1-Methylimidazole → 2-chloro-4-(3-chlorophenyl)-alpha-(4-fluorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol

HRID 1788045Notes

Reaction equation

HRID 1788045 reaction equation
[Li]CCCC.CCCCCC.[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1.Cl[Si](CC)(CC)CC.[Cl:26][C:27]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:44]([C:46]3[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=3)=[O:45])[CH:33]=2)[N:28]=1>C1COCC1.CCOC(C)=O.O>[Cl:26][C:27]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:44]([C:46]3[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=3)([C:17]3[N:13]([CH3:12])[CH:14]=[N:15][CH:16]=3)[OH:45])[CH:33]=2)[N:28]=1

Participants

9

Reactant 5

HCID 13901-MethylimidazoleHCID 8058Hexane2×HCID 13819ChlorotriethylsilaneHCID 17976100[2-Chloro-4-(3-chlorophenyl)-6-quinazolinyl](4-fluorophenyl)-methanoneHCID 178418339Butyllithium2×

Product 1

HCID 179761032-chloro-4-(3-chlorophenyl)-alpha-(4-fluorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanolYield 0.8%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-70 °C

Procedure

BuLi 1.6M in hexane (46.5 ml, 0.0744 mol) was added dropwise at −70° C. to a mixture of 1-methyl-1H-imidazole (0.0744 mol) in THF (70 ml) under N2 flow. Chlorotriethyl-silane (0.0765 mol) was added dropwise at −70° C. The mixture was stirred at −70° C. for 15 minutes. BuLi 1.6M in hexane (41 ml, 0.0659 mol) was added dropwise at −70° C. The mixture was stirred at −70° C. for 15 minutes. A solution of intermediate 6 (0.0425 mol) in THF (150 ml) was added dropwise at −70° C. The mixture was stirred at −70° C. for 1 hour and poured out into water. EtOAc was added. The mixture was extracted with EtOAc. The organic layer was washed twice with water, separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (15-35 μm) (eluent: DCM/MeOH/NH4OH 97/3/0.5). The pure fractions were collected and the solvent was evaporated. Part (0.5 g) of the residue (14.6 g, 72%) was crystallized from 2-propanone/CH3CN. The precipitate was filtered off and dried under a vacuo, yielding 0.17 g of 2-chloro-4-(3-chlorophenyl)-α-(4-fluorophenyl)-α-(1-methyl-1H-imidazol-5-yl)-6-quinazolinemethanol (intermediate 7), mp. 212° C.

Workup

  1. stirringThe mixture was stirred at −70° C. for 15 minutes
  2. stirringThe mixture was stirred at −70° C. for 1 hour
  3. extractionThe mixture was extracted with EtOAc
  4. washThe organic layer was washed twice with water
  5. customseparated
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered
  8. customthe solvent was evaporated
  9. customThe residue was purified by column chromatography over silica gel (15-35 μm) (eluent: DCM/MeOH/NH4OH 97/3/0.5)
  10. customThe pure fractions were collected
  11. customthe solvent was evaporated
  12. customPart (0.5 g) of the residue (14.6 g, 72%) was crystallized from 2-propanone/CH3CN
  13. filtrationThe precipitate was filtered off
  14. customdried under a vacuo

Sources & evidence

ORD record
ord-6d8bca8ea5284e3f8ed438df0067ff81
Source dataset
uspto-grants-2009_03
Patent number
US07511138B2

Reaction notes

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