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

HRID 1842627Notes

Reaction equation

HRID 1842627 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]([N:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1.O.C(Cl)Cl>[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]([N:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1

Participants

7

Reactant 3

HCID 13140Acryloyl chlorideHCID 81531DiisopropylethylamineHCID 73292722N'-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine2×

Product 1

HCID 73292363N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamideYield 42%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Acryloyl chloride (0.621 mL, 1M in THF, 0.62 mmol) was added dropwise to N′-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 74, 288 mg, 0.62 mmol) and DIPEA (0.119 mL, 0.68 mmol) in THF (15 mL) at 0° C. under N2. The resulting suspension was stirred at 0° C. for 1 h, and then allowed to warm to r.t. The mixture was then diluted with water (15 mL) and concentrated in vacuo. The resulting residue was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL) and the resulting solution was washed with water and sat. brine. The organic solution was dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% 7M methanolic ammonia in CH2Cl2 gave crude product as a pale brown dry film. This material was dissolved in CH2Cl2 and a beige solid precipitated from the solution. The solution was diluted with diethyl ether and then mixture filtered. The collected solid was washed with further diethyl ether and dried to give the title compound (134 mg, 42%) as a beige solid; 1H NMR: 2.27 (3H, s), 2.53-2.59 (4H, m), 2.87-2.94 (4H, m), 3.79 (3H, s), 5.70 (1H, d), 6.17 (1H, dd), 6.60 (1H, dd), 6.89 (1H, s), 7.01 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 8.20 (1H, s), 8.27 (1H, d), 8.35 (1H, s), 8.43 (1H, s), 8.49 (1H, d), 8.96 (1H, s), 11.81 (1H, s); m/z: ES+ MH+ 518.51.

Workup

  1. temperatureto warm to r.t
  2. concentrationconcentrated in vacuo
  3. dissolutionThe resulting residue was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL)
  4. washthe resulting solution was washed with water and sat. brine
  5. dry with materialThe organic solution was dried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customPurification by FCC
  8. washeluting with 1-8% 7M methanolic ammonia in CH2Cl2
  9. customgave crude product as a pale brown dry film
  10. customa beige solid precipitated from the solution
  11. additionThe solution was diluted with diethyl ether
  12. filtrationmixture filtered
  13. washThe collected solid was washed with further diethyl ether
  14. customdried

Sources & evidence

ORD record
ord-835f259ebdba4dbda67f90ed0bee8cd1
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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