Diisopropylamine → HCID 136404660, compound

HRID 1107384Notes

Reaction equation

HRID 1107384 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH3:24])[N:18]([C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1)[C:17]2=[O:32].[C:33]([C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])#[N:34]>O1CCCC1>[C:33]([C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38])#[N:34].[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([CH:24]=[C:37]([C:36]1[CH:41]=[CH:42][CH:43]=[CH:44][C:35]=1[C:33]#[N:34])[OH:38])[N:18]([C:25]1[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=1)[C:17]2=[O:32]

Participants

7

Reactant 4

HCID 7912DiisopropylamineHCID 582554Methyl 2-cyanobenzoateHCID 223474246-fluoro-2-methyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-oneHCID 178418339Butyllithium

Product 2

HCID 582554Methyl 2-cyanobenzoateHCID 136404660HCID 136404660, compoundYield 10%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

A solution of diisopropylamine (0.046 mL, 0.47 mmol) in tetrahydrofuran (2.7 mL) was chilled to -78° C. and butyllithium (0.13 mL, 0.32 mmol, 2.5 N in hexanes) was added dropwise. The solution was stirred 10 minutes and then a solution 6-fluoro-2-methyl-3-(2-methyl-pyridin-3-yl)-3H-quinazolin-4-one (0.10 g, 0.37 mmol) in tetrahydrofuran (0.7 mL) was added dropwise. The solution became intense red and was stirred 30 minutes. In a separate vessel a solution of methyl 2-cyanobenzoate (0.50 g, 3.1 mmol) in tetrahydrofuran (10 mL) was prepared and chilled to -78° C. The cold red anion solution was added to the cold methyl 2-cyanobenzoate solution via canula over 30 seconds. The resulting mixture was stirred 30 minutes at -78° C. and then quenched with saturated aqueous bicarbonate and warmed to ambient temperature. The mixture was diluted with water and repeatedly extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20×100 mm) with elution proceeding as follows: 10% ethyl acetate/hexane (50 mL), nil; 20% ethyl acetate/hexane (50 mL), unweighedrecovered 3-(2-methyl-pyridin-3-yl)-6-fluoro-2-methyl-3H-quinazolin-4-one; 30% ethyl acetate/hexane (50 mL), nil; 40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate; 50% ethyl acetate/hexane (50 mL), unweighed impurity; 60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product; 70% ethyl acetate/hexane (50 mL), product. The product containing fractions were combined and concentrated. The residue was triturated with 1% ethyl acetate/ether and the yellow solid which formed was collected and dried to yield 0.017 g (10%) of 2-{2-[6-fluoro-3-(2-methyl-pyridin-3-yl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1-hydroxy-vinyl}-benzonitrile which had: mp 213-215° C.; 1H NMR δ8.70 (d, J=4 Hz, 1 H), 7.85 (dd, J=3, 8 Hz, 1 H), 7.67 (d, J=7 Hz, 1 H), 7.60 (d, J=9 Hz, 1 H), 7.58-7.38 (m, 6 H), 4.94 (s, 1 H), 2.44 (s, 3 H). Analysis calculated for C23H15FN4O2.0.25 H2O: C, 68.57; H, 3.88; N, 13.91. Found: C, 68.52, 68,91; H, 4.13, 4.21; N, 13.25, 13.28.

Workup

  1. stirringwas stirred 30 minutes
  2. stirringThe resulting mixture was stirred 30 minutes at -78° C.
  3. customquenched with saturated aqueous bicarbonate
  4. temperaturewarmed to ambient temperature
  5. additionThe mixture was diluted with water
  6. extractionrepeatedly extracted with ethyl acetate
  7. washThe combined extracts were washed with water and brine
  8. dry with materialdried over magnesium sulfate
  9. concentrationconcentrated
  10. customchromatographed on silica gel (20×100 mm) with elution proceeding
  11. custom40% ethyl acetate/hexane (50 mL), unweighed recovered methyl 2-cyanobenzoate
  12. addition60% ethyl acetate/hexane (50 mL), mixture of impurity and desired product
  13. additionThe product containing fractions
  14. concentrationconcentrated
  15. customThe residue was triturated with 1% ethyl acetate/ether
  16. customthe yellow solid which formed
  17. customwas collected
  18. customdried

Sources & evidence

ORD record
ord-41885251e2b84a909cbb8c677243c0f4
Source dataset
uspto-grants-2000_05
Patent number
US06060479

Reaction notes

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