Methyl iodide → 1,3-Dichloro-7-methoxy-4-methylisoquinoline

Temperature

25 °C

To a solution of i-Pr2NH (1.95 g, 19.3 mmol) in anhydrous THF (40 mL) was added dropwise n-BuLi (7.72 mL, 19.3 mmol, 2.50 M in hexane) at −78° C. under N2 atmosphere. After 30 minutes, 1,3-dichloro-7-methoxyisoquinoline (described in step 2 of Intermediate 12) (4.00 g, 17.5 mmol) in anhydrous THF (20 mL) was added to the reaction. After 15 minutes, MeI (4.97 g, 35.0 mmol) was added dropwise. The resulting mixture was warmed to 25° C. and allowed to stir for 16 hours. The reaction was quenched with H2O (150 mL) followed by an ethyl acetate extraction/workup to give the crude product, which was purified by prep-HPLC (0.1% TFA as additive). Most of CH3CN was removed under reduced pressure and extracted with EtOAc (50 mL×3). The combined organic layers were washed with H2O (50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 1,3-dichloro-7-methoxy-4-methylisoquinoline (2.0 g, yield 47%) as an off-white solid.

1. waitAfter 15 minutes
2. customThe reaction was quenched with H2O (150 mL)
3. extractionfollowed by an ethyl acetate extraction/workup
4. customto give the crude product, which
5. customwas purified by prep-HPLC (0.1% TFA as additive)
6. customMost of CH3CN was removed under reduced pressure
7. extractionextracted with EtOAc (50 mL×3)
8. washThe combined organic layers were washed with H2O (50 mL) and brine (50 mL)
9. dry with materialdried over anhydrous Na2SO4
10. filtrationfiltered
11. concentrationconcentrated in vacuo

ORD record

ord-f9c4daa2b574406e8782b1e394724eea

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09221810B2