Formaldehyde → N-(3-Fluoro-4-(2-(1-methylpiperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

A round-bottomed flask was charged with N-(3-fluoro-4-(2-(piperidin-4-yl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-2-(4-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 154, Step C, 20.0 mg, 0.0357 mmol), formaldehyde (8.68 mg, 0.107 mmol, 37%), NaBH(OAc)3 (37.9 mg, 0.179 mmol) and THF (10 mL). The reaction mixture was stirred at room temperature until the starting material had been consumed (overnight). Then the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL). The phases were separated and the aqueous phase was re-extracted with EtOAc (3×100 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (dichloromethane/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (19.1 mg, 93.2%). LRMS (APCI pos): >99% purity, 254 nm, m/e 573 (M). 1H NMR (400 MHz, CDCl3) δ 11.83 (s, 1H), 8.44 (d, 1H), 8.41 (d, 1H), 8.24 (d, 1H), 7.94 (dd, 1H), 7.61 (m, 2H), 7.38 (m, 1H), 7.21-7.28 (m, 4H), 6.46 (d, 1H), 2.99 (m, 2H), 2.91 (m, 1H), 2.34 (s, 3H), 2.06-2.17 (m, 4H), 1.94 (m, 2H).

1. customhad been consumed (overnight)
2. customThen the reaction was partitioned between EtOAc (100 mL) and H2O (100 mL)
3. customThe phases were separated
4. extractionthe aqueous phase was re-extracted with EtOAc (3×100 mL)
5. dry with materialThe combined organic layers were dried (Na2SO4)
6. filtrationfiltered
7. concentrationconcentrated
8. customto yield a crude product
9. customThe crude product was purified by silica gel chromatography (dichloromethane/7 M NH3 in MeOH from 100/1 to 10/1

ORDレコード

ord-fb35791d439f4a4fbea81122b433c257

出典データセット

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08003662B2