Disubstituted 1-Aryl-4-Aminopiperidine Library Synthesis Using Computational Drug Design and High-Throughput Batch and Flow Technologies

Abstract

A platform that incorporates computational library design, parallel solution-phase synthesis, continuous flow hydrogenation, and automated high throughput purification and reformatting technologies was applied to the production of a 120-member library of 1-aryl-4-aminopiperidine analogues for drug discovery screening. The application described herein demonstrates the advantages of computational library design coupled with a flexible, modular approach to library synthesis. The enabling technologies described can be readily adopted by the traditional medicinal chemist without extensive training and lengthy process development times.

The expanding utility of continuous flow hydrogenation

“…45 As an example hydrogenation of 21 with 4%Pt-4%Re/TiO 2 catalyst at 20 bar and 120°C afforded the tertiary amine 22 from the corresponding amide 21 in quantitative yields (Scheme 5). 49 Traditionally the most robust and expedient method for the reduction of aliphatic azo moieties was the employment of a bacterial reductase. amide reduction) with 10% Pd/C at low pressures and mild temperatures providing clean access to 24 and 26 from azido-23 and 25 respectively in near quantitative yields (Scheme 6).…”

“…2,12 These solid supports function to improve surface area and serve to aid catalyst recovery. 24,28 Hydrogenations reactions 2,14 In addition to platinum group metals, RANEY® nickel, RANEY® cobalt, and RANEY® copper are also extensively used as unsupported catalysts for hydrogenation reactions.…”

Accessing New Chemical Entities through Microfluidic Systems

“…Coil reactors may be incorporated as part of an intricate platform for performing key reactions. As such, researchers at Amgen have recently reported flow hydrogenation as an intermediate step to acquire a 120‐member library of 1‐aryl‐4‐aminopiperidines,42 while Ley and co‐workers described a focused library of druglike pyrrolidines through an integrated flow and batch method 43…”

Neue chemische Strukturen durch Mikrofluidiksysteme

“…Coil‐Reaktoren können aber auch für schwierige Reaktionen verwendet werden. Wissenschaftler bei Amgen haben kürzlich die Hydrierung im Durchfluss eines Zwischenproduktes zur Herstellung einer 120‐teiligen Bibliothek von 1‐Aryl‐4‐aminopiperidinen veröffentlicht,42 und auch Ley und Mitarbeiter haben die Synthese einer fokussierten Bibliothek von wirkstoffähnlichen Pyrrolidinen in einer integrierten Fluss‐ und Batch‐Synthese beschrieben 43…”