Acetonitrile → 2-(10-Fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 1022126Notes

Reaction equation

HRID 1022126 reaction equation
[CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:30]=[C:21]3[CH2:22][N:23]([CH:26]4[CH2:29][O:28][CH2:27]4)[CH2:24][CH2:25][N:20]3[N:19]=2)[C:3]1=[O:31].Cl[C:33]1[C:38]([CH:39]=[O:40])=[C:37]([N:41]2[CH2:53][CH2:52]C3N4[C:45]([CH2:46][CH2:47][CH2:48][CH2:49]4)=[C:44]([F:54])[C:43]=3[C:42]2=[O:55])[N:36]=[CH:35][CH:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+].[C:69](#[N:71])C>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].O>[F:54][C:44]1[C:45]2[CH2:46][CH2:47][CH2:48][CH2:49][C:69]=2[N:71]2[CH2:52][CH2:53][N:41]([C:37]3[N:36]=[CH:35][CH:34]=[C:33]([C:6]4[CH:5]=[C:4]([NH:17][C:18]5[CH:30]=[C:21]6[CH2:22][N:23]([CH:26]7[CH2:29][O:28][CH2:27]7)[CH2:24][CH2:25][N:20]6[N:19]=5)[C:3](=[O:31])[N:2]([CH3:1])[CH:7]=4)[C:38]=3[CH:39]=[O:40])[C:42](=[O:55])[C:43]=12

Participants

8

Reactant 5

HCID 6342AcetonitrileHCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 866842921-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-oneHCID 866844464-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrido[3,4-b]indolizin-2(1H)-yl)nicotinaldehyde

Product 1

HCID 866842912-(10-Fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(1-methyl-5-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeYield 60%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
100 °C

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and reflux condenser was charged with 1-methyl-3-(5-(oxetan-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 163a (354 mg, 0.83 mmol), 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (289 mg, 0.83 mmol), PdCl2(dppf) (68 mg, 0.08 mmol), K3PO4 (352 mg, 1.66 mmol), sodium acetate (136 mg, 1.66 mmol), acetonitrile (50 mL), and water (3 mL). The system was evacuated and refilled with N2. The reaction mixture was heated at 100° C. 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 30:1 dichloromethane/methanol to afford 284a (305 mg, 60%) as a brown solid. MS-ESI: [M+H]+: 613.6.

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer
  2. temperaturereflux condenser
  3. customThe system was evacuated
  4. additionrefilled with N2
  5. temperatureIt was then cooled to room temperature
  6. filtrationfiltered
  7. concentrationThe filtrate was concentrated under reduced pressure
  8. customthe resulting residue was purified by silica-gel column chromatography
  9. washeluting with 30:1 dichloromethane/methanol

Sources & evidence

ORD record
ord-365c17f37f9542ac81bbaaf31fc03dd0
Source dataset
uspto-grants-2014_05
Patent number
US08716274B2

Reaction notes

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