Formic Acid → 3-(2-Chloro-phenyl)-6-fluoro-2-[(6-methyl-pyridin-2-ylamino)-methyl]-3h-quinazolin-4-one

HRID 1169267Notes

Reaction equation

HRID 1169267 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[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1.C(O)=O.C(=O)(O)[O-].[Na+]>CO.C(O)C.[Pd]>[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[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1

Participants

8

Reactant 4

HCID 284Formic AcidHCID 157652-Amino-6-methylpyridineHCID 516892Sodium BicarbonateHCID 106858093-(2-Chlorophenyl)-6-fluoro-3,4-dihydroquinazolin-4-one-2-carboxaldehyde

Product 1

HCID 102375793-(2-Chloro-phenyl)-6-fluoro-2-[(6-methyl-pyridin-2-ylamino)-methyl]-3h-quinazolin-4-oneYield 82%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 702EthanolSolventHCID 887MethanolSolvent

Procedure

A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.170 g, 0.56 mmol) and 2-amino-6-picoline (0.050 g, 0.46 mmol), in methanol (10 mL) was refluxed overnight. The reaction was concentrated and the residue was flash chromatographed on silica gel (25 g). Elution proceeded as follows: 10% ethyl acetate/hexane (500 mL), nil; 20% ethyl acetate t hexane (300 mL), nil; (100 mL), 0.082 g of intermediate imine; (300 mL), 0.192 g of a mixture of starting material and imine. The pure imine (0.082 g 0.21 mmol) was dissolved in ethanol (10 mL) and 10% palladium on carbon (0.082 g) and formic acid (0.357 mL, 9.45 mmol) were added. The reaction was stirred at ambient temperature for 24 hours. The reaction was carefully neutralized with sodium bicarbonate and then filtered through celite. The pad was well washed with ethyl acetate. The filtrate was concentrated to afford 0.068 g (82%) of 3-(2-chloro-phenyl)-6-fluoro-2-[(6-methyl-pyridin-2-ylamino)-methyl]-3H-quinazolin-4-one as a colorless oil which had: 1H NMR δ 7.92 (dd, J=3, 8 Hz, 1H), 7.80 (dd, J=5, 9 Hz, 1H), 7.65-7.64 (m, 1H), 7.53-7.48 (m, 4H), 7.43-7.40 (m, 1H), 7.37-7.31 (m, 1H), 6.47 (d, J=7 Hz, 1H), 6.25 (d, J=8 Hz, 1H), 4.18 (dd, J=5, 18 Hz, 1H), 4.00 (dd, J=5, 18 Hz, 1H), 2.37 (s, 3H); APCI MS m/z=395 (P+1).

Workup

  1. concentrationThe reaction was concentrated
  2. customchromatographed on silica gel (25 g)
  3. washElution
  4. filtrationfiltered through celite
  5. washThe pad was well washed with ethyl acetate
  6. concentrationThe filtrate was concentrated

Sources & evidence

ORD record
ord-547e7eb0df164797953eb7e4581d53f4
Source dataset
uspto-grants-2003_09
Patent number
US06627755B1

Reaction notes

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