CN112794875A - Electrocatalytic oxidation production process and device for 19-nor-4-androstene-3, 17-dione - Google Patents
Electrocatalytic oxidation production process and device for 19-nor-4-androstene-3, 17-dione Download PDFInfo
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Abstract
The invention discloses a 19-nor-4-androstene-3, 17-dione electrocatalytic oxidation production process and a device, wherein the process comprises the following steps: adding 19-hydroxymethyl-4-androstene-3, 17-dione, nitroxide free radical and mixed solvent into an anode chamber to form an anode reaction solution, adding an alkaline buffer solution into a cathode chamber, dividing an electrolytic reaction tank into a left pole chamber and a right pole chamber by a cation exchange membrane, driving the anode reaction solution to circularly flow between the anode chamber and the left pole chamber of the electrolytic reaction tank, simultaneously driving the alkaline buffer solution to circularly flow between the cathode chamber and the right pole chamber of the electrolytic reaction tank, generating an aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione through electrocatalytic oxidation reaction, and directly heating and stirring to react to obtain a product 19-nor-4-androstene-3, 17-dione. Compared with the prior art for preparing the 19-nor-4-androstene-3, 17-dione, which has the technical problems of high cost, great environmental pollution, low yield and the like, the process provided by the invention has the advantages of low production cost, high yield of target products, short production period and the like.
Description
Technical Field
The invention relates to a chemical synthesis method of steroid hormone drugs, belongs to the technical field of fine chemical production, and particularly relates to an electrocatalytic oxidation production process and device for 19-nor-4-androstene-3, 17-dione.
Background
19-nor-4-androstene-3, 17-dione (III) is an important steroid hormone drug intermediate, and can be used for preparing norethindrone, dienogest, mifepristone, ulipristal acetate, tibolone and the like. In the prior art, the method for preparing 19-nor-4-androstene-3, 17-dione (III) usually takes 19-hydroxymethyl-4-androstene-3, 17-dione (I) as a raw material, and obtains a 19-nor-4-androstene-3, 17-dione (III) product through oxidation and elimination of two steps. The oxidation step is typically carried out using an equivalent chromium-containing Jones oxidizer (chromic acid/concentrated sulfuric acid) (Templeton J. F., et al Steroids, 2000, 65, 219-; Templeton J. F., et al, J. Chem. Soc., Perkin Trans. 1, 1994, 9, 1149-. However, the method has high environmental cost, hexavalent chromium has great environmental pollution, and the generated chromium sludge is difficult to treat.
In the preparation methods disclosed in chinese patent 200580040795.8 and chinese patent 200680026352.8, 2,6, 6-tetramethylpiperidine-N-oxide (TEMPO) is used as a catalyst, and hypochlorite is used as an oxidizing agent. Chinese patent 201010511558 also uses 2,2,6, 6-tetramethyl piperidine-N-oxide (TEMPO) as catalyst and N-halogenated amide compound as oxidant. Chinese patent 201410020100 is prepared by oxidizing 2-iodoxybenzoic acid and sodium chlorite, and decarboxylating under acidic condition. However, the preparation methods of the above inventions all use chemical oxidants, which has the following technical problems that the production process generates a large amount of heavy metal waste residues, pollutes water and soil, and the post-treatment cost is high. The search for more environmentally friendly production processes and corresponding equipment has become the focus of research in fine chemical synthesis at present. In addition, the prior 19-nor-4-androstene-3, 17-dione is mainly produced by a batch reaction kettle production process, a batch production device has limited single set of capacity, large product quality fluctuation, high energy consumption and low automation degree.
Disclosure of Invention
Aiming at the technical problems in the prior art, the invention aims to provide a process and a device for producing 19-nor-4-androstene-3, 17-dione through electrocatalytic oxidation.
The invention provides a preparation method of 19-nor-4-androstene-3, 17-dione, which takes 19-hydroxymethyl-4-androstene-3, 17-dione (I) as a raw material, obtains an aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione (II) by electrocatalytic oxidation in the presence of nitroxide free radicals, and then obtains a product 19-nor-4-androstene-3, 17-dione (III) by reaction under the conditions of heating and stirring. The invention aims to solve the technical problems of high cost, great environmental pollution, low yield, complex operation, long production period and the like of the existing process route for preparing 19-nor-4-androstene-3, 17-dione, and provides a green chemical production process and a production device thereof, wherein the green chemical production process has the advantages of low production cost, high yield of target products, short production period and more market competitiveness.
In order to solve the technical problems, the preparation method of the invention is shown as the following reaction formula:
the electrocatalytic oxidation production process of 19-nor-4-androstene-3, 17-dione is characterized by mainly comprising the following two steps:
(1) electrocatalytic oxidation reaction:
adding 19-hydroxymethyl-4-androstene-3, 17-dione and mixed solvent shown in formula (I) into the anode chamber, adding a certain amount of nitroxide free radical as catalyst, and stirring; adding an alkaline buffer solution into the cathode chamber; the device comprises an electrolytic reaction tank, a positive ion exchange membrane, a negative ion exchange membrane, a positive electrode, a negative electrode, a positive electrode, a negative electrode, a positive electrode;
starting a first circulating pump to enable the reaction liquid in the anode chamber to circularly flow between the anode chamber and the left pole chamber of the electrolytic reaction tank, and simultaneously starting a second circulating pump to enable the alkaline buffer solution in the cathode chamber to circularly flow between the cathode chamber and the right pole chamber of the electrolytic reaction tank; then starting a constant current instrument to start an electrocatalytic oxidation reaction, and meanwhile, continuously adding alkali liquor into the anode chamber to maintain the pH value of the anode reaction to be stable; detecting by TLC until the reaction is finished, closing a galvanostat to stop the reaction to generate an aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione shown in a formula (II);
(2) heating and stirring for reaction:
continuously starting stirring in the anode chamber, heating to the heating reaction temperature, heating, stirring and reacting for a certain time, detecting by TLC (thin layer chromatography) until the reaction is finished, closing heating, discharging the reaction liquid in the anode chamber, filtering, adding an organic solvent for extraction, concentrating under reduced pressure, pulping and centrifuging to obtain a 19-nor-4-androstene-3, 17-dione product shown in the formula (III); the reaction formula is as follows:
the electrocatalytic oxidation production process of 19-nor-4-androstene-3, 17-dione is characterized in that in the step (1), in a reaction liquid which is uniformly stirred and mixed in an anode chamber, the concentration of 19-hydroxymethyl-4-androstene-3, 17-dione shown in a formula (I) is 0.1-1.0M; in the step (1), the pH value of the reaction liquid in the anode chamber is maintained at 9.0-12.0 during the electrocatalytic oxidation reaction.
The electrocatalytic oxidation production process of 19-nor-4-androstene-3, 17-dione is characterized in that in the step (1), the mixed solvent is formed by mixing a main solvent and a secondary solvent, wherein the main solvent is a sodium carbonate aqueous solution, and the secondary solvent is one of tetrahydrofuran, dichloromethane, acetonitrile and acetone; the volume ratio of the main solvent to the secondary solvent in the mixed solvent is 8: 2-6: 4, and the pH value of the mixed solvent is 9.0-12.0; the concentration of the sodium carbonate aqueous solution is 0.3-1.5M.
The electrocatalytic oxidation production process of 19-nor-4-androstene-3, 17-dione is characterized in that in the step (1), the nitroxide radical is TEMPO, 4-acetamido-TEMPO, 4-amino-TEMPO or 4-hydroxy-TEMPO; in the step (1), in the reaction liquid which is uniformly stirred and mixed in the anode chamber, the mass of the nitroxide radical is 1.0-5.0% of that of the 19-hydroxymethyl-4-androstene-3, 17-dione shown in the formula (I).
The electrocatalytic oxidation production process of 19-nor-4-androstene-3, 17-dione is characterized in that in the step (1), an alkaline buffer solution in a cathode chamber is formed by mixing a sodium carbonate solution with the concentration of 0.5-1.5M and a sodium bicarbonate solution with the concentration of 0.5-1.5M according to the mass ratio of 3: 7-8: 2, and the pH value of the alkaline buffer solution in the cathode chamber is 10.0-12.0.
The electrocatalytic oxidation production process of 19-nor-4-androstene-3, 17-dione is characterized in that in the step (1), when the electrocatalytic oxidation reaction is carried out, the constant current is 3-10A, the tank pressure is within 2.0-4.0V, the reaction temperature is 20-40 ℃, and the reaction time is 1-5 hours.
The electrocatalytic oxidation production process of 19-nor-4-androstene-3, 17-dione is characterized in that in the step (1), an alkali liquor continuously added into the anode chamber is one of a sodium carbonate solution, a sodium hydroxide solution, a potassium hydroxide solution and an ammonia water solution, and the concentration of the alkali liquor is 0.5-1.0M.
The electrocatalytic oxidation production process of 19-nor-4-androstene-3, 17-dione is characterized in that in the step (2), the heating and stirring reaction temperature is 60-90 ℃, and the reaction time is 2-20 hours; the organic solvent for extraction is at least one of ethyl acetate, dichloromethane, chloroform, toluene and benzene.
The electrocatalytic oxidation production device of 19-nor-4-androstene-3, 17-dione is characterized by comprising an electrolytic reaction tank, an anode chamber, a cathode chamber and a constant current instrument, wherein a cation exchange membrane is arranged in the electrolytic reaction tank and divides the electrolytic reaction tank into a left polar chamber and a right polar chamber; an anode is arranged in the left electrode chamber, a cathode is arranged in the right electrode chamber, and the anode and the cathode are respectively connected with a constant current instrument through a circuit so as to control reaction current and voltage through the constant current instrument; an upper outlet of the left pole chamber is connected with an upper inlet of the anode chamber through a pipeline, a bottom outlet of the anode chamber is connected with a lower inlet of the left pole chamber through a first circulating pump through a pipeline, and an anolyte circulating flow loop is formed; the upper outlet of the right polar chamber is connected with the upper inlet of the cathode chamber through a pipeline, and the bottom outlet of the cathode chamber is connected with the lower inlet of the right polar chamber through a circulating pump II through a pipeline to form a catholyte circulating flow loop.
The 19-nor-4-androstene-3, 17-dione electrocatalytic oxidation production device is characterized by further comprising an alkali liquor storage tank, a pH controller, a pH meter and a delivery pump, wherein the pH meter is connected with the pH controller through a circuit, and a test end of the pH meter extends into the anode chamber; the alkali liquor storage tank is filled with alkali liquor, and a liquid outlet of the alkali liquor storage tank is connected with an upper liquid inlet of the anode chamber through a pipeline by a delivery pump; the pH controller is in signal connection with the delivery pump, the pH meter transmits detected pH data to the pH controller, and the pH controller feeds back and regulates the delivery flow of the delivery pump so as to control the pH of the anolyte in the anode chamber to be maintained within a set value range.
Compared with the prior process for industrially producing 19-nor-4-androstene-3, 17-dione, the invention has the technical advantages that:
1) according to the invention, electrons are used as an oxidant in the electrocatalytic oxidation step, so that the use of a chromium oxidant and other oxidants is completely avoided;
2) in the production process, the consumption of the nitroxide free radical catalyst is small, the production cost is reduced, and the production process is environment-friendly;
3) in the production process, acid solution is not needed for deacidification in the heating and stirring step, and aldehyde groups in the intermediate 19-formaldehyde-4-androstene-3, 17-diketone (II) can fall off under the heating and stirring conditions, so that the operation is simplified;
4) the preparation method is prepared by two steps of reactions, the conversion rate of raw materials is high, the yield of the electrocatalytic oxidation reaction in the step (1) reaches more than 95%, the selectivity of an aldehyde intermediate reaches more than 95%, the yield of the heating and stirring reaction in the step (2) reaches more than 95%, the selectivity of a final product 19-nor-4-androstene-3, 17-dione (III) reaches more than 90%, and the two steps of reactions have very high yield and selectivity and are suitable for industrial production;
5) in the production process, two reactions are completed in the anode chamber, the process operation period is short, the waste water emission is reduced by 60 percent, and the three-waste treatment cost is also reduced.
Drawings
FIG. 1 is a schematic structural diagram of a 19-nor-4-androstene-3, 17-dione electrocatalytic oxidation production apparatus according to the present invention;
in fig. 1: 1-a constant current instrument, 2-a pH controller, 3-a pH meter, 4-an alkali liquor storage tank, 5-an anode chamber, 6-a cathode chamber, 7-an electrolytic reaction tank, 8-a first circulating pump, 9-a second circulating pump and 10-a conveying pump.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
The structural schematic diagram of the 19-nor-4-androstene-3, 17-dione electrocatalytic oxidation production device is shown in figure 1.
Referring to fig. 1, the production apparatus of the present invention comprises an electrolytic reaction tank 7, an anode chamber 5, a cathode chamber 6 and a galvanostat 1, wherein a cation exchange membrane is arranged in the electrolytic reaction tank 7, and the electrolytic reaction tank 7 is divided into a left polar chamber and a right polar chamber by the cation exchange membrane; the left pole chamber is internally provided with an anode, the right pole chamber is internally provided with a cathode, and the anode and the cathode are respectively connected with a constant current instrument 1 through a circuit so as to control reaction current and voltage through the constant current instrument 1.
An upper outlet of the left pole chamber is connected with an upper inlet of the anode chamber 5 through a pipeline, a bottom outlet of the anode chamber 5 is connected with a lower inlet of the left pole chamber through a circulating pump I8 through a pipeline, and an anolyte circulating flow loop is formed; the upper outlet of the right polar chamber is connected with the upper inlet of the cathode chamber 6 through a pipeline, the bottom outlet of the cathode chamber 6 is connected with the lower inlet of the right polar chamber through a second circulating pump 9 through a pipeline, and a catholyte circulating flow loop is formed.
Further, the anode chamber 5 is provided with a stirring device for stirring the liquid therein.
Further, in carrying out the reaction, the anode chamber 5, the cathode chamber 6 and the electrolytic reaction tank 7 may be placed in a constant temperature water bath to control the reaction temperature.
Furthermore, the production device of the invention also comprises an alkali liquor storage tank 4, a pH controller 2, a pH meter 3 and a delivery pump 10, wherein the pH meter 3 is in circuit connection with the pH controller 2, and the testing end of the pH meter 3 extends into the anode chamber 5; the alkali liquor storage tank 4 is filled with alkali liquor, and a liquid outlet of the alkali liquor storage tank 4 is connected with a liquid inlet at the upper part of the anode chamber 5 through a pipeline by a delivery pump 10; the pH controller 2 is in signal connection with the delivery pump 10, the pH meter 3 transmits the detected pH data to the pH controller 2, and the pH controller 2 feeds back and regulates the delivery flow of the delivery pump 10 so as to control the pH of the anolyte in the anode chamber 5 to be maintained within a set value range.
In the following examples, the reaction formulae of the electrocatalytic oxidation reaction of the first step are all:
the reaction formula of the heating stirring reaction in the second step is as follows:
in the following examples, the apparatus shown in FIG. 1 was used to carry out the reaction, which mainly comprises the following two steps:
(1) electrocatalytic oxidation reaction:
adding 19-hydroxymethyl-4-androstene-3, 17-dione and mixed solvent shown in formula (I) into the anode chamber, adding a certain amount of nitroxide free radical as catalyst, and stirring; adding an alkaline buffer solution into the cathode chamber; the device comprises an electrolytic reaction tank, a positive ion exchange membrane, a negative ion exchange membrane, a positive electrode, a negative electrode, a positive electrode, a negative electrode, a positive electrode;
starting a first circulating pump to enable the reaction liquid in the anode chamber to circularly flow between the anode chamber and the left pole chamber of the electrolytic reaction tank, and simultaneously starting a second circulating pump to enable the alkaline buffer solution in the cathode chamber to circularly flow between the cathode chamber and the right pole chamber of the electrolytic reaction tank; then starting a constant current instrument to start an electrocatalytic oxidation reaction, and meanwhile, continuously adding alkali liquor into the anode chamber to maintain the pH value of the anode reaction to be stable; detecting by TLC until the reaction is finished, closing a galvanostat to stop the reaction to generate an aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione shown in a formula (II);
(2) heating and stirring for reaction:
and (2) continuing stirring in the anode chamber, heating to the heating reaction temperature, heating, stirring and reacting for a certain time, detecting by TLC (thin layer chromatography) until the reaction is finished, closing heating, discharging the reaction liquid in the anode chamber, filtering, adding an organic solvent for extraction, concentrating under reduced pressure, pulping and centrifuging to obtain the 19-nor-4-androstene-3, 17-dione product shown in the formula (III).
The detailed process conditions for producing 19-nor-4-androstene-3, 17-dione are detailed in the following examples.
Example 1
Step one, electrocatalytic oxidation reaction: adding 30 g of a compound 19-hydroxymethyl-4-androstene-3, 17-dione (I) into a 3-liter anode chamber, adding 1.5 g of 4-amino-TEMPO as a catalyst, adding 400 ml of tetrahydrofuran and 600 ml of 0.5M sodium carbonate solution as a mixed solvent, and uniformly stirring; 500 ml of 0.5M sodium carbonate solution and 500 ml of 0.5M sodium bicarbonate solution were added to the cathode chamber as alkaline buffer solution. In the electrolytic reaction cell, a graphite plate was used as the anode, and a 304 stainless steel plate was used as the cathode. Starting a first circulating pump to enable the reaction liquid in the anode chamber to circularly flow between the anode chamber and the left pole chamber of the electrolytic reaction tank at the flow rate of 300 ml/min; and simultaneously starting a second circulating pump to enable the alkaline buffer solution in the cathode chamber to circularly flow between the cathode chamber and the right polar chamber of the electrolytic reaction tank at the flow rate of 300 ml/min. Controlling the reaction temperature to be 40 ℃ through a constant-temperature water bath, starting a constant current instrument, controlling the voltage to be 2.5-4V and the current to be 2.0A, and starting the electrocatalytic oxidation reaction for 6 hours. Meanwhile, 1M sodium carbonate solution is continuously added into the anode chamber to maintain the pH value of the anode reaction to be stable at about 10.5. And (3) detecting the reaction by TLC (thin layer chromatography), closing a galvanostat to stop the reaction to obtain an aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione (II), and detecting and analyzing the reaction liquid in the anode chamber by HPLC (high performance liquid chromatography), wherein the conversion rate of the raw material is 96.4% and the selectivity of the intermediate (II) is 95.8%. The reaction was used directly in the next reaction without purification.
Step two, heating and stirring for reaction: and (2) in the anode chamber containing the aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione (II), continuously starting stirring, increasing the temperature to 70 ℃, heating and stirring for reaction for 10 hours, detecting by TLC (thin layer chromatography), closing heating when the reaction is finished, discharging reaction liquid in the anode chamber, cooling, filtering, adding ethyl acetate into filtrate for extraction for 3 times (500 ml multiplied by 3), combining ethyl acetate layers, washing with a 5% sodium thiosulfate solution, washing twice with a saturated saline solution, drying an organic layer after layering with anhydrous sodium sulfate for 2 hours, filtering, concentrating under reduced pressure, pulping and centrifuging to obtain a crude product 19-nor-4-androstene-3, 17-dione (III) 23.7 g, wherein the total yield of the target product is 87.8%.
From the experimental results in example 1 of the present application, it can be seen that the reaction achieves a good technical effect, and in the present application, the purpose of promoting the anolyte circulation flow and the catholyte circulation flow is: the electrode surface in the electrolytic reaction tank 7 is ensured not to be polluted by the by-product generated by excessive oxidation of the raw material or the product, and in addition, the solution circularly flows, so that the mass transfer and the heat transfer can be well carried out, and the problem of more side reactions possibly caused by poor heat transfer in the reaction is solved.
Comparative example 1:
the reaction is carried out by adopting a conventional electrolysis mode, and the process is as follows:
1. comparative example 1 a conventional type H cell was used in place of the electrolysis apparatus as in figure 1 for the production of 19-nor-4-androstene-3, 17-dione (iii) target product. The anode chamber and the cathode chamber of the H-shaped electrolytic cell are separated by a cation exchange membrane, the volumes of the anode chamber and the cathode chamber of the H-shaped electrolytic cell are both 3L, the anode of the H-shaped electrolytic cell is made of a graphite plate, and the cathode of the H-shaped electrolytic cell is made of a 304 stainless steel plate.
2. Comparative example 1 when the reaction was carried out, example 1 was repeated in the experimental procedure except that "comparative example 1 was carried out using an H-type electrolytic cell, the anolyte and the catholyte did not flow during the reaction, the voltage control range was 2.5 to 4V, the experimental procedure was checked by TLC until the reaction was completed", and example 1 was repeated under the remaining operating conditions. Comparative example 1 the results of the experiment were: in the same cell voltage range as in example 1, the reaction of comparative example 1 has a very low current, resulting in a long reaction time, increased by-products, resulting in a decrease in product selectivity, and the final product 19-nor-4-androstene-3, 17-dione (III) has an overall yield of substantially 70% or less.
Example 2
Step one, electrocatalytic oxidation reaction: adding 30 g of a compound 19-hydroxymethyl-4-androstene-3, 17-dione (I) into a 3-liter anode chamber, adding 1.0 g of 4-hydroxy-TEMPO as a catalyst, adding 500 ml of acetonitrile and 500 ml of 1.0M sodium carbonate solution as a mixed solvent, and uniformly stirring; 300 ml of 0.5M sodium carbonate solution and 700 ml of 0.5M sodium bicarbonate solution were added to the cathode chamber as alkaline buffer solutions. In the electrolytic reaction cell, graphite plates were used as the anode, and 316 stainless steel plates were used as the cathode. Starting a first circulating pump to enable the reaction liquid in the anode chamber to circularly flow between the anode chamber and the left pole chamber of the electrolytic reaction tank at the flow rate of 400 ml/min; and simultaneously starting a second circulating pump to enable the alkaline buffer solution in the cathode chamber to circularly flow between the cathode chamber and the right polar chamber of the electrolytic reaction tank at the flow rate of 400 ml/min. Controlling the reaction temperature to be 30 ℃ through a constant-temperature water bath, starting a constant current instrument, controlling the voltage to be 2.5-4V and the current to be 3.0A, and starting the electrocatalytic oxidation reaction for 4 hours. Meanwhile, 0.5M sodium hydroxide solution is continuously added into the anode chamber to maintain the pH value of the anode reaction to be about 11.5. And (3) detecting the reaction by TLC (thin layer chromatography), closing a galvanostat to stop the reaction to obtain an aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione (II), and detecting and analyzing the reaction liquid in the anode chamber by HPLC (high performance liquid chromatography), wherein the conversion rate of the raw material is 97.8 percent, and the selectivity of the intermediate (II) is 96.2 percent. The reaction was used directly in the next reaction without purification.
Step two, heating and stirring for reaction: and (2) in the anode chamber containing the aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione (II), continuously starting stirring, increasing the temperature to 80 ℃, heating and stirring for reaction for 8 hours, detecting by TLC (thin layer chromatography) until the reaction is finished, closing heating, discharging reaction liquid in the anode chamber, cooling, filtering, adding ethyl acetate into filtrate for extraction for 3 times (500 ml multiplied by 3), combining ethyl acetate layers, washing with a 10% sodium thiosulfate solution, washing twice with a saturated saline solution, drying an organic layer after layering for 3 hours by adding anhydrous sodium sulfate, filtering, concentrating under reduced pressure, pulping and centrifuging to obtain a crude product of 19-nor-4-androstene-3, 17-dione (III), wherein the total yield of the target product is 90.7%.
Example 3
Step one, electrocatalytic oxidation reaction: adding 30 g of a compound 19-hydroxymethyl-4-androstene-3, 17-dione (I) into a 3-liter anode chamber, adding 1.5 g of TEMPO as a catalyst, adding 350 ml of acetone and 650 ml of 1.0M sodium carbonate solution as a mixed solvent, and uniformly stirring; 450 ml of 1.0M sodium carbonate solution and 550 ml of 1.0M sodium bicarbonate solution were added to the cathode chamber as alkaline buffer solution. In the electrolytic reaction tank, a graphite plate is used as an anode, and a high-purity nickel plate is used as a cathode. Starting a first circulating pump to enable the reaction liquid in the anode chamber to circularly flow between the anode chamber and the left pole chamber of the electrolytic reaction tank at the flow rate of 300 ml/min; and simultaneously starting a second circulating pump to enable the alkaline buffer solution in the cathode chamber to circularly flow between the cathode chamber and the right polar chamber of the electrolytic reaction tank at the flow rate of 300 ml/min. Controlling the reaction temperature to be 45 ℃ through a constant-temperature water bath, starting a constant current instrument, controlling the voltage to be 2.5-4V and the current to be 4.0A, and starting the electrocatalytic oxidation reaction for 3 hours. Meanwhile, 1.0M potassium hydroxide solution is continuously added into the anode chamber to maintain the pH value of the anode reaction to be about 12.0. And (3) detecting the reaction by TLC (thin layer chromatography), closing a galvanostat to stop the reaction to obtain an aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione (II), and detecting and analyzing the reaction liquid in the anode chamber by HPLC (high performance liquid chromatography), wherein the conversion rate of the raw material is 95.2 percent, and the selectivity of the intermediate (II) is 97.4 percent. The reaction was used directly in the next reaction without purification.
Step two, heating and stirring for reaction: and (2) in the anode chamber containing the aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione (II), continuously starting stirring, increasing the temperature to 60 ℃, heating and stirring for reaction for 15 hours, detecting by TLC (thin layer chromatography) until the reaction is finished, closing heating, discharging reaction liquid in the anode chamber, cooling, filtering, adding ethyl acetate into filtrate for extraction for 3 times (500 ml multiplied by 3), combining ethyl acetate layers, washing with a 5% sodium thiosulfate solution, washing twice with a saturated saline solution, drying the organic layer after layering for 2 hours by adding anhydrous sodium sulfate, filtering, concentrating under reduced pressure, pulping and centrifuging to obtain a crude product of 19-nor-4-androstene-3, 17-dione (III), wherein the crude product is 24.6 g, and the total yield of the target product is 91.1%.
Example 4
Step one, electrocatalytic oxidation reaction: adding 30 g of a compound 19-hydroxymethyl-4-androstene-3, 17-dione (I) into a 3-liter anode chamber, adding 1.0 g of 4-acetamido-TEMPO as a catalyst, adding 450 ml of dichloromethane and 550 ml of 0.5M sodium carbonate solution as a mixed solvent, and uniformly stirring; 500 ml of 0.5M sodium carbonate solution and 500 ml of 0.5M sodium bicarbonate solution were added to the cathode chamber as alkaline buffer solution. In the electrolytic reaction cell, a graphite plate was used as the anode, and a 304 stainless steel plate was used as the cathode. Starting a first circulating pump to enable the reaction liquid in the anode chamber to circularly flow between the anode chamber and the left pole chamber of the electrolytic reaction tank at the flow rate of 500 ml/min; and simultaneously starting a second circulating pump to enable the alkaline buffer solution in the cathode chamber to circularly flow between the cathode chamber and the right polar chamber of the electrolytic reaction tank at the flow rate of 500 ml/min. Controlling the reaction temperature to be 50 ℃ through a constant-temperature water bath, starting a constant current instrument, controlling the voltage to be 2.5-4V and the current to be 3.0A, and starting the electrocatalytic oxidation reaction for 4 hours. Meanwhile, 0.5M sodium hydroxide solution is continuously added into the anode chamber to maintain the pH value of the anode reaction to be about 11.5. And (3) detecting the reaction by TLC (thin layer chromatography), closing a galvanostat to stop the reaction to obtain an aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione (II), and detecting and analyzing the reaction liquid in the anode chamber by HPLC (high performance liquid chromatography), wherein the conversion rate of the raw material is 97.3 percent, and the selectivity of the intermediate (II) is 96.8 percent. The reaction was used directly in the next reaction without purification.
Step two, heating and stirring for reaction: and (2) in the anode chamber containing the aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione (II), continuously starting stirring, increasing the temperature to 80 ℃, heating and stirring for reaction for 10 hours, stopping heating when the TLC detection reaction is finished, cooling, filtering, adding ethyl acetate into filtrate, extracting for 3 times (500 ml × 3), combining ethyl acetate layers, washing with a 5% sodium thiosulfate solution, washing with a saturated saline solution for two times, adding anhydrous sodium sulfate into an organic layer after layering, drying for 3 hours, filtering, concentrating under reduced pressure, pulping and centrifuging to obtain 25.2 g of a crude product 19-nor-4-androstene-3, 17-dione (III), wherein the total yield of the target product is 93.3%.
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (10)
1. An electrocatalytic oxidation production process of 19-nor-4-androstene-3, 17-dione is characterized by mainly comprising the following two steps:
(1) electrocatalytic oxidation reaction:
adding 19-hydroxymethyl-4-androstene-3, 17-dione and mixed solvent shown in formula (I) into the anode chamber, adding a certain amount of nitroxide free radical as catalyst, and stirring; adding an alkaline buffer solution into the cathode chamber; the device comprises an electrolytic reaction tank, a positive ion exchange membrane, a negative ion exchange membrane, a positive electrode, a negative electrode, a positive electrode, a negative electrode, a positive electrode;
starting a first circulating pump to enable the reaction liquid in the anode chamber to circularly flow between the anode chamber and the left pole chamber of the electrolytic reaction tank, and simultaneously starting a second circulating pump to enable the alkaline buffer solution in the cathode chamber to circularly flow between the cathode chamber and the right pole chamber of the electrolytic reaction tank; then starting a constant current instrument to start an electrocatalytic oxidation reaction, and meanwhile, continuously adding alkali liquor into the anode chamber to maintain the pH value of the anode reaction to be stable; detecting by TLC until the reaction is finished, closing a galvanostat to stop the reaction to generate an aldehyde intermediate 19-formaldehyde-4-androstene-3, 17-dione shown in a formula (II);
(2) heating and stirring for reaction:
continuously starting stirring in the anode chamber, heating to the heating reaction temperature, heating, stirring and reacting for a certain time, detecting by TLC (thin layer chromatography) until the reaction is finished, closing heating, discharging the reaction liquid in the anode chamber, filtering, adding an organic solvent for extraction, concentrating under reduced pressure, pulping and centrifuging to obtain a 19-nor-4-androstene-3, 17-dione product shown in the formula (III); the reaction formula is as follows:
2. the electrocatalytic oxidation process of 19-nor-4-androstene-3, 17-dione as claimed in claim 1, wherein in step (1), the concentration of 19-hydroxymethyl-4-androstene-3, 17-dione represented by formula (I) in the reaction solution uniformly mixed and stirred in the anode chamber is 0.1-1.0M; in the step (1), the pH value of the reaction liquid in the anode chamber is maintained at 9.0-12.0 during the electrocatalytic oxidation reaction.
3. The electrocatalytic oxidation process of 19-nor-4-androstene-3, 17-dione as claimed in claim 1, wherein in step (1), the mixed solvent is a mixture of a primary solvent and a secondary solvent, the primary solvent is an aqueous solution of sodium carbonate, and the secondary solvent is one of tetrahydrofuran, dichloromethane, acetonitrile and acetone; the volume ratio of the main solvent to the secondary solvent in the mixed solvent is 8: 2-6: 4, and the pH value of the mixed solvent is 9.0-12.0; the concentration of the sodium carbonate aqueous solution is 0.3-1.5M.
4. The electrocatalytic oxidation process of 19-nor-4-androstene-3, 17-dione as claimed in claim 1 wherein in step (1) the nitroxide radical is TEMPO, 4-acetamido-TEMPO, 4-amino-TEMPO or 4-hydroxy-TEMPO; in the step (1), in the reaction liquid which is uniformly stirred and mixed in the anode chamber, the mass of the nitroxide radical is 1.0-5.0% of that of the 19-hydroxymethyl-4-androstene-3, 17-dione shown in the formula (I).
5. The process according to claim 1, wherein in the step (1), the alkaline buffer solution in the cathode chamber is formed by mixing 0.5-1.5M sodium carbonate solution and 0.5-1.5M sodium bicarbonate solution according to a mass ratio of 3: 7-8: 2, and the pH of the alkaline buffer solution in the cathode chamber is 10.0-12.0.
6. The electrocatalytic oxidation process of 19-nor-4-androstene-3, 17-dione as claimed in claim 1, wherein in step (1), the electrocatalytic oxidation is carried out at a constant current of 3-10A, a bath pressure of 2.0-4.0V, a reaction temperature of 20-40 ℃ and a reaction time of 1-5 hours.
7. The electrocatalytic oxidation process of 19-nor-4-androstene-3, 17-dione as claimed in claim 1, wherein in step (1), the alkali solution continuously added to the anode chamber is one of sodium carbonate solution, sodium hydroxide solution, potassium hydroxide solution and ammonia solution, and the concentration of the alkali solution is 0.5-1.0M.
8. The electrocatalytic oxidation process of 19-nor-4-androstene-3, 17-dione as claimed in claim 1, wherein in step (2), the temperature for heating and stirring reaction is 60-90 ℃, and the reaction time is 2-20 hours; the organic solvent for extraction is at least one of ethyl acetate, dichloromethane, chloroform, toluene and benzene.
9. An electrocatalytic oxidation production device of 19-nor-4-androstene-3, 17-dione is characterized by comprising an electrolytic reaction tank (7), an anode chamber (5), a cathode chamber (6) and a galvanostat (1), wherein a cation exchange membrane is arranged in the electrolytic reaction tank (7) and divides the electrolytic reaction tank (7) into a left polar chamber and a right polar chamber; an anode is arranged in the left electrode chamber, a cathode is arranged in the right electrode chamber, and the anode and the cathode are respectively connected with a constant current instrument (1) through a circuit so as to control reaction current and voltage through the constant current instrument (1); an upper outlet of the left polar chamber is connected with an upper inlet of the anode chamber (5) through a pipeline, a bottom outlet of the anode chamber (5) is connected with a lower inlet of the left polar chamber through a first circulating pump (8) through a pipeline, and an anolyte circulating flow loop is formed; the upper outlet of the right polar chamber is connected with the upper inlet of the cathode chamber (6) through a pipeline, the bottom outlet of the cathode chamber (6) is connected with the lower inlet of the right polar chamber through a second circulating pump (9) through a pipeline, and a catholyte circulating flow loop is formed.
10. The electrocatalytic oxidation production device of 19-nor-4-androstene-3, 17-dione as claimed in claim 9, further comprising an alkaline storage tank (4), a pH controller (2), a pH meter (3) and a delivery pump (10), wherein the pH meter (3) is electrically connected with the pH controller (2), and a testing end of the pH meter (3) extends into the anode chamber (5); the alkali liquor storage tank (4) is filled with alkali liquor, and a liquid outlet of the alkali liquor storage tank (4) is connected with a liquid inlet at the upper part of the anode chamber (5) through a conveying pump (10) by a pipeline; the pH controller (2) is in signal connection with the delivery pump (10), the pH meter (3) transmits detected pH data to the pH controller (2), and the pH controller (2) feeds back and regulates the delivery flow of the delivery pump (10) so as to control the pH of the anolyte in the anode chamber (5) to be maintained within a set value range.
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| CN114622228A (en) * | 2022-02-22 | 2022-06-14 | 浙江工业大学 | Method for preparing steroid hormone carbonyl intermediate by electrocatalytic oxidation |
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