Diisopropylethylamine → 4-(1H-Indol-3-yl)-N-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-5-methylpyrimidin-2-amine

HRID 1256055Notes

Reaction equation

HRID 1256055 reaction equation
[NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:20]=[C:19]([C:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[NH:23][CH:22]=4)[C:18](Cl)=[CH:17][N:16]=3)=[C:10]([O:31][CH3:32])[CH:9]=2)[CH2:4][C@H:3]1F.COC1C=[C:41]([N:43]2[CH2:48]CC(N3CCN(C)CC3)[CH2:45][CH2:44]2)[CH:40]=CC=1N.[CH3:56]CN(C(C)C)C(C)C>C(O)CCCC.C(Cl)Cl.CO>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([C:19]2[C:18]([CH3:56])=[CH:17][N:16]=[C:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([N:5]4[CH2:6][CH2:7][CH:2]([N:1]5[CH2:45][CH2:44][N:43]([CH3:48])[CH2:41][CH2:40]5)[CH2:3][CH2:4]4)=[CH:9][C:10]=3[O:31][CH3:32])[N:20]=2)=[CH:22]1

Participants

7

Reactant 3

HCID 81531DiisopropylethylamineHCID 457899912-Methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline2×HCID 66710159(trans)-N-(4-(4-amino-3-fluoropiperidin-1-yl)-2-methoxyphenyl)-5-chloro-4-(1H-indol-3-yl)pyrimidin-2-amine2×

Product 1

HCID 566553734-(1H-Indol-3-yl)-N-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-5-methylpyrimidin-2-amineYield 54%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 62761-PentanolSolventHCID 6344DichloromethaneSolvent

Procedure

As an alternate procedure to the compound described in Example 9, a solution of 3-(2-chloro-5-methylpyrimidin-4-yl)-1H-indole (INTERMEDIATE 1, 3.39 g, 13.9 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27, 4.23 g, 13.89 mmol), and PTSA monohydrate (6.61 g, 34.74 mmol) in n-pentanol (56 mL) was heated in an oil bath at 140° C. overnight. The reaction mixture was allowed to cool to RT. Hunig's base (10 mL) was added. Solvent was removed in vacuo and to the residue was added methanol (500 mL). Silica gel (120 g) was added to the mixture. Concentration in vacuo removed the solvent, and the residue was loaded to silica gel column and eluted with 10% MeOH, 1% NH4OH in CH2Cl2. The collected fractions were concentrated and the residue was triturated with diethyl ether. Filtration afforded the solid and it was dissolved in a mixture of CH2Cl2 (100 mL) and MeOH (500 mL). Concentration in vacuo reduced the solvent volume to 70 mL and filtration yielded the solid as the title compound (3.8 g, 54% yield).

Workup

  1. customSolvent was removed in vacuo and to the residue
  2. additionwas added methanol (500 mL)
  3. additionSilica gel (120 g) was added to the mixture
  4. concentrationConcentration in vacuo
  5. customremoved the solvent
  6. washeluted with 10% MeOH, 1% NH4OH in CH2Cl2
  7. concentrationThe collected fractions were concentrated
  8. customthe residue was triturated with diethyl ether
  9. filtrationFiltration
  10. customafforded the solid and it
  11. concentrationConcentration in vacuo
  12. filtrationto 70 mL and filtration

Sources & evidence

ORD record
ord-07996d46421848ada6e00503484f0e0c
Source dataset
uspto-grants-2013_06
Patent number
US08461170B2

Reaction notes

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