Citric Acid → 6-Chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

HRID 19682Notes

Reaction equation

HRID 19682 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)O.[CH2:26](N(CC)CC)[CH3:27].S(Cl)(Cl)=O.C([Mg]Br)C.C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH2:26][CH3:27])[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1

Participants

9

Reactant 6

HCID 311Citric AcidHCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 593465986-chloro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-oneHCID 178418443HCID 178418443, compound

Product 1

HCID 118538106-Chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

Reagents, catalysts & solvents 2

HCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a −15° C. solution of 6-chloro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (6.20 g, 16.5 mmol) in anhydrous toluene (60 mL) was added triethylamine (11.5 mL, 82.7 mmol). The reaction was stirred for 5 min and then thionyl chloride (1.27 mL, 17.4 mmol) was added dropwise maintaining the temperature <−5° C. After 15 min, 1M ethylmagnesium bromide in THF (51.3 mL, 51.3 mmol) was added over 35 min maintaining the temperature <−5° C. The reaction was warmed from −15° C. to 0° C. over 30 min and then poured into a vigorously stirred mixture of aqueous 10% citric acid (30 mL), ice (30 g), and ethyl acetate (50 mL). The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organics were washed with water (50 mL), brine (60 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (0-25% EtOAc/hexanes) gave a crude light yellow oil. Crystallization of the oil from hexane gave racemic 6-chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one as an off-white solid. 1H NMR (CDCl3, 400 MHz) 8.19 (s, NH); 7.39 (m, 2H, ArH); 7.09 (m, 3H, ArH); 6.68 (d, J=8.51 Hz, 1H, ArH); 6.46 (d, J=2.11 Hz, 1H, ArH); 3.84 (m, 1H, CH2); 3.56 (m, 1H, CH2); 2.40 (m, 1H, CH2); 2.22 (m, 1H, CH2); 0.90 (t, J=7.15 Hz, 3H, CH3); MS (Electrospray): m/z 387.1 (M+H). Racemic 6-chloro-4-ethyl-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (2.76 g) was resolved using chiral reverse phase chromatography (ChiralPak AD packing, 10-30% iPrOH/hexanes with DEA modifier at 1.0 mL/L). The enantiomers were obtained as crystalline solids from hexane to give (+) compound as Peak 1 and (−) compound as Peak 2. Data for Peak 2: 1H NMR (CDCl3, 400 MHz) 8.69 (s, NH); 7.39 (m, 2H, ArH); 7.09 (m, 3H, ArH); 6.70 (d, J=8.60 Hz, 1H, ArH); 6.45 (d, J=2.20 Hz, 1H, ArH); 3.81 (m, 1H, CH2); 3.59 (m, 1H, CH2); 2.40 (m, 1H, CH2); 2.22 (m, 1H, CH2); 0.90 (t, J=7.14 Hz, 3H, CH3); MS (Electrospray): m/z 387.0894 (M+H); [α]D=−8.5° (c0.0024, CH2Cl2). Data for Peak 1, the (+)-enantiomer, [α]D=+7.9° (c0.0027, CH2Cl2).

Workup

  1. temperaturemaintaining the temperature <−5° C
  2. waitAfter 15 min
  3. temperaturemaintaining the temperature <−5° C
  4. temperatureThe reaction was warmed from −15° C. to 0° C. over 30 min
  5. extractionThe aqueous phase was extracted with ethyl acetate (3×50 mL)
  6. washThe combined organics were washed with water (50 mL), brine (60 mL)
  7. dry with materialdried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification by normal phase chromatography (0-25% EtOAc/hexanes)
  11. customgave a crude light yellow oil
  12. customCrystallization of the oil from hexane

Sources & evidence

ORD record
ord-8bc4678064a942b3a0fd08b7c22794c5
Source dataset
uspto-grants-2010_06
Patent number
US07745452B2

Reaction notes

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