Water → 5-Benzyl-6-(piperidin-4-yloxy)-isoquinoline

HRID 1022868Notes

Reaction equation

HRID 1022868 reaction equation
O.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:17](Br)=[C:18]3[C:23](=[CH:24][CH:25]=2)[CH:22]=[N:21][CH:20]=[CH:19]3)[CH2:11][CH2:10]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:33]([B-](F)(F)F)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[K+]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:33]([C:17]1[C:16]([O:15][CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][N:21]=[CH:22]2)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1

Participants

7

Reactant 4

HCID 962WaterHCID 10796Cesium carbonateHCID 23692459Potassium benzyltrifluoroboranuideHCID 576469744-(5-Bromo-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 576469395-Benzyl-6-(piperidin-4-yloxy)-isoquinolineYield 5.5%

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Procedure

0.3 mL of water were added to a solution of 81 mg (0.2 mmol) of 4-(5-bromo-isoquinoline-6-yloxy)-piperidin-1-carboxylic acid tert-butyl ester (11), 195 mg (0.6 mmol) of Cs2CO3, 14.6 mg (0.02 mmol) of Pd(dppf)Cl2 and 51 mg (0.26 mmol) of potassium benzyltrifluoroborate in 3 mL of THF. Argon was bubbled through the mixture for 10 minutes and then the reaction was heated to reflux for 16 h (incomplete conversion). After cooling to room temperature water and ethyl acetate were added. The organic layer was separated, dried over Na2SO4. After removal of the solvents 2 mL 5-6 N HCl in isopropanol was added. After 2 h the solvents were distilled off and the remainder was subjected twice to preparative HPLC to give 3.5 mg compound 29 as trifluoroacetate.

Workup

  1. customArgon was bubbled through the mixture for 10 minutes
  2. temperaturethe reaction was heated
  3. temperatureto reflux for 16 h (incomplete conversion)
  4. additionwere added
  5. customThe organic layer was separated
  6. dry with materialdried over Na2SO4
  7. customAfter removal of the solvents 2 mL 5-6 N HCl in isopropanol
  8. additionwas added
  9. distillationAfter 2 h the solvents were distilled off

Sources & evidence

ORD record
ord-27994516d3ac41088d1c5f6cc59732a3
Source dataset
uspto-grants-2014_05
Patent number
US08722671B2

Reaction notes

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