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

HRID 1804509Notes

Reaction equation

HRID 1804509 reaction equation
[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]

Participants

6

Reactant 3

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

Product 1

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

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Procedure

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.

Workup

  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

Sources & evidence

ORD record
ord-5794f62de12145c5a966a36b708765a5
Source dataset
uspto-grants-2013_01
Patent number
US08354398B2

Reaction notes

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