Preparation method of levonorgestrel

Abstract

The invention discloses a preparation method of levonorgestrel, which comprises the following steps: carrying out iodine substitution on 18-hydroxy-4-estriene-3, 17-diketone to obtain a compound as shown in a formula 1; performing acetylene addition on the compound as shown in the formula 1 to obtain a compound as shown in a formula 2; performing ketal protection on the compound as shown in the formula 2 to obtain a compound as shown in a formula 3; methylating the compound as shown in the formula 3 to obtain a compound as shown in a formula 4; and carrying out hydrolysis ketal reaction on the compound as shown in the formula 4 to obtain levonorgestrel. The preparation method is easy and convenient to operate, high in safety and environmentally friendly, the safety, environmental protection and compliance cost in process production is greatly reduced, auxiliary materials are low in price and easy to obtain, industrial production and purchase are facilitated, and meanwhile the conversion rate is high.

Description

Technical Field

[0001] The present application relates to the technical field of preparation of steroidal drugs, and in particular to a method for preparing levonorgestrel. Background Art

[0002] The chemical name of levonorgestrel is D(-–)-17α-ethynyl-17β-hydroxy-18-methylestr-4-en-3-one, and its English name is levonorgestrel. It was first synthesized by the German Schering Company in the 1960s. The drug mainly acts on the hypothalamus and pituitary gland, which can reduce or eliminate the peak levels of follicle-stimulating hormone and luteinizing hormone in the middle of the menstrual period, inhibiting ovulation. It has progestin activity and the ability to bind to androgen receptors. It is often used as emergency contraception and long-acting contraceptives, 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, Wohlers oxidation, hydrolysis, and acetylation reactions.

[0004] The synthetic route is as follows:

[0005]

[0006] The method uses expensive catalyst palladium carbon in step 1, which greatly increases the cost of production auxiliary materials. The hydrogen reduction reaction used is highly dangerous, difficult to control in industrial production, and has the risk of explosion; step 2 lithium ammonia reduction, many by-products, low material conversion rate, and a large amount of ammonia nitrogen compounds are produced during production, which will cause the ammonia nitrogen content of production waste liquid to exceed the standard, which is unfriendly to the environment; step 3 The hydrolysis reaction after Wo's oxidation, the generated hydrolysis isomers are difficult to remove, which brings great challenges to the subsequent reaction and refining process. The current levonorgestrel production process has problems such as high production cost, low conversion rate, unfriendly environment, poor safety, and unfavorable 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-substituted 18-hydroxy-4-estren-3,17-dione to obtain a compound of formula 1;

[0011]

[0012] Step 2) subjecting the compound of formula 1 to acetylene addition to obtain a compound of 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) hydrolyzing the compound represented by formula 4 to obtain levonorgestrel.

[0019] The present application uses 18-hydroxy-4-estrene-3,17-dione as the starting material, firstly performs iodine substitution on the hydroxyl group at position 18 to obtain the compound shown in formula 1, then performs acetylene addition on the carbonyl group at position 17 to obtain the compound shown in formula 2, performs ketal protection on the carbonyl group at position 3 to obtain the compound shown in formula 3, then performs methylation reaction at position 18 to obtain the compound shown in formula 4, and finally performs hydrolysis ketal reaction to obtain levonorgestrel. 18-hydroxy-4-estrene-3,17-dione as the raw material is low in cost and easy to obtain; the obtained product has good quality, HPLC purity is above 99.5%, and the yield is high. The reaction route is as follows:

[0020]

[0021] The present application first mixes 18-hydroxy-4-estrene-3,17-dione, iodine and a solvent to perform an iodine substitution reaction to obtain a compound shown in Formula 1. In some specific implementations, the step 1) is specifically: under the action of a catalyst, 18-hydroxy-4-estrene-3,17-dione reacts with an iodination reagent to obtain a compound shown in Formula 1. In some specific implementations, in 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, and 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, filtered and dried to obtain the compound shown in Formula 1. In some specific implementations, the present application has no special restrictions on the source of the compound of Formula (1), which can be purchased from the market or prepared according to the method disclosed in the prior art, for example, 19-nor-4AD is fermented by the fungus Leptoporus fissilis. For specific methods, refer to G.DENISMEAKIN, 16P, 18-Dihydroxylation of Oxygenated 5a-Androstanes with the Fungus Leptoporus fzssilis.

[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, and the first catalyst is added for reaction. 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 compound of formula 2 is obtained after reduced pressure concentration, recrystallization, filtration and drying; 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 obtains the compound of formula 3 by ketal protection. In some specific implementations, the step 3) is specifically: under the action of a catalyst, the compound of formula 2 reacts with 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, and the present application has no special requirements for the selection of the 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 and stirred, the water 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 shown in 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-propylene glycol.

[0024] The present application then mixes the compound shown in Formula 3, a tetrahydrofuran solution of a methylating agent and a solvent, reacts, and methylates to obtain a compound shown in Formula 4. In some specific implementations, the step 4) is specifically: under the action of a reaction aid, the compound shown in Formula 3 reacts with a methylating agent to obtain a compound shown in Formula 4. In some specific implementations, the molar ratio of the compound shown in Formula 3 to the methylating agent is 1:1.5 to 1:2.5; the molar ratio of the compound shown in 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] In the present application, the compound shown in Formula 4 is reacted 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 condition 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, and 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, acetylation, ketalization, methylation and hydrolysis reactions; adopts 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, environmental friendliness and the like, and is suitable for industrial large-scale production; avoids the problems of many by-products, low conversion rate, expensive auxiliary materials and the like; the three wastes generated have mature treatment methods, and the treatment cost is low, which greatly reduces 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 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 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.

[0031] 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.

[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 is still operable. In addition, two or more steps or actions can be performed simultaneously.

[0033] The use of any and all examples or exemplary language, such as "for example" or "including", herein is intended only to better illustrate the present application and does not limit the scope of the present application unless the claims are set forth. No language in this specification should be construed as indicating that any non-claimed element is essential to the practice of the present application.

[0034] In addition, the numerical ranges and parameters used to define the present application 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.

[0035] The present application provides a method for preparing levonorgestrel, comprising the following steps:

[0036] Step 1) iodine-substituted 18-hydroxy-4-estren-3,17-dione to obtain a compound of formula 1;

[0037]

[0038] Step 2) subjecting the compound of formula 1 to acetylene addition to obtain a compound of 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) hydrolyzing the compound represented by formula 4 to obtain levonorgestrel.

[0045] The preparation method described in the present application prepares levonorgestrel through halogenation, acetylation, ketalization, methylation, and hydrolysis reactions; a new starting material is used 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; it avoids the problems of many by-products, low conversion rate, and expensive auxiliary materials; the three wastes generated have mature treatment methods, and the treatment cost is low, which greatly reduces the safety, environmental protection, and compliance costs in the process production, and the auxiliary materials are cheap and easy to obtain.

[0046] The present application is further described below in conjunction with the following embodiments. The protection scope of the present application is not limited by the following embodiments.

[0047] Example 1

[0048] Preparation of the compound shown in formula 1:

[0049]

[0050] 20.00g18-hydroxy-4-estrene-3,17-dione, add 300mL dichloromethane, stir and dissolve at room temperature, add 24.00g triphenylphosphine and 22.00g iodine, stir and heat to 20℃; add 14.00g imidazole, react at 30℃ for 3 hours. After the reaction, sodium thiosulfate solution (16.00g sodium thiosulfate, 160mL water) is put into the reaction bottle, stirred for 20 minutes, the water layer is separated, and the organic layer is washed with sodium bicarbonate solution (14.00g sodium bicarbonate, 160mL water). Concentrate dichloromethane, add acetonitrile for recrystallization, filter and dry. The compound shown in formula 1 is obtained with a mass yield of 128.35%.

[0051] Preparation of the compound shown in formula 2:

[0052]

[0053] 25.00g of the compound shown in formula 1 was dissolved in 200mL of tetrahydrofuran for standby use. 50.00g of potassium tert-butoxide was added to 500mL of tetrahydrofuran, and the temperature was stirred and cooled to below -20°C; acetylene gas was introduced for 1 hour until the solution turned yellow and turbid; the prepared tetrahydrofuran solution was added dropwise, the temperature was controlled to be less than -15°C, the addition time was about 20 minutes, and acetylene gas was slowly introduced to react for 3 hours. 15.00g of potassium tert-butoxide was added and the reaction was continued for 1 hour. After the reaction was completed, 200mL of water was slowly added dropwise; tetrahydrofuran was removed by concentrating under reduced pressure; dilute hydrochloric acid aqueous solution was added and the pH was adjusted to neutral. 250mL of ethyl acetate was extracted twice, concentrated under reduced pressure, recrystallized, filtered and dried. 25.53g of the compound shown in formula 2 was obtained, with a mass yield of 102.12%.

[0054] Preparation of the compound shown in formula 3:

[0055]

[0056] 25.00g of the compound shown in formula 2 was dissolved in 250mL of chloroform, and 18.75g of ethylene glycol and 1.25g of p-toluenesulfonic acid were added, and the mixture was stirred and heated to 30°C; 22.5g of triethyl orthoformate was added dropwise, and the mixture was kept at 30°C for 20 minutes and reacted for 1.5 hours. Sodium bicarbonate solution (7.50g of sodium bicarbonate, 250mL of water) was added and stirred at 30°C for 30 minutes, and the water layer was separated and the organic layer was washed with 125mL of water. The mixture was concentrated under reduced pressure, and ethyl acetate was added, and the mixture was recrystallized from petroleum ether, and filtered and dried. 25.37g of the compound shown in formula 3 was obtained, and the mass yield was 101.48%.

[0057] Preparation of the compound shown in formula 4:

[0058]

[0059] 25.00g of the compound shown in formula 3 was added to 250mL of tetrahydrofuran, stirred and dissolved, and the temperature was lowered to below -20°C; 0.75g of cuprous chloride was added, and 107mL of 1M methylmagnesium bromide tetrahydrofuran solution was added dropwise, and the temperature was controlled to be less than -20°C for reaction for 3 hours; 250mL of saturated ammonium chloride solution was added for washing, the water layer was separated, and the organic layer was washed with 200mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, added with anhydrous ethanol for recrystallization, and filtered and dried. 18.04g of the compound shown in formula 4 was obtained, and the mass yield was 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 shown in Formula 1: 20.00g 18-hydroxy-4-estren-3,17-dione, add 250mL chloroform, stir and dissolve at room temperature, add 23.00g triphenylphosphine and 22.00g iodine; add 12.00g imidazole, and react at about 30°C for 3 hours. After the reaction, sodium thiosulfate solution (16.00g sodium thiosulfate, 150mL water) is put into the reaction bottle, stirred for 20 minutes, the water layer is separated, and the organic layer is washed with sodium bicarbonate solution (13.00g sodium bicarbonate, 150mL water). Concentrate chloroform, add acetonitrile for recrystallization, and filter and dry. 25.26g of the compound shown in Formula 1 is obtained, and the mass yield is 126.30%.

[0065] Preparation of the compound shown in Formula 2: 24.00g of the compound shown in Formula 1 is dissolved in 220mL of tetrahydrofuran for standby use. Add 45.00g of potassium tert-butoxide to 450mL of tetrahydrofuran, stir and cool to below -12°C; pass acetylene gas for 45 minutes until the solution becomes yellow and turbid; drip the configured tetrahydrofuran solution, control the temperature to less than -5°C, and add acetylene gas slowly for about 20 minutes, and react for 3 hours below -5°C. Add 18.00g of potassium tert-butoxide and continue to react for 1 hour. After the reaction, slowly drip 200mL of water; concentrate under reduced pressure at 40°C to remove tetrahydrofuran; add dilute hydrochloric acid aqueous solution and adjust the pH to neutral. Extract twice with 300mL of ethyl acetate, concentrate under reduced pressure, recrystallize, filter and dry. Obtain 24.17g of the compound shown in Formula 2, with a mass yield of 100.71%.

[0066] Preparation of the compound shown in Formula 3: 24.00g of the compound shown in Formula 2 was dissolved in 300mL of dichloromethane, 18.00g of ethylene glycol and 1.15g of p-toluenesulfonic acid were added, and the mixture was stirred and heated to 40°C; 23.00g of triethyl orthoformate was slowly added dropwise; the mixture was heated and refluxed for 1.5 hours. Sodium bicarbonate solution (8.00g of sodium bicarbonate, 300mL of water) was added and stirred at 30°C for 45 minutes, the water layer was separated, and the organic layer was washed with 150mL of water. The mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was recrystallized from petroleum ether, and filtered and dried. 24.65g of the compound shown in Formula 3 was obtained, and the mass yield was 102.71%.

[0067] Preparation of the compound shown in Formula 4: 24.00g of the compound shown in Formula 3 was added to 250mL of tetrahydrofuran, stirred and dissolved, and the temperature was lowered to below -15°C; 0.75g of cuprous chloride was added, 105mL of 1M methylmagnesium bromide tetrahydrofuran solution was added dropwise, and the temperature was controlled to be less than -10°C for reaction for 3 hours; 250mL of saturated ammonium chloride solution was added for washing, the water layer was separated, and the organic layer was washed with 250mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, added with anhydrous ethanol for recrystallization, and filtered and dried. 17.15g of the compound shown in Formula 4 was obtained, and the mass yield was 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 with 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 shown in Formula 1: 20.00g 18-hydroxy-4-estren-3,17-dione, add 300mL dichloromethane, stir and dissolve at room temperature, add 25.00g triphenylphosphine and 22.00g iodine, stir and dissolve; add 12.00g imidazole, keep warm at 20℃ for 3 hours. After the reaction, sodium thiosulfate solution (15.00g sodium thiosulfate, 180mL water) is put into the reaction bottle, stirred for 20 minutes, the water layer is separated, and the organic layer is washed with sodium bicarbonate solution (15.00g sodium bicarbonate, 180mL water). Concentrate dichloromethane, add acetonitrile for recrystallization, filter and dry. 24.71g of the compound shown in Formula 1 is obtained, with a mass yield of 123.58%.

[0071] Preparation of the compound shown in Formula 2: 24.00g of the compound shown in Formula 1 was dissolved in 200mL of tetrahydrofuran for standby use. 48.00g of potassium tert-butoxide was added to 500mL of tetrahydrofuran, and the temperature was cooled to below -20°C with stirring; acetylene gas was introduced for 1 hour until the solution became yellow and turbid; the configured tetrahydrofuran solution was added dropwise, the temperature was controlled to be less than -15°C, the addition time was about 20 minutes, and acetylene gas was slowly introduced for reaction for 3 hours. 13.00g of potassium tert-butoxide was added and the reaction was continued for 1 hour. After the reaction was completed, 200mL of water was slowly added dropwise; tetrahydrofuran was removed by concentrating under reduced pressure at 40°C; dilute hydrochloric acid aqueous solution was added and the pH was adjusted to neutral. 300mL of ethyl acetate was extracted twice, concentrated under reduced pressure, recrystallized, filtered and dried. 24.43g of the compound shown in Formula 2 was obtained, with a mass yield of 101.82%.

[0072] Preparation of the compound shown in Formula 3: 24.00g of the compound shown in Formula 2 was dissolved in 250mL of dichloromethane, 18.00g of ethylene glycol and 1.20g of p-toluenesulfonic acid were added, and the mixture was stirred and dissolved at room temperature; 24.00g of triethyl orthoformate was added dropwise, and the mixture was reacted at 45°C for 2 hours. Sodium bicarbonate solution (8.00g of sodium bicarbonate, 250mL of water) was added and stirred at 30°C for 30 minutes, the water layer was separated, and the organic layer was washed with 125mL of water. The mixture was concentrated under reduced pressure, ethyl acetate was added, and the mixture was recrystallized from petroleum ether, and filtered and dried. 24.39g of the compound shown in Formula 3 was obtained, and the mass yield was 101.62%.

[0073] Preparation of the compound shown in Formula 4: 24.00g of the compound shown in Formula 3 was added to 250mL of tetrahydrofuran, stirred and dissolved, and the temperature was lowered to below -20°C; 0.72g of cuprous chloride was added, 110mL of 1M methylmagnesium bromide tetrahydrofuran solution was added dropwise, and the temperature was controlled to be less than -20°C for reaction for 3 hours; 250mL of saturated ammonium chloride solution was added for washing, the water layer was separated, and the organic layer was washed with 250mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, added anhydrous ethanol for recrystallization, and filtered and dried. 17.47g of the compound shown in Formula 4 was obtained, and the mass yield was 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 hydrogen sulfate, 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 with 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 manner of the present application, but the protection scope of the present application is not limited thereto. Any technician familiar with the technical field can make equivalent substitutions or changes within the technical scope disclosed in the present application according to the technical solution and application concept of the present application, which should be covered by the protection scope of the present application.

Claims

1. A method for preparing levonorgestrel, characterized in that: The following steps are involved: Step 1) iodine-substituted 18-hydroxy-4-estren-3,17-dione to obtain a compound of formula 1; Step 2) subjecting the compound of formula 1 to acetylene addition to obtain a compound of 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) hydrolyzing 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 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 1h to 1.5h.

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 agent is 1:(0.1-0.2); the methylating agent is methylmagnesium bromide; the reaction auxiliary agent 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 ketalization 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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