Acetic Acid → (R/S)-N-(2-acetamidoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide

HRID 77181Notes

Reaction equation

HRID 77181 reaction equation
[NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:34])[CH:6]([OH:33])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1.[C:35](O)(=[O:37])[CH3:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:35]([NH:1][CH2:2][CH2:3][NH:4][C:5](=[O:34])[CH:6]([OH:33])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[O:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]=3[C:29]([F:32])([F:31])[F:30])[O:15][N:14]=2)=[CH:9][CH:8]=1)(=[O:37])[CH3:36]

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 53495536HCID 53495536, compound

Product 1

HCID 53495670(R/S)-N-(2-acetamidoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamideYield 30.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(R/S)-N-(2-Aminoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (Example 52, 30 mg, 0.063 mmol), acetic acid (7.61 mg, 0.127 mmol), HATU (36.1 mg, 0.095 mmol), and 4-methylmorpholine (32.0 mg, 0.317 mmol) were added to DMF (1 mL). This was stirred for 30 min and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, 20 mL/min, 220 nM, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 15 min (The product retention time was 18.4 min.) to yield (R/S)-N-(2-acetamidoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (10 mg, 0.019 mmol, 29.8% yield): LCMS=516.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=8.35 Hz), 7.54-7.73 (7 H, m), 5.12(1 H, s), 3.34-3.39(2 H, m), 3.24-3.29(2 H, m), 1.89(3 H, s); HPLC peak RT=7.4 min (Method A).

Workup

  1. customwas purified by prep HPLC (
  2. washPHENOMENEX® Luna 5u 21.2×100 mm, 20 mL/min, 220 nM, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid
  3. customover 15 min

Sources & evidence

ORD record
ord-00829bbd04d844c7a41b4924ff5a9d8b
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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