Synthesis method of ethinyl estradiol

Abstract

The present invention belongs to the field of organic chemical synthesis or pharmaceutical synthesis technology, and specifically relates to a method for synthesizing ethinyl estradiol. The method comprises: reacting an organometallic reagent with trialkylsilyl acetylene, adding trimethylchlorosilane and estrone, performing hydroxyl protection and acetylation reactions to obtain a reaction solution; adding alcohol and water to the reaction solution for hydrolysis, and then purifying the solution to obtain ethinyl estradiol. This method utilizes a one-pot process to synthesize ethinyl estradiol, eliminating the need for intermediate separation and purification. The process is simple, has a short cycle, and does not require the use of acetylene gas. It offers excellent process safety, high yield, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis or drug synthesis, and particularly relates to a synthesis method of ethinylestradiol. Background Art

[0002] Ethinyl estradiol is an estrogen, chemically known as 3-hydroxy-19-nor-17a-pregnane-1,3,5(10)-trien-20-yn-17-ol. Its structural formula is shown below, and its English name is Ethinyl estradiol. Ethinyl estradiol is combined with drospirenone to form the contraceptive Yasmin, a low-dose oral contraceptive with good safety, effectiveness, and tolerability. It is one of the most commonly used contraceptives in clinical practice and has performed well in the market.

[0003]

[0004] The common method for synthesizing ethinyl estradiol is to use estrone as the raw material and introduce an acetylene group through carbonyl addition to produce ethinyl estradiol. Specifically, a metal acetylide reacts with the carbonyl group of estrone to introduce the acetylene group. The preparation of the metal acetylide generally uses acetylene gas and Grignard reagent, n-butyl lithium, potassium tert-butoxide, potassium hydroxide, etc. The common method is as follows:

[0005] 1. Format method

[0006]

[0007] 2. Lithium Alkyne Method

[0008]

[0009] 3. Potassium acetylene method

[0010]

[0011]

[0012] In the preparation process of the above-mentioned metal acetylide, since acetylene gas is a flammable and explosive gas, it will form an explosive mixed gas when mixed with air, and the explosion limit is 2.3% to 72.3% (volume ratio), the explosion range is wide, and it is very easy to explode, and the process safety is poor. In addition, the solubility of acetylene gas in a reaction system solvent such as tetrahydrofuran is very limited, resulting in a large amount of solvent, and the acetylene and alkali used need to be greatly excessive, and the raw material reaction is incomplete. The ethinylestradiol impurities obtained by the preparation method of the above-mentioned ethinylestradiol are more, the yield is not high, and a large amount of highly basic and acetylene are used, causing environmental pollution. Summary of the Invention

[0013] Based on this, in order to solve the above technical problems, the present invention uses estrone and a trialkyl acetylenic lithium reagent to carry out acetylation reaction and hydrolysis reaction to prepare high-purity ethinyl estradiol.

[0014] An embodiment of the present invention provides a method for synthesizing ethinylestradiol, the method comprising:

[0015] An organometallic reagent is mixed with trialkylsilyl acetylene to obtain a trialkyl acetylene lithium reagent, and trimethylsilyl chloride and compound I are added to perform hydroxyl protection and acetylation reactions to obtain a reaction solution containing compound II;

[0016] Alcohol and water are added to the reaction solution to carry out a hydrolysis reaction, and then ethinylestradiol is obtained through purification.

[0017] The structural formulas of the compounds I and II are as follows:

[0018]

[0019] Wherein, the group -TRS is a trialkylsilyl group.

[0020] In some specific embodiments, the reaction temperature of the hydroxyl protection and acetylation reaction is -30 to 10° C., and the reaction time is 1 to 6 hours.

[0021] In some specific embodiments, the reaction temperature of the hydrolysis reaction is 10-50° C.; and the reaction time is 5-16 h.

[0022] In some specific embodiments, the mass ratio of compound I to trimethylchlorosilane is 1:0.3-0.6.

[0023] In some specific embodiments, the mass ratio of the compound I to trialkylsilyl acetylene is 1:1-2.

[0024] In some specific embodiments, the ratio of the mass of the compound I to the volume of the alcohol is 1 g: 2-20 mL; and / or

[0025] The alcohol is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, ethylene glycol and ethylene glycol monomethyl ether; and / or

[0026] The volume ratio of the alcohol to water is 2 to 10:1.

[0027] In some specific embodiments, the mixing reaction of the organometallic reagent and trialkylsilyl acetylene comprises:

[0028] The organic metal reagent solution and the first solvent are mixed, cooled to -30 to 10° C., trialkylsilyl acetylene is added, and the mixture is reacted at -30 to 10° C. for 0.4 to 1 hour.

[0029] In some specific embodiments, the organometallic reagent is n-butyl lithium or lithium diisopropylamide; the concentration of the organometallic reagent solution is 2.0-3.0 mol / L, and the ratio of the volume of the organometallic reagent solution to the mass of trialkylsilyl acetylene is 3-6 ml:1 g; and / or

[0030] The first solvent is at least one selected from diethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether and toluene; and / or

[0031] The trialkylsilyl acetylene includes at least one of trimethylsilyl acetylene, triethylsilyl acetylene, triisopropylsilyl acetylene and tri-n-propylsilyl acetylene; and / or

[0032] The ratio of the mass of the compound I to the volume of the first solvent is 1 g: 5-30 mL.

[0033] In some specific embodiments, the method for synthesizing ethinyl estradiol further comprises:

[0034] adding acid to the solution after the hydrolysis reaction for neutralization, concentrating, and then adding water for crystallization to obtain crude ethinyl estradiol;

[0035] The crude ethinyl estradiol and the second solvent are mixed, heated and dissolved, and then cooled for crystallization to obtain ethinyl estradiol.

[0036] In one embodiment, the second solvent is selected from at least one of methanol, ethanol, ethyl acetate, isopropyl acetate, acetone, butanone and tetrahydrofuran.

[0037] Compared with the prior art, the synthesis method of ethinylestradiol of the present invention has the following beneficial effects:

[0038] In the present invention's method for synthesizing ethinylestradiol, trimethylchlorosilane is used as a protecting group for the hydroxyl group, increasing the solubility of the reaction system and preventing the hydroxyl group from reacting with a trialkyl acetylenic lithium reagent to form a lithium salt, thereby improving raw material utilization. The hydroxyl-protected compound then reacts with an acetylation reagent to obtain a reaction solution containing Compound II, which is then directly hydrolyzed by the addition of alcohol and water to obtain ethinylestradiol. This synthesis method utilizes a one-pot process for synthesizing ethinylestradiol, eliminating intermediate separation and purification steps. The process is simple, has a short cycle, and does not require the use of acetylene gas. It offers excellent process safety, high yield, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 The HPLC chromatogram of ethinylestradiol provided in Example 1 of the present invention;

[0040] Figure 2 The H NMR spectrum of ethinyl estradiol provided in Example 1 of the present invention;

[0041] Figure 3 This is the NMR carbon spectrum of ethinyl estradiol provided in Example 1 of the present invention. DETAILED DESCRIPTION

[0042] To make the above-mentioned objects, features, and advantages of the present invention more readily apparent, specific embodiments of the present invention are described in detail below with reference to the accompanying drawings. The following description sets forth numerous specific details to facilitate a full understanding of the present invention. However, the present invention can be implemented in many other ways than those described herein, and those skilled in the art may make similar modifications without departing from the scope of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed below.

[0043] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of the technical features being referred to. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "plurality" means at least two, such as two, three, etc., unless otherwise specifically defined.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention pertains. The terms used herein in the specification of the present invention are for the purpose of describing specific embodiments only and are not intended to limit the present invention. The term "and / or" as used herein includes any and all combinations of one or more of the associated listed items.

[0045] The weights of the relevant components mentioned in the description of the embodiments of the present invention may not only refer to the specific content of each component, but also represent the weight ratio between the components. Therefore, as long as the content of the relevant components is proportionally increased or decreased according to the description of the embodiments of the present invention, it is within the scope disclosed in the description of the embodiments of the present invention. Specifically, the weights mentioned in the description of the embodiments of the present invention may be mass units known in the chemical industry, such as μg, mg, g, and kg.

[0046] The embodiment of the present invention provides a method for synthesizing ethinylestradiol, which comprises:

[0047] An organometallic reagent is mixed with trialkylsilyl acetylene to obtain a trialkyl acetylene lithium reagent, and trimethylsilyl chloride and compound I are added to perform hydroxyl protection and acetylation reactions to obtain a reaction solution containing compound II;

[0048] Alcohol and water are added to the reaction solution to carry out a hydrolysis reaction, and then ethinylestradiol is obtained through purification.

[0049] The reaction route is as follows:

[0050]

[0051] Wherein, the group -TRS is a trialkylsilyl group.

[0052] The chemical name of compound I is 3-hydroxyestra-1,3,5(10)-triene-17-one, also known as estrone; the chemical name of compound II is 3-hydroxy-19-nor-17a-pregnane-1,3,5(10)-triene-20-trialkylalkynyl-17-ol.

[0053] In the above reaction process, trimethylsilyl chloride is first used to protect the hydroxyl group of the compound of formula (I), and the solubility of the generated silyl ether compound is greatly increased, which can effectively increase the solubility of the system. Then, trialkylsilyl acetylene lithium is added for acetylation. The reaction is always clear, and the reaction is carried out in a homogeneous system. The compound of formula (I) reacts completely. If trimethylsilyl chloride is not added, the compound of formula (I) and the trialkyl acetylene lithium reagent are acetylated, and the hydroxyl group will react to form a lithium salt. The solubility of the lithium salt is very low, and a large amount of precipitation will occur in the reaction system, encapsulating the unreacted raw materials, causing the compound of formula (I) to fail to react completely, and a large amount of residue will remain. The specific reaction principle is as follows:

[0054]

[0055] In a specific example, the mixing reaction of the organometallic reagent and trialkylsilyl acetylene comprises:

[0056] The organic metal reagent solution is mixed with the first solvent, cooled to -30 to 10° C., trialkylsilyl acetylene is added, and the mixture is reacted at -30 to 10° C. for 0.5 to 2 hours.

[0057] In a specific example, the organometallic reagent is n-butyl lithium or lithium diisopropylamide. Preferably, the organometallic reagent is n-butyl lithium. The concentration of the organometallic reagent solution is 2.0 to 3.0 mol / L, preferably 2.5 mol / L, and the ratio of the organometallic reagent solution volume to the mass of trialkylsilyl acetylene is 3 to 6 ml:1 g.

[0058] In a specific example, the first solvent is at least one selected from diethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether, and toluene. Preferably, the first organic solvent is at least one selected from tetrahydrofuran, methyltetrahydrofuran, dioxane, and ethylene glycol dimethyl ether.

[0059] In a specific example, the number of carbon atoms in the alkyl group of the trialkylsilyl acetylene is 1 to 5. Preferably, the number of carbon atoms in the alkyl group of the trialkylsilyl acetylene is 1 to 2. Specifically including:

[0060] At least one of trimethylsilyl acetylene, triethylsilyl acetylene, triisopropylsilyl acetylene and tri-n-propylsilyl acetylene. Preferably, the trialkylsilyl acetylene is trimethylsilyl acetylene.

[0061] In a specific example, the ratio of the mass of the compound I to the volume of the first solvent is 1 g: 5 to 30 mL. Alternatively, the ratio of the mass of the compound I to the volume of the first solvent is 1 g: 10 to 20 mL; further, the ratio of the mass of the compound I to the volume of the first solvent is 1 g: 15 mL.

[0062] In a specific example, the hydroxyl protection and acetylation reaction is carried out at -30 to 10° C. for 1 to 6 hours. Furthermore, the hydroxyl protection and acetylation reaction is carried out at -15 to 0° C. for 3 hours.

[0063] In a specific example, the mass ratio of the compound I to trimethylchlorosilane is 1:0.3-0.6.

[0064] In a specific example, the mass ratio of the compound I to trialkylsilyl acetylene is 1:1-2.

[0065] In a specific example, the alcohol is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, ethylene glycol and ethylene glycol monomethyl ether; further, the alcohol is selected from at least one of methanol and ethanol.

[0066] The ratio of the mass of the compound I to the volume of the alcohol is 1g:2-20mL; optionally, the ratio of the mass of the compound I to the volume of the alcohol is 1g:2-10mL; preferably, the ratio of the mass of the compound I to the volume of the alcohol is 1g:5mL.

[0067] The volume ratio of the alcohol to water is 2 to 10:1. Optionally, the volume ratio of the alcohol to water is 3 to 6:1; preferably, the volume ratio of the alcohol to water is 5:1.

[0068] In a specific example, the reaction temperature of the hydrolysis reaction is 10-50° C. and the reaction time is 5-16 hours. Preferably, the reaction temperature is 30-40° C. and the reaction time is 6-8 hours.

[0069] In the hydrolysis reaction of the present invention, an alcohol solvent reacts with an organometallic reagent to form a metal alcoholate, which is further reacted with water to form a metal hydroxide, without the need to add an additional base. This effectively avoids the problem of the organometallic reagent catching fire when it comes into contact with water. Compound II is reacted with the metal hydroxide to remove the trialkylsilyl group to obtain ethinyl estradiol.

[0070] In a specific example, the synthesis method of ethinylestradiol also includes a purification process:

[0071] adding acid to the solution after the hydrolysis reaction for neutralization, concentrating, and then adding water for crystallization to obtain crude ethinyl estradiol;

[0072] The crude ethinyl estradiol and the second solvent are mixed, heated and dissolved, and then cooled for crystallization to obtain ethinyl estradiol.

[0073] In a specific example, the second solvent is selected from at least one of methanol, ethanol, ethyl acetate, isopropyl acetate, acetone, butanone, and tetrahydrofuran. Alternatively, the second solvent is selected from at least one of methanol, ethanol, ethyl acetate, acetone, and tetrahydrofuran.

[0074] In the present invention's method for synthesizing ethinylestradiol, trimethylchlorosilane is used as a protecting group for the hydroxyl group, increasing the solubility of the reaction system and preventing the hydroxyl group from reacting with a trialkyl acetylenic lithium reagent to form a lithium salt, thereby improving raw material utilization. The hydroxyl-protected compound then reacts with an acetylation reagent to obtain a reaction solution containing Compound II, which is then directly hydrolyzed by the addition of alcohol and water to obtain ethinylestradiol. This synthesis method utilizes a one-pot process for synthesizing ethinylestradiol, eliminating intermediate separation and purification steps. The process is simple, has a short cycle, and does not require the use of acetylene gas. It offers excellent process safety, high yield, and is suitable for large-scale industrial production.

[0075] The following examples are given according to the synthesis method of ethinylestradiol of the present invention. It should be understood that the synthesis method of melengestrol acetate of the present invention is not limited to the following examples.

[0076] Example 1

[0077] To 280 mL of n-butyllithium (2.5M) solution, add 750 mL of THF to dilute, cool to -15°C, add 55 g of trimethylsilyl acetylene dropwise, and keep warm at -15 to 0°C to react for 0.5 hours. Add 20 g of trimethylchlorosilane, then add 50 g of estrone, and keep warm at -15 to 0°C to react for 3 hours. After adding 250 mL of methanol, add 50 mL of water, heat to 30°C to 40°C and react for 8 hours. Add glacial acetic acid to neutralize, concentrate to a small amount, add 500 mL of water to precipitate, filter, and obtain crude ethinylestradiol. Add ethanol to the crude ethinylestradiol and heat to dissolve it, cool it for crystallization, filter it, and then refine it once with methanol to obtain 46.4 g of white solid with HPLC purity of 99.8%. After testing, the HPLC spectrum of the white solid is as follows Figure 1 As shown; its peak time is 33.913min, with high separation and low impurity content. The nuclear magnetic hydrogen spectrum of the white solid is as follows Figure 2 As shown; the NMR carbon spectrum of the white solid is as follows Figure 3 As shown; that is, the white solid is ethinyl estradiol.

[0078] The hydrogen and carbon spectrum data are:

[0079] 1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),7.03~7.05(d,1H),6.43~6.53(m,2H),5 .32(s,1H),3.38(s,1H),2.62~2.82(m,2H),2.27~2.30(m,1H),0.76(s,3H).

[0080] 13 C NMR (400MHz, DMSO-d6) δ155.38,137.58,130.76,126.52,115.37,113.19,89.43,78.62 ,75.43,49.46,47.15,43.78,39.70,39.28,33.06,29.65,27.49,26.61,22.94,13.19.

[0081] Example 2

[0082] To 280 mL of 2.5 M n-butyllithium solution, add 750 mL of methyltetrahydrofuran (MTHF), dilute, and cool to -20°C. Add 65 g of trimethylsilyl acetylene dropwise. After addition, allow to react at -10-0°C for 1 hour. Add 30 g of trimethylchlorosilane, followed by 50 g of estrone, and allow to react at -10-0°C for 3 hours. Add 250 mL of ethanol, then 50 mL of water, raise the temperature to 30-40°C, and react for 12 hours. Neutralize with glacial acetic acid, concentrate to a small amount, add 500 mL of water, and filter to obtain crude ethinyl estradiol. Add ethanol, heat, dissolve, and evaporate to a small amount to obtain a white solid. Refine once with ethanol to obtain 44.6 g of ethinyl estradiol with an HPLC purity of 99.6%.

[0083] Example 3

[0084] To 300mL of n-butyllithium (2.5M) solution, add 600mL of dioxane to dilute the mixture, cool to -20°C, and add 75g of trimethylsilyl acetylene dropwise. After addition, incubate at -20--10°C for 2 hours. Add 20g of trimethylchlorosilane, followed by 50g of estrone, and incubate at -15-0°C for 3 hours. Add 150mL of ethanol, then 50mL of water, raise the temperature to 30-40°C, and incubate for 16 hours. Neutralize the mixture with glacial acetic acid, concentrate to a minimum, add 500mL of water for precipitation, and filter to obtain crude ethinylestradiol. The crude product is purified twice with ethyl acetate to yield 40.2g of ethinylestradiol with an HPLC purity of 99.3%.

[0085] Example 4

[0086] To 280 mL of 2.5 M n-butyllithium solution, add 750 mL of tetrahydrofuran to dilute the mixture, cool to -30°C, and add 56 g of triethylsilyl acetylene dropwise. After addition, incubate at -15-0°C for 0.5 hours. Add 20 g of trimethylchlorosilane, followed by 50 g of estrone, and incubate at -20-10°C for 5 hours. Add 200 mL of n-propanol, then 50 mL of water, raise the temperature to 30-40°C, and incubate for 10 hours. Neutralize the mixture with glacial acetic acid, concentrate to a minimum, add 500 mL of water for precipitation, and filter to obtain crude ethinyl estradiol. This crude product is purified twice with ethanol to yield 43.9 g of ethinyl estradiol with an HPLC purity of 99.5%.

[0087] Example 5

[0088] To 300 mL of n-butyllithium (2.5 M) solution, add 500 mL of THF to dilute the solution, cool to -20°C, and add 60 g of trimethylsilyl acetylene dropwise. After addition, keep the mixture at -10-0°C and react for 0.5 hours. Add 20 g of trimethylchlorosilane, then add 50 g of estrone, and keep the mixture at -10-0°C and react for 3 hours. Add 350 mL of ethanol, then 50 mL of water, raise the temperature to 30-40°C and react for 8 hours. Neutralize the mixture with glacial acetic acid, concentrate to a minimum, add 500 mL of water to precipitate, and filter to obtain crude ethinylestradiol. The crude product is purified twice with acetone to obtain 44.2 g of ethinylestradiol with an HPLC purity of 99.2%.

[0089] Example 6

[0090] To 280 mL of n-butyllithium (2.5 M) solution, add 750 mL of THF to dilute the mixture, cool to -15°C, and add 90 g of trimethylsilyl acetylene dropwise. After addition, incubate at -15-0°C for 1 hour. Add 20 g of trimethylchlorosilane, followed by 50 g of estrone, and incubate at -30-20°C for 4 hours. Add 400 mL of isopropyl alcohol, then 50 mL of water, raise the temperature to 30-40°C, and incubate for 12 hours. Neutralize the mixture with glacial acetic acid, concentrate to a minimum, add 500 mL of water, and precipitate the mixture. Filter to obtain crude ethinylestradiol. The crude product is purified once with methanol and once with ethyl acetate to yield 42.1 g of ethinylestradiol with an HPLC purity of 99.0%.

[0091] Example 7

[0092] To 300 mL of n-butyllithium (2.5M) solution, dilute with 1000 mL of THF, cool to -20°C, and dropwise add 60 g of trimethylsilyl acetylene. After addition, allow to react at -15-0°C for 1 hour. Add 20 g of trimethylchlorosilane, followed by 50 g of estrone, and allow to react at -20-10°C for 3 hours. Add 150 mL of methanol, then 50 mL of water, raise the temperature to 30-40°C, and react for 8 hours. Neutralize with glacial acetic acid, concentrate to a minimum, add 500 mL of water, and precipitate. Filter to obtain crude ethinyl estradiol. This crude product is purified once with methanol and once with ethanol to yield 43.5 g of ethinyl estradiol with an HPLC purity of 99.6%.

[0093] Example 8

[0094] To 280 mL of 2.5 M n-butyllithium solution, add 400 mL of methyltetrahydrofuran (MTHF), dilute, and cool to -15°C. Add 60 g of trimethylsilyl acetylene dropwise. After addition, incubate at -15-0°C for 1 hour. Add 20 g of trimethylchlorosilane, followed by 50 g of estrone, and incubate at -15-0°C for 3 hours. Add 200 mL of n-propanol, then 50 mL of water, raise the temperature to 30-40°C, and incubate for 10 hours. Neutralize with glacial acetic acid, concentrate to a minimum, add 500 mL of water, and precipitate. Filter to obtain crude ethinylestradiol. Refine the crude product once with isopropyl acetate and once with methanol to yield 41.6 g of ethinylestradiol with an HPLC purity of 99.1%.

[0095] Example 9

[0096] To 300 mL of 2.5 M n-butyllithium solution, add 500 mL of methyltetrahydrofuran (MTHF), dilute, and cool to -20°C. Add 70 g of trimethylsilyl acetylene dropwise. After addition, incubate at -20 to -10°C and react for 1 hour. Add 20 g of trimethylchlorosilane, followed by 50 g of estrone, and incubate at -15 to 0°C and react for 3 hours. Add 400 mL of methanol, then 50 mL of water, raise the temperature to 30 to 40°C, and react for 8 hours. Neutralize with glacial acetic acid, concentrate to a minimum, add 500 mL of water, and precipitate. Filter to obtain crude ethinylestradiol. This crude product is purified once with methanol and once with tetrahydrofuran to yield 41.2 g of ethinylestradiol with an HPLC purity of 99.4%.

[0097] Comparative Example 1

[0098] To 280 mL of n-butyllithium (2.5 M) solution, add 750 mL of THF to dilute the mixture, cool to -15°C, and dropwise add 55 g of trimethylsilyl acetylene. After addition, incubate at -15-0°C for 0.5 hours. Then, add 50 g of estrone, incubate at -15-0°C for 3 hours. Add 250 mL of methanol, then add 50 mL of water, raise the temperature to 30-40°C, and react for 8 hours. Neutralize with glacial acetic acid, concentrate to a minimum, add 500 mL of water to precipitate, and filter to obtain crude ethinylestradiol. Add ethanol to the crude ethinylestradiol, heat to dissolve, cool to crystallize, filter, and then refine once more with methanol to obtain 41.3 g of a white solid with an HPLC purity of 94.6%.

[0099] Comparative Example 2

[0100] Add 1000 mL of THF and 31 g of potassium tert-butoxide, stir to dissolve, cool to 0-5°C, and introduce 40 g of acetylene gas. Maintain at 0-5°C for 1 hour. Add 50 g of estrone and maintain at 0-5°C for 3 hours. Neutralize with glacial acetic acid, concentrate to a small amount, add 500 mL of water, precipitate, and filter to obtain crude ethinyl estradiol. Refine the crude ethinyl estradiol twice with methanol to obtain 37.9 g of ethinyl estradiol with an HPLC purity of 96.6%.

[0101] Comparative Example 3

[0102] To 280 mL of 2.5 M n-butyllithium solution, add 750 mL of tetrahydrofuran (THF), dilute, and cool to -20°C. Add 40 g of acetylene gas and allow to react at -15 to 0°C for 2 hours. Add 50 g of estrone and allow to react at -10 to -0°C for 5 hours. Neutralize with glacial acetic acid, concentrate to a minimum, add 500 mL of water, and precipitate. Filter to obtain crude ethinylestradiol. Refine the crude product twice with acetone to yield 32.7 g of ethinylestradiol with an HPLC purity of 95.8%.

[0103] Comparative Example 4

[0104] To 150g of potassium hydroxide, add 1500mL of tetrahydrofuran and 75ml of acetone, cool to -10°C, introduce 60g of acetylene gas, and maintain the temperature at -15-0°C for 2 hours. Add 50g of estrone and maintain the temperature at 0-5°C for 4 hours. Neutralize with dilute hydrochloric acid, concentrate to a small amount, add 500mL of water for precipitation, and filter to obtain crude ethinyl estradiol. This crude product is purified twice with methanol to yield 30.2g of ethinyl estradiol with an HPLC purity of 94.7%.

[0105] Comparative Example 5

[0106] To 280 mL of n-butyllithium (2.5 M) solution, add 750 mL of tetrahydrofuran to dilute the mixture, cool to -15°C, and dropwise add 60 g of trimethylsilyl acetylene. After addition, incubate at -15-0°C for 1 hour. Then, add 50 g of estrone and incubate at -15-0°C for 3 hours. Add 400 mL of acetone and 50 mL of water, then heat to 30-40°C and incubate for 24 hours. Neutralize the mixture with glacial acetic acid, concentrate to a minimum, add 500 mL of water for precipitation, and filter to obtain crude ethinylestradiol. The crude product is purified twice with ethanol to obtain 34.3 g of ethinylestradiol with an HPLC purity of 96.9%.

[0107] The types of the first organic solvent, trimethylsilyl chloride and alcohol used in each example and comparative example, as well as the yield and purity are shown in Table 1.

[0108] Table 1

[0109]

[0110]

[0111] As shown in the Examples and Comparative Examples, the acetylation method using a trialkyl acetylenic lithium reagent is superior to the acetylenic method using acetylene gas, resulting in a high product yield and high purity. This is because the trialkyl acetylenic lithium reagent is highly active, allowing the raw materials to react completely and achieving good reaction specificity. The acetylenic method using acetylene gas has low reactivity, resulting in some raw materials not reacting completely and generating a large amount of impurities.

[0112] As shown in Example 1 and Comparative Example 1, the addition of trimethylsilyl chloride significantly improves the purity of the product when using a trialkylacetylenic lithium reagent for acetylation; without trimethylsilyl chloride, the product purity is significantly reduced. This is because the addition of trimethylsilyl chloride protects the hydroxyl group of estrone, increasing its solubility during the reaction, preventing the precipitation of large amounts of solids, and promoting the complete reaction of the raw materials.

[0113] The technical features of the above-mentioned embodiments can be combined arbitrarily. In order to make the description concise, not all possible combinations of the technical features in the above-mentioned embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0114] The above-described embodiments merely represent several implementation methods of the present invention, and their descriptions are relatively specific and detailed, but they should not be construed as limiting the scope of the patent. It should be noted that a person skilled in the art may make several modifications and improvements without departing from the concept of the present invention, and these modifications and improvements fall within the scope of protection of the present invention. Therefore, the scope of protection of the patent for this invention shall be based on the appended claims, and the description and drawings may be used to interpret the content of the claims.

Claims

1. A method for synthesizing ethinylestradiol, characterized in that: The synthesis method comprises: An organometallic reagent is mixed with trialkylsilyl acetylene to generate a trialkyl acetylene lithium reagent, and trimethylsilyl chloride and compound I are added to perform hydroxyl protection and acetylation reactions to obtain a reaction solution containing compound II; adding alcohol and water to the reaction solution to carry out a hydrolysis reaction to prepare the ethinyl estradiol; The structural formulas of the compounds I and II are as follows: Compound I Compound II; Wherein, the group -TRS is a trialkylsilyl group; The reaction temperature of the hydroxyl protection and acetylation reaction is -30~10°C, and the reaction time is 1~6h; The mass ratio of the compound I to trimethylchlorosilane is 1:0.3-0.6; The organometallic reagent is n-butyllithium or lithium diisopropylamide.

2. The method for synthesizing ethinylestradiol according to claim 1, wherein The reaction temperature of the hydrolysis reaction is 10-50° C.; and the reaction time is 5-16 hours.

3. The method for synthesizing ethinylestradiol according to claim 1, wherein The mass ratio of the compound I to trialkylsilyl acetylene is 1:1-2.

4. The method for synthesizing ethinylestradiol according to claim 1, wherein The ratio of the mass of the compound I to the volume of the alcohol is 1 g: 2-20 mL; and / or The alcohol is selected from at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol and ethylene glycol; and / or The volume ratio of the alcohol to water is 2-10:

1.

5. The method for synthesizing ethinylestradiol according to claim 1, wherein The method of mixing the organometallic reagent with trialkylsilyl acetylene comprises: Mix the organometallic reagent solution and the first solvent, cool to -30-10°C, add trialkylsilyl acetylene, and react at -30-10°C for 0.4-1h; The first solvent is selected from at least one of diethyl ether, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, isopropyl ether, ethylene glycol dimethyl ether and toluene.

6. The method for synthesizing ethinylestradiol according to claim 5, wherein The concentration of the organometallic reagent solution is 2.0-3.0 mol / L, and the ratio of the volume of the organometallic reagent solution to the mass of trialkylsilyl acetylene is 3-6 ml:1 g; and / or The first solvent is selected from at least one of tetrahydrofuran, methyltetrahydrofuran and dioxane; and / or The trialkylsilyl acetylene includes at least one of trimethylsilyl acetylene, triethylsilyl acetylene, triisopropylsilyl acetylene and tri-n-propylsilyl acetylene; and / or The ratio of the mass of the compound I to the volume of the first solvent is 1 g: 5-30 mL.

7. The method for synthesizing ethinylestradiol according to claim 1, wherein The synthesis method of the ethinylestradiol also includes: adding acid to the solution after the hydrolysis reaction for neutralization, concentrating, and then adding water for crystallization to obtain crude ethinyl estradiol; mixing the crude ethinyl estradiol with a second solvent, heating and dissolving the mixture, and then cooling and crystallizing the mixture to obtain ethinyl estradiol; The second solvent is selected from at least one of methanol, ethanol, ethyl acetate, isopropyl acetate, acetone, butanone and tetrahydrofuran.

8. The method for synthesizing ethinylestradiol according to claim 7, wherein The second solvent is selected from at least one of methanol, ethanol, ethyl acetate and acetone.

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