Lithium hydroxide, monohydrate → 2-[(Biphenyl-4-ylmethyl)-amino]-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone

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Reaction Steps

A mixture of biphenyl-4-yl-methanol (250 mg, 1.35 mmol) and aqueous HBr (48%) (3 mL) was stirred at 10° C. for 3 hrs. After completion of the reaction, the mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer collected was concentrated under reduced pressure to afford 330 mg (98.5% Yield) 4-bromomethyl-biphenyl. 4-Bromomethyl-biphenyl (120 mg, 0.485 mmol) was added to a stirred mixture of 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (134 mg, 0.44 mmol) (prepared according to Step 1 and 5 of the General Scheme), LiOH.H2O (40 mg, 0.97 mmol) and 4 Å molecular sieves (350 mg) in DMF (4 mL) and stirring was continued overnight. The reaction mixture was filtered and filtrate was diluted with cold water, extracted with ethyl acetate and organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using neutral alumina and 5% MeOH in DCM as eluent) to afford 22 mg (11.4% Yield) of 2-[(biphenyl-4-ylmethyl)-amino]-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone. LC/MS [M+H]+: 435, 90.56%. 1H NMR (CDCl3): δ7.64-7.52 (m, 4H), 7.5-7.3 (m, 6H), 7.24-7.15 (dt, 1H), 7.0-6.86 (m, 2H), 4.6 (q, 1H), 4.0-3.8 (m, 3H), 3.7-3.6 (m, 3H), 3.5 (s, 2H), 3.4-3.3 (m, 1H), 2.0-1.8 (m, 4H).

Provenance & Evidence