Tetrahydrofuran → 5-(5-Fluoro-2-(hydroxymethyl)-3-(6,6-dimethyl-3,4,6,7-tetrahydro-5H-cyclopenta[4,5]thieno[2,3-c]pyridine-1 (2H)-yl)phenyl)-1-methyl-3-(2-methylisoindolin-5-ylamino)pyrazin-2(1H)-one

A 100-mL three-neck round-bottomed flask equipped with a reflux condenser, magnetic stirrer and nitrogen inlet was charged with 231e (150 mg, 0.447 mmol), 131a (340 mg, 0.581 mmol), sodium carbonate (142 mg, 1.34 mmol), water (2 mL) and 1,4-dioxane (8 mL). After bubbling nitrogen through the resulting suspension for 30 min, tetrakis-(triphenylphosphine)palladium(0) (52 mg, 0.045 mmol) was added, and the reaction mixture was heated at reflux for 2 h. After that time, the mixture was cooled to room temperature and diluted with methylene chloride (100 mL) and water (30 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (3×30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford a brown residue. A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with the crude residue, THF (10 mL) and a 1 M solution of tetrabutylammonium fluoride in THF (4.50 mmol, 4.5 mL). The resulting mixture was stirred at room temperature for 2 h. After this time, the mixture was diluted with methylene chloride (100 mL) and washed with water (30 mL). The organic layer was separated, and the aqueous layer was extracted with methylene chloride (3×30 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 44% yield (120 mg) of 235 as an off-white solid: mp 218-220° C. (dec); 1H NMR (500 MHz, DMSO-d6) d 9.21 (s, 1H), 7.89 (d, 1H, J=1.0 Hz), 7.70 (dd, 1H, J=8.1, 2.0 Hz), 7.50 (s, 1H), 7.34 (dd, 1H, J=9.9, 3.0 Hz), 7.30 (dd, 1H, J=9.1, 2.5 Hz), 7.13 (d, 1H, J=8.0 Hz), 4.82 (m, 1H), 4.50 (m, 1H), 4.04 (m, 1H), 4.04 (m, 1H), 3.84 (m, 1H), 3.75 (m, 4H), 3.54 (s, 3H), 3.02 (m, 1H), 2.89 (m, 1H), 2.75 (s, 2H), 2.53 (d, 2H, J=6.5 Hz), 2.46 (s, 3H), 1.23 (s, 6H); MS (ESI+) m/z 600.2 (M+H).

1. customA 100-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 2 h
5. customThe organic layer was separated
6. extractionthe aqueous layer was extracted with methylene chloride (3×30 mL)
7. dry with materialThe combined organic layers were dried over sodium sulfate
8. concentrationconcentrated under reduced pressure
9. customto afford a brown residue
10. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer
11. customwas purged with nitrogen
12. additioncharged with the crude residue, THF (10 mL)
13. washwashed with water (30 mL)
14. customThe organic layer was separated
15. extractionthe aqueous layer was extracted with methylene chloride (3×30 mL)
16. dry with materialThe combined organic layers were dried over sodium sulfate
17. concentrationconcentrated under reduced pressure
18. customThe residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride)

ORD record

ord-4334ddd5dd6d461290d97071d8721b0a

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08618107B2