Optimization and Scale-Up of an Asymmetric Route to the LTB₄ Inhibitor Ontazolast

Abstract

An efficient asymmetric synthesis of the LTB 4 inhibitor Ontazolast is described. Commercially available (S)-r-pinene, which contains a 93.5% enantiomeric excess (ee) of the desired isomer, can be oxidized using phase-transfer conditions to the corresponding (R)-hydroxy ketone. Condensation of this keto alcohol with 2-(aminomethyl)pyridine provides an intermediate imine that can be alkylated with cyclohexylmethyl bromide or iodide. The alkylation proceeds with nearly complete transfer of chirality under mild conditions. Cleavage of the chiral auxiliary and isolation of the resulting (S)-pyridylamine by crystallization with L-tartaric acid furnishes the key amine building block in >99% ee and in excellent overall yield. The tartrate salt is then directly converted to the final product. The reaction sequence is described on a multigram scale.

Asymmetric Synthesis of Active Pharmaceutical Ingredients

“…Ontazolast (BIRM270, Scheme ) is a novel LTB 4 inhibitor discovered by Boehringer Ingelheim . To support further development activities, a scalable asymmetric route was established by using a highly diastereoselective alkylation of a chiral Schiff base …”

“…Ontazolast (BIRM270, Scheme 15) is a novel LTB 4 inhibitor discovered by Boehringer Ingelheim. 33 To support further development activities, a scalable asymmetric route was established by using a highly diastereoselective alkylation of a chiral Schiff base. 34 In preliminary studies, alkylation of the Schiff base prepared from amine 53 and camphor provided only modest selectivity (35% e.e.…”

Chirality-Economy Catalysis: Asymmetric Transfer Hydrogenation of Ketones by Ru-Catalysts of Minimal Stereogenicity

“…Catalytic reduction of 43 produced the desired cyclohexyl (1-(pyridine-2-yl)­methanmine in 90% yield and >99% ee. The method is more efficient and economic than the conventional chiral auxiliary-based strategy …”

“…The method is more efficient and economic than the conventional chiral auxiliary-based strategy. 14 In summary, we have described the design and discovery of new Ru-catalysts in which a single element of chirality induces high enantioselectivity in the asymmetric transfer hydrogenation for a broad range of carbonyl substrates (39 examples, >90% ee), including substrates that are not possible with literature-known protocols. This work would suggest a strategy for catalyst design and help stimulate structural tailoring of some catalysts toward high levels of simplicity, efficiency, and practicality.…”

Asymmetric Synthesis of 2-(α-Aminoalkyl)oxazoles, 2-Oxazolylpyrrolidines, 2-Oxazolylpiperidines: Total Synthesis of 4,5-Dihydroxypipecolinic Acid

“…8,10 The same strategy was applied in the asymmetric alkylation of 2aminomethylpyridine used for the synthesis of Ontazolast ® , a potent LTB 4 -inhibitor. 11 Optically active piperidine and pyrrolidine-2-carboxylic acids could be synthesized by alkylation of imines of hydroxypinanone and a-amino ester using a,w-dihaloalkanes, cleaving the imine and final intramolecular alkylation of the resulting amino group. 12 In the oxazole and oxadiazole series a diastereoselective a-alkylation was achieved at prolinolylmethyl side chains.…”