Sodium Carbonate → 5-tert-Butyl-2-(2-(hydroxymethyl)-3-(1-methyl-6-oxo-5-(pyridin-2-ylamino)-1,6-dihydropyridazin-3-yl)phenyl)isoindolin-1-one

A 50-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 104a (236 mg, 1.00 mmol), 102f (536 mg, 1.20 mmol), sodium carbonate (318 mg, 3.00 mmol), DMF (5 mL), water (2.5 mL) and 1,4-dioxane (8 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.100 mmol) was added, and the reaction mixture was heated at reflux for 14 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in a mixture of THF (8 mL), methanol (4 mL) and water (4 mL). To the resulting solution was added lithium hydroxide monohydrate (420 mg, 10.0 mmol). The mixture was stirred for 4 h at room temperature and then concentrated in vacuo. The residue was partitioned between ethyl acetate (150 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride) to afford a 38% yield (187 mg) of 104 as an off-white solid: mp 236-237° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.40 (s, 1H), 8.58 (s, 1H), 8.28 (dd, 1H, J=5.0, 1.6 Hz), 7.71 (m, 3H), 7.61 (dd, 1H, J=7.9, 1.5 Hz), 7.50 (m, 4H), 6.96 (m, 1H), 4.93 (s, 2H), 4.68 (t, 1H, J=4.9 Hz), 4.42 (d, 2H, J=5.0 Hz), 3.79 (s, 3H), 1.36 (s, 9H); MS (ESI+) m/z 496.2 (M+H).

1. customA 50-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet
2. customAfter bubbling nitrogen through the resulting suspension for 30 min
3. temperaturethe reaction mixture was heated
4. temperatureat reflux for 14 h
5. customThe organic layer was separated
6. extractionthe aqueous layer was extracted with ethyl acetate (3×50 mL)
7. dry with materialThe combined organic layers were dried over sodium sulfate
8. concentrationconcentrated under reduced pressure
9. dissolutionThe residue was dissolved in a mixture of THF (8 mL), methanol (4 mL) and water (4 mL)
10. concentrationconcentrated in vacuo
11. customThe residue was partitioned between ethyl acetate (150 mL) and water (30 mL)
12. customThe organic layer was separated
13. extractionthe aqueous layer was extracted with ethyl acetate (3×50 mL)
14. dry with materialThe combined organic layers were dried over sodium sulfate
15. concentrationconcentrated under reduced pressure
16. customThe residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride)

ORDレコード

ord-e64d6ba371fc4d94b8dab9d60700b880

出典データセット

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08975260B2