Acryloyl chloride → N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-[1-methyl-3,6-dihydro-2H-pyridin-4-yl]phenyl)prop-2-enamide

HRID 1842615Notes

Reaction equation

HRID 1842615 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH:27]=3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1

Participants

5

Reactant 3

HCID 13140Acryloyl chlorideHCID 81531DiisopropylethylamineHCID 86677231N'-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine2×

Product 1

HCID 86677230N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-[1-methyl-3,6-dihydro-2H-pyridin-4-yl]phenyl)prop-2-enamideYield 32.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Acryloyl chloride (0.217 mL, 1M in THF, 0.22 mmol) was added dropwise to a slurry of N′-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)benzene-1,3-diamine (Intermediate 7, 100 mg, 0.22 mmol) and DIPEA (0.057 mL, 0.33 mmol) in THF (3 mL) at −5° C. over a period of 1 minute under N2. The resulting mixture was stirred at 0° C. for 15 minutes and then concentrated in vacuo. The residue was dissolved in CH2Cl2 (5 mL) plus a few drops of CH3OH, and washed with sat. NaHCO3 (2 mL). The organic solution was then dried (MgSO4) and loaded onto silica in vacuo. Purification by FCC, eluting with 5-25% CH3OH in CH2Cl2 and concentration of appropriate fractions in vacuo provided a residue that was washed with CH3OH (0.3 mL) and dried in air to give the title compound (37 mg, 31%) as a beige crystalline solid. 1H NMR: 2.28 (3H, s), 2.38 (2H, m), 2.55 (2H, m), 2.98 (2H, d), 3.85 (3H, s), 5.6-5.72 (2H, m), 6.15 (1H, m), 6.41 (1H, m), 6.88 (1H, s), 7.10 (1H, t), 7.18 (1H, t), 7.47 (1H, d), 7.98 (1H, s), 8.33 (1H, s), 8.36 (1H, d), 8.42 (1H, s), 8.49 (1H, s), 9.29 (1H, s), 11.86 (1H, s); m/z: ES+ MH+ 515.

Workup

  1. concentrationconcentrated in vacuo
  2. dissolutionThe residue was dissolved in CH2Cl2 (5 mL)
  3. washa few drops of CH3OH, and washed with sat. NaHCO3 (2 mL)
  4. dry with materialThe organic solution was then dried (MgSO4)
  5. customPurification by FCC
  6. washeluting with 5-25% CH3OH in CH2Cl2 and concentration of appropriate fractions in vacuo
  7. customprovided a residue that
  8. washwas washed with CH3OH (0.3 mL)
  9. customdried in air

Sources & evidence

ORD record
ord-314476a549924f92a80f0e56f0f8a48c
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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