Diisopropylethylamine → 5-Chloro-4-(1H-indol-3-yl)-N-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidin-2-amine

HRID 1256056Notes

Reaction equation

HRID 1256056 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:30])=[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.CCN(C(C)C)C(C)C>C(O)CCCC.C(Cl)Cl.CO>[Cl:30][C:18]1[C:19]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[N:20][C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([N:5]3[CH2:6][CH2:7][CH:2]([N:1]4[CH2:45][CH2:44][N:43]([CH3:48])[CH2:41][CH2:40]4)[CH2:3][CH2:4]3)=[CH:9][C:10]=2[O:31][CH3:32])=[N:16][CH:17]=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 566553745-Chloro-4-(1H-indol-3-yl)-N-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidin-2-amineYield 53%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 62761-PentanolSolventHCID 6344DichloromethaneSolvent

Procedure

As an alternate procedure to the compound described in Example 10, a solution of 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) (3.67 g, 13.89 mmol), 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27) (4.23 g, 13.89 mmol), and PTSA monohydrate (6.6 g, 34.7 mmol) in n-pentanol (56 mL) was heated in an oil bath at 140° C. overnight. The reaction mixture was cooled to RT. Hunig's base (10 mL) was added. 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 (3.9 g, 53% yield).

Workup

  1. concentrationConcentration in vacuo
  2. customremoved the solvent
  3. washeluted with 10% MeOH, 1% NH4OH in CH2Cl2
  4. concentrationThe collected fractions were concentrated
  5. customthe residue was triturated with diethyl ether
  6. filtrationFiltration
  7. customafforded the solid and it
  8. concentrationConcentration in vacuo
  9. filtrationto 70 mL and filtration

Sources & evidence

ORD record
ord-528cb122924343a7891cccbe674eb3ca
Source dataset
uspto-grants-2013_06
Patent number
US08461170B2

Reaction notes

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