Methyl 6-methylpyridine-2-carboxylate → 2-(6-Bromoquinolin-4-yl)-1-(6-methylpyridin-2-yl)ethanone

Participants

Reaction Conditions

Reaction Steps

Dissolve 6-bromo-4-methyl-quinoline (38.5 g, 153 mmol) in 600 mL dry THF. Cool to −70° C. and treat with the dropwise addition of 0.5 M potassium hexamethyldisilazane (KN(SiMe3)2 (400 mL, 200 mmol) over 2 hours while keeping the temperature below −65° C. Stir the resultant solution at −70° C. for 1 hour and add a solution of 6-methylpyridine-2-carboxylic acid methyl ester (27.2, 180 mmol) in 100 mL dry THF dropwise over 15 minutes. During the addition, the mixture will turn from dark red to pea-green and form a precipitate. Stir the mixture at −70° C. over 2 hours then allow it to warm to ambient temperature with stirring for 5 hours. Cool the mixture then quench with 12 N HCl to pH=1. Raise the pH to 9 with solid potassium carbonate. Decant the solution from the solids and extract twice with 200 mL ethyl acetate. Combine the organic extracts, wash with water and dry over potassium carbonate. Stir the solids in 200 mL water and 200 mL ethyl acetate and treat with additional potassium carbonate. Separate the organic portion and dry with the previous ethyl acetate extracts. Concentrate the solution in vacuo to a dark oil. Pass the oil through a 300 mL silica plug with methylene chloride then ethyl acetate. Combine the appropriate fractions and concentrate in vacuo to yield an amber oil. Rinse the oil down the sides of the flask with methylene chloride then dilute with hexane while swirling the flask to yield 38.5 g (73.8%) of the desired subtitled intermediate as a yellow solid.

Provenance & Evidence