Method for synthesis of chiral piperidine derivative through iridium-catalyzed asymmetric hydrogenation of pyridine

Abstract

A method for synthesis of chiral piperidine derivatives through iridium-catalyzed asymmetric hydrogenation of pyridine employs a catalytic system of chiral diphosphine complex of iridium. The reaction can be carried out under the following conditions: temperature of 25-60 DEG C; a mixed solvent of toluene / dichloromethane (V / V=1:1); pressure of 13-50 barometric pressure; a ratio of substrate and catalyst of 50 / 1; and a catalyst of a complex of (1,5-cyclo-octadiene) iridium chloride dimer and diphosphine ligand. Hydrogenation of pyridine salt can obtain a corresponding chiral 2-substituted piperidine derivative, whose enantiomeric excess can reach 93%. The invention has advantages of simple and practical operation, easily available raw materials, high enantioselectivity, and good yield; in addition, the reaction has green atom economy and is friendly to environment.

Description

technical field [0001] The invention relates to a method for synthesizing chiral piperidine derivatives by using a homogeneous system of iridium to catalyze the hydrogenation of pyridine with high enantioselectivity. technical background [0002] Piperidine and its derivatives are a class of heterocyclic compounds with a wide range of physiological and pharmacological activities, and have high research value and application prospects. These compounds have a variety of potential pharmaceutical activities, such as: anti-cancer, anti-inflammatory, sedative, hypnotic and anti-Alzemer's disease properties. Over the years, the research on the structure and biological activity of these compounds has attracted the attention of the pharmaceutical community. Three common drugs of formula 1 below all contain piperidine structural units: [0003] [0004] In addition to being a drug, piperidine and its derivatives have also been successfully used as chiral auxiliaries and chiral re...

AI Technical Summary

Problems solved by technology

In 2000, studer et al first reported the asymmetric hydrogenation of rhodium-catalyzed 2 or 3-ester substituent pyridine, but the ee value was as low as 25% (Document 1: Studer, M.; Wedemeyer-Exl, C.; Spindler, F.; Blaser, H.U. Monatsh. Chem. 2000, 131, 1335.)

In 2005, Charrette et al. realized the asymmetric hydrogenation of N-pyridine ylides catalyzed by iridium, and the highest ee value reached 90%. The research found that the results for the 2-position alkyl substituent were better, but the 2-position aryl substituent has not been reported. (Document 6: (a) Legault, C.Y.; Charette, A.B.J. Am. Chem. Soc. 2005, 127, 8966. (b) Legault, C.Y.; Charette, A.B.; Cozzi, P.G. Heterocycles 2008, 76, 1271.)

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