4-Methylmorpholine → N-(cyanomethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide

HRID 77130Notes

Reaction equation

HRID 77130 reaction equation
[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.CN(C(O[N:47]1N=[N:54][C:49]2C=CC=N[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCOC(C)=O>CN(C=O)C>[C:48]([CH2:49][NH:54][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)#[N:47]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 8857Ethyl AcetateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 674589572-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid

Product 1

HCID 53496461N-(cyanomethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamideYield 76%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 50 mg, 0.116 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.102 mL, 0.927 mmol), 2-aminoacetonitrile, HCl (13.94 mg, 0.151 mmol), and HATU (66.1 mg, 0.174 mmol). This was stirred overnight before EtOAc was added. The EtOAc solution was washed with 1N HCl, sat NaHCO3, and brine. The organic layer was then dried with MgSO4 and concentrated to give N-(cyanomethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (51 mg, 0.088 mmol, 76% yield): LCMS=470.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.15-8.23 (2 H, m), 7.65-7.76 (4 H, m), 7.53-7.64 (3 H, m), 5.21 (1 H, s), 4.19 (2 H, d, J=2.86 Hz). HPLC Peak RT=9.5 min (Analytical Method A).

Workup

  1. additionwas added
  2. washThe EtOAc solution was washed with 1N HCl
  3. dry with materialThe organic layer was then dried with MgSO4
  4. concentrationconcentrated

Sources & evidence

ORD record
ord-9a891fb91eea4cb5a93dd34cbffe0816
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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