Methyl iodide → 3-Iodo-5-methoxy-1-methyl-1H-indazole

Temperature

0 °C

To a solution of 3-iodo-5-methoxy-1H-indazole (442 mg, 1.61 mmol) in THF (10.0 mL) at 0° C. was added KOtBu 1M in THF (2.26 mL, 2.26 mmol) and the mixture stirred at 0° C. for 30 min where it became a pale brown reddish solution then added MeI (320 mg, 141 μL, 2.26 mmol). The reaction mixture was stirred at 0° C. for 30 min then warmed to 25° C. and stirred for 1.5 h. The reaction mixture was quenched with saturated ammonium chloride in water and extracted with dichloromethane (3×30 mL), organics dried over MgSO4 and concentrated to a clear oil. Then dissolved in toluene and purified by chromatography (80 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min to afford 3-iodo-5-methoxy-1-methyl-1H-indazole (355 mg, 1.23 mmol, 76.4%) as an off-white solid. MS (M+H)+=288.9 (>90% purity); 1H NMR (CDCl3) δ: 7.24 (d, J=9.1 Hz, 1H), 7.10 (dd, J=9.1, 2.6 Hz, 1H), 6.75 (d, J=2.6 Hz, 1H), 4.06 (s, 3H), 3.88 (s, 3H). The regioisomer 3-iodo-5-methoxy-2-methyl-2H-indazole (89 mg, 309 μmol, 19.2%) was also obtained as a white solid.

1. stirringThe reaction mixture was stirred at 0° C. for 30 min
2. temperaturethen warmed to 25° C.
3. stirringstirred for 1.5 h
4. customThe reaction mixture was quenched with saturated ammonium chloride in water
5. extractionextracted with dichloromethane (3×30 mL)
6. dry with materialorganics dried over MgSO4
7. concentrationconcentrated to a clear oil
8. dissolutionThen dissolved in toluene
9. custompurified by chromatography (80 g column, 50 μm from Analogix, 0-20% EtOAc in hexanes over 20 min

ORD record

ord-34f38ff1f1164811ad275c2fb8da891f

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08658646B2