反应详情

A mixture of N1-{4-[4-amino-1-(4-formylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide (Intermediate 2) (0.075 g, 0.14 mmol), 4-amino-1-butanol (0.024 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken for 3 days. Additional portions of 4-amino-1-butanol (0.1 mL) and sodium triacetoxyborohydride (0.089 g, 0.42 mmol) were added and the reaction mixture was shaken for 3 days. Acetic acid (0.1 mL) was added and the reaction mixture was shaken for 7 days. An additional portion of sodium triacetoxyborohydride (0.098 g, 0.46 mmol) was added and the reaction mixture was shaken for 16 h. 1N NaOH (1 mL) was added and the reaction mixture was concentrated, dissolved in DMF (2 mL), filtered through a syringe-tip Acrodisc filter, and purified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min); the fraction eluting from 12.5-14.8 min was collected, concentrated, and lyopholized to N1-{4-[4-amino-1-(4-{[(4-hydroxybutyl)amino]methyl}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-(trifluoromethyl)benzamide as a white solid. (0.030 g, 0.048 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, d, J=4.4 Hz), 8.35-8.40 (2H, m), 8.17 (2H, d, J=8.0 Hz), 8.00 (1H, t, J=7.4 Hz), 7.90 (1H, d, J=10.4 Hz), 7.75 (1H, d, J=7.2 Hz), 7.53-7.57 (2H, m), 7.45 (1H, s), 7.40 (1H, d, J=8.8 Hz), 3.96 (3H, s), 3.83 (2H, s), 3.39 (2H, t, J=6.2 Hz), 2.45-2.50 (2H, m), and 1.45-1.51 (4H, m); RP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min). Rt 9.93 min. MS: MH+624.3.

1. stirringthe reaction mixture was shaken for 3 days
2. stirringthe reaction mixture was shaken for 7 days
3. stirringthe reaction mixture was shaken for 16 h
4. concentrationthe reaction mixture was concentrated
5. dissolutiondissolved in DMF (2 mL)
6. filtrationfiltered through a syringe-tip Acrodisc
7. filtrationfilter
8. custompurified by preparative RP-HPLC (Rainin C18, 8 μm, 300 Å, 25 cm; 20-80% acetonitrile—0.05 M ammonium acetate over 25 min, 21 mL/min)
9. washthe fraction eluting from 12.5-14.8 min
10. customwas collected
11. concentrationconcentrated
12. customRP-HPLC (Hypersil C18, 5 μm, 100 Å, 15 cm; 5%-100% acetonitrile—0.1 M ammonium acetate over 15 min, 1 mL/min)