Potassium Phosphate, Tribasic → (4-(1-Methyl-5-(4-(1-methylazetidin-3-yl)phenylamino)-6-oxo-1,6-dihydro-pyridin-3-yl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-3-yl)methyl Acetate

HRID 1022034Notes

Reaction equation

HRID 1022034 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:20][N:19]([CH3:21])[CH2:18]3)=[CH:13]N=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[N:29][CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1)(=[O:24])[CH3:23].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[C:64]([O-])(=O)C.[Na+]>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].C(#N)C.O>[C:22]([O:25][CH2:26][C:27]1[C:28]([N:42]2[CH2:54][CH2:53][N:45]3[C:46]4[CH2:47][CH2:48][CH2:49][CH2:50][C:51]=4[CH:52]=[C:44]3[C:43]2=[O:55])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:64]=[CH:13][C:14]([CH:17]3[CH2:20][N:19]([CH3:21])[CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:24])[CH3:23]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 580440835-Bromo-1-methyl-3-(5-(1-methylazetidin-3-yl)pyridin-2-ylamino)pyridine-2(1H)-oneHCID 86684143(2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methyl acetate

Product 1

HCID 86684455(4-(1-Methyl-5-(4-(1-methylazetidin-3-yl)phenylamino)-6-oxo-1,6-dihydro-pyridin-3-yl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-3-yl)methyl AcetateYield 54.9%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Procedure

A 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 239c (106 mg, 0.30 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexa-hydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (115 mg, 0.30 mmol), Pd(dppf)Cl2 (25 mg, 0.030 mmol), K3PO4 (127 mg, 0.60 mmol), sodium acetate (49 mg, 0.60 mmol), water (1 mL) and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated under reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 15:1 dichloromethane/methanol to afford 239d as white solid (100 mg, 49%). MS-ESI: [M+H]+ 607.3

Workup

  1. customA 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/argon flush
  3. temperaturethe mixture was heated
  4. temperatureunder reflux for 2 h
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated under reduced pressure
  7. customthe resulting residue was purified by silica-gel column chromatography
  8. washeluting with 15:1 dichloromethane/methanol

Sources & evidence

ORD record
ord-0ae4f9be33454dbc996f6a2425378e4d
Source dataset
uspto-grants-2014_05
Patent number
US08716274B2

Reaction notes

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