Diisopropylethylamine → Tert-butyl 1-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate

HRID 1804509ノート

反応式

HRID 1804509 の反応式
[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10](F)=[O:11])[C:6]=1[C:13]([F:16])([F:15])[F:14])[CH:2]([CH3:4])[CH3:3].O[N:18]=[C:19]([C:21]1[CH:38]=[CH:37][C:24]([CH2:25][N:26]2[CH2:29][CH:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27]2)=[CH:23][CH:22]=1)[NH2:20].CCN(C(C)C)C(C)C>C(#N)C.ClCCl>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]2[O:11][N:20]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]([CH2:25][N:26]4[CH2:27][CH:28]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:29]4)=[CH:37][CH:38]=3)[N:18]=2)[C:6]=1[C:13]([F:16])([F:15])[F:14])[CH:2]([CH3:4])[CH3:3]

参加物

6

反応物 3

HCID 81531DiisopropylethylamineHCID 76806751tert-butyl 1-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]azetidine-3-carboxylateHCID 866563945-Isobutyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride

生成物 1

HCID 67454074Tert-butyl 1-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate収率 80%

試薬・触媒・溶媒 2

HCID 6342Acetonitrile溶媒HCID 6344Dichloromethane溶媒

実験手順

A mixture of 5-isobutyl-4-(trifluoromethyl)isoxazole-3-carbonyl fluoride (0.130 g, 0.544 mmol), tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 0.166 g, 0.544 mmol), and Hunig's Base (0.123 mL, 0.707 mmol) in acetonitrile (2 mL) was stirred at room temperature for 2 days. By HPLC, there was ˜7% of the uncyclized intermediate remaining The reaction mixture was gently heated with a heat gun for ˜15 min., resulting in further cyclization. The homogenous mixture was diluted with dichloromethane and washed with a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane, and the organic layers were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 1% mixture of methanol in dichloromethane afforded tert-butyl 1-(4-(5-(5-isobutyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (0.219 g, 0.432 mmol, 80% yield) as a clear, viscous yellow oil. The product had an HPLC ret. time=3.03 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=507.4.

後処理

  1. temperaturewas gently heated with a heat gun for ˜15 min.
  2. customresulting in further cyclization
  3. washwashed with a saturated aqueous solution of sodium bicarbonate
  4. extractionThe aqueous layer was extracted with dichloromethane
  5. dry with materialdried over anhydrous sodium sulfate
  6. concentrationConcentration under reduced pressure
  7. customfollowed by purification by flash silica gel chromatography

出典と根拠

ORDレコード
ord-5794f62de12145c5a966a36b708765a5
出典データセット
uspto-grants-2013_01
特許番号
US08354398B2

反応ノート

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