Trifluoroacetic acid → ethyl 5-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)-1H-1,2,4-triazole-3-carboxylate

HRID 77237Notes

Reaction equation

HRID 77237 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](O)=[O:4].[NH2:32][CH2:33][C:34]1[NH:38][N:37]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:35]=1.C(O)(C(F)(F)F)=O.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([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:29])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]1[NH:38][N:37]=[C:36]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[N:35]=1)=[O:4]

Participants

7

Reactant 5

HCID 6422Trifluoroacetic 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 10727000Ethyl 5-(aminomethyl)-1H-1,2,4-triazole-3-carboxylateHCID 674589572-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid

Product 1

HCID 67459010ethyl 5-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)-1H-1,2,4-triazole-3-carboxylateYield 20.77%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 120 mg, 0.278 mmol), ethyl 5-(aminomethyl)-1H-1,2,4-triazole-3-carboxylate, TFA (Int-XIV, 95 mg, 0.334 mmol), 4-methylmorpholine (113 mg, 1.113 mmol), and HATU (138 mg, 0.362 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=30.1 min) to provide ethyl 5-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)-1H-1,2,4-triazole-3-carboxylate (40 mg, 0.058 mmol, 20.77% yield) as a single enantiomer. LCMS=584.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.08-8.22 (2 H, m), 7.50-7.78 (7 H, m), 5.22 (1 H, s), 4.48-4.72 (2 H, m), 4.42 (2 H, q, J=7.04 Hz), 1.39 (3 H, t, J=7.04 Hz); HPLC peak RT=10.0 min (Method A).

Workup

  1. customwas purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=30.1 min)

Sources & evidence

ORD record
ord-031d3c1a658e4a33a7d52bffd487fdfb
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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