6-chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one → 4-(6-Chloro-4-cyclopropyl-2-oxo-3-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinazolin-4-yl)benzonitrile

HRID 19698Notes

Reaction equation

HRID 19698 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([CH:25]1[CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.[Cu][C:29]#[N:30]>CN(C=O)C.CCOCC>[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([CH:25]1[CH2:27][CH2:26]1)[C:18]1[CH:23]=[CH:22][C:21]([C:29]#[N:30])=[CH:20][CH:19]=1

Participants

5

Reactant 2

HCID 118540706-chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-oneHCID 178418546HCID 178418546, compound

Product 1

HCID 118540714-(6-Chloro-4-cyclopropyl-2-oxo-3-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroquinazolin-4-yl)benzonitrile

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
190 °C

Procedure

To a solution of 0.39 g (0.85 mmol) 6-chloro-4-cyclopropyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 2.5 mL DMF was added 0.13 g (1.4 mmol) copper(I) cyanide and the mixture heated in a sealed tube at 190° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted with 125 mL ether, washed 2×100 mL water and 1×100 mL brine, dried over dried over MgSO4, filtered, and concentrated in vacuo. Purification by normal phase chromatography (40 g silica gel cartridge, linear gradient 5-75% EtOAc/hexanes) followed by preperative chiral chromatography (5×50 mm Chiralcel OD, 100% MeOH) provided the first peak (−) 6-chloro-4-cyclopropyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. Optical rotation −83° (c=0.00175 g/mL in CH2Cl2, Na lamp,) 1H NMR (CDCl3, 400 MHz) δ 8.18 (s, NH); 7.64 (br d, 2H, J=7.88 Hz); 7.39 (br d, 2H, J=6.22 Hz); 7.26 (obscured, 1H); 6.85 (br m, 1H); 6.74 (d, 1H, J=8.24 Hz); 4.34 (m, 1H); 4.23 (br m, 1H); 1.62 (m, 1H); 0.82 (m, 2H); 0.20 (m, 1H); 0.097 (m, 1H); MS (Electrospray): exact mass calculated for C20H15ClF3N3O+H 406.0925 found 406.0935 Collect 0.1 g second peak Optical rotation +100° (c=0.002 g/mL in CH2Cl2, Na lamp,).

Workup

  1. temperatureAfter cooling to room temperature
  2. washwashed 2×100 mL water and 1×100 mL brine
  3. customdried
  4. dry with materialover dried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. customPurification by normal phase chromatography (40 g silica gel cartridge, linear gradient 5-75% EtOAc/hexanes)

Sources & evidence

ORD record
ord-63a6548f9391412eb2c3b32d801e8fbf
Source dataset
uspto-grants-2010_06
Patent number
US07745452B2

Reaction notes

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