Triethylamine → N-{4-Methoxy-2-[1-methyl-3,6-dihydro-2H-pyridin-4-yl]-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamide

HRID 1842659Notes

Reaction equation

HRID 1842659 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=23)[CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>C1COCC1>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=34)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[CH:13]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 13140Acryloyl chloride2×HCID 866773074-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N'-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine2×

Product 1

HCID 86677306N-{4-Methoxy-2-[1-methyl-3,6-dihydro-2H-pyridin-4-yl]-5-[(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]phenyl}prop-2-enamideYield 25.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of acryloyl chloride (20 μL, 0.25 mmol) was added dropwise to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 150, 180 mg, 0.42 mmol) and triethylamine (73 lilt, 0.53 mmol) in THF (3 mL) at −5° C. over a period of 1 minute under an atmosphere of N2. The resulting mixture was stirred at 0° C. for 0.25 h. The reaction was judged to be incomplete so further acryloyl chloride (10 μL, 0.125 mmol) was added dropwise and the mixture was stirred at 0° C. for a further 15 minutes. The mixture was then concentrated in vacuo and the resulting residue was dissolved in CH2Cl2 (5 mL) plus a few drops of CH3OH. This solution was washed with sat. NaHCO3 (2 mL), dried (MgSO4) and filtered through a 1 g silica pad, eluting with 4:1 CH2Cl2—CH3OH. Eluent that contained desired product was concentrated in vacuo. Purification by FCC, eluting with 5-20% CH3OH in CH2Cl2 gave the title compound (31 mg, 14%) as a cream crystalline solid; 1H NMR: 2.33 (3H, s), 2.40 (2H, s), 2.57 (2H, d), 3.03 (2H, s), 3.89 (3H, s), 5.70 (2H, m), 6.17 (1H, m), 6.46 (1H, m), 6.88 (1H, s), 7.09 (1H, t), 7.32 (1H, d), 7.47 (1H, t), 8.12 (1H, s), 8.21 (1H, s), 8.39 (1H, d), 8.51 (1H, d), 8.81 (2H, m), 9.36 (1H, s); m/z: ES+ MH+ 482.

Workup

  1. additionwas added dropwise
  2. stirringthe mixture was stirred at 0° C. for a further 15 minutes
  3. concentrationThe mixture was then concentrated in vacuo
  4. dissolutionthe resulting residue was dissolved in CH2Cl2 (5 mL)
  5. washThis solution was washed with sat. NaHCO3 (2 mL)
  6. dry with materialdried (MgSO4)
  7. filtrationfiltered through a 1 g silica pad
  8. washeluting with 4:1 CH2Cl2—CH3OH
  9. concentrationwas concentrated in vacuo
  10. customPurification by FCC
  11. washeluting with 5-20% CH3OH in CH2Cl2

Sources & evidence

ORD record
ord-4a18788b334540fa97f35a5e0276be08
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

Loading…