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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 (4) as an upregulator of the LDL receptor has been developed. 1-(3-Phenylpropyl)piperidin-4-amine (7) was synthesized with 71% yield by the alkylation of 4-aminopyridine (5) with 3-phenylpropylbromide followed by reduction with NaBH 4 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 (8) to increase the yield of 7. The amidation of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid (1) with the primary amine (7) using EDCI in the presence of HOBt (0.2 equiv) provided 4 in 94% yield.

An efficient and practical synthetic process for an α-carboline-based Aurora B kinase inhibitor was achieved using an integrated Pd-catalyzed cross-coupling strategy. The process features a mild and efficient method for construction of the α-carboline core by employing a Pd-catalyzed sequence of Buchwald–Hartwig amination and intramolecular direct C–H arylation at the ortho position of an unsubstituted aniline moiety, which is a key functionality for further derivatization with a Suzuki coupling via Sandmeyer iodination. The process has eliminated expensive starting materials and column chromatography purifications and enabled considerable enhancement of the total yield from 11% to 48%.

An efficient large-scale synthesis of a novel DPP-4 inhibitor 1, an isoquinolone derivative bearing an aminomethyl group at the 3-position and carbamoylmethoxy group at the 6-position, is described. We have developed an effective and convenient synthetic method utilizing a key intermediate possessing a cyano group at the 3-position and a halogen atom at the 6-position. The key reaction, the insertion of an oxygen atom at the 6-position of isoquinolone was achieved by a cross-coupling reaction using 6-bromoisoquinolone and sodium tert-butoxide ( t BuONa) in the presence of Pd(OAc)2 and rac-BINAP as a catalyst to afford 6-tert-butoxyisoquinolone in good yield. The cyano group at the 3-position was hydrogenated in the presence of Raney nickel to give the aminomethyl moiety of compound 1. The synthetic route has been successfully applied to multikilogram-scale preparations in good yield and high quality.

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