Sodium Carbonate → Tert-butyl 4-{5-[2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyridin-2-yl}piperazine-1-carboxylate

HRID 577521Notes

Reaction equation

HRID 577521 reaction equation
[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:31])[C:20]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:21][C:22]=3Br)[C:17]2=[O:32])=[C:13]([CH3:33])[CH:12]=[C:11]([CH3:34])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:43]2[CH:44]=[CH:45][C:46]([N:49]3[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]3)=[N:47][CH:48]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].C(Cl)Cl.O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:31])[C:20]([O:27][CH:28]([CH3:30])[CH3:29])=[CH:21][C:22]=3[C:43]3[CH:44]=[CH:45][C:46]([N:49]4[CH2:54][CH2:53][N:52]([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:51][CH2:50]4)=[N:47][CH:48]=3)[C:17]2=[O:32])=[C:13]([CH3:33])[CH:12]=[C:11]([CH3:34])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 3

HCID 10340Sodium CarbonateHCID 16217947Tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylateHCID 867237472-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one

Product 1

HCID 86723748Tert-butyl 4-{5-[2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyridin-2-yl}piperazine-1-carboxylateYield 58%

Reagents, catalysts & solvents 2

HCID 178478472(1,1'-Bis(diphenylphosphino)ferrocene)dichloropalladium-dichloromethane (1:1)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (77e, 60 mg, 0.110 mmol), tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate (64 mg, 0.164 mmol), Na2CO3 (200 μL, 0.400 mmol, 2 M solution), PdCl2(dPPf)-DCM (9 mg, 0.011 mmol), and 1,4-dioxane (2 mL) was stirred at 120° C. in microwave for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was separated, washed with brine (1×20 mL), dried over sodium sulfate, concentrated under vacuum, and purified by column chromatography (0-100% EtOAc/heptanes) to give tert-butyl 4-{5-[2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinolin-5-yl]pyridin-2-yl}piperazine-1-carboxylate (77f, 46 mg, 58% yield) as a solid.

Workup

  1. temperatureAfter cooling to room temperature
  2. customthe reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL)
  3. customThe organic phase was separated
  4. washwashed with brine (1×20 mL)
  5. dry with materialdried over sodium sulfate
  6. concentrationconcentrated under vacuum
  7. custompurified by column chromatography (0-100% EtOAc/heptanes)

Sources & evidence

ORD record
ord-c138c88880e04d2a9a729dcaa1f5fa79
Source dataset
uspto-grants-2015_05
Patent number
US09040515B2

Reaction notes

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