Preparation method of levo-ethyl stenedione

Abstract

The invention provides a preparation method of levoethyl stenedione, which comprises the following steps: a) performing ketal protection on a compound in a formula (1) to obtain a compound in a formula (2); b) converting the compound of formula (2) into a compound of formula (3); c) methylating the compound in the formula (3) to obtain a compound in a formula (4); and d) carrying out hydrolysis ketal reaction on the compound in the formula (4) to obtain the levo-ethyl stenedione. According to the invention, 18-hydroxystenedione is used as a starting raw material, and ketal reaction, halogenation reaction, methylation reaction and hydrolysis reaction are carried out to prepare the levoethyl stenedione. The process route provided by the invention has the advantages of short reaction path, few byproducts and high conversion rate, and effectively solves the problems of more byproducts, low yield, high safety risk, environmental protection pressure and high comprehensive production cost in the existing process.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, in particular to a method for preparing levorotatory ethyl sterenedione. Background Art

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

[0003]

[0004] The prior art generally uses fermented oxide 13β-ethyl-3-methoxy-estra-1,3,5(10),8(9),14(15)-pentaen-17β alcohol as raw material, and prepares it through hydrogen reduction, lithium ammonia reduction, Wohlers oxidation, and hydrolysis reaction. The synthesis route is as follows:

[0005]

[0006] This method has many by-products and low yield. Summary of the invention

[0007] In view of this, the present application provides a method for preparing levorotatory ethyl sterenedione. The preparation method provided by the present application has few by-products and a high conversion rate.

[0008] The present application provides a method for preparing levorotatory ethyl sterenedione, 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) methylating the compound of formula (3) to obtain a compound of formula (4);

[0014]

[0015] d) subjecting the compound of formula (4) to a hydrolysis ketal reaction to obtain levorotatory ethyl sterenedione.

[0016] The present application uses the compound of formula (1) as a raw material, firstly performs ketal protection on the carbonyl groups at positions 3 and 17 to obtain the compound of formula (2), then replaces the hydroxyl group at position 18 with iodine to obtain the compound of formula (3), then performs methylation reaction at position 18 to obtain the compound of formula (4), and finally performs hydrolysis ketal reaction to obtain levorotatory ethyl sterenedione. The synthetic route is as follows:

[0017]

[0018] The present application uses the compound of formula (1) as the starting material, and its chemical name is: 18-hydroxy-4-estrene-3,17-dione. The present application has no special restrictions on the source of the compound of formula (1), and it can be purchased from the market, or prepared according to the method disclosed in the prior art, for example, by fermenting 19-nor-4AD with the fungus Leptoporus fissilis. For the specific method, refer to G.DENIS MEAKIN, 16P,18-Dihydroxylation of Oxygenated 5a-Androstanes with the Fungus Leptoporus fissilis.

[0019] The present invention first performs ketal protection on the compound of formula (1), specifically:

[0020] In the presence of a catalyst, the compound of formula (1) reacts with ethylene glycol to obtain a 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 catalyst is 20-40:10-30:20-40.

[0022] Specifically, the present application first dissolves the compound of formula (1), adds p-toluenesulfonic acid and ethylene glycol to dissolve, then drips triethyl orthoformate, and keeps warm for reaction. In some specific implementations, the solvent of the reaction is selected from dichloromethane or chloroform, preferably dichloromethane. The reaction temperature is 30°C to 50°C, preferably 40°C, and the reaction time is 1h to 2h, preferably 1.5h.

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

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

[0025] Under the action of a catalyst, the compound of formula (2) reacts with an iodination agent to obtain a compound of formula (3).

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

[0027] Specifically, the present application first adds the compound of formula (2) to a solvent to dissolve, then adds triphenylphosphine and iodine, and stirs to dissolve; then adds imidazole and keeps warm for reaction. In some specific implementations, the solvent of the reaction is dichloromethane or chloroform, preferably dichloromethane. In some specific implementations, the reaction temperature is 20°C to 40°C, preferably 30°C, and the reaction time is 2h to 3h, preferably 2.5h.

[0028] After the reaction is completed, the obtained reaction product is washed with sodium thiosulfate solution and sodium bicarbonate solution in sequence, concentrated and dried under reduced pressure, and then acetonitrile is added for recrystallization, filtered and dried to obtain a compound of formula (3).

[0029] After obtaining the compound of formula (3), it is methylated to obtain the compound of formula (4), which is specifically:

[0030] Under the action of a reaction aid, the compound of formula (3) reacts with a methylating agent to obtain a 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) to the reaction aid is 30 to 50:1 to 5. In some specific implementations, the molar ratio of the compound of formula (3) to the methylating agent is 1:2 to 3.

[0032] Specifically, the present application firstly stirs and dissolves compound (3) with a solvent, cools the temperature, adds cuprous chloride, and drips methylmagnesium bromide tetrahydrofuran solution at a controlled temperature, and keeps the temperature for reaction. In some specific implementations, the solvent of the reaction is tetrahydrofuran or ether. In some specific implementations, the reaction temperature is -35°C to -20°C, preferably -35°C to -30°C; the reaction time is 3h to 4h, preferably 3.5h.

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

[0034] In some specific implementations, the compound of formula (4) is subjected to a hydrolysis ketal reaction to obtain levorotatory ethyl sterenedione, specifically: the compound of formula (4) is subjected to a hydrolysis ketal reaction under acidic conditions to obtain levorotatory ethyl sterenedione. The acidic reagent of the acidic conditions is potassium hydrogen sulfate, sodium hydrogen sulfate, dilute sulfuric acid or hydrochloric acid, preferably potassium hydrogen sulfate.

[0035] In some specific implementations, the mass ratio of the compound of formula (4) and the acidic reagent is 20-40:5-30. Specifically, the acidic condition is an aqueous solution of an acidic reagent, and in the acidic reagent aqueous solution, the mass ratio of the acidic reagent to water is 5-30:150-350. Specifically, the present application dissolves the compound of formula (4), puts into the acid reagent aqueous solution, and stirs the reaction. In some specific implementations, the solvent of the hydrolysis ketal reaction is dichloromethane or chloroform, preferably dichloromethane. In some specific implementations, the temperature of the hydrolysis ketal reaction is 20°C to 50°C, preferably 40°C, and the time is 3h to 4h, preferably 3.5h.

[0036] After the reaction is completed, an alkaline reagent aqueous solution is added for stirring, the water layer is separated, and the organic layer is washed with water until the pH is close to neutral; it is concentrated under reduced pressure, ethyl acetate and methanol are added for recrystallization, and filtered and dried to obtain levorotatory ethyl sterenedione. In some specific implementations, the alkaline reagent can be selected from potassium carbonate and sodium carbonate, preferably potassium carbonate. In some specific implementations, the volume ratio of ethyl acetate to methanol is 1 to 5:1, preferably 3:1.

[0037] The present application uses the compound of formula (1) as a raw material, first performs ketal protection on the carbonyl groups at positions 3 and 17 to obtain the compound of formula (2), then replaces the hydroxyl group at position 18 with iodine to obtain the compound of formula (3), then performs a methylation reaction at position 18 to generate the compound of formula (4), and finally performs a hydrolysis ketal reaction to obtain levorotatory ethyl sterenedione, with a short reaction path, few by-products, high conversion rate, and high finished product quality. The process route provided in the present application is green and environmentally friendly, highly safe, and highly compliant. The auxiliary materials used are cheap, low-toxic or non-toxic, and easy to obtain. The reaction operation of each step is simple, and it can be converted into an automated and mechanized process after simple transformation, which greatly improves production efficiency, can effectively solve the problems of many by-products, low yield, high safety risk, environmental pressure, and high comprehensive production cost in the existing process, and the economic benefits are more obvious, and it is more suitable for industrial production. The experimental results show that the chromatographic purity of levorotatory ethyl sterenedione prepared by the method provided in the present application can reach more than 99.7%. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is the HPLC spectrum of L-ethyl sterenedione prepared in the comparative example of this application;

[0039] Figure 2 The HPLC spectrum of the levorotatory ethyl sterenedione prepared in Example 1;

[0040] Figure 3 The HPLC spectrum of the levorotatory ethyl sterenedione prepared in Example 2;

[0041] Figure 4 This is the HPLC spectrum of the 1-ethyl-1-stenedione prepared in Example 3. DETAILED DESCRIPTION

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

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

[0044] It should be understood that the order of steps or the order in which certain actions are performed is not important as long as the present invention remains operable. In addition, two or more steps or actions may be performed simultaneously.

[0045] The use of any and all examples or exemplary language, such as "for example" or "including", herein is intended only to better illustrate the invention and does not limit the scope of the invention unless otherwise claimed. No language in this specification should be construed as indicating that any non-claimed element is essential to the practice of the invention.

[0046] In addition, the numerical ranges and parameters used to define the present invention are approximate values, and the relevant values ​​in the specific embodiments have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. Therefore, unless otherwise expressly stated, it should be understood that all ranges, quantities, values ​​and percentages used in this disclosure are modified by "about". Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1% or 0.5% of a specific value or range.

[0047] The present application provides a method for preparing levorotatory ethyl sterenedione, comprising the following steps:

[0048] a) performing ketal protection on the 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) methylating the compound of formula (3) to obtain a compound of formula (4);

[0053]

[0054] d) subjecting the compound of formula (4) to a hydrolysis ketal reaction to obtain levorotatory ethyl sterenedione.

[0055] The present application uses the compound of formula (1) as a raw material, firstly performs ketal protection on the carbonyl groups at positions 3 and 17 to obtain the compound of formula (2), then replaces the hydroxyl group at position 18 with iodine to obtain the compound of formula (3), then performs methylation reaction at position 18 to obtain the compound of formula (4), and finally performs hydrolysis ketal reaction to obtain levorotatory ethyl sterenedione. The synthetic route is as follows:

[0056]

[0057] The process route provided by this application has a short reaction path, few by-products, high conversion rate, high finished product quality, green environmental protection, high safety, strong compliance, and the auxiliary materials used are cheap, low-toxic or non-toxic, and easy to obtain. The reaction operation of each step is simple, and it can be converted into an automated and mechanized process after simple transformation, which greatly improves production efficiency. It can effectively solve the problems of many by-products, low yield, high safety risks, environmental pressure, and high comprehensive production costs in the existing process, and the economic benefits are more obvious, which is more suitable for industrial production. The experimental results show that the chromatographic purity of the levorotatory ethyl sterenedione prepared by the method provided by this application can reach more than 99.7%.

[0058] The preparation method of levorotatory ethyl sterenedione provided in the present application is further described below in conjunction with the examples.

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

[0060] Comparative Example 1

[0061] The lithium ammine 18-methyl-3-methoxy-2,5(10)-estren-17-ol (compound of formula a) is oxidized with aluminum isopropoxide and cyclohexanone to obtain the Woll's compound (compound of formula b), which is then hydrolyzed under acidic conditions to obtain the levorotatory ethyl estenedione (compound of formula (I)).

[0062] 1) Wohl's oxidation: Take 30.00g of compound (a), add 270ml toluene, stir to dissolve, stir and heat to 115℃; add 75.00g cyclohexanone, stir and reflux at 115℃, and separate the water layer with a water separator. Cool down to 110℃, add 3.00g aluminum isopropoxide, heat to 116℃ and reflux for 2 hours. After the reaction is completed, cool down to 80℃, add dilute sulfuric acid (2ml sulfuric acid, 100ml water) for washing, separate 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 27.35g Wohl's product (compound of formula b), with a mass yield of 91.16%.

[0063] 2) Hydrolysis reaction: Take 27.00g of the Woll's compound (compound b), add 300ml of dichloromethane and stir to dissolve, add potassium hydrogen sulfate solution (16.00g potassium hydrogen sulfate, 200ml water), and stir at room temperature for 5 hours. After the reaction is completed, add potassium carbonate solution (27.00g potassium carbonate, 200ml water) and stir for 20 minutes, separate the water layer, add 300ml water to wash, separate the water layer, concentrate the organic layer under reduced pressure, add ethyl acetate and methanol (volume ratio 3:1) for recrystallization, filter and dry to obtain 22.28g of levorotatory ethyl sterenedione, with a mass yield of 82.52% and a chromatographic purity of 96.61%, see Figure 1 .

[0064] The reaction is as follows:

[0065]

[0066] It can be seen from the HPLC spectrum that after the hydrolysis reaction of the Wollastonite, the carbonyl group at the 3-position is not completely formed, and a part of it is hydrolyzed into the 3-hydroxyl group. After recrystallization and purification, there is still 3% residue in the finished product, resulting in low cost yield and poor quality.

[0067] Example 1

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

[0069] The reaction is as follows:

[0070]

[0071] 2) Preparation of compound (3): 35.00g of compound (2) was added to 400ml of dichloromethane and stirred to dissolve, 42.00g of triphenylphosphine and 38.50g of iodine were added, the temperature was stirred and raised to 30°C; 24.50g of imidazole was added, and the temperature was controlled at 20°C to 30°C for 2 to 3 hours. After the reaction was completed, sodium thiosulfate solution (28.00g of sodium thiosulfate, 300ml of water) was added and stirred for 20 minutes, the water layer was separated, sodium bicarbonate solution (24.50g of sodium bicarbonate, 300ml of water) was added and stirred for 15 minutes, and the water layer was separated. Concentrate under reduced pressure, add acetonitrile for recrystallization, filter and dry. 43.92g of compound (3) was obtained, with a mass yield of 125.51%.

[0072] The reaction is as follows:

[0073]

[0074] 3) Preparation of compound (4): 42.00 g of compound (3) was added to 500 ml of tetrahydrofuran, stirred and dissolved, and the temperature was lowered to below -30°C; 1.26 g of cuprous chloride was added, and 180 ml of 1M methylmagnesium bromide tetrahydrofuran solution was slowly added dropwise, and the temperature was controlled at -35°C to -30°C for reaction for 3 to 4 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 dried with 21.00 g of anhydrous sodium sulfate; the tetrahydrofuran was concentrated, and dichloromethane and ethyl acetate were added in a volume ratio of 1:3 for recrystallization, and filtered and dried. 30.49 g of compound (4) was obtained, with a mass yield of 72.60%.

[0075] The reaction is as follows:

[0076]

[0077] 4) Preparation of levorotatory ethyl sterenedione: 30.00 g of compound (4) was dissolved in 360 ml of dichloromethane, and the prepared hydrochloric acid solution (9.00 g of hydrochloric acid, 200 ml of water) was added, and the reaction was carried out at room temperature for 3 to 4 hours. After the reaction, potassium carbonate solution (27.00 g of potassium carbonate, 200 ml of water) was added and stirred for 15 minutes, the water layer was separated, and 240 ml of water was added for washing. The solvent was concentrated under reduced pressure, and ethyl acetate and methanol were added in a volume ratio of 3:1 for recrystallization, and filtered and dried. 21.39 g of levorotatory ethyl sterenedione was obtained, with a mass yield of 71.31% and a chromatographic purity of 99.78%, see Figure 2 , Figure 2 This is the HPLC spectrum of the 1-ethyl-1-stenedione prepared in Example 1.

[0078] The reaction is as follows:

[0079]

[0080] Example 2

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

[0082] The reaction is as follows:

[0083]

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

[0085] The reaction is as follows:

[0086]

[0087] 3) Preparation of compound (4): 42.00 g of compound (3) was dissolved in 500 ml of tetrahydrofuran by stirring, and the solution was cooled to -25°C; 1.47 g of cuprous chloride was added, and 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, it was washed with 420 ml of saturated ammonium chloride solution and 420 ml of saturated sodium chloride solution in sequence, the water layer was separated, and the organic layer 21.00 g was dried over anhydrous sodium sulfate; it was concentrated under reduced pressure, and dichloromethane and ethyl acetate were added in a volume ratio of 1:3 for recrystallization, and filtered and dried. 30.82 g of compound (4) was obtained, and the mass yield was 73.38%.

[0088] The reaction is as follows:

[0089]

[0090] 4) Preparation of 1-ethyl-1-osteline: 30.00 g of compound (4) was dissolved in 300 ml of chloroform, and the prepared potassium bisulfate solution (22.50 g of potassium bisulfate, 240 ml of water) was added, and the mixture was reacted at 50°C for 3 hours. After the reaction, potassium carbonate solution (30.00 g of potassium carbonate, 300 ml of water) was added, stirred and washed, the water layer was separated, and the organic layer was washed with 300 ml of water until the pH was about neutral. The chloroform was concentrated under reduced pressure, and recrystallized by adding ethyl acetate and methanol in a volume ratio of 3:1, and filtered and dried. 21.81 g of 1-ethyl-1-osteline was obtained, with a mass yield of 72.70% and a chromatographic purity of 99.77%, see Figure 3 , Figure 3 This is the HPLC spectrum of the 1-ethyl-1-stenedione prepared in Example 2.

[0091] The reaction is as follows:

[0092]

[0093] Example 3

[0094] 1) Preparation of compound (2): Take 30.00g of compound (1), add 300ml of dichloromethane and stir to dissolve, add 1.20g of p-toluenesulfonic acid and 20.00g of ethylene glycol and stir to dissolve; add 30.00g of triethyl orthoformate dropwise at 30°C, keep at 30°C and react for 1.5 to 2 hours. After the reaction, add sodium bicarbonate solution (12.00g of sodium bicarbonate, 300ml of water) and stir at 30°C for 30 minutes, separate the water layer, wash the organic layer with 150ml of water, separate the water layer, and dry the organic layer with 15.00g of anhydrous sodium sulfate. The filtrate is concentrated under reduced pressure, and recrystallized by adding ethyl acetate and petroleum ether in a volume ratio of 2:1, and filtered and dried. 37.50g of compound (1) is obtained, with a mass yield of 125.00%.

[0095] The reaction is as follows:

[0096]

[0097] 2) Preparation of compound (3): 35.00g of compound (2) was added to 350ml of dichloromethane and stirred to dissolve. 38.50g of triphenylphosphine and 38.50g of iodine were added and the temperature was raised to 30°C. 26.25g of imidazole was added and the temperature was kept at 30°C for reaction for 2.5 hours. After the reaction, sodium thiosulfate solution (29.75g of sodium thiosulfate, 300ml of water) was added and stirred for 20 minutes. The water layer was separated and sodium bicarbonate solution (28.00g of sodium bicarbonate, 300ml of water) was added and stirred for 15 minutes. The water layer was separated. The dichloromethane was concentrated and recrystallized by adding acetonitrile, and filtered and dried. 43.53g of compound (3) was obtained with a mass yield of 124.37%.

[0098] The reaction is as follows:

[0099]

[0100] 3) Preparation of compound (4): 42.00g of compound (3) was dissolved in 500ml of tetrahydrofuran by stirring, and the temperature was lowered to below -20°C; 1.05g of cuprous chloride was added, and 165ml of 1M methylmagnesium bromide tetrahydrofuran solution was slowly added dropwise while controlling the temperature to be below -20°C, and the mixture was reacted at -20°C for 3 hours; after the reaction, 420ml 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 420ml of saturated sodium chloride solution, and then dried with 21.00g of anhydrous sodium sulfate; the solvent was concentrated, and the mixture was recrystallized with dichloromethane and ethyl acetate in a volume ratio of 1:3, and filtered and dried. 30.76g of compound (4) was obtained, and the mass yield was 73.23%.

[0101] The reaction is as follows:

[0102]

[0103] 4) Preparation of levorotatory ethyl sterenedione: 30.00 g of compound (4) was dissolved in 390 ml of dichloromethane, and the prepared potassium hydrogen sulfate solution (24.00 g of potassium hydrogen sulfate, 300 ml of water) was added, and the mixture was reacted at 30°C for about 4 hours. After the reaction, sodium carbonate solution (24.00 g of potassium carbonate, 300 ml of water) was added and stirred for 20 minutes, the water layer was separated, and 300 ml of water was added to wash until it was nearly neutral. The dichloromethane was concentrated to dryness, and ethyl acetate and methanol were added in a volume ratio of 3:1 to recrystallize, and the mixture was filtered and dried. 21.16 g of levorotatory ethyl sterenedione was obtained, with a mass yield of 70.53% and a chromatographic purity of 99.75%, see Figure 4 , Figure 4 This is the HPLC spectrum of the 1-ethyl-1-stenedione prepared in Example 3.

[0104] The reaction is as follows:

[0105]

[0106] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

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: In the presence of a catalyst, the compound of formula (1) reacts with ethylene glycol to obtain a 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 1h to 2h.

4. The preparation method according to claim 1, characterized in that: The step b) is specifically: Under the action of a catalyst, the compound of formula (2) reacts with an iodination agent 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 aid, 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 aid 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: The compound of formula (4) undergoes a hydrolysis ketalization 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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