Triethylamine → 5-fluoro-N-[(1R,3R)-3-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide

HRID 724301Notes

Reaction equation

HRID 724301 reaction equation
[CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[N:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([OH:34])[CH2:29]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:16][C:13]1[CH:14]=[N:15][C:7]([O:6][C:5]2[CH:17]=[CH:18][CH:19]=[C:3]([S:2][CH3:1])[CH:4]=2)=[C:8]([CH:12]=1)[C:9]([NH:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][C@@H:30]([OH:34])[CH2:29]1)=[O:11]

Participants

7

Reactant 5

HCID 8471TriethylamineHCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 113918232-[3-(Methylsulfanyl)phenoxy]-5-fluoronicotinic acidHCID 25630527(1R,3R)-3-aminocyclohexanol

Product 1

HCID 587462125-fluoro-N-[(1R,3R)-3-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamideYield 36.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

2-[3-(Methylsulfanyl)phenoxy]-5-fluoronicotinic acid (345 mg, 1.26 mmol) was dissolved in dimethylformamide (10 ml) and triethylamine (865 μl, 11.8 mmol) was added followed by (1R,3R)-3-aminocyclohexanol hydroformate (200 mg, 1.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (715 mg, 3.73 mmol) and 1-hydroxybenzotriazole (185 mg, 1.37 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between 10% aq. citric acid solution (50 ml) and diethyl ether (50 ml). The organic was washed with sat. sodium bicarbonate solution (50 ml), water (25 ml) and brine (10 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate:cyclohexane (10:90 to 70:30) as eluant to give 5-fluoro-N-[(1R,3R)-3-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (171 mg) as a colourless gum.

Workup

  1. customthe solvent was removed under reduced pressure
  2. customThe residue was partitioned between 10% aq. citric acid solution (50 ml) and diethyl ether (50 ml)
  3. washThe organic was washed with sat. sodium bicarbonate solution (50 ml), water (25 ml) and brine (10 ml)
  4. dry with materialdried over MgSO4
  5. customthe solvent was removed under reduced pressure
  6. customThe residue was purified by flash column chromatography

Sources & evidence

ORD record
ord-c07f3f42293e4c059a30650b2b5f7118
Source dataset
uspto-grants-2006_11
Patent number
US07141586B2

Reaction notes

Loading…