Triethylamine → (-)-4-ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

HRID 19679Notes

Reaction equation

HRID 19679 reaction equation
[F: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(O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:25](N(CC)CC)[CH3:26].S(Cl)(Cl)=O.C([Mg]Br)C>C1COCC1.C(Cl)Cl>[CH2:25]([C:5]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[NH:8][C:7](=[O:12])[N:6]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH3:26]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 593465816-fluoro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-oneHCID 178418443HCID 178418443, compound

Product 1

HCID 11853562(-)-4-ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a −15° C. solution of 6-fluoro-4-hydroxy-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (3.00 g, 8.82 mmol) in THF (40 mL) was added triethylamine (6.14 mL, 44.08 mmol). The reaction was stirred for a couple of minutes and then thionyl chloride (0.68 mL, 9.26 mmol) was added dropwise. After 25 min, 1M ethylmagnesium bromide in THF (27.33 mL, 27.33 mmol) was added over 10 min. After an additional 30 min at −15° C., the reaction was quenched with saturated ammonium chloride solution (60 mL) and extracted with CH2Cl2 (120 mL×2). The combined organics were washed with brine (60 mL), dried over dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (0-70% EtOAc/hexanes) followed by chiral reverse phase chromatography (ChiralPak AD packing, 10-60% iPrOH/hexanes with DEA modifier) yielded a yellow residue that was taken up in a minimal amount of CH2Cl2, diluted with hexanes, and then concentrated in vacuo to give (−)-4-ethyl-6-fluoro-4-phenyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) 8.26 (s, NH); 7.38 (m, 5H, ArH); 6.85 (m, 1H, ArH); 6.70 (m, 1H, ArH); 6.25 (m, 1H, ArH); 3.92 (m, 1H, CH2); 3.48 (m, 1H, CH2); 2.35 (m, 2H, CH2); 0.91 (t, J=6.87 Hz, 3H, CH3); MS (Electrospray): m/z 353.1292 (M+H); [α]D=−41.8° (c0.11, MeOH). For the (+)-enantiomer, [α]D=+41.1° (c0.12, MeOH).

Workup

  1. waitAfter an additional 30 min at −15° C.
  2. customthe reaction was quenched with saturated ammonium chloride solution (60 mL)
  3. extractionextracted with CH2Cl2 (120 mL×2)
  4. washThe combined organics were washed with brine (60 mL)
  5. customdried
  6. dry with materialover dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customPurification by normal phase chromatography (0-70% EtOAc/hexanes)
  10. customyielded a yellow residue that
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-725ac8cf6b124911af13317f289863a8
Source dataset
uspto-grants-2010_06
Patent number
US07745452B2

Reaction notes

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