Practical Synthesis of Low-Density Lipoprotein Receptor Upregulator, N-[1-(3-Phenylpropane-1-yl)piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4- carboxamide

A shorter and more practical method for the preparation of N-[1-(3-phenylpropane-1-yl)piperidin-4-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide (<BO>4</BO>) as an upregulator of the LDL receptor has been developed. 1-(3-Phenylpropyl)piperidin-4-amine (<BO>7</BO>) was synthesized with 71% yield by the alkylation of 4-aminopyridine (<BO>5</BO>) with 3-phenylpropylbromide followed by reduction with NaBH<INF>4</INF> in the presence of base in a mixture of 2-propanol and methanol. The addition of base (1 equiv), for example, KOH and NaOMe, in the above reduction afforded a decrease of 1-(3-phenylpropyl)-N-[1-(3-phenylpropyl)piperidin-4-yl]piperidin-4-amine (<BO>8</BO>) to increase the yield of <BO>7</BO>. The amidation of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (<BO>1</BO>) with the primary amine (<BO>7</BO>) using EDCI in the presence of HOBt (0.2 equiv) provided <BO>4</BO> in 94% yield.