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

HRID 527437Notes

Reaction equation

HRID 527437 reaction equation
[CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH: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.C(N(C(C)C)CC)(C)C.C(O)(C(F)(F)F)=O.CC#N>C(O)(C)(C)C.C(O)(C(F)(F)F)=O.O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]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

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 21924481TFA acetonitrileHCID 574160862-Methoxy-4-(1-methylpiperidin-4-yl)anilineHCID 86732024HCID 86732024, compound

Product 1

HCID 78319001N-(3-(2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamideYield 5.2%

Reagents, catalysts & solvents 2

HCID 6386tert-ButanolSolventHCID 22392675Trifluoroacetic acid waterSolvent

Conditions

Temperature
100 °C

Procedure

To a suspension of 2-methoxy-4-(1-methylpiperidin-4-yl)aniline (19b, 363 mg, 1.65 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b, 300 mg, 0.81 mmol) in tert-butanol (15 mL) at RT was added diisopropylethylamine (0.43 mL, 2.443 mmol). The mixture was heated at 100° C. for 48 h. The reaction mixture was concentrated on the rotovap and the crude residue was suspended in Et2O and filtered. The resulting light yellow amorphous solid was washed with Et2O (3×50 mL) and chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column, using a gradient of 0-15% MeOH in DCM) affording enriched product. It was repurifed on a Gilson (Gemini Phenomenex; 30×150 mm, 5 u, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water), concentrated in the genevac overnight and then passed through a Silicycle SPE-R66030B-20× SiliaSep OT, 5 g/25 mL carbonate column using 20% MeOH/DCM to remove any residual salt then dried under vacuum affording N-(3-(2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (22 mg) as a light yellow solid. m/z (ESI, +ve ion) 525.0 (M+H)+. 1H NMR (400 MHz, DMSO6) δ ppm 10.34 (1H, s), 8.85 (1H, s), 8.16 (1H, s), 7.85 (1H, d, J=9.2 Hz), 7.63 (1H, s), 7.48-7.56 (1H, m), 7.36 (1H, d, J=8.4 Hz), 7.00 (1H, d, J=7.8 Hz), 6.80 (1H, d, J=1.4 Hz), 6.38-6.47 (1H, In), 6.30-6.38 (2H, m), 6.19-6.29 (1H, m), 5.70-5.78 (1H, m), 3.80 (3H, s), 2.84 (2H, d, J=11.2 Hz), 2.47 (3H, s), 2.25-2.36 (1H, m), 2.19 (3H, s), 1.92 (2H, td, J=11.1, 3.7 Hz), 1.52-1.69 (4H, m).

Workup

  1. concentrationThe reaction mixture was concentrated on the rotovap
  2. filtrationfiltered
  3. washThe resulting light yellow amorphous solid was washed with Et2O (3×50 mL)
  4. customchromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column
  5. customaffording
  6. concentrationconcentrated in the genevac overnight
  7. customto remove any residual salt
  8. customthen dried under vacuum

Sources & evidence

ORD record
ord-b2e0b752afe84c99a722078c3794826d
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Reaction notes

Loading…