Cesium carbonate → (4-(1-Methyl-5-(7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-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 593037Notes

Reaction equation

HRID 593037 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[N:8]=[C:9]([NH2:11])[N:10]=[C:4]2[CH2:3]1.[C:12]([O:15][CH2:16][C:17]1[C:18]([N:32]2[CH2:44][CH2:43][N:35]3[C:36]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[CH:42]=[C:34]3[C:33]2=[O:45])=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27](Br)[C:26](=[O:30])[N:25]([CH3:31])[CH:24]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].CN(C=O)C>[C:12]([O:15][CH2:16][C:17]1[C:18]([N:32]2[CH2:44][CH2:43][N:35]3[C:36]4[CH2:37][CH2:38][CH2:39][CH2:40][C:41]=4[CH:42]=[C:34]3[C:33]2=[O:45])=[N:19][CH:20]=[CH:21][C:22]=1[C:23]1[CH:28]=[C:27]([NH:11][C:9]2[N:10]=[C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][N:5]3[N:8]=2)[C:26](=[O:30])[N:25]([CH3:31])[CH:24]=1)(=[O:14])[CH3:13]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 838726777-Methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-amineHCID 86684400(4-(5-Bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-3-yl)methyl Acetate

Product 1

HCID 86684512(4-(1-Methyl-5-(7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-3-yl)methyl AcetateYield 41%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6228DimethylformamideSolvent

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 270f (100 mg, 0.65 mmol, 1.7 eq.), (4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-3-yl)methyl acetate 217a (200 mg, 0.38 mmol, 1.0 eq.), DMF (10 mL), and cesium carbonate (499 mg, 1.52 mmol, 4.0 eq.). After bubbling nitrogen through the resulting solution for 10 minutes, Xantphos (44 mg, 0.076 mmol, 0.20 eq.) and tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.038 mmol, 0.10 eq.) were added. The reaction mixture was subjected to three cycles of vacuum/argon flush and heated at 100° C. for 16 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (50 mL) and water (10 mL). The aqueous layer was separated and extracted with ethyl acetate (3×20 mL). The combined organic layer was concentrated under reduced pressure. The residue was purified on silica-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 270g (90 mg, 41%). MS-ESI: [M+H]+ 598.3.

Workup

  1. customA 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter bubbling nitrogen through the resulting solution for 10 minutes
  3. customflush
  4. temperatureAfter this time the reaction was cooled to room temperature
  5. filtrationfiltered
  6. customThe filtrate was partitioned between ethyl acetate (50 mL) and water (10 mL)
  7. customThe aqueous layer was separated
  8. extractionextracted with ethyl acetate (3×20 mL)
  9. concentrationThe combined organic layer was concentrated under reduced pressure
  10. customThe residue was purified on silica-gel column chromatography
  11. washeluting with 50:1 dichloromethane/methanol

Sources & evidence

ORD record
ord-32cc4fd9239d4a529ab9d740a9ee2f5e
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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