反应详情

A solution of 4-(tert-butoxycarbonyl-hydrazino)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 15; 1.80 g, 5.71 mmol), diisopropylethylamine (2.0 mL, 11.3 mmol), and 4,6-dichloropyrimidine-5-carbaldehyde (Intermediate 16; 1.00 g, 5.65 mmol) in tetrahydrofuran (10 mL) was stirred at 0° C. for 30 min, then it was warmed up to rt and stirred for 4 h. The solid was filtered. The filtrate was washed with brine (10 mL) and the aqueous layer was extracted with methyl tert-butyl ether (1×10 mL). The combined organic layers were washed with brine (1×10 mL) and concentrated to give an orange-red semi-solid. Toluene (10 mL) was added and the solution was heated to 110° C. for 6 h. The reaction mixture was cooled to room temperature and concentrated to give a semi-solid. This crude solid was dissolved in the minimum amount of dichloromethane and passed through a pad of silica gel, eluting with 9% ethyl acetate/hexanes. Concentration of fractions homogeneous for the product gave 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.33 g, 70%) as a cream white solid. 1H NMR (CDCl3) δ 1.49 (s, 9H), 1.9-2.1 (m, 2H), 2.25 (qd, 2H, J=12.6, 4.5 Hz), 2.97 (t, 2H, J=12.0 Hz), 4.30 (br, 2H), 4.96 (tt, 1H, J=11.4, 4.2 Hz), 8.15 (s, 1H), 8.75 (s, 1H).

1. filtrationThe solid was filtered
2. washThe filtrate was washed with brine (10 mL)
3. extractionthe aqueous layer was extracted with methyl tert-butyl ether (1×10 mL)
4. washThe combined organic layers were washed with brine (1×10 mL)
5. concentrationconcentrated
6. customto give an orange-red semi-solid
7. temperaturethe solution was heated to 110° C. for 6 h
8. temperatureThe reaction mixture was cooled to room temperature
9. concentrationconcentrated
10. customto give a semi-solid
11. washeluting with 9% ethyl acetate/hexanes