1,3-Dichloroisoquinoline → 4-(3-Chloro-isoquinolin-1-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

HRID 2355572Notes

Reaction equation

HRID 2355572 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([Cl:12])[N:3]=1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O(C(C)(C)C)[K].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([Cl:12])[N:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]

Participants

7

Reactant 4

HCID 2986251,3-DichloroisoquinolineHCID 634876Binap, (A+-)-HCID 12682914-Amino-1-Boc-piperidineHCID 178418922HCID 178418922, compound

Product 1

HCID 866185584-(3-Chloro-isoquinolin-1-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

To a degassed solution of 1,3-dichloro-isoquinoline (3.00 g, 15.15 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.64 g, 18.18 mmol, 1.2 equiv; commercially available) in toluene (35 mL) was added KOtert-Bu (2.38 g, 21.21 mmol, 1.4 equiv), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.38 g, 0.61 mmol, 0.04 equiv) and tris(dibenzylideneacetone)-dipalladium(0) (0.31 g, 0.30 mmol, 0.02 equiv). The reaction mixture was stirred at 80° C. for 18 h, concentrated by evaporation under reduced pressure and the residue purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 1.14 g (21%) of the title compound. 1H NMR (300 MHz, DMSO): δ1.41-1.48 (m, 2H), 1.43 (s, 9H), 1.90-1.91 (m, 2H), 2.87-2.93 (m, 2H), 3.97-4.02 (m, 2H), 4.24-4.27 (m, 1H), 6.96 (s, 1H), 7.45-7.48 (m, 2H), 7.64-7.66 (m, 2H), 8.29 (d, J=8.4 Hz, 1H). MS (ISN): 360.0 [M−H]−.

Workup

  1. concentrationconcentrated by evaporation under reduced pressure
  2. customthe residue purified by silica column chromatography
  3. washeluting with a gradient of heptane (+1% triethylamine)/ethyl acetate providing 1.14 g (21%) of the title compound

Sources & evidence

ORD record
ord-e1c20018acb6446fa8e6af2b9e03effa
Source dataset
uspto-grants-2010_07
Patent number
US07754744B2

Reaction notes

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