4-Methylmorpholine → (R/S)-N-ethyl-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanamide

HRID 77198Notes

Reaction equation

HRID 77198 reaction equation
[OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]=3[C:33]([F:36])([F:35])[F:34])[O:19][N:18]=2)=[CH:13][CH:12]=1)[C:3]([NH:5][CH2:6][CH2:7][C:8](O)=[O:9])=[O:4].Cl.[CH2:38]([NH2:40])[CH3:39].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:38]([NH:40][C:8](=[O:9])[CH2:7][CH2:6][NH:5][C:3](=[O:4])[CH:2]([OH:1])[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]=[C:20]([C:22]3[O:26][N:25]=[C:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C:23]=3[C:33]([F:36])([F:34])[F:35])[O:19][N:18]=2)=[CH:15][CH:16]=1)[CH3:39]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 11198Ethylamine hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 534964603-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid

Product 1

HCID 53496096(R/S)-N-ethyl-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanamideYield 34.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

(R/S)-3-(2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanoic acid (Example 22, 22 mg, 0.044 mmol), ethanamine-HCl (5.36 mg, 0.066 mmol), 4-methylmorpholine (17.72 mg, 0.175 mmol), and HATU (21.65 mg, 0.057 mmol) were added to DMF (1 mL). This was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention 13.4) to provide (R/S)-N-ethyl-3-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)propanamide (8 mg, 0.015 mmol, 33.5% yield): LCMS=530.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.23 (2 H, m), 7.52-7.74 (7 H, m), 5.11 (1 H, s), 3.43-3.57 (2 H, m), 3.17 (2 H, q, J=7.41 Hz), 2.40 (2 H, t, J=6.71 Hz), 1.09 (3 H, t, J=7.26 Hz); HPLC peak RT=8.6 min (Method A).

Workup

  1. custompurified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention 13.4)

Sources & evidence

ORD record
ord-91bff3f58e7b4267bb23aeaec9f42b1e
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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