A process for the preparation of levomethyletdalone

Abstract

The application provides a preparation method of levomethyltestosterone, comprising the following steps: a) performing ketal protection on a compound of formula (1) to obtain a compound of formula (2); b) converting the compound of formula (2) into a compound of formula (3); c) performing methylation on the compound of formula (3) to obtain a compound of formula (4); and d) performing a hydrolysis ketal reaction on the compound of formula (4) to obtain levomethyltestosterone. The application takes 18-hydroxyltestosterone as a starting material, and levomethyltestosterone is prepared through ketalization, halogenation, methylation and hydrolysis reactions. The process route provided by the application has the advantages of short reaction path, few by-products, high conversion rate, and effectively solves the problems of the existing process, such as many by-products, low yield, high safety risk, environmental pressure, and high comprehensive production cost.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, and particularly relates to a preparation method of levomethyltestosterone. BACKGROUND

[0002] Levomethyltestosterone, chemical name 18-methyl-4-estrene-3, 17-dione, structural formula as shown in formula (1), is a key intermediate for synthesizing steroid drugs such as levonorgestrel, gestodene, desogestrel and etogestrel, and has great application value in the industrial production of these drugs.

[0003]

[0004] The prior art generally uses fermented oxidant 13beta-ethyl-3-methoxy-estrane-1, 3, 5 (10), 8 (9), 14 (15)-pentene-17beta alcohol as raw material, and is prepared through hydrogen reduction, lithium ammonia reduction, wu's oxidation and hydrolysis reaction, and the synthetic route is as follows:

[0005]

[0006] The method has more by-products and low yield. SUMMARY

[0007] Therefore, the present application provides a preparation method of levomethyltestosterone, and the preparation method has less by-products and high conversion rate.

[0008] The present application provides a preparation method of levomethyltestosterone, comprising the following steps:

[0009] a) performing ketal protection on the compound of formula (1) to obtain a compound of formula (2);

[0010]

[0011] b) converting the compound of formula (2) into a compound of formula (3);

[0012]

[0013] c) performing methylation on the compound of formula (3) to obtain a compound of formula (4);

[0014]

[0015] d) performing hydrolysis ketal reaction on the compound of formula (4) to obtain levomethyltestosterone.

[0016] The present application takes the compound of formula (1) as a starting material, first protects the carbonyl groups at positions 3 and 17 to obtain a compound of formula (2), then substitutes the hydroxyl group at position 18 with iodine to obtain a compound of formula (3), then performs methylation at position 18 to obtain a compound of formula (4), and finally performs hydrolysis and ketalization to obtain levomethylestrenedione, and the synthetic route is as follows:

[0017]

[0018] The present application takes the compound of formula (1) as a starting material, and its chemical name is 18-hydroxy-4-estren-3, 17-dione. The source of the compound of formula (1) is not particularly limited and can be purchased on the market or prepared according to the method disclosed in the prior art, for example, prepared by fermenting 19-nor-4AD with the fungus Leptoporus fissilis. For details, refer to G. DENIS MEAKIN, 16P, 18-Dihydroxylation of Oxygenated 5a-Androstanes with the Fungus Leptoporus fissilis.

[0019] The present application first performs ketalization on the compound of formula (1), specifically:

[0020] Under the action of a catalyst, the compound of formula (1) is reacted with ethylene glycol to obtain the compound of formula (2).

[0021] In some specific implementations, the catalyst is p-toluenesulfonic acid and triethyl orthoformate, and the mass ratio thereof is preferably 1-5:20-30. In some specific implementations, the mass ratio of the compound of formula (1), ethylene glycol and the catalyst is 20-40:10-30:20-40.

[0022] Specifically, the compound of formula (1) is first dissolved, p-toluenesulfonic acid and ethylene glycol are added, and then triethyl orthoformate is added dropwise, and the reaction is performed under heat. In some specific implementations, the solvent of the reaction is selected from dichloromethane or trichloromethane, and preferably dichloromethane. The temperature of the reaction is 30-50°C, and preferably 40°C. The time is 1-2h, and preferably 1.5h.

[0023] After the reaction is completed, sodium bicarbonate solution is added to the reaction mixture and stirred, the water layer is separated, water is added and stirred for washing, the water layer is separated, and the organic layer is dried with anhydrous sodium sulfate; concentrated under reduced pressure, and then recrystallized with ethyl acetate and petroleum ether, filtered and dried to obtain the compound of formula (2). In some specific implementations, the volume ratio of ethyl acetate and petroleum ether is 1-5:1, and preferably 2:1.

[0024] After obtaining the compound of formula (2), it is converted into the compound of formula (3), specifically as follows:

[0025] Under the action of a catalyst, the compound of formula (2) and an iodinating agent react to obtain the compound of formula (3).

[0026] In some specific implementations, the iodinating agent is iodine element. In some specific implementations, the catalyst is triphenylphosphine and imidazole, and the mass ratio of the triphenylphosphine and the imidazole is 30-50:20-30. In some specific implementations, the mass ratio of the compound of formula (2), the iodinating agent and the catalyst is 30-40:30-40:50-80.

[0027] Specifically, the compound of formula (2) is first dissolved in a solvent, and then triphenylphosphine, iodine and imidazole are stirred and dissolved; and then the imidazole is kept warm for reaction. In some specific implementations, the solvent of the reaction is dichloromethane or trichloromethane, and preferably dichloromethane. In some specific implementations, the temperature of the reaction is 20-40℃, and preferably 30℃, and the time is 2-3h, and preferably 2.5h.

[0028] After the reaction is completed, the obtained reaction product is sequentially washed with sodium thiosulfate solution and sodium bicarbonate solution, and then concentrated and dried under reduced pressure, and then recrystallized by adding acetonitrile, filtered and dried to obtain the compound of formula (3).

[0029] After obtaining the compound of formula (3), it is subjected to methylation to obtain the compound of formula (4), specifically as follows:

[0030] Under the action of a reaction aid, the compound of formula (3) and a methylating agent react to obtain the compound of formula (4).

[0031] In some specific implementations, the methylating agent is methylmagnesium bromide. In some specific implementations, the reaction aid is cuprous chloride or lithium chloride. In some specific implementations, the mass ratio of the compound of formula (3) and the reaction aid is 30-50:1-5. In some specific implementations, the molar ratio of the compound of formula (3) and the methylating agent is 1:2-3.

[0032] Specifically, the compound (3) is first stirred and dissolved in a solvent, cooled, and then cuprous chloride is added, and a methylmagnesium bromide tetrahydrofuran solution is added dropwise under temperature control, and kept warm for reaction. In some specific implementations, the solvent of the reaction is tetrahydrofuran or diethyl ether. In some specific implementations, the temperature of the reaction is -35℃ to -20℃, and preferably -35℃ to -30℃; and the time is 3-4h, and preferably 3.5h.

[0033] After the reaction is completed, the obtained reaction product is washed with saturated ammonium chloride solution, saturated sodium chloride solution, dried by adding anhydrous sodium sulfate, concentrated under reduced pressure, recrystallized by adding dichloromethane and ethyl acetate, filtered and dried to obtain the compound of formula (4). In some specific embodiments, the volume ratio of dichloromethane and ethyl acetate is 1:1-5, preferably 1:3.

[0034] In some specific embodiments, the compound of formula (4) is subjected to a hydrolytic ketal reaction to obtain levorotatory ethylidene ketone, specifically, the compound of formula (4) is subjected to a hydrolytic ketal reaction under acidic conditions to obtain levorotatory ethylidene ketone. The acidic reagent of the acidic conditions is potassium bisulfate, sodium bisulfate, dilute sulfuric acid or hydrochloric acid, preferably potassium bisulfate.

[0035] In some specific embodiments, the mass ratio of the compound of formula (4) to the acidic reagent is 20-40:5-30. Specifically, the acidic conditions are an aqueous solution of the acidic reagent, and the mass ratio of the acidic reagent to water in the aqueous solution of the acidic reagent is 5-30:150-350. Specifically, the compound of formula (4) is dissolved and added to the aqueous solution of the acidic reagent, and the reaction is stirred. In some specific embodiments, the solvent of the hydrolytic ketal reaction is dichloromethane or trichloromethane, preferably dichloromethane. In some specific embodiments, the temperature of the hydrolytic ketal reaction is 20-50°C, preferably 40°C, and the time is 3-4h, preferably 3.5h.

[0036] After the reaction is completed, an aqueous solution of a basic reagent is added and stirred, the water layer is separated, and the organic layer is washed with water until the pH is near neutral; concentrated under reduced pressure, recrystallized by adding ethyl acetate and methanol, filtered and dried to obtain levorotatory ethylidene ketone. In some specific embodiments, the basic reagent can be selected from potassium carbonate and sodium carbonate, preferably potassium carbonate. In some specific embodiments, the volume ratio of ethyl acetate and methanol is 1-5:1, preferably 3:1.

[0037] The present application takes the compound of formula (1) as a raw material, first protects the carbonyl groups at positions 3 and 17 to obtain a compound of formula (2), then substitutes the hydroxyl group at position 18 with iodine to obtain a compound of formula (3), then performs a methylation reaction at position 18 to obtain a compound of formula (4), and finally performs a hydrolysis-ketalization reaction to obtain levorotatory ethylstilbene diketone. The reaction path is short, has few by-products, has high conversion rate, and has high product quality. The process route provided by the present application is green, safe, and highly compliant, the auxiliary materials used are inexpensive, low-toxic or non-toxic, and easy to obtain, the operation of each step is simple, and the process can be easily converted into an automated and mechanized process after simple modification, greatly improving the production efficiency, and effectively solving the problems of the existing process, such as many by-products, low yield, high safety risk, environmental pressure, and high comprehensive production cost, and the economic benefit is more obvious, and it is more suitable for industrialized production. Experimental results show that the levorotatory ethylstilbene diketone prepared by the method provided by the present application has a chromatographic purity of more than 99.7%. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 HPLC spectrum of levorotatory ethylstilbene diketone prepared for the comparative example of the present application;

[0039] Figure 2 HPLC spectrum of levorotatory ethylstilbene diketone prepared for Example 1;

[0040] Figure 3 HPLC spectrum of levorotatory ethylstilbene diketone prepared for Example 2;

[0041] Figure 4 HPLC spectrum of levorotatory ethylstilbene diketone prepared for Example 3. DETAILED DESCRIPTION

[0042] It should be understood that the expression "one or more of something" includes each of the objects of the recited expression individually as well as various combinations of two or more of the recited objects, unless otherwise understood from the context and usage. The expression "and / or" in combination with three or more recited objects should be understood to have the same meaning, unless otherwise understood from the context.

[0043] The terms "comprising", "having", or "including", including the use of their grammatical synonyms, should generally be understood to be open-ended and non-limiting, for example, not excluding other non-recited elements or steps, unless otherwise specifically stated or understood from the context.

[0044] It should be understood that the order of steps or the order of performing certain actions is not important as long as the present application is still operable. In addition, two or more steps or actions can be performed simultaneously.

[0045] The use of any and all examples, or exemplary language (e.g., "such as" or "including") provided herein, is intended merely to better illuminate the application and does not pose a limitation on the scope of the application unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the application.

[0046] Further, the numerical ranges and parameters setting forth the broadest scope of the application are approximations, and are only chosen to encompass the more precise values inherent to the specific instances described. Any numerical values, however, are not intended to be bound by a strict limitation, unless the context indicates otherwise. Thus, unless specifically stated otherwise, it is intended that all ranges and numbers provided herein are approximations.

[0047] The present application provides a preparation method of levomethyltestosterone, comprising the following steps:

[0048] a) performing ketal protection on a compound of formula (1) to obtain a compound of formula (2);

[0049]

[0050] b) converting the compound of formula (2) into a compound of formula (3);

[0051]

[0052] c) performing methylation on the compound of formula (3) to obtain a compound of formula (4);

[0053]

[0054] d) performing hydrolytic ketal reaction on the compound of formula (4) to obtain levomethyltestosterone.

[0055] The present application takes a compound of formula (1) as a raw material, first performs ketal protection on the carbonyl groups at positions 3 and 17 to obtain a compound of formula (2), then substitutes the hydroxyl group at position 18 with iodine to obtain a compound of formula (3), then performs methylation at position 18 to generate a compound of formula (4), and finally performs hydrolytic ketal reaction to obtain levomethyltestosterone, and the synthetic route is as follows:

[0056]

[0057] The process route provided by the application has a short reaction path, less by-products, high conversion rate, high product quality, green environmental protection, high safety, strong compliance, the auxiliary materials used are cheap, low-toxic or non-toxic, and easy to obtain, the operation of each step is simple, and the process can be converted into an automatic and mechanized process through simple modification, thereby greatly improving the production efficiency, effectively solving the problems of existing processes, such as more by-products, low yield, high safety risk, environmental pressure, and high comprehensive production cost, and more obvious economic benefits, and being more suitable for industrialized production. Experimental results show that the chromatographic purity of the levorotatory ethyl steroene diketone prepared by the method provided by the application can reach more than 99.7%.

[0058] The preparation method of the levorotatory ethyl steroene diketone provided by the application is further described below in combination with examples.

[0059] In each of the following examples, compound (1) is obtained by fermenting 19-nor-4AD by the fungus Leptoporus fissilis, and the specific method is referred to G. DENIS MEAKIN, 16P, 18-Dihydroxylation of Oxygenated 5a-Androstanes with the Fungus Leptoporus fzssilis.

[0060] Comparative Example 1

[0061] The lithium amine 18-methyl-3-methoxy-2,5(10)-oestradien-17-ol (compound of formula a) is oxidized by isopropyl aluminum, cyclohexanone to obtain the Wills material (compound of formula b), and the levorotatory ethyl steroene diketone (compound of formula (I)) is prepared by hydrolysis reaction under acidic conditions.

[0062] 1) Wills oxidation: take compound (a) 30.00 g, add 270 ml of toluene and stir to dissolve, and then heat to 115°C; add 75.00 g of cyclohexanone, and stir to reflux at 115°C, and remove the water layer by a water separator. Cool to 110°C, add 3.00 g of isopropyl aluminum, heat to 116°C and reflux for 2 hours. After the reaction is completed, cool to 80°C, add dilute sulfuric acid (2 ml of sulfuric acid and 100 ml of water) for washing, and remove the water layer; wash the organic layer with water until neutral. Concentrate under reduced pressure, cool to room temperature, add methanol for recrystallization, filter and dry to obtain 27.35 g of the Wills material (compound of formula b), with a mass yield of 91.16%.

[0063] 2) Hydrolysis reaction: Take the Wills material (compound of formula b) 27.00 g, add 300 ml dichloromethane and stir to dissolve, add potassium bisulfate solution (16.00 g potassium bisulfate, 200 ml water), stir at room temperature for 5 hours. After the reaction is complete, add potassium carbonate solution (27.00 g potassium carbonate, 200 ml water) and stir for 20 minutes, separate the water layer, add 300 ml water and wash, separate the water layer, add ethyl acetate and methanol (volume ratio 3:1) to recrystallize, filter and dry to obtain 22.28 g of levorotatory ethylstilbene diketone, mass yield 82.52%, chromatographic purity 96.61%, see Figure 1 .

[0064] Reaction as follows:

[0065]

[0066] From the HPLC spectrum, after the hydrolysis reaction of the Wills material, the 3-position does not form a carbonyl group completely, and a part of it is hydrolyzed to a 3-position hydroxyl compound, and after recrystallization, there is still 3% of the residue in the finished product, resulting in low cost yield and poor quality.

[0067] Example 1

[0068] 1) Preparation of compound (2): Take compound (1) 30.00 g, add 300 ml dichloromethane and stir to dissolve, add 1.20 g p-toluenesulfonic acid, 19.80 g ethylene glycol, and stir to dissolve; heat to 40°C, add 27.00 g triethyl orthoformate dropwise, and keep the temperature at 30°C-40°C for 1-1.5 hours. After the reaction is complete, add sodium bicarbonate solution (9.00 g sodium bicarbonate, 300 ml water) and stir at 30°C for 30 minutes, separate the water layer, wash the organic layer with 150 ml water, and add 15.00 g anhydrous sodium sulfate to dry. After drying, the filtrate is concentrated under reduced pressure, and recrystallized with ethyl acetate and petroleum ether in a volume ratio of 2:1, filtered and dried. 37.02 g of compound (2) is obtained, mass yield 123.43%.

[0069] Reaction as follows:

[0070]

[0071] 2) Preparation of compound (3): 35.00 g of compound (2) was dissolved in 400 ml of dichloromethane with stirring, 42.00 g of triphenylphosphine, 38.50 g of iodine was added, and the temperature was raised to 30°C with stirring; 24.50 g of imidazole was added, and the temperature was controlled at 20-30°C for 2-3 hours. After the reaction was completed, 28.00 g of sodium thiosulfate was dissolved in 300 ml of water to form a solution, which was stirred for 20 minutes, and the water layer was separated. 24.50 g of sodium bicarbonate was dissolved in 300 ml of water to form a solution, which was stirred for 15 minutes, and the water layer was separated. The solvent was concentrated under reduced pressure, and recrystallization was performed by adding acetonitrile. After filtration and drying, 43.92 g of compound (3) was obtained, and the mass yield was 125.51%.

[0072] The reaction was as follows:

[0073]

[0074] 3) Preparation of compound (4): 42.00 g of compound (3) was dissolved in 500 ml of tetrahydrofuran with stirring, and the temperature was lowered to below -30°C; 1.26 g of cuprous chloride was added, and 180 ml of 1M methyl magnesium bromide tetrahydrofuran solution was slowly added dropwise, and the temperature was controlled at -35°C to -30°C for 3-4 hours. After the reaction was completed, 420 ml of saturated ammonium chloride solution was added, and the mixture was stirred for 20 minutes. The water layer was separated, and the organic layer was washed with 420 ml of saturated sodium chloride solution, and 21.00 g of anhydrous sodium sulfate was added for drying. The tetrahydrofuran was concentrated, and recrystallization was performed by adding dichloromethane and ethyl acetate in a volume ratio of 1:3. After filtration and drying, 30.49 g of compound (4) was obtained, and the mass yield was 72.60%.

[0075] The reaction was as follows:

[0076]

[0077] 4) Preparation of levorotatory ethyl stellene dione: 30.00 g of compound (4) was dissolved in 360 ml of dichloromethane, and a prepared hydrochloric acid solution (9.00 g of hydrochloric acid, 200 ml of water) was added, and the reaction was performed at room temperature for 3-4 hours. After the reaction was completed, 27.00 g of potassium carbonate was dissolved in 200 ml of water to form a solution, which was stirred for 15 minutes, and the water layer was separated. 240 ml of water was added for washing. The solvent was concentrated under reduced pressure, and recrystallization was performed by adding ethyl acetate and methanol in a volume ratio of 3:1. After filtration and drying, 21.39 g of levorotatory ethyl stellene dione was obtained, and the mass yield was 71.31%, and the chromatographic purity was 99.78%. See Figure 2 , Figure 2 HPLC spectrum of levorotatory ethyl stellene dione prepared in Example 1.

[0078] The reaction was as follows:

[0079]

[0080] Example 2

[0081] 1) Preparation of compound (2): 30.00 g of compound (1) was dissolved in 300 ml of chloroform, 1.20 g of p-toluenesulfonic acid was added, 20.00 g of ethylene glycol was added and stirred to dissolve; the solution was warmed to 50°C, 25.00 g of triethyl orthoformate was slowly added dropwise over a period of 20 minutes, and after the addition was completed, the reaction was maintained at 50°C for 1-1.5 hours. After the reaction was completed, 40°C, 20 minutes of stirring was performed with the addition of a sodium bicarbonate solution (10.00 g of sodium bicarbonate, 250 ml of water), the aqueous layer was separated, 200 ml of water was added and washed, the aqueous layer was separated, and the organic layer was dried with 15.00 g of anhydrous sodium sulfate. The volume was concentrated under reduced pressure, recrystallized with ethyl acetate and petroleum ether in a volume ratio of 2:1, and dried by filtration. 36.61 g of compound (2) was obtained with a mass yield of 122.03%.

[0082] The reaction was as follows:

[0083]

[0084] 2) Preparation of compound (3): 35.00 g of compound (2) was dissolved in 350 ml of chloroform, 38.50 g of triphenylphosphine, 35.00 g of iodine was added, and stirred to warm to 40°C; after warming, 24.50 g of imidazole was added, and the reaction was maintained at 40°C for 2-3 hours. After the reaction was completed, a prepared sodium thiosulfate solution (30.00 g of sodium thiosulfate, 300 ml of water) was added dropwise, stirred for 20 minutes, the aqueous layer was separated, a sodium bicarbonate solution (24.50 g of sodium bicarbonate, 300 ml of water) was added, stirred for 15 minutes, and the aqueous layer was separated. The chloroform was concentrated and recrystallized with acetonitrile, and dried by filtration. 43.14 g of compound (3) was obtained with a mass yield of 123.25%.

[0085] The reaction was as follows:

[0086]

[0087] 3) Preparation of compound (4): 42.00 g of compound (3) was stirred and dissolved in 500 ml of tetrahydrofuran, the solution was cooled to -25°C; 1.47 g of cuprous chloride was added, 180 ml of 1M methylmagnesium bromide tetrahydrofuran solution was slowly added dropwise, and the temperature was controlled at -30°C to -25°C for 3 hours; after the reaction was completed, 420 ml of saturated ammonium chloride solution, 420 ml of saturated sodium chloride solution was sequentially added, the aqueous layer was separated, and the organic layer was dried with 21.00 g of anhydrous sodium sulfate; the volume was concentrated under reduced pressure, recrystallized with dichloromethane and ethyl acetate in a volume ratio of 1:3, and dried by filtration. 30.82 g of compound (4) was obtained with a mass yield of 73.38%.

[0088] The reaction was as follows:

[0089]

[0090] 4) Preparation of levorotatory ethyl steroenedione: 30.00 g of compound (4) was dissolved in 300 ml of chloroform, and a prepared solution of hydrogen potassium sulfate (22.50 g of hydrogen potassium sulfate, 240 ml of water) was added, and the reaction was carried out at 50 °C for 3 hours. After the reaction, a potassium carbonate solution (30.00 g of potassium carbonate, 300 ml of water) was added, and the mixture was washed and stirred, and the water layer was separated. The organic layer was washed with 300 ml of water until the pH became neutral. The chloroform was concentrated under reduced pressure, and recrystallization was carried out using ethyl acetate and methanol in a volume ratio of 3:1, and the mixture was filtered and dried. As a result, 21.81 g of levorotatory ethyl steroenedione was obtained at a yield of 72.70%, and the chromatographic purity was 99.77%. See Fig. 1. Figure 3 , Figure 3 HPLC chart of levorotatory ethyl steroenedione prepared in Example 2.

[0091] The reaction was carried out as follows:

[0092]

[0093] Example 3

[0094] 1) Preparation of compound (2): 30.00 g of compound (1) was dissolved in 300 ml of dichloromethane, and 1.20 g of p-toluenesulfonic acid, 20.00 g of ethylene glycol were added, and the mixture was stirred and dissolved. Then, 30.00 g of triethyl orthoformate was added dropwise at 30 °C, and the reaction was carried out at 30 °C for 1.5 to 2 hours. After the reaction, a sodium bicarbonate solution (12.00 g of sodium bicarbonate, 300 ml of water) was added, and the mixture was stirred at 30 °C for 30 minutes, and the water layer was separated. The organic layer was washed with 150 ml of water, and the water layer was separated. Then, 15.00 g of anhydrous sodium sulfate was added to the organic layer, and the mixture was dried. The filtrate was concentrated under reduced pressure, and recrystallization was carried out using ethyl acetate and petroleum ether in a volume ratio of 2:1, and the mixture was filtered and dried. As a result, 37.50 g of compound (1) was obtained at a yield of 125.00%.

[0095] The reaction was carried out as follows:

[0096]

[0097] 2) Preparation of compound (3): 35.00 g of compound (2) was dissolved in 350 ml of dichloromethane, and 38.50 g of triphenylphosphine, 38.50 g of iodine were added, and the mixture was warmed to 30 °C. Then, 26.25 g of imidazole was added, and the reaction was carried out at 30 °C for 2.5 hours. After the reaction, a sodium thiosulfate solution (29.75 g of sodium thiosulfate, 300 ml of water) was added, and the mixture was stirred for 20 minutes, and the water layer was separated. Then, a sodium bicarbonate solution (28.00 g of sodium bicarbonate, 300 ml of water) was added, and the mixture was stirred for 15 minutes, and the water layer was separated. The dichloromethane was concentrated under reduced pressure, and recrystallization was carried out using acetonitrile, and the mixture was filtered and dried. As a result, 43.53 g of compound (3) was obtained at a yield of 124.37%.

[0098] Reaction as follows:

[0099]

[0100] 3) Preparation of compound (4): 42.00 g of compound (3) was dissolved in 500 ml of tetrahydrofuran and cooled to below -20 °C; 1.05 g of cuprous chloride was added and 165 ml of 1 M methyl magnesium bromide tetrahydrofuran solution was slowly added dropwise while controlling the temperature to be less than -20 °C, and the reaction was carried out at -20 °C for 3 hours; after the reaction, 420 ml of saturated ammonium chloride solution was added and stirred for 20 minutes, the water layer was separated, and the organic layer was washed with 420 ml of saturated sodium chloride solution and 21.00 g of anhydrous sodium sulfate was added for drying; the solvent was concentrated, recrystallized with dichloromethane and ethyl acetate at a volume ratio of 1:3, and dried by filtration. 30.76 g of compound (4) was obtained with a mass yield of 73.23%.

[0101] Reaction as follows:

[0102]

[0103] 4) Preparation of levorotatory ethyl steroen diketone: 30.00 g of compound (4) was dissolved in 390 ml of dichloromethane, and a prepared potassium hydrogen sulfate solution (24.00 g of potassium hydrogen sulfate, 300 ml of water) was added, and the reaction was carried out at 30 °C for about 4 hours. After the reaction, 24.00 g of potassium carbonate was added to 300 ml of water to form a sodium carbonate solution, and stirred for 20 minutes, the water layer was separated, and 300 ml of water was added to wash to near neutral. The dichloromethane was concentrated and dried, and recrystallized with ethyl acetate and methanol at a volume ratio of 3:1, and dried by filtration. 21.16 g of levorotatory ethyl steroen diketone was obtained with a mass yield of 70.53%, and a chromatographic purity of 99.75%, see Figure 4 , Figure 4 HPLC spectrum of levorotatory ethyl steroen diketone prepared in Example 3.

[0104] Reaction as follows:

[0105]

[0106] The above only describes the preferred embodiments of the present application, and it should be noted that for those skilled in the art, without departing from the principles of the present application, a number of improvements and refinements can be made, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A method for preparing levorotatory ethyl sterenedione, comprising the following steps: a) performing ketal protection on the compound of formula (1) to obtain a compound of formula (2); b) converting the compound of formula (2) into a compound of formula (3); c) methylating the compound of formula (3) to obtain a compound of formula (4); d) subjecting the compound of formula (4) to a hydrolysis ketal reaction to obtain levorotatory ethyl sterenedione.

2. The preparation method according to claim 1, characterized in that The step a) is specifically as follows: In the presence of a catalyst, the compound of formula (1) reacts with ethylene glycol to obtain the compound of formula (2).

3. The preparation method according to claim 2, characterized in that In the step a), the catalyst is p-toluenesulfonic acid and triethyl orthoformate in a mass ratio of 1 to 5:20 to 30; The mass ratio of the compound of formula (1), ethylene glycol and catalyst is 20-40:10-30:20-40; The solvent of the reaction is selected from dichloromethane or chloroform; The reaction temperature is 30° C. to 50° C., and the reaction time is 1 h to 2 h.

4. The preparation method according to claim 1, characterized in that The step b) is specifically as follows: Under the action of a catalyst, the compound of formula (2) reacts with an iodination reagent to obtain a compound of formula (3).

5. The preparation method according to claim 4, characterized in that In the step b), the iodination reagent is elemental iodine; The catalyst is triphenylphosphine and imidazole in a mass ratio of 30-50:20-30; The mass ratio of the compound of formula (2), the iodination reagent and the catalyst is 30-40:30-40:50-80; The solvent of the reaction is dichloromethane or chloroform; The reaction temperature is 20°C to 40°C, and the reaction time is 2h to 3h.

6. The preparation method according to claim 1, characterized in that The step c) is specifically as follows: Under the action of a reaction auxiliary agent, the compound of formula (3) reacts with a methylating agent to obtain a compound of formula (4).

7. The preparation method according to claim 6, characterized in that In the step c), the methylating agent is methylmagnesium bromide; The reaction aid is cuprous chloride or lithium chloride; The mass ratio of the compound of formula (3) to the reaction auxiliary agent is 30-50:1-5; The molar ratio of the compound of formula (3) to the methylating agent is 1:2-3; The solvent of the reaction is tetrahydrofuran or diethyl ether; The reaction temperature is -35°C to -20°C, and the reaction time is 3h to 4h.

8. The preparation method according to claim 1, characterized in that The step d) is specifically as follows: The compound of formula (4) undergoes a hydrolysis ketal reaction under acidic conditions to obtain levorotatory ethyl sterenedione.

9. The preparation method according to claim 8, characterized in that In the step d), the acidic reagent of the acidic condition is potassium bisulfate, sodium bisulfate, dilute sulfuric acid or hydrochloric acid; The mass ratio of the compound of formula (4) to the acidic reagent is 20-40:5-30; The solvent for the hydrolysis ketal reaction is dichloromethane or chloroform; The temperature of the hydrolysis ketal reaction is 20° C. to 50° C., and the time is 3 h to 4 h.

10. The preparation method according to claim 9, characterized in that After the hydrolysis ketal reaction is completed, the following steps are also included: The obtained crude product was recrystallized from ethyl acetate and methanol.

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