Study On Synthesis Of A 5,6,7,8-Tetrahydroquinoline-Arylpiperidine ORL1 Receptor Antagonism

Methyl quinoline-6-carboxylate was used as raw material and catalytic hydrogenation, pyridine oxidation, Boekelheide reaction, TES protection, ester reduction, chiral separation and then sulfonylation were carried out sequentially to give compound B21(TES) ((6R,8S)-8-(triethylsilyloxy)-5,6,7,8-tetra-hydroquinolin-6-yl)methyl)- 4-methylbenzene-sulfonate.Piperidine-4-one hydrochloride salt was exposed to Boc protection, enol triflation, Miyaura borylation, Suzuki coupling, Asymmetric Brown hydroboration-oxidation, deprotection and chiral separation to give compound B2 (3R,4R)-4-(2-chloro-4-fluorophenyl)-piperidin-3-ol.The target compound was obtained via the alkylation of compound B21(TES) with compound B2 followed by deprotection and salification with hydrochloric acid.The reaction mechanism of catalytic hydrogenation, pyridine oxidation, Boekelheide reaction, ester reduction, Miyaura borylation, Suzuki coupling, asymmetric Brown hydroboration-oxidation reaction were discussed. Detailed analysis by NMR spectra of compound B4-trans isomers and compound B4-cis isomers afforded the possibility to identify the trans-isomer and cis-isomer.An efficient operation mode to improve the yield of scaled up catalytic hydrogenation reaction of Methyl quinoline-6-carboxylate was established. Lower costs and less toxic reaction system (hydrogen peroxide/acetic acid) instead of m-CPBA/chloroform system was used to oxidize pyridine derivate. Trifluoroacetic anhydride instead of acetic anhydride was further used to improve the yield of Boekelheide reaction.