N,N-Diethyl-2,3-dimethylbenzamide → 4-({Methyl-[4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester

HRID 717078Notes

Reaction equation

HRID 717078 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:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]([C:37](=[O:46])[C:38]2[CH:43]=[CH:42]C(C#N)=[CH:40][CH:39]=2)[CH3:36])[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][N:35]([CH3:36])[C:37](=[O:46])[C:38]2[CH:39]=[CH:40][C:15]([C:14]3[NH:3][C:4](=[O:13])[C:5]4[C:6]([CH:12]=3)=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=4)=[CH:42][CH:43]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]

Participants

5

Reactant 3

HCID 15621069N,N-Diethyl-2,3-dimethylbenzamideHCID 1179927504-{[(4-Cyano-benzoyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl esterHCID 178418339Butyllithium

Product 1

HCID 717375334-({Methyl-[4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl esterYield 36%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-78 °C

Procedure

N,N-Diethyl-2,3-dimethyl-benzamide (200 mg, 0.97 mmol) was dissolved in anhydrous THF (4 mL) under a N2 and cooled to −78° C. n-BuLi (2.5M in n-hexanes, 0.82 mL, 2.04 mmol) was added dropwise to yield a deep red coloured solution and the reaction mixture was stirred at −78° C. for 30 minutes. 4-{[(4-Cyano-benzoyl)-methyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (348 mg, 0.97 mmol) was dissolved in anhydrous THF (4 mL) and added dropwise, and the reaction stirred at −78° C. for 2 h. The reaction mixture was quenched with ice/water, allowed to warm to RT and extracted with CH2Cl2 and EtOAc. The combined organic phase was passed through a phase separation cartridge and concentrated in vacuo. The crude compound was triturated with isohexane/diethyl ether (80:20), the solid filtered and dried in vacuo to give 4-({methyl-[4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzoyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester as a light beige solid (171 mg, 36%).

Workup

  1. additionwas added dropwise
  2. customto yield a deep red coloured solution
  3. additionadded dropwise
  4. stirringthe reaction stirred at −78° C. for 2 h
  5. customThe reaction mixture was quenched with ice/water
  6. temperatureto warm to RT
  7. extractionextracted with CH2Cl2 and EtOAc
  8. customThe combined organic phase was passed through a phase separation cartridge
  9. concentrationconcentrated in vacuo
  10. customThe crude compound was triturated with isohexane/diethyl ether (80:20)
  11. filtrationthe solid filtered
  12. customdried in vacuo

Sources & evidence

ORD record
ord-4513048ea1f24f6bb041614e4c8c32d7
Source dataset
uspto-grants-2015_11
Patent number
US09193689B2

Reaction notes

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