4-allyl-6-chloro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one → (-)-6-chloro-4-(4-fluorophenyl)-4-propyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

HRID 19684Notes

Reaction equation

HRID 19684 reaction equation
[CH2:1]([C:4]1([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][C:6](=[O:15])[N:5]1[CH2:16][C:17]([F:20])([F:19])[F:18])[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[Cl:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:15])[N:5]([CH2:16][C:17]([F:19])([F:18])[F:20])[C:4]2([C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[CH2:1][CH2:2][CH3:3]

Participants

4

Reactant 1

HCID 118538114-allyl-6-chloro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

Product 1

HCID 11853812(-)-6-chloro-4-(4-fluorophenyl)-4-propyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-oneYield 100.4%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4-allyl-6-chloro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (22.1 g, 55.4 mmol) in ethyl acetate (450 mL) and under a nitrogen atmosphere was added 10% palladium on carbon (224 mg). A balloon of hydrogen was bubbled into the stirring mixture. The reaction was then stirred over night under an atmosphere of hydrogen. The reaction was purged with nitrogen, filtered through a pad of celite and the filtrate concentrated in vacuo to give 22.3 gm (100%) of (±)-6-chloro-4-(4-fluorophenyl)-4-propyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as a white solid. Further purification by chiral chromatography (ChiralPak AD packing, 30% iPrOH/heptane with DEA modifier at 1.0 mL/L) followed by crystallization from hexanes provided individual enantiomers of 6-chloro-4-(4-fluorophenyl)-4-propyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (Peak 1 and Peak 2). Data for Peak 2: 1H NMR (d6-DMSO, 400 MHz) δ 10.02 (s, 1H); 7.43 (m, 2H); 7.20 (m, 3H); 6.84 (d, J=8.61 Hz, 1H); 6.59 (d, J=2.19 Hz, 1H); 3.80 (q, J=9.34 Hz, 2H); 2.33 (m, 2H); 1.24 (m, 1H); 0.94 (m, 1H); 0.89 (t, J=6.87 Hz, 3H). Exact Mass (Electrospray, M+H): Calc'd, 401.1039; Found, 401.1040. [α]D=−6.7° (c0.0045, MeOH). Optical rotation for Peak 1: [α]D=+5.2° (c0.0062, MeOH).

Workup

  1. customA balloon of hydrogen was bubbled into the stirring mixture
  2. customThe reaction was purged with nitrogen
  3. filtrationfiltered through a pad of celite
  4. concentrationthe filtrate concentrated in vacuo

Sources & evidence

ORD record
ord-2676f6143fd84e5d93b94b0a03d66698
Source dataset
uspto-grants-2010_06
Patent number
US07745452B2

Reaction notes

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