Preparation method and application of high-purity steroid compound

Abstract

The invention provides a preparation method and application of a high-purity steroid compound, 4, 9-diene is taken as a raw material, 5 (10), 9 (11)-diene is obtained through pyrrolidine protection and deprotection reaction, industrial pyrrolidine is pretreated and then used for reaction, peroxidation by-products in the reaction process can be obviously reduced, and the high-purity 5 (10), 9 (11)-diene compound is obtained. Compared with the prior art, the preparation method has the advantages that the purity of the 1, 9 (11)-diene is 99% or above, the content of peroxide impurities is 0.2-0.3%, the molar yield of protection and deprotection two steps reaches 85% or above, the yield is remarkably improved compared with that of pyrrolidine which is not pretreated, impurities in the product are also remarkably reduced, and the overall yield and the product quality of the gestotrienone are improved.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediates, and in particular to a preparation method and application of a high-purity steroid compound. Background Art

[0002] Steroidal intermediate 5(10),9(11)-diene (△ 5(10),9(11) -diene) is an important intermediate for the preparation of 4,9,11-triene steroids and is an important intermediate for pregnenone.

[0003]

[0004] Gestrinone is a moderate-strength progestin with strong anti-progestin and anti-estrogen activity, as well as weak estrogenic and androgenic activity. It was first developed by the French company Russell. It is primarily used clinically for endometriosis, contraception during visits with relatives, and post-coital contraception. It offers advantages such as a low dosage and minimal liver side effects.

[0005] Patent CN101704871B reports the 4,9 -diene as raw material, through pyrrolidine protection and deprotection reaction, to obtain △ 5(10),9(11) -diene, with a reported two-step yield of up to 90%, but no purity data were disclosed.

[0006] However, when the inventors used industrial-grade pyrrolidine for comparative experiments according to the patented method, they found that a large unknown impurity was generated during the protection and deprotection reaction. Its relative retention time RRT on HPLC was 0.26, and the content of this impurity in the reaction solution was relatively high. Due to the large amount of impurities, the subsequent refining and purification process was seriously affected, and even the refining and crystallization were difficult. The final target product △ 5(10),9(11) The yield of the diene is only about 40%, the purity is 94.78%, the RRT is 0.26 and the impurities are as high as 2.45%, which is far from meeting the requirements of direct industrial application.

[0007] △ 5(10),9(11) -diene is an important intermediate of gestrinone, which can be obtained by dehydrogenation in one step. Therefore, its quality is directly related to the quality of gestrinone raw materials, and its yield and cost also directly affect the yield and cost of the overall gestrinone route. Therefore, it is necessary to provide a high-purity, high-yield △ 5(10),9(11) -The preparation process of dienes is of great significance. Summary of the Invention

[0008] Therefore, the application provides a preparation method and application of high-purity steroidal compounds. 5(10),9(11) - purity and yield of diene.

[0009] The technical scheme of the application is as follows:

[0010] In one aspect, the application provides a preparation method of high-purity steroidal compounds. 4,9 - diene as raw material, and the protected and deprotected reaction of the pretreated pyrrolidine is carried out to obtain the steroidal compound of formula I 5(10),9(11) - diene, and the reaction route is as follows:

[0011]

[0012] When the industrial-grade pyrrolidine without pretreatment is used for reaction, it is found that a large amount of unknown impurity with RRT=0.26 is generated, and the content of the impurity in the reaction solution is more than 11%. 5(10),9(11) - diene is analyzed by LC-MS, the molecular weight of the impurity with RRT=0.26 is confirmed to be 342.2, and the molecular structure of the impurity with RRT=0.26 is inferred according to the structural characteristics of the reactant and the reaction condition as follows:

[0013] Obviously, the impurity is generated due to the oxidation of the steroidal compound of formula I 5(10),9(11) - diene under the oxidation condition:

[0014]

[0015] In the preparation process, the main ways to cause the oxidation of the steroidal compound of formula I 5(10),9(11) - diene are as follows:

[0016] ① N-oxide oxidation: the industrial-grade pyrrolidine is easily oxidized during production or storage to generate N-oxide, which has oxidizing property;

[0017] ② air oxidation: a small amount of oxygen may be dissolved in the solvent used for reaction; nitrogen protection is insufficient during the reaction; the material inevitably contacts with air during the material transfer in the post-treatment process, etc., which all cause the oxidation of the steroidal compound of formula I 5(10),9(11) - diene by oxygen to generate peroxide by-products.

[0018] On the basis of the above scheme, preferably, the pretreatment method of the pyrrolidine is as follows: under nitrogen protection, an antioxidant is added to the industrial-grade pyrrolidine, and after stirring at 10-30°C for 1-2h, the protection and deprotection reactions are directly carried out.

[0019] On the basis of the above scheme, preferably, the antioxidant is one or more of butylated hydroxyanisole, dibutylated hydroxytoluene, propyl gallate, and tocopherol; further preferably, the antioxidant is tocopherol.

[0020] On the basis of the above scheme, preferably, the antioxidant is added in an amount of 1-5% of the mass of the pyrrolidine.

[0021] On the basis of the above scheme, preferably, the antioxidant is added in an amount of 1-3% of the mass of the pyrrolidine, and further preferably, the antioxidant is added in an amount of 3% of the mass of the pyrrolidine.

[0022] First, the pyrrolidine is pretreated with 3wt% tocopherol under nitrogen protection, and the tocopherol is not separated and removed, but directly used in the reaction, wherein the tocopherol continues to play an antioxidant role in the reaction process, avoiding the generation of peroxide impurities; methanol is used as the solvent, and the compound of formula II 4,9 The diene and the pyrrolidine undergo the following reaction, and the product is directly crystallized from methanol to obtain the pyrrolidine protector of formula III:

[0023]

[0024] The pyrrolidine protector of formula III is then subjected to a hydrolysis reaction in an aqueous acetic acid solution, extracted, concentrated, and crystallized with ethyl acetate to obtain the compound of formula I 5(10),9(11) diene.

[0025]

[0026] In the second aspect, a high-purity steroidal compound is provided, which is preferably prepared by the above-mentioned method for preparing a high-purity steroidal compound.

[0027] On the basis of the above scheme, preferably, the purity of the high-purity steroidal compound is greater than 99%, the yield is greater than 85%, and the peroxide impurity is reduced to 0.2-0.3%.

[0028] In the third aspect, the use of a high-purity steroidal compound in the preparation of a 4,9,11-triene steroidal compound is provided, and preferably, the use of a high-purity steroidal compound in the preparation of pregnatrienone is provided, wherein the high-purity steroidal compound is prepared by the above-mentioned method for preparing a high-purity steroidal compound 5(10),9(11)-dienes, the gestrinone prepared by DDQ dehydrogenation, has a molar yield of 96.4%, a purity of 99.82%, and a maximum single impurity of 0.12%; after another purification and refining, the gestrinone with all single impurities less than 0.05% can be obtained.

[0029] The preparation method of the high-purity steroid compound and its application of the present invention have the following beneficial effects compared with the prior art:

[0030] (1) The present invention first discovered that the presence of peroxide impurities when using ordinary industrial-grade pyrrolidine for the reaction will lead to a decrease in product purity and yield. Then, ordinary industrial-grade pyrrolidine is pretreated to address the peroxide problem, and then the reaction is carried out, and the reaction results can reach or even exceed those of reagent-grade pyrrolidine, thereby reducing production costs, reducing reaction impurities, and increasing product purity.

[0031] (2) The present invention uses an antioxidant to pretreat pyrrolidine and directly uses it in the reaction, thereby avoiding the generation of peroxidation by-products during the reaction. The process is simple and no additional process steps are added;

[0032] (3) Food-grade tocopherol is selected as the antioxidant, which has low safety risk and small dosage. After crystallization and separation, it can be completely removed with the mother liquor, and there is no residual risk.

[0033] (4) Using the high-purity Δ 5(10),9(11) - Dienes are used in the preparation of gestrinone, and the purity of crude gestrinone can reach over 99%. After a simple one-time refining, the single impurity can be less than 0.05%, which greatly improves the overall yield of gestrinone and product quality. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. 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 any creative work.

[0035] Figure 1 This is the LC-MS detection chromatogram of the RRT=0.26 impurity of the present invention;

[0036] Figure 2 This is the LC-MS mass spectrum of the RRT=0.26 impurity of the present invention;

[0037] Figure 3 △ prepared in Example 2 of the present invention 5(10),9(11) - Liquid phase chromatogram of diene;

[0038] Figure 4HPLC chromatogram of the crude allopregnanone prepared in Example 5 of the present application 5(10),9(11) HPLC chromatogram of the crude allopregnanone prepared in Example 5 of the present application

[0039] Figure 5 HPLC chromatogram of the crude allopregnanone prepared in Example 5 of the present application 5(10),9(11) HPLC chromatogram of the crude allopregnanone prepared in Example 5 of the present application

[0040] Figure 6 HPLC chromatogram of the crude allopregnanone prepared in Example 5 of the present application 5(10),9(11) HPLC chromatogram of the crude allopregnanone prepared in Example 5 of the present application

[0041] Figure 7 HPLC chromatogram of the crude allopregnanone prepared in Example 5 of the present application

[0042] Figure 8 HPLC chromatogram of the crude allopregnanone prepared in Example 5 of the present application DETAILED DESCRIPTION

[0043] The technical solutions in the embodiments of the present application will be clearly and completely described in combination with the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments of the present application, all other embodiments obtained by a person of ordinary skill in the art without creative labor fall within the protection scope of the present application.

[0044] The HPLC detection method conditions in the present application are as follows:

[0045] HPLC method 1:

[0046] Chromatographic column: InfinityLab Poroshell 120 EC-C18 (4.6x150mm, 4Micron), Agilent.

[0047] Mobile phase: water and acetonitrile isocratic, as shown in Table 1:

[0048] Table 1 HPLC method 1 mobile phase

[0049] Time Water (%) Acetonitrile (%) Flow (mL / min) 0 55 45 1.0 20 55 45 1.0

[0050] Detector: ultraviolet detector (VWD); signal polarity: positive; wavelength: 236nm

[0051] Column oven temperature: 35℃

[0052] Injection volume: 2μL

[0053] Flow rate: 1.0mL / min

[0054] Collection time: 20min

[0055] Preparation of Test Solution: An appropriate quantity of sample was accurately weighed, dissolved in acetonitrile and diluted to make a solution containing about 1 mg per 1 mL as the test solution.

[0056] HPLC Method 2:

[0057] Chromatographic column: InfinityLab Poroshell 120 EC-C18 (4.6 x 150 mm, 4 Micron), Agilent.

[0058] Mobile phase: water and methanol isocratic, as shown in Table 2;

[0059] Table 2 HPLC Method 2 mobile phase

[0060] Time Water (%) Acetonitrile (%) Flow (mL / min) 0 35 65 1.0 20 35 65 1.0

[0061] Detector: UV detector (VWD); signal polarity: positive; wavelength: 323 nm

[0062] Column oven temperature: 35℃

[0063] Injection volume: 2 μL

[0064] Flow rate: 1.0 mL / min

[0065] Collection time: 20 min

[0066] Preparation of Test Solution: An appropriate quantity of sample was accurately weighed, dissolved in acetonitrile and diluted to make a solution containing about 1 mg per 1 mL as the test solution.

[0067] In the present application, the manufacturer of industrial-grade pyrrolidine is Jianjie Biotechnology Co., Ltd., the manufacturer of reagent-grade pyrrole is Adamas, and the manufacturer of DL-α-tocopherol is Weishi reagent. 4,9 - Diene is a self-made intermediate.

[0068] Example 1

[0069] In the present application, the LC-MS detection of RRT = 0.26 impurity.

[0070] When using unpretreated industrial-grade pyrrolidine for reaction, it was found that a large amount of unknown impurity with RRT = 0.26 was produced, and the content of the impurity in the reaction solution was more than 11%. For this reason, the mother liquor of formula I diene was analyzed by LC-MS, and the LC-MS spectrum thereof is shown in 5(10),9(11) - Diene is a self-made intermediate. Figure 1 and Figure 2 , Figure 1 The box in the middle corresponds to the impurity peak.

[0071] Example 2

[0072] Preparation of Formula I 5(10),9(11) - diene.

[0073] Pyrrolidine pretreatment: under nitrogen protection, 1 L reaction bottle was added industrial grade pyrrolidine 500 mL (433 g, 6.08 mol) and DL-α-tocopherol 13 g (30.18 mmol), stirred at room temperature for 1.5 h, and used as is.

[0074] Protection reaction: under nitrogen protection, 5 L reaction bottle was added methanol 2.5 L and Formula II 4,9 - diene 500 g (1.61 mol); temperature was raised to 60°C, and the above pyrrolidine was slowly added. After completion of the addition, the reaction was continued at 60°C for 1 h. TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin). The reaction solution was cooled to 0-10°C and stirred for 0.5 h. Filtration, drying, and Formula III pyrrolidine protector were obtained.

[0075] Deprotection reaction: under nitrogen protection, 5 L reaction bottle was added 1.6 L of 25 vol% acetic acid aqueous solution, and the above Formula III pyrrolidine protector was added with stirring. Hydrolysis was carried out at room temperature for 15 min. TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin).

[0076] Ethyl acetate 1.6 L was added to the reaction solution for extraction. After standing, the water phase was extracted with ethyl acetate twice, 1 L each time. The organic phase was combined and washed with saturated sodium bicarbonate solution twice, and then washed with water until the pH was 6-8.

[0077] After the organic phase was dried with anhydrous sodium sulfate, it was concentrated under reduced pressure at 45°C to a residual volume of about 500-700 mL. Crystallization was carried out at 0-10°C for 30 min. Filtration, drying, and Formula I 5(10),9(11) - diene 441.5 g, yield 88.3%, purity 99.55% (as shown in Table 3), peroxide content 0.21%, detected by HPLC method 1, and the spectrum is shown in Figure 3 .

[0078] Example 3

[0079] Preparation of Formula I 5(10),9(11) - diene.

[0080] Pyrrolidine pretreatment: under nitrogen protection, 1 L reaction bottle was added industrial grade pyrrolidine 500 mL (433 g, 6.08 mol) and DL-α-tocopherol 4.33 g (10.06 mmol), stirred at room temperature for 1.5 h, and used as is.

[0081] Protection reaction: under nitrogen protection, 5 L reaction flask was added methanol 2.5 L and formula II △ 4,9 - diene 500 g (1.61 mol); heated to 60 °C, slowly added above pyrrolidine, after finished, continued to react at 60 °C for 1 h, TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin); the reaction solution was cooled to 0-10 °C and stirred for 0.5 h, filtered, dried, to obtain formula III pyrrolidine protected product.

[0082] Deprotection reaction: under nitrogen protection, 5 L reaction flask was added 1.6 L of 25 vol% acetic acid aqueous solution, and the above formula III pyrrolidine protected product was added under stirring. Hydrolysis for 15 min at room temperature, TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin).

[0083] Ethyl acetate 1.6 L was added to the reaction solution for extraction, and the water phase was extracted with ethyl acetate twice, 1 L each time; the organic phase was combined, washed with saturated sodium bicarbonate solution twice, and then washed with water until pH 6-8.

[0084] The organic phase was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure at 45 °C to a remaining volume of about 500-700 mL. Stirring at 0-10 °C for 30 min, filtering, drying, and drying the filter cake under reduced pressure at 30-40 °C to constant weight to obtain formula I △ 5(10),9(11) - diene 427 g, yield 85.4%, purity 99.21% (as shown in Table 3), peroxide content 0.25%.

[0085] Example 4

[0086] The reaction was carried out using pretreated industrial grade pyrrolidine to prepare formula I △ 5(10),9(11) - diene.

[0087] Pyrrolidine pretreatment: under nitrogen protection, 1 L reaction flask was added industrial grade pyrrolidine 500 mL (433 g, 6.08 mol) and DL-α-tocopherol 21.65 g (50.3 mmol), stirred at room temperature for 1.5 h, and used as is.

[0088] Protection reaction: under nitrogen protection, 5 L reaction flask was added methanol 2.5 L and formula II △ 4,9 - diene 500 g (1.61 mol); heated to 60 °C, slowly added above pyrrolidine, after finished, continued to react at 60 °C for 1 h, TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin); the reaction solution was cooled to 0-10 °C and stirred for 0.5 h, filtered, dried, to obtain formula III pyrrolidine protected product.

[0089] Deprotection reaction: under nitrogen protection, 5 L reaction bottle was added 1.6 L of 25 vol% acetic acid aqueous solution, and the above-mentioned pyrrolidine protected product of formula III was added under stirring, and hydrolysis was carried out at room temperature for 15 min. TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin).

[0090] Ethyl acetate 1.6 L was added to the reaction solution for extraction, and the water phase was extracted with ethyl acetate twice, each time 1 L; the organic phase was combined, washed with saturated sodium bicarbonate solution twice, and then washed with water until pH 6-8.

[0091] The organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure at 45°C to a remaining volume of about 500-700 mL. Crystallization was carried out at 0-10°C for 30 min under stirring; filtration was carried out, and the filter cake was dried under reduced pressure at 30-40°C to a constant weight to obtain formula I 5(10),9(11) - diene 439.7 g, yield 87.9%, purity 99.62% (as shown in Table 3), peroxide content 0.20%.

[0092] Example 5

[0093] Reagent-grade pyrrolidine was used for the reaction to prepare formula I 5(10),9(11) - diene.

[0094] Protection reaction: under nitrogen protection, 500 mL reaction bottle was added methanol 250 mL and formula II 4,9 - diene 50 g (161.06 mmol); temperature was raised to 60°C, and reagent-grade pyrrolidine 50 mL was slowly added. After completion of addition, the reaction was continued at 60°C for 1 h. TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin); the reaction solution was cooled to 0-10°C for 0.5 h under stirring, and filtration was carried out. The filter cake was dried to obtain pyrrolidine protected product of formula III.

[0095] Deprotection reaction: under nitrogen protection, 500 mL reaction bottle was added 160 mL of 25 vol% acetic acid aqueous solution, and the above-mentioned pyrrolidine protected product of formula III was added under stirring, and hydrolysis was carried out at room temperature for 15 min. TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin).

[0096] Ethyl acetate 160 mL was added to the reaction solution for extraction, and the water phase was extracted with ethyl acetate twice, each time 100 mL; the organic phase was combined, washed with saturated sodium bicarbonate solution twice, and then washed with water until pH 6-8.

[0097] The organic phase was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure at 45°C to a remaining volume of about 500-700 mL. Crystallization was carried out at 0-10°C for 30 min under stirring; filtration was carried out, and the filter cake was dried under reduced pressure at 30-40°C to a constant weight to obtain formula I5(10),9(11) - diene 36.05 g, yield 72.1%, purity 99.54% (as shown in Table 3), peroxide content 0.31%, detected by HPLC method 1, chromatogram as shown in Figure Figure 4

[0098] Example 6

[0099] The reaction was carried out using industrial-grade pyrrolidine to prepare formula I Δ 5(10),9(11) - diene.

[0100] Protection reaction: under nitrogen protection, 5 L reaction bottle was added with 2.5 L of methanol and 500 g of formula II Δ 4,9 - diene (1.61 mol); the temperature was raised to 60°C, and 500 mL of industrial-grade pyrrolidine was slowly added. After the addition was completed, the reaction was continued at 60°C for 1 h. TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin). The reaction solution was cooled to 0-10°C and stirred for 0.5 h. Filtration, drying, and formula III pyrrolidine protection product were obtained.

[0101] Deprotection reaction: under nitrogen protection, 5 L reaction bottle was added with 1.6 L of 25 vol% acetic acid aqueous solution. The above-mentioned formula III pyrrolidine protection product was added with stirring. Hydrolysis was carried out at room temperature for 15 min. TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin).

[0102] Ethyl acetate 1.6 L was added to the reaction solution for extraction. After standing, the water phase was extracted with ethyl acetate twice, 1 L each time. The organic phases were combined and washed with saturated sodium bicarbonate solution twice, and then washed with water until the pH was 6-8.

[0103] The organic phase was dried with anhydrous sodium sulfate, and then concentrated under reduced pressure at 45°C to a residual volume of about 500-700 mL. Crystallization was carried out at 0-10°C for 3 h. Filtration, drying, and formula I Δ 5(10),9(11) - diene 201 g, yield 40.2%, purity 94.78% (as shown in Table 3), peroxide content 2.45%, detected by HPLC method 1, chromatogram as shown in Figure Figure 5

[0104] Example 7

[0105] Industrial-grade pyrrolidine was treated by redistillation to prepare formula I Δ 5(10),9(11) - diene.

[0106] Redistillation of tetrahydropyrrole: 100 mL of industrial-grade pyrrolidine was added to a 250 mL reaction bottle. The oil bath temperature was set to 100°C. Distillation was carried out under micro-nitrogen flow protection. The fraction with a boiling range of 85-92°C was collected to obtain colorless redistilled pyrrolidine.​​

[0107] Protection reaction: under nitrogen protection, 500 mL reaction bottle was added with 250 mL of methanol and formula II Δ 4,9 - diene 50 g (161.06 mmol); heated to 60 °C, slowly added with 50 mL of redistilled pyrrolidine, after completion of addition, continued to react at 60 °C for 1 h, TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin); the reaction solution was cooled to 0-10 °C and stirred for 0.5 h, filtered, dried, to obtain formula III pyrrolidine protected product.

[0108] Deprotection reaction: under nitrogen protection, 500 mL reaction bottle was added with 160 mL of 25 vol% acetic acid aqueous solution, and the above formula III pyrrolidine protected product was added with stirring, hydrolyzed at room temperature for 15 min, TLC showed that the reaction reached the end point (developing agent: PE / EA = 7 / 3, color developing agent: vanillin).

[0109] The reaction solution was extracted with 160 mL of ethyl acetate, and the water phase was extracted twice with 100 mL of ethyl acetate each time; the combined organic phase was washed twice with saturated sodium bicarbonate solution, and then washed with water until the pH was 6-8.

[0110] The organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 45 °C to a remaining volume of about 50-70 mL, and stirred at 0-10 °C for 30 min; filtered, dried, and the filter cake was dried under reduced pressure at 30-40 °C to constant weight, to obtain formula I Δ 5(10),9(11) - diene 30.15 g, yield 60.3%, purity 98.88% (as shown in Table 3), peroxide content 0.82%, detected by HPLC method 1, and the spectrum is shown in Figure 6 .

[0111] Table 3 Δ 5(10),9(11) - diene composition and yield data

[0112]

[0113]

[0114] According to the data in Table 3, the reaction effect was improved after the industrial grade pyrrolidine was redistilled and used in the reaction, and the peroxide impurity in the reaction solution was reduced from more than 10% to 3.28%, but it was still higher than 0.93% when reagent grade pyrrolidine was used;

[0115] After the industrial grade pyrrolidine was pretreated with 3% tocopherol and directly used in the reaction, the reaction effect was obviously improved, and the peroxide impurity in the reaction solution was directly reduced to about 0.7%, and the product formula I Δ 5(10),9(11)-The peroxide impurity in the diene is reduced to 0.2-0.3%, the purity is greater than 99%, and the product yield is also increased to more than 85%.

[0116] Example 8

[0117] Preparation of gestrinone.

[0118] To a 5L reaction flask, 3L of chloroform and the compound of formula I prepared in Example 1 were added in sequence. 5(10),9(11) -diene 150g, DDQ 165g, keep at 30 ℃ stirring and react for 2.5h. TLC shows that the reaction has reached the end point (developing solvent: PE / EA = 7 / 3, color developer: vanillin). Filter and collect the filtrate. The filtrate is washed three times with 5% sodium hydroxide solution and then washed twice with water until the pH is 6-8 to obtain an organic phase.

[0119] 30 g of activated carbon and 30 g of anhydrous sodium sulfate were added to the organic phase, and the mixture was stirred at room temperature for 30 min to decolorize and dry, and then filtered. The filtrate was concentrated to near dryness under reduced pressure at 45 ° C, 300 mL of ethyl acetate was added, and crystallization was stirred at 0-10 ° C for 1 h, filtered, and dried. The filter cake was air-dried at 50 ° C to constant weight to obtain 143.6 g of crude gestrinone, with a molar yield of 96.4%, a purity of 99.82% (detected by HPLC method 2), and a maximum single impurity of 0.12%. The results are as follows Figure 7 shown.

[0120] In a 5L reaction flask, 2.8L of ethyl acetate, 140g of crude gestrinone and 28g of activated carbon were added in sequence, the temperature was raised to reflux and stirred for 1.5h, the carbon was filtered while hot, and the filtrate was concentrated under reduced pressure at 45°C to a solution volume of about 420mL, stirred and crystallized at 0-10°C for 1h, filtered, and dried. The filter cake was air-dried at 50°C to constant weight to obtain 130.2g of gestrinone with a refined yield of 93.0%, a purity of 99.92% (detected by HPLC method 2), and a maximum single impurity of 0.04%. Figure 8 shown.

[0121] 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 scope of protection of the present invention.

Claims

1. A method for preparing a high-purity steroid compound, characterized in that: Using 4,9-diene as raw material, the pretreated pyrrolidine undergoes protection and deprotection reactions to obtain a steroid compound 5(10),9(11)-diene; the structure of the 4,9-diene is shown in Formula II: The structure of the 5(10),9(11)-diene is shown in Formula I:

2. The method for preparing a high-purity steroid compound according to claim 1, wherein: The pyrrolidine pretreatment method comprises: adding an antioxidant to industrial-grade pyrrolidine under nitrogen protection, stirring at 10-30° C. for 1-2 hours, and then directly performing protection and deprotection reactions.

3. The method for preparing a high-purity steroid compound according to claim 2, wherein: The antioxidant is one or more of butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and tocopherol.

4. The method for preparing a high-purity steroid compound according to claim 2, wherein: The added amount of the antioxidant is 1-5% of the mass of pyrrolidine.

5. The method for preparing a high-purity steroid compound according to claim 4, wherein: The added amount of the antioxidant is 1-3% of the mass of pyrrolidine.

6. The method for preparing a high-purity steroid compound according to claim 2, wherein: The protection reaction uses methanol as solvent; the deprotection reaction is a hydrolysis reaction of the pyrrolidine protected product in an acetic acid aqueous solution, followed by extraction, concentration and crystallization.

7. A high-purity steroid compound, characterized in that: The high-purity steroid compound is prepared by the method for preparing the high-purity steroid compound according to any one of claims 1 to 6.

8. A high-purity steroid compound according to claim 7, characterized in that: The purity of the high-purity steroid compound is greater than 99%, and the peroxide impurity is reduced to 0.2-0.3%.

9. Use of a high-purity steroid compound according to claim 7 or 8 in the preparation of 4,9,11-trienoid compounds.

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