Sodium Sulfate → 2-{[3-(2-Chloro-phenyl)-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl]-amino}-nicotinonitrile

HRID 897031Notes

Reaction equation

HRID 897031 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.[NH2:22][C:23]1[N:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:22][C:23]1[N:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]

Participants

6

Reactant 4

HCID 24436Sodium SulfateHCID 8182592-Amino-3-cyanopyridineHCID 5049666Sodium triacetoxyborohydrideHCID 106858093-(2-Chlorophenyl)-6-fluoro-3,4-dihydroquinazolin-4-one-2-carboxaldehyde

Product 1

HCID 103097692-{[3-(2-Chloro-phenyl)-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl]-amino}-nicotinonitrile

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.439 g, 1.45 mmol), 2-aminonicotinonitrile (0.150 g, 1.26 mmol) and anhydrous sodium sulfate (2.1 g, 14.5 mmol) in acetic acid (10 mL) was stirred at ambient temperature for 24 hours. The mixture was now warmed to 80° C. for 24 hours. The reaction was cooled to ambient temperature and sodium triacetoxyborohydride (1.3 g, 6.13 mmol) was added portionwise. The reaction was stirred for 16 hours and then quenched by carefully pouring it into a mixture of saturated aqueous sodium bicarbonate (150 mL) and ethyl acetate (20 mL). This quenching solution was stirred 30 min. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (50 g) with elution proceeding as follows: 20% ethyl acetate/hexane (350 mL), nil; 30% ethyl acetate/hexane (350 mL), unweighed 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-methanol; 40% ethyl acetate/hexane (400 mL), impure product. This partially purified product was flash chromatographed on silica gel (20 g) with elution proceeding as follows: 5% ethyl acetate/hexane (1000 mL), nil; 10% ethyl acetate/hexane (1000 mL), nil; 15% ethyl acetate/hexane (750 mL), nil; (500 mL), unweighed impurity; 20% ethyl acetate/hexane (1000 mL), nil; (1000 mL), unweighed impurity; 30% ethyl acetate/hexane (600 mL), 0.050 g (10%) of 2-{[3-(2-chloro-phenyl]-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl]-amino}-nicotinonitrile as a light tan solid which had: mp 145-150° C.; 1H NMR δ 8.16 (d, J=5 Hz, 1 H), 7.93 (dd, J=3, 8 Hz, 1 H), 7.84 (dd, J=5, 9 Hz, 1 H), 7.71-7.63 (m, 2 H), 7.56-7.51 (m, 3 H), 7.40 (d, J=7 Hz, 1 H), 6.85 (s, 1 H), 6.62 (dd, J=5, 7 Hz, 1 H), 4.23 (ABq, Δv1-3=74 Hz, J=19 Hz, 2 H); APCI MS m/z=406.2 (P+1).

Workup

  1. temperatureThe mixture was now warmed to 80° C. for 24 hours
  2. temperatureThe reaction was cooled to ambient temperature
  3. stirringThe reaction was stirred for 16 hours
  4. customquenched
  5. additionby carefully pouring it
  6. additioninto a mixture of saturated aqueous sodium bicarbonate (150 mL) and ethyl acetate (20 mL)
  7. stirringThis quenching solution was stirred 30 min
  8. customThe phases were separated
  9. washthe organic layer was washed with brine
  10. dry with materialdried over magnesium sulfate
  11. concentrationconcentrated
  12. customchromatographed on silica gel (50 g) with elution proceeding
  13. customchromatographed on silica gel (20 g) with elution proceeding

Sources & evidence

ORD record
ord-806ac3878b95474eb1eb677b29028254
Source dataset
uspto-grants-2005_07
Patent number
US06921764B2

Reaction notes

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