Isopropylamine → 2-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amine

HRID 713213Notes

Reaction equation

HRID 713213 reaction equation
Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[F-].[K+].CC[N:31](C(C)C)[CH:32]([CH3:34])[CH3:33].CC(N)C>CS(C)=O.O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:31][CH:32]([CH3:34])[CH3:33])[CH2:13][CH2:14]1

Participants

7

Reactant 4

HCID 6363IsopropylamineHCID 81531DiisopropylethylamineHCID 522689Potassium FluorideHCID 1181593003-Chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine

Product 1

HCID 1181593612-(4-(2,4-difluorobenzyl)piperazin-1-yl)-N-isopropylpyrido[3,4-b]pyrazin-3-amineYield 60%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent

Conditions

Temperature
23 °C

Procedure

To a flask charged with 3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine (2.34 g, 6.23 mmol) and potassium fluoride (0.470 g, 8.09 mmol) in DMSO (12 mL) was added DIPEA (2.169 mL, 12.45 mmol) and propan-2-amine (1.605 mL, 18.68 mmol) at 23° C. The reaction was stirred at 23° C. for 22 hr and diluted with water (48 mL) to furnish an orange, oily sludge. The crude product was extracted with EtOAc (25 mL) to furnish a suspension. The resulting solid was filtered, rinsed with EtOAc, and the filtrate was allowed to separate into two layers. The organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo. The crude material was dissolved in toluene (5 mL) and purified via medium pressure chromatography using a 20% to 100% gradient eluant of EtOAc in heptane on an NH 60 μM, size 400 column (Shoko Scientific Purif-Pack™) to give the title compound (1.489 g, 60.0%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.24 (d, J=6.4 Hz, 6H), 2.62 (t, J=4.9 Hz, 4H), 3.34-3.41 (m, 4H), 3.59 (s, 2H), 4.22-4.42 (m, 1H), 6.46 (d, J=7.8 Hz, 1H), 7.04-7.17 (m, 1H), 7.22 (td, J=10.0, 2.4 Hz, 1H), 7.40-7.44 (m, 1H), 7.49 (td, J=8.5, 6.8 Hz, 1H), 8.27 (d, J=5.9 Hz, 1H), 8.76 (s, 1H); ESI-MS m/z [M+H]+ 399.0.

Workup

  1. customto furnish an orange, oily sludge
  2. extractionThe crude product was extracted with EtOAc (25 mL)
  3. customto furnish a suspension
  4. filtrationThe resulting solid was filtered
  5. washrinsed with EtOAc
  6. customto separate into two layers
  7. washThe organic phase was washed with brine
  8. dry with materialdried over Na2SO4
  9. filtrationfiltered
  10. washrinsed with EtOAc
  11. customdried in vacuo
  12. dissolutionThe crude material was dissolved in toluene (5 mL)
  13. custompurified via medium pressure chromatography

Sources & evidence

ORD record
ord-fc9ce0ea715342a4814c5505556e0b93
Source dataset
uspto-grants-2015_11
Patent number
US09181249B2

Reaction notes

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