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

A technology that catalyzes pyridine and asymmetry is applied in asymmetric synthesis, organic chemistry methods, chemical instruments and methods, etc. It can solve problems such as low ee value and 2-aryl substituents that have not been reported, and achieve convenient separation, Simple and practical reaction operation, high reactivity and enantioselectivity

Active Publication Date: 2013-11-13
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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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.)

Method used

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

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Experimental program
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Embodiment 1

[0032] Embodiment 1: condition optimization

[0033] In a nitrogen-filled glove box, add (1,5-cyclooctadiene) iridium chloride dimer (0.0025 mmol, 1.7 mg) and chiral ligand (0.0055 mmol) to the reaction vial Add 1mL mixed solvent toluene / dichloromethane (v / v=1:1), stir at room temperature for 10-30 minutes, then transfer the prepared catalyst to another N-benzylpyridinium salt (0.25mL mol) into the reaction flask, add 2mL solvent mixture solvent toluene / dichloromethane (v / v=1:1). Put the reaction bottle into a stainless steel autoclave, feed hydrogen gas at 600psi, and react at room temperature for 20-24 hours. Slowly release hydrogen, and add saturated Na to the system 2 CO 3 The aqueous solution was stirred for 10 min, then extracted three times with dichloromethane, the organic phases were combined and dried, and the solvent was removed by a rotary evaporator, followed by direct column chromatography (the volume ratio of eluent sherwood oil and ethyl acetate was 10:1-5:1...

Embodiment 2

[0038] Example 2: Synthesis of various chiral piperidine derivatives by iridium-catalyzed asymmetric pyridine hydrogenation

[0039]In a nitrogen-filled glove box, (1,5-cyclooctadiene) iridium chloride dimer (0.0025 mmol, 1.7 mg) and chiral ligand (R)-SynPhos (0.0055 mmol ) into the reaction bottle of 1mL mixed solvent toluene / dichloromethane (v / v=1:1), stirred at room temperature for 10-30 minutes, and then transferred the prepared catalyst to another containing raw material pyridinium salt (0.25 millimoles), add 3mL solvent mixture solvent toluene / dichloromethane (v / v=1:1). Put the reaction bottle into a stainless steel autoclave, feed hydrogen gas at 600psi, and react at room temperature for 20-24 hours. Slowly release hydrogen, and add saturated Na to the system 2 CO 3 The aqueous solution was stirred for 10 min, then extracted three times with dichloromethane, the organic phases were combined and dried, and after removing the solvent with a rotary evaporator, direct co...

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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...

Claims

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Application Information

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IPC IPC(8): C07D211/14C07B53/00
Inventor 周永贵叶智识时磊
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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