Cesium carbonate → 4-(3-(1-(7-chloroquinolin-2-yl)piperidin-4-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide

HRID 624514Notes

Reaction equation

HRID 624514 reaction equation
Cl.Cl.Cl.[F:4][C:5]1[CH:14]=[C:13]([C:15]2[C:20]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[N:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8].Cl[C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=2)[N:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O1CCOCC1>[Cl:38][C:32]1[CH:31]=[C:30]2[C:35]([CH:36]=[CH:37][C:28]([N:24]3[CH2:25][CH2:26][CH:21]([C:20]4[C:15]([C:13]5[CH:12]=[CH:11][C:6]([C:7]([NH:9][CH3:10])=[O:8])=[C:5]([F:4])[CH:14]=5)=[N:16][CH:17]=[CH:18][N:19]=4)[CH2:22][CH2:23]3)=[N:29]2)=[CH:34][CH:33]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 151495062,7-DichloroquinolineHCID 867054032-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride

Product 1

HCID 727147534-(3-(1-(7-chloroquinolin-2-yl)piperidin-4-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamideYield 38.2%

Reagents, catalysts & solvents 2

HCID 178418851HCID 178418851, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

To a mixture of 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride (315 mg, 0.743 mmol), 2,7-dichloroquinoline (192 mg, 0.969 mmol), cesium carbonate (1211 mg, 3.72 mmol), dioxane (4 mL), and bis(tri-t-butylphosphine)palladium(0) (89 mg, 0.174 mmol). The solution was stirred at 90° C. After stirring for 5 h, the reaction was allowed to cool to room temperature and filtered. The solids were washed with EtOAc. The filtrate was concentrated to ½ it's original volume and purified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini column (10 micron, C18, 110 Å, Axia, 100×50 mm) eluting at 90 mL/min with a linear gradient of 10-60% MeCN (0.1% TFA) in water (0.1% TFA) over 20 min. The desired fractions were poured into 10% Na2CO3 and extracted with dichloromethane (DCM) (8×10 mL). The combined DCM layers were dried over MgSO4 and concentrated in vacuo to give 4-(3-(1-(7-chloroquinolin-2-yl)piperidin-4-yl)pyrazin-2-yl)-2-fluoro-N-methylbenzamide (135 mg, 0.284 mmol, 38.2% yield), as an off white solid. m/z=476 (M+1). 1H NMR (300 MHz, CDCl3) δ 8.54 (d, J=2.34 Hz, 1H), 8.49 (d, J=2.34 Hz, 1H), 8.27 (t, J=8.04 Hz, 1H), 7.83 (d, J=9.35 Hz, 1H), 7.67 (d, J=2.05 Hz, 1H), 7.49 (d, J=8.62 Hz, 1H), 7.44 (dd, J=1.46, 8.04 Hz, 1H), 7.35 (dd, J=1.46, 12.42 Hz, 1H), 7.15 (dd, J=2.05, 8.48 Hz, 1H), 6.98 (d, J=9.35 Hz, 1H), 6.79 (d, J=6.28 Hz, 1H), 4.68 (d, J=13.30 Hz, 2H), 3.16-3.31 (m, 1H), 3.09 (dd, J=0.80, 4.75 Hz, 3H), 2.86-3.02 (m, 2H), 2.01-2.19 (m, 2H), 1.82 (d, J=11.55 Hz, 2H).

Workup

  1. stirringAfter stirring for 5 h
  2. temperatureto cool to room temperature
  3. filtrationfiltered
  4. washThe solids were washed with EtOAc
  5. concentrationThe filtrate was concentrated
  6. custompurified by reverse-phase preparative HPLC (Shimadzu) on a Phenomenex Gemini column (10 micron, C18, 110 Å, Axia, 100×50 mm)
  7. washeluting at 90 mL/min with a linear gradient of 10-60% MeCN (0.1% TFA) in water (0.1% TFA) over 20 min
  8. additionThe desired fractions were poured into 10% Na2CO3
  9. extractionextracted with dichloromethane (DCM) (8×10 mL)
  10. dry with materialThe combined DCM layers were dried over MgSO4
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-f77ca166de7043d3abf33aeeb5115bbe
Source dataset
uspto-grants-2016_04
Patent number
US09303028B2

Reaction notes

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