Dimethylformamide → Trifluoroacetic acid

HRID 77231Notes

Reaction equation

HRID 77231 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.[NH:32]1[CH:36]=[CH:35][N:34]=[C:33]1[C@@H:37]([NH2:39])[CH3:38].CN(C([O:47]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.CN([CH:74]=[O:75])C>>[NH:32]1[CH:36]=[CH:35][N:34]=[C:33]1[C@@H:37]([NH:39][C:3](=[O:5])[CH:2]([OH:1])[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:29])([F:31])[F:30])[O:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:38].[C:74]([OH:75])([C:28]([F:31])([F:30])[F:29])=[O:47]

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 51683332HCID 51683332, compoundHCID 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 44.4%HCID 68233046N-((S)-1-(1H-imidazol-2-yl)ethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)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, 20 mg, 0.046 mmol), (S)-1-(1H-imidazol-2-yl)ethanamine (5.15 mg, 0.046 mmol), HATU (22.92 mg, 0.060 mmol), and 4-methylmorpholine (18.76 mg, 0.185 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 10 min, 20 mL/min, 220 nM, product retention=11.3 min) to provide N-((S)-1-(1H-imidazol-2-yl)ethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide, TFA (17 mg, 0.021 mmol, 44.4% yield) as a single enantiomer. LCMS=525.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.27 (2 H, m), 7.42-7.77 (11 H, m), 5.26-5.33 (1 H, m), 5.23 (1 H, s), 1.68 (3 H, d, J=7.26 Hz); HPLC peak RT=8.4 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 10 min, 20 mL/min, 220 nM, product retention=11.3 min)

Sources & evidence

ORD record
ord-98c12426d7504f7194ed98cb511de49f
Source dataset
uspto-grants-2014_09
Patent number
US08835470B2

Reaction notes

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