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

HRID 724300Notes

Reaction equation

HRID 724300 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 117882853-Aminocyclohexanol, (1S,3S)-

Product 1

HCID 587461885-fluoro-N-[(1S,3S)-3-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamideYield 45.4%

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 (1S,3S)-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-[(1S,3S)-3-hydroxycyclohexyl]-2-[3-(methylsulfanyl)phenoxy]nicotinamide (212 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-ec60d81c44fa4976997189696ebb1fdd
Source dataset
uspto-grants-2006_11
Patent number
US07141586B2

Reaction notes

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