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

HRID 527430Notes

Reaction equation

HRID 527430 reaction equation
[CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8](S(C)=O)=[N:7][C:6]=2[N:5]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:18]=[CH:19][CH:20]=2)[C:4](=[O:26])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[CH3:1][C:2]1[C:11]2[CH:10]=[N:9][C:8]([NH:38][C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:40][CH:39]=3)=[N:7][C:6]=2[N:5]([C:15]2[CH:16]=[C:17]([NH:21][C:22](=[O:25])[CH:23]=[CH2:24])[CH:18]=[CH:19][CH:20]=2)[C:4](=[O:26])[CH:3]=1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 7372534-(4-Methylpiperazin-1-yl)anilineHCID 86732024N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide

Product 1

HCID 78318941N-(3-(5-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamideYield 19.3%

Reagents, catalysts & solvents 1

HCID 6386tert-ButanolSolvent

Conditions

Temperature
100 °C

Procedure

A microwave tube was charged with N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b; 210 mg, 0.57 mmol), 4-(4-methylpiperazino)aniline (136 mg, 0.71 mmol) and DIEA (0.20 mL, 1.14 mmol) in tert-butanol (5.5 mL). The tube was sealed and the mixture was heated to 100° C. for 3 d. The mixture was concentrated and then the brown solid was suspended in Et2O and collected by filtration. The brown solid was washed with Et2O to afford 270 mg of crude material. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0-20% MeOH in DCM. This enriched product was repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water). The product containing fractions were combined and concentrated. A saturated solution of aqueous NaHCO3 was added and the mixture was extracted with 3:1 CHCl3/IPA (3×30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to provide N-(3-(5-methyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (52 mg, 0.11 mmol, 18% yield) as a yellow solid. m/z (ESI, +ve ion) 496.1 (M+H)+. NMR (400 MHz, DMSO-d6) δ ppm 10.35 (1H, s), 8.82 (1H, s), 7.93 (1H, d, J=8.61 Hz), 7.57-7.56 (1H, m), 7.53 (1H, t, J=8.12 Hz), 7.17-7.19 (2H, m), 6.95-7.02 (1H, m), 6.53-6.56 (1H, m), 6.37-6.48 (1H, m), 6.31 (1H, d, J=0.39 Hz), 6.21-6.28 (1H, m), 5.72-5.80 (1H, m), 2.91-3.02 (4H, m), 2.46 (3H, s), 2.39-2.44 (4H, m) 2.21 (3H, s).

Workup

  1. customThe tube was sealed
  2. concentrationThe mixture was concentrated
  3. filtrationcollected by filtration
  4. washThe brown solid was washed with Et2O
  5. customto afford 270 mg of crude material
  6. customThe crude material was absorbed onto a plug of silica gel
  7. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (12 g)
  8. washeluting with a gradient of 0-20% MeOH in DCM
  9. customThis enriched product was repurified on a Gilson preparatory HPLC (Gemini Phenomenex; 30×150 mm, 5μ, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water)
  10. additionThe product containing fractions
  11. concentrationconcentrated
  12. additionA saturated solution of aqueous NaHCO3 was added
  13. extractionthe mixture was extracted with 3:1 CHCl3/IPA (3×30 mL)
  14. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  15. filtrationfiltered
  16. concentrationconcentrated

Sources & evidence

ORD record
ord-1f9b104bb4b549a6b9b6808465745639
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Reaction notes

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