Sodium borohydride → 5-fluoro-2-(1-(2-hydroxyethyl)-1H-indazol-5-yloxy)benzonitrile

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Reaction Steps

To a solution of methyl 2-(5-(2-cyano-4-fluorophenoxy)-1H-indazol-1-yl)acetate 77 (prepared as in Example 3) (60.0 g, 184.4 mmol) in MeOH (370 mL) was added NaBH4 (24.42 g) in five 5 gram portions over 90 minutes. The temperature rose from 25° C. to 44.7° C. at the final addition of NaBH4. The mixture was concentrated under vacuum. To the concentrate was added saturated NH4Cl (600 mL) and EtOAc (600 mL) and the mixture was vigorously stirred for 1 hour. The layers were separated and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organics were washed with saturated NH4Cl (2×100 mL), water (200 mL), brine (500 mL), dried over MgSO4, filtered thru GF/F paper and concentrated to a bright orange solid. The crude solid was dissolved in CH2Cl2 (1 L) and hexanes (2.25 L) were added with stirring. A light brown solid formed and after stirring for 30 min the solid was collected and dried under high vacuum to yield 45.5 g. The filtrate was concentrated under reduced pressure. This material was redissolved in CH2Cl2 (100 mL) and hexanes were added (200 mL). The resulting solid (6.2 g) was collected via filtration. The two crops were combined to give 51.7 g (94.3%) of 78A. 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.49 (d, 1H), 7.39-7.36 (m, 2H), 7.21-7.16 (m, 2H), 6.90 (dd, 1H), 4.49 (t, 2H), 4.17-4.13 (m, 2H), 2.81 (t, 10H).

Provenance & Evidence