Preparation method of 17alpha-hydroxypregna-4-ene-3, 11, 20-triketone and intermediate compound prepared by preparation method of 17alpha-hydroxypregna-4-ene-3, 11, 20-triketone

Abstract

The invention provides a preparation method of 17 alpha-hydroxypregna-4-ene-3, 11, 20-triketone and an intermediate compound prepared by the preparation method, and relates to the technical field of medicine synthesis. The target product disclosed by the invention is prepared by taking 11 alpha-hydroxy-4-androstenedione as a starting material and carrying out six-step reaction, namely oxidation, ethynylation, ketalation, sulfonylation, etherification and hydrolysis. The starting material 11 alpha-hydroxy-4-androstenedione of the process is prepared from 4-androstenedione through enzyme transfer, and compared with 11 alpha, 17 alpha-dihydroxyprogesterone prepared from 17 alpha-hydroxyprogesterone through enzyme transfer, the enzyme transfer technology of the former is more mature, the conversion rate and the yield are higher, and the cost is lower. Meanwhile, the preparation method disclosed by the invention is easy to operate and implement in production and high in reaction conversion rate, avoids the use of a highly toxic reagent acetone cyanohydrin, and is more beneficial to large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and particularly relates to a preparation method of 17α-hydroxy pregn-4-ene-3,11,20-trione and an intermediate compound prepared thereby. Background Art

[0002] Steroid hormones have strong pharmacological effects of anti-infection, anti-allergy, anti-virus and anti-shock, and are important drugs for the treatment of rheumatism, cardiovascular diseases, lymphocytic leukemia, cytopathic encephalitis, skin diseases, anti-tumor and rescuing critically ill patients. Among them, important ones such as cortisone acetate are commonly used for the treatment of rheumatoid arthritis, rheumatic fever, gout, bronchial asthma, etc. Methylprednisolone has powerful pharmacological effects of anti-inflammatory, immunosuppressive, anti-allergy, anti-shock, etc., and is widely used clinically in respiratory diseases, endocrine disorders, rheumatic diseases, collagen diseases, blood diseases, skin diseases, nervous system diseases, etc.

[0003] And 17α-hydroxy pregn-4-ene-3,11,20-trione is an important intermediate for the synthesis of these drugs. It is particularly important to find a synthetic route with high yield, low cost and suitable for industrial production.

[0004] Currently, the commonly used industrial preparation method is to use 4-androstenedione (4-AD) as the starting material, and prepare 17α-hydroxyprogesterone through cyanidation, ketal protection, Grignard addition, and hydrolysis, and then prepare 17α-hydroxy pregn-4-ene-3,11,20-trione through a total of six steps of 11-position enzymatic trans-hydroxylation and oxidation, such as a preparation method mentioned in the patent CN107286215 "A Preparation Method of Steroid Compounds with Multiple Olefin Groups". The reaction route is as follows:

[0005]

[0006] In this process, in the cyanidation step, highly toxic chemical acetone cyanohydrin must be used; the Grignard addition reaction requires strict anhydrous and anaerobic conditions, and the yield is relatively low; in addition, placing the enzymatic trans-hydroxylation with relatively low feeding concentration in the later steps imposes certain limitations on the production capacity of this product.

[0007] Therefore, there is an urgent need to develop a method with relatively environmentally friendly, safe and easy-to-implement production route for the industrial preparation of 17α-hydroxy pregn-4-ene-3,11,20-trione. Summary of the Invention

[0008] In view of this, the present invention provides a preparation method of 17α-hydroxy pregn-4-ene-3,11,20-trione and an intermediate compound prepared thereby.

[0009] In a first aspect, the present invention provides a method for preparing 17α-hydroxy-pregn-4-ene-3,11,20-trione, and the 17α-hydroxy-pregn-4-ene-3,11,20-trione has a structure shown in formula (I):

[0010]

[0011] The 17α-hydroxy-pregn-4-ene-3,11,20-trione uses 11α-hydroxy-4-androstenedione as a starting material and comprises the following six steps:

[0012] Step 1: 11α-hydroxy-4-androstenedione undergoes an oxidation reaction to obtain an oxide;

[0013] Step 2: The oxide prepared in Step 1 undergoes an alkynylation reaction to obtain an alkynylated product;

[0014] Step 3: The alkynylated product prepared in Step 2 undergoes a ketalization reaction to obtain a ketalized product;

[0015] Step 4: The sulfonylated product prepared in Step 3 undergoes a sulfonylation reaction to obtain a sulfonylated product;

[0016] Step 5: The sulfonylated product prepared in Step 4 undergoes an etherification reaction to obtain an etherified product;

[0017] Step 6: The etherified product prepared in Step 5 undergoes a hydrolysis reaction to obtain 17α-hydroxy-pregn-4-ene-3,11,20-trione.

[0018] That is, in the present invention, the synthetic route of the 17α-hydroxy-pregn-4-ene-3,11,20-trione is as follows:

[0019]

[0020] In formulas (V) to (VII), R1 and R2 are both H;

[0021] Or, R1 and R2 each independently selected from alkyl groups having 1 to 20 carbon atoms, and R1 and R2 form a cyclic compound at the 3-position.

[0022] Based on the above technical solutions, preferably, in formulas (V) to (VII), when R1 and R2 are both H, a 3-keto-4-ene structure is formed; when R1 and R2 each independently selected from alkyl groups having 1 to 20 carbon atoms, and R1 and R2 form a cyclic compound at the 3-position, the cyclic compound is selected from one of spiroheterocycles, five-membered rings or six-membered rings.

[0023] Based on the above technical solutions, preferably, in step one, the 11α-hydroxy-4-androstenedione, as shown in formula (II), undergoes an oxidation reaction with chromium trioxide in acetic acid solution to obtain an oxide as shown in formula (III).

[0024] More preferably, the molar ratio of 11α-hydroxy-4-androstenedione, manganese chloride, and chromium trioxide is 1:(0.5 - 0.8):(1.2 - 1.8); the mass-volume ratio of 11α-hydroxy-4-androstenedione to glacial acetic acid is 1 g:(1.6 - 2.4) ml.

[0025] Based on the above technical solutions, preferably, in step two, the oxide shown in formula (III) uses tetrahydrofuran as a solvent and undergoes an alkynylation reaction with potassium acetylide to obtain an alkynide as shown in formula (IV).

[0026] More preferably, the molar ratio of the oxide, tetrahydrofuran, and potassium acetylide is 1:(44.8 - 67.2):(17.6 - 26.4).

[0027] Based on the above technical solutions, preferably, in step three, the alkynide shown in formula (IV) uses triethyl orthoformate as a dehydrating agent and p-toluenesulfonic acid as a catalyst in an organic solvent to undergo a ketalization reaction to obtain a ketal as shown in formula (V).

[0028] Based on the above technical solutions, preferably, the organic solvent is selected from one or more of methanol, ethanol, ethylene glycol, or 2,2-dimethyl-1,3-propanediol.

[0029] More preferably, the organic solvent is ethylene glycol.

[0030] Based on the above technical solutions, more preferably, the molar ratio of the alkynide, triethyl orthoformate, and p-toluenesulfonic acid is 1:(1.68 - 2.52):(0.04 - 0.06); the mass-volume ratio of the alkynide to ethylene glycol is 1 g:(240 - 360) ml.

[0031] Based on the above technical solutions, preferably, in step four, the ketal uses dichloromethane as a solvent and undergoes a sulfonylation reaction with benzenesulfinyl chloride under the action of triethylamine and acetic acid to obtain a sulfonylated product.

[0032] More preferably, when the organic solvent is dichloromethane, a ketal as shown in formula (VI-1) can be obtained. At this time, the molar ratio of the ketal, triethylamine, acetic acid, and benzenesulfinyl chloride is 1:(2.48 - 3.72):(0.94 - 1.44):(1.76 - 2.64); the mass-volume ratio of the ketal to dichloromethane is 1 g:(1120 - 1680) ml.

[0033] On the basis of the above technical solutions, preferably, in step five, the sulfide shown in formula (VI) uses methanol as a solvent. After adding sodium hydroxide and trimethyl phosphite successively, an etherification reaction is carried out to obtain an ether compound shown in formula (VII).

[0034] More preferably, the molar ratio of the sulfide, sodium hydroxide, and trimethyl phosphite is 1:(0.36 - 0.54):(0.59 - 0.89); the mass-volume ratio of sodium hydroxide to methanol is 1 g:(120 - 180) ml.

[0035] On the basis of the above technical solutions, preferably, in step six, the reaction solution containing the ether compound shown in formula (VII) obtained through the etherification reaction is hydrolyzed under acidic conditions to obtain 17α-hydroxy-pregn-4-ene-3,11,20-trione shown in formula (I).

[0036] More preferably, the volume-mass ratio of the reaction solution of the ether compound to the acid is (24 - 36) ml:1 g.

[0037] In a second aspect, the present invention provides an intermediate compound, and the structure of the compound includes those shown in formula (VI), (VII), (VI-1), or (VII-1):

[0038]

[0039] In formula (VI) and / or (VII), R1 and R2 each independently selected from alkyl groups having 1 to 20 carbon atoms, and R1 and R2 form a cyclic compound at the 3-position.

[0040] On the basis of the above technical solutions, preferably, in formulas (V) to (VII), the cyclic group is selected from one of spiroheterocycles, five-membered rings, or six-membered rings.

[0041] The preparation method of 17α-hydroxy-pregn-4-ene-3,11,20-trione and the intermediate compound prepared by the present invention have the following beneficial effects compared with the prior art:

[0042] The method for preparing 17α-hydroxy-pregn-4-ene-3,11,20-trione of the present invention is easy to operate and implement, has a high reaction conversion rate, and avoids the use of highly toxic reagent acetone cyanohydrin, which is more conducive to large-scale industrial production. Description of the Drawings

[0043] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for the description of the embodiments or the prior art. Obviously, the drawings in the following description are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0044] Figure 1 1H NMR spectrum of the sulfonylated product prepared in Example 1 of the present invention;

[0045] Figure 2 13C NMR spectrum of the sulfonylated product prepared in Example 1 of the present invention;

[0046] Figure 3 1H NMR spectrum of the etherified product prepared in Example 1 of the present invention;

[0047] Figure 4 13C NMR spectrum of the etherified product prepared in Example 1 of the present invention;

[0048] Figure 5 1H NMR spectrum of 17α - hydroxypregn - 4 - ene - 3,11,20 - trione prepared in Example 1 of the present invention;

[0049] Figure 6 13C NMR spectrum of 17α - hydroxypregn - 4 - ene - 3,11,20 - trione prepared in Example 1 of the present invention. Detailed implementation manners

[0050] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in combination with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, rather than all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0051] In view of the methods for preparing 17α - hydroxypregn - 4 - ene - 3,11,20 - trione in the prior art, none of them meet the inventor's expectations. Through further research and exploration, the inventor made the present invention.

[0052] The present invention uses 11α-hydroxy-4-androstenedione as the starting material, which can be directly obtained commercially. This starting material is prepared by enzymatic conversion of 4-androstenedione, and this enzymatic conversion technology is more mature. It not only simplifies the process flow, reduces the generation of by-products and the handling of intermediates, but also improves production efficiency and environmental friendliness, thus making the overall production process more efficient and economical. Compared with the preparation of 17α-hydroxyprogesterone from 4-androstenedione and then the enzymatic conversion to 11α,17α-dihydroxyprogesterone, the preparation method of the present invention has higher conversion rate, yield and cost-effectiveness.

[0053] The following will further describe the present invention in conjunction with specific embodiments. The protection scope of the present invention is not limited by the following embodiments. The material sources mainly involved in the embodiments are all conventional commercially available products.

[0054] The relevant tests in the following embodiments are all carried out with reference to the following methods:

[0055] HPLC method:

[0056] Chromatographic column: InfinityLab Poroshell 120 EC-C18 (4.6×150 mm, 4-Micron), Agilent.

[0057] Mobile phase: water and methanol gradient.

[0058] Time (min) Water (%) Methanol (%) Flow rate (mL / min) 0 60 40 0.5 15 10 90 0.5 20 10 90 0.5 21 60 40 0.5 25 60 40 0.5

[0059] Preparation of test solution: Take an appropriate amount of the sample, weigh it accurately, dissolve it with methanol and dilute it to make a solution containing about 1 mg per 1 mL as the test solution.

[0060] Flow rate: 0.5 mL / min;

[0061] Detector: ultraviolet detector (VWD), signal polarity: positive; wavelength: 254 nm or 205 nm; column oven temperature: 35 °C; injection volume: 5 μL; acquisition time: 25 min.

[0062] Example 1

[0063] Step 1. Oxidation reaction to prepare the oxide shown in formula (III)

[0064] In a 1 L reaction flask, add 200 g of 11α-hydroxy-4-androstenedione, 400 mL of glacial acetic acid, 120 g of 50% manganese chloride aqueous solution and 200 g of 50% chromium trioxide aqueous solution, stir and react at room temperature for 5 h until the reaction is monitored to be complete by TLC (developer: petroleum ether / ethyl acetate, v / v = 1 / 1).

[0065] Pour the reaction solution into 4 L of water, continue stirring at room temperature for 1 h, filter, and wash the filter cake with water until it is neutral. The filter cake is dried in a blast dryer at 40 °C until a constant weight is obtained, yielding 195 g of a white solid of the oxide, with a yield of 98.2% and a purity of 96.5% (254 nm).

[0066] Step 2: Alkynylation reaction to prepare the alkynide shown in formula (IV)

[0067] Add 1500 mL of tetrahydrofuran and 400 g of potassium hydroxide to a 5 L dry reaction flask, and introduce acetylene gas at room temperature for 2 - 3 h to prepare potassium alkynide; cool the potassium alkynide reaction solution to 10 °C, slowly add a 500 mL tetrahydrofuran solution of 100 g of the oxide, and keep the temperature at 0 °C for reaction for 1.5 h until the reaction is monitored to be complete by TLC (developing agent: dichloromethane / methanol, v / v = 50 / 1).

[0068] Slowly add 800 mL of water to the reaction solution to quench it, let it stand for liquid separation, extract the aqueous layer with tetrahydrofuran twice, 400 mL each time; combine the organic phases and wash them twice with water, 400 mL each time; concentrate the organic phase under reduced pressure at 40 °C until it is nearly dry, add 1 L of water for water precipitation, stir at room temperature for 0.5 h, filter, and wash the filter cake with water. The filter cake is dried in a blast dryer at 40 °C until a constant weight is obtained, yielding 104.8 g of a pale yellow solid of the alkynide, with a yield of 96.4% and a purity of 92.4% (254 nm).

[0069] Step 3: Ketalization reaction to prepare the ketal shown in formula (V)

[0070] Add 300 mL of ethylene glycol, 100 g of the alkynide, 2.6 g of p-toluenesulfonic acid, and 127 g of triethyl orthoformate to a 1 L reaction flask, and keep the temperature at 30 °C for reaction for 1.5 h until the reaction is monitored to be complete by TLC (developing agent: toluene / acetone, v / v = 4 / 1).

[0071] Slowly add 1500 mL of water to the reaction solution, cool it to 0 - 5 °C and stir for 0.5 - 1 h, filter, wash the filter cake with water until it is neutral, and drain it. The filter cake is dried in a blast dryer at 50 °C until a constant weight is obtained, yielding 110.3 g of a grayish-white solid of the ketal, with a yield of 97.2% and a purity of 98.9% (205 nm).

[0072] Step 4: Sulfonylation reaction to prepare the sulfonide shown in formula (VI)

[0073] Under nitrogen protection, add 1000 mL of dichloromethane, 100 g of the ketal, and 85 g of triethylamine to a 2 L reaction flask, stir and cool to -15 °C, and add 20 g of acetic acid. Slowly dropwise add a 400 mL dichloromethane solution of 80 g of benzenesulfinyl chloride, controlling the internal temperature not to exceed -10 °C during the dropping process. After the dropping is completed, keep the temperature at -15 °C for reaction for 0.5 h until the raw materials are detected to react completely by TLC (developing agent: toluene / acetone, v / v = 4 / 1).

[0074] 800 mL of 5% aqueous sodium hydroxide solution was added to the reaction solution, and the mixture was stirred for 20 minutes, allowed to stand for liquid separation, and the aqueous phase was extracted once with 200 mL of dichloromethane. The organic phases were combined, washed successively with 400 mL of 30% aqueous ammonium chloride solution and 400 mL of water once, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure at 40 °C to obtain the sulfonyl compound, which was directly used for the next etherification reaction.

[0075] The sulfonyl compound was purified by column separation, and the structure confirmation data are as Figure 1 、 2 shown below:

[0076] 1 H NMR (600 MHz, CDCl3) δ 7.63 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.5 Hz, 2H), 7.49 (t, J = 7.4 Hz, 1H), 6.16 (d, J = 4.0 Hz, 1H), 5.36–5.33 (m, 1H), 3.97–3.90 (m, 4H), 2.85–2.76 (m, 1H), 2.72–2.54 (m, 3H), 2.31 (s, 2H), 2.18–2.10 (m, 2H), 1.91 (s, 7H), 1.64 (dd, J = 13.7, 3.5 Hz, 1H), 1.50 (ddd, J = 21.9, 12.4, 9.5 Hz, 1H), 1.22 (s, 3H), 0.87 (s, 3H).

[0077] 13 C NMR (151 MHz, CDCl3) δ 208.86, 195.94, 144.85, 141.29, 130.95, 129.31, 129.22, 124.20, 120.30, 119.39, 109.03, 105.88, 64.42, 64.28, 60.73, 54.13, 53.93, 48.51, 41.62, 37.17, 37.15, 35.10, 33.05, 32.45, 30.83, 28.23, 24.92, 19.85, 18.05.

[0078] LC-MS: [M+H] + calcd. for C 29 H 34 O4S: 479.65; found: 479.6

[0079] Step 5. Etherification reaction to prepare the ether compound shown in formula (VII)

[0080] In a 2 L reaction flask, add the above sulfonyl compound, 600 mL of methanol and 4 g of sodium hydroxide. Heat the mixture to 65 °C and react for 1 hour. Add 25 g of trimethyl phosphite, continue to keep the temperature at 60 °C and react for 1.5 hours until the raw materials are completely reacted as monitored by TLC (developing agent: toluene / acetone, v / v = 4 / 1). Cool the reaction mixture to room temperature to obtain an etherified compound solution, which is directly used for the next hydrolysis reaction.

[0081] Cool the etherified compound solution to 0 - 10 °C to precipitate the solid etherified compound. The structure confirmation data are as Figure 3 , 4 shown below:

[0082] 1 H NMR (600 MHz, CDCl3) δ 5.36 (s, 1H), 4.31–4.21 (m, 1H), 4.10 (d, J = 3.2 Hz, 1H), 3.98–3.91 (m, 4H), 3.55 (d, J = 1.9 Hz, 3H), 2.66–2.55 (m, 3H), 2.40–2.29 (m, 3H), 2.11 (dd, J = 14.2, 2.9 Hz, 2H), 2.03–1.77 (m, 7H), 1.65 (dt, J = 13.7, 3.4 Hz, 1H), 1.33 (d, J = 3.7 Hz, 1H), 1.22 (s, 3H), 0.59 (s, 3H).

[0083] 13 C NMR (151 MHz, CDCl3) δ 212.00, 163.09, 141.15, 120.79, 109.16, 84.87, 82.52, 64.41, 64.24, 60.38, 54.94, 50.88, 50.08, 48.64, 41.61, 37.07, 35.11, 33.85, 33.65, 32.66, 30.86, 23.48, 18.01, 16.25.

[0084] LC-MS: [M + H] + calcd. for C 24 H 34 O5: 403.53; found: 403.53.

[0085] Step 6: Hydrolysis reaction to prepare 17α-hydroxy pregn-4-ene-3,11,20-trione shown in formula (I)

[0086] Add 20 g of concentrated hydrochloric acid to the above etherified compound solution, adjust the pH of the solution to 1, and stir the reaction at room temperature for 3 hours until the raw materials are completely reacted as monitored by TLC (developing agent: toluene / acetone, v / v = 4 / 1).

[0087] The reaction solution was neutralized by adding 300 mL of 5% aqueous sodium bicarbonate solution, and stirring was continued at room temperature for 0.5 h. The mixture was filtered, and the filter cake was washed with water until neutral and then dried by suction. The filter cake was dried in a blast dryer at 40-50 °C to constant weight, and 79 g of white solid of 17α-hydroxy-pregn-4-ene-3,11,20-trione was obtained. The overall yield of the three steps of sulfonylation, etherification and hydrolysis was 85%, and the purity was 98.2%.

[0088] The hydrolysis product was confirmed by NMR structure as Figure 5 , 6 shown below:

[0089] 1 H NMR(600MHz,CDCl3)δ5.72(d,J=5.9Hz,1H),2.84(d,J=12.4Hz,1H),2.79–2.72(m,2H),2.50–2.36(m,3H),2.33–2.23(m,5H),2.09(dd,J=12.4,2.4Hz,1H),2.01–1.90(m,4H),1.78–1.70(m,1H),1.64(t,J=14.5Hz,1H),1.46(td,J=11.8,6.1Hz,1H),1.40(dd,J=5.2,2.4Hz,3H),1.35–1.27(m,1H),0.73–0.67(m,3H).

[0090] 13 C NMR(151MHz,CDCl3)δ210.55,209.66,199.84,168.77,124.54,88.81,62.52,51.45,50.08,49.45,38.19,36.45,34.69,33.85,33.69,32.32,32.26,27.62,23.51,17.22,16.20.

[0091] LC-MS:[M+H] + calcd.for C 21 H 28 O4:344.45;found:344.5.

[0092] Comparative Example 1

[0093] The difference from Example 1 was that in Step 1, the oxidant used was 96 g of 50% aqueous manganese chloride solution and 160 g of 50% aqueous chromium trioxide solution. The yield was 88.4% and the purity was 94.5%.

[0094] The possible reasons for this may be as follows: the reduction of the oxidant means a weakened oxidation ability, which may cause some raw materials to fail to be completely converted into the target product. At the same time, the unreacted raw materials and other by-products may be mixed into the final product, resulting in a decrease in the overall yield.

[0095] Comparative Example 2

[0096] The difference from Example 1 lies in that: in Step 3, ethylene glycol dimethyl ether is used instead of ethylene glycol. The yield is 93.7% and the purity is 92.6%.

[0097] The possible reasons for this may be as follows: the polarity of ethylene glycol dimethyl ether (DME) is lower than that of ethylene glycol, which may affect the solubility of the reactants and the catalyst, resulting in a change in the reaction efficiency.

[0098] Example 2

[0099] Step 1: Oxidation reaction to prepare the oxide shown in Formula (Ⅲ)

[0100] In a 1L reaction flask, add 200g of 11α-hydroxy-4-androstenedione, 320mL of glacial acetic acid, 60g of 50% manganese chloride aqueous solution, and 160g of 50% chromium trioxide aqueous solution. Stir the reaction at room temperature for 6h until the reaction is complete as monitored by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 1 / 1).

[0101] Pour the reaction solution into 4L of water, continue to stir at room temperature for 2h, filter, and wash the filter cake with water until neutral. Dry the filter cake in a blast dryer at 50℃ to constant weight to obtain 189g of a white solid of the oxide, with a yield of 95.18% and a purity of 95.5% (at 254nm).

[0102] Step 2: Alkynylation reaction to prepare the alkynide shown in Formula (Ⅳ)

[0103] Add 1200mL of tetrahydrofuran and 320g of potassium hydroxide to a 5L dry reaction flask, and introduce acetylene gas at room temperature to prepare potassium alkynide for 2 - 3h; cool the potassium alkynide reaction solution to 10℃, and slowly add a 400mL tetrahydrofuran solution of 100g of the oxide. Keep the temperature at 10℃ and react for 1.5 hours until the reaction is complete as monitored by TLC (developing agent: dichloromethane / methanol, v / v = 50 / 1).

[0104] Slowly add 640mL of water to quench the reaction solution, let it stand for liquid separation. Extract the aqueous layer with tetrahydrofuran twice, 320mL each time; combine the organic phases and wash them twice, 320mL each time; concentrate the organic phase under reduced pressure at 0℃ until nearly dry, add 1L of water for precipitation, stir at room temperature for 1h, filter, and wash the filter cake with water. Dry the filter cake in a blast dryer at 50℃ to constant weight to obtain 102g of a pale yellow solid of the alkynide, with a yield of 93.82% and a purity of 91.5% (at 254nm).

[0105] Step 3: Ketalization reaction to prepare the ketal compound shown in formula (V).

[0106] In a 1 L reaction flask, add 240 mL of ethylene glycol, 100 g of alkynide, 2.08 g of p-toluenesulfonic acid, and 101.6 g of triethyl orthoformate. Keep the temperature at 40 °C and react for 1 hour until the reaction is complete as monitored by TLC (developing solvent: toluene / acetone, v / v = 4 / 1).

[0107] Slowly add 1500 mL of water to the reaction solution, cool down to 2 °C, stir for 0.8 hour, filter, wash the filter cake with water until neutral, and drain. Dry the filter cake in a blast dryer at 45 °C to constant weight to obtain 108 g of off-white solid ketal compound, with a yield of 95.17% and a purity of 98.5% (at 205 nm).

[0108] Step 4: Sulfonylation reaction to prepare the sulfonyl compound shown in formula (VI).

[0109] Under nitrogen protection, in a 2 L reaction flask, add 800 mL of dichloromethane, 100 g of ketal compound, and 68 g of triethylamine. Stir and cool down to -15 °C, then add 16 g of acetic acid. Slowly dropwise add a 320 mL dichloromethane solution of 64 g of benzenesulfinyl chloride, controlling the internal temperature not to exceed -10 °C during the dropping process. After the dropping is complete, keep the temperature at -15 °C and react for 0.5 h until the reaction of the raw materials is complete as detected by TLC (developing solvent: toluene / acetone, v / v = 4 / 1).

[0110] Add 640 ml of 5% sodium hydroxide aqueous solution to the reaction solution, stir for 20 minutes, let it stand for liquid separation, and extract the aqueous phase with 160 mL of dichloromethane once. Combine the organic phases, wash them once with 320 mL of 30% ammonium chloride aqueous solution and 320 mL of water in sequence. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness at 50 °C to obtain the sulfonyl compound, which is directly used for the next etherification reaction.

[0111] Step 5: Etherification reaction to prepare the ether compound shown in formula (VII).

[0112] In a 2 L reaction flask, add the above-mentioned sulfonyl compound, 480 mL of methanol, and 3.2 g of sodium hydroxide. Heat up to 65 °C and react for 1 hour; add 20 g of trimethyl phosphite, continue to keep the temperature at 65 °C and react for 1.5 hours until the reaction of the raw materials is complete as monitored by TLC (developing solvent: toluene / acetone, v / v = 4 / 1). Cool down to room temperature to obtain the ether compound solution, which is directly used for the next hydrolysis reaction.

[0113] Step 6: Hydrolysis reaction to prepare 17α-hydroxy-pregn-4-ene-3,11,20-trione shown in formula (I).

[0114] To the above-mentioned etherified solution, 16 g of concentrated hydrochloric acid was added, and the pH of the solution was adjusted to 2. The reaction was stirred at room temperature for 3 hours until the raw material reaction was complete as monitored by TLC (developing agent: toluene / acetone, v / v = 4 / 1).

[0115] 240 mL of 5% aqueous sodium bicarbonate solution was added to the reaction solution for neutralization, and stirring was continued at room temperature for 1 h. The mixture was filtered, and the filter cake was washed with water until neutral and then dried by suction. The filter cake was dried in a blast dryer at 50 °C to constant weight to obtain a white solid of 17α-hydroxy pregn-4-ene-3,11,20-trione, approximately 76 g was expected. The overall yield of the three steps of sulfonylation, etherification and hydrolysis was about 81.77%, and the purity was 97.8%.

[0116] Example 3

[0117] Step 1: Oxidation reaction to prepare the oxide shown in formula (Ⅲ)

[0118] In a 1 L reaction flask, 200 g of 11α-hydroxy-4-androstenedione, 480 mL of glacial acetic acid, 144 g of 50% aqueous manganese chloride solution and 240 g of 50% aqueous chromium trioxide solution were added. The reaction was stirred at room temperature for 6 h until the reaction was complete as monitored by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 1 / 1).

[0119] The reaction solution was poured into 4 L of water, and stirring was continued at room temperature for 2 h. The mixture was filtered, and the filter cake was washed with water until neutral. The filter cake was dried in a blast dryer at 50 °C to constant weight to obtain 198.2 g of a white solid of the oxide, with a yield of 99.81% and a purity of 97.0% (254 nm).

[0120] Step 2: Alkynylation reaction to prepare the alkynide shown in formula (Ⅳ)

[0121] 1800 mL of tetrahydrofuran and 480 g of potassium hydroxide were added to a 5 L dry reaction flask. Acetylene gas was introduced at room temperature for 2.5 h to prepare potassium alkynide. The reaction solution of potassium alkynide was cooled to 5 °C, and a 600 mL tetrahydrofuran solution of 100 g of the oxide was slowly added. The reaction was carried out at 5 °C for 1.5 h until the reaction was complete as monitored by TLC (developing agent: dichloromethane / methanol, v / v = 50 / 1).

[0122] 960 mL of water was slowly added to the reaction solution for quenching, and the mixture was allowed to stand for liquid separation. The aqueous layer was extracted with tetrahydrofuran twice, 480 mL each time. The combined organic phases were washed twice with 480 mL of water each time. The organic phase was concentrated under reduced pressure at 45 °C to near dryness, 1 L of water was added for water precipitation, and the mixture was stirred at room temperature for 0.8 h, filtered, and the filter cake was washed with water. The filter cake was dried in a blast dryer at 45 °C to constant weight to obtain 107 g of a light yellow solid of the alkynide, with a yield of 98.42% and a purity of 93.0% (254 nm).

[0123] Step 3: Ketalization reaction to prepare the ketal shown in formula (Ⅴ)

[0124] In a 1 L reaction flask, add 360 mL of ethylene glycol, 100 g of alkynide, 3.12 g of p-toluenesulfonic acid, and 152.4 g of triethyl orthoformate. Keep the temperature at 30 °C and react for 1 hour until the reaction is complete as monitored by TLC (developing agent: toluene / acetone, v / v = 4 / 1).

[0125] Slowly add 1500 mL of water to the reaction solution, cool down to 5 °C, stir for 0.5 hour, filter, wash the filter cake with water until neutral, and drain. The filter cake is dried in a blast dryer at 40 °C until constant weight to obtain 112 g of a ketal compound as a grayish-white solid, with a yield of 98.7% and a purity of 99.0% (at 205 nm).

[0126] Step 4: Sulfonylation reaction to prepare the sulfonylated compound shown in formula (VI)

[0127] Under nitrogen protection, in a 2 L reaction flask, add 1200 mL of dichloromethane, 100 g of the ketal compound, and 102 g of triethylamine. Stir and cool down to -15 °C, then add 24 g of acetic acid. Slowly dropwise add a 480 mL dichloromethane solution of 96 g of benzenesulfinyl chloride, controlling the internal temperature not to exceed -10 °C during the dropping process. After the dropping is complete, keep the temperature at -15 °C and react for 0.5 h until the reaction of the raw materials is complete as detected by TLC (developing agent: toluene / acetone, v / v = 4 / 1).

[0128] Add 960 ml of 5% sodium hydroxide aqueous solution to the reaction solution, stir for 10 minutes, let it stand for liquid separation, and extract the aqueous phase with 240 mL of dichloromethane once. Combine the organic phases, wash them once with 480 mL of 30% ammonium chloride aqueous solution and 480 mL of water in sequence. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness at 40 °C to obtain the sulfonylated compound, which is directly used for the next etherification reaction.

[0129] Step 5: Etherification reaction to prepare the etherified compound shown in formula (VII)

[0130] In a 2 L reaction flask, add the above sulfonylated compound, 720 mL of methanol, and 4.8 g of sodium hydroxide. Heat up to 60 °C and react for 1 hour; add 30 g of trimethyl phosphite, continue to keep the temperature at 60 °C and react for 1 hour until the reaction of the raw materials is complete as monitored by TLC (developing agent: toluene / acetone, v / v = 4 / 1). Cool down to room temperature to obtain a solution of the etherified compound, which is directly used for the next hydrolysis reaction.

[0131] Step 6: Hydrolysis reaction to prepare 17α-hydroxypregn-4-ene-3,11,20-trione shown in formula (I)

[0132] Add 24 g of concentrated hydrochloric acid to the above solution of the etherified compound, adjust the pH of the solution to 1, stir and react at room temperature for 2 hours until the reaction of the raw materials is complete as monitored by TLC (developing agent: toluene / acetone, v / v = 4 / 1).

[0133] 360 mL of 5% aqueous sodium bicarbonate solution was added to the reaction solution for neutralization, and stirring was continued at room temperature for 1 h. The mixture was filtered, and the filter cake was washed with water until neutral and then dried by suction. The filter cake was dried in a blast dryer at 50 °C to constant weight to obtain 17α-hydroxy pregn-4-ene-3,11,20-trione as a white solid, approximately 82 g was expected. The overall yield of the three steps of sulfonylation, etherification and hydrolysis was about 88.23%, and the purity was 98.5%.

[0134] Example 4

[0135] Step 1: Oxidation reaction to prepare the oxide shown in formula (Ⅲ)

[0136] In a 1 L reaction flask, 200 g of 11α-hydroxy-4-androstenedione, 440 mL of glacial acetic acid, 108 g of 50% aqueous manganese chloride solution and 180 g of 50% aqueous chromium trioxide solution were added. The mixture was stirred at room temperature for 6 h until the reaction was monitored to be complete by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 1 / 1).

[0137] The reaction solution was poured into 4 L of water, and stirring was continued at room temperature for 2 h. The mixture was filtered, and the filter cake was washed with water until neutral. The filter cake was dried in a blast dryer at 50 °C to constant weight to obtain 193 g of an oxide as a white solid, with a yield of 97.19% and a purity of 96.0% (254 nm).

[0138] Step 2: Alkynylation reaction to prepare the alkynide shown in formula (Ⅳ)

[0139] 1650 mL of tetrahydrofuran and 360 g of potassium hydroxide were added to a 5 L dry reaction flask, and acetylene gas was introduced at room temperature for 2 h to prepare potassium alkynide. The reaction solution of potassium alkynide was cooled to 8 °C, and a 550 mL tetrahydrofuran solution of 100 g of the oxide was slowly added. The mixture was kept at 8 °C for reaction for 2 h until the reaction was monitored to be complete by TLC (developing agent: dichloromethane / methanol, v / v = 50 / 1).

[0140] 880 mL of water was slowly added to the reaction solution for quenching, and the mixture was allowed to stand for liquid separation. The aqueous layer was extracted with tetrahydrofuran twice, 440 mL each time; the combined organic phases were washed twice, 360 mL each time; the organic phase was concentrated under reduced pressure at 400 °C until nearly dry, 1 L of water was added for water precipitation, and the mixture was stirred at room temperature for 0.5 h, filtered, and the filter cake was washed with water. The filter cake was dried in a blast dryer at 40 °C to constant weight to obtain 105 g of an alkynide as a pale yellow solid, with a yield of 96.58% and a purity of 92.5% (254 nm).

[0141] Step 3: Ketalization reaction to prepare the ketal shown in formula (Ⅴ)

[0142] In a 1 L reaction flask, add 330 mL of ethylene glycol, 100 g of alkynide, 2.34 g of p-toluenesulfonic acid, and 114.7 g of triethyl orthoformate. Keep the temperature at 30 °C and react for 1.2 hours until the reaction is complete as monitored by TLC (developing solvent: toluene / acetone, v / v = 4 / 1).

[0143] Slowly add 1500 mL of water to the reaction solution, cool down to 5 °C, stir for 0.5 hour, filter, wash the filter cake with water until neutral, and drain. Dry the filter cake in a blast dryer at 45 °C to constant weight to obtain 111 g of a ketal product as a grayish-white solid, with a yield of 97.82% and a purity of 98.7% (at 205 nm).

[0144] Step 4: Sulfonylation reaction to prepare the sulfonylated product shown in formula (VI)

[0145] Under nitrogen protection, in a 2 L reaction flask, add 1100 mL of dichloromethane, 100 g of the ketal product, and 76.5 g of triethylamine. Stir and cool down to -15 °C, then add 22 g of acetic acid. Slowly drip a 440 mL dichloromethane solution of 88 g of benzenesulfinyl chloride, controlling the internal temperature not to exceed -10 °C during the dripping process. After the dripping is completed, keep the temperature at -15 °C and react for 0.5 h until the reaction of the raw materials is complete as detected by TLC (developing solvent: toluene / acetone, v / v = 4 / 1).

[0146] Add 880 ml of 5% aqueous sodium hydroxide solution to the reaction solution, stir for 15 minutes, let it stand for liquid separation, and extract the aqueous phase with 180 mL of dichloromethane once. Combine the organic phases, wash them once with 360 mL of 30% aqueous ammonium chloride solution and 440 mL of water in sequence. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness at 45 °C to obtain the sulfonylated product, which is directly used for the next etherification reaction.

[0147] Step 5: Etherification reaction to prepare the etherified product shown in formula (VII)

[0148] In a 2 L reaction flask, add the above sulfonylated product, 660 mL of methanol, and 3.6 g of sodium hydroxide. Heat up to 60 °C and react for 1 hour; add 27.5 g of trimethyl phosphite, continue to keep the temperature at 65 °C and react for 1 hour until the reaction of the raw materials is complete as monitored by TLC (developing solvent: toluene / acetone, v / v = 4 / 1). Cool down to room temperature to obtain a solution of the etherified product, which is directly used for the next hydrolysis reaction.

[0149] Step 6: Hydrolysis reaction to prepare 17α-hydroxy-pregn-4-ene-3,11,20-trione shown in formula (I)

[0150] Add 22 g of concentrated hydrochloric acid to the above solution of the etherified product, adjust the pH of the solution to 1, stir and react at room temperature for 2 hours until the reaction of the raw materials is complete as monitored by TLC (developing solvent: toluene / acetone, v / v = 4 / 1).

[0151] 270 mL of 5% aqueous sodium bicarbonate solution was added to the reaction solution for neutralization, and stirring was continued at room temperature for 0.8 h. The mixture was filtered, and the filter cake was washed with water until neutral and then dried by suction. The filter cake was dried in a blast dryer at 45 °C to a constant weight to obtain 17α-hydroxy-pregn-4-ene-3,11,20-trione as a white solid, approximately 80 g was expected. The overall yield of the three steps of sulfonylation, etherification and hydrolysis was about 86.08%, and the purity was 98.3%.

[0152] Example 5

[0153] Step 1: Oxidation reaction to prepare the oxide shown in formula (III)

[0154] In a 1 L reaction flask, 200 g of 11α-hydroxy-4-androstenedione, 360 mL of glacial acetic acid, 132 g of 50% aqueous manganese chloride solution and 220 g of 50% aqueous chromium trioxide solution were added. The reaction was stirred at room temperature for 6 h until the reaction was monitored to be complete by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 1 / 1).

[0155] The reaction solution was poured into 4 L of water, and stirring was continued at room temperature for 2 h. The mixture was filtered, and the filter cake was washed with water until neutral. The filter cake was dried in a blast dryer at 50 °C to a constant weight to obtain 196 g of an oxide as a white solid, with a yield of 98.7% and a purity of 96.8% (254 nm).

[0156] Step 2: Alkynylation reaction to prepare the alkynide shown in formula (IV)

[0157] 1350 mL of tetrahydrofuran and 440 g of potassium hydroxide were added to a 5 L dry reaction flask. Acetylene gas was introduced at room temperature for 2 h to prepare potassium alkynide. The reaction solution of potassium alkynide was cooled to 5 °C, and a 550 mL tetrahydrofuran solution of 100 g of the oxide was slowly added. The reaction was carried out at 5 °C for 3 h until the reaction was monitored to be complete by TLC (developing agent: dichloromethane / methanol, v / v = 50 / 1).

[0158] 880 mL of water was slowly added to the reaction solution to quench it. The mixture was allowed to stand and layer. The aqueous layer was extracted with tetrahydrofuran twice, 440 mL each time. The combined organic phases were washed with water twice, 440 mL each time. The organic phase was concentrated under reduced pressure at 50 °C to near dryness, 1 L of water was added for water precipitation, and stirring was carried out at room temperature for 1 h. The mixture was filtered, and the filter cake was washed with water. The filter cake was dried in a blast dryer at 50 °C to a constant weight to obtain 106 g of an alkynide as a pale yellow solid, with a yield of 97.5% and a purity of 93.5% (254 nm).

[0159] Step 3: Ketalization reaction to prepare the ketal shown in formula (V)

[0160] In a 1 L reaction flask, add 270 mL of ethylene glycol, 100 g of alkynide, 2.86 g of p-toluenesulfonic acid, and 139.7 g of triethyl orthoformate. Keep the temperature at 40 °C and react for 1.5 hours until the reaction is complete as monitored by TLC (developing solvent: toluene / acetone, v / v = 4 / 1).

[0161] Slowly add 1500 mL of water to the reaction solution, cool down to 5 °C, stir for 1 hour, filter, wash the filter cake with water until neutral, and drain it. Dry the filter cake in a blast dryer at 50 °C to constant weight to obtain 110 g of a ketal compound as a grayish-white solid, with a yield of 96.94% and a purity of 99.0% (at 205 nm).

[0162] Step 4: Sulfonylation reaction to prepare the sulfonylated compound shown in formula (VI)

[0163] Under nitrogen protection, in a 2 L reaction flask, add 900 mL of dichloromethane, 100 g of the ketal compound, and 93.5 g of triethylamine. Stir and cool down to -15 °C, then add 22 g of acetic acid. Slowly drip a 440 mL dichloromethane solution of 88 g of benzenesulfinyl chloride, controlling the internal temperature not to exceed -10 °C during the dripping process. After the dripping is completed, keep the temperature at -12 °C and react for 0.5 h until the raw materials are completely reacted as detected by TLC (developing solvent: toluene / acetone, v / v = 4 / 1).

[0164] Add 880 ml of 5% sodium hydroxide aqueous solution to the reaction solution, stir for 18 minutes, let it stand for liquid separation, and extract the aqueous phase with 220 mL of dichloromethane once. Combine the organic phases, wash them once with 440 mL of 30% ammonium chloride aqueous solution and 440 mL of water in sequence. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness at 50 °C to obtain the sulfonylated compound, which is directly used for the next etherification reaction.

[0165] Step 5: Etherification reaction to prepare the etherified compound shown in formula (VII)

[0166] In a 2 L reaction flask, add the above sulfonylated compound, 540 mL of methanol, and 4.4 g of sodium hydroxide. Heat up to 60 °C and react for 1 hour; add 27.5 g of trimethyl phosphite, continue to keep the temperature at 60 °C and react for 1.5 hours until the raw materials are completely reacted as monitored by TLC (developing solvent: toluene / acetone, v / v = 4 / 1). Cool down to room temperature to obtain an etherified compound solution, which is directly used for the next hydrolysis reaction.

[0167] Step 6: Hydrolysis reaction to prepare 17α-hydroxy-pregn-4-ene-3,11,20-trione shown in formula (I)

[0168] Add 18 g of concentrated hydrochloric acid to the above etherified compound solution, adjust the pH of the solution to 2, and stir and react at room temperature for 3 hours until the raw materials are completely reacted as monitored by TLC (developing solvent: toluene / acetone, v / v = 4 / 1).

[0169] The reaction solution was neutralized by adding 330 mL of 5% aqueous sodium bicarbonate solution, and stirring was continued at room temperature for 0.5 h. The mixture was filtered, and the filter cake was washed with water until neutral and then dried by suction. The filter cake was dried in a blast dryer at 45 °C until constant weight to obtain 17α-hydroxy-pregn-4-ene-3,11,20-trione as a white solid, approximately 81 g was expected. The overall yield of the three steps of sulfonylation, etherification and hydrolysis was about 87.15%, and the purity was 98.4%.

[0170] Example 6

[0171] Step 1: Oxidation reaction to prepare the oxide shown in formula (Ⅲ)

[0172] In a 1 L reaction flask, 200 g of 11α-hydroxy-4-androstenedione, 440 mL of glacial acetic acid, 132 g of 50% aqueous manganese chloride solution and 220 g of 50% aqueous chromium trioxide solution were added. The reaction was stirred at room temperature for 6 h until the reaction was monitored to be complete by TLC (developing agent: petroleum ether / ethyl acetate, v / v = 1 / 1).

[0173] The reaction solution was poured into 4 L of water, and stirring was continued at room temperature for 2 h. The mixture was filtered, and the filter cake was washed with water until neutral. The filter cake was dried in a blast dryer at 50 °C until constant weight to obtain 198 g of an oxide as a white solid, with a yield of 99.71% and a purity of 97.4% (254 nm).

[0174] Step 2: Alkynylation reaction to prepare the alkynide shown in formula (Ⅳ)

[0175] 1650 mL of tetrahydrofuran and 440 g of potassium hydroxide were added to a 5 L dry reaction flask. Acetylene gas was introduced at room temperature for 2 h to prepare potassium alkynide. The reaction solution of potassium alkynide was cooled to 10 °C, and a 550 mL tetrahydrofuran solution of 100 g of the oxide was slowly added. The reaction was carried out at 8 - 10 °C for 3 h until the reaction was monitored to be complete by TLC (developing agent: dichloromethane / methanol, v / v = 50 / 1).

[0176] 880 mL of water was slowly added to the reaction solution to quench it. The mixture was allowed to stand for phase separation. The aqueous layer was extracted with tetrahydrofuran twice, 440 mL each time. The combined organic phases were washed with water twice, 440 mL each time. The organic phase was concentrated under reduced pressure at 50 °C until nearly dry, 1 L of water was added for water precipitation, and the mixture was stirred at room temperature for 0.5 h. The mixture was filtered, and the filter cake was washed with water. The filter cake was dried in a blast dryer at 40 °C until constant weight to obtain 107 g of an alkynide as a pale yellow solid, with a yield of 98.42% and a purity of 93.0% (254 nm).

[0177] Step 3: Ketalization reaction to prepare the ketal shown in formula (Ⅴ)

[0178] In a 1 L reaction flask, add 330 mL of ethylene glycol, 100 g of alkynide, 2.86 g of p-toluenesulfonic acid, and 139.7 g of triethyl orthoformate. Keep the temperature at 35 °C and react for 1 hour until the reaction is complete as monitored by TLC (developing solvent: toluene / acetone, v / v = 4 / 1).

[0179] Slowly add 1500 mL of water to the reaction solution, cool it to 0 °C, stir for 0.5 hour, filter, wash the filter cake with water until neutral, and drain it. Dry the filter cake in a blast dryer at 50 °C to constant weight to obtain 112 g of off-white solid of the ketal, with a yield of 98.7% and a purity of 99.0% (at 205 nm).

[0180] Step 4: Sulfonylation reaction to prepare the sulfonylated compound shown in formula (VI)

[0181] Under nitrogen protection, in a 2 L reaction flask, add 1100 mL of dichloromethane, 100 g of the ketal, and 93.5 g of triethylamine. Stir and cool to -15 °C, then add 22 g of acetic acid. Slowly add dropwise a 440 mL dichloromethane solution of 88 g of benzenesulfinyl chloride, controlling the internal temperature not to exceed -10 °C during the addition. After the addition is complete, keep the temperature at -15 °C and react for 0.5 h until the reaction of the raw materials is complete as detected by TLC (developing solvent: toluene / acetone, v / v = 4 / 1).

[0182] Add 880 ml of 5% sodium hydroxide aqueous solution to the reaction solution, stir for 10 minutes, let it stand for phase separation, and extract the aqueous phase once with 220 mL of dichloromethane. Combine the organic phases, wash them once with 440 mL of 30% ammonium chloride aqueous solution and 440 mL of water in sequence. Dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness at 40 °C to obtain the sulfonylated compound, which is directly used for the next etherification reaction.

[0183] Step 5: Etherification reaction to prepare the etherified compound shown in formula (VII)

[0184] In a 2 L reaction flask, add the above sulfonylated compound, 660 mL of methanol, and 4.4 g of sodium hydroxide. Heat to 60 °C and react for 1 hour; add 27.5 g of trimethyl phosphite, continue to keep the temperature at 65 °C and react for 1.5 hours until the reaction of the raw materials is complete as monitored by TLC (developing solvent: toluene / acetone, v / v = 4 / 1). Cool to room temperature to obtain a solution of the etherified compound, which is directly used for the next hydrolysis reaction.

[0185] Step 6: Hydrolysis reaction to prepare 17α-hydroxy-pregn-4-ene-3,11,20-trione shown in formula (I)

[0186] Add 22 g of concentrated hydrochloric acid to the above solution of the etherified compound, adjust the pH of the solution to 2, stir and react at room temperature for 3 hours until the reaction of the raw materials is complete as monitored by TLC (developing solvent: toluene / acetone, v / v = 4 / 1).

[0187] The reaction solution was neutralized by adding 330 mL of 5% aqueous sodium bicarbonate solution, and stirring was continued at room temperature for 1 h. Then, filtration was carried out, and the filter cake was washed with water until neutral and then dried by suction. The filter cake was dried in a blast dryer at 40 °C until a constant weight was obtained, and a white solid of 17α-hydroxy-pregn-4-ene-3,11,20-trione was obtained, with an expected amount of about 81.3 g. The overall yield of the three steps of sulfonylation, etherification and hydrolysis was about 87.47%, and the purity was 98.4%.

[0188] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Claims

1. A method for preparing 17α-hydroxypregnane-4-ene-3,11,20-trione, characterized in that: The 17α-hydroxypregnane-4-ene-3,11,20-trione has a structure as shown in formula (I): The 17α-hydroxypregnane-4-ene-3,11,20-trione uses 11α-hydroxy-4-androstenedione as a starting material and comprises the following six steps: Step 1, 11α-hydroxy-4-androstenedione is subjected to oxidation reaction to obtain an oxide; Step 2: The oxide prepared in step 1 is subjected to an acetylation reaction to obtain an acetylide; Step 3: The acetylide prepared in step 2 is subjected to a ketal reaction to obtain a ketal product; Step 4: The sulfonylated product prepared in step 3 is subjected to a sulfonylation reaction to obtain a sulfonylated product; Step 5: The sulfonylated product prepared in step 4 is subjected to etherification reaction to obtain an etherified product; Step 6: The etherified product prepared in step 5 is subjected to hydrolysis reaction to obtain 17α-hydroxypregnane-4-ene-3,11,20-trione.

2. The method for preparing 17α-hydroxypregnane-4-ene-3,11,20-trione according to claim 1, characterized in that: In step 1, the 11α-hydroxy-4-androstenedione is subjected to an oxidation reaction with chromium trioxide in an acetic acid solution to obtain an oxide.

3. The method for preparing 17α-hydroxypregnane-4-ene-3,11,20-trione according to claim 1, characterized in that: In step 2, the oxide is subjected to an acetylation reaction with potassium acetylene using tetrahydrofuran as a solvent to obtain an acetylide.

4. The method for preparing 17α-hydroxypregnane-4-ene-3,11,20-trione according to claim 1, characterized in that: In step 3, the acetylide is subjected to a ketal reaction in an organic solvent with triethyl orthoformate as a dehydrating agent and p-toluenesulfonic acid as a catalyst to obtain a ketal product.

5. The method for preparing 17α-hydroxypregnane-4-ene-3,11,20-trione according to claim 4, characterized in that: The organic solvent is selected from one or more of methanol, ethanol, ethylene glycol or 2,2-dimethylpropylene glycol.

6. The method for preparing 17α-hydroxypregnane-4-ene-3,11,20-trione according to claim 1, characterized in that: In step 4, the ketal is subjected to a sulfonylation reaction with benzenesulfonyl chloride in the presence of triethylamine and acetic acid using dichloromethane as solvent to obtain a sulfonylated product.

7. The method for preparing 17α-hydroxypregnane-4-ene-3,11,20-trione according to claim 1, characterized in that: In step 5, the sulfonylated product is subjected to an etherification reaction in the presence of sodium hydroxide and trimethyl phosphite using methanol as solvent to obtain an etherified product.

8. The method for preparing 17α-hydroxypregnane-4-ene-3,11,20-trione according to claim 7, characterized in that: In step six, the reaction solution containing the etherified product obtained by the etherification reaction is hydrolyzed under acidic conditions to obtain 17α-hydroxypregnane-4-ene-3,11,20-trione as shown in formula (I).

9. A compound, characterized in that The structure of the compound includes formula (VI), (VII), (VI-1) or (VII-1): In formula (VI) and / or (VII), R1 and R2 are each independently selected from an alkyl group having 1 to 20 carbon atoms, and R1 and R2 form a cyclic compound at the 3-position.

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