Synthesis method of estradiol semihydrate

Abstract

The invention discloses a synthesis method of estradiol semihydrate. The synthesis method is particularly suitable for a process of synthesizing the estradiol semihydrate by taking ADD (1.4-androstenedione) as an initial raw material. The method comprises the following steps: firstly, carrying out ketal reaction on ADD and ethylene glycol to generate ketal, reacting the ketal with a lithiation reagent prepared from biphenyl, diphenylmethane, lithium and tetrahydrofuran to generate 17-ketal estrone, then hydrolyzing the 17-ketal estrone through inorganic acid to obtain estrone, reducing the estrone through a reducing agent to obtain an estradiol crude product, and purifying the estradiol crude product. And refining the estradiol crude product with an alcohol or ketone solvent and pure water, and drying to obtain the estradiol semihydrate. By using the method, impurities such as biphenyl, diphenylmethane and the like in lithiation reaction are removed in advance, the refining operation of the estrone is reduced (the refining of the estrone requires 30 times of volume of a solvent), the productivity is improved, the refining and drying processes of the estradiol semihydrate ensure that the content of crystal water is qualified, the single impurity of the synthesized product is less than 0.1%, and the yield is improved. The product meets the quality standards of the Chinese pharmacopoeia 2020 edition and the European pharmacopoeia 11 edition.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical technology, and more specifically, to a method for synthesizing estradiol hemihydrate. Background Technology

[0002] Estradiol hemihydrate is an important estrogen drug and also serves as a pharmaceutical intermediate. It is listed in both the European Pharmacopoeia and the Chinese Pharmacopoeia, and demand in the European market is very strong. Initially, its synthesis used saponins from turmeric extract as the starting material. However, this process was highly polluting, involved a long synthetic route, and was costly, resulting in a lack of price competitiveness in the market. With the gradual development of bio-enzymatic catalysis technology, a process has been explored that uses phytosterols to produce 1,4-androstenedione (ADD) via enzyme catalysis, and then uses ADD as a raw material to produce estradiol hemihydrate. The current common production route first synthesizes a ketal from ADD, then synthesizes estrone, then purifies estrone, and finally synthesizes crude estradiol, which is then purified to obtain estradiol. However, this process route has a low overall yield, requires a large amount of solvent, has low production efficiency, and does not easily yield qualified estradiol hemihydrate.

[0003] Therefore, the existing production process has certain defects, the production efficiency is not high, and it is not easy to obtain qualified products. Summary of the Invention

[0004] In view of this, in order to overcome the shortcomings of the above-mentioned technologies, the problem to be solved by the present invention is to provide a method for synthesizing pharmaceutical grade estradiol hemihydrate, by separating 17-ketoestrone as an intermediate, timely removing byproducts such as biphenyl and diphenylmethane from the product, reducing the impact on subsequent reactions; controlling crystallization conditions and drying conditions to ensure product quality, improving production capacity and product quality, and having significant economic value.

[0005] To achieve the above objectives, the technical solution of the present invention is as follows:

[0006] A method for synthesizing estradiol hemihydrate, comprising the following steps:

[0007] (1) 1,4-Androstenedione was reacted with ethylene glycol to obtain a ketal;

[0008] (2) The obtained ketal was mixed with a lithium reagent and reacted. After the reaction was completed, it was distilled, separated into solid and liquid, and washed with hot water to obtain 17-ketoestrone.

[0009] (3) The obtained 17-ketal estrone was hydrolyzed with an inorganic acid to obtain estrone, and estrone was reduced with a reducing agent to obtain crude estradiol. The crude estradiol was purified with alcohol or ketone solvent and pure water, and then dried under reduced pressure to obtain estradiol hemihydrate.

[0010] This invention separates the intermediate 17-ketal estrone during the preparation of estradiol hemihydrate. By controlling the filtration temperature and hot water washing, byproducts and residual raw materials (biphenyl, diphenylmethane, etc.) are removed in a timely manner, preventing impurities from being introduced into the final product. This avoids the need for subsequent purification of estrone and reduces solvent usage (the purification of estrone requires a large amount of solvent, about 30 times its volume, i.e., the ratio of estrone to solvent is 1g:30ml). This invention reduces the purification process of estrone, thereby reducing solvent usage, improving production efficiency, and ensuring product purity and yield.

[0011] Further, in step (1), the reaction of 1,4-androstenedione with ethylene glycol specifically involves:

[0012] 1,4-Androstenedione, ethylene glycol, trimethyl orthoformate, solvent A and p-toluenesulfonic acid were mixed and reacted. After the reaction was completed, triethylamine was added to stop the reaction. The mixture was heated to dissolve, water was added to crystallize, the mixture was cooled, filtered, and dried to obtain the ketal.

[0013] Solvent A includes at least one of methanol, ethanol, or acetone;

[0014] The amount of ethylene glycol added is 1 to 2 times the mass of 1,4-androstenedione, the amount of trimethyl orthoformate added is 0.6 to 1.5 times the mass of 1,4-androstenedione, the amount of solvent A added is 1 to 3 times the mass of 1,4-androstenedione, the amount of p-toluenesulfonic acid added is 0.01 to 0.03 times the mass of 1,4-androstenedione, the amount of triethylamine added is 0.02 to 0.04 times the mass of 1,4-androstenedione, and the amount of water added is 1 to 2 times the mass of 1,4-androstenedione.

[0015] Trimethyl orthoformate is used as a dehydrating agent, and p-toluenesulfonic acid is used as a catalyst.

[0016] Furthermore, in step (2), the temperature during solid-liquid separation is 40-75°C, and the temperature of the hot water is 40-75°C. If the temperature during solid-liquid separation is too low, impurities will precipitate, making it impossible to effectively remove the impurities. Similarly, if the temperature of the hot water is too low, the residual impurities will not be effectively removed. By controlling the temperature during solid-liquid separation and hot water washing within a suitable range, this invention can ensure the effective removal of impurities and avoid the dissolution of related products, thereby ensuring the yield and purity of the final product.

[0017] Furthermore, in step (2), the mass of the hot water used is 4 to 8 times the mass of the ketal substance. If the amount of hot water used is too low, the residual impurities cannot be fully washed away.

[0018] Further, in step (2), the lithium reagent is obtained by mixing lithium metal, biphenyl, diphenylmethane and tetrahydrofuran, wherein the peroxide content in the tetrahydrofuran is <0.1%.

[0019] In some embodiments, the lithium metal in the lithiumizing agent can also be other alkali metals such as sodium or potassium; biphenyl can also be one or more of other similar reagents such as naphthalene, methylnaphthalene, dimethylnaphthalene, tetramethylnaphthalene, anthracene, methylanthracene, dimethylanthracene, tetramethylanthracene, phenanthrene, methylphenanthrene, dimethylphenanthrene, trimethylphenanthrene, tetramethylphenanthrene, pyrene, methylpyrene, dimethylpyrene, trimethylpyrene, tetramethylpyrene, methylbiphenyl, dimethylbiphenyl, and tetramethylbiphenyl; diphenylmethane can also be other similar reagents such as triphenylmethane; tetrahydrofuran can also be used as a solvent, or other solvents such as DMF or dimethyl sulfoxide can be used.

[0020] It should be noted that in this invention, tetrahydrofuran is preferably used as the reaction solvent in step (2), and the peroxide content in tetrahydrofuran must be controlled to be <0.1% to ensure that the purity of the produced 17-ketoestrone is high enough.

[0021] Furthermore, in step (2),

[0022] First, dissolve the ketal in tetrahydrofuran to obtain a tetrahydrofuran solution containing the ketal;

[0023] Lithium, biphenyl, diphenylmethane, and tetrahydrofuran were mixed and reacted. After the reaction was completed, the temperature was lowered to 30-35°C, and a tetrahydrofuran solution containing the ketal was added to continue the reaction. After the reaction was completed, the temperature was lowered, water was added, and the reaction was stopped. Then, the mixture was distilled under reduced pressure to 65-75°C, and then cooled to 40-75°C. Solid-liquid separation was performed to obtain a filter cake, which was washed with hot water at 40-75°C and discharged to obtain 17-ketal estradiol ketone.

[0024] Further, in step (2), the mass-to-volume ratio of the ketal to the total tetrahydrofuran is 1 g: 5-10 ml; the mass ratio of the ketal to lithium is 1: 0.08-0.2; the mass ratio of the ketal to biphenyl is 1: 1-2; the mass ratio of the ketal to diphenylmethane is 1: 0.5-0.9; when water is added to stop the reaction, the mass ratio of the amount of ketal to water added is 1: 0.4-0.8.

[0025] Furthermore, in step (2), when lithium, biphenyl, diphenylmethane and tetrahydrofuran are mixed and reacted, the temperature is raised to reflux and the reaction is maintained for 1.5 to 3 hours; the reaction time is 1.5 to 3 hours after adding tetrahydrofuran solution containing ketal.

[0026] Further, in step (3), the process of obtaining estradiol ketone via inorganic acid hydrolysis includes:

[0027] The 17-ketal estrone obtained in step (2) was mixed with solvent B, the pH was adjusted to <2 with inorganic acid, the temperature was raised to reflux for 1-3 hours, the temperature was lowered to 20-30℃, water was added, the mixture was filtered and washed to obtain estrone.

[0028] Solvent B is methanol, ethanol, or isopropanol; the inorganic acid is hydrochloric acid, a type of sulfuric acid.

[0029] The mass-to-volume ratio of 17-ketoestrone to solvent B is 1 g: 3-8 ml; the mass-to-volume ratio of 17-ketoestrone to added water is 1 g: 2-4 ml.

[0030] Further, in step (3), the reduction of estrone with a reducing agent to obtain crude estradiol includes:

[0031] The obtained estrone was mixed with solvent C, and 10% sodium hydroxide (mass fraction) and reducing agent were added to carry out the reduction reaction. After the reaction was completed, acetic acid was added to adjust the pH to 4-5, water was added to precipitate crystals, and the mixture was filtered to obtain crude estradiol.

[0032] Solvent C is methanol or ethanol; reducing agent is sodium borohydride or potassium borohydride; the reduction reaction temperature is 0–10℃ and the time is 0.5–1.5 hours.

[0033] The mass-volume ratio of estrone to solvent C is 1g:3-8ml; the mass ratio of estrone to reducing agent is 1:0.08-0.15; and the mass ratio of estrone to 10% sodium hydroxide is 1:1.1-1.3.

[0034] Further, in step (3), the refining process includes:

[0035] The obtained crude estradiol product was mixed with solvent D, activated carbon was added, the temperature was raised to reflux, and the reflux was maintained for 20-40 minutes. The temperature was then lowered to 50-70°C, and the mixture was hot-filtered. Pure water was added dropwise to the filtrate. After the addition was complete, the temperature was lowered to -5°C to 5°C, and the mixture was kept at this temperature for 0.5-1.5 hours to allow crystals to precipitate. The mixture was then filtered, dried, and the wet product of estradiol hemihydrate was obtained.

[0036] In this process, solvent D (i.e., alcohol or ketone solvent) is ethanol, methanol or acetone; the mass-volume ratio of crude estradiol to solvent D is 1g:6-12ml; the mass ratio of crude estradiol to activated carbon is 1:0.05-0.15; and the mass ratio of pure water added to the filtrate to crude estradiol is 1.5-2.5:1.

[0037] Further, in step (3), the drying is to vacuum dry the obtained estradiol hemihydrate wet product, with a vacuum degree < -0.07 MPa, a drying temperature of 30 to 50°C, and a drying time of 1 to 3 hours.

[0038] Specifically, the reaction route of this invention is as follows:

[0039]

[0040] Compared with the prior art, the present invention has the following advantages:

[0041] (1) The method for synthesizing estradiol hemihydrate provided by this invention optimizes the synthesis process. First, ADD is reacted with ethylene glycol to produce a ketal, which is then reacted with lithium, biphenyl, and diphenylmethane in tetrahydrofuran of a specific specification. After the reaction, the mixture is filtered at high temperature to remove impurities, and simultaneously washed with hot water to remove some impurities, producing high-quality 17-ketal estrone. This estrone is then hydrolyzed in a solvent to obtain estrone, which is then reduced and purified to obtain pharmaceutical-grade estradiol hemihydrate. The innovation of this process lies in controlling the peroxide content in tetrahydrofuran when using it as a solvent to ensure the production... The purity of 17-ketoestrone is sufficiently high, and solid-liquid separation is performed in this step to separate the required intermediate (17-ketoestrone). Byproducts and residual raw materials such as biphenyl and diphenylmethane are removed in a timely manner by controlling the filtration temperature and hot water washing to prevent impurities from being derived into the final product. In the step of synthesizing estradiol hemihydrate, the crystallization process conditions and drying conditions are controlled. The estradiol hemihydrate produced by this process has the advantages of meeting the crystallization water standard, high purity (>99.5%), low impurities (each individual impurity <0.1%), and high yield (total yield can reach 72%).

[0042] (2) The estradiol hemihydrate synthesized by this method has the advantages of higher production capacity and better quality, and has significant economic value, which is in line with the development trend of green chemistry. Attached Figure Description

[0043] Figure 1 This is a schematic diagram of the synthetic route of the present invention;

[0044] Figure 2 This is the chromatogram of estradiol hemihydrate in Example 1 of the present invention, according to the European Pharmacopoeia method. Detailed Implementation

[0045] Numerous specific details are set forth in the following description to provide a full understanding of the invention. However, the invention can be practiced in many other ways different from those described herein, and similar modifications can be made by those skilled in the art without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0046] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0047] Unless otherwise specified, all materials and reagents used in this invention are available from commercially available products in the field.

[0048] Example 1

[0049] (1) Kettal synthesis:

[0050] Add 100g of ADD, 150g of ethylene glycol, 100g of trimethyl orthoformate, 100g of methanol, and 1g of p-toluenesulfonic acid to a reaction flask. Keep the reaction at 25°C for 8 hours. Add 2g of triethylamine to stop the reaction. Heat the mixture to dissolve the ketone. Add 140g of water dropwise. Then cool the mixture to 4°C, filter the mixture, and dry it to obtain 110.0g of ketal, with a yield of 95.2%.

[0051] (2) Synthesis of 17-ketoestrone:

[0052] Add 500 ml of tetrahydrofuran (peroxide content <0.1%), 100 g of biphenyl, and 80 g of diphenylmethane to a reaction flask. Add 10 g of lithium metal in portions (2 g each time, 5 times). Heat to reflux and maintain the reaction temperature for 2 hours. Cool to 30°C and slowly add 300 ml of tetrahydrofuran solution containing 100 g of ketal. After the addition is complete, maintain the reaction temperature at 30°C for 2 hours. Cool to 4°C and add 50 g of water to stop the reaction. Then distill under reduced pressure to 70°C, cool to 45°C, filter, dry under vacuum, wash with 500 g of 50°C hot water, and discharge to obtain 88.1 g of 17-ketal estradiol, yield 92.03%; purity greater than 98%.

[0053] (3) Synthesis of estrone:

[0054] 80g of 17-ketal estrone and 400ml of methanol were added to a reaction flask, and 40g of 30% hydrochloric acid was added dropwise. The pH was measured to be <2. The mixture was heated to reflux and reacted for 2 hours. The temperature was then lowered to 20℃, and 240ml of water was added dropwise. The mixture was filtered, washed with 80ml of methanol, and dried to obtain 65.2g of estrone, with a yield of 94.77%.

[0055] (4) Synthesis of estradiol hemihydrate:

[0056] Add 60g of estrone, 300ml of methanol, and 70g of 10% sodium hydroxide solution. Stir until completely dissolved, cool to 4℃, add 6g of sodium borohydride in portions (2g each time, 3 times), keep warm for 1 hour, neutralize with acetic acid to pH=4-5, add 100g of water dropwise, filter, wash with 200g of water, discharge, dry 60g of wet material, return to the bottle, add 540ml of ethanol and 0.6g of activated carbon, heat to reflux, keep reflux for 30 minutes, cool to 50℃, hot filter, wash the filter cake with 60ml of ethanol, add 120g of water dropwise to the filtrate, cool to -5℃, keep warm to crystallize for 1 hour, filter, dry under vacuum, discharge, vacuum dry at -0.075MPa, drying temperature at 45℃, drying time for 2 hours, yielding 54.2g. Yield 86.80%, purity greater than 99.5%, individual impurities <0.1%, moisture content 3.3%.

[0057] Example 2

[0058] (1) Kettal synthesis:

[0059] Add 200g of ADD, 300g of ethylene glycol, 200g of trimethyl orthoformate, 250g of ethanol, and 4g of p-toluenesulfonic acid to a reaction flask. Keep the reaction at 35°C for 6 hours. Add 6g of triethylamine to stop the reaction. Heat the mixture until it dissolves, add 320g of water dropwise, cool to 5°C, filter, and dry to obtain 222.5g of ketal, with a yield of 96.35%.

[0060] (2) Synthesis of 17-ketoestrone:

[0061] 1000 ml of tetrahydrofuran (peroxide content <0.1%), 210 g of biphenyl, and 170 g of diphenylmethane were added to a reaction flask. 20 g of lithium metal was added in portions (4 g each time, 5 times). The mixture was heated to reflux and kept at this temperature for 2 hours. The temperature was then lowered to 35°C, and 700 ml of tetrahydrofuran solution containing 200 g of ketal was slowly added. After the addition was complete, the mixture was kept at 35°C for 2 hours. The temperature was then lowered to 5°C, and 110 g of water was added to stop the reaction. The mixture was then distilled under reduced pressure to 70°C, cooled to 50°C, filtered, dried, and washed with 900 g of hot water at 55°C. The product yielded 185.2 g of 17-ketal estradiol, with a yield of 92.12%.

[0062] (3) Synthesis of estrone:

[0063] 170g of 17-ketal estrone and 850ml of methanol were added to the reaction flask, and 40g of sulfuric acid was added dropwise. The pH was measured to be <2. The mixture was heated to reflux and reacted for 2 hours. The temperature was then lowered to 30℃, and 500ml of water was added dropwise. The mixture was filtered, washed with 170ml of ethanol, and dried to obtain 135.2g of estrone, with a yield of 92.47%.

[0064] (4) Synthesis of estradiol hemihydrate:

[0065] Add 130g of estradiol, 650ml of ethanol, and 155g of 10% sodium hydroxide solution. Stir until completely dissolved, cool to 6℃, add 13g of sodium borohydride in four portions (3g for the first three portions and 4g for the last portion), keep warm for 1 hour, add acetic acid to neutralize the pH to 4-5, add 220g of water dropwise, filter, wash with 450g of water, discharge, dry to 131g, return the wet material to the bottle, add 1170ml of methanol and 1.3g of activated carbon, heat to reflux, keep reflux for 30 minutes, cool to 70℃, hot filter, wash the filter cake with 130ml of methanol, add 260g of water dropwise to the filtrate, cool to -5℃~5℃, keep warm to crystallize for 1 hour, filter, dry under vacuum, discharge, vacuum dry at -0.079MPa, drying temperature at 40℃ for 1.5 hours, dry to 119.5g. The yield was 88.32%, the purity was greater than 99.5%, the number of individual impurities was less than 0.1%, and the moisture content was 3.2%.

[0066] Comparative Example 1

[0067] The only difference between this invention and Example 1 is that the temperature during solid-liquid separation and the temperature of the washing water are both 30°C during the synthesis of 17-ketoestrone.

[0068] That is, during the synthesis of 17-ketoestrone:

[0069] Add 500 ml of tetrahydrofuran (peroxide content <0.1%), 100 g of biphenyl, and 80 g of diphenylmethane to a reaction flask. Add 10 g of lithium metal in portions. Heat to reflux and maintain the reaction temperature for 2 hours. Cool down to 30°C and slowly add 300 ml of tetrahydrofuran solution containing 100 g of ketal. After the addition is complete, maintain the reaction temperature at 30°C for 2 hours. Cool down to 4°C and add 50 g of water to stop the reaction. Then distill under reduced pressure to 70°C, cool down to 30°C, filter, dry under vacuum, wash with 500 g of hot water at 30°C, and discharge to obtain 95.2 g of 17-ketal estradiol, with a yield of 94.7% (the yield is high because of the high amount of residual biphenyl).

[0070] The final synthesized estradiol hemihydrate had a purity of 98.8%, with a biphenyl content >0.10%. The product quality did not meet the requirements of the European Pharmacopoeia and was therefore unqualified.

[0071] Comparative Example 2

[0072] The only difference between this embodiment and Example 1 is that solid-liquid separation is not performed after the synthesis of 17-ketoestrone; all other aspects remain the same.

[0073] Kettal synthesis:

[0074] Add 100g of ADD, 150g of ethylene glycol, 100g of trimethyl orthoformate, 100g of methanol, and 1g of p-toluenesulfonic acid to a reaction flask. Keep the reaction at 25°C for 8 hours. Add 2g of triethylamine to stop the reaction. Heat to reflux, add 130g of water dropwise, cool to 4°C, filter, and dry to obtain 110.0g of ketal, with a yield of 95.2%.

[0075] Synthesis of 17-ketoestrone and estrone:

[0076] Add 500 ml of tetrahydrofuran (peroxide content <0.1%), 100 g of biphenyl, and 80 g of diphenylmethane to a reaction flask. Add 10 g of lithium metal in portions (2 g each time, 5 times). Heat to reflux and maintain the reaction temperature for 2 hours. Cool to 30°C and slowly add 300 ml of tetrahydrofuran solution containing 100 g of ketal. After the addition is complete, maintain the reaction temperature at 30°C for 2 hours. Cool to 4°C and add 50 g of water to stop the reaction. Add 400 ml of methanol and dropwise add 40 g of 30% hydrochloric acid. The pH is measured to be <2. Heat to reflux and react for 2 hours. Cool to 20°C and dropwise add 240 ml of water. Filter under vacuum, wash with 80 ml of methanol, and dry to obtain 95.8 g of estradiol, yield 95.3%.

[0077] Synthesis of estradiol hemihydrate:

[0078] Add 60g of estradiol, 300ml of methanol, and 70g of 10% sodium hydroxide solution. Stir until completely dissolved, cool to 4℃, add 6g of sodium borohydride in portions (2g each time, 3 times), keep warm for 1 hour, neutralize with acetic acid to pH=4-5, add 100g of water dropwise, filter, wash with 200g of water, discharge, dry 60g of wet material, return to bottle, add 540ml of ethanol and 0.6g of activated carbon, heat to reflux, keep reflux for 30 minutes, cool to 50℃, hot filter, wash the filter cake with 60ml of ethanol, add 120g of water dropwise to the filtrate, cool to -5℃, keep warm to crystallize for 1 hour, filter, dry under vacuum, discharge, vacuum dry at -0.075MPa, drying temperature at 45℃, drying time for 2 hours. The final purity of synthesized estradiol hemihydrate is 98.6%, of which biphenyl content is >0.1%. The product quality does not meet the requirements of the European Pharmacopoeia and is unqualified.

[0079] Comparative Example 3

[0080] The only difference between this embodiment and Example 2 is that the peroxide content in tetrahydrofuran is 0.15% when synthesizing 17-ketoestrone.

[0081] The 17-ketoestrone prepared in this embodiment is an oily substance, and the solid and liquid phases cannot be separated, so no product can be obtained.

[0082] Comparative Example 4

[0083] The only difference between this embodiment and Example 2 is that, during the synthesis of estradiol hemihydrate, the vacuum drying temperature is 60°C and the drying time is 1 hour.

[0084] The weight, yield, and purity of the estradiol hemihydrate obtained in this embodiment remained unchanged, but the water content was 2.75%, which did not meet the European Pharmacopoeia standard and was therefore unqualified.

[0085] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above 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.

[0086] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for synthesizing estradiol hemihydrate, characterized in that, Includes the following steps: (1) 1,4-Androstenedione was reacted with ethylene glycol to obtain a ketal; (2) The obtained ketal was mixed with a lithium reagent and reacted. After the reaction was completed, it was distilled, separated into solid and liquid, and washed with hot water to obtain 17-ketoestrone. (3) The obtained 17-ketoestrone was hydrolyzed with an inorganic acid to obtain estrone, and estrone was reduced with a reducing agent to obtain crude estradiol. The crude estradiol was purified with alcohol or ketone solvent and pure water, and then dried under reduced pressure to obtain estradiol hemihydrate.

2. The synthesis method according to claim 1, characterized in that, In step (1), the reaction of 1,4-androstenedione with ethylene glycol is specifically as follows: 1,4-Androstenedione, ethylene glycol, trimethyl orthoformate, solvent A and p-toluenesulfonic acid were mixed and reacted. After the reaction was completed, triethylamine was added to stop the reaction. The mixture was heated to dissolve, water was added to crystallize, the mixture was cooled, filtered, and dried to obtain the ketal. Solvent A includes at least one of methanol, ethanol, and isopropanol; The amount of ethylene glycol added is 1 to 2 times the mass of 1,4-androstenedione, the amount of trimethyl orthoformate added is 0.6 to 1.5 times the mass of 1,4-androstenedione, the amount of solvent A added is 1 to 3 times the mass of 1,4-androstenedione, the amount of p-toluenesulfonic acid added is 0.01 to 0.03 times the mass of 1,4-androstenedione, the amount of triethylamine added is 0.02 to 0.04 times the mass of 1,4-androstenedione, and the amount of water added is 1 to 2 times the mass of 1,4-androstenedione.

3. The synthesis method according to claim 1, characterized in that, In step (2), the lithium reagent is obtained by reacting lithium metal, biphenyl, diphenylmethane and tetrahydrofuran, wherein the peroxide content in the tetrahydrofuran is <0.1%.

4. The synthesis method according to claim 1, characterized in that, In step (2), the mass of the hot water used for washing is 4 to 8 times the mass of the ketal.

5. The synthesis method according to claim 1, characterized in that, In step (2), the temperature during solid-liquid separation is 40-75℃, and the temperature of the hot water is 40-75℃.

6. The synthesis method according to claim 3, characterized in that, In step (2), First, dissolve the ketal in tetrahydrofuran to prepare a tetrahydrofuran solution containing the ketal; Lithium, biphenyl, diphenylmethane, and tetrahydrofuran were mixed and reacted. The mixture was heated to reflux and maintained at that temperature for 1.5–3 hours. After the reaction was completed, the temperature was lowered to 30–35°C, and a tetrahydrofuran solution containing the ketal was added. The reaction was continued for 1.5–3 hours. After the reaction was completed, the temperature was lowered, water was added, and the reaction was stopped. The mixture was then distilled under reduced pressure to 65–75°C, and then cooled to 40–75°C. The mixture was filtered, and the solid and liquid were separated to obtain a filter cake. The filter cake was washed with hot water at 40–75°C and discharged to obtain 17-ketoestrone.

7. The synthesis method according to claim 6, characterized in that, In step (2), the mass-to-volume ratio of the ketal to the total tetrahydrofuran is 1 g: 5-10 ml; the mass ratio of the ketal to lithium is 1: 0.08-0.2; the mass ratio of the ketal to biphenyl is 1: 1-2; the mass ratio of the ketal to diphenylmethane is 1: 0.5-0.9; when water is added to stop the reaction, the mass ratio of the ketal to water added is 1: 0.4-0.

8.

8. The synthesis method according to claim 1, characterized in that, In step (3), the process of obtaining estradiol ketone via inorganic acid hydrolysis includes: The 17-ketal estrone obtained in step (2) was mixed with solvent B, the pH was adjusted to <2 with inorganic acid, the temperature was raised to reflux for 1-3 hours, the temperature was lowered to 20-30℃, water was added, the mixture was filtered and washed to obtain estrone. Solvent B is methanol, ethanol, or acetone; the inorganic acid is hydrochloric acid, a type of sulfuric acid. The mass-to-volume ratio of 17-ketoestrone to solvent B is 1 g: 3-8 ml; the mass-to-volume ratio of 17-ketoestrone to added water is 1 g: 2-4 ml.

9. The synthesis method according to claim 8, characterized in that, In step (3), the reduction of estrone with a reducing agent to obtain crude estradiol includes: The obtained estrone was mixed with solvent C, and 10% sodium hydroxide and reducing agent were added to carry out the reduction reaction. After the reaction was completed, acetic acid was added to adjust the pH to 4-5, water was added to precipitate crystals, and the mixture was filtered to obtain crude estradiol. Solvent C is methanol or ethanol; reducing agent is sodium borohydride or potassium borohydride; the reduction reaction temperature is 0–10℃ and the time is 0.5–1.5 hours. The mass-volume ratio of estrone to solvent C is 1g:3-8ml; the mass ratio of estrone to reducing agent is 1:0.08-0.15; and the mass ratio of estrone to 10% sodium hydroxide is 1:1.1-1.

3.

10. The synthesis method according to claim 1, characterized in that, In step (3), the refining process includes: The obtained crude estradiol was mixed with solvent D, activated carbon was added, the temperature was raised to reflux, and the reflux was maintained for 20-40 minutes. The temperature was then lowered to 50-70°C, and the mixture was hot-filtered. Pure water was added dropwise to the filtrate. After the addition was complete, the temperature was lowered to -5°C to 5°C, and the mixture was kept at this temperature for 0.5-1.5 hours to allow crystals to precipitate. The mixture was then filtered, dried, and the crude estradiol was obtained. In this process, solvent D is ethanol, methanol, or acetone; the mass-to-volume ratio of crude estradiol to solvent D is 1 g: 6–12 ml; the mass ratio of crude estradiol to activated carbon is 1:0.05–0.15; and the mass ratio of added pure water to crude estradiol is 1.5–2.5:

1.

11. The synthesis method according to claim 10, characterized in that, In step (3), the drying process involves vacuum drying of the obtained estradiol hemihydrate wet product, with a vacuum degree of <-0.07MPa, a drying temperature of 30-50℃, and a drying time of 1-3 hours.

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