Triethylamine → 2-Fluoro-4-(3-(1-(7-fluoroquinolin-2-YL)piperidin-4-YL)pyrazin-2-YL)-N-methylbenzamide

HRID 624517Notes

Reaction equation

HRID 624517 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].C(N(CC)CC)C.FC(F)(F)S(O[C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][C:44]([F:50])=[CH:45][CH:46]=2)[N:41]=1)(=O)=O>CS(C)=O.O>[F:4][C:5]1[CH:14]=[C:13]([C:15]2[C:20]([CH:21]3[CH2:26][CH2:25][N:24]([C:40]4[CH:49]=[CH:48][C:47]5[C:42](=[CH:43][C:44]([F:50])=[CH:45][CH:46]=5)[N:41]=4)[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]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 866941337-Fluoroquinolin-2-yl trifluoromethanesulfonateHCID 867054032-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride

Product 1

HCID 727147542-Fluoro-4-(3-(1-(7-fluoroquinolin-2-YL)piperidin-4-YL)pyrazin-2-YL)-N-methylbenzamideYield 46.1%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolvent2×HCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

To a RT solution of 2-fluoro-N-methyl-4-(3-(piperidin-4-yl)pyrazin-2-yl)benzamide trihydrochloride (1.00 g, 3.18 mmol, prepared according to Step 2 of Example 1) and triethylamine (2.00 ml, 14.35 mmol) in DMSO (10 ml) was added a solution of 7-fluoroquinolin-2-yl trifluoromethanesulfonate (1.10 g, 3.73 mmol, prepared according to Step 3 of Example 2) in DMSO (2 mL). The reaction mixture was heated at 60° C. for 2.5 h. The reaction was cooled RT and diluted with water. The mixture was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine and dried over Na2SO4. The solution was filtered and the solution was evaporated onto silica gel and purified by flash chromatography (Isco (80 gram)) eluting with EtOAc:hexanes (0:1→3:1). The fractions containing product were concentrated in vacuo and the residue was stirred vigorously over Et2O for 3 h. The solid was filtered, washed with Et2O and dried to give 674 mg (46%) of the desired product. m/z=460 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.62 (d, J=2.34 Hz, 1 H), 8.59 (d, J=2.34 Hz, 1 H), 8.39 (br. s., 1 H), 8.04 (d, J=9.21 Hz, 1 H), 7.69-7.83 (m, 2 H), 7.45-7.58 (m, 2 H), 7.18-7.28 (m, 2 H), 7.08 (td, J=8.77, 2.63 Hz, 1 H), 4.66 (d, J=13.30 Hz, 2 H), 3.13-3.29 (m, 1 H), 2.86-3.03 (m, 2 H), 2.82 (d, J=4.68 Hz, 3 H), 1.72-1.97 (m, 4 H).

Workup

  1. temperatureThe reaction was cooled RT
  2. extractionThe mixture was extracted with CH2Cl2 (3×)
  3. washThe combined organic layers were washed with brine
  4. dry with materialdried over Na2SO4
  5. filtrationThe solution was filtered
  6. customthe solution was evaporated onto silica gel
  7. custompurified by flash chromatography (Isco (80 gram))
  8. washeluting with EtOAc:hexanes (0:1→3:1)
  9. additionThe fractions containing product
  10. concentrationwere concentrated in vacuo
  11. filtrationThe solid was filtered
  12. washwashed with Et2O
  13. customdried

Sources & evidence

ORD record
ord-fefa0acb9bbf433caa54e1169caeaea2
Source dataset
uspto-grants-2016_04
Patent number
US09303028B2

Reaction notes

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