Dimethyl Sulfoxide → 2-fluoro-4-(3-(1-(6-fluoroquinolin-2-yl)piperidin-4-yl)pyrazin-2-yl)-N-methylbenzamide

HRID 2364574Notes

Reaction equation

HRID 2364574 reaction equation
[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:17]([CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].Cl[C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[C:30]([F:35])[CH:31]=2)[N:26]=1.CS(C)=O.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)C>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:17]([CH:18]3[CH2:23][CH2:22][N:21]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[C:30]([F:35])[CH:31]=5)[N:26]=4)[CH2:20][CH2:19]3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]

Participants

7

Reactant 4

HCID 679Dimethyl Sulfoxide2×HCID 11430Potassium CarbonateHCID 150594332-Chloro-6-fluoroquinolineHCID 867054042-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide

Product 1

HCID 727147562-fluoro-4-(3-(1-(6-fluoroquinolin-2-yl)piperidin-4-yl)pyrazin-2-yl)-N-methylbenzamideYield 39.8%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 3283Diethyl EtherSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide (155 mg, 0.493 mmol, prepared according to Step 2 of Example 1), 2-chloro-6-fluoroquinoline (108 mg, 0.595 mmol, Combi-blocks), and DMSO (2 mL) was added potassium carbonate (240 mg, 1.737 mmol). The solution was stirred at 100° C. After 72 h, the reaction was allowed to cool to room temperature and diluted with water (50 mL). After stirring for 30 min, the solution was filtered and the filtered solid adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0-80% EtOAc in hexane, to provide a light yellow solid, which contained residual DMSO as measure by NMR. The solids were redissolved in diethyl ether and washed with water, brine, and concentrated in vacuo to give 2-fluoro-4-(3-(1-(6-fluoroquinolin-2-yl)piperidin-4-yl)pyrazin-2-yl)-N-methylbenzamide (90 mg, 0.196 mmol, 39.7% yield), as a light yellow solid. m/z=460 (M+1). 1H NMR (300 MHz, CDCl3) δ ppm 8.55 (d, J=2.48 Hz, 1H), 8.49 (d, J=2.48 Hz, 1H), 8.26 (t, J=8.04 Hz, 1H), 7.82 (d, J=9.21 Hz, 1H), 7.65 (dd, J=5.26, 9.06 Hz, 1H), 7.44 (dd, J=1.61, 8.04 Hz, 1H), 7.36 (dd, J=1.61, 12.42 Hz, 1H), 7.28-7.32 (m, 1H), 7.22 (dd, J=2.92, 8.92 Hz, 1H), 7.04 (d, J=9.21 Hz, 1H), 6.77 (br. s., 1H), 4.64 (d, J=13.45 Hz, 2H), 3.14-3.31 (m, 1H), 3.03-3.14 (m, 3H), 2.81-3.02 (m, 2H), 2.05-2.21 (m, 2H), 1.82 (d, J=11.69 Hz, 2H).

Workup

  1. temperatureto cool to room temperature
  2. stirringAfter stirring for 30 min
  3. filtrationthe solution was filtered
  4. customchromatographed through a Redi-Sep® pre-packed silica gel column (12 g)
  5. washeluting with 0-80% EtOAc in hexane
  6. customto provide a light yellow solid, which
  7. washwashed with water, brine
  8. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-c32726aab93c4ee19168fe93ab6bf480
Source dataset
uspto-grants-2014_04
Patent number
US08691986B2

Reaction notes

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