A process for the preparation of levonorgestrel
By improving the preparation method of levonorgestrel, using cheap and readily available raw materials and simple process steps, the problems of high production cost, low conversion rate and environmental friendliness in the existing technology are solved, and the production of high-purity and high-yield levonorgestrel is achieved, which is suitable for industrial application.
Patent Information
- Application Number
- CN202411965991.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-30
- Publication Date
- 2025-10-21
- Estimated Expiration
- 2044-12-30
AI Technical Summary
Existing levonorgestrel synthesis methods have problems such as high production cost, low conversion rate, environmental unfriendliness, and poor safety. In particular, the method uses expensive catalysts and highly dangerous hydrogen reduction reactions, and produces many by-products, making it difficult to industrialize.
Levonorgestrel is prepared from 18-hydroxy-4-estren-3,17-dione as a starting material through iodine substitution, acetylene addition, ketal protection, methylation and hydrolysis reactions, avoiding the use of expensive catalysts and highly dangerous hydrogen reduction reactions, and using cheap and readily available raw materials and simple process steps.
The production of levonorgestrel with high conversion rate and high purity was achieved, with HPLC purity reaching above 99.5% and yield reaching 80%, which reduced production costs, improved safety and environmental friendliness, and was suitable for industrial large-scale production.
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Abstract
Description
Technical Field
[0001] The present application relates to the technical field of preparation of steroid drugs, and in particular to a method for preparing levonorgestrel. Background Art
[0002] Levonorgestrel, chemically known as D(-–)-17α-ethynyl-17β-hydroxy-18-methylestradiol-4-en-3-one, was first synthesized by the German company Schering in the 1960s. The drug primarily acts on the hypothalamus and pituitary gland, reducing or eliminating the peak levels of follicle-stimulating hormone and luteinizing hormone during mid-cycle, thereby inhibiting ovulation. It has progestin activity and the ability to bind to androgen receptors. It is often used as an emergency contraceptive and long-acting contraceptive, and its oral contraceptives occupy a large market share.
[0003] The current synthesis method of levonorgestrel mainly uses the fermentation oxide 13β-ethyl-3-methoxy-estra-1,3,5(10),8(9),14(15)-pentaen-17β-ol as the raw material, and obtains the target product through hydrogen reduction, lithium ammonia reduction, Wohlbacher oxidation, hydrolysis, and acetylation reactions.
[0004] The synthetic route is as follows:
[0005]
[0006] This method uses an expensive palladium-on-carbon catalyst in step 1, significantly increasing the cost of production auxiliary materials. The hydrogen reduction reaction employed is highly dangerous, difficult to control in industrial production, and carries the risk of explosion. Step 2, the lithium-ammonia reduction, produces numerous byproducts and low material conversion rates. It also generates a large amount of ammonia-nitrogen compounds, causing excessive ammonia-nitrogen content in the wastewater, which is environmentally unfriendly. Step 3, the hydrolysis reaction following the Walsh oxidation produces hydrolyzed isomers that are difficult to remove, posing significant challenges to subsequent reactions and purification processes. Current levonorgestrel production processes suffer from high production costs, low conversion rates, environmental concerns, poor safety, and are unsuitable for industrial production.
[0007] Therefore, developing an environmentally friendly method for preparing levonorgestrel with low production cost and high conversion rate is an urgent problem to be solved by those skilled in the art. Summary of the Invention
[0008] In view of this, the present application provides a method for preparing levonorgestrel, wherein the raw materials of the preparation method are cheap and readily available, the yield is high, and the preparation method has good comprehensive performance.
[0009] The present application provides a method for preparing levonorgestrel, comprising the following steps:
[0010] Step 1) iodine substitution is performed on 18-hydroxy-4-estren-3,17-dione to obtain a compound represented by Formula 1;
[0011]
[0012] Step 2) subjecting the compound represented by Formula 1 to acetylene addition to obtain a compound represented by Formula 2;
[0013]
[0014] Step 3) performing ketal protection on the compound represented by Formula 2 to obtain a compound represented by Formula 3;
[0015]
[0016] Step 4) methylating the compound represented by Formula 3 to obtain a compound represented by Formula 4;
[0017]
[0018] Step 5) performing a hydrolysis ketal reaction on the compound represented by formula 4 to obtain levonorgestrel.
[0019] This application uses 18-hydroxy-4-estrene-3,17-dione as the starting material. Iodine is first substituted at the 18-hydroxyl group to obtain the compound shown in Formula 1. Acetylene is then added to the 17-carbonyl group to produce the compound shown in Formula 2. Ketal protection is performed on the 3-carbonyl group to produce the compound shown in Formula 3. Methylation is then performed at the 18-position to produce the compound shown in Formula 4. Finally, a hydrolysis ketal reaction is performed to obtain levonorgestrel. 18-hydroxy-4-estrene-3,17-dione, the raw material, is low-cost and readily available. The resulting product is of high quality, with an HPLC purity of over 99.5% and a high yield. The reaction scheme is as follows:
[0020]
[0021] The present application first mixes 18-hydroxy-4-estren-3,17-dione, iodine, and a solvent to perform an iodine substitution reaction to obtain a compound represented by Formula 1. In some specific implementations, step 1) is specifically as follows: in the presence of a catalyst, 18-hydroxy-4-estren-3,17-dione reacts with an iodination reagent to obtain a compound represented by Formula 1. In some specific implementations, in the step 1), the iodination reagent is elemental iodine, the catalyst is triphenylphosphine and imidazole in a mass ratio of (12-25): (7-15), preferably triphenylphosphine and imidazole in a mass ratio of 12:7; the molar ratio of 18-hydroxy-4-estren-3,17-dione to the iodination reagent is 1:1.1 to 1:1.5, preferably 1:1.1 to 1:1.2; the mass ratio of 18-hydroxy-4-estren-3,17-dione to the catalyst is (10-20): (21-40); the solvent used in the reaction includes but is not limited to dichloromethane and / or chloroform. The present application has no special requirements for the selection of the solvent, preferably dichloromethane; the reaction temperature is 10°C to 30°C, preferably 30°C, and the reaction time is 2h to 3h, preferably 3h. In some specific implementations, after the reaction is completed, sodium thiosulfate solution is added, stirred and washed, the water layer is separated, the organic layer is washed with sodium bicarbonate solution, the solvent is evaporated to dryness, acetonitrile is added for recrystallization, and filtration is dried to obtain the compound represented by Formula 1. In some specific implementations, the present application has no particular limitation on the source of the compound of Formula (1), which can be purchased from the market or prepared according to methods disclosed in the prior art, for example, by fermenting 19-nor-4AD with the fungus Leptoporus fissilis. For specific methods, refer to G. DENISMEAKIN, 16P, 18-Dihydroxylation of Oxygenated 5a-Androstanes with the Fungus Leptoporus fissilis.
[0022] The present application then mixes the compound shown in Formula 1 with a solvent, passes acetylene, and performs acetylene addition to obtain a compound shown in Formula 2. In some specific implementations, the step 2) is specifically: under the action of a catalyst, the compound shown in Formula 1 reacts with acetylene to obtain a compound shown in Formula 2. In some specific implementations, after passing acetylene, tetrahydrofuran is added and then acetylene is slowly passed through, and the first catalyst is added to react. In some specific implementations, in the step 2), the molar ratio of the compound shown in Formula 1 to the catalyst is 1:7 to 1:10, preferably 1:8 to 1:9; the catalyst includes potassium tert-butoxide; the ventilation time of the acetylene is 3h to 4h; the solvent used in the reaction includes but is not limited to tetrahydrofuran, and the present application has no special requirements for the selection of the solvent; the reaction temperature is -25°C to -5°C, preferably -25°C to -15°C; the reaction time is 1h to 3h, preferably 3h. In some specific implementations, a neutralizing agent is added after the reaction to adjust the pH to neutral, and then ethyl acetate is added for extraction, and the mixture is concentrated under reduced pressure, recrystallized, filtered, and dried to obtain a compound of formula 2; the neutralizing agent includes but is not limited to hydrochloric acid, and the present application has no special requirements for the selection of the neutralizing agent.
[0023] The present application then mixes the compound of Formula 2, diol and solvent, reacts, and performs ketal protection to obtain the compound of Formula 3. In some specific implementations, the step 3) is specifically: under the action of a catalyst, the compound of Formula 2 reacts with the diol to obtain the compound of Formula 3. In some specific implementations, in the step 3), the catalyst is p-toluenesulfonic acid and triethyl orthoformate in a mass ratio of (1.15-1.25):(22.5-24), preferably p-toluenesulfonic acid and triethyl orthoformate in a mass ratio of (1.2-1.25):(23-24); the solvent used in the reaction includes but is not limited to dichloromethane and / or chloroform. This application has no special requirements for the selection of solvent, preferably dichloromethane; the molar ratio of the compound represented by Formula 2 to the diol is 1:4 to 1:6; the mass ratio of the compound represented by Formula 2 to the catalyst is (24-25):(24-26); the reaction temperature is 25°C to 45°C, preferably 40°C; the reaction time is 1h to 1.5h, preferably 1.5h. In some specific implementations, after the reaction is completed, sodium bicarbonate solution is added with stirring, the aqueous layer is separated, the organic layer is washed with water, concentrated under reduced pressure, and then ethyl acetate and petroleum ether are added for recrystallization, filtered and dried to obtain the compound represented by Formula 3. In some specific implementations, the diol is selected from one or more of ethylene glycol, 1,3-propylene glycol, and 2,2-dimethyl-1,3-propanediol.
[0024] The present application then mixes the compound represented by Formula 3, a tetrahydrofuran solution of a methylating agent, and a solvent to react, and methylates to obtain a compound represented by Formula 4. In some specific implementations, the step 4) is specifically as follows: under the action of a reaction aid, the compound represented by Formula 3 reacts with a methylating agent to obtain a compound represented by Formula 4. In some specific implementations, the molar ratio of the compound represented by Formula 3 to the methylating agent is 1:1.5 to 1:2.5; the molar ratio of the compound represented by Formula 3 to the reaction aid is 1:(0.1-0.2); the methylating agent is methylmagnesium bromide; the reaction aid includes cuprous chloride or lithium chloride; the solvent used in the reaction includes but is not limited to tetrahydrofuran, and the present application has no special requirements for the selection of the solvent; the reaction temperature is -30°C to -10°C, preferably -30°C to -20°C, and the reaction time is 2h to 3h, preferably 3h. In some specific implementations, after the reaction is completed, the mixture is washed with a saturated ammonium chloride solution, the water layer is separated, the organic layer is washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, recrystallized by adding anhydrous ethanol, filtered and dried to obtain the compound shown in Formula 4.
[0025] The present application is to react the compound shown in Formula 4 under acidic conditions to hydrolyze the ketal to obtain levonorgestrel. In some specific implementations, the step 5) is specifically: the compound shown in Formula 4 is subjected to a hydrolysis ketal reaction under acidic conditions to obtain levonorgestrel. In some specific implementations, in the step 5), the acidic reagent of the acidic conditions is potassium bisulfate, sodium bisulfate, dilute sulfuric acid or hydrochloric acid; the molar ratio of the compound shown in Formula 4 to the acidic reagent is 10:5 to 1:2; the solvent used in the hydrolysis ketal reaction includes but is not limited to dichloromethane or chloroform. The present application has no special requirements for the selection of solvents, preferably dichloromethane; the temperature of the hydrolysis ketal reaction is 10°C to 30°C, preferably 15°C to 25°C, and the time is 3h to 4h, preferably 4h. In some specific implementations, after the reaction is completed, an alkaline solvent is added for washing, the water layer is separated, the organic layer is washed with water, concentrated under reduced pressure, methanol is added, recrystallized, filtered and dried to obtain levonorgestrel. In some specific implementations, the alkaline reagent includes one or more of potassium carbonate, sodium carbonate or sodium bicarbonate, preferably potassium carbonate.
[0026] The preparation method described in the present application prepares levonorgestrel through halogenation, alkynylation, ketalization, methylation, and hydrolysis reactions; uses new starting materials to obtain a new levonorgestrel production route, which has the advantages of high conversion rate, good finished product quality, simple process operation, good safety, low production cost, and environmental friendliness, and is suitable for industrial large-scale production; avoids the problems of many by-products, low conversion rate, and expensive auxiliary materials; the three wastes generated have mature treatment methods and low treatment costs, greatly reducing the safety, environmental protection, and compliance costs in the process production, and the auxiliary materials are cheap and easily available; the HPLC purity can reach more than 99.5%, and the yield can reach 80%. BRIEF DESCRIPTION OF THE DRAWINGS
[0027] Figure 1 The HPLC spectrum of levonorgestrel provided in Example 1 of the present application;
[0028] Figure 2 The HPLC spectrum of levonorgestrel provided in Example 2 of the present application;
[0029] Figure 3 This is the HPLC spectrum of levonorgestrel provided in Example 3 of the present application. DETAILED DESCRIPTION
[0030] It should be understood that the expression "one or more of" includes individually each of the items recited after the expression and various combinations of two or more of the recited items, unless otherwise apparent from the context and usage. The expression "and / or" in conjunction with three or more recited items should be understood to have the same meaning, unless otherwise apparent from the context.
[0031] The terms "comprising", "having" or "containing", including their grammatical synonyms, should generally be understood as open and non-restrictive, e.g., not excluding other unrecited elements or steps, unless otherwise specifically stated or understood from the context.
[0032] 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 application remains operable. Additionally, two or more steps or actions may be performed simultaneously.
[0033] The use of any and all examples or exemplary language, such as "such as" or "including," herein is intended merely to better illustrate the present application and does not limit the scope of the present application unless otherwise claimed. No language in this specification should be construed as indicating any non-claimed element as essential to the practice of the present application.
[0034] In addition, the numerical ranges and parameters used to define this application are approximate values. The relevant numerical values in the specific examples have been presented as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual testing methods. Therefore, unless otherwise expressly stated, all ranges, amounts, values, and percentages used in this disclosure should be understood to be modified by the word "about." As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range.
[0035] The present application provides a method for preparing levonorgestrel, comprising the following steps:
[0036] Step 1) iodine substitution is performed on 18-hydroxy-4-estren-3,17-dione to obtain a compound represented by Formula 1;
[0037]
[0038] Step 2) subjecting the compound represented by Formula 1 to acetylene addition to obtain a compound represented by Formula 2;
[0039]
[0040] Step 3) performing ketal protection on the compound represented by Formula 2 to obtain a compound represented by Formula 3;
[0041]
[0042] Step 4) methylating the compound represented by Formula 3 to obtain a compound represented by Formula 4;
[0043]
[0044] Step 5) performing a hydrolysis ketal reaction on the compound represented by formula 4 to obtain levonorgestrel.
[0045] The preparation method described in the present application prepares levonorgestrel through halogenation, alkynylation, ketalization, methylation, and hydrolysis reactions; uses new starting materials to obtain a new levonorgestrel production route, which has the advantages of high conversion rate, good finished product quality, simple process operation, good safety, low production cost, and environmental friendliness, and is suitable for industrial large-scale production; avoids the problems of many by-products, low conversion rate, and expensive auxiliary materials; the three wastes generated have mature treatment methods and low treatment costs, which greatly reduces the safety, environmental protection, and compliance costs in process production, and the auxiliary materials are cheap and easily available.
[0046] The present application is further described below with reference to the following examples. The scope of protection of the present application is not limited by the following examples.
[0047] Example 1
[0048] Preparation of the compound shown in Formula 1:
[0049]
[0050] Add 300 mL of dichloromethane to 20.00 g of 18-hydroxy-4-estren-3,17-dione and stir at room temperature until dissolved. Then add 24.00 g of triphenylphosphine and 22.00 g of iodine, stir, and heat to 20°C. Add 14.00 g of imidazole and react at 30°C for 3 hours. After the reaction, add sodium thiosulfate solution (16.00 g of sodium thiosulfate and 160 mL of water) to the reaction flask and stir for 20 minutes. The aqueous layer is separated and the organic layer is washed with sodium bicarbonate solution (14.00 g of sodium bicarbonate and 160 mL of water). The dichloromethane is concentrated to dryness, recrystallized from acetonitrile, and filtered to dryness. This yields the compound shown in Formula 1 with a mass yield of 128.35%.
[0051] Preparation of the compound shown in Formula 2:
[0052]
[0053] Dissolve 25.00g of the compound represented by Formula 1 in 200mL of tetrahydrofuran and set aside. Add 50.00g of potassium tert-butoxide to 500mL of tetrahydrofuran, stir, and cool to below -20°C. Pass acetylene gas through the mixture for 1 hour until the solution turns yellow and turbid. Add the prepared tetrahydrofuran solution dropwise, maintaining the temperature below -15°C for approximately 20 minutes. Continue to slowly pass acetylene gas through the mixture and allow to react for 3 hours. Add 15.00g of potassium tert-butoxide and continue the reaction for 1 hour. After the reaction, slowly add 200mL of water dropwise. Concentrate under reduced pressure to remove the tetrahydrofuran. Add dilute aqueous hydrochloric acid and adjust the pH to neutral. Extract the mixture with 250mL of ethyl acetate twice, concentrate under reduced pressure, recrystallize, and filter to dry. This yields 25.53g of the compound represented by Formula 2, with a mass yield of 102.12%.
[0054] Preparation of the compound shown in formula 3:
[0055]
[0056] Dissolve 25.00 g of the compound represented by Formula 2 in 250 mL of chloroform. Add 18.75 g of ethylene glycol and 1.25 g of p-toluenesulfonic acid, stir, and heat to 30°C. Add 22.5 g of triethyl orthoformate dropwise, and let react for 20 minutes. Keep the mixture at 30°C for 1.5 hours. Add sodium bicarbonate solution (7.50 g of sodium bicarbonate in 250 mL of water) and stir at 30°C for 30 minutes. The aqueous layer is separated and the organic layer is washed with 125 mL of water. Concentrate under reduced pressure, then add ethyl acetate and recrystallize with petroleum ether. Filter and dry. This yields 25.37 g of the compound represented by Formula 3, with a mass yield of 101.48%.
[0057] Preparation of the compound shown in formula 4:
[0058]
[0059] 25.00 g of the compound represented by Formula 3 was added to 250 mL of tetrahydrofuran, stirred and dissolved, and the temperature was lowered to below -20°C. 0.75 g of cuprous chloride was added, and 107 mL of a 1M methylmagnesium bromide solution in tetrahydrofuran was added dropwise. The reaction was maintained at below -20°C for 3 hours. The mixture was washed with 250 mL of saturated ammonium chloride solution, the aqueous layer was separated, and the organic layer was washed with 200 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, recrystallized from anhydrous ethanol, and filtered to dryness. 18.04 g of the compound represented by Formula 4 was obtained, with a mass yield of 72.16%.
[0060] Preparation of levonorgestrel:
[0061]
[0062] 17.00g of the compound shown in formula 4 was dissolved in 255mL of dichloromethane, and potassium bisulfate solution (10.20g of potassium bisulfate, 170mL of water) was added and stirred at room temperature for 4 hours. Potassium carbonate solution (17.00g of potassium carbonate, 170mL of water) was added for washing, and then washed with 170mL of water. Concentrated under reduced pressure, recrystallized from methanol, filtered and dried. 13.92g of levonorgestrel was obtained, with a mass yield of 81.88% and a chromatographic purity of 99.61%. The HPLC spectrum of levonorgestrel provided in this embodiment is shown in FIG. Figure 1 shown.
[0063] Example 2
[0064] Preparation of the compound represented by Formula 1: Add 250 mL of chloroform to 20.00 g of 18-hydroxy-4-estren-3,17-dione and stir at room temperature until dissolved. Then add 23.00 g of triphenylphosphine and 22.00 g of iodine; then add 12.00 g of imidazole and react at approximately 30°C for 3 hours. After the reaction, add sodium thiosulfate solution (16.00 g of sodium thiosulfate in 150 mL of water) to the reaction flask and stir for 20 minutes. The aqueous layer is separated and the organic layer is washed with sodium bicarbonate solution (13.00 g of sodium bicarbonate in 150 mL of water). The chloroform is concentrated to dryness, recrystallized from acetonitrile, and filtered to dryness. This yields 25.26 g of the compound represented by Formula 1, with a mass yield of 126.30%.
[0065] Preparation of the compound represented by Formula 2: Dissolve 24.00 g of the compound represented by Formula 1 in 220 mL of tetrahydrofuran and set aside. Add 45.00 g of potassium tert-butoxide to 450 mL of tetrahydrofuran, stir, and cool to below -12°C. Pass acetylene gas through the solution for 45 minutes until the solution turns yellow and turbid. Add the prepared tetrahydrofuran solution dropwise, maintaining the temperature below -5°C for approximately 20 minutes. Continue to slowly pass acetylene gas through the solution and allow the reaction to proceed below -5°C for 3 hours. Add an additional 18.00 g of potassium tert-butoxide and continue the reaction for 1 hour. After the reaction, slowly add 200 mL of water dropwise. Concentrate under reduced pressure at 40°C to remove the tetrahydrofuran. Add dilute aqueous hydrochloric acid and adjust the pH to neutral. Extract the solution twice with 300 mL of ethyl acetate, concentrate under reduced pressure, recrystallize, and filter to dry. This yields 24.17 g of the compound represented by Formula 2, with a mass yield of 100.71%.
[0066] Preparation of the compound represented by Formula 3: Dissolve 24.00 g of the compound represented by Formula 2 in 300 mL of dichloromethane, add 18.00 g of ethylene glycol and 1.15 g of p-toluenesulfonic acid, and stir. Raise the temperature to 40°C. Slowly add 23.00 g of triethyl orthoformate dropwise. Reflux at 30°C for 1.5 hours. Add sodium bicarbonate solution (8.00 g of sodium bicarbonate in 300 mL of water) and stir at 30°C for 45 minutes. Remove the aqueous layer and wash the organic layer with 150 mL of water. Concentrate under reduced pressure, then add ethyl acetate and recrystallize with petroleum ether. Filter and dry. This yields 24.65 g of the compound represented by Formula 3, with a mass yield of 102.71%.
[0067] Preparation of the compound represented by Formula 4: 24.00 g of the compound represented by Formula 3 was dissolved in 250 mL of tetrahydrofuran with stirring, and the temperature was lowered to below -15°C. 0.75 g of cuprous chloride was added, and 105 mL of a 1M methylmagnesium bromide solution in tetrahydrofuran was added dropwise. The reaction was controlled at below -10°C for 3 hours. The mixture was washed with 250 mL of saturated ammonium chloride solution, the aqueous layer was separated, and the organic layer was washed with 250 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, recrystallized from anhydrous ethanol, and filtered to dryness. 17.15 g of the compound represented by Formula 4 was obtained, with a mass yield of 71.47%.
[0068] Preparation of levonorgestrel: 16.00g of the compound shown in formula 4 was dissolved in 240mL of chloroform, and sodium bisulfate solution (9.60g of sodium bisulfate, 160mL of water) was added and stirred at room temperature for 4 hours. Sodium bicarbonate solution (16.80g of sodium bicarbonate, 160mL of water) was added for washing, and then washed with 160mL of water. Concentrated under reduced pressure, recrystallized from methanol, filtered and dried. 12.49g of levonorgestrel was obtained, with a mass yield of 78.06% and a chromatographic purity of 99.59%. The HPLC spectrum of levonorgestrel provided in the embodiment is shown in FIG. Figure 2 shown.
[0069] Example 3
[0070] Preparation of the compound represented by Formula 1: Add 300 mL of dichloromethane to 20.00 g of 18-hydroxy-4-estren-3,17-dione and stir at room temperature until dissolved. Then add 25.00 g of triphenylphosphine and 22.00 g of iodine and stir to dissolve. Add 12.00 g of imidazole and allow to react at 20°C for 3 hours. After the reaction, add sodium thiosulfate solution (15.00 g of sodium thiosulfate and 180 mL of water) to the reaction flask and stir for 20 minutes. The aqueous layer is separated and the organic layer is washed with sodium bicarbonate solution (15.00 g of sodium bicarbonate and 180 mL of water). The dichloromethane is concentrated to dryness, recrystallized from acetonitrile, and filtered to dryness. 24.71 g of the compound represented by Formula 1 is obtained with a mass yield of 123.58%.
[0071] Preparation of the compound represented by Formula 2: Dissolve 24.00 g of the compound represented by Formula 1 in 200 mL of tetrahydrofuran and set aside. Add 48.00 g of potassium tert-butoxide to 500 mL of tetrahydrofuran, stir, and cool to below -20°C. Pass acetylene gas through the mixture for 1 hour until the solution turns yellow and turbid. Add the prepared tetrahydrofuran solution dropwise, maintaining the temperature below -15°C for approximately 20 minutes. Continue to slowly pass acetylene gas through the mixture for 3 hours. Add 13.00 g of potassium tert-butoxide and continue to react for 1 hour. After the reaction, slowly add 200 mL of water dropwise. Concentrate under reduced pressure at 40°C to remove the tetrahydrofuran. Add dilute aqueous hydrochloric acid and adjust the pH to neutral. Extract the mixture twice with 300 mL of ethyl acetate, concentrate under reduced pressure, recrystallize, and filter to dry. This yields 24.43 g of the compound represented by Formula 2, with a mass yield of 101.82%.
[0072] Preparation of the compound represented by Formula 3: Dissolve 24.00 g of the compound represented by Formula 2 in 250 mL of dichloromethane. Add 18.00 g of ethylene glycol and 1.20 g of p-toluenesulfonic acid, stirring at room temperature to dissolve. Add 24.00 g of triethyl orthoformate dropwise, and react at 45°C for 2 hours. Add sodium bicarbonate solution (8.00 g of sodium bicarbonate in 250 mL of water), stir at 30°C for 30 minutes, separate the aqueous layer, and wash the organic layer with 125 mL of water. Concentrate under reduced pressure, then add ethyl acetate and recrystallize with petroleum ether, then filter and dry. This yields 24.39 g of the compound represented by Formula 3, with a mass yield of 101.62%.
[0073] Preparation of the compound represented by Formula 4: 24.00 g of the compound represented by Formula 3 was dissolved in 250 mL of tetrahydrofuran with stirring, and the temperature was lowered to below -20°C. 0.72 g of cuprous chloride was added, and 110 mL of a 1M methylmagnesium bromide solution in tetrahydrofuran was added dropwise. The reaction was controlled at below -20°C for 3 hours. The mixture was washed with 250 mL of saturated ammonium chloride solution, the aqueous layer was separated, and the organic layer was washed with 250 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, recrystallized from anhydrous ethanol, and filtered to dryness. 17.47 g of the compound represented by Formula 4 was obtained, with a mass yield of 72.82%.
[0074] Preparation of levonorgestrel: 17.00g of the compound shown in formula 4 was dissolved in 255mL of dichloromethane, and hydrochloric acid solution (5.1g of potassium bisulfate, 170mL of water) was added and stirred at room temperature for 4 hours. Sodium carbonate solution (17.00g of sodium carbonate, 170mL of water) was added for washing, and then washed with 170mL of water. Concentrated under reduced pressure, recrystallized from methanol, filtered and dried. 13.56g of levonorgestrel was obtained, with a mass yield of 79.76% and a chromatographic purity of 99.55%. The HPLC spectrum of levonorgestrel provided in the embodiment is shown in FIG. Figure 3 shown.
[0075] The above is only a preferred specific implementation method of the present application, but the scope of protection of the present application is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes based on the technical solution and application concept of the present application within the technical scope disclosed in the present application, and they should be covered by the scope of protection of the present application.
Claims
1. A method for preparing levonorgestrel, characterized in that: The following steps are involved: Step 1) iodine substitution is performed on 18-hydroxy-4-estren-3,17-dione to obtain a compound represented by Formula 1; Step 2) subjecting the compound represented by Formula 1 to acetylene addition to obtain a compound represented by Formula 2; Step 3) performing ketal protection on the compound represented by Formula 2 to obtain a compound represented by Formula 3; Step 4) methylating the compound represented by Formula 3 to obtain a compound represented by Formula 4; Step 5) performing a hydrolysis ketal reaction on the compound represented by formula 4 to obtain levonorgestrel.
2. The preparation method according to claim 1, characterized in that The step 1) is specifically as follows: Under the action of a catalyst, 18-hydroxy-4-estren-3,17-dione reacts with an iodination reagent to obtain a compound shown in Formula 1.
3. The preparation method according to claim 2, characterized in that In the step 1), the iodination reagent is elemental iodine, the catalyst is triphenylphosphine and imidazole in a mass ratio of (12-25):(7-15); the molar ratio of 18-hydroxy-4-estren-3,17-dione to the iodination reagent is 1:1.1 to 1:1.5; the mass ratio of 18-hydroxy-4-estren-3,17-dione to the catalyst is (10-20):(21-40); the solvent used in the reaction includes dichloromethane and / or chloroform; the reaction temperature is 10°C to 30°C, and the reaction time is 2h to 3h.
4. The preparation method according to claim 1, characterized in that The step 2) is specifically as follows: Under the action of a catalyst, the compound represented by Formula 1 reacts with acetylene to obtain a compound represented by Formula 2.
5. The preparation method according to claim 4, characterized in that In the step 2), the molar ratio of the compound represented by Formula 1 to the catalyst is 1:7 to 1:10; the catalyst includes potassium tert-butoxide; the ventilation time of the acetylene is 1 hour to 1.5 hours; the solvent used in the reaction includes tetrahydrofuran; the reaction temperature is -25°C to -5°C; and the reaction time is 3 hours to 4 hours.
6. The preparation method according to claim 1, characterized in that The step 3) is specifically as follows: Under the action of a catalyst, the compound represented by Formula 2 reacts with diol to obtain a compound represented by Formula 3.
7. The preparation method according to claim 6, characterized in that In the step 3), the catalyst is p-toluenesulfonic acid and triethyl orthoformate in a mass ratio of (1.15-1.25):(22.5-24); the solvent used in the reaction includes dichloromethane and / or chloroform; the molar ratio of the compound represented by Formula 2 to the diol is 1:4 to 1:6; the mass ratio of the compound represented by Formula 2 to the catalyst is (24-25):(24-26); the reaction temperature is 25°C to 45°C; and the reaction time is 1 hour to 1.5 hours.
8. The preparation method according to claim 1, characterized in that The step 4) is specifically as follows: Under the action of a reaction aid, the compound represented by Formula 3 reacts with a methylating agent to obtain a compound represented by Formula 4; The molar ratio of the compound represented by Formula 3 to the methylating agent is 1:1.5 to 1:2.5; the molar ratio of the compound represented by Formula 3 to the reaction auxiliary is 1:(0.1-0.2); the methylating agent is methylmagnesium bromide; the reaction auxiliary includes cuprous chloride or lithium chloride; the solvent used in the reaction includes tetrahydrofuran; the reaction temperature is -30°C to -10°C, and the reaction time is 2h to 3h.
9. The preparation method according to claim 1, characterized in that The step 5) is specifically as follows: The compound represented by formula 4 undergoes a hydrolysis ketal reaction under acidic conditions to obtain levonorgestrel.
10. The preparation method according to claim 9, characterized in that In the step 5), the acidic reagent of the acidic condition is potassium bisulfate, sodium bisulfate, dilute sulfuric acid or hydrochloric acid; The molar ratio of the compound represented by formula 4 to the acidic reagent is 10:5 to 1:2; The solvent used in the hydrolysis ketal reaction includes dichloromethane or chloroform; The temperature of the hydrolysis ketal reaction is 10° C. to 30° C., and the time is 3 h to 4 h.
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