Preparation method of exemestane
The new synthesis route for exemestane using copper catalysts and sodium sulfite oxidizing agent addresses the high cost and low yield issues of existing methods, achieving improved yields and safety in industrial production.
Patent Information
- Application Number
- CN202510477826.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-04-16
- Publication Date
- 2025-07-15
AI Technical Summary
The existing chemical synthesis methods of exemetam have problems such as low yield, high cost, high toxicity of the oxidants used and are not suitable for industrial production.
The iodine reaction was carried out under the catalyzed cuprous oxide catalyzed with androthenone, and then reacted with diethanol formaldehyde to form an intermediate, and then oxidized with disulfate, and finally obtained exemetam by recrystallization.
It improves the total yield and purity of exemestane, reduces production costs, reduces the use of toxic oxidants, and improves the safety and economic benefits of the product.
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Figure CN120309679A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to exemestane, and particularly to a preparation method of exemestane, belonging to the technical field of preparation of bulk drugs. Background Art
[0002] Exemestane, chemical name: 6-methyleneandrosta-1,4-diene-3,17-dione, has the following structural formula:
[0003]
[0004] Exemestane was developed by Pfizer, and was first approved for marketing in the UK on December 16, 1998. Then it was approved by the US Food and Drug Administration (FDA) on October 21, 1999, and approved by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan on July 5, 2002. It is marketed by Pfizer in the UK under the trade name Aromasin. Exemestane is an irreversible aromatase inhibitor, which blocks estrogen production by inhibiting aromatase and selectively treats postmenopausal hormone-dependent breast cancer. This drug is suitable for early breast cancer with positive estrogen receptor in postmenopausal women who have previously received tamoxifen treatment for 2 to 3 years and then switch to Aromasin to complete continuous five-year adjuvant hormone therapy, and for the treatment of advanced breast cancer in postmenopausal women whose condition has progressed after tamoxifen treatment. Aromasin is an oral tablet, each tablet containing 25 mg of exemestane. The recommended dose is 25 mg each time, once a day, taken after meals.
[0005] Exemestane is a steroid drug, and its main synthesis methods are mainly divided into two categories: microbial transformation method and chemical synthesis method. Bondzynski and Humnicki first proposed the use of the microbial transformation method to prepare steroid compounds. The biological method is generally used for steps that are difficult to achieve by chemical methods. The biological transformation method of exemestane is actually to dehydrogenate at the C-1 and C-2 positions using microorganisms after synthesizing 6-methyleneandrosta-4-ene-3,17-dione, thereby obtaining exemestane. During the preparation of exemestane by the Deng Le research group, in the last step, Arthrobacter simplex was used to dehydrogenate at the C-1 and C-2 positions to obtain the target product, with simple operation, but the yield of this step only reached 13.6%. Due to the spatial configuration of exemestane, the reaction of the biological transformation method is currently difficult and the progress is slow.
[0006] The chemical synthesis method has a more mature process route compared with the microbial transformation method, with a higher yield and is suitable for large-scale industrial production. The main chemical synthesis methods of exemestane are as follows:
[0007] 1. Using androstenedione as the raw material, through the Mannich reaction to obtain 6-methylene-4-ene-3,17-androstenedione, and finally obtaining exemestane through oxidation with DDQ or tetrachlorobenzoquinone. The synthetic route is as follows:
[0008]
[0009] The yield of the Mannich reaction in this route is relatively low, only 70%, and the purity is about 70 - 75%. Moreover, the second-step oxidation dehydrogenation and recrystallization have great technical difficulties, and both DDQ and tetrachlorobenzoquinone are genotoxic impurities and expensive (the price per kilogram is even more expensive than androstenedione), resulting in high production costs and being not conducive to industrial production and cost control.
[0010] 2. Using dehydrotestosterone as the starting material, through the Mannich reaction to prepare 6-methylene dehydrotestosterone, and then obtaining exemestane through oxidation with Jones reagent. The synthetic route is as follows:
[0011]
[0012] In this method, the C-1 and C-2 positions of the raw material dehydrotestosterone are already double bonds, which reduces the difficulty of preparing exemestane. Its defect is that the raw material and Jones reagent are expensive, and Jones reagent has a large pollution; and due to the influence of the C-1 / C-2 double bond, the yield of the methylation reaction is relatively low, about 30%, which is not suitable for industrial production.
[0013] 3. Using androstenedione (2) as the raw material, first undergoing a condensation reaction to obtain intermediate 5, and then obtaining exemestane through bromination and elimination. The synthetic route is as follows:
[0014]
[0015] This route has many reaction steps, and the total yield is only 28.8%. Moreover, the bromine liquid equipment has strong corrosion, and there are industrial bromine-containing three wastes, which is not suitable for industrial production. SUMMARY OF THE INVENTION
[0016] In view of the above problems, the present invention provides a method for preparing exemestane to reduce the production cost and improve the yield and purity of the product.
[0017] To achieve the above object, the technical solution of the present invention is: A method for preparing exemestane, comprising the following steps:
[0018] Step S1: Using androstenedione as the raw material, under the catalysis of copper oxide, undergoing an iodination reaction to obtain 2-iodo-4-ene-3,17-androstenedione (intermediate-1);
[0019] Step S2: 2-Iodo-4-en-3,17-androstadione reacts with diethylformal under the action of phosphorus oxychloride to form 2-iodo-6-methylene-4-en-3,17-androstadione (Intermediate-2);
[0020] Step S3: 2-Iodo-6-methylene-4-en-3,17-androstadione undergoes an oxidation reaction to obtain a crude product, which is then refined to obtain exemestane;
[0021] The reaction synthesis route is as follows:
[0022]
[0023] Furthermore, in step S1, for the iodination reaction, iodine, androstenedione, and cuprous oxide are added to glacial acetic acid, and the reaction is carried out at room temperature for 40 - 80 h under a nitrogen atmosphere; after the reaction is completed, acetic acid is concentrated under reduced pressure, the residue is added to water, the product is extracted with ethyl acetate, after liquid separation, the organic phase is washed with a sodium thiosulfate solution until neutral, then washed with saturated sodium carbonate, and then dried and concentrated to obtain a crude product, which is further recrystallized to obtain 2-iodo-4-en-3,17-androstadione.
[0024] Furthermore, in step S1, the weight ratio of iodine, androstenedione, and cuprous oxide is 105 - 110:100:75 - 80.
[0025] Furthermore, in step S2, for the reaction, sodium acetate and diethoxymethane are added to chloroform, refluxed and stirred for 10 min - 2 h, then 2-iodo-4-en-3,17-androstadione is added, phosphorus oxychloride is slowly added, and the temperature is raised to 50 - 70 °C for reaction for 2 - 8 h; the obtained reaction solution is cooled to room temperature, an aqueous sodium carbonate solution is slowly added until the pH of the aqueous layer is neutral, filtered, liquid-separated, the organic phase is washed with water until neutral, dried and concentrated, the residue is added to water, filtered, the filter cake is collected, dried, and recrystallized to obtain 2-iodo-6-methylene-4-en-3,17-androstadione.
[0026] Furthermore, in step S2, the weight ratio of diethoxymethane, 2-iodo-4-en-3,17-androstadione, and phosphorus oxychloride is 500 - 800 g:130 g:250 - 400 g.
[0027] Furthermore, in step S3, for the oxidation reaction, 2-iodo-6-methylene-4-en-3,17-androstadione and THF are added to a reactor, and a persulfate solution is slowly added, then the reaction is carried out at room temperature for 2 - 7 h. After the reaction is completed, water is added for crystallization, and the crude product is obtained by filtration, and then exemestane is obtained by recrystallization and purification.
[0028] Further, in step S3, the weight ratio of 2-iodo-6-methylene-4-en-3,17-androstenedione to persulfate is 95 g:5 - 20 g.
[0029] Further, in step S3, after filtration to obtain the crude product, the crude product is recrystallized with methanol - water (1:1), and the obtained solid is recrystallized with ethanol again to obtain white crystalline solid exemestane.
[0030] Further, the yield of 2-iodo-4-en-3,17-androstenedione obtained in step S1 is 90 - 95%, the yield of 2-iodo-6-methylene-4-en-3,17-androstenedione obtained in step S2 is 70 - 75%, and the yield of purified exemestane obtained in step S3 is 70 - 75%, and the HPLC purity is 99.85 - 99.95%.
[0031] The beneficial effects of a method for preparing exemestane of the present invention are as follows:
[0032] For the new preparation route of the present invention, inexpensive persulfate is used instead of expensive oxidation reagents such as DDQ, so the cost is reduced, and the relatively high yield of the oxidation step further improves the economic benefits.
[0033] The present invention uses 2-position iodination and then conducts an oxidation reaction to form a double bond to prepare exemestane, thus avoiding the use of highly toxic and high-dose gene-toxic oxidants such as DDQ and tetrachlorobenzoquinone, reducing the purification pressure of exemestane, and improving the drug safety.
[0034] The total yield of preparing exemestane at the API level from androstenedione as the raw material in the present invention is about 48%, and the purity is about 99.93%. Considering the comprehensive quality and yield, it has great advantages compared with the existing level.
[0035] The present invention designs and implements a brand-new preparation route for exemestane, which has not been reported in the literature; using persulfate instead of expensive oxidants such as DDQ reduces the production cost. BRIEF DESCRIPTION OF THE DRAWINGS
[0036] The present invention will be further described in detail below with reference to the drawings and specific embodiments.
[0037] Figure 1 is the HPLC chromatogram of exemestane, the product of the present invention;
[0038] Figure 2 is the 1H NMR spectrum of exemestane, the product of the present invention;
[0039] Figure 3 is the 13C NMR spectrum of exemestane, the product of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS
[0040] Combined with the accompanying drawings in the embodiments of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described. In the following description, many specific details are set forth in order to fully understand the present invention. However, the present invention can also be implemented in other ways different from those described herein. Those skilled in the art can make similar generalizations without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.
[0041] In view of the current process status of exemestane, the present invention has developed a new preparation route. The new preparation process uses inexpensive persulfate to replace expensive oxidation reagents such as DDQ, reducing the cost, and the high yield of the oxidation step further improves the economic benefits.
[0042] The specific process flow is as follows:
[0043]
[0044] Specifically, it includes the following steps:
[0045] Step S1: Using androstenedione as a raw material, an iodination reaction occurs under the catalysis of cuprous oxide to obtain 2-iodo-4-en-3,17-androstenedione; specifically,
[0046] For the iodination reaction, iodine, androstenedione and cuprous oxide are added to glacial acetic acid, and the reaction is carried out at room temperature for 40 - 80 h under a nitrogen atmosphere; after the reaction is completed, acetic acid is concentrated under reduced pressure, the residue is added to water, the product is extracted with ethyl acetate, after liquid separation, the organic phase is washed with a sodium thiosulfate solution until neutral, then washed with saturated sodium carbonate, and then dried and concentrated to obtain a crude product, which is then recrystallized to obtain 2-iodo-4-en-3,17-androstenedione. Among them, the weight ratio of iodine, androstenedione and cuprous oxide is 105 - 110:100:75 - 80.
[0047] Step S2: 2-iodo-4-en-3,17-androstenedione reacts with diethyleneglycol formal under the action of phosphorus oxychloride to form 2-iodo-6-methylene-4-en-3,17-androstenedione; specifically,
[0048] The reaction is to add sodium acetate and diethoxymethane into chloroform, reflux and stir for 10 min - 2 h. After completion, add 2-iodo-4-en-3,17-androstadione, slowly add phosphorus oxychloride, and raise the temperature to 50 - 70 °C for reaction for 2 - 8 h; cool the obtained reaction solution to room temperature, slowly add an aqueous sodium carbonate solution until the pH of the aqueous layer is neutral, filter, separate the liquid, wash the organic phase with water until neutral, concentrate after drying, add water to the residue, filter, collect the filter cake, dry, and recrystallize to obtain 2-iodo-6-methylene-4-en-3,17-androstadione. Among them, the weight ratio of diethoxymethane, 2-iodo-4-en-3,17-androstadione and phosphorus oxychloride is 500 - 800 g : 130 g : 250 - 400 g.
[0049] Step S3: 2-iodo-6-methylene-4-en-3,17-androstadione undergoes an oxidation reaction to obtain a crude product, and exemestane can be obtained after purification. Specifically,
[0050] The oxidation reaction is to add 2-iodo-6-methylene-4-en-3,17-androstadione and THF into a reactor, and then slowly add a persulfate solution. After completion, react at room temperature for 2 - 7 h. After the reaction is completed, add water for crystallization, filter to obtain a crude product, and purify it by recrystallization to obtain exemestane. Among them, the weight ratio of 2-iodo-6-methylene-4-en-3,17-androstadione and persulfate is 95 g : 5 - 20 g; after filtering to obtain the crude product, the crude product is recrystallized with methanol-water (1:1), and the obtained solid is recrystallized with ethanol again to obtain white crystalline solid exemestane.
[0051] Example 1
[0052] A method for preparing exemestane, comprising the following steps:
[0053] Step S1, 107.4 g (423 mmol) of iodine is added to 3 L of glacial acetic acid containing 100 g (349 mmol) of androstenedione and 78.7 g (423 mmol) of CuO, and stirred at room temperature. It is stirred at 24 °C for 60 hours under a nitrogen atmosphere. Under reduced pressure, acetic acid is distilled off. The residue is added to 6 L of water, the product is extracted with ethyl acetate, the ethyl acetate phase is washed with a sodium thiosulfate solution until neutral, then washed with a saturated sodium carbonate solution and dried over sodium sulfate. The solution is concentrated to obtain a crude product, and then recrystallized with acetonitrile to obtain 134.2 g of intermediate-1 (2-iodo-4-en-3,17-androstadione) with a yield of 93.2%.
[0054] Step S2: In a reactor, add sodium acetate (94.6 g) and diethoxymethane (677 g), then add anhydrous chloroform (2.6 L), and reflux for 0.5 h with stirring. Subsequently, add 2-iodo-4-en-3,17-androstadione (130 g, 315 mmol) and stir to dissolve to form a reaction solution. Then, slowly add phosphorus oxychloride (338 g, 2.2 mol) to the reaction solution through a dropping funnel, and raise the temperature to 60 °C and react for 2.5 h. After the addition is completed, continue to stir and react under reflux conditions for 5 h. Cool the reaction solution to room temperature, then slowly add an aqueous sodium carbonate solution dropwise with stirring until the pH value of the aqueous layer is 7 - 8. Filter, allow to stand for complete separation, separate the organic layer, wash it with water until neutral, dry the organic layer with anhydrous sodium sulfate, concentrate under reduced pressure, add water to the residue, filter, collect the filter cake, dry it, and recrystallize it with acetone / petroleum ether (v / v = 1:3) to obtain 95.3 g of intermediate-2 (2-iodo-6-methylene-4-en-3,17-androstadione) with a yield of 71.2%.
[0055] Step S3: In a reactor, add 95 g of 2-iodo-6-methylene-4-en-3,17-androstadione, then add 800 ml of THF, and slowly add a saturated solution of potassium persulfate (containing 10.08 g of potassium persulfate). After the addition is complete, stir and react at room temperature for 5 h. After the reaction is completed, add 2000 mL of a large amount of deionized water, stir and crystallize at room temperature for 1 h, and filter to obtain the crude product. The crude product is recrystallized with methanol-water (1:1), and the resulting solid is recrystallized with ethanol again to obtain 48.05 g of white crystalline solid exemestane with a yield of 72.4% and an HPLC purity of 99.93%.
[0056] Among them, the purity detection is carried out according to the high performance liquid chromatography method (General Principles 0512). Specifically:
[0057] Test solution: Take an appropriate amount of this product, dissolve and dilute it with the mobile phase to prepare a solution containing about 0.5 mg per 1 ml.
[0058] Control solution: Accurately measure 1 ml of the test solution, place it in a 200 ml volumetric flask, dilute it to the mark with the mobile phase, and shake well.
[0059] System suitability solution: Take appropriate amounts of exemestane reference substance and impurity I reference substance, dissolve them with the mobile phase and dilute to prepare a mixed solution containing 2.5 μg of both exemestane and impurity I per 1 ml.
[0060] Chromatographic conditions: Use octadecylsilane chemically bonded silica gel as the filler, with acetonitrile-water (35:65) as the mobile phase; the detection wavelength is 249 nm; the column temperature is 40 °C; the injection volume is 20 μl.
[0061] System suitability requirements: In the chromatogram of the system suitability solution, the resolution between exemestane peak and impurity I should be greater than 2.5.
[0062] Assay: Accurately measure the test solution and the reference solution, and inject them into the liquid chromatograph respectively. Record the chromatogram until 2.5 times the retention time of the main component peak.
[0063] Limit: If there are impurity peaks in the chromatogram of the test solution, the area of a single impurity peak shall not be greater than the area of the main peak of the reference solution (0.5%), and the sum of the areas of each impurity peak shall not be greater than 2 times the area of the main peak of the reference solution (1.0%).
[0064] As Figure 1 shown, the HPLC chromatogram of purified exemestane in this example; Figure 2 is the hydrogen spectrum of purified exemestane, Figure 3 is the carbon spectrum of purified exemestane.
[0065] Example 2
[0066] Example 2 is a conditional improvement based on Example 1. Specifically:
[0067] Step S1, 105 g of iodine was added to 3 L of glacial acetic acid containing 100 g of androstenedione and 75 g of CuO, and stirred at room temperature. It was stirred for 80 hours at 24 °C under a nitrogen atmosphere. Under reduced pressure, acetic acid was distilled off. The residue was added to 6 L of water, and the product was extracted with ethyl acetate. The ethyl acetate phase was washed with sodium thiosulfate solution until neutral, then washed with saturated sodium carbonate solution and dried over sodium sulfate. The solution was concentrated to obtain the crude product, which was recrystallized from acetonitrile to obtain 130.7 g of intermediate-1 (2-iodo-4-ene-3,17-androstenedione), with a yield of 90.8%.
[0068] Step S2, in the reactor, add sodium acetate (94 g), diethoxymethane (500 g), and then add anhydrous chloroform (2.5 L), and reflux and stir for 0.5 h. Subsequently, add 2-iodo-4-ene-3,17-androstenedione (130 g) and stir to dissolve to form a reaction solution. Then, slowly add phosphorus oxychloride (400 g) to the reaction solution through a dropping funnel, and raise the temperature to 50 °C and react for 8 h. After the addition is completed, continue to stir and react for 8 h under reflux conditions. The reaction solution was cooled to room temperature, and then an aqueous sodium carbonate solution was added dropwise with stirring until the pH value of the aqueous layer was 7-8. It was filtered, and after standing for complete separation, the organic layer was separated, washed with water until neutral, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the residue was added to water, filtered, the filter cake was collected, dried, and recrystallized from acetone / petroleum ether (v / v = 1:3) to obtain 98.78 g of intermediate-2 (2-iodo-6-methylene-4-ene-3,17-androstenedione), with a yield of 73.8%.
[0069] Step S3: In a reactor, add 95 g of 2-iodo-6-methylene-4-en-3,17-androstenedione, then add 820 ml of THF, and slowly dropwise add a saturated solution of potassium persulfate (containing 5 g of potassium persulfate). After addition, stir the reaction at room temperature for 5 h. After the reaction is completed, add 2000 mL of a large amount of deionized water, stir and crystallize at room temperature for 1 h, and filter to obtain the crude product. The crude product is recrystallized with methanol-water (1:1), and the obtained solid is recrystallized with ethanol again to obtain 46.99 g of white crystalline exemestane, with a yield of 70.8% and an HPLC purity of 99.95%.
[0070] Example 3
[0071] Example 3 is a conditional improvement based on Example 1. Specifically:
[0072] Step S1: Add 110 g of iodine to 3 L of glacial acetic acid containing 100 g of androstenedione and 80 g of CuO, and stir at room temperature. It is stirred at 24 °C for 40 hours under a nitrogen atmosphere. Under reduced pressure, acetic acid is distilled off. The residue is added to 6 L of water, the product is extracted with ethyl acetate, the ethyl acetate phase is washed with a sodium thiosulfate solution until neutral, then washed with a saturated sodium carbonate solution and dried over sodium sulfate. The solution is concentrated to obtain the crude product, and then recrystallized from acetonitrile to obtain 136.2 g of intermediate-1 (2-iodo-4-en-3,17-androstenedione), with a yield of 94.7%.
[0073] Step S2: In a reactor, add sodium acetate (95 g) and diethoxymethane (800 g), then add anhydrous chloroform (3 L), and reflux and stir for 0.5 h. Subsequently, add 2-iodo-4-en-3,17-androstenedione (130 g) and stir to dissolve to form a reaction solution. Then, slowly dropwise add phosphorus oxychloride (250 g) to the reaction solution through a dropping funnel, and raise the temperature to 70 °C and react for 2 h. After the addition is completed, continue to stir and react under reflux conditions for 4 h. Cool the reaction solution to room temperature, then dropwise add an aqueous sodium carbonate solution with stirring until the pH value of the water layer is 7-8, filter, and after standing for complete separation, separate the organic layer, wash it with water until neutral, dry the organic layer over anhydrous sodium sulfate, concentrate under reduced pressure, add water to the residue, filter, collect the filter cake, dry it, and recrystallize it with acetone / petroleum ether (v / v = 1:3) to obtain 99.98 g of intermediate-2 (2-iodo-6-methylene-4-en-3,17-androstenedione), with a yield of 74.7%.
[0074] Step S3: Add 95 g of 2-iodo-6-methylene-4-en-3,17-androstadione into the reactor, then add 780 ml of THF, and slowly dropwise add a saturated solution of potassium persulfate (containing 20 g of potassium persulfate). After the addition is complete, stir and react at room temperature for 5 h. After the reaction is completed, add 2000 mL of a large amount of deionized water, stir and crystallize at room temperature for 1 h, and filter to obtain the crude product. The crude product is recrystallized with methanol-water (1:1), and the obtained solid is recrystallized with ethanol again to obtain 49.77 g of white crystalline exemestane, with a yield of 75% and an HPLC purity of 99.94%.
[0075] Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of them. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts fall within the scope of protection of the present invention.
Claims
1. A preparation method of exemestane, characterized in that, It includes the following steps: Step S1: Using androstenedione as a raw material, under the catalysis of cuprous oxide, an iodination reaction occurs to obtain 2-iodo-4-en-3,17-androstenedione; Step S2: 2-iodo-4-en-3,17-androstenedione reacts with diethylformal under the action of phosphorus oxychloride to generate 2-iodo-6-methylene-4-en-3,17-androstenedione; Step S3: 2-iodo-6-methylene-4-en-3,17-androstenedione undergoes an oxidation reaction to obtain a crude product, and exemestane can be obtained after purification; The reaction synthesis route is as follows:
2. The preparation method of exemestane according to claim 1, characterized in that, In step S1, for the iodination reaction, iodine, androstenedione, and cuprous oxide are added to glacial acetic acid, and the reaction is carried out at room temperature for 40 - 80 h under a nitrogen atmosphere; after the reaction is completed, acetic acid is concentrated under reduced pressure, water is added to the residue, the product is extracted with ethyl acetate, after liquid separation, the organic phase is washed with a sodium thiosulfate solution until neutral, then washed with saturated sodium carbonate, and then dried and concentrated to obtain a crude product, and 2-iodo-4-en-3,17-androstenedione is obtained after recrystallization.
3. The preparation method of exemestane according to claim 2, characterized in that, In step S1, the weight ratio of iodine, androstenedione, and cuprous oxide is 105 - 110:100:75 - 80.
4. A preparation method of exemestane according to claim 1, characterized in that, In step S2, for the reaction, sodium acetate and diethoxymethane are added to chloroform, refluxed and stirred for 10 min - 2 h, then 2-iodo-4-en-3,17-androstenedione is added, phosphorus oxychloride is slowly added, and the temperature is raised to 50 - 70 °C for reaction for 2 - 8 h; the obtained reaction solution is cooled to room temperature, an aqueous sodium carbonate solution is slowly added until the pH of the aqueous layer is neutral, filtered, liquid-separated, the organic phase is washed with water until neutral, dried and concentrated, water is added to the residue, filtered, the filter cake is collected, dried, and 2-iodo-6-methylene-4-en-3,17-androstenedione is obtained after recrystallization.
5. The preparation method of exemestane according to claim 4, characterized in that, In step S2, the weight ratio of diethoxymethane, 2-iodo-4-en-3,17-androstenedione, and phosphorus oxychloride is 500 - 800 g:130 g:250 - 400 g.
6. The preparation method of exemestane according to claim 1, characterized in that, In step S3, for the oxidation reaction, 2-iodo-6-methylene-4-en-3,17-androstenedione and THF are added to a reactor, and then a persulfate solution is slowly added, and the reaction is carried out at room temperature for 2 - 7 h. After the reaction is completed, water is added for crystallization, and the crude product is obtained by filtration, and exemestane is obtained after purification by recrystallization.
7. A preparation method of exemestane according to claim 6, characterized in that, In step S3, the weight ratio of 2-iodo-6-methylene-4-en-3,17-androstenedione and persulfate is 95 g:5 - 20 g.
8. The preparation method of exemestane according to claim 6, characterized in that, In step S3, after filtering to obtain the crude product, the crude product is recrystallized with methanol - water (1:1), and the obtained solid is recrystallized with ethanol again to obtain white crystalline exemestane.
9. The preparation method of exemestane according to claim 1, characterized in that, The yield of 2-iodo-4-en-3,17-androstenedione obtained in step S1 is 90 - 95%, the yield of 2-iodo-6-methylene-4-en-3,17-androstenedione obtained in step S2 is 70 - 75%, the yield of purified exemestane obtained in step S3 is 70 - 75%, and the HPLC purity is 99.85 - 99.95%.