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

HRID 1842645Notes

Reaction equation

HRID 1842645 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:39])[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:24]([CH3:37])=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH2:38])[CH2:9]1>C(Cl)Cl.CO.CC#N>[CH3:39][N:7]([CH3:6])[CH:8]1[CH2:9][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:24]([CH3:37])=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH:38][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11]1

Participants

6

Reactant 2

HCID 13140Acryloyl chlorideHCID 866772814-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine2×

Product 1

HCID 86677280N-(2-{3-Dimethylaminoazetidin-1-yl}-4-methoxy-5-{[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamideYield 31.4%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

A solution of acryloyl chloride (0.024 mL, 0.30 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 114, 130 mg, 0.28 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/brine bath to approx 0° C. The mixture was stirred for 1 h, then diluted with CH2Cl2 (50 mL) and CH3OH (to fully dissolve suspension that had formed). This solution was then washed with sat. NaHCO3 (100 mL) which had been diluted with water (10 mL). The aqueous wash solution was then extracted with CH2Cl2 (2×50 mL) and the combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 gave a dark brown solid. This solid was heated in CH3CN and isolated by vacuum filtration, to give the title compound (45 mg, 31%) as a pale brown solid. The mother liquors were concentrated in vacuo and also retained as a second batch of the title compound (30 mg, 21%) as a darker brown solid. Total yield of title compound=75 mg, 52%; 1H NMR: 2.08 (6H, s), 2.34 (3H, s), 3-3.1 (1H, m), 3.55 (2H, t), 3.83 (3H, s), 3.88 (3H, s), 3.93 (2H, t), 5.65 (1H, dd), 6.15 (1H, dd), 6.24 (1H, s), 6.44 (1H, dd), 7.13 (1H, t), 7.21 (1H, t), 7.47 (1H, d), 7.66 (1H, s), 7.81 (1H, s), 7.99 (1H, s), 8.17 (1H, s), 8.37 (1H, d), 9.19 (1H, s); m/z: ES+ MH+ 512.14.

Workup

  1. customhad formed)
  2. washThis solution was then washed with sat. NaHCO3 (100 mL) which
  3. additionhad been diluted with water (10 mL)
  4. extractionThe aqueous wash solution was then extracted with CH2Cl2 (2×50 mL)
  5. dry with materialthe combined organic solutions were dried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. customPurification by FCC
  8. washeluting with 0-5% 7N methanolic ammonia in CH2Cl2
  9. customgave a dark brown solid
  10. customisolated by vacuum filtration

Sources & evidence

ORD record
ord-e1ed7264efd940048562012cdc7f239c
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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