A preparation method of epiandrosterone

Abstract

The invention provides a preparation method of epiandrosterone, comprising the following steps: step S1, using 1,4-androstenedione as a raw material, adding acetic anhydride and a benzenesulfonic acid compound under gas protection, stirring, reacting, and obtaining product one; step S2, adding ethylene glycol and a benzenesulfonic acid compound to the product one in step S1, and then adding a molecular sieve, stirring, reacting, and obtaining product two; step S3, adding a borohydride salt to the product two in step S2 under an ice bath, after the reaction is completed, adding an acid solution until the hydrolysis reaction is completed, obtaining product three, transferring to a glove box, adding a nickel catalyst and hydrogen, reacting for 10-14 hours, and obtaining the epiandrosterone; after the acetic anhydride is introduced and subjected to esterification, ketalization, reduction and hydrolysis, the controllability of the reaction is improved, and the addition of a zero-valent nickel catalyst avoids the pollution of a palladium-carbon catalyst; in addition, the lithium molecular sieve not only removes water in the reaction, but also improves the activity of the ketal reaction, the obtained product has fewer isomers, the post-treatment is simple, and the process is relatively green and environmentally friendly.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical synthesis, and in particular to a method for preparing epiandrosterone. Background Art

[0002] Epiandrosterone is a widely used steroid hormone intermediate. On the one hand, it can be used to synthesize high-end male hormone drugs such as rocuronium bromide and vecuronium bromide. On the other hand, it can also be used as an additive for beauty cosmetics. In terms of pharmacology, it has certain anti-cancer and anti-aging functions. It has good application prospects in industry.

[0003] In recent years, most of the synthesis methods of epiandrosterone are to first prepare dehydroepiandrosterone (DHEA), and then prepare it through hydrogen reduction. However, in the prior art, most of the new methods for synthesizing DHEA focus on using androstenedione (4-AD) as the base material, and synthesizing it through esterification reaction, ketal reaction, reduction reaction and hydrolysis reaction. In the reduction reaction step, borohydride salt is often used as a reducing agent, and the α isomer at the 3rd position is easily introduced during the reduction process, and the α isomer and the final product epiandrosterone each account for about 50%, and the α isomer and epiandrosterone have almost the same polarity and content, which brings great inconvenience to the later separation and purification; there are also methods for synthesizing DHEA using biotechnology. The patent with publication number CN105483198A mentions the use of carbonyl reductase to reduce the 3rd carbonyl to β-hydroxyl, and then prepare DHEA. However, on the one hand, such engineered bacteria are expensive, and on the other hand, there are also pollution sources in the fermentation production of engineered bacteria, which affect the synthesis and purity of epiandrosterone. On the other hand, the patent with publication number CN114409718A provides a method for preparing epiandrosterone by catalytic hydrogenation of DHEA, but it requires the preparation of a microchannel reactor. Not only is the preparation process of the reactor mold complicated, but it also requires the assistance of an ultrasonic instrument. In addition, the price of the palladium catalyst is high, it has certain pollution to the environment, and the reuse rate is low. All of these limit the development of the route for preparing epiandrosterone from DHEA.

[0004] Therefore, the current preparation method of epiandrosterone still needs to be further improved. Summary of the invention

[0005] In view of this, the present invention proposes a method for preparing epiandrosterone, which solves the technical problems that when synthesizing epiandrosterone from DHEA in the prior art, there are more α isomers of DHEA, the route is long resulting in low yield, and the reusability of palladium catalyst is low, which leads to serious pollution sources.

[0006] The technical solution of the present invention is achieved as follows: The present invention provides a method for preparing epiandrosterone, comprising the following steps:

[0007] Step S1, using 1,4-androstenedione as a raw material, adding acetic anhydride and a benzenesulfonic acid compound under gas protection, stirring, reacting, and obtaining a product 1;

[0008] Step S2, adding ethylene glycol and benzenesulfonic acid compounds to the product 1 in step S1, and then adding molecular sieves, stirring, reacting, and obtaining product 2;

[0009] Step S3, adding borohydride salt to the product 2 in step S2 under an ice bath, and after the reaction is completed, adding acid solution until the hydrolysis reaction is completed to obtain product 3, transferring to a glove box, adding a nickel catalyst and hydrogen, and reacting for 10-14 hours to obtain the epiandrosterone.

[0010] On the basis of the above technical solution, preferably, the molar ratio of 1,4-androstenedione, acetic anhydride and benzenesulfonic acid compound in step S1 is 1:(8.2-9):(0.32-0.4).

[0011] On the basis of the above technical solution, preferably, the benzenesulfonic acid compound in step S1 includes p-toluenesulfonic acid or benzenesulfonic acid.

[0012] Based on the above technical solution, preferably, the gas in step S1 includes one of argon, helium or nitrogen.

[0013] On the basis of the above technical solution, preferably, the molar ratio of the product 1 described in step S2 to the benzenesulfonic acid compound is 1:0.01-0.012.

[0014] On the basis of the above technical solution, preferably, the molecular sieve in step S2 includes 4A molecular sieve, 5A molecular sieve or lithium molecular sieve.

[0015] Based on the above technical solution, preferably, the diameter of the molecular sieve in step S2 is 1.6-2.5 mm.

[0016] On the basis of the above technical solution, preferably, the molar ratio of the product 2 described in step S3 to the borohydride salt is 1:(5.4-6.2).

[0017] On the basis of the above technical solution, preferably, the nickel catalyst in step S3 is Ni(cod) 2 .

[0018] Based on the above technical solution, preferably, the molar ratio of the nickel catalyst in step S3 to the product three is 0.1-0.12:1.

[0019] On the basis of the above technical solution, preferably, the molar ratio of the product 2 described in step S3 to the acid solution is 1:(0.15-0.3).

[0020] On the basis of the above technical solution, preferably, the acid solution in step S3 includes glacial acetic acid or dilute hydrochloric acid, and the molar concentration is 1.5M-2M.

[0021] On the basis of the above technical solution, preferably, after the hydrolysis reaction in step S3 is completed, the following steps are further included:

[0022] After the reaction is completed, the insoluble matter is filtered off, extracted, dried, and the organic layer is evaporated and spin-dried. The organic layer is separated and purified using a chromatographic silica gel column to obtain the epiandrosterone.

[0023] On the basis of the above technical solution, preferably, the separation and purification is carried out using a chromatographic silica gel column, the eluent is petroleum ether and acetone, and the volume ratio of petroleum ether:acetone is 1:(2-4).

[0024] On the basis of the above technical solution, preferably, the glove box reaction conditions are 60-65° C. and 0.4-0.6 MPa.

[0025] The preparation method of epiandrosterone of the present invention has the following beneficial effects compared with the prior art:

[0026] (1) In the prior art, the preparation method of epiandrosterone uses 1,4-androstenedione as a substrate for synthesis, and needs to undergo carbonyl acetylation, carbonyl protection, reduction and hydrolysis reactions in sequence. The introduction of acetyl chloride in the acetylation process is toxic and dangerous. The present invention provides a better preparation method of epiandrosterone, which does not require the introduction of toxic raw materials such as pyridine and acetyl chloride, nor does it use heavy metal Lindela catalysts. Acetic anhydride is introduced to undergo esterification, ketalization, reduction and hydrolysis to obtain DHEA, which is then hydrogenated and reduced to obtain epiandrosterone. Compared with the existing four-step method, there is one more reduction reaction. Although the controllability of the overall reaction is improved, the conversion rate of epiandrosterone is reduced.

[0027] (2) Therefore, in the process of catalytic hydrogenation of DHEA in step S3, compared with the metal palladium carbon catalysis in the prior art, the present invention also uses a zero-valent nickel catalyst to replace the palladium catalyst. The zero-valent nickel attacks the 5,6 carbon-carbon double bond of DHEA, generates an H at the adjacent position of the nickel through the intramolecular carbon-carbon bond, and then eliminates it to obtain a divalent nickel intermediate. The divalent nickel is then reduced to form zero-valent nickel, and the recycling rate is high, which makes up for the problem of low conversion rate. In addition, the zero-valent nickel catalyst is low in cost, has an ideal catalytic effect, is simple in post-treatment, and is relatively green and environmentally friendly. It has a good prospect in the application field of epiandrosterone.

[0028] (3) In addition, compared with the existing method of adding dimethyl formate or dimethyl orthoformate after the first step of the synthesis, the present invention further adds a lithium molecular sieve, which can not only remove water in the reaction, but also effectively improve the activity of the ketal reaction. The final reactant has fewer isomers after purification, and the product yield is basically consistent with the existing reported yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0030] Figure 1 The present invention is a flow chart of the preparation method of epiandrosterone;

[0031] Figure 2 This is a liquid chromatogram of epiandrosterone prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0032] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0033] Example 1

[0034] This embodiment provides a method for preparing epiandrosterone, such as Figure 1 As shown, the following steps are included:

[0035] Step S1, using 10 g of 1,4-androstenedione as a raw material, adding acetic anhydride and p-toluenesulfonic acid under gas protection, stirring, and reacting at 20° C. for 4 hours to obtain product 1; wherein the molar ratio of 1,4-androstenedione, acetic anhydride and p-toluenesulfonic acid is 1:8.2:0.32, and the gas is argon.

[0036] Step S2: Add 50 ml of ethylene glycol and p-toluenesulfonic acid to the product 1 in step S1, and then add a molecular sieve twice the mass of the product 1, stir, and react at 20°C for 5 hours to obtain product 2; wherein the molar ratio of the product 1 to p-toluenesulfonic acid is 1:0.01, the molecular sieve is 4A molecular sieve, and the molecular sieve diameter is 1.6 mm.

[0037] Step S3, adding borohydride salt to the product 2 in step S2 under ice bath, stirring for 5 hours to complete the reaction, then adding acid solution to continue the reaction until the hydrolysis reaction is completed to obtain product 3, transferring all of product 3 to a glove box, adding a nickel catalyst at 60° C. and 0.4 MPa, pumping in hydrogen, and reacting for 10 hours to obtain the epiandrosterone, wherein the molar ratio of the product 2 to the borohydride salt is 1:5.4, the molar ratio of the product 2 to the acid solution is 1:0.15, and the acid solution is glacial acetic acid with a molar concentration of 1.5M; the nickel catalyst in step S3 is Ni(cod) 2 The molar ratio of the nickel catalyst to the product three is 0.1:1.

[0038] A white powder solid was obtained with a yield of 79.1% and an α-isomer content of 5.2%.

[0039] The H NMR spectrum of epiandrosterone is: 1 H NMR (400 MHz, CDCl 3 )δ5.29(3H,s),1.79(3H,s),1.44(3H,s),0.12-3.40(23H,m), and its HPLC chromatogram is as follows Figure 2 shown.

[0040] Example 2

[0041] This embodiment provides a method for preparing epiandrosterone, comprising the following steps:

[0042] Step S1, using 10 g of 1,4-androstenedione as a raw material, adding acetic anhydride and p-toluenesulfonic acid under gas protection, stirring, and reacting at 20° C. for 4 hours to obtain product 1; wherein the molar ratio of 1,4-androstenedione, acetic anhydride and p-toluenesulfonic acid is 1:9:0.4, and the gas includes argon.

[0043] In step S2, add 60 ml of ethylene glycol and p-toluenesulfonic acid to the product 1 in step S1, then add a molecular sieve twice the mass of the product 1, stir, and react at 20° C. for 5 hours to obtain product 2; the molar ratio of the product 1 and p-toluenesulfonic acid in step S2 is 1:0.012, the molecular sieve includes a 4A molecular sieve, and the molecular sieve has a diameter of 1.6 mm.

[0044] Step S3, adding borohydride salt to the product 2 in step S2 under ice bath, stirring for 5 hours to complete the reaction, then adding acid solution to continue the reaction until the hydrolysis reaction is completed to obtain product 3, transferring all of product 3 to a glove box at 65° C., 0.6 MPa, adding nickel catalyst, pumping in hydrogen, and reacting for 14 hours to obtain the epiandrosterone, the molar ratio of the product 2 in step S3 to the borohydride salt is 1:6.2, the molar ratio of the product 2 to the acid solution is 1:0.2, the acid solution includes glacial acetic acid, and the molar concentration is 1.8M, and the nickel catalyst in step S3 is Ni(cod) 2 The molar ratio of the nickel catalyst to the product three is 0.12:1, and epiandrosterone is obtained as a white powder solid with a yield of 78.4% and an α-isomer content of 6.5%.

[0045] Example 3

[0046] This embodiment provides a method for preparing epiandrosterone, comprising the following steps:

[0047] Step S1, using 10 g of 1,4-androstenedione as a raw material, adding acetic anhydride and p-toluenesulfonic acid under gas protection, stirring, and reacting at 20° C. for 4 hours to obtain product 1; wherein the molar ratio of 1,4-androstenedione, acetic anhydride and p-toluenesulfonic acid is 1:8.5:0.35, and the gas includes argon.

[0048] In step S2, add 55 ml of ethylene glycol and p-toluenesulfonic acid to the product 1 in step S1, then add a molecular sieve twice the mass of the product 1, stir, and react at 20°C for 5 hours to obtain product 2; the molar ratio of the product 1 and p-toluenesulfonic acid in step S2 is 1:0.012, the molecular sieve includes a 4A molecular sieve, and the molecular sieve has a diameter of 1.6 mm.

[0049] Step S3, adding borohydride salt to the product 2 in step S2 under ice bath, stirring for 5 hours to complete the reaction, then adding acid solution to continue the reaction until the hydrolysis reaction is completed to obtain product 3, transferring all of product 3 to a glove box, adding a nickel catalyst at 62° C. and 0.5 MPa, pumping in hydrogen, and reacting for 12 hours to obtain the epiandrosterone, wherein the molar ratio of the product 2 to the acid solution is 1:0.3, the acid solution includes glacial acetic acid, and the molar concentration is 2M, and the nickel catalyst in step S3 is Ni(cod) 2 The molar ratio of the nickel catalyst to the product three is 0.11:1, and epiandrosterone is obtained as a white powder solid with a yield of 78.8% and an α-isomer content of 6.2%.

[0050] Example 4

[0051] This embodiment provides a method for preparing epiandrosterone, comprising the following steps:

[0052] Step S1, using 10 g of 1,4-androstenedione as a raw material, adding acetic anhydride and p-toluenesulfonic acid under gas protection, stirring, and reacting at 20° C. for 4 hours to obtain product 1; wherein the molar ratio of 1,4-androstenedione, acetic anhydride and p-toluenesulfonic acid is 1:9:0.4, and the gas includes nitrogen.

[0053] In step S2, add 50 ml of ethylene glycol and p-toluenesulfonic acid to the product 1 in step S1, then add a molecular sieve twice the mass of the product 1, stir, and react at 20°C for 5 hours to obtain product 2; the molar ratio of the product 1 and p-toluenesulfonic acid in step S2 is 1:0.012, and the molecular sieve includes a 4A molecular sieve, and the molecular sieve includes a diameter of 1.6 mm.

[0054] Step S3, add borohydride salt to the product 2 in step S2 under ice bath, stir for 5 hours, and then add acid solution, the molar ratio of the product 2 to the acid solution is 1:0.2, the acid solution includes dilute hydrochloric acid, and the molar concentration is 1.5M, until the hydrolysis reaction is completed, filter out the insoluble matter, extract, dry, evaporate and spin dry the organic layer, use a chromatographic silica gel column for separation and purification, the chromatographic silica gel column is used for separation and purification, the eluent is petroleum ether and acetone, and the volume ratio of petroleum ether: acetone is 1:2, and the product 3 is transferred to a glove box, a nickel catalyst is added at 60°C and 0.4MPa, hydrogen is pumped in, and the reaction is carried out for 10 hours. The nickel catalyst in step S3 is Ni(cod) 2 The molar ratio of the nickel catalyst to the product three is 0.1:1, and the epiandrosterone is obtained as a white powder solid with a yield of 78.0% and an α-isomer content of 5.9%.

[0055] Example 5

[0056] This embodiment provides a method for preparing epiandrosterone, comprising the following steps:

[0057] Step S1, taking 10 g of 1,4-androstenedione as a raw material, adding acetic anhydride and p-toluenesulfonic acid under gas protection, stirring, and reacting at 20° C. for 4 hours to obtain product 1; wherein the molar ratio of 1,4-androstenedione, acetic anhydride and p-toluenesulfonic acid is 1:8.2:0.32, and the gas includes nitrogen.

[0058] In step S2, add 50 ml of ethylene glycol and p-toluenesulfonic acid to the product 1 in step S1, then add a molecular sieve twice the mass of the product 1, stir, and react at 20°C for 5 hours to obtain product 2; the molar ratio of the product 1 and p-toluenesulfonic acid in step S2 is 1:0.01, the molecular sieve in step S2 includes a 4A molecular sieve, and the molecular sieve in step S2 includes a 1.6 mm diameter molecular sieve.

[0059] Step S3, add borohydride salt to the product 2 in step S2 under ice bath, stir for 5 hours, and then add acid solution, the molar ratio of the product 2 to the acid solution is 1:0.2, the acid solution includes dilute hydrochloric acid, and the molar concentration is 1.5M, until the hydrolysis reaction is completed, filter out the insoluble matter, extract, dry, evaporate and spin dry the organic layer, use a chromatographic silica gel column for separation and purification, the chromatographic silica gel column is used for separation and purification, the eluent is petroleum ether and acetone, and the volume ratio of petroleum ether: acetone is 1:4, and product 3 is obtained, all of product 3 is transferred to a glove box, a nickel catalyst is added at 65°C and 0.6MPa, hydrogen is pumped in, and the reaction is carried out for 14 hours. The nickel catalyst in step S3 is Ni(cod) 2 The molar ratio of the nickel catalyst to the product three is 0.12:1, and the epiandrosterone is obtained as a white powder solid with a yield of 77.5% and an α-isomer content of 6.1%.

[0060] Example 6

[0061] This embodiment provides a method for preparing epiandrosterone, which is different from that of Embodiment 1 in that the molecular sieve in step S2 includes a 5A molecular sieve, and the molecular sieve in step S2 has a diameter of 1.6 mm. Epiandrosterone is obtained as a white powder solid with a yield of 77.6% and an α isomer content of 5.8%.

[0062] Example 7

[0063] This embodiment provides a method for preparing epiandrosterone, which is different from Embodiment 1 in that the molecular sieve in step S2 includes a lithium molecular sieve, and the diameter of the molecular sieve in step S2 is 1.6 mm. Epiandrosterone is obtained as a white powder solid with a yield of 79.2% and an α isomer content of 5.4%.

[0064] Example 8

[0065] This embodiment provides a method for preparing epiandrosterone, which is different from Embodiment 1 in that the molecular sieve in step S2 includes a lithium molecular sieve, and the diameter of the molecular sieve in step S2 is 2.5 mm. Epiandrosterone is obtained as a white powder solid with a yield of 79.5% and an α isomer content of 5.6%.

[0066] Example 9

[0067] This embodiment provides a method for preparing epiandrosterone, which is different from that of embodiment 1 in that the benzenesulfonic acid compound is benzenesulfonic acid, and epiandrosterone is obtained as a white powder solid with a yield of 77.5% and an α-isomer content of 6.4%.

[0068] Comparative Example 1

[0069] A method for preparing epiandrosterone, with reference to the preparation method with publication number CN102603839A, obtains epiandrosterone as a white powder solid with a yield of 78.8% and an alpha isomer content of 7.4%.

[0070] Comparative Example 2

[0071] A method for preparing epiandrosterone, which differs from Example 1 in that, in step S2, molecular sieves are not added, but dimethyl formate is added to obtain epiandrosterone as a white powder solid with a yield of 79.0% and an α-isomer content of 6.7%.

[0072] Comparative Example 3

[0073] A method for preparing epiandrosterone, which differs from Example 1 in that, in step S3, a nickel catalyst is not added, but a palladium catalyst of the same amount is added to obtain epiandrosterone as a white powder solid with a yield of 79.2% and an α-isomer content of 6.0%.

[0074] Comparative Example 4

[0075] A method for preparing epiandrosterone, which differs from Example 1 in that a nickel catalyst is added in step S3, but the nickel catalyst is divalent nickel NiCl 2 DME, epiandrosterone white powder solid, yield 77.3%, α isomer content 5.8%.

[0076] Comparative Example 5

[0077] A method for preparing epiandrosterone, which differs from Example 1 in that a catalyst with publication number CN106582757A is used to carry out the reaction in step S3 to obtain epiandrosterone as a white powder solid with a yield of 76.5% and an α-isomer content of 6.6%.

[0078] Comparative Example 6

[0079] A method for preparing epiandrosterone, which differs from Example 1 in that the molecular sieve added in step S2 has a diameter of 4 mm, and epiandrosterone is obtained as a white powder solid with a yield of 76.9% and an α-isomer content of 6.1%.

[0080] The results of Example 1 and Comparative Example 1 show that, compared with the existing "four-step method" for synthesizing epiandrosterone, although this embodiment has one more step of reaction, the addition of the zero-valent nickel catalyst compensates for the problem of decreased conversion rate caused by the one more catalytic hydrogenation step, and the yield is slightly better than the existing scheme, the number of isomers is small, and the effect is good.

[0081] The results of Examples 1, 7-9 and Comparative Example 2 show that, compared with the existing epiandrosterone synthesis method, the introduction of molecular sieves, especially lithium molecular sieves, finally leads to a higher conversion rate of DHEA, indicating that on the one hand, the activity of the ketal reaction is effectively improved, water in the reaction is removed, and the final reactant has fewer isomers after purification.

[0082] The results of Example 1 and Comparative Example 3 show that, compared with the existing palladium-carbon catalyst, the nickel catalyst can effectively catalyze the hydrogenation reaction, and effectively avoid the problem of decreased conversion rate caused by an additional catalytic hydrogenation step, and has a good conversion rate. The results of Example 1 and Comparative Example 4 show that the catalytic effect of the existing conventional divalent nickel catalyst is not as good as the zero-valent nickel of the present invention, which may be because the catalytic reaction of divalent nickel may require the presence of a ligand or a manganese reducing agent.

[0083] The results of Example 1 and Comparative Example 5 show that the existing hydrogenation catalyst uses a palladium / calcium carbonate catalyst, which has palladium residual pollution on the one hand, and its preparation method is cumbersome and the reduction effect is not good on the other hand. The results of Example 1 and Comparative Example 6 show that the size of the molecular sieve has a certain influence on removing water in the reaction and improving the activity of the ketal reaction.

[0084] In summary, the present invention provides a method for preparing epiandrosterone, wherein acetic anhydride is introduced to undergo esterification, ketalization, reduction and hydrolysis, thereby improving the controllability of the synthesis to DHEA, and in the process of hydrogenation reduction of DHEA to epiandrosterone, zero-valent nickel is used to replace the existing palladium-carbon catalysis method, thereby greatly reducing the cost, while maintaining good catalytic efficiency; in addition, the addition of a lithium molecular sieve can not only remove water in the reaction, but also effectively improve the activity of the ketalization reaction, and the final reactant has fewer isomers after purification, the post-treatment is simple, and the process is relatively green and environmentally friendly.

[0085] 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 in the protection scope of the present invention.

Claims

1. A method for preparing epiandrosterone, characterized in that: The steps include: Step S1, using 1,4-androstenedione as a raw material, adding acetic anhydride and a benzenesulfonic acid compound under gas protection, stirring, reacting, and obtaining a product 1; Step S2, adding ethylene glycol and benzenesulfonic acid compounds to the product 1 in step S1, and then adding molecular sieves, stirring, reacting, and obtaining product 2; Step S3, adding borohydride salt to the product 2 in step S2 under an ice bath, and after the reaction is completed, adding acid solution until the hydrolysis reaction is completed to obtain product 3, transferring to a glove box, adding a nickel catalyst and hydrogen, and reacting for 10-14 hours to obtain the epiandrosterone; The nickel catalyst in step S3 is Ni(cod)2; In step S1, the molar ratio of 1,4-androstenedione, acetic anhydride and benzenesulfonic acid compound is 1:8.2-9:0.32-0.4; The benzenesulfonic acid compound in step S1 includes p-toluenesulfonic acid or benzenesulfonic acid; The molecular sieve in step S2 includes 4A molecular sieve, 5A molecular sieve or lithium molecular sieve; The molecular sieve in step S2 has a diameter of 1.6-2.5 mm.

2. The method for preparing epiandrosterone according to claim 1, characterized in that: The molar ratio of the product 1 described in step S2 to the benzenesulfonic acid compound is 1:0.01-0.

012.

3. The method for preparing epiandrosterone according to claim 1, characterized in that: The molar ratio of the product 2 in step S3 to the borohydride salt is 1:5.4-6.

2.

4. The method for preparing epiandrosterone according to claim 1, characterized in that: The molar ratio of the nickel catalyst to the product three in step S3 is 0.1-0.12:

1.

5. The method for preparing epiandrosterone according to claim 1, characterized in that: After the hydrolysis reaction in step S3 is completed, the following steps are also included: After the reaction is completed, the insoluble matter is filtered off, extracted, dried, and the organic layer is evaporated and spin-dried. The organic layer is separated and purified using a chromatographic silica gel column to obtain the epiandrosterone.

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