychloride (POCl3) (10 mL) was heated to 55° C. The reaction was heated for 2 h then concentrated in vacuo and the crude oil was cooled to 0° C. in an ice-bath and quenched with 2M NH3 in isopropanol (IPA) until slightly basic. This crude reaction mixture was concentrated in vacuo and was partitioned between DCM and H2O and separated. The aqueous layer was extracted with DCM (3×) and the combined organic fractions were dried over sodium sulfate (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 5% MeOH in DCM], resulting in the title compound as an off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.86-1.96 (m, 1H), 2.00-2.13 (m, 1H); 2.26-2.46 (m, 4H); 3.87-4.00 (m, 1H); 7.71 (s, 1H); 7.87 (d, J=3.6 Hz, 1H); 11.7 (brs, 1H); MS (ES+): m/z 191.27 (100) [MH+], HPLC: tR=2.06 min (MicromassZQ, polar—5 min).

Workup

  1. temperatureThe reaction was heated for 2 h
  2. concentrationthen concentrated in vacuo
  3. customquenched with 2M NH3 in isopropanol (IPA) until slightly basic
  4. customThis crude reaction mixture
  5. concentrationwas concentrated in vacuo
  6. customwas partitioned between DCM and H2O
  7. customseparated
  8. extractionThe aqueous layer was extracted with DCM (3×)
  9. dry with materialthe combined organic fractions were dried over sodium sulfate (Na2SO4)
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe crude material was purified by chromatography on silica gel [eluting with 5% MeOH in DCM]

Sources & evidence

ORD record
ord-e891ab8a39ba489bb7fcffbf8193277d
Source dataset
uspto-grants-2012_11
Patent number
US08314111B2

Reaction notes

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