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Method for preparing azabicyalo compound by efficient catalysis of o-aminobenzenesulfonic acid and zirconocene Lewis acid

A technology of anthranilic acid and azabicyclo, which is applied in the field of synthesis of azabicyclic skeleton compounds, achieving the effects of high atom economy, short time and broad application prospects

Inactive Publication Date: 2017-03-01
SHAANXI NORMAL UNIV
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The technical problem to be solved by the present invention is to overcome the shortcomings of existing azabicyclic compound preparation methods, and provide a method for preparing azabicyclic compound with mild reaction conditions, short reaction time and high yield

Method used

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  • Method for preparing azabicyalo compound by efficient catalysis of o-aminobenzenesulfonic acid and zirconocene Lewis acid
  • Method for preparing azabicyalo compound by efficient catalysis of o-aminobenzenesulfonic acid and zirconocene Lewis acid
  • Method for preparing azabicyalo compound by efficient catalysis of o-aminobenzenesulfonic acid and zirconocene Lewis acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] Preparation of 2,3-diphenyl-2-azabicyclo[2.2.2]cyclooctane-5-one with the following structural formula

[0013]

[0014] Add 0.0146 g (0.05 mmol) zirconocene dichloride, 0.0172 g (0.1 mmol) anthranilic acid, 100 μL (1.1 mmol) aniline, 102 μL (1 mmol) benzaldehyde, 194 μL (2 mmol) 2 - cyclohexen-1-one, 1 mL of absolute ethanol, stirred and reacted at 35 ° C for 4 hours, stopped the reaction, added 15 mL of ethyl acetate, removed ethyl acetate by rotary evaporation, and separated and removed zirconocene dichloride ( The eluent is a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:5), to obtain 2,3-diphenyl-2-azabicyclo[2.2.2]cyclooctane-5-one, which The yield is 71%, and the dr value is 60:40. The resulting product is characterized by a Bruker Avance type superconducting Fourier digital nuclear magnetic resonance spectrometer, and the characterization data are: E configuration: 1 H NMR (400MHz, CDCl 3 )δ7.41(dt, J=15.0,7.6Hz,4H),7.31(t,J=6.9Hz,1H),...

Embodiment 2

[0016] Preparation of 2-(4-methoxyphenyl)-3-phenyl-2-azabicyclo[2.2.2]cyclooctane-5-one with the following structural formula

[0017]

[0018] In Example 1, the aniline used is replaced with equimolar 4-methoxyaniline, and other steps are the same as in Example 1 to obtain 2-(4-methoxyphenyl)-3-phenyl-2-nitrogen Heterobicyclo[2.2.2]cyclooctan-5-one, its yield rate is 71%, dr value is 80:20, the characterization data of the obtained product is: E configuration: 1 H NMR (400MHz, CDCl 3 )δ7.45-7.35 (m, 4H), 7.29 (t, J = 7.1Hz, 1H), 6.74 (d, J = 9.0Hz, 2H), 6.56 (d, J = 9.1Hz, 2H), 4.71 ( s,1H),4.44(s,1H),3.70(s,3H),2.75(dd,J=12.2,9.4Hz,1H),2.66(d,J=2.8Hz,1H),2.38(d,J =18.7Hz,1H),1.94-1.84(m,1H),1.79-1.69(m,1H),1.66-1.57(m,2H); 13 C NMR (101MHz, CDCl 3 )δ 213.82, 152.07, 142.69, 140.46, 128.79, 127.37, 126.27, 114.89, 114.32, 62.67, 55.67, 51.07, 48.94, 41.95, 26.33, 16.35.

Embodiment 3

[0020] Preparation of 3-(4-methoxyphenyl)-2-phenyl-2-azabicyclo[2.2.2]cyclooctane-5-one with the following structural formula

[0021]

[0022] In Example 1, the benzaldehyde used is replaced with equimolar 4-methoxybenzaldehyde, and other steps are the same as in Example 1 to obtain 3-(4-methoxyphenyl)-2-phenyl-2 -Azabicyclo[2.2.2]cyclooctane-5-one, the yield is 72%, the dr value is 62:38, and the characterization data of the obtained product are: E configuration: 1 H NMR (400MHz, CDCl 3 )δ7.32(d, J=8.6Hz, 2H), 7.15(t, J=7.9Hz, 2H), 6.92(d, J=8.6Hz, 2H), 6.71(t, J=7.2Hz, 1H) ,6.61(d,J=8.5Hz,2H),4.73(s,1H),4.54(s,1H),3.82(s,3H),2.78-2.64(m,2H),2.40(d,J=18.0 Hz,1H),1.94-1.85(m,1H),1.78-1.58(m,3H); 13 C NMR (101MHz, CDCl 3 )δ 213.84, 158.89, 148.20, 131.77, 129.26, 127.16, 117.60, 114.19, 113.05, 61.82, 55.24, 51.13, 48.13, 42.21, 25.97, 16.25.

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Abstract

The invention discloses a method for preparing azabicyalo compounds by efficient catalysis of o-aminobenzenesulfonic acid and zirconocene Lewis acid. The method takes 2-cyclohexene-1-ketone, aromatic aldehyde, and arylamine as raw materials, takes ethanol as a solvent, and takes zirconocene dichloride as a catalyst; under condition that Bronsted acid- o-aminobenzenesulfonic acid is added, the zirconocene dichloride can prepare a series of azabicyalo compounds with high efficiency and high yield. The catalyst has the advantages of little amount, low cost, no toxicity, stabilization on air, mild reaction condition, and high atom economy, after a reaction is complete, the product is subjected to simple separation and recrystallization to obtain the azabicyalo compound. The preparation of the azabicyalo compound opens up a novel approach of low cost, and environmental protection and high efficiency, and has wide application prospect.

Description

technical field [0001] The invention belongs to the technical field of synthesis of azabicyclic skeleton compounds, and in particular relates to a method for synthesizing azabicyclic compounds under the condition of using zirconocene dichloride as a catalyst and anthranilic acid as an additive. Background technique [0002] The azabicyclic skeleton is an important intermediate in the construction of natural products, and its derivatives also have important biological activities, such as: orexin receptor antagonists, monoamine neurotransmitter reuptake inhibitors, etc. And it is identified as a preferred structure in pharmaceutical intermediates, which is of great significance in organic synthesis. Therefore, adopting a simple method to prepare azabicyclic compounds has attracted much attention in the organic and pharmaceutical fields. [0003] The catalysts currently used to prepare azabicyclic framework compounds include Lewis acids, Bronsted acids, transition metal carbon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D453/06B01J31/22
CPCB01J31/2295B01J2531/48C07D453/06
Inventor 高子伟徐珊杨丹丹张伟强郑绍华孙华明张国防
Owner SHAANXI NORMAL UNIV
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