Method for synthesis of 3-piperidone derivatives through iridium catalytic hydrogenation

A technology of piperidone and hydrogen catalysis, which is applied in the field of synthesizing 3-piperidone derivatives, can solve the problems of cumbersome steps, difficult to scale up synthesis, and long routes, and achieve simple reaction operations, short synthetic routes, and high atom economy Effect

Active Publication Date: 2016-06-22
DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Most existing synthetic methods have long routes, cumbersome steps, and are difficult to enlarge and synthesize [(a) Calvez, O.; Langlois, N. Tetrahedro...

Method used

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  • Method for synthesis of 3-piperidone derivatives through iridium catalytic hydrogenation
  • Method for synthesis of 3-piperidone derivatives through iridium catalytic hydrogenation
  • Method for synthesis of 3-piperidone derivatives through iridium catalytic hydrogenation

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Experimental program
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Embodiment 1

[0031] Embodiment 1: optimization of conditions

[0032] In a nitrogen-filled glove box, the (1,5-cyclooctadiene) iridium chloride dimer (0.001 mmol, 0.7 mg) and the phosphine ligand (0.0022 mmol or 0.0044 mmol) Add 1 milliliter of 1,2-dichloroethane solvent in the reaction bottle, stir at room temperature for 10-15 minutes, then transfer the prepared catalyst to another container containing raw material 3-hydroxypyridinium salt 2a (0.20 mmol, 68.5 mg) and sodium bicarbonate (0.2 mmol, 16.8 mg), wash the bottle with 2 ml of solvent, transfer the residual catalyst, and share 3 ml of solvent 1,2-dichloroethane. The reaction bottle was put into a stainless steel autoclave, hydrogen gas was introduced at 600 psi, and the reaction was carried out at 50° C. for 20 hours. Slowly release hydrogen, filter the reaction solution, remove the solvent with a rotary evaporator and then directly column chromatography (the volume ratio of the eluent petroleum ether and ethyl acetate is 5:1), ...

Embodiment 2

[0037] Embodiment 2: Synthesis of 3-piperidone derivatives by homogeneous iridium catalyzed hydrogenation

[0038] In a nitrogen-filled glove box, (1,5-cyclooctadiene) iridium chloride dimer (0.001 mmol, 0.7 mg) and triphenylphosphine ligand (0.0044 mmol, 1.2 mg ) into the reaction flask of 1 milliliter of solvent 1,2-dichloroethane, stirred at room temperature for 10-15 minutes, then transferred the prepared catalyst to another containing raw material 3-hydroxypyridinium salt 2 (0.20 mmol ) and sodium bicarbonate (0.2 mmol, 16.8 mg), wash the bottle with 2 ml of solvent, transfer the residual catalyst, and share 3 ml of solvent 1,2-dichloroethane. Put the reaction bottle into a stainless steel autoclave, feed hydrogen gas at 600psi, and react at 50°C for 20-30 hours. Slowly release hydrogen, filter the reaction solution, remove the solvent with a rotary evaporator, and then direct column chromatography (the volume ratio of eluent petroleum ether and ethyl acetate is 10:1-3:1...

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Abstract

A method for synthesis of 3-piperidone derivatives through iridium catalytic hydrogenation is provided, wherein a used catalyst is a triphenylphosphine complex of iridium. A reaction can be carried out under the following conditions: the temperature is 40-60 DEG C; the solvent is 1,2-dichloroethane; the pressure is 20-50 atmospheric pressures; the ratio of a substrate to a catalyst is 100 to 1; and the catalyst is a complex of chloro(1,5-cyclooctadiene)iridium(I) dimer and triphenylphosphine. Hydrogenation of 3-hydroxypyridine benzyl bromide salt can obtain the 3-piperidone derivatives with excellent chemoselectivity, the highest yield can reach 97%, and the chemical selectivity of ketones and alcohols is greater than 20:1. The method has the advantages of simple and convenient operation, easily obtained raw materials, high chemoselectivity, and good yield, and provides an atom economic and environment-friendly route for synthesis of a series of 3-piperidone derivatives.

Description

technical field [0001] The invention relates to a method for synthesizing 3-piperidone derivatives through iridium-catalyzed hydrogenation of 3-hydroxypyridinium salt with high chemoselectivity and high yield. technical background [0002] 3-piperidone is a very important intermediate in the synthesis of 3-hydroxyl and 3-aminopiperidine, and 2-substituted 3-hydroxyl or 3-aminopiperidine structures are widely found in natural products and pharmaceutically active molecules. Natural products such as Febrifugine and Isofebrifugine, the former having potent antimalarial activity [(a) Koepfli, J.B.; Mead, J.F.; Brockman, Jr., J.A., J. Am. Chem. Soc. 1949, 71, 1048.]. Pharmaceutically active molecules such as (+)-L-733,060 and (+)-CP-99,994 exhibit regulatory effects on multiple physiological processes, such as neurogenic inflammation, pain transmission, immune response regulation, etc. [(a) Baker, R .; Harrison, T.; Hollingworth, G.J.; Swain, C.J.; Williams, B.J. EP528, 495A1, 1...

Claims

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Application Information

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IPC IPC(8): C07D211/74
Inventor 周永贵黄文学吴波宋波陈木旺
Owner DALIAN INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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