تفاعل #680171

معادلة التفاعل

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

المردود 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

المردود 37.0%

المذيبات

water

acetonitrile

ظروف التفاعل

المعالجة

1. 1
   أخرىA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser
2. 2
   أخرىAfter three cycles of vacuum/argon flush
3. 3
   درجة الحرارةThe reaction mixture was cooled to room temperature
4. 4
   ترشيحfiltered
5. 5
   تركيزThe filtrate was concentrated under reduced pressure
6. 6
   workup.ADDITIONThe residue was diluted with dichloromethane (50 mL) and water (50 mL)
7. 7
   أخرىThe aqueous layer was separated
8. 8
   استخلاصextracted with dichloromethane (3×20 mL)
9. 9
   تجفيفThe combined organic layer was dried over Na2SO4
10. 10
    ترشيحfiltered
11. 11
    تركيزThe filtrate was concentrated under reduced pressure
12. 12
    أخرىthe dark residue was purified by silica-gel column chromatography
13. 13
    غسيلeluting with dichloromethane/methanol (80:1 to 50:1)

الإجراء التجريبي

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

المصدر