Dimethylformamide → Trifluoroacetic acid

HRID 77233Notes

Reaction equation

HRID 77233 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.[N:32]1[CH:37]=[CH:36][N:35]=[CH:34][C:33]=1[CH2:38][CH2:39][NH2:40].CN(C([O:48]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN([CH:75]=[O:76])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:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:40][CH2:39][CH2:38][C:33]1[CH:34]=[N:35][CH:36]=[CH:37][N:32]=1)=[O:5].[C:75]([OH:76])([C:28]([F:31])([F:30])[F:29])=[O:48]

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 79724-MethylmorpholineHCID 31524872-(Pyrazin-2-yl)ethan-1-amineHCID 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 2

HCID 6422Trifluoroacetic acidYield 30.6%HCID 674585382-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(2-(pyrazin-2-yl)ethyl)acetamide

Procedure

2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 25 mg, 0.058 mmol), 2-pyrazin-2-yl-ethylamine (10.71 mg, 0.087 mmol), HATU (28.7 mg, 0.075 mmol), and 4-methylmorpholine (23.45 mg, 0.232 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was 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=13.6 min) to provide 2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(2-(pyrazin-2-yl)ethyl)acetamide, TFA (10 mg, 0.018 mmol, 30.6% yield) as a single enantiomer. LCMS=537.4 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.05-8.58 (5 H, m), 7.49-7.78 (7 H, m), 5.06 (1 H, s), 3.67 (2 H, dt, J=13.59, 6.74 Hz), 3.05 (2 H, t, J=6.71 Hz); HPLC peak RT=9.1 min (Method A).

Workup

  1. customwas 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=13.6 min)

Sources & evidence

ORD record
ord-78c64e97dbf14084b22aa74463006055
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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