Diisopropylamine → 4-[4-(5-Bromo-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester

HRID 717081Notes

Reaction equation

HRID 717081 reaction equation
C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[C:15]([CH3:27])=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([N:19]([CH2:22][CH3:23])CC)=[O:18].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46]C(C#N)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]>C1COCC1>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:23]([C:22]3[NH:19][C:17](=[O:18])[C:16]4[C:15]([CH:27]=3)=[C:14]([Br:13])[CH:26]=[CH:25][CH:24]=4)=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29]

Participants

6

Reactant 4

HCID 7912DiisopropylamineHCID 183822571-Boc-4-(4-Cyanobenzyl)piperazineHCID 655438803-bromo-N,N-diethyl-2-methyl-benzamideHCID 178418339Butyllithium

Product 1

HCID 717351534-[4-(5-Bromo-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl esterYield 66.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
-78 °C

Procedure

To a stirred solution of N,N-diisopropylamine (1.56 mL, 11.10 mmol) in THF (5 mL) under N2 at −78° C. was added n-BuLi (2.5M in hexanes) (4.44 mL, 11.10 mmol) and the reaction stirred at −78° C. for 20 min, after which time a solution of 3-bromo-N,N-diethyl-2-methyl-benzamide (1 g, 3.70 mmol) in THF (5 mL) was added, and the reaction stirred at −78° C. for 30 minutes. A solution of 4-(4-cyano-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (1.15 g, 3.70 mmol) in THF (5 mL) was added and the reaction stirred at −78° C. for 2 h. The reaction was quenched with ice and water, EtOAc added and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 100% EtOAc to afford 4-[4-(5-bromo-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester as a cream solid (1.22 g, 66%).

Workup

  1. stirringthe reaction stirred at −78° C. for 30 minutes
  2. stirringthe reaction stirred at −78° C. for 2 h
  3. customThe reaction was quenched with ice and water, EtOAc
  4. additionadded
  5. concentrationconcentrated in vacuo
  6. customThe crude material was purified by silica gel column chromatography
  7. washeluting with isohexane
  8. temperatureincreasing the polarity to 100% EtOAc

Sources & evidence

ORD record
ord-a8caf5504b0a463abffcb360a16ff69a
Source dataset
uspto-grants-2015_11
Patent number
US09193689B2

Reaction notes

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