1,2-Dichloroethane → Tert-butyl 1-(4-(5-(4-propyl-5-(pyridin-2-yl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate

HRID 1951942Notes

Reaction equation

HRID 1951942 reaction equation
[CH2:1]([C:4]1[C:5]([C:15]([OH:17])=O)=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2][CH3:3].[Na].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl.O[N:43]=[C:44]([C:46]1[CH:63]=[CH:62][C:49]([CH2:50][N:51]2[CH2:54][CH:53]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:52]2)=[CH:48][CH:47]=1)[NH2:45].N1C=CC=CC=1C1C(C(F)(F)F)=C(C2ON=C(C3C=CC(CN4CC(C(O)=O)C4)=CC=3)N=2)ON=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C:4]1[C:5]([C:15]2[O:17][N:45]=[C:44]([C:46]3[CH:47]=[CH:48][C:49]([CH2:50][N:51]4[CH2:52][CH:53]([C:55]([O:57][C:58]([CH3:59])([CH3:61])[CH3:60])=[O:56])[CH2:54]4)=[CH:62][CH:63]=3)[N:43]=2)=[N:6][O:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:2][CH3:3]

Participants

10

Reactant 7

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 5360545SodiumHCID 468359141-(4-(5-(3-(Pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acidHCID 580628294-Propyl-5-(pyridin-2-yl)isoxazole-3-carboxylic acidHCID 76806751tert-butyl 1-[[4-(N'-hydroxycarbamimidoyl)phenyl]methyl]azetidine-3-carboxylate

Product 1

HCID 66678195Tert-butyl 1-(4-(5-(4-propyl-5-(pyridin-2-yl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A solution of 4-propyl-5-(pyridin-2-yl)isoxazole-3-carboxylic acid, sodium salt (13.5 mg, approx 0.053 mmol), HOBt (16.0 mg, 0.105 mmol), and diisopropylethylamine (0.041 mL, 0.233 mmol) in acetonitrile (1 mL) was added EDC (26.1 mg, 0.136 mmol) and tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int. 1 (17.8 mg, 0.058 mmol). The reaction mixture was stirred at 80° C. for 2 h, cooled to room temperature, and concentrated to yield the crude product. The residue was dissolved in ethyl acetate (3 mL), washed with a saturated aqueous solution of sodium bicarbonate (1 mL), washed with water (1 mL), washed with brine (1 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by preparative HPLC afforded tert-butyl 1-(4-(5-(4-propyl-5-(pyridin-2-yl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate. [Prep HPLC: Column: PHENOMENEX® S10 30×100 mm; Gradient time: 10 min; Flow rate=40 ml/min; Solvent A=10% MeOH—90% Water—0.1% TFA; Solvent B=90% MeOH—10% water—0.1% TFA; Start % B=20; Final % B=100.]

Workup

  1. temperaturecooled to room temperature
  2. concentrationconcentrated
  3. customto yield the crude product
  4. washwashed with a saturated aqueous solution of sodium bicarbonate (1 mL)
  5. washwashed with water (1 mL)
  6. washwashed with brine (1 mL)
  7. dry with materialdried over anhydrous sodium sulfate
  8. concentrationConcentration
  9. customfollowed by purification by preparative HPLC

Sources & evidence

ORD record
ord-4b15fa2d85c649d3b4a49d51341bab21
Source dataset
uspto-grants-2013_03
Patent number
US08404672B2

Reaction notes

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