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

HRID 1842630Notes

Reaction equation

HRID 1842630 reaction equation
[C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:40])[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)[C:25]([CH3:38])=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH2:39])[CH2:9]1.CCN(C(C)C)C(C)C>C1COCC1.O.C(Cl)Cl.C(OCC)C>[CH3:40][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)[C:25]([CH3:38])=[CH:24][N:23]=3)=[CH:15][C:14]=2[NH:39][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:9]1

Participants

8

Reactant 3

HCID 13140Acryloyl chlorideHCID 81531DiisopropylethylamineHCID 866772564-[(3R)-3-Dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,3-diamine2×

Product 1

HCID 86677255N-(2-{(3R)-3-Dimethylaminopyrrolidin-1-yl}-4-methoxy-5-{[5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}phenyl)prop-2-enamideYield 47.7%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

Acryloyl chloride (0.043 mL, 1M in THF, 0.53 mmol) was added dropwise to a mixture of 4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxy-N-[5-methyl-4-(1-methylindol-3-yl)-pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 83, 252 mg, 0.53 mmol) and DIPEA (0.103 mL, 0.59 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 material was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL). The resulting solution was washed with water and sat. brine. The aqueous washes were re-extracted three times using CH2Cl2. The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% CH3OH in CH2Cl2 gave a yellow dry film after concentration of the appropriate fractions in vacuo. This material was dissolved in CH2Cl2 and the resulting solution was diluted with diethyl ether. The resulting mixture was stirred for 30 minutes and then concentrated in vacuo to give the title compound (133 mg, 47%) as a yellow solid; 1H NMR: 1.67-1.81 (1H, m), 2.09 (1H, s), 2.19 (6H, s), 2.35 (3H, s), 2.72 (1H, s), 3.20 (3H, t), 3.30-3.43 (1H, m), 3.84 (3H, s), 3.89 (3H, s), 5.66 (1H, d), 6.16 (1H, d), 6.49 (1H, dd), 6.55 (1H, s), 7.12 (1H, t), 7.22 (1H, t), 7.48 (1H, d), 7.75 (1H, s), 7.92 (1H, s), 8.02 (1H, s), 8.18 (1H, s), 8.40 (1H, d), 9.32 (1H, s); m/z: ES+ MH+ 526.66.

Workup

  1. temperatureto warm to r.t
  2. concentrationconcentrated in vacuo
  3. dissolutionThe resulting material 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. extractionThe aqueous washes were re-extracted three times
  6. dry with materialThe combined organic solutions were dried (MgSO4)
  7. concentrationconcentrated in vacuo
  8. customPurification by FCC
  9. washeluting with 1-8% CH3OH in CH2Cl2
  10. customgave a yellow dry film after concentration of the appropriate fractions in vacuo
  11. stirringThe resulting mixture was stirred for 30 minutes
  12. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-3e4ba29cbc754efabe69abe9b396a43c
Source dataset
uspto-grants-2015_02
Patent number
US08946235B2

Reaction notes

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