Electrochemical oxidation synthesis method of 7-ketone-cholesteryl acetate

Abstract

The invention discloses an electrochemical oxidation synthesis method of 7-ketone-cholesteryl acetate, which comprises the following steps: enabling current to pass through a solution containing cholesteryl acetate from an anode to a cathode, and carrying out electrochemical oxidation on an allyl C-H bond of the cholesteryl acetate to obtain the 7-ketone-cholesteryl acetate. The reaction is milder, green and environment-friendly, an exogenous oxidizing agent or reducing agent does not need to be used, the generation of byproducts is reduced, and the selectivity is remarkably improved.

Description

Technical Field

[0001] The invention belongs to the field of vitamin preparation, and particularly relates to an electrochemical oxidation synthesis method of 7-keto-cholesterol acetate. Background Art

[0002] 7-Keto-cholesterol acetate (B) is an important raw material for the synthesis of 7-dehydrocholesterol, an intermediate of vitamin D3. The existing technology is to obtain 7-dehydrocholesterol from 7-keto-cholesterol acetate through several steps of hydrazolation, dehydrazolation, and saponification. However, the preparation of 7-keto-cholesterol acetate still has many problems. Currently, it is mainly prepared by oxidizing the allyl C-H bond of cholesterol acetate (A).

[0003]

[0004] The traditional method for preparing 7-keto-cholesterol acetate is catalyzed by transition metals and their complexes, such as Cr, Fe, Cu, and Co. Chromium salts, including chromium oxide, potassium dichromate, and sodium dichromate, are common oxides. However, when chromium salts are used as oxidants, the amount of oxidant required is large, which can easily cause heavy metal pollution to the environment and is difficult to adapt to the development of green industries. Another common method is to oxidize allyl groups using catalytic amounts of selenides. However, this method uses relatively large amounts of selenides, which poses serious environmental risks and is difficult to widely use. In addition, a new method for oxidizing allyl C-H bonds using oxygen in the presence of nitrogen oxide catalysts has received increasing attention and reports. However, this method, which uses oxygen for oxidation, carries significant potential risks and is not conducive to industrial production.

[0005] In recent years, electrochemical synthesis technology has developed rapidly. Compared with traditional chemical synthesis methods, electrochemical synthesis methods have advantages such as mild reaction conditions, environmental friendliness, and the absence of exogenous oxidants or reducing agents, which has attracted extensive discussion and research among scientists. Unfortunately, there are still no reports on the synthesis of 7-keto-cholesterol acetate using electrochemical synthesis methods. Therefore, the development of a greener and safer electrochemical synthesis method for 7-keto-cholesterol acetate has important application value. Summary of the Invention

[0006] The present invention aims to provide an electrochemical oxidation synthesis method for 7-keto-cholesterol acetate, which has the advantages of mild reaction conditions, environmental friendliness, and no need for exogenous oxidants or reducing agents, and is more suitable for industrial production.

[0007] In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is:

[0008] The invention provides a method for synthesizing 7-keto-cholesterol acetate. The method comprises the following steps: passing an electric current from an anode to a cathode through a solution containing cholesterol acetate, and electrochemically oxidizing the allyl C—H bonds of the cholesterol acetate to obtain 7-keto-cholesterol acetate.

[0009] Preferably, the anode material includes but is not limited to carbon felt, graphite felt, and foamed glassy carbon.

[0010] More preferably, the anode material is heat-treated in a muffle furnace at 300-1000° C. for 1-10 hours to obtain modified carbon felt or graphite felt.

[0011] The cathode material is not a critical factor. Any material that is chemically stable and conductive in the electrolyte can be used, such as carbon materials such as carbon felt, graphite felt, foamed glassy carbon (RVC), and metal materials such as platinum, silver and nickel.

[0012] Preferably, the organic solvent includes but is not limited to acetone, acetonitrile, dichloromethane, pyridine, N,N-dimethylformamide, toluene, tetrahydrofuran, and methanol.

[0013] Preferably, the electrolyte includes but is not limited to perchlorate, quaternary ammonium salt, and sulfonate.

[0014] Preferably, the catalyst includes but is not limited to N-hydroxy derivatives such as N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxy-2,3-naphthalimide, N-hydroxy-3,4,5,6-tetraphenylphthalimide, 3-picolyl-N-hydroxyphthalimide, N-hydroxytetrachlorophthalimide and N-hydroxytetrafluorophthalimide.

[0015] Preferably, the co-oxidant includes but is not limited to tert-butyl hydroperoxide, benzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, cyclohexanone peroxide, and peracetic acid.

[0016] Preferably, the initiator includes but is not limited to Co 2+ 、Cu 2+ 、Ni 2+ Cr 3+ 、Fe 3+ 、V 3+ 、Ti 2+ 、Mn 2+ 、Fe 2+ 、Zn 2+ , pyridine, picoline, lutidine and trimethylpyridine.

[0017] Due to the adoption of the above technical solution, the present invention has the following beneficial effects:

[0018] The present invention prepares 7-keto-cholesterol acetate through an electrochemical oxidation method. This synthesis method suppresses the generation of by-products, significantly improves selectivity, has the advantages of mild reaction conditions, is environmentally friendly, and does not require the use of exogenous oxidants or reducing agents. It is more suitable for industrial production and is a high-efficiency, low-cost synthesis method. DETAILED DESCRIPTION

[0019] The content of 7-keto-cholesterol acetate in the examples was determined using high-performance liquid chromatography. The HPLC analysis conditions were: a chromatographic column (250 mm length × 4.6 mm ID, 5 μm particle size) as the separation column, a mobile phase consisting of a 95 / 5 mixture of acetonitrile and methanol (containing 100 μl / L glacial acetic acid) in a volume ratio, a 20 μL injection volume, an injection temperature of 30°C, an isocratic elution flow rate of 1 mL / min, an ultraviolet detector at a wavelength of 210 nm, and an external standard method for determining the standard curve for product quantification.

[0020] Example 1

[0021] Cut the carbon felt into 1.5cm×2.5cm pieces, clean the grease on the electrode surface with acetone ultrasonic for 15 minutes, and then wash it with deionized water 2-3 times. In a single-chamber electrolytic cell, the pretreated carbon felt is used as the cathode and anode, and the distance between the cathode and anode is 1cm. Then, 12mL of acetone solution containing 0.1mmol / L cholesterol acetate, 0.1mol / L sodium perchlorate, 0.02mmol / L N-hydroxytetrachlorophthalimide, 0.04mmol / L nickel nitrate hexahydrate and 0.15mmol / L tert-butyl hydroperoxide is used as the electrolyte, and 0.8mA / cm 2 The electrolysis was carried out at a current density of ; the temperature was 30°C, the solution pH was controlled at 7, the reaction time was 5h, and the yield of the product 7-keto-cholesterol acetate was 88%.

[0022] Example 2 to Example 18

[0023] Examples 2 to 18 were carried out according to the experimental parameters in Table 1, and the experimental operations were the same as those in Example 1.

[0024] Table 1: Experimental parameters of Examples 2 to 18.

[0025]

[0026]

[0027]

[0028]

[0029] Example 19

[0030] Cut the carbon felt into 1.5cm×2.5cm pieces, use acetone ultrasonic treatment for 15 minutes to clean the grease on the electrode surface, then wash it with deionized water 2-3 times, put it in an oven to dry, and then heat treat it at 500℃ in a muffle furnace for 2 hours to obtain a modified carbon felt electrode. Then, in a single-chamber electrolytic cell, the modified carbon felt electrodes were used as cathode and anode, with a distance of 1cm between the cathode and anode. Then, 12mL of acetone solution containing 0.1mmol / L cholesterol acetate, 0.1mol / L sodium perchlorate, 0.02mmol / L N-hydroxytetrachlorophthalimide, 0.04mmol / L nickel nitrate hexahydrate and 0.15mmol / L tert-butyl hydroperoxide was used as the electrolyte, and 0.8mA / cm 2 The electrolysis was carried out at a current density of ; the temperature was 30°C, the solution pH was controlled at 7, the reaction time was 5h, and the yield of the product 7-keto-cholesterol acetate was 97%.

[0031] Example 20

[0032] Cut graphite felt of 1.5cm×2.5cm, use acetone ultrasonic for 15min to clean the grease on the electrode surface, and then wash it with deionized water 2-3 times. Then use the pretreated graphite felt as cathode and anode in a single-chamber electrolytic cell, with a distance of 1cm between the cathode and anode. Then use 12mL of acetone solution containing 0.1mmol / L cholesterol acetate, 0.1mol / L sodium perchlorate, 0.02mmol / L N-hydroxytetrachlorophthalimide, 0.04mmol / L nickel nitrate hexahydrate and 0.15mmol / L tert-butyl hydroperoxide as the electrolyte, and apply 0.8mA / cm 2 The electrolysis was carried out at a current density of ; the temperature was 30°C, the solution pH was controlled at 7, the reaction time was 5h, and the yield of the product 7-keto-cholesterol acetate was 87%.

[0033] Example 21

[0034] Cut graphite felt of 1.5cm×2.5cm, use acetone ultrasonic treatment for 15 minutes to clean the grease on the electrode surface, then wash it with deionized water 2-3 times, put it in an oven to dry, and then heat treat it at 500℃ in a muffle furnace for 2h to obtain a modified carbon felt electrode. Then, in a single-chamber electrolytic cell, the pretreated graphite felt is used as the cathode and anode, and the distance between the cathode and anode is 1cm. Then, 12mL of acetone solution containing 0.1mmol / L cholesterol acetate, 0.1mol / L sodium perchlorate, 0.02mmol / L N-hydroxytetrachlorophthalimide, 0.04mmol / L nickel nitrate hexahydrate and 0.15mmol / L tert-butyl hydroperoxide is used as the electrolyte, and 0.8mA / cm 2The electrolysis was carried out at a current density of ; the temperature was 30°C, the solution pH was controlled at 7, the reaction time was 5h, and the yield of the product 7-keto-cholesterol acetate was 96%.

[0035] Comparative Example 1

[0036] Cut a 1.5cm×2.5cm piece of carbon felt and clean the grease on the electrode surface with acetone ultrasonic treatment for 15 minutes, then rinse with deionized water 2-3 times. In a single-chamber electrolytic cell, the pretreated carbon felt is used as the cathode and anode, with a distance of 1cm between the cathode and anode. Then, 12mL of acetone solution containing 0.1mmol / L cholesterol acetate and 0.1mol / L sodium perchlorate is used as the electrolyte, and 0.8mA / cm is applied. 2 The electrolysis was carried out at a current density of ; the temperature was 30°C, the solution pH was controlled at 7, the reaction time was 5h, and the yield of the product 7-keto-cholesterol acetate was 11%.

[0037] Comparative Example 2

[0038] Cut the carbon felt into 1.5cm×2.5cm pieces, clean the grease on the electrode surface with acetone ultrasonic for 15 minutes, and then wash it with deionized water 2-3 times. In a single-chamber electrolytic cell, the pretreated carbon felt is used as the cathode and anode, with a distance of 1cm between the cathode and anode. Then, 12mL of acetone solution containing 0.1mmol / L cholesterol acetate, 0.1mol / L sodium perchlorate, and 0.02mmol / L N-hydroxytetrachlorophthalimide is used as the electrolyte, and 0.8mA / cm is applied. 2 The electrolysis was carried out at a current density of ; the temperature was 30°C, the solution pH was controlled at 7, the reaction time was 5h, and the yield of the product 7-keto-cholesterol acetate was 41%.

[0039] Comparative Example 3

[0040] Cut the carbon felt into 1.5cm×2.5cm pieces, clean the grease on the electrode surface with acetone ultrasonic for 15 minutes, and then wash it with deionized water 2-3 times. In a single-chamber electrolytic cell, the pretreated carbon felt is used as the cathode and anode, and the distance between the cathode and anode is 1cm. Then, 12mL of acetone solution containing 0.1mmol / L cholesterol acetate, 0.1mol / L sodium perchlorate, 0.02mmol / L N-hydroxytetrachlorophthalimide, and 0.04mmol / L nickel nitrate hexahydrate is used as the electrolyte, and 0.8mA / cm is applied. 2 The electrolysis was carried out at a current density of ; the temperature was 30°C, the solution pH was controlled at 7, the reaction time was 5h, and the yield of the product 7-keto-cholesterol acetate was 55%.

[0041] Comparative Example 4

[0042] Cut the carbon felt into 1.5cm×2.5cm pieces, clean the grease on the electrode surface with acetone ultrasonic for 15 minutes, and then wash it with deionized water 2-3 times. In a single-chamber electrolytic cell, the pretreated carbon felt is used as the cathode and anode, and the distance between the cathode and anode is 1cm. Then, 12mL of acetone solution containing 0.1mmol / L cholesterol acetate, 0.1mol / L sodium perchlorate, 0.04mmol / L nickel nitrate hexahydrate and 0.15mmol / L tert-butyl hydroperoxide is used as the electrolyte, and 0.8mA / cm 2 The electrolysis was carried out at a current density of ; the temperature was 30°C, the solution pH was controlled at 7, the reaction time was 5h, and the yield of the product 7-keto-cholesterol acetate was 21%.

[0043] The above are only specific embodiments of the present invention, but the technical features of the present invention are not limited thereto. Any simple changes, equivalent substitutions, or modifications based on the present invention to solve substantially the same technical problems and achieve substantially the same technical effects are included within the scope of protection of the present invention.

Claims

1. A method for electrochemical oxidation synthesis of 7-keto-cholesterol acetate, characterized in that: An electric current is passed from the anode to the cathode through a solution containing cholesterol acetate, and the allyl CH bond of cholesterol acetate is electrochemically oxidized to produce 7-keto-cholesterol acetate.

2. The electrochemical oxidation synthesis method of 7-keto-cholesterol acetate according to claim 1, characterized in that: Anode materials include but are not limited to carbon felt, graphite felt, and foamed glassy carbon.

3. The electrochemical oxidation synthesis method of 7-keto-cholesterol acetate according to claim 1, characterized in that: The anode material is heat-treated at 300-1000 DEG C in a muffle furnace for 1-10 hours to obtain modified carbon felt or graphite felt.

4. The electrochemical oxidation synthesis method of 7-keto-cholesterol acetate according to claim 1, characterized in that: Cathode materials include, but are not limited to, carbon felt, graphite felt, foamed glassy carbon, platinum, silver, and nickel.

5. The electrochemical oxidation synthesis method of 7-keto-cholesterol acetate according to claim 1, characterized in that: The solution containing cholesterol acetate includes an organic solvent and an electrolyte, and further includes one or more of a catalyst, an oxidant promoter and an initiator.

6. The electrochemical oxidation synthesis method of 7-keto-cholesterol acetate according to claim 5, characterized in that: Organic solvents include, but are not limited to, acetone, acetonitrile, dichloromethane, pyridine, N,N-dimethylformamide, toluene, tetrahydrofuran, and methanol.

7. The electrochemical oxidation synthesis method of 7-keto-cholesterol acetate according to claim 5, characterized in that: Electrolytes include, but are not limited to, perchlorates, quaternary ammonium salts, and sulfonates.

8. The electrochemical oxidation synthesis method of 7-keto-cholesterol acetate according to claim 5, characterized in that: Catalysts include, but are not limited to, N-hydroxy derivatives such as N-hydroxysuccinimide, N-hydroxyphthalimide, N-hydroxy-2,3-naphthalimide, N-hydroxy-3,4,5,6-tetraphenylphthalimide, 3-picolyl-N-hydroxyphthalimide, N-hydroxytetrachlorophthalimide, and N-hydroxytetrafluorophthalimide.

9. The electrochemical oxidation synthesis method of 7-keto-cholesterol acetate according to claim 5, characterized in that: Co-oxidants include, but are not limited to, tert-butyl hydroperoxide, benzoyl peroxide, lauroyl peroxide, cumene hydroperoxide, cyclohexanone peroxide, and peracetic acid.

10. The electrochemical oxidation synthesis method of 7-keto-cholesterol acetate according to claim 5, characterized in that: Initiators include but are not limited to Co 2+ 、Cu 2+ 、Ni 2+ Cr 3+ 、Fe 3+ 、V 3+ 、Ti 2+ 、Mn 2+ 、Fe 2+ 、Zn 2+ , pyridine, picoline, lutidine and trimethylpyridine.

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