Tert-Butylamine → tert-Butyl-(7-chloro-6-fluoro-isoquinolin-1-yl)-amine

Temperature

0 °C

A solution of 5.0 g (25.3 mmol) of 7-chloro-6-fluoro-isoquinoline-2-oxide (9) in 120 mL of benzotrifluoride was treated with 15.9 mL (11.1 g, 152 mmol) of tert-butylamine and cooled to 0° C. Then, 17.3 g (53.1 mmol) of p-toluenesulfonic anhydride were added portionwise with temperature control (<10° C.). The reaction mixture was stirred at room temperature for 16 h, before being cooled to 0° C. and another 8.0 mL (76.1 mmol) of tert-butylamine and 8.26 g (25.3 mmol) of p-toluenesulfonic anhydride were added. The reaction mixture was stirred for 24 h at room temperature, then concentrated and partitioned between 120 mL of water and 150 mL of dichloromethane. The phases were separated and the organic phase was washed eight times with 3N aqueous sodium hydroxide, to extract excess p-toluenesulfonic acid, dried over magnesium sulphate, filtered and evaporated to dryness. The crude product was purified twice by silica gel chromatography (dichloromethane:methanol) to give 277 mg of pure desired product (95) and 714 mg of the product slightly contaminated with p-toluenesulfonic acid. Rt=2.35 min (Method 2). Detected mass: 253.1 (M+H+).

1. temperaturebefore being cooled to 0° C.
2. stirringThe reaction mixture was stirred for 24 h at room temperature
3. concentrationconcentrated
4. custompartitioned between 120 mL of water and 150 mL of dichloromethane
5. customThe phases were separated
6. washthe organic phase was washed eight times with 3N aqueous sodium hydroxide
7. extractionto extract excess p-toluenesulfonic acid
8. dry with materialdried over magnesium sulphate
9. filtrationfiltered
10. customevaporated to dryness
11. customThe crude product was purified twice by silica gel chromatography (dichloromethane:methanol)

ORD record

ord-6cca2d7eb62440799b7262e250f764f1

Source dataset

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08541449B2