反应详情

A mixture of 3-(1-(4-amino-3-(3-fluoro-5-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-(1-(azetidine-3-carbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-isochromen-1-one formate (Example 150, 71.0 mg, 0.113 mmol), DIPEA (0.020 ml, 0.113 mmol), paraformaldehyde (69.3 mg, 2.30 mmol) and a spatula of Na2SO4 in DCM (2 ml) was stirred for 10 min at rt. Acetic acid (0.033 ml, 0.589 mmol) was then added followed by sodium triacetoxyhydroborate (82.2 mg, 0.387 mmol). After 6 hrs stirring at rt, volatiles were removed under reduced pressure. The residue was dissolved in DCM/EtOH 95:5 (10 ml) and washed with saturated sodium bicarbonate, then filtered on a phase separator and concentrated under reduced pressure. The residue was dissolved in DCM/MeOH 10:1 (1 ml), then formaldehyde (0.016 ml, 0.170 mmol) and AcOH (0.014 ml, 0.250 mmol) were added. After 5 min stirring, NaBH(OAc)3 (25 mg, 0.118 mmol) was added. The resulting mixture was stirred for 30 min at rt, then it was concentrated under reduced pressure. Purification by RP flash chromatography (Biotage Isolera, 12 g C18 column, gradient elution from 100:0 to 60:40 A/B in 15 CV; A: water/MeCN 95/5+0.01% HCOOH, B: water/MeCN 5/95+0.01% HCOOH) yielded title compound (59.8 mg, 0.093 mmol, 82% yield) as a white solid.

1. customvolatiles were removed under reduced pressure
2. dissolutionThe residue was dissolved in DCM/EtOH 95:5 (10 ml)
3. washwashed with saturated sodium bicarbonate
4. filtrationfiltered on a phase separator
5. concentrationconcentrated under reduced pressure
6. dissolutionThe residue was dissolved in DCM/MeOH 10:1 (1 ml)
7. stirringAfter 5 min stirring
8. stirringThe resulting mixture was stirred for 30 min at rt
9. concentrationit was concentrated under reduced pressure
10. customPurification by RP flash chromatography (Biotage Isolera, 12 g
11. washC18 column, gradient elution from 100:0 to 60:40 A/B in 15 CV