Cesium carbonate → 6-Chloro-4-(5-((3S,5S)-3,5-dimethylmorpholine-4-carbonyl)pyridine-2-ylamino)-2-methylpyridazin-3(2H)-one

HRID 593146Notes

Reaction equation

HRID 593146 reaction equation
C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:7][C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[C@@H:21]([CH3:22])[CH2:20][O:19][CH2:18][C@@H:17]2[CH3:23])=[O:15])=[CH:10][CH:9]=1.Br[C:25]1[C:26](=[O:33])[N:27]([CH3:32])[N:28]=[C:29]([Cl:31])[CH:30]=1.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].O1CCOCC1>[Cl:31][C:29]1[CH:30]=[C:25]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([N:16]3[C@@H:21]([CH3:22])[CH2:20][O:19][CH2:18][C@@H:17]3[CH3:23])=[O:15])=[CH:12][N:13]=2)[C:26](=[O:33])[N:27]([CH3:32])[N:28]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 592164744-Bromo-6-chloro-2-methyl-2,3-dihydropyridazin-3-oneHCID 86684581(6-Aminopyridin-3-yl)((3S,5S)-3,5-dimethylmorpholino)methanone

Product 1

HCID 866845826-Chloro-4-(5-((3S,5S)-3,5-dimethylmorpholine-4-carbonyl)pyridine-2-ylamino)-2-methylpyridazin-3(2H)-oneYield 31.1%

Reagents, catalysts & solvents 2

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

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 1,4-dioxane (8 mL), cesium carbonate (221 mg, 0.68 mmol), 324a (80 mg, 0.34 mmol), and 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (80 mg, 0.36 mmol). After bubbling nitrogen through the suspension for 5 minutes, Xantphos (40 mg, 0.068 mmol) and tris(dibenzylideneacetone)dipalladium(0) (24 mg, 0.034 mmol) were added. The system was subjected to three cycles of vacuum/nitrogen flush and heated at reflux for 2.5 h. It was then cooled to room temperature and filtered. The solid was washed with dichloromethane (3×10 mL). The combined filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with petroleum ether/ethyl acetate (2/1 to 100% ethyl acetate) to afford 324b (40 mg, 31%) as a yellow solid. MS-ESI: [M+H]+ 378.3

Workup

  1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
  2. customAfter bubbling nitrogen through the suspension for 5 minutes
  3. customflush
  4. temperatureheated
  5. temperatureat reflux for 2.5 h
  6. filtrationfiltered
  7. washThe solid was washed with dichloromethane (3×10 mL)
  8. concentrationThe combined filtrate was concentrated under reduced pressure
  9. customThe residue was purified by silica-gel column chromatography
  10. washeluting with petroleum ether/ethyl acetate (2/1 to 100% ethyl acetate)

Sources & evidence

ORD record
ord-13c753a0ee7343ee8c66a2358303ef72
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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