Cesium carbonate → tert-Butyl 3-(3-(6-Chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)-1H-pyrazol-1-yl)azetidine-1-carboxylate

A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was charged with 105b (677 mg, 2.84 mmol), 103a (635 mg, 2.84 mmol), cesium carbonate (1.85 g, 5.68 mmol) and 1,4-dioxane (14 mL). After bubbling nitrogen through the resulting suspension for 30 min, Xantphos (246 mg, 0.426 mmol) and tris(dibenzylideneacetone)dipalladium(0) (260 mg, 0.284 mmol) were added. A reflux condenser was attached to the flask, and the reaction mixture was heated at reflux for 2.5 h. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (200 mL) and water (75 mL), and the layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic layers were dried over sodium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by flash column chromatography (silica, 95:5 methylene chloride/methanol) to afford a 73% yield of 105c (794 mg) as an amorphous white solid: mp 154-156° C.; 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.60 (s, 1H), 7.43 (d, J=2.5 Hz, 1H), 6.01 (d, J=2.5 Hz, 1H), 5.00-4.95 (m, 1H), 4.39-4.32 (m, 4H), 3.79 (s, 3H), 1.48 (s, 9H); MS (ESI+) m/z 403.1 (M+Na).

1. customA 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet
2. customAfter bubbling nitrogen through the resulting suspension for 30 min
3. customA reflux condenser was attached to the flask
4. temperaturethe reaction mixture was heated
5. temperatureat reflux for 2.5 h
6. customthe layers were separated
7. extractionThe aqueous layer was extracted with ethyl acetate (50 mL)
8. dry with materialthe combined organic layers were dried over sodium sulfate
9. customThe drying agent was removed by filtration
10. concentrationThe filtrate was concentrated under reduced pressure
11. customthe resulting residue was purified by flash column chromatography (silica, 95:5 methylene chloride/methanol)

ORDレコード

ord-0add878569d044b5984ce53c3fb9b9a2

出典データセット

uspto-grants-2015_03

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08975260B2