Reaction #680171

Reaction equation

248b

6-Chloro-2-methyl-4-[(5-{[(3R)-3-methylmorpholin-4-yl]carbonyl}pyridin-2-yl)amino]-2,3-dihydropyridazin-3-one

{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

{3-[(Acetyloxy)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

K3PO4

sodium acetate

→

248c

Yield 37.0%

(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

Yield 37.0%

Solvents

water

acetonitrile

Conditions

Workup

1. 1
   OtherA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
2. 2
   OtherAfter three cycles of vacuum/argon flush
3. 3
   TemperatureThe reaction mixture was cooled to room temperature
4. 4
   Filtrationfiltered
5. 5
   ConcentrationThe filtrate was concentrated under reduced pressure
6. 6
   workup.ADDITIONThe residue was diluted with dichloromethane (50 mL) and water (50 mL)
7. 7
   OtherThe aqueous layer was separated
8. 8
   Extractionextracted with dichloromethane (3×20 mL)
9. 9
   DryingThe combined organic layer was dried over Na2SO4
10. 10
    Filtrationfiltered
11. 11
    ConcentrationThe filtrate was concentrated under reduced pressure
12. 12
    Otherthe dark residue was purified by silica-gel column chromatography
13. 13
    Washeluting with dichloromethane/methanol (80:1 to 50:1)

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

Source