Diisopropylethylamine → N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide

HRID 527412Notes

Reaction equation

HRID 527412 reaction equation
[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:17][C:18]1[C:27]2[CH:26]=[N:25][C:24](S(C)=O)=[N:23][C:22]=2[N:21]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=2)[C:20](=[O:42])[CH:19]=1.CCN(C(C)C)C(C)C>C(O)(C)(C)C.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:24]1[N:25]=[CH:26][C:27]2[C:18]([CH3:17])=[CH:19][C:20](=[O:42])[N:21]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[C:22]=2[N:23]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 201362532-Methoxy-4-(4-methylpiperazin-1-yl)anilineHCID 86732024HCID 86732024, compound

Product 1

HCID 72201501N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamideYield 31%

Reagents, catalysts & solvents 2

HCID 6386tert-ButanolSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

To a suspension of 2-methoxy-4-(4-methylpiperazin-1-yl)aniline (Green Chempharm; 3.45 g, 15.57 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b) (4.59 g, 12.46 mmol) in anhydrous tert-butanol (40 mL) and dioxane (5 mL) at RT was added DIEA (4.33 mL, 24.92 mmol). The mixture was heated at 100° C. for 40 h. The reaction mixture was concentrated under reduced pressure (rotary evaporator) to remove the volatiles and the resulting crude residue was suspended in Et2O and filtered. The greenish-brown amorphous solid was washed with Et2O (3×50 mL) and this removed most of the remaining aniline starting material. The crude material was dry-packed on silica gel and purified on a silica gel column (1-20% MeOH in DCM) affording N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5) (2.03 g, 3.86 mmol, 31% yield) as a yellow amorphous solid. m/z (ESI, +ve ion) 526.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (1H, s), 8.80 (1H, s), 8.09 (1H, s), 7.88 (1H, d, J=8.2 Hz), 7.56 (1H, J=1.9 Hz), 7.50 (1H, t, 1=8.1 Hz), 7.27 (1H, d, J=8.8 Hz), 6.97 (1H, dt, J=6.9, 1.0 Hz), 6.52 (1H, d, J=2.5 Hz), 6.37-6.48 (1H, m), 6.29-6.35 (1H, m), 6.19-6.29 (1H, m), 6.01 (1H, br. s.), 5.71-5.80 (1H, m), 3.78 (3H, s), 3.02 (4H, br. s.), 2.46 (3H, s), 2.43 (4H, t, J=4.9 Hz), 2.22 (3H, s).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure (rotary evaporator)
  2. customto remove the volatiles
  3. filtrationfiltered
  4. washThe greenish-brown amorphous solid was washed with Et2O (3×50 mL)
  5. customthis removed most of the remaining aniline starting material
  6. custompurified on a silica gel column (1-20% MeOH in DCM)

Sources & evidence

ORD record
ord-10da0146600d4246b38c8333cdb083c6
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Reaction notes

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