Phthalide → 2-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,3-dihydro-1H-isoindol-1-one

HRID 734558Notes

Reaction equation

HRID 734558 reaction equation
C[Al](C)C.[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=3)[NH2:27])[CH2:18][CH2:17]2)[N:7]=1.[C:31]1([C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34]O1)=[O:32].C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O>ClCCl>[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[N:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]3[CH:25]=[C:26]([N:27]4[CH2:34][C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:31]4=[O:32])[CH:28]=[CH:29][CH:30]=3)[CH2:20][CH2:21]2)[N:7]=1

Participants

7

Reactant 5

HCID 6885PhthalideHCID 31297Methanesulfonyl chlorideHCID 81531DiisopropylethylamineHCID 16682925TrimethylaluminumHCID 498521053-(2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline

Product 1

HCID 574783532-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2,3-dihydro-1H-isoindol-1-oneYield 45%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of trimethylaluminum (2.0 M in hexane, 1 eq) was added slowly to a stirred solution of 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 1 eq) in dichloromethane (0.1 M) at 0° C. The reaction mixture was stirred for 15 min then a solution of phthalide (1 eq) in dichloromethane was added dropwise. The solution was stirred for 2 h at 0° C. then partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The organic phase was dried over sodium sulfate and the solution was concentrated under reduced pressure. The crude 2-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in dichloromethane then N,N-diisopropylethylamine (1 eq.) and methanesulfonyl chloride (1 eq.) were added successively. The reaction mixture was stirred for 2 hours at room temperature then partitioned between saturated aqueous ammonium chloride solution and dichloromethane. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (SPE cartridge, Silica) eluting with a gradient from dichloromethane-methanol (100:2) to (98:2) affording the title compound (yield 45%).

Workup

  1. stirringThe solution was stirred for 2 h at 0° C.
  2. customthen partitioned between saturated aqueous ammonium chloride solution and ethyl acetate
  3. dry with materialThe organic phase was dried over sodium sulfate
  4. concentrationthe solution was concentrated under reduced pressure
  5. dissolutionThe crude 2-(hydroxymethyl)-N-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)benzamide was dissolved in dichloromethane
  6. stirringThe reaction mixture was stirred for 2 hours at room temperature
  7. customthen partitioned between saturated aqueous ammonium chloride solution and dichloromethane
  8. dry with materialThe organic phase was dried over sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by chromatography (SPE cartridge, Silica)
  11. washeluting with a gradient from dichloromethane-methanol (100:2) to (98:2)

Sources & evidence

ORD record
ord-c8678d1a9d36447a99406dfd05dc6f98
Source dataset
uspto-grants-2009_09
Patent number
US07592346B2

Reaction notes

Loading…