Preparation method of androstane-4-ene-3, 6, 17-triketone

Abstract

The invention relates to the technical field of organic synthesis of steroid compounds, in particular to a preparation method of androstane-4-ene-3, 6, 17-triketone. Dehydroepiandrosterone acetate is used as an initial raw material to prepare androstane-4-ene-3, 6, 17-triketone through four steps of reactions including chlorohydrination, hydrolysis, oxidation and elimination, the yield and purity of androstane-4-ene-3, 6, 17-triketone are improved, 4-AD impurities are not generated, the total yield of a route reaches 80%, and the purity is larger than or equal to 98.0%; and the preparation process does not involve the use of dangerous chemicals and environment-polluting chromium oxidants, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology of steroidal compounds, and more particularly to a method for preparing androst-4-ene-3,6,17-trione. Background Technology

[0002] Androst-4-en-3,6,17-trione can stimulate testosterone production in men, maintain relatively stable estrogen levels, and increase the testosterone / estrogen (T / E) ratio. 4-methoxy and 4-hydroxy derivatives synthesized from androst-4-en-3,6,17-trione, as well as 7α-acetoxy-4-en-3,6-dione steroids, have been evaluated as inhibitors of human placental aromatase. Its 3α and 3β-reducing derivatives and 19-demethyl derivatives can also inhibit aromatase in a time-dependent manner. Aromatase inhibitors specifically inactivate aromatase, block aromatization reactions, inhibit estrogen production, and reduce blood estrogen levels, thereby achieving the goal of treating breast cancer.

[0003] Currently, there are three main methods for synthesizing androst-4-ene-3,6,17-trione: Method 1: Michael P. Doyle et al. reported in patent US2009093638A1 that androst-4-ene-3,6,17-trione was prepared by direct oxidation using 4-AD as the starting material. The yield reached 80% when 1,2-dichloroethane was used as the solvent, and 62% when water was used as the solvent.

[0004]

[0005] Although this method requires only one reaction step, 1,2-dichloroethane is a Class I organic reagent and is not suitable for production use. Water as a solvent only yields 62%, and the use of expensive tetracaprolactam dirhodium(II) as a catalyst results in excessive costs. Tert-butyl hydroperoxide is used as an oxidant, but the peroxide is unstable and prone to explosion, so its use should be avoided in production.

[0006] Method 2: Jiang Renwang and Liang Guangping et al. reported in patent CN105585607A that androst-4-ene-3,6,17-trione was prepared from dehydroepiandrosterone as the starting material through epoxy ring-opening, oxidation and dehydration reaction, with a total yield of 60%.

[0007]

[0008] This method uses peroxidizing agents such as m-chloroperoxybenzoic acid during the epoxidation reaction, which also poses safety risks in production.

[0009] Method 3: In their article "Synthesis and biological evaluation of steroidal derivatives as selective inhibitors of AKR1B10" published in Steroids 86 (2014) 39-44, Wei Zhang and Ling Wanga et al. reported the direct oxidation of dehydroepiandrosterone (DHEA) to prepare androstenedin-4-ene-3,6,17-trione with a yield of 83%.

[0010]

[0011] Although this method requires only one reaction step, it uses chromic anhydride as an oxidant, which causes significant environmental pollution and is subject to strict production regulations. It also carries the risk of chromium residue in the final product. In addition, the method inevitably produces the difficult-to-remove impurity 4-AD during the reaction, which increases the difficulty of purification and affects the purity of the final product.

[0012] Based on the problems of low product purity, low yield, easy generation of impurities, and unsuitability for industrial production caused by the above preparation methods, there is an urgent need for a high-yield, high-purity method for the synthesis of androst-4-ene-3,6,17-trione that is more suitable for industrial production. Summary of the Invention

[0013] In view of this, the present invention proposes a method for preparing androst-4-ene-3,6,17-trione. Using dehydroepiandrosterone acetate as the starting material, androst-4-ene-3,6,17-trione is prepared through a four-step reaction involving chlorohydrinization, hydrolysis, oxidation, and elimination. This method improves the yield and purity of the product, avoids the generation of 4-AD impurities, achieves an overall yield of 80%, and a purity ≥98.0%.

[0014] This invention provides a method for preparing androstrol-4-ene-3,6,17-trione, using dehydroepiandrosterone acetate as the starting material, and sequentially undergoing a chlorohydrin reaction to obtain a chlorohydrin, a hydrolysis reaction to obtain a hydrolysate, an oxidation reaction to obtain an oxide, and an elimination reaction to obtain androstrol-4-ene-3,6,17-trione; the structure of the dehydroepiandrosterone acetate is shown in Formula II: ; The structural formula of the androstrol-4-ene-3,6,17-trione is shown in Formula I: .

[0015] Based on the above technical solutions, the preferred synthetic route for androstrol-4-ene-3,6,17-trione of the present invention is as follows: .

[0016] Based on the above technical solutions, preferably, the structures of the hydrolysate and the oxide are as shown in Formula IV and Formula V, respectively: .

[0017] Based on the above technical solutions, preferably, the dehydroepiandrosterone acetate is reacted with calcium hypochlorite in an aqueous acetone solution to obtain a chlorohydrin.

[0018]

[0019] Based on the above technical solutions, preferably, the molar ratio of dehydroepiandrosterone acetate to calcium hypochlorite is 1:(2.5~3.0).

[0020] Based on the above technical solution, a further preferred embodiment is that, in an acetone-water mixed solution, in the presence of acetic acid, a chlorohydrin reaction occurs with a molar ratio of dehydroepiandrosterone acetate to calcium hypochlorite of 1:2.77. The reaction solution is then post-treated, concentrated, precipitated with water, and purified by slurrying with ethyl acetate to obtain the chlorohydrin.

[0021] Based on the above technical solutions, preferably, the chlorohydrin is hydrolyzed with hydrochloric acid using methanol as a solvent to obtain the hydrolysate.

[0022]

[0023] Based on the above technical solutions, preferably, the molar ratio of the chlorohydrin to hydrochloric acid is 1:(3.5~4).

[0024] Based on the above technical solutions, a further preferred method is to use methanol as a solvent and a chlorohydrin and hydrochloric acid in a molar ratio of 1:3.68 to carry out a hydrolysis reaction. The reaction solution is then post-treated, concentrated and purified by water precipitation, and then slurried with ethyl acetate to obtain the hydrolysate.

[0025] Based on the above technical solutions, preferably, the hydrolysate is reacted with sodium hypochlorite solution using dichloromethane as solvent and TEMPO (2,2,6,6-tetramethylpiperidine oxide) as catalyst to obtain oxide.

[0026]

[0027] Based on the above technical solutions, preferably, the molar ratio of the hydrolysate, TEMPO and sodium hypochlorite solution is 1:(0.03~0.05):(2~4).

[0028] Based on the above technical solutions, a further preferred method is to use dichloromethane as a solvent, and in the presence of sodium bicarbonate and potassium bromide, the molar ratio of hydrolysate, TEMPO and sodium hypochlorite solution is 1:0.0435:3.11 to undergo an oxidation reaction. The reaction solution is then post-treated, concentrated, and precipitated with water to obtain oxides.

[0029] Based on the above technical solutions, preferably, the oxide is reacted with potassium acetate in anhydrous ethanol as solvent to obtain androst-4-ene-3,6,17-trione.

[0030]

[0031] Based on the above technical solutions, preferably, the molar ratio of the oxide to potassium acetate is 1:(3~4).

[0032] Based on the above technical solution, a further preferred method is to use anhydrous ethanol as solvent, with an elimination reaction occurring at a molar ratio of 1:3.47 between the oxide and potassium acetate. The reaction solution is then concentrated, purified by water precipitation, and purified by methanol slurry to obtain androst-4-ene-3,6,17-trione.

[0033] The method for preparing androstrol-4-ene-3,6,17-trione of the present invention has the following advantages over the prior art: This invention proposes a method for preparing androstrol-4-ene-3,6,17-trione. Using dehydroepiandrosterone acetate as the starting material, and employing a four-step reaction involving chlorohydrinization, hydrolysis, oxidation, and elimination, androstrol-4-ene-3,6,17-trione is prepared. This method improves the yield and purity of the product, avoids the generation of 4-AD impurities, achieves an overall yield of 80%, and a purity ≥98.0%. Furthermore, the preparation process does not involve the use of hazardous chemicals or environmentally polluting chromium oxidants, making it suitable for industrial production. Attached Figure Description

[0034] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0035] Figure 1 The hydrolysate in Example 4 of this invention 1 H-NMR spectrum; Figure 2 The oxide in Example 7 of this invention 1 H-NMR spectrum; Figure 3The HPLC chromatogram of androst-4-ene-3,6,17-trione in Example 10 of this invention; Figure 4 Androst-4-ene-3,6,17-trione in Example 10 of this invention 1 H-NMR spectrum. Detailed Implementation

[0036] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0037] The main materials used in this invention are as follows: dehydroepiandrosterone acetate is produced by Kyodo Pharmaceuticals, calcium hypochlorite is purchased from Maclean, and sodium hypochlorite solution and TEMPO (2,2,6,6-tetramethylpiperidine oxide) are both purchased from Adamas.

[0038] The HPLC detection method used in this invention is as follows: Detection Method 1: Column: InfinityLab Poroshell 120 EC-C18 (4.6×150mm, 4-Micron), Agilent; Mobile phase: gradient of acetonitrile and water, as shown in Table 1.

[0039] Table 1

[0040] Flow rate: 1 ml / min; Detector: UV detector (VWD); Wavelength: 254 nm; Column oven: 30 ℃; Injection volume: 10 μL; Acquisition time: 26 min, Post-run: 4 min; Sample preparation solvent: Acetonitrile (0.5 mg / ml).

[0041] Detection Method 2: Column: InfinityLab Poroshell 120 EC-C18 (4.6×150mm, 4-Micron), Agilent; The mobile phase was a mixture of acetonitrile and water at a volume ratio of 40:60; the flow rate was 0.8 ml / min; the detector was a differential detector (RID); the column oven temperature was 35℃; the optical equipment temperature was 45℃; the injection volume was 10 μL; the acquisition time was 30 min; and the sample preparation solvent was acetonitrile (1 mg / ml).

[0042] Example 1 Chlorohydration reaction—Preparation of (III) chlorohydrins.

[0043] Add 50g of dehydroepiandrosterone acetate, 1000mL of acetone, 150mL of water, and 20mL of acetic acid to a 2L reaction flask. Stir and cool to -36±2℃. Add 60g of calcium hypochlorite (i.e., the molar ratio of dehydroepiandrosterone acetate to calcium hypochlorite is 1:2.77) and 140mL of 50% acetic acid in batches. After the addition is complete, keep the temperature at -36±2℃ and stir for 2h. Monitor the complete conversion of the starting materials by TLC (developing solvent: PE / EA=7:3, phosphomolybdic acid for color development).

[0044] The reaction was quenched by slowly adding 300 mL of 10% sodium sulfite solution at a temperature below -15℃. The mixture was stirred at room temperature for 0.5 h, then concentrated under reduced pressure at 40-50℃ to remove acetone. Crystallization was carried out at 0-5℃ for 1 h, and the mixture was filtered. The filter cake was washed with water until neutral, then slurried with 100 mL of ethyl acetate for 0.5 h, filtered, and dried in a forced-air dryer at 45-50℃ to constant weight, yielding 55.6 g of a white chlorohydrin, with a yield of 96.0% and a purity of 97.87% (detection method 2).

[0045] Example 2 Chlorohydration reaction—Preparation of (III) chlorohydrins.

[0046] The preparation method of this embodiment is basically the same as that of Example 1, except that: 54.2g of calcium hypochlorite (i.e., the molar ratio of dehydroepiandrosterone acetate to calcium hypochlorite is 1:2.5) is added to obtain 56.1g of off-white chlorohydrin, with a yield of 96.8% and a purity of 97.73% (detection method 2).

[0047] Example 3 Chlorohydration reaction—Preparation of (III) chlorohydrins.

[0048] The preparation method of this embodiment is basically the same as that of Example 1, except that: 65.0g of calcium hypochlorite (i.e., the molar ratio of dehydroepiandrosterone acetate to calcium hypochlorite is 1:3) is added to obtain 55.4g of off-white chlorohydrin, with a yield of 95.6% and a purity of 96.53% (detection method 2).

[0049] Example 4 Hydrolysis reaction—Preparation of (IV) hydrolysate.

[0050] Add 500 mL of methanol, 50 g of the chlorohydrin prepared in Example 1, and 40 mL of concentrated hydrochloric acid to a 1 L reaction flask (i.e., the molar ratio of chlorohydrin to hydrochloric acid is 1:3.68). Heat to 55-60 °C and stir for 2 h. TLC (developing solvent: PE / EA=1:1, phosphomolybdic acid color development) monitors that the raw materials are basically completely converted.

[0051] The reaction solution was cooled to below 15°C, neutralized with 350 ml of saturated sodium bicarbonate solution, concentrated under reduced pressure at 40-50°C to remove methanol, 500 mL of water was added, and the mixture was stirred to crystallize for 1 hour. The mixture was filtered, and the filter cake was washed with water until neutral. Then, it was slurried with 100 mL of ethyl acetate for 0.5 hours, filtered, and the filter cake was dried under forced air at 45-50°C to constant weight, yielding 40.6 g of off-white hydrolysate with a yield of 91.2% and a purity of 96.78% (detection method 2).

[0052] 1 H NMR (600 MHz, DMSO) δ 5.33 (s, 1H), 4.57 (s, 1H), 3.96 (tt, J =10.6, 5.4 Hz, 1H), 3.75 (d, J = 3.2 Hz, 1H), 2.42 – 2.33 (m, 1H), 2.27 (dd, J = 13.9, 10.5 Hz, 1H), 2.01 (dt, J = 18.6, 9.0 Hz, 1H), 1.94 – 1.81 (m, 3H), 1.77 (ddd, J = 13.9, 5.2, 1.6 Hz, 1H), 1.74 – 1.67 (m, 1H), 1.67 – 1.58 (m,2H), 1.55 – 1.35 (m, 6H), 1.35 – 1.24 (m, 2H), 1.22 (s, 3H), 1.16 (td, J =12.8, 3.6 Hz, 1H), 0.79 (s, 3H).

[0053] MS(ESI): m / z = 323.2[M-18+1] + .

[0054] Example 5 Hydrolysis reaction—Preparation of (IV) hydrolysate.

[0055] The preparation method in this embodiment is basically the same as that in Example 4, except that the amount of concentrated hydrochloric acid used is 38.1 ml (i.e., the molar ratio of chlorohydrin to hydrochloric acid is 1:3.5), and 40.3 g of off-white hydrolysate is obtained, with a yield of 90.5% and a purity of 96.84% (detection method 2).

[0056] Example 6 Hydrolysis reaction—Preparation of (IV) hydrolysate.

[0057] The preparation method of this embodiment is basically the same as that of Example 4, except that the amount of concentrated hydrochloric acid used is 43.6 ml (i.e., the molar ratio of chlorohydrin to hydrochloric acid is 1:4), and 40.6 g of off-white hydrolysate is obtained, with a yield of 91.2% and a purity of 96.12% (detection method 2).

[0058] Example 7 Oxidation reaction—preparation of (V) oxides.

[0059] Add 140 mL of dichloromethane, 40 g of the hydrolysate prepared in Example 4, and 0.8 g of 2,2,6,6-tetramethylpiperidine oxide (TEMPO) to a 500 mL reaction flask. Stir at room temperature until dissolved, then add 2.5 g of potassium bromide and 5 g of sodium bicarbonate. Cool to 0-5 °C and add 100 g of sodium hypochlorite solution (13% available chlorine) dropwise. At this point, the molar ratio of hydrolysate, TEMPO, and sodium hypochlorite solution is 1:0.0435:3.11. After the addition is complete, maintain the reaction at 0-5 °C and stir for 1 h. Monitor the complete conversion of the starting materials by TLC (developing solvent: PE / EA = 1:1, vanillin for color development).

[0060] The reaction solution was quenched with 40 mL of 10% sodium thiosulfate solution, concentrated under reduced pressure at 40-50 °C to remove dichloromethane, 120 mL of water was added, and the mixture was stirred at 0-10 °C for 1 h to crystallize. The mixture was then filtered, the filter cake was washed with water until neutral, and dried to obtain a wet oxide product with a purity of 97.53% (detection method 2). The wet product was not dried before proceeding directly to the next elimination reaction.

[0061] 1 H NMR (600 MHz, CDCl3) δ 3.05 – 2.94 (m, 2H), 2.72 (dd, J = 16.5, 2.1Hz, 1H), 2.53 – 2.34 (m, 4H), 2.20 – 2.04 (m, 3H), 2.01 – 1.88 (m, 4H), 1.76– 1.71 (m, 1H), 1.63 – 1.52 (m, 2H), 1.46 – 1.37 (m, 2H), 1.14 (s, 3H), 0.88 (s, 3H).

[0062] MS(ESI): m / z = 337.2 [M+1] + .

[0063] Example 8

[0064] Oxidation reaction—preparation of (V) oxides.

[0065] The preparation method of this embodiment is basically the same as that of Example 7, except that: the amount of TEMPO used is 0.55g, and 64.1g of sodium hypochlorite solution (available chlorine 13%) is added dropwise, that is, the molar ratio of hydrolysate, TEMPO and sodium hypochlorite solution is 1:0.03:2, and the wet oxide product is obtained with a purity of 96.32% (detection method 2).

[0066] Example 9 Oxidation reaction—preparation of (V) oxides.

[0067] The preparation method of this embodiment is basically the same as that of Example 7, except that: the amount of TEMPO used is 0.92g, and 128.2g of sodium hypochlorite solution (available chlorine 13%) is added dropwise, that is, the molar ratio of hydrolysate, TEMPO and sodium hypochlorite solution is 1:0.05:4, and the wet oxide product is obtained with a purity of 96.84% (detection method 2).

[0068] Example 10 Elimination reaction - preparation of formula (I) androst-4-ene-3,6,17-trione.

[0069] Add the wet oxide prepared in Example 7, 240 mL of anhydrous ethanol and 40 g of potassium acetate (i.e., the molar ratio of oxide to potassium acetate is 1:3.47) to a 500 mL reaction flask, heat to reflux, stir and react for 1 h, and monitor the complete conversion of the raw materials by TLC (developing solvent: PE / EA=1:1, vanillin color development).

[0070] The reaction solution was concentrated under reduced pressure at 40-50℃ to remove ethanol, 400mL of water was added, and the mixture was stirred to crystallize for 1 hour. The mixture was filtered, washed with water until neutral, and dried under vacuum. The filter cake was heated to reflux in 200mL of methanol for 0.5 hours, cooled to 0-10℃, stirred to crystallize for 1 hour, filtered, and dried under forced air at 45-50℃ to constant weight to obtain 32.0g of white androst-4-ene-3,6,17-trione. The yield of the two-step oxidation and elimination process was 90.8% (calculated based on hydrolysate), and the purity was 98.44% (detection method 1).

[0071] 1 H NMR (600 MHz, CDCl3) δ 6.20 (s, 1H), 2.84 – 2.74 (m, 1H), 2.59 – 2.43 (m, 3H), 2.20 – 2.05 (m, 4H), 2.02 – 1.88 (m, 3H), 1.84 – 1.77 (m, 1H), 1.66 – 1.42 (m, 4H), 1.37 (td, J = 13.1, 4.3 Hz, 1H), 1.19 (s, 3H), 0.93 (s, 3H).

[0072] MS(ESI): m / z = 301.2[M+1] + .

[0073] Example 11 Elimination reaction - preparation of formula (I) androst-4-ene-3,6,17-trione.

[0074] The preparation method of this embodiment is basically the same as that of Example 10, except that the amount of potassium acetate used is 34.6g (i.e., the molar ratio of oxide to potassium acetate is 1:3), and 31.2g of white androst-4-ene-3,6,17-trione is obtained. The yield of the two-step oxidation and elimination process is 88.5% (calculated based on hydrolysate), and the purity is 98.82% (detection method 1).

[0075] Example 12 Elimination reaction - preparation of formula (I) androst-4-ene-3,6,17-trione.

[0076] The preparation method of this embodiment is basically the same as that of Example 10, except that: the amount of potassium acetate used is 46.1g (i.e., the molar ratio of oxide to potassium acetate is 1:4), and 30.4g of white androst-4-ene-3,6,17-trione is obtained. The yield of the two-step oxidation and elimination process is 86.2% (calculated based on hydrolysate), and the purity is 97.59% (detection method 1).

[0077] Comparative Example 1 Chlorohydration reaction—Preparation of (III) chlorohydrins.

[0078] The preparation method of this embodiment is basically the same as that of Example 1, except that: 49.8g of calcium hypochlorite (i.e., the molar ratio of dehydroepiandrosterone acetate to calcium hypochlorite is 1:2.3) was added to obtain 53.6g of off-white chlorohydrin, with a yield of 92.5% and a purity of 97.64% (detection method 2).

[0079] Comparative Example 2

[0080] Chlorohydration reaction—Preparation of (III) chlorohydrins.

[0081] The preparation method of this embodiment is basically the same as that of Example 1, except that: 69.3g of calcium hypochlorite (i.e., the molar ratio of dehydroepiandrosterone acetate to calcium hypochlorite is 1:3.2) was added to obtain 55.7g of off-white chlorohydrin, with a yield of 96.2% and a purity of 97.92% (detection method 2).

[0082] In conjunction with Examples 1-3 and Comparative Examples 1-2, controlling the amounts of dehydroepiandrosterone acetate and calcium hypochlorite within a reasonable range is crucial to ensuring the yield of chlorohydrins when preparing (III) chlorohydrins. Insufficient calcium hypochlorite will result in incomplete reaction of the raw materials, leading to a decrease in yield, but will not significantly affect the purity of the product. Further increasing the amount of calcium hypochlorite will not improve the yield or purity.

[0083] Comparative Example 3 Hydrolysis reaction—Preparation of (IV) hydrolysate.

[0084] The preparation method in this embodiment is basically the same as that in Example 4, except that the amount of concentrated hydrochloric acid used is 35.9 ml (i.e., the molar ratio of chlorohydrin to hydrochloric acid is 1:3.3), and 40.4 g of off-white hydrolysate is obtained, with a yield of 90.7% and a purity of 96.93% (detection method 2).

[0085] Comparative Example 4 Hydrolysis reaction—Preparation of (IV) hydrolysate.

[0086] The preparation method in this embodiment is basically the same as that in Example 4, except that the amount of concentrated hydrochloric acid used is 45.7 ml (i.e., the molar ratio of chlorohydrin to hydrochloric acid is 1:4.2), and 40.5 g of off-white hydrolysate is obtained, with a yield of 91.0% and a purity of 96.84% (detection method 2).

[0087] As can be seen from Examples 4-6 and Comparative Examples 3-4, when the ratio of chlorohydrin to concentrated hydrochloric acid is too high or too low during the hydrolysis reaction, the yield and purity are not significantly affected. However, when the amount of concentrated hydrochloric acid is too low, the reaction time will be significantly extended to more than 3 hours.

[0088] Comparative Example 5 Oxidation reaction—preparation of (V) oxides.

[0089] The preparation method of this embodiment is basically the same as that of Example 7, except that: the amount of TEMPO used is 0.48g, and 57.7g of sodium hypochlorite solution (available chlorine 13%) is added dropwise, that is, the molar ratio of hydrolysate, TEMPO and sodium hypochlorite solution is 1:0.026:1.8, and the wet oxide product is obtained with a purity of 87.52% (detection method 2).

[0090] Comparative Example 6 Oxidation reaction—preparation of (V) oxides.

[0091] The preparation method of this embodiment is basically the same as that of Example 7, except that: the amount of TEMPO used is 1.1g, and 134.6g of sodium hypochlorite solution (available chlorine 13%) is added dropwise, that is, the molar ratio of hydrolysate, TEMPO and sodium hypochlorite solution is 1:0.055:4.2, and the wet oxide product is obtained with a purity of 97.45% (detection method 2).

[0092] In conjunction with Examples 7-9 and Comparative Examples 5-6, the low amounts of TEMPO and sodium hypochlorite may lead to incomplete reaction of the raw materials, resulting in a decrease in product purity. Furthermore, increasing the amounts of TEMPO and sodium hypochlorite will not further improve the product purity.

[0093] Comparative Example 7 Elimination reaction - preparation of formula (I) androst-4-ene-3,6,17-trione.

[0094] The preparation method of this embodiment is basically the same as that of Example 10, except that the amount of potassium acetate used is 30.0g (i.e., the molar ratio of oxide to potassium acetate is 1:2.6), and 32.2g of white androst-4-ene-3,6,17-trione is obtained. The yield of the two-step oxidation and elimination process is 91.3% (calculated based on hydrolysate), and the purity is 97.58% (detection method 1).

[0095] Comparative Example 8 Elimination reaction - preparation of formula (I) androst-4-ene-3,6,17-trione.

[0096] The preparation method of this embodiment is basically the same as that of Example 10, except that the amount of potassium acetate used is 50.7g (i.e., the molar ratio of oxide to potassium acetate is 1:4.4), and 31.4g of white androst-4-ene-3,6,17-trione is obtained. The yield of the two-step oxidation and elimination process is 89.1% (calculated based on hydrolysate), and the purity is 98.04% (detection method 1).

[0097] Based on Examples 10-12 and Comparative Examples 7-8, it can be seen that when the amount of potassium acetate exceeds a certain range, it has no significant effect on the yield and purity of the product. However, when the amount of potassium acetate is too low, the reaction time is significantly extended to 2.5 h.

[0098] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of androsta-4-ene-3,6,17-trione, characterized in that: The hydrolyzate is obtained by hydrolysis reaction of the chlorohydrate; the oxidate is obtained by oxidation reaction of the hydrolyzate; and the androst-4-ene-3,6,17-trione is obtained by elimination reaction of the oxidate; the structure of the hydrolyzate is as shown in formula IV; and the structure of the oxidate is as shown in formula V: ； The structure of the androst-4-ene-3,6,17-trione is as shown in formula I: 。 2. The process for the preparation of androsta-4-ene-3,6,17-trione as claimed in claim 1 wherein: The structure of the hydrolyzate and the oxidate is as shown in formula IV and formula V respectively: 。 3. The process for the preparation of androsta-4-ene-3,6,17-trione as claimed in claim 1 wherein: The chlorohydrate is obtained by chlorohydration reaction of the dehydroepiandrosterone with calcium hypochlorite, with an acetone aqueous solution as a solvent.

4. The process for the preparation of androsta-4-ene-3,6,17-trione according to claim 3, characterized in that: The molar ratio of the dehydroepiandrosterone to calcium hypochlorite is 1: (2.5-3.0).

5. The process for the preparation of androsta-4-ene-3,6,17-trione as claimed in claim 1 wherein: The hydrolyzate is obtained by hydrolysis reaction of the chlorohydrate with hydrochloric acid, with methanol as a solvent.

6. The process for the preparation of androsta-4-ene-3,6,17-trione according to claim 5, characterized by the fact that: The molar ratio of the chlorohydrate to hydrochloric acid is 1: (3.5-4).

7. The process for the preparation of androsta-4-ene-3,6,17-trione as claimed in claim 1 wherein: The oxidate is obtained by oxidation reaction of the hydrolyzate with a sodium hypochlorite solution, with dichloromethane as a solvent and TEMPO as a catalyst.

8. The process for the preparation of androsta-4-ene-3,6,17-trione according to claim 7, characterized by the fact that: The molar ratio of the hydrolyzate, TEMPO and the sodium hypochlorite solution is 1: (0.03-0.05): (2-4).

9. The process for the preparation of androsta-4-ene-3,6,17-trione as claimed in claim 1 wherein: The androst-4-ene-3,6,17-trione is obtained by elimination reaction of the oxidate with potassium acetate, with anhydrous ethanol as a solvent.

10. The process for the preparation of androsta-4-ene-3,6,17-trione as claimed in claim 9 wherein: The molar ratio of the oxidate to potassium acetate is 1: (3-4).

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