Pyrazole → 1-Hydroxy-N-[(1S,2S)-2-hydroxycyclohexyl]-4-{[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}-2-naphthamide

HRID 335053Notes

Reaction equation

HRID 335053 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([O:19]C)=[C:11]([C:21]([NH:23][C@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[OH:30])=[O:22])[CH:10]=2)=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CS(C)=O.[Cu]I>[OH:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([CH2:8][C:5]2[CH:6]=[N:7][C:2]([N:31]3[CH:35]=[CH:34][CH:33]=[N:32]3)=[CH:3][CH:4]=2)=[CH:10][C:11]=1[C:21]([NH:23][C@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[OH:30])=[O:22]

Participants

7

Reactant 4

HCID 1048PyrazoleHCID 10796Cesium carbonateHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamine2×HCID 547556014-[(6-Chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide

Product 1

HCID 547557181-Hydroxy-N-[(1S,2S)-2-hydroxycyclohexyl]-4-{[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}-2-naphthamide

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Catalyst2×HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-1-methoxy-2-naphthamide (Example 3, 0.050 g, 0.12 mmol) and pyrazole (8.0 mg, 0.12 mmol) in 2 mL of DMSO under an atmosphere of nitrogen was added aqueous cesium carbonate (1 N, 0.23 mL, 1 N aqueous, 0.23 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (2.2 mg, 0.015 mmol), and copper(I) iodide (1.4 g, 0.0076 mmol). The mixture was heated at 120° C. for 20 hours, cooled to room temperature, and additional trans-N,N′-dimethylcyclohexane-1,2-diamine (2.16 mg, 0.015 mmol) and copper(I) iodide (1.4 mg, 0.0076 mmol) were added. The reaction was heated at 140° C. for 24 hours, cooled to room temperature, filtered, and purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 442.9 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.50-8.47 (m, 2H), 8.33 (s, 1H), 7.84-7.81 (m, 1H), 7.76-7.74 (m, 2H), 7.60-7.51 (m, 2H), 7.24-7.20 (m, 2H), 6.48 (br s, 1H), 6.37 (d, J=6.2 Hz, 1H), 4.36 (s, 2H), 3.95-3.92 (m, 1H), 3.58-3.51 (m, 1H), 2.16-2.13 (m, 2H), 1.81-1.78 (m, 2H), 1.46-1.25 (m, 4H).

Workup

  1. temperaturecooled to room temperature
  2. temperatureThe reaction was heated at 140° C. for 24 hours
  3. temperaturecooled to room temperature
  4. filtrationfiltered
  5. custompurified via preparative reverse phase HPLC

Sources & evidence

ORD record
ord-93e7780467f24e07b83d6e9d778c34e6
Source dataset
uspto-grants-2014_11
Patent number
US08883850B2

Reaction notes

Loading…