Trifluoroacetic acid → 2-(2,4-Difluorophenyl)-6-(1-hydroxy-1-methylethyl)-N-{(1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethyl}isonicotinamide

HRID 1909126Notes

Reaction equation

HRID 1909126 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]([OH:21])([CH3:20])[CH3:19])[N:17]=1)[C:12]([OH:14])=O.[O-:22][N+:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[C:25]([C@H:33]([NH2:35])[CH3:34])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]([OH:21])([CH3:20])[CH3:19])[N:17]=1)[C:12]([NH:35][C@@H:33]([C:25]1[CH:24]=[N+:23]([O-:22])[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:26]=1)[CH3:34])=[O:14]

Participants

8

Reactant 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59539683(1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamineHCID 673396622-(2,4-Difluorophenyl)-6-(1-hydroxy-1-methylethyl)isonicotinic acid

Product 1

HCID 426030672-(2,4-Difluorophenyl)-6-(1-hydroxy-1-methylethyl)-N-{(1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethyl}isonicotinamideYield 83.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Procedure

To a solution of 2-(2,4-difluorophenyl)-6-(1-hydroxy-1-methylethyl)isonicotinic acid (19.5 mg, 0.07 mmol) in DMF (0.67 mL) were added hydrochloride salt of (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (24.2 mg, 0.10 mmol), HATU (0.5 M in DMA; 0.2 mL, 0.10 mmol) and diisopropylethylamine (46.5 uL, 0.27 mmol). The mixture was stirred at ambient temperature. After 30 min, small amount of water and trifluoroacetic acid were added and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (28 mg). HRMS 482.1462 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.38 (s, 1H); 8.09-8.01 (m, 1H); 7.94 (s, 1H); 7.73 (s, 1H); 7.67 (d, J=8.3 Hz, 1H); 7.38 (d, J=8.3 Hz, 1H); 7.07-6.98 (m, 1H); 6.99-6.90 (m, 1H); 6.74 (d, J=6.9 Hz, 1H); 5.32-5.25 (m, 1H); 4.38 (s, 1H); 1.67 (d, J=7.1 Hz, 3H); 1.62 (s, 6H).

Workup

  1. customthe mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid)

Sources & evidence

ORD record
ord-1bc1070321c848e2af0053418b9ceb68
Source dataset
uspto-grants-2013_12
Patent number
US08598209B2

Reaction notes

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