Acryloyl chloride → N-(2-{(3S)-3-Dimethylaminopyrrolidin-1-yl}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamide

HRID 1842658Notes

Reaction equation

HRID 1842658 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:39])[C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:38])[CH2:9]1>C(Cl)Cl>[CH3:39][N:7]([CH3:6])[C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([NH:21][C:22]3[N:27]=[C:26]([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[CH:25]=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:38][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1

Participants

4

Reactant 2

HCID 13140Acryloyl chlorideHCID 866773054-[(3S)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine2×

Product 1

HCID 86677304N-(2-{(3S)-3-Dimethylaminopyrrolidin-1-yl}-4-methoxy-5-{[4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamideYield 36.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
0 °C

Procedure

A solution of acryloyl chloride (1M in CH2Cl2, 0.36 mL, 0.36 mmol) was added dropwise to a solution of 4-[(3S)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[4-(1-methy-lindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 148, 183 mg, 0.40 mmol) in CH2Cl2 (5 mL) at −10° C. over a period of 2 minutes under an atmosphere of N2. The resulting mixture was stirred at 0° C. for 10 minutes and was then allowed to warm to r.t. over 20 minutes. The mixture was then washed with sat. NaHCO3 (2 mL), dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 3-25% CH3OH in CH2Cl2 gave an oil which later crystallised. This solid was triturated and washed with EtOAc (3 mL) to give the title compound (67 mg, 33%) as a pale yellow solid; 1H NMR: 1.77 (1H, m), 2.08 (1H, s), 2.18 (6H, s), 2.72 (1H, m), 3.17 (1H, s), 3.21 (2H, d), 3.32-3.45 (1H, m), 3.87 (3H, s), 3.89 (3H, s), 5.70 (1H, d), 6.22 (1H, d), 6.48-6.58 (1H, m), 6.59 (1H, s), 7.20 (3H, m), 7.51 (1H, d), 7.76 (1H, s), 8.17 (1H, s), 8.28 (1H, d), 8.32 (1H, d), 8.39 (1H, s), 9.33 (1H, s); m/z: ES+ MH+ 512.7.

Workup

  1. temperatureto warm to r.t. over 20 minutes
  2. washThe mixture was then washed with sat. NaHCO3 (2 mL)
  3. dry with materialdried (MgSO4)
  4. concentrationconcentrated in vacuo
  5. customPurification by FCC
  6. washeluting with 3-25% CH3OH in CH2Cl2
  7. customgave an oil which
  8. customlater crystallised
  9. customThis solid was triturated
  10. washwashed with EtOAc (3 mL)

Sources & evidence

ORD record
ord-ee7a1ae18d7a486bb6fa3781dbb8b8a8
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

Loading…