Tetrahydrofuran → Tert-butyl 3-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate

HRID 71273Notes

Reaction equation

HRID 71273 reaction equation
C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[OH:16][C:17]1([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[N:36][OH:37])[NH2:35])=[CH:30][CH:29]=2)[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1.[Cl:38][C:39]1[CH:40]=[C:41]([C:46]2([CH2:52][CH2:53][C:54](O)=O)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:42]=[C:43]([Cl:45])[CH:44]=1.C(N(C(C)C)CC)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>CN(C=O)C.C(OCC)(=O)C>[Cl:38][C:39]1[CH:40]=[C:41]([C:46]2([CH2:52][CH2:53][C:54]3[O:37][N:36]=[C:34]([C:31]4[CH:32]=[CH:33][C:28]([C:17]5([OH:16])[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]5)=[CH:29][CH:30]=4)[N:35]=3)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]2)[CH:42]=[C:43]([Cl:45])[CH:44]=1

Participants

9

Reactant 6

HCID 8028TetrahydrofuranHCID 81531DiisopropylethylamineHCID 152842Bis(2-oxo-3-oxazolidinyl)phosphinic chlorideHCID 2724141Tetrabutylammonium FluorideHCID 66686108HCID 66686108, compoundHCID 86688207tert-butyl 3-hydroxy-3-(4-(N'-hydroxycarbamimidoyl)phenyl)azetidine-1-carboxylate2×

Product 1

HCID 66692429Tert-butyl 3-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylateYield 75.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

BOP-Cl (36.4 mg, 0.143 mmol) was added to a mixture of crude tert-butyl 3-hydroxy-3-(4-(N′-hydroxycarbamimidoyl)phenyl)azetidine-1-carboxylate (Intermediate 4, 40 mg, 0.13 mmol), 3-(1-(3,5-dichlorophenyl)cyclohexyl)propanoic acid (39.2 mg, 0.13 mmol) and diisopropylethyl amine (0.045 mL, 0.26 mmol) in DMF (3 mL). The mixture was stirred at room temperature for 2 h, and a 1M solution of tetra-n-butylammonium fluoride in THF (0.13 mL, 0.13 mmol) was added. The mixture was heated to 80° C. overnight, diluted with ethyl acetate, and washed with saturated aqueous NaCl solution. The organic layer was dried (MgSO4), filtered, and concentrated. The crude product was purified on a 24 g ISCO cartridge and eluted with EtOAc-hexanes gradient to obtain tert-butyl 3-(4-(5-(2-(1-(3,5-dichlorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate (56 mg, 50% yield, HPLC purity: 80%). HPLC retention time=4.71 minutes (Waters Sunfire C18 4.6×50 mm) eluting with 10-90% aqueous methanol with 0.1% TFA over a 4 minute gradient. LC/MS: m/e 572.25 (M+H)+.

Workup

  1. temperatureThe mixture was heated to 80° C. overnight
  2. washwashed with saturated aqueous NaCl solution
  3. dry with materialThe organic layer was dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product was purified on a 24 g ISCO cartridge
  7. washeluted with EtOAc-hexanes gradient

Sources & evidence

ORD record
ord-4f4cf390d2904f1ca08bbfc063a9f30b
Source dataset
uspto-grants-2014_09
Patent number
US08822510B2

Reaction notes

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