Cesium carbonate → (S)-2-(3,4,6,7,8,9-Hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehyde

HRID 592905Notes

Reaction equation

HRID 592905 reaction equation
Cl[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]5[CH2:32][O:31][CH2:30]5)[CH2:25][C@@H:24]4[CH3:33])=[CH:19][N:18]=3)[C:13](=[O:34])[N:12]([CH3:35])[CH:11]=2)[C:3]=1[CH:4]=[O:5].[CH2:36]1[C:41]2=[CH:42][C:43]3[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=3[N:40]2[CH2:39][CH2:38][NH:37]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:36]1[C:41]2=[CH:42][C:43]3[CH2:44][CH2:45][CH2:46][CH2:47][C:48]=3[N:40]2[CH2:39][CH2:38][N:37]1[C:2]1[N:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][CH2:27][N:26]([CH:29]5[CH2:32][O:31][CH2:30]5)[CH2:25][C@@H:24]4[CH3:33])=[CH:19][N:18]=3)[C:13](=[O:34])[N:12]([CH3:35])[CH:11]=2)[C:3]=1[CH:4]=[O:5]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 86684406(S)-2-Chloro-4-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeHCID 866844081,2,3,4,6,7,8,9-Octahydropyrazino[1,2-a]indole

Product 1

HCID 86684407(S)-2-(3,4,6,7,8,9-Hexahydropyrazino[1,2-a]indol-2(1H)-yl)-4-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)nicotinaldehydeYield 26%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 220a (300 mg, 1.0 eq., 0.61 mmol), 1,2,3,4,6,7,8,9-octahydropyrazino[1,2-a]indole (128 mg, 1.2 eq., 0.73 mmol), Pd2(dba)3 (55 mg, 0.1 eq., 0.060 mmol), X-Phos (30 mg, 0.1 eq., 0.060 mmol), Cs2CO3 (390 mg, 2.0 eq., 1.22 mmol), and dioxane (15.0 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 16 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 40:1 dichloromethane/EtOH to afford 220b (100 mg, 26%) as yellow solid. MS-ESI: [M+H]+ 635.3.

Workup

  1. customA 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter three cycles of vacuum/argon flush
  3. temperatureIt was then cooled to room temperature
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. customthe resulting residue was purified by silica-gel column chromatography
  7. washeluting with 40:1 dichloromethane/EtOH

Sources & evidence

ORD record
ord-aac2030910e3491692a019aa7e6de024
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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