Synthesis method of canrenone

Abstract

The present invention provides a method for synthesizing canrenone, and relates to the technical field of chemical synthesis. The method for synthesizing canrenone comprises the following steps: (a) adding a compound of formula 1 to an organic solvent to obtain a solution containing the compound of formula 1; (b) passing the solution in step (a) into a microchannel reactor for decarboxylation reaction to obtain canrenone. The present invention can react completely in a short time, reduce the side reactions caused by long-term high temperature, and can react continuously in a microchannel reactor, with high mass transfer efficiency, fast reaction, short time, and few side reactions, which greatly improves the experimental operability, and the yield is equivalent to the original process, which solves the problems of slow reaction and dangerous and complicated operation of the current process method, and improves the production applicability of the reaction.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing canrenone. Background Art

[0002] Canrenone, chemical name: 17β-hydroxy-3-oxo-17α-pregnane-4,6-diene-21-carboxylic acid-γ-lactone. It is a commonly used diuretic and an important intermediate for the synthesis of aldosterone receptor antagonists spironolactone and eplerenone. Since 1957, spironolactone has been used clinically to treat hypertension and congestive heart failure; while eplerenone is the first approved and selective aldosterone receptor antagonist. Its efficacy is similar to that of spironolactone, but it has almost no endocrine side effects of spironolactone and has better tolerability. Therefore, the research on the synthesis process of canrenone has high application value.

[0003] The synthetic route reported in patent US3919198: 4-androstenedione is used as a substrate to obtain canrenone through the following reaction:

[0004]

[0005] In the above reaction route, the third step is to carry out the cyclization esterification reaction of the E ring, and the fourth step is to carry out the dehydrogenation reaction. When the product is treated with sodium hydroxide, the lactone will be hydrolyzed to open the ring, and the ethyl formate group on the lactone ring is easily hydrolyzed. Moreover, the product after hydrolysis is difficult to react completely in the last step, and new impurities are generated, resulting in extremely low yield and purity.

[0006] In order to solve the above problems, patent CN108033989A proposes the following improvement scheme: compound I is used as the starting material for the reaction, an organic solvent, sodium ethoxide, diethyl malonate and a catalyst are added to a reaction vessel in sequence, the temperature is raised to reflux, compound I is added, and after the reaction is complete, the pH of the reaction solution is adjusted to neutral, ethanol is concentrated, toluene and water are added, and canrenone is obtained after high-pressure reaction; the reaction formula is as follows:

[0007]

[0008] This method requires high pressure, high temperature, long reaction time, and is relatively dangerous. In addition, there are many inorganic salts in the reaction solution, and toluene as a solvent cannot dissolve these inorganic salts. During the reaction, these insoluble substances are likely to wrap up the raw materials, making it difficult for the reaction to be completed.

[0009] In view of this, the present invention is proposed. Summary of the invention

[0010] The main purpose of the present invention is to provide a method for synthesizing canrenone, in order to at least partially solve at least one of the above-mentioned technical problems.

[0011] The present invention provides a method for synthesizing canrenone, comprising the following steps:

[0012] (a) adding the compound of formula 1 into an organic solvent to obtain a solution containing the compound of formula 1;

[0013] (b) passing the solution in step (a) into a microchannel reactor for decarboxylation reaction to obtain canrenone; the reaction formula is as follows:

[0014]

[0015] The method for synthesizing canrenone provided by the present invention comprises the following steps: dissolving a compound of formula 1 in an organic solvent, and then passing the solution into a microchannel reactor, so that the reaction can be completed in a short time, and the side reaction caused by long-term high temperature can be reduced. Moreover, the reaction can be continuously carried out in the microchannel reactor, and the mass transfer efficiency is high, the reaction is fast, the time is short, and the side reaction is less, so that the experimental operability is greatly improved, and the yield is equivalent to that of the original process, so that the problems of slow reaction and dangerous and complicated operation of the current process method are solved, and the production applicability of the reaction is improved.

[0016] Furthermore, in step (a), the organic solvent is selected from one or a combination of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), ethylene glycol, N-methylpyrrolidone (NMP) or N,N-dimethylacetamide (DMAC).

[0017] Furthermore, in the step (a), the mass volume ratio of the compound of formula I to the organic solvent is 1: (2-10) g / mL.

[0018] In the present invention, a typical but non-limiting mass volume ratio of the compound of formula I and the organic solvent can be, for example, 1:2 g / mL, 1:3 g / mL, 1:4 g / mL, 1:5 g / mL, 1:6 g / mL, 1:7 g / mL, 1:8 g / mL, 1:9 g / mL or 1:10 g / mL.

[0019] The present invention optimizes the mass volume ratio of the compound of formula 1 and the organic solvent. When the mass volume ratio of the compound of formula I and the organic solvent is 1: (2-10) g / mL, it can ensure that the compound of formula 1 is fully dissolved to avoid clogging the microchannel pipeline, and can also make the compound of formula 1 react at an appropriate concentration, thereby increasing the reaction rate and shortening the reaction time.

[0020] Furthermore, in the step (a), the compound of formula 1 and water are added to an organic solvent to obtain a solution containing the compound of formula 1, and the mass volume ratio of the compound of formula 1 to water is 1: (0.25-1) g / mL.

[0021] In the present invention, a typical but non-limiting mass volume ratio of the compound of formula I and water can be, for example, 1:0.25 g / mL, 1:0.3 g / mL, 1:0.35 g / mL, 1:0.4 g / mL, 1:0.45 g / mL, 1:0.5 g / mL, 1:0.55 g / mL, 1:0.6 g / mL, 1:0.65 g / mL, 1:0.7 g / mL, 1:0.75 g / mL, 1:0.8 g / mL, 1:0.85 g / mL, 1:0.9 g / mL, 1:0.95 g / mL or 1:1 g / mL.

[0022] In the present invention, a certain amount of water is added in the reaction to play the role of a catalyst. Since water is a poor solvent, the addition of too much water will cause the compound of formula 1 to precipitate from the organic solvent. By optimizing the mass volume ratio of the compound of formula I and water, when the mass volume ratio of the compound of formula I and water is 1: (0.25-1) g / mL, it can ensure that the compound of formula 1 is fully dissolved and avoid clogging the microchannel pipeline, and can also increase the reaction rate and shorten the reaction time.

[0023] Furthermore, in the step (b), the reaction temperature of the solution in the microchannel reactor is 90°C to 140°C.

[0024] In the present invention, typical but non-limiting temperatures for the reaction may be, for example, 90°C, 92°C, 94°C, 96°C, 98°C, 100°C, 102°C, 104°C, 106°C, 108°C, 110°C, 112°C, 114°C, 116°C, 118°C, 120°C, 122°C, 124°C, 126°C, 128°C, 130°C, 132°C, 134°C, 136°C, 138°C or 140°C.

[0025] The compound of formula 1 in the present invention is a steroidal compound, the C3 position of its A ring is a carbonyl group, and the E ring is a lactone ring. If the reaction temperature is not properly controlled, it is easy to cause the A ring or the E ring to break, resulting in side reactions. Therefore, controlling the reaction temperature is very important for the reaction. By optimizing the reaction temperature, when the reaction temperature is 90°C to 140°C, the reaction rate can be increased, the reaction time can be shortened, and the side reactions of the compound of formula 1 can be avoided, thereby improving the product quality.

[0026] Furthermore, in the step (b), the flow rate of the solution in the microchannel reactor is 10 g / min to 50 g / min.

[0027] In the present invention, typical but non-limiting flow rates for the reaction can be, for example, 10 g / min, 12 g / min, 14 g / min, 16 g / min, 18 g / min, 20 g / min, 22 g / min, 24 g / min, 26 g / min, 28 g / min, 30 g / min, 32 g / min, 34 g / min, 36 g / min, 38 g / min, 40 g / min, 42 g / min, 44 g / min, 46 g / min, 48 g / min or 50 g / min.

[0028] Furthermore, in the step (b), the reaction time of the mixture in the microchannel reactor is 1 min to 10 min.

[0029] In the present invention, a typical but non-limiting time for the reaction is 1 min, 2 min, 3 min, 4 min, 5 min, 6 min, 7 min, 8 min, 9 min or 10 min.

[0030] The compound of formula 1 in the present invention is a steroidal compound, the C3 position of its A ring is a carbonyl group, and the E ring is a lactone ring. If the reaction time is not properly controlled, it is easy to cause the A ring or the E ring to break, resulting in side reactions. Therefore, controlling the reaction time is very important for the reaction. By optimizing the reaction time, when the reaction time is 1min to 10min, it can not only ensure that the compound of formula 1 is completely converted, but also avoid the occurrence of side reactions in the compound of formula 1, thereby improving the product quality.

[0031] Furthermore, a step (s) is provided between the step (a) and the step (b): preheating the solution in the step (a), wherein the preheating temperature is 25° C. to 50° C.

[0032] In the present invention, typical but non-limiting temperatures for preheating may be, for example, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49 or 50°C.

[0033] The present invention provides a preheating step, which can preheat the solution containing the compound of formula 1 to prevent the reaction module from being overheated and causing side reactions when entering the reaction zone.

[0034] Furthermore, after step (b), step (o) is provided: cooling the reaction solution containing canrenone in step (b), and the cooling temperature is 20° C. to 50° C.

[0035] The present invention provides a cooling step, which can quickly cool the reaction solution, terminate the reaction, and reduce side reactions caused by long-term high temperature.

[0036] In the present invention, typical but non-limiting temperatures for cooling may be, for example, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49 or 50°C.

[0037] Further, the following steps are included:

[0038] (a) adding compound 1 and water to an organic solvent to obtain a solution containing the compound of formula 1, wherein the mass volume ratio of the compound of formula 1 to the organic solvent is 1: (5-8) g / mL, and the mass volume ratio of the compound of formula 1 to water is 1: (0.25-0.5) g / mL;

[0039] (s) preheating the solution in step (a) at 30° C. to 50° C. to obtain a preheated solution;

[0040] (b) passing the preheated solution in step (s) into a microchannel reactor at a flow rate of 10 g / min to 30 g / min, reacting at 90° C. to 120° C. for 5 min to 8 min to perform a decarboxylation reaction to obtain a reaction solution containing canrenone;

[0041] (o) Cooling the reaction solution containing canrenone in step (b) at 20°C to 40°C.

[0042] Compared with the prior art, the present invention has the following beneficial effects:

[0043] The method for synthesizing canrenone provided by the present invention comprises the following steps: dissolving a compound of formula 1 in an organic solvent, and then passing the solution into a microchannel reactor, so that the reaction can be completed in a short time, and the side reaction caused by long-term high temperature can be reduced. Moreover, the reaction can be continuously carried out in the microchannel reactor, and the mass transfer efficiency is high, the reaction is fast, the time is short, and the side reaction is less, so that the experimental operability is greatly improved, and the yield is equivalent to that of the original process, so that the problems of slow reaction and dangerous and complicated operation of the current process method are solved, and the production applicability of the reaction is improved. DETAILED DESCRIPTION

[0044] The embodiments of the present invention will be described in detail below in conjunction with the examples, but those skilled in the art will appreciate that the following examples are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the examples, conventional conditions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

[0045] The microchannel reactor used in the present invention is a Corning G1 glass reactor.

[0046] Example 1

[0047]

[0048] Material preparation:

[0049] Add 100 g of compound 1, 500 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0050] System Preparation:

[0051] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0052] Preparation of canrenone:

[0053] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 5 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 85.0 g of canrenone with a yield of 95.6% and an HPLC purity of 99.6%.

[0054] Example 2

[0055]

[0056] Material preparation:

[0057] 100 g of compound 1, 800 mL of DMSO and 50 mL of water were added to a 2 L plastic beaker, mixed evenly, and stirred to dissolve.

[0058] System Preparation:

[0059] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 30°C, the temperature of the reaction module in the reaction zone to 120°C, the temperature of the heat transfer oil in the cooling zone to 40°C, and wait for temperature equilibrium.

[0060] Preparation of canrenone:

[0061] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 30 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 8 minutes after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 minutes, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 84.7 g of canrenone, with a yield of 95.2% and an HPLC purity of 99.5%.

[0062] Example 3

[0063]

[0064] Material preparation:

[0065] 100 g of compound 1, 1000 mL of NMP and 100 mL of water were added to a 2 L plastic beaker, mixed evenly, and stirred to dissolve.

[0066] System Preparation:

[0067] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 25°C, the temperature of the reaction module in the reaction zone to 140°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0068] Preparation of canrenone:

[0069] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 50 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 1 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 83.3 g of canrenone with a yield of 93.6% and an HPLC purity of 98.6%.

[0070] Example 4

[0071]

[0072] Material preparation:

[0073] 100 g of compound 1, 200 mL of DMF and 25 mL of water were added to a 2 L plastic beaker, mixed evenly, and stirred to dissolve.

[0074] System Preparation:

[0075] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 50°C, and wait for temperature equilibrium.

[0076] Preparation of canrenone:

[0077] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 10 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 83.7 g of canrenone with a yield of 94.1% and an HPLC purity of 98.8%.

[0078] Example 5

[0079]

[0080] Material preparation:

[0081] 100 g of compound 1, 600 mL of DMAC and 40 mL of water were added to a 2 L plastic beaker, mixed evenly, and stirred to dissolve.

[0082] System Preparation:

[0083] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 40°C, the temperature of the reaction module in the reaction zone to 100°C, the temperature of the heat transfer oil in the cooling zone to 30°C, and wait for temperature equilibrium.

[0084] Preparation of canrenone:

[0085] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 25 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 6 minutes after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 minutes, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 84.8 g of canrenone with a yield of 95.3% and an HPLC purity of 99.1%.

[0086] Example 6

[0087]

[0088] Material preparation:

[0089] Add 100 g of compound 1, 800 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0090] System Preparation:

[0091] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0092] Preparation of canrenone:

[0093] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 5 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 84.5 g of canrenone with a yield of 95.0% and an HPLC purity of 99.2%.

[0094] Example 7

[0095]

[0096] Material preparation:

[0097] Add 100 g of compound 1, 200 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0098] System Preparation:

[0099] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0100] Preparation of canrenone:

[0101] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 5 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 83.1 g of canrenone with a yield of 93.4% and an HPLC purity of 98.7%.

[0102] Example 8

[0103]

[0104] Material preparation:

[0105] Add 100 g of compound 1, 1000 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0106] System Preparation:

[0107] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0108] Preparation of canrenone:

[0109] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 5 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 83.0 g of canrenone with a yield of 93.3% and an HPLC purity of 98.4%.

[0110] Example 9

[0111]

[0112] Material preparation:

[0113] Add 100 g of compound 1, 500 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0114] System Preparation:

[0115] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0116] Preparation of canrenone:

[0117] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 30 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 5 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 84.8 g of canrenone with a yield of 95.3% and an HPLC purity of 99.4%.

[0118] Example 10

[0119]

[0120] Material preparation:

[0121] Add 100 g of compound 1, 500 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0122] System Preparation:

[0123] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0124] Preparation of canrenone:

[0125] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 50 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 5 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 83.6 g of canrenone with a yield of 94.0% and an HPLC purity of 98.7%.

[0126] Embodiment 11

[0127]

[0128] Material preparation:

[0129] Add 100 g of compound 1, 500 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0130] System Preparation:

[0131] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 120°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0132] Preparation of canrenone:

[0133] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 5 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 84.8 g of canrenone with a yield of 95.3% and an HPLC purity of 99.4%.

[0134] Example 12

[0135]

[0136] Material preparation:

[0137] Add 100 g of compound 1, 500 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0138] System Preparation:

[0139] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 140°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0140] Preparation of canrenone:

[0141] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 5 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 83.2 g of canrenone with a yield of 93.5% and an HPLC purity of 98.5%.

[0142] Embodiment 13

[0143]

[0144] Material preparation:

[0145] Add 100 g of compound 1, 500 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0146] System Preparation:

[0147] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 145°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0148] Preparation of canrenone:

[0149] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 5 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 81.0 g of canrenone with a yield of 91.1% and an HPLC purity of 86.2%.

[0150] Embodiment 14

[0151]

[0152] Material preparation:

[0153] Add 100 g of compound 1, 500 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0154] System Preparation:

[0155] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0156] Preparation of canrenone:

[0157] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 8 minutes after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 minutes, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 84.8 g of canrenone with a yield of 95.3% and an HPLC purity of 99.5%.

[0158] Embodiment 15

[0159]

[0160] Material preparation:

[0161] Add 100 g of compound 1, 500 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0162] System Preparation:

[0163] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0164] Preparation of canrenone:

[0165] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 1 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 82.8 g of canrenone with a yield of 93.1% and a purity of 97.9%.

[0166] Example 16

[0167]

[0168] Material preparation:

[0169] Add 100 g of compound 1, 500 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0170] System Preparation:

[0171] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0172] Preparation of canrenone:

[0173] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 10 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 83.0 g of canrenone with a yield of 93.3% and an HPLC purity of 98.3%.

[0174] Embodiment 17

[0175]

[0176] Material preparation:

[0177] Add 100 g of compound 1, 500 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0178] System Preparation:

[0179] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0180] Preparation of canrenone:

[0181] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 0.5 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 80.5 g of canrenone with a yield of 90.5% and a purity of 96.5%.

[0182] Embodiment 18

[0183]

[0184] Material preparation:

[0185] Add 100 g of compound 1, 500 mL of ethylene glycol and 25 mL of water into a 2 L plastic beaker, mix them evenly, and stir to dissolve them.

[0186] System Preparation:

[0187] Start the microchannel reaction system, set the temperature of the heat transfer oil in the preheating zone to 50°C, the temperature of the reaction module in the reaction zone to 90°C, the temperature of the heat transfer oil in the cooling zone to 20°C, and wait for temperature equilibrium.

[0188] Preparation of canrenone:

[0189] After the temperature of the heat transfer oil is stable, the prepared solution is pumped into the microchannel system at a rate of 10 g / min using a horizontal flow pump. When material flows out from the outlet end of the cooling zone of the microchannel system, the material residence time is 15 min after the system is stabilized. The reactor outlet liquid is subjected to liquid chromatography analysis. After the reaction is completed, 500 g of ice water is placed in the container receiving the reaction liquid in advance. After the product flows out, solids are rapidly precipitated in the ice water. After all the products flow out, the receiving barrel is stirred at room temperature for 30 min, filtered, the filter cake is washed with water twice, filtered, and dried in an oven to obtain 80.3 g of canrenone with a yield of 90.3% and a purity of 85.7%.

[0190] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or replace some or all of the technical features therein with equivalents. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for synthesizing canrenone, characterized in that: The following steps are involved: (a) adding the compound of formula 1 into an organic solvent to obtain a solution containing the compound of formula 1; (b) passing the solution in step (a) into a microchannel reactor for decarboxylation reaction to obtain canrenone; the reaction formula is as follows:

2. The method for synthesizing canrenone according to claim 1, characterized in that In the step (a), the organic solvent is selected from one or a combination of N,N-dimethylformamide, dimethyl sulfoxide, ethylene glycol, N-methylpyrrolidone or N,N-dimethylacetamide.

3. The method for synthesizing canrenone according to claim 1, characterized in that In the step (a), the mass volume ratio of the compound of formula I to the organic solvent is 1: (2-10) g / mL.

4. The method for synthesizing canrenone according to claim 3, characterized in that: In the step (a), the compound of formula 1 and water are added to an organic solvent to obtain a solution containing the compound of formula 1, and the mass volume ratio of the compound of formula 1 to water is 1: (0.25-1) g / mL.

5. The method for synthesizing canrenone according to claim 1, characterized in that: In the step (b), the reaction temperature of the solution in the microchannel reactor is 90° C. to 140° C.

6. The method for synthesizing canrenone according to claim 1, characterized in that: In the step (b), the flow rate of the solution in the microchannel reactor is 10 g / min to 50 g / min.

7. The method for synthesizing canrenone according to claim 1, characterized in that: In the step (b), the reaction time of the solution in the microchannel reactor is 1 min to 10 min.

8. The method for synthesizing canrenone according to any one of claims 1 to 7, characterized in that: A step (s) is provided between the step (a) and the step (b): preheating the solution in the step (a), wherein the preheating temperature is 25° C. to 50° C.

9. The method for synthesizing canrenone according to claim 8, characterized in that: After step (b), step (o) is provided: cooling the reaction solution containing canrenone in step (b), and the cooling temperature is 20°C to 50°C.

10. The method for synthesizing canrenone according to claim 9, characterized in that: The following steps are involved: (a) adding compound 1 and water to an organic solvent to obtain a solution containing the compound of formula 1, wherein the mass volume ratio of the compound of formula 1 to the organic solvent is 1: (5-8) g / mL, and the mass volume ratio of the compound of formula 1 to water is 1: (0.25-0.5) g / mL; (s) preheating the solution in step (a) at 30° C. to 50° C. to obtain a preheated solution; (b) passing the preheated solution in step (s) into a microchannel reactor at a flow rate of 10 g / min to 30 g / min, reacting at 90° C. to 120° C. for 5 min to 8 min to perform a decarboxylation reaction to obtain a reaction solution containing canrenone; (o) Cooling the reaction solution containing canrenone in step (b) at 20°C to 40°C.

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