Triethylamine → 4-allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

HRID 19687Notes

Reaction equation

HRID 19687 reaction equation
[F:1][C:2]1[C:3]([C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[C:4]([NH:9][C:10]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].F[C:28]1[C:37](F)=CC=C2[C:29]=1C(C1C=CC(F)=CC=1)(O)N(CC(F)(F)F)C(=O)N2.C(N(CC)CC)C.S(Cl)(Cl)=O.C([Mg]Br)C=C>C1COCC1>[CH2:37]([C:18]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:3]2[C:4](=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[NH:9][C:10](=[O:11])[N:12]1[CH2:13][C:14]([F:17])([F:16])[F:15])[CH:28]=[CH2:29]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 59346588N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N'-(2,2,2-trifluoroethyl)ureaHCID 593465935,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-oneHCID 178455850HCID 178455850, compound

Product 1

HCID 118538134-allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 5.0 g (13.289 mmol) N-[3,4-difluoro-2-(4-fluorobenzoyl)phenyl]-N′-(2,2,2-trifluoroethyl)urea (open form) and 5,6-difluoro-4-(4-fluorophenyl)-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one (closed form) in 25 ml THF was added 9.261 mL (66.443 mmol) triethylamine. After 1 h at 80° C., the reaction mixture was cooled to −78° C. To this solution was added 0.969 mL (13.289 mmol) thionyl chloride. After 30 mins at −78° C., 45 mL (41.195 mmol) allylmagnesium bromide (1.0M solution in dibutyl ether) was added dropwise. After 30 minutes at −78° C., the reaction mixture was quenched with saturated NH4Cl and warmed to room temperature. The reaction mixture was extracted three times with EtOAc and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 0-35% EtOAc:hexane) afforded 4-allyl-5,6-difluoro-4-(4-fluorophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) δ 7.46 (br s, 1H, ArNHC═O); 7.42-7.40 (m, 2H, ArH); 7.10-7.00 (m, 3H, ArH); 6.44 (m, 1H, ArH); 5.73-5.66 (m, 1H, CH2CH═CH2); 5.13-5.09 (m, 2H, CH2CH═CH2); 3.73 (m, 2H, NCH2CF3); 3.15 (m, 2H, CH2CH═CH2). HRMS (ES) exact mass calcd for C19H14F6N2O: 401.1083, Found: 401.1075.

Workup

  1. waitAfter 30 mins at −78° C.
  2. waitAfter 30 minutes at −78° C.
  3. customthe reaction mixture was quenched with saturated NH4Cl
  4. temperaturewarmed to room temperature
  5. extractionThe reaction mixture was extracted three times with EtOAc
  6. washwashed with brine
  7. dry with materialThe organic layer was dried over NaSO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. customPurification by flash chromatography (1×14 cm silica gel, linear gradient 0-35% EtOAc:hexane)

Sources & evidence

ORD record
ord-dc601955ac54456c83cf10f90f945335
Source dataset
uspto-grants-2010_06
Patent number
US07745452B2

Reaction notes

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