Potassium Phosphate, Tribasic → (2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-{1-methyl-5-[(5-{[(3R)-3-methylmorpholin-4-yl] carbonyl}pyridin-2-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl}pyridin-3-yl)methyl Acetate

HRID 592989Notes

Reaction equation

HRID 592989 reaction equation
Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:26]([O:29][CH2:30][C:31]1[C:32]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:33][CH:34]=[CH:35][C:36]=1B(O)O)(=[O:28])[CH3:27].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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(#N)C>[C:26]([O:29][CH2:30][C:31]1[C:32]([N:40]2[CH2:51][CH2:50][N:49]3[C:42](=[CH:43][C:44]4[CH2:45][C:46]([CH3:53])([CH3:52])[CH2:47][C:48]=43)[C:41]2=[O:54])=[N:33][CH:34]=[CH:35][C:36]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@H:20]3[CH3:25])=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:28])[CH3:27]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 517045Sodium AcetateHCID 86684340[4-(Dihydroxyboranyl)-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-3-yl]methyl acetateHCID 86684473HCID 86684473, compound

Product 1

HCID 86684474(2-{4,4-Dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}-4-{1-methyl-5-[(5-{[(3R)-3-methylmorpholin-4-yl] carbonyl}pyridin-2-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl}pyridin-3-yl)methyl AcetateYield 37%

Reagents, catalysts & solvents 3

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
100 °C

Procedure

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 248b (364 mg, 1.0 mmol), {3-[(acetoxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (596 mg, 1.5 mmol), K3PO4 (424 mg, 2.0 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (73 mg, 0.10 mmol), sodium acetate (164 mg, 2.0 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the reaction mixture was heated at 100° C. for 2.5 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and water (50 mL). The aqueous layer was separated and extracted with dichloromethane (3×20 mL). The combined organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80:1 to 50:1) to afford 248c (250 mg, 37%) as yellow oil. MS-ESI: [M+H]+ 681.3

Workup

  1. customA 100-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 reaction mixture was cooled to room temperature
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated under reduced pressure
  6. additionThe residue was diluted with dichloromethane (50 mL) and water (50 mL)
  7. customThe aqueous layer was separated
  8. extractionextracted with dichloromethane (3×20 mL)
  9. dry with materialThe combined organic layer was dried over Na2SO4
  10. filtrationfiltered
  11. concentrationThe filtrate was concentrated under reduced pressure
  12. customthe dark residue was purified by silica-gel column chromatography
  13. washeluting with dichloromethane/methanol (80:1 to 50:1)

Sources & evidence

ORD record
ord-32991aa661454f93825309c56b2b74c7
Source dataset
uspto-grants-2016_01
Patent number
US09238655B2

Reaction notes

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