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

HRID 1441455ノート

反応式

HRID 1441455 の反応式
[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

参加物

9

反応物 5

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

生成物 1

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

試薬・触媒・溶媒 3

HCID 962Water溶媒HCID 8028Tetrahydrofuran溶媒2 回HCID 8857Ethyl Acetate溶媒

反応条件

温度
-70 °C

実験手順

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 (15-35μm) (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.

後処理

  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 (15-35μm) (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

出典と根拠

ORDレコード
ord-7dc3f61449bb4ecb86b4dbcbadb4aa55
出典データセット
uspto-grants-2010_02
特許番号
US07655654B2

反応ノート

読み込み中…