Water → N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-(1-methyl-piperidin-4-yl)-benzamide

HRID 717080Notes

Reaction equation

HRID 717080 reaction equation
C([N:3]([CH2:14][CH3:15])[C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12])C.[Li]CCCC.C(C1[CH:39]=[CH:38][C:26]([C:27]([N:29]([CH3:37])[CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][CH:24]=1)#N.O>C1COCC1>[CH3:37][N:29]([CH:30]1[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]1)[C:27](=[O:28])[C:26]1[CH:38]=[CH:39][C:15]([C:14]2[NH:3][C:4](=[O:13])[C:5]3[C:6]([CH:12]=2)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=3)=[CH:24][CH:25]=1

Participants

6

Reactant 4

HCID 962WaterHCID 24024774-cyano-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamideHCID 15621069N,N-Diethyl-2,3-dimethylbenzamideHCID 178418339Butyllithium

Product 1

HCID 71735152N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-(1-methyl-piperidin-4-yl)-benzamideYield 44.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

To a solution of N,N-diethyl-2,3-dimethyl-benzamide (578 mg, 2.82 mmol) in anhydrous THF (3 mL) under N2 at −78° C. was added dropwise n-BuLi (2.5M in n-hexanes, 2.4 mL, 5.92 mmol) to give a deep red solution. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was transferred dropwise, via syringe, to a reaction vessel containing 4-cyano-N-methyl-N-(1-methyl-piperidin-4-yl)-benzamide (725 mg, 2.82 mmol) in anhydrous THF (5 mL) at −78° C. and under N2. The reaction mixture was stirred at −78° C. for 3.5 h. Water (10 mL) was added and the reaction mixture was extracted with EtOAc (10 mL) and CH2Cl2 (10 mL). The combined organic layers concentrated in vacuo and the resultant solid was triturated with 2:1 isohexane/EtOAc, filtered and dried in vacuo. The crude material was purified by silica gel column chromatography, eluting with CH2Cl2 and increasing the polarity to 15% MeOH/CH2Cl2 to afford N-methyl-4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-N-(1-methyl-piperidin-4-yl)-benzamide as a white solid (487 mg, 44%).

Workup

  1. customto give a deep red solution
  2. customThe reaction mixture was transferred dropwise, via syringe, to a reaction vessel
  3. stirringThe reaction mixture was stirred at −78° C. for 3.5 h
  4. extractionthe reaction mixture was extracted with EtOAc (10 mL) and CH2Cl2 (10 mL)
  5. concentrationThe combined organic layers concentrated in vacuo
  6. customthe resultant solid was triturated with 2:1 isohexane/EtOAc
  7. filtrationfiltered
  8. customdried in vacuo
  9. customThe crude material was purified by silica gel column chromatography
  10. washeluting with CH2Cl2
  11. temperatureincreasing the polarity to 15% MeOH/CH2Cl2

Sources & evidence

ORD record
ord-e80ed2a6021e4e23b9ceade4a34c0f1d
Source dataset
uspto-grants-2015_11
Patent number
US09193689B2

Reaction notes

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