Triethylamine → Tert-butyl 1-(4-(5-(3-phenyl-4-(2,2,2-trifluoroethylcarbamoyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate

HRID 1804498Notes

Reaction equation

HRID 1804498 reaction equation
[C:1]([O:5][C:6]([CH:8]1[CH2:11][N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]4[O:28][N:27]=[C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:25]=4[C:35]([OH:37])=O)[O:21][N:20]=3)=[CH:15][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:38][C:39]([F:43])([F:42])[CH2:40][NH2:41].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(CC)CC>CN(C=O)C>[C:29]1([C:26]2[C:25]([C:35](=[O:37])[NH:41][CH2:40][C:39]([F:43])([F:42])[F:38])=[C:24]([C:22]3[O:21][N:20]=[C:19]([C:16]4[CH:17]=[CH:18][C:13]([CH2:12][N:10]5[CH2:11][CH:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9]5)=[CH:14][CH:15]=4)[N:23]=3)[O:28][N:27]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 9773Ethanamine, 2,2,2-trifluoro-HCID 152842Bis(2-oxo-3-oxazolidinyl)phosphinic chlorideHCID 67459061HCID 67459061, compound

Product 1

HCID 67458998Tert-butyl 1-(4-(5-(3-phenyl-4-(2,2,2-trifluoroethylcarbamoyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylateYield 51.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 5-(3-(4-((3-(tert-butoxycarbonyl)azetidin-1-yl)methyl)phenyl)-1,2,4-oxadiazol-5-yl)-3-phenylisoxazole-4-carboxylic acid (30 mg, 0.060 mmol), 2,2,2-trifluoroethylamine (7.15 μL, 0.090 mmol), BOP-Cl (18.24 mg, 0.072 mmol) and Et3N (0.025 mL, 0.179 mmol) in DMF (0.5 mL) was stirred at rt over the weekend. The reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was washed with water (2×30 mL) and brine (30 mL). After drying (MgSO4) and filtration, the organic layer was concentrated to a colorless solid that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-70% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(3-phenyl-4-(2,2,2-trifluoroethylcarbamoyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (18 mg, 0.031 mmol, 51.7% yield) as a white solid. This material was deemed suitable to use in the next step without further purification. HPLC retention time=1.71 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient. MS: (M+H)=584.10.

Workup

  1. customThe reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL)
  2. washThe organic layer was washed with water (2×30 mL) and brine (30 mL)
  3. customAfter drying
  4. filtration(MgSO4) and filtration
  5. concentrationthe organic layer was concentrated to a colorless solid
  6. customthat was chromatographed on a 4 gm Isco silica gel cartridge
  7. washeluting with a 0-70% EtOAc/Hex gradient
  8. additionThe essentially pure fractions containing product
  9. concentrationwere concentrated

Sources & evidence

ORD record
ord-e19574db595949aa9823b72e27647168
Source dataset
uspto-grants-2013_01
Patent number
US08354398B2

Reaction notes

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