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Asymmetric catalytic hydrogenation method for 2-pyridinone compounds

An asymmetric and compound technology, applied in the direction of organic chemistry, etc., to achieve good industrialization prospects, good catalytic effect, and high catalytic efficiency

Inactive Publication Date: 2015-09-09
WUHAN UNIV
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

For the asymmetric hydrogenation of 2-pyridine aryl ketones, there are only relatively few reports, and the existing reports have great limitations on the substrate - when the substrate is 2-pyridine-aryl ketone, The ortho position of the aryl group must have a substituent to ensure a high enantioselectivity, otherwise it is very low

Method used

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  • Asymmetric catalytic hydrogenation method for 2-pyridinone compounds
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  • Asymmetric catalytic hydrogenation method for 2-pyridinone compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Example 1: Preparation of (2a) by hydrogenation of (1a)

[0027]

[0028] In a glove box, rhodium bis(1,5-cyclooctadiene)tetrafluoroborate (0.41 mg, 0.001 mmol, 1 mol%) and the chiral ligand (R)-Binapine, 0.0011 mmol, 0.81 mg, 1.1 mol %) was dissolved in dichloromethane (1 mL), stirred at 25° C. for 1 hour, and compound 1a (0.1 mmol) and dichloromethane (1 mL) were added. The reaction system was placed in an autoclave at 25 °C and H 2 (10atm) under the condition of stirring and reacting for 20 hours. Then the solvent was removed under reduced pressure, separated by column chromatography (taking silica gel column, eluent: ethyl acetate / petroleum ether=1 / 2), to obtain pure product 2a, the product was a colorless liquid, and the conversion rate was 99%. HPLC analysis, measured ee value (ee=99%). 1 H NMR (400MHz, CDCl 3 )δ8.53(d,J=4.8Hz,1H),7.70(td,J=8.0,2.0Hz,1H),7.30(d,J=7.6Hz,1H),7.19–7.22(m,1H), 4.90(dd,J=12.8,6.4Hz,1H),4.53(s,1H),1.51(d,J=6.8Hz,3H); 13 C NMR (...

Embodiment 2

[0030] Example 2: Preparation of (2b) by hydrogenation of (1b)

[0031]

[0032] In a glove box, rhodium bis(1,5-cyclooctadiene)tetrafluoroborate (0.41 mg, 0.001 mmol, 1 mol%) and the chiral ligand (R)-Binapine, 0.0011 mmol, 0.81 mg, 1.1 mol %) was dissolved in dichloromethane (1 mL), stirred at 25° C. for 1 hour, and compound 1b (0.1 mmol) and dichloromethane (1 mL) were added. The reaction system was placed in an autoclave at 25 °C and H 2 (10atm) under the condition of stirring and reacting for 20 hours. Then the solvent was removed under reduced pressure, separated by column chromatography (taking silica gel column, eluent: ethyl acetate / petroleum ether=1 / 2), to obtain pure product 2b, the product was analyzed by NMR, and the conversion rate was 99%, and it was analyzed by HPLC Analysis, measured ee value (ee=91%). 1 H NMR (400MHz, CDCl 3 )δ8.51(d, J=4.8Hz, 1H), 7.67(td, J=7.6, 1.2Hz, 1H), 7.28(d, J=8.0Hz, 1.0H), 7.16-7.19(m, 1H) ,4.68(dd,J=6.4,5.2Hz,1H),4.48(s,1H)...

Embodiment 3

[0033] Example 3: Preparation of (2c) by hydrogenation of (1c)

[0034]

[0035] In a glove box, rhodium bis(1,5-cyclooctadiene)tetrafluoroborate (0.41 mg, 0.001 mmol, 1 mol%) and the chiral ligand (R)-Binapine, 0.0011 mmol, 0.81 mg, 1.1 mol %) was dissolved in dichloromethane (1 mL), stirred at 25° C. for 1 hour, and compound 1c (0.1 mmol) and dichloromethane (1 mL) were added. The reaction system was placed in an autoclave at 25 °C and H 2 (10atm) under the condition of stirring and reacting for 20 hours. Then the solvent was removed under reduced pressure, separated by column chromatography (taking silica gel column, eluent: ethyl acetate / petroleum ether=1 / 2), to obtain pure product 2c, the product was analyzed by NMR, and the conversion rate was 99%, and it was analyzed by HPLC Analysis, measured ee value (ee=84%).1 H NMR (400MHz, CDCl 3 )δ8.57(d, J=4.8Hz, 1H), 7.70(td, J=7.6, 1.6Hz, 1H), 7.20-7.27(m, 2H), 4.58(d, J=4.4Hz, 1H), 4.26(s,1H),2.01-2.09(m,1H),1.04(d,J=7....

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Abstract

The invention belongs to the chemical field of medicine synthesis, and relates to an asymmetric catalytic hydrogenation method for 2-pyridinone compounds. The asymmetric catalytic hydrogenation method includes steps of firstly, enabling chiral ligand and metal rhodium precursors to react with one another in organic solvents for 0.5-2 hours at the temperatures of 20-40 DEG C to obtain in-situ catalysts; secondly, arranging reaction systems in an autoclave, adding the 2-pyridinone compounds into the autoclave, enabling the reaction systems and the 2-pyridinone compounds to react with one another for 20-24 hours in hydrogen atmosphere at the reaction temperatures of 0-50 DEG C under the hydrogen pressures of 2-50 atmospheric pressures. The chiral ligand is (R)-Binapine. The asymmetric catalytic hydrogenation method has the advantages that the asymmetric catalytic hydrogenation method is high in catalytic efficiency, and products can be quickly obtained within short time under low-pressure conditions; only a few catalysts are utilized; most 2-pyridone substrates can have conversion rates of 99% and the optimal stereoselectivity of 99%, and accordingly the asymmetric catalytic hydrogenation method has an excellent industrial prospect.

Description

technical field [0001] The invention belongs to the field of pharmaceutical synthesis chemistry and relates to a method for asymmetric hydrogenation of ketone compounds, in particular to an asymmetric catalytic hydrogenation method for 2-pyridone compounds. Background technique [0002] Optically active alcohol compounds are widely used in fine chemicals such as drugs, pesticides, and spices. In recent years, research on various synthesis methods has been increasing. Asymmetric hydrogenation of prochiral ketones is one of the most important methods for preparing optically active alcohols. This method has high catalytic activity, fast reaction time, good atom economy, convenient product separation, simple post-treatment, and few side reactions, thus attracting widespread attention. [0003] For this reason, many chiral ligands have been developed for the asymmetric hydrogenation of prochiral ketones, among which the chiral binaphthyl ligand invented by Japanese scientist Ryo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/30C07D215/26C07D277/64
CPCC07D213/30C07D215/26C07D277/64
Inventor 张绪穆杨海龙
Owner WUHAN UNIV
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