Diisopropylethylamine → HCID 67456721、化合物

HRID 1804445ノート

反応式

HRID 1804445 の反応式
[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16](F)=[O:17])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].CCN(C(C)C)C(C)C>C(#N)C>[C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[O:17][N:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([CH2:27][N:28]5[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:31]5)=[CH:39][CH:40]=4)[N:20]=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1

参加物

5

反応物 3

HCID 81531DiisopropylethylamineHCID 58374067HCID 58374067、化合物HCID 58504340HCID 58504340、化合物

生成物 1

HCID 67456721HCID 67456721、化合物収率 78%

試薬・触媒・溶媒 1

HCID 6342Acetonitrile溶媒

実験手順

A suspension of 3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl fluoride (2.91 g, 11.2 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (Int.1, 3.43 g, 11.2 mmol), and Hunig's Base (2.55 mL, 14.6 mmol) in acetonitrile (20 mL) was stirred at room temperature over the weekend. The reaction mixture had completely solidified (pinkish-tan in color), but was judged complete by HPLC and LCMS. The reaction mixture was partitioned between a saturated aqueous of sodium bicarbonate (150 mL) and dichloromethane (150 mL). The aqueous layer was extracted with dichloromethane (2×100 mL), and the combined organic layers were dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded a tan solid which was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane (0-50%) to afford tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl) isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (4.60 g; 78%) as a white, crystalline solid. The material was suspended in methanol (−75 mL) and was sonicated for 5 minutes. The MeOH was removed under reduce pressure, and the residue was re-suspended in methanol (−50 mL) with sonication. Vacuum filtration and drying afforded tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (4.04 g, 7.67 mmol, 68% yield) as a white, crystalline solid. The methanol filtrate was concentrated to afford additional tert-butyl 1-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (570 mg; 10%) as a slightly off-white solid. The compound had an HPLC retention time=3.12 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. LC/MS M+1=527.1. 1H NMR (500 MHz, CDCl3) δ ppm 1.47 (s, 9H) 3.28-3.37 (m, 3H), 3.60 (br. s., 2H), 3.74 (br. s., 2H), 7.49 (d, J=7.70 Hz, 2H), 7.53-7.62 (m, 3H), 7.69 (d, J=7.15 Hz, 2H), and 8.16 (d, J=7.70 Hz, 2H).

後処理

  1. customThe reaction mixture was partitioned between a saturated aqueous of sodium bicarbonate (150 mL) and dichloromethane (150 mL)
  2. extractionThe aqueous layer was extracted with dichloromethane (2×100 mL)
  3. dry with materialthe combined organic layers were dried over anhydrous sodium sulfate
  4. concentrationConcentration under reduced pressure
  5. customafforded a tan solid which
  6. customwas purified by flash silica gel chromatography
  7. additiona mixture of ethyl acetate in hexane (0-50%)

出典と根拠

ORDレコード
ord-ea7894c71477454e918ac18aa8ef777a
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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