Acryloyl chloride → N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)-2-propenamide

HRID 527407Notes

Reaction equation

HRID 527407 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][C:20]=4[O:32][CH3:33])[N:16]=[CH:17][C:12]=3[CH:11]=[CH:10][C:9]2=[O:34])[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:44](Cl)(=[O:47])[CH:45]=[CH2:46].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[CH3:33][O:32][C:20]1[CH:21]=[C:22]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[CH:23]=[CH:24][C:19]=1[NH:18][C:15]1[N:16]=[CH:17][C:12]2[CH:11]=[CH:10][C:9](=[O:34])[N:8]([C:4]3[CH:3]=[C:2]([NH:1][C:44](=[O:47])[CH:45]=[CH2:46])[CH:7]=[CH:6][CH:5]=3)[C:13]=2[N:14]=1

Participants

7

Reactant 4

HCID 13140Acryloyl chloride3×HCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 867320178-(3-aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one

Product 1

HCID 72201349N-(3-(2-((2-methoxy-4-(4-methyl-1-piperazinyl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)-2-propenamide

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

8-(3-Aminophenyl)-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (1b) (2.17 g, 4.74 mmol) in DCM (30 mL) and THF (30 mL) at 0° C. was treated with DIEA (1.66 mL, 9.49 mmol) and acryloyl chloride (0.46 mL, 5.69 mmol) dropwise over 15 min and stirred at 0° C. After 1.5 h, additional acryloyl chloride (0.20 mL) was added slowly over 10 min then the suspension was stirred at 0° C. for another 20 min. Additional acryloyl chloride (0.1 mL) was added and the reaction mixture stirred another 15 min. The reaction mixture was treated with a saturated solution of NaHCO3, extracted with DCM (5×100 mL), dried over Na2SO4, filtered and concentrated. Purification of the crude residue on a silica gel column (1-20% MeOH in DCM) afforded the desired product as a yellow solid. This material was treated with 20 mL of EtOH and the slurry was filtered through a medium porosity sintered glass frit and washed with additional EtOH (10 mL) and Et2O (3×10 mL) affording N-(3-(2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-7-oxopyrido[2,3-d]pyrimidin-8(71-1)-yl)phenyl)acrylamide (1) (680 mg, 1.33 mmol, 28% yield) as a yellow solid after drying overnight at 36° C. in a vacuum oven. m/z (ESI, +ve ion) 512.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.35 (1H, s), 8.75 (1H, br. s.), 8.17 (1H, br. s.), 7.92 (2H, d, J=9.4 Hz), 7.59 (1H, br. s.), 7.52 (1H, t, 0.1=8.1 Hz), 7.29 (1H, d, J=9.0 Hz), 7.01 (1H, d, J=8.0 Hz), 6.54 (1H, br. s.), 6.37-6.50 (2H, m), 6.20-6.33 (1H, m), 6.03 (1H, br. s.), 5.77 (1H, d, J=10.0 Hz), 3.78 (3H, s), 3.07 (4H, br. s.), 2.43 (3H, s), 2.34 (4H, br. s.).

Workup

  1. stirringthe suspension was stirred at 0° C. for another 20 min
  2. stirringthe reaction mixture stirred another 15 min
  3. extractionextracted with DCM (5×100 mL)
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customPurification of the crude residue on a silica gel column (1-20% MeOH in DCM)

Sources & evidence

ORD record
ord-e83890d61ec748639c0ff3b811ad4281
Source dataset
uspto-grants-2016_05
Patent number
US09346801B2

Reaction notes

Loading…