Method for synthesizing 7-carbonyl cholesterol through photoelectric promotion

Abstract

The invention relates to the field of synthetic chemistry, and particularly discloses a method for synthesizing 7-carbonyl cholesterol through photoelectric promotion, which comprises the following steps: taking cholesterol as a raw material, adding N-hydroxyphthalimide, electrolyte and a polar solvent to form a reaction system, illuminating the reaction system and applying current to enable the cholesterol to be subjected to oxidation reaction to obtain 7-carbonyl cholesterol, according to the method, carbon positive ion free radicals generated on line under photo / electrochemical promotion are directly used, the carbon positive ion free radicals and singlet oxygen can directly generate the 7-carbonyl cholesterol, generation of by-products can be reduced, repeated purification operation does not need to be carried out, the yield is high, and the method is suitable for industrial production. The 7-carbonyl cholesterol pure product can be conveniently obtained, the synthesis cost is greatly reduced, and the synthesis time efficiency is improved.

Description

Technical Field

[0001] The invention relates to the field of synthetic chemistry, and in particular to a method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol. Background Art

[0002] 7-Carbonyl cholesterol is considered to be one of the cholesterol metabolites caused by oxidative stress or free radical damage. It may have toxic effects on cells in the body through various mechanisms, including damaging cell membranes, activating immune responses, and inducing inflammation. 7-Carbonyl cholesterol may play a key role in the occurrence of atherosclerosis. Studies have shown that 7-carbonyl cholesterol can promote macrophage activation, inflammatory responses, and lipid deposition, leading to vascular endothelial damage. In the nervous system, 7-carbonyl cholesterol is believed to be associated with the occurrence of neurodegenerative diseases such as Alzheimer's disease. It may participate in degenerative changes in the nervous system by causing oxidative damage to nerve cells, inflammatory responses, and abnormal neurotransmission.

[0003] At present, the methods for synthesizing 7-carbonyl cholesterol are mainly enzymatic reactions or through the action of other oxidants. However, the above reaction processes often involve disadvantages such as strong oxidants and poor selectivity, which may produce other cholesterol oxides and require multiple purifications. Excessive operations will make it difficult to control the oxidation yield and purity of the product. Summary of the invention

[0004] In view of the above-mentioned deficiencies in the prior art, the object of the present invention is to provide a method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol.

[0005] In order to achieve the above object, the technical solution of the present invention is:

[0006] A method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol comprises the following steps: cholesterol is used as a raw material, N-hydroxyphthalimide is used as an electron transfer carrier, and an electrolyte and a polar solvent are added to form a reaction system, current and light are applied to the reaction system, cholesterol is oxidized with air under photoelectric conditions, and after the reaction is completed, 7-carbonyl cholesterol is obtained by separation and purification through silica gel column chromatography.

[0007] Furthermore, the electrolyte is tetrabutylammonium chloride and / or tetrabutylammonium bromide, and the concentration of the electrolyte in the system is 0.01 to 0.05 mmol / mL.

[0008] Furthermore, the dosage ratio of cholesterol to N-hydroxyphthalimide is: 0.09 mmol N-hydroxyphthalimide is added for every 0.3 mmol cholesterol.

[0009] Furthermore, the polar solvent is one or more of acetonitrile, N,N-dimethylformamide, dichloromethane, and acetone, and the usage ratio of the polar solvent to cholesterol is: 5 to 10 mL of reaction solvent is added for every 0.3 mmol of cholesterol, that is, the concentration range of cholesterol in the polar solvent is 0.03 mmol to 0.06 mmol / mL.

[0010] Furthermore, the constant current is 5 to 20 mA, the illumination wavelength is 370 nm, the oxidation reaction time is 5 to 10 h, and a constant current of appropriate size is used to avoid the current being too small, resulting in the voltage failing to reach the redox potential of the compound, and the current being too large, resulting in excessive oxidation of the compound.

[0011] Furthermore, during the oxidation reaction, nuclear magnetic resonance spectroscopy and mass spectrometry were used to monitor the progress of the reaction, and the reaction was terminated when the cholesterol was completely consumed.

[0012] Furthermore, the electrode materials used in the oxidation reaction are a carbon electrode and a platinum electrode, the carbon electrode serves as an anode, and the platinum electrode serves as a cathode.

[0013] Furthermore, the carbon electrode is one of carbon cloth, carbon felt, carbon plate, and carbon rod, and the platinum electrode is a platinum sheet.

[0014] Furthermore, after the oxidation reaction is completed, the polar solvent is dried under vacuum, and then 7-carbonyl cholesterol is separated and purified by silica gel column chromatography, and the eluent is dried under vacuum to obtain pure 7-carbonyl cholesterol.

[0015] Furthermore, the silica gel selected for the silica gel column chromatography is 200-300 mesh, the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 10-1:1.

[0016] The beneficial effects of the present invention are as follows: the present invention directly uses carbon cation free radicals generated online under the promotion of light / electrochemistry to directly generate 7-carbonyl cholesterol with singlet oxygen, thereby reducing the generation of by-products and eliminating the need for repeated purification operations. Pure 7-carbonyl cholesterol can be easily obtained, thereby reducing the risk of yield reduction, greatly reducing the synthesis cost, and improving the synthesis time efficiency; in addition, the reactants are cheap and easily available, the reaction process is simple and controllable, easy to operate, low in cost, and easy to carry out scaled-up synthesis. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Synthesis route of 7-carbonylcholesterol under photoelectric conditions;

[0018] Figure 2 is the carbon NMR spectrum of 7-carbonyl cholesterol;

[0019] Figure 3 7-Carbonylcholesterol [M+H]+ High-resolution mass spectrum. DETAILED DESCRIPTION

[0020] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field belong to the protection scope of the present invention.

[0021] Embodiment 1

[0022] A method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol, Figure 1 The synthetic route is shown, and the specific method is as follows:

[0023] Cholesterol (116 mg, 0.3 mmol), N-hydroxyphthalimide (14.7 mg, 0.09 mmol) and electrolyte tetra-n-butylammonium chloride (83 mg, 0.3 mmol) were added to a three-mouth reaction tube, a stirrer was added, a 1 cm*1 cm*0.3 mm carbon cloth electrode and a platinum sheet electrode were fixed to a 24# rubber stopper through an electrode clamp, respectively, as the anode and cathode of the reaction, and then fixed to the three-mouth reaction tube, and the three ports of the three-mouth reaction tube were sealed with rubber stoppers. Next, 1 mL of dichloromethane and 5 mL of acetone were added to the above three-mouth reaction tube as reaction solvents, and then reacted for 5 hours under constant current 10 mA and 370 nm illumination conditions. After the reaction is completed, the solvent is dried under vacuum, and 7-carbonyl cholesterol is separated and purified by 200-300 mesh silica gel column chromatography, the eluent is a mixture of petroleum ether and ethyl acetate, the volume ratio of petroleum ether to ethyl acetate is 10:1, and the eluting solvent is dried under vacuum to obtain the product 7-carbonyl cholesterol. The theoretical yield of 7-carbonyl cholesterol is 120 mg, and the actual mass of the obtained product is 84 mg, the yield is 70%, and the product purity is>98% (NMR).

[0024] Comparative Example

[0025] Oxidant method, a method for synthesizing 7-carbonyl cholesterol by oxidation of tert-butyl hydrogen peroxide, the specific process is as follows:

[0026] Cholesterol (116 mg, 0.3 mmol), 70% tert-butyl hydroperoxide aqueous solution (1.37 mL, 10 mmol), dichloromethane (1 mL) and acetone (5 mL) were added to a 10 mL round-bottom flask, a stirring bar was added, the bottle mouth was sealed with a rubber stopper, and replaced with a nitrogen atmosphere. The reaction was carried out at 50 ° C for 12 hours. After the reaction was completed, the solvent was dried under vacuum, and 7-carbonyl cholesterol was separated and purified by 200-300 mesh silica gel column chromatography. The eluent was a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate was 10:1. The elution solvent was dried under vacuum to obtain the product 7-carbonyl cholesterol. The theoretical yield of 7-carbonyl cholesterol was 120 mg, and the actual mass of the obtained product was 9 mg, the yield was 7.5%, and the product purity was >98% (NMR).

[0027] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. All modifications, equivalent substitutions, improvements, etc. within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol, characterized in that: The steps are as follows: cholesterol is used as a raw material, N-hydroxyphthalimide, an electrolyte and a polar solvent are added to form a reaction system, the reaction system is illuminated and an electric current is applied to allow the cholesterol to undergo an oxidation reaction, and after the reaction is completed, separation and purification are performed by silica gel column chromatography to obtain 7-carbonyl cholesterol.

2. The method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol according to claim 1, characterized in that: The electrolyte is tetrabutylammonium chloride and / or tetrabutylammonium bromide, and the concentration of the electrolyte in the system is 0.01-0.05 mmol / mL.

3. The method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol according to claim 1, characterized in that: The dosage ratio of cholesterol to N-hydroxyphthalimide is: 0.09 mmol N-hydroxyphthalimide is added for every 0.3 mmol cholesterol.

4. The method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol according to claim 1, characterized in that: The polar solvent is one or more of acetonitrile, N,N-dimethylformamide, dichloromethane, and acetone. The usage ratio of the polar solvent to cholesterol is: 5 to 10 mL of reaction solvent is added for every 0.3 mmol of cholesterol.

5. The method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol according to claim 1, characterized in that: The current is a constant current of 5 to 20 mA, the light wavelength is 370 nm, and the oxidation reaction time is 5 to 10 hours.

6. The method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol according to claim 1, characterized in that: During the oxidation reaction, nuclear magnetic resonance spectroscopy and mass spectrometry were used to monitor the progress of the reaction. When the cholesterol was completely consumed, the reaction was completed.

7. The method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol according to claim 1, characterized in that: The electrode materials used in the oxidation reaction are a carbon electrode and a platinum electrode, wherein the carbon electrode serves as an anode and the platinum electrode serves as a cathode.

8. The method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol according to claim 7, characterized in that: The carbon electrode is one of carbon cloth, carbon felt, carbon plate and carbon rod, and the platinum electrode is a platinum sheet.

9. The method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol according to claim 1, characterized in that: After the oxidation reaction is completed, the polar solvent is dried by vacuum spin drying, and then 7-carbonyl cholesterol is separated and purified by silica gel column chromatography, and the eluent is dried by vacuum spin drying to obtain pure 7-carbonyl cholesterol.

10. The method for photoelectrically promoting the synthesis of 7-carbonyl cholesterol according to claim 1, characterized in that: The silica gel selected for the silica gel column chromatography is 200-300 meshes, the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of petroleum ether to ethyl acetate is 10-1:1.

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