Triethylamine → 6-chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

HRID 19708Notes

Reaction equation

HRID 19708 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:19]1[CH2:21][CH2:20]1)O.CCN(CC)CC.O=S(Cl)Cl.[CH2:33]([Mg]Br)[CH:34]([CH3:36])[CH3:35]>C1(C)C=CC=CC=1>[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:19]1[CH2:21][CH2:20]1)[CH2:33][CH:34]([CH3:36])[CH3:35]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 593465896-chloro-4-cyclopropyl-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-oneHCID 178418816HCID 178418816, compound2×

Product 1

HCID 118569796-chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a 0° C. solution of 0.08 g (0.25 mmol) 6-chloro-4-cyclopropyl-4-hydroxy-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 3 mL toluene was added 0.17 mL (1.25 mmol) Et3N and 0.018 mL (0.25 mmol) SOCl2. After 20 min at 0° C. 1 mL (1 mmol, 1M solution in ether) isobutyl magnesium bromide was added and the reaction mixture was stirred 30 minutes before an additional 0.5 mL (0.5 mmol) isobutyl magnesium bromide was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was quenched with 75 mL saturated aqueous NH4Cl solution and extracted with 100 mL EtOAc. The extract was washed with 75 mL brine, dried over MgSO4, filtered, and concentrated. Purification by flash chromatography (1×10 cm silica gel, linear gradient 10-35% EtOAc/hexanes) followed by preparative HPLC (YMC C18 PRO20×150 mm, linear gradient 5-95% CH3CN/H2O 0.05% added TFA, over 30 min) to afford afforded 6-chloro-4-cyclopropyl-4-isobutyl-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) 8.17 (s, 1H); 7.43 (d, J=2.20 Hz, 1H); 7.15 (dd, J=2.38 and 8.61 Hz, 1H); 6.62 (d, J=8.42 Hz, 1H); 4.50 (dq, J=15.4 and 8.61 Hz, 1H); 3.96 (dq, J=15.4 and 8.60 Hz, 1H); 1.56 (m, 1H); 1.41 (dd, J=14.8 and 5.31 Hz, 1H); 1.23 (dd, J=14.8 and 5.68 Hz, 1H); 0.88 (m, 1H); 0.80 (d, J=6.59 Hz, 3H); 0.78 (m, 1H); 0.69 (m, 2H); 0.55 (d, J=6.59 Hz, 3H). High resolution mass spec (FT/ICR): calc M+H=361.1289, found 361.1283.

Workup

  1. additionwas added
  2. customThe reaction mixture was quenched with 75 mL saturated aqueous NH4Cl solution
  3. extractionextracted with 100 mL EtOAc
  4. washThe extract was washed with 75 mL brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customPurification by flash chromatography (1×10 cm silica gel, linear gradient 10-35% EtOAc/hexanes)
  9. additionfollowed by preparative HPLC (YMC C18 PRO20×150 mm, linear gradient 5-95% CH3CN/H2O 0.05% added TFA, over 30 min)
  10. customto afford

Sources & evidence

ORD record
ord-3e35d77232c34bffb41778aa2b37b6e3
Source dataset
uspto-grants-2010_06
Patent number
US07745452B2

Reaction notes

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