Sodium Hydroxide → HCID 86586279, compound

Participants

Reaction Steps

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), L-histidine methyl ester dihydrochloride (0.046 g, 0.27 mmol), and sodium triacetoxyborohydride (0.087 g, 0.41 mmol) in dichloroethane (1.4 mL) was shaken at room temperature for 3 days. Additional portions of), L-histidine methyl ester dihydrochloride (0.100 g, 0.59 mmol) and sodium triacetoxyborohydride (0.085 g, 0.40 mmol) were added and the reaction mixture was shaken for 2 days. 1N NaOH (1 mL) was added and the brown precipitate was collected by filtration. The filtrate was extracted with dichloromethane (5 mL) and the organic extract was concentrated and combined with the aforementioned brown solid. The crude mixture was 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 18.9-20.5 min was collected, concentrated, and lyopholized to afford methyl (2S)-2-({4-[4-amino-3-(4-{[2-fluoro-4-(trifluoromethyl)benzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]benzyl}amino)-3-(4H-4-imidazolyl)propanoate as a white solid. (0.029 g, 0.041 mmol): 1H NMR (d6-DMSO, 400 MHz): δH 9.94 (1H, s), 8.35-8.38 (2H, m), 8.13 (2H, d, J=8.0 Hz), 7.99-8.02 (1H, m), 7.90 (1H, d, J=10.8 Hz), 7.75 (1H, d, J=8.4 Hz), 7.51 (1H, s), 7.39-7.45 (5H, m), 6.78 (1H, bs), 3.96 (3H, s), 3.82 (1H, d, J=14.0 Hz), 3.59 (3H, s), 3.47 (1H, t, J=6.4 Hz), 2.80-2.89 (2H, m), and 1.91 (3H, s); 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 11.15 min. MS: MH+ 704.2.

Provenance & Evidence