Dimethylformamide → 2-(10-Fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(4-methyl-5-oxo-6-(pyridin-3-ylamino)-4,5-dihydropyrazin-2-yl)nicotinaldehyde

HRID 1021844Notes

Reaction equation

HRID 1021844 reaction equation
[CH3:1][N:2]1[C:7](=[O:8])[C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[N:5][C:4](B(O)O)=[CH:3]1.Cl[C:20]1[C:25]([CH:26]=[O:27])=[C:24]([N:28]2[CH2:41][CH2:40][N:31]3[C:32]4[CH2:33][CH2:34][CH2:35][CH2:36][C:37]=4[C:38]([F:39])=[C:30]3[C:29]2=[O:42])[N:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)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:39][C:38]1[C:37]2[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=2[N:31]2[CH2:40][CH2:41][N:28]([C:24]3[N:23]=[CH:22][CH:21]=[C:20]([C:4]4[N:5]=[C:6]([NH:9][C:10]5[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=5)[C:7](=[O:8])[N:2]([CH3:1])[CH:3]=4)[C:25]=3[CH:26]=[O:27])[C:29](=[O:42])[C:30]=12

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 10340Sodium CarbonateHCID 866842384-Chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehydeHCID 866843344-Methyl-5-oxo-6-(pyridin-3-ylamino)-4,5-dihydropyrazin-2-ylboronic acid

Product 1

HCID 866843352-(10-Fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(4-methyl-5-oxo-6-(pyridin-3-ylamino)-4,5-dihydropyrazin-2-yl)nicotinaldehydeYield 49.4%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
50 °C

Procedure

A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 186b (127 mg, 0.52 mmol), 4-chloro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)nicotinaldehyde 134c (180 mg, 0.52 mmol), Na2CO3 (110 mg, 1.04 mmol), PdCl2(dppf) (38 mg, 0.052 mmol), DMF (12 mL), and water (1 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 50° C. for 8 hours under nitrogen. The reaction was then cooled to room temperature and concentrated under reduce pressure. The residue was purified by silica-gel column chromatography eluting with 30:1 methylene chloride/methanol to afford 186c (132 mg, 49%) as a brown solid. MS-ESI: [M+H]+ 514.3.

Workup

  1. customA 50-mL round-bottomed flask equipped with a reflux condenser
  2. customAfter bubbling nitrogen through the mixture for 30 minutes
  3. temperatureThe reaction was then cooled to room temperature
  4. concentrationconcentrated
  5. customThe residue was purified by silica-gel column chromatography
  6. washeluting with 30:1 methylene chloride/methanol

Sources & evidence

ORD record
ord-494547f56c184227a4130bb13091b661
Source dataset
uspto-grants-2014_05
Patent number
US08716274B2

Reaction notes

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