Tetrahydrofuran → (S)-4-Fluoro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)benzyl Acetate

HRID 519362Notes

Reaction equation

HRID 519362 reaction equation
[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:25][CH2:24][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[C:22]([F:23])=[C:14]3[C:13]2=[O:26])=[CH:10][C:9]([F:27])=[CH:8][C:7]=1Br)(=[O:3])[CH3:2].[CH3:29][N:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][C@@H:53]3[CH3:62])=[CH:48][N:47]=2)[C:31]1=[O:63].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1COCC1>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>[C:1]([O:4][CH2:5][C:6]1[C:7]([C:34]2[CH:33]=[C:32]([NH:45][C:46]3[CH:51]=[CH:50][C:49]([N:52]4[CH2:57][CH2:56][N:55]([CH:58]5[CH2:59][O:60][CH2:61]5)[CH2:54][C@@H:53]4[CH3:62])=[CH:48][N:47]=3)[C:31](=[O:63])[N:30]([CH3:29])[CH:35]=2)=[CH:8][C:9]([F:27])=[CH:10][C:11]=1[N:12]1[CH2:25][CH2:24][N:15]2[C:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=3[C:22]([F:23])=[C:14]2[C:13]1=[O:26])(=[O:3])[CH3:2]

Participants

7

Reactant 4

HCID 8028TetrahydrofuranHCID 62657Potassium Phosphate, TribasicHCID 866837011-methyl-3-((5-((2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-oneHCID 866837502-Bromo-4-fluoro-6-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)benzyl Acetate

Product 1

HCID 86683749(S)-4-Fluoro-2-(10-fluoro-1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)benzyl AcetateYield 37.5%

Reagents, catalysts & solvents 2

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

Procedure

A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 119c (150 mg, 1.0 eq., 0.33 mmol), (S)-1-methyl-3-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 113f (160 mg, 1.0 eq., 0.33 mmol), K3PO4 (210 mg, 3.0 eq., 0.99 mmol), PdCl2(dppf) (27.0 mg, 0.10 eq., 0.033 mmol), THF (20 mL), and water (0.1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 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 40:1 dichloromethane/methanol to afford 119d as a yellow solid (90 mg, 37%). MS: [M+H]+ 728.3.

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. temperaturethe mixture was heated
  4. temperatureat 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 40:1 dichloromethane/methanol

Sources & evidence

ORD record
ord-a970266c243f43b88b245b695d27313f
Source dataset
uspto-grants-2015_08
Patent number
US09115152B2

Reaction notes

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