1-Hydroxybenzotriazole → 5-fluoro-N-[trans-2-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide

HRID 724312Notes

Reaction equation

HRID 724312 reaction equation
Cl.[OH:2][CH2:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[NH2:10].[F:11][C:12]1[CH:13]=[N:14][C:15]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)=[C:16]([CH:20]=1)[C:17](O)=[O:18].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[F:11][C:12]1[CH:13]=[N:14][C:15]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([S:28][CH3:29])[CH:23]=2)=[C:16]([CH:20]=1)[C:17]([NH:10][C@@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C@H:4]1[CH2:3][OH:2])=[O:18]

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2724654trans-2-Hydroxymethyl-1-cyclohexylamine hydrochlorideHCID 113918232-[3-(Methylsulfanyl)phenoxy]-5-fluoronicotinic acid

Product 1

HCID 695861635-fluoro-N-[trans-2-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamideYield 70.9%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8471TriethylamineSolvent

Procedure

A solution of trans-2-hydroxymethyl-1-cyclohexylamine hydrochloride (130 mg, 0.78 mmol) and triethylamine (300 μl) in dimethylformamide (5 ml) was added to a solution of 5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinic acid (218 mg, 0.78 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol) and 1-hydroxybenzotriazole (116 mg, 0.86 mmol) in dimethylformamide (4 ml) and the reaction was stirred under nitrogen at room temperature for 48 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (25 ml) and water (25 ml). The organic phase was removed and washed with sat. sodium bicarbonate solution (25 ml) followed by 1M citric acid (25 ml) and brine (25 ml). The organic layer was dried over MgSO4 and the solvent was removed by reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (20:80 changing to 30:70 then 50:50, by volume) to give 5-fluoro-N-[trans-2-hydroxymethyl-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (216 mg) as a colourless oil.

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. customthe residue was partitioned between ethyl acetate (25 ml) and water (25 ml)
  3. customThe organic phase was removed
  4. washwashed with sat. sodium bicarbonate solution (25 ml)
  5. dry with materialThe organic layer was dried over MgSO4
  6. customthe solvent was removed by reduced pressure
  7. customThe residue was purified by flash column chromatography on silica gel eluting with a solvent gradient of ethyl acetate:pentane (20:80 changing to 30:70

Sources & evidence

ORD record
ord-176fdaa5bdf246deae9ab68ec9c61659
Source dataset
uspto-grants-2006_11
Patent number
US07141586B2

Reaction notes

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