N-BOC-4-(4'-FLUORO) BENZYL-4-PIPERIDINE CARBOXYLIC ACID synthesis

Yield:-

Reaction Conditions:

Stage #1: 1-tert-butyl 4-methyl 4-(4-fluorobenzyl)piperidine-1,4-dicarboxylatewith methanol;lithium hydroxide;water in tetrahydrofuran at 65; for 1 h;
Stage #2: with sodium hydroxide in diethyl ether;
Stage #3: with hydrogenchloride in diethyl ether; pH=1;

Steps:

13.1

A solution of lithium hydroxide monohydrate (11.2 g, 267 mmol) in water (50 mL) was added to a solution of l-tert-butyl 4-methyl 4-(4-fluoro-phenylmethyl)-piperidine-l,4- dicarboxylate (9.37 g, 26.7 mmol), prepared using procedures similar to those in Reference 12, in THF/MeOH (200 mL, 1 :1 v/v). The mixture then was heated to 65 °C for 1 day. The mixture was allowed to cool to room temperature and a solution of sodium hydroxide (I M, 100 mL) and ether (300 mL) was added. The aqueous phase was separated and acidified with cone, hydrochloric acid (~35 mL) to pH 1. The aqueous phase was extracted with ethyl acetate (200 mL, 100 mL) and the organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The ethereal layer was acidified with cone, hydrochloric acid and the aqueous phase separated. The ethereal layer then was dried over Na₂SO₄, filtered to give l-tert-butoxycarbonyl-4-(4-fluoro-phenylmethyl)-piperidine-4- EPO carboxylic acid as a white powder (8.16 g). ¹H NMR (400 MHz, d₆-DMSO) δ 1.29-1.39 (m, 2H), 1.37 (s, 9H), 1.84 (brd, 2H₅ J= 13.2 Hz)₅ 2.78 (brs, 4H), 3.77 (brd, 2H, J= 13.2 Hz)₅ 7.06-7.16 (m, 4H)₅ 12.58 (brs, IH). MS(ES) m/z 336.4 (M-I)-; MS cald: 337.2 (M).

References:

WO2006/86609,2006,A2 Location in patent:Page/Page column 161-162