WO2024045950A1 - Steroid compound and crystal form a thereof, and preparation methods therefor and use thereof - Google Patents

Abstract

Provided in the present invention are a steroid compound and a crystal form A thereof, and preparation methods therefor and the use thereof. The structure of the steroid compound is as shown in formula (II). An X-ray powder diffraction pattern, collected with Cu-Kα radiation, of the crystal form A of the steroid compound comprises diffraction peaks at the following 2θ angles: 9.9 ± 0.2º, 12.3 ± 0.2º, 14.9 ± 0.2º, and 15.3 ± 0.2º. The steroid compound and the crystal form A thereof are suitable for preparing Clascoterone, and the obtained product is easy to purify, and has a higher final purity and a high yield.

Description

A kind of steroid compound, its crystal form A and their preparation method and use Technical field

The present invention relates to a pharmaceutical intermediate, and more specifically to a steroid compound, 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20 - Diketones, their crystalline form A and their preparation methods and uses.

Background technique

The chemical name of Clascoterone is 21-hydroxy-17-(1-oxopropoxy)pregnant-4-en-3,20-dione, which is mainly used to treat acne, alopecia and other skin and skin appendage diseases. This small molecule structure can penetrate the skin, act on androgen receptors in sebaceous glands and hair follicles, inhibit the local effect of dihydrotestosterone (DHT), thereby inhibiting the secretion of lipids in sebaceous gland cells and reducing the condition of acne patients. On August 26, 2020, the U.S. FDA approved Clascoterone cream for the treatment of acne in patients 12 years of age and older. The chemical structural formula of Clascoterone is as follows (I):

R. Gardi et al. first disclosed in Tetrahedron Letter, 448, 1961, that in the presence of an acid catalyst, 17α,21-dihydroxy-pregnant-4-ene-3,20-dione reacted with orthoester to obtain 17α, 21-Ortho acid esterification product, the latter can be hydrolyzed to obtain 17α-monoester. The synthesis route is as shown in Route 1 below:

Route 1

Clascoterone can be prepared by referring to this method. However, the monoester obtained by this method is prone to side reactions in which the esterified acyl group migrates from position 17 to position 21, and the monoester at position 17 (target product, compound represented by formula (II)) and monoester at position 21 (by-product , the compound represented by formula (IV)) has similar properties, is difficult to separate, and cannot be mass-produced.

In order to solve the above problems, WO2009019138 and Tetrahedron Letters 49(2008)4610–4612 proposed an enzymatic method to combine the 17-position α and The 21-position double esterification product is selectively hydrolyzed by enzymatic method to obtain Clascoterone. The synthesis route is shown in Route 2 below. At the same time, it was also mentioned that the 21-position monoester by-product (compound represented by formula (IV)) in the chemical synthesis method is about 3%, which cannot meet the purity requirements of the drug (it needs to be controlled within 0.15%), and purification is very difficult. Care and fine control are required to achieve purification.

Route 2

However, this method is still not suitable for industrial large-scale production due to limitations in the amount of substrate input in the enzyme-catalyzed reaction.

CN112028956A describes the many drawbacks of the enzymatic method and believes that the chemical method is more suitable for industrial preparation of Clascoterone. Its reported synthesis route is shown in Route 3 below:

Route 3

The disadvantages of this method are that the steps are long and the selective acylation in step 1 has poor reproducibility.

In addition, the prior art does not disclose the specific compound represented by the following formula (II):

Contents of the invention

In view of the shortcomings of the prior art, one aspect of the present invention aims to provide an intermediate compound of Clascoterone and its crystals. Clascoterone can be prepared by using the intermediate compound or its crystals through a one-step reaction. The final product is easy to purify, especially 21 The monoester by-product (compound represented by formula (IV)) is well controlled, meets pharmaceutical purity requirements (controlled within 0.15%), and has a high yield.

In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

A steroidal compound whose structure is shown in the following formula (II):

Another object of the present invention is to provide a method for preparing a steroid compound represented by formula (II), which includes the steps of: converting the compound represented by formula (III) (17α,21-dihydroxy-pregnant-4-ene-3 , 20-diketone) and trimethyl orthopropionate react in a reaction solvent under the action of an acid catalyst to obtain a compound represented by formula (II). The reaction formula is as follows:

Preferably, the above reaction solvent is selected from nitrile solvents containing 2 to 4 carbon atoms, alcohol solvents containing 1 to 3 carbon atoms, ester solvents containing 3 to 5 carbon atoms, and ester solvents containing 4 to 5 carbon atoms. One or more of the ether solvents.

Preferably, the above-mentioned nitrile solvent is selected from one or more of acetonitrile, propionitrile and butyronitrile, with acetonitrile being more preferred.

Preferably, the above-mentioned alcoholic solvent is selected from one or more of methanol, ethanol and isopropyl alcohol, more preferably methanol.

Preferably, the above-mentioned ester solvent is selected from one or more of ethyl acetate, methyl acetate and isopropyl acetate, more preferably ethyl acetate.

Preferably, the above-mentioned ether solvent is selected from tetrahydrofuran and/or 2-methyltetrahydrofuran.

Preferably, the above-mentioned acid catalyst is selected from pyridine p-toluenesulfonate and/or p-toluenesulfonic acid.

Preferably, the temperature of the above reaction is 40-80°C and the time is 2-5 hours. More preferably, the temperature is 45-55°C and the time is 2-5 hours.

Preferably, in the above reaction, the molar ratio of the compound represented by formula (III) and the acid catalyst is 1:0.01-0.03, more preferably 1:0.015-0.02.

Preferably, in the above reaction, the molar ratio of the compound represented by formula (III) and trimethyl orthopropionate is 1:1.0~3.0, more preferably 1:1.2~2.0.

Another object of the present invention is to provide crystalline form A of the steroid compound represented by formula (II), using Cu-Kα radiation, and the X-ray powder diffraction pattern of the crystalline form A includes a diffraction peak represented by the 2θ angle: 9.9±0.2°, 12.3±0.2°, 14.9±0.2°, 15.3±0.2°,

Preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern of the above-mentioned Form A also includes one or more of the following diffraction peaks expressed in 2θ angles:

8.8±0.2°, 10.3±0.2°, 11.0±0.2°, 12.7±0.2°, 15.7±0.2°, 16.8±0.2°, 17.1±0.2°, 17.5±0.2°, 18.6±0.2°, 18.9±0.2°, 19.5±0.2°, 20.9±0.2°, 21.2±0.2°, 22.4±0.2°, 22.8±0.2°, 23.7±0.2°, 25.8±0.2°, 26.2±0.2°, 27.2±0.2°, 27.9±0.2°, 29.0±0.2°, 30.3±0.2°, 31.0±0.2°, 31.6±0.2°, 32.2±0.2°, 33.2±0.2°, 34.2±0.2°, 34.7±0.2°, 35.5±0.2°, 36.1±0.2°, 36.7±0.2°, 37.1±0.2°, 37.9±0.2°, 39.4±0.2°, 39.8±0.2°.

Preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern of the above-mentioned crystal form A includes diffraction peaks expressed in 2θ angles: 9.9±0.2°, 12.3±0.2°, 14.9±0.2°, 15.3±0.2°, 16.8±0.2°, 17.1±0.2°, 17.5±0.2°, 18.6±0.2°.

Preferably, using Cu-Kα radiation, the X-ray powder diffraction pattern of the above crystalline form A is substantially as shown in Figure 1.

Preferably, the differential thermal analysis diagram of the above-mentioned crystal form A shows an endothermic peak, with an Onset value of 191.99°C, which is a melting endothermic peak.

Another object of the present invention is to provide a preparation method of crystalline form A of the steroid compound represented by formula (II). The preparation method includes the following steps:

(1) Add the steroid compound represented by formula (II) or the steroid compound represented by formula (II) in the form of a residue to an organic solvent, and heat it to 20 to 120°C, so that the steroid compound represented by formula (II) The steroid compound represented by formula (II) in the form of a body compound or residue is completely dissolved;

(2) Cool the solution to -5~-15°C, crystallize and separate the crystals to obtain the crystal form A.

Preferably, in the above step (1), the organic solvent is selected from alcohol solvents containing 1 to 3 carbon atoms and/or ether solvents containing 3 to 5 carbon atoms.

Preferably, in the above step (1), the alcoholic solvent is selected from one or more of methanol, ethanol and isopropyl alcohol, with methanol being more preferred.

Preferably, in the above step (1), the ether solvent is selected from isopropyl ether and/or methyl tert-butyl ether.

Preferably, in the above step (1), the volume to weight ratio of the organic solvent to the steroid compound is 3 to 30 L/kg.

More preferably, in the above step (2), the solution is cooled to -10~-15°C, more preferably, -10°C.

Preferably, the crystallization process in step (2) is carried out at -5 to -15°C under stirring conditions.

More preferably, in step (2), the solution is cooled to -5 to -15°C with stirring, and after cooling to the target temperature, stirring is continued at this temperature for 3 to 8 hours, and more preferably, stirring is continued for 4 to 6 hours. hours, most preferably, continue stirring for 5 hours.

Preferably, the crystals are separated by filtration or centrifugation.

Preferably, the above preparation method further includes drying the crystals after separating the crystals.

Preferably, the drying is vacuum drying, the temperature is 40-70°C, and the time is 8-14 hours. More preferably, the vacuum drying temperature is 40-60°C and the time is 10-12 hours.

Preferably, the preparation method of the above-mentioned crystal form A also includes washing the crystals to remove impurities on the surface of the crystals after isolating the crystals and before drying the crystals.

Preferably, the organic solvent used in the crystallization process is used in the process of washing the crystals.

Preferably, the number of washings is 2 to 5 times.

Preferably, the steroid compound represented by formula (II) in the form of a residue is prepared by the following step (1):

17α,21-dihydroxy-pregnant-4-ene-3,20-dione represented by formula (III) and trimethyl orthopropionate are reacted in a reaction solvent under the action of an acid catalyst, and the reaction is The liquid is concentrated, water is added to the concentrate, and extracted with an organic solvent. The separated organic phase is concentrated to dryness to obtain the steroid compound represented by formula (II) in the form of a residue:

Preferably, the organic solvent used for extraction is selected from methylene chloride.

Another object of the present invention is to provide the steroid compound represented by the above formula (II) for the preparation of the compound represented by the formula (I) (21-hydroxy-17-(1-oxopropoxy)pregnantrol-4- The use of alkene-3,20-dione),

Another object of the present invention is to provide the crystal form A of the steroid compound represented by the above formula (II) for the preparation of 21-hydroxy-17-(1-oxopropoxy)pregnantrol represented by the formula (I). -Use of 4-ene-3,20-dione,

Preferably, the method for preparing the compound represented by formula (I) includes the following steps:

(1) Hydrolyze the steroid compound represented by formula (II) or crystal form A in an acidic solvent system, and treat the reaction solution to obtain the residue of the compound represented by formula (I). The reaction formula is as follows:

The pH of the acidic solvent system is 2 to 6, more preferably 3 to 5;

(2) Add the residue of step (1) to an organic solvent and heat it to 50 to 120°C to completely dissolve the compound of formula (I) in the form of the residue, and cool the solution to -5 to -15°C. crystallize and separate crystals,

The organic solvent is selected from methyl tert-butyl ether and/or isopropyl ether.

Preferably, the acid used in the acidic solvent system is selected from inorganic acids, organic acids, or buffers formed by acids and their salts,

Preferably, the inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof,

Preferably, the organic acid is a medium-strength acid selected from acetic acid, formic acid, citric acid, or a combination thereof;

Preferably, the solvent is selected from methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, acetonitrile, or combinations thereof; and/or

Preferably, the temperature at which hydrolysis is performed is 50 to 100°C, more preferably 55 to 90°C.

Preferably, the process of treating the reaction solution in step (1) is: concentrating the reactant under reduced pressure, then adding water, extracting with an organic solvent, and concentrating the layered organic phase to dryness under reduced pressure to obtain a residue.

Preferably, the organic solvent used for extraction is selected from esters with 4 to 6 carbon atoms, ethers with 5 to 6 carbon atoms, aromatic hydrocarbons with 6 to 8 carbon atoms, and haloalkanes with 1 to 3 carbon atoms. Hydrocarbons, or combinations thereof.

Preferably, the ester is selected from isopropyl acetate. Preferably, the ether solvent is selected from methyl tert-butyl ether. Preferably, the aromatic hydrocarbons are selected from toluene. Preferably, the haloalkanes are selected from methylene chloride.

The beneficial effects of the present invention are:

The steroidal compound represented by formula (II) of the present invention, 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione, especially Its crystal form A, when used to prepare Clascoterone (Compound I) in an acidic reaction system, greatly reduces the production of the 21-position monoester (Compound IV) and other impurities. The final product is easy to purify, has higher purity, and meets pharmaceutical quality. requirements, suitable for industrial production.

The preparation method of crystal form A of the steroid compound shown in (II) provided by the present invention is simple and convenient to operate, and is more suitable for industrial production.

The purity of the crystal form A of the steroid compound represented by formula (II) of the present invention is not less than 99.5% and can reach 100 (area normalization method), and the yield is not less than 80%.

Description of drawings

Figure 1 is the XRPD pattern of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A.

Figure 2 is a DSC spectrum of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A.

Figure 3 is a mass spectrum of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A.

Figure 4 is a hydrogen spectrum of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A.

Figure 5 is a mass spectrum of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione.

Figure 6 is a hydrogen spectrum of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione.

Figure 7 is the carbon spectrum of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione.

Detailed ways

In view of the shortcomings of the prior art, the inventor of the present application has discovered through in-depth research that the steroid compound (17,21-[(1-methoxypropylene)bis(oxy)]pregnantrol represented by formula (II) -4-ene-3,20-dione), especially its crystal form A, as an intermediate, has stable physical and chemical properties and is not easily degraded during storage. In an acidic solvent system, the final product of Clascoterone prepared has relatively high purity and yield. Moreover, the applicant found that the steroid compound represented by formula (II) can be easily crystallized in a conventional solvent to obtain its crystal form A, which is suitable for industrial production. On this basis, the present invention was completed.

In the description of the present invention, the preparation method of the steroid compound represented by formula (II) includes the steps of: combining 17α,21-dihydroxy-pregnant-4-ene-3,20-dione represented by formula (III) and Trimethyl orthopropionate is reacted in a reaction solvent under the action of an acid catalyst to obtain the steroid compound. The preparation method also includes that after the reaction is completed (which can be detected by conventional detection methods in the art (such as HPLC or TLC), the reaction end point is when the content of the compound shown in (III) no longer changes), the reaction solution is concentrated, and then added Water is extracted with an organic solvent, such as methylene chloride, and the separated organic phase is concentrated to dryness under reduced pressure to obtain the steroid compound shown in (II) in the form of a residue. The preparation method further includes the step of purifying the steroid compound represented by (II) in the form of a residue, for example, by crystallization or purification by column chromatography.

In the description of the present invention, the preparation method of crystal form A of the steroid compound represented by formula (II) includes the steps: (1) converting the steroid compound represented by formula (II) (amorphous or other than crystal form A Crystal form), or its residue form, is added to the organic solvent, and the solution is heated to 20 to 120°C to completely dissolve the steroid compound and obtain a clear solution; (2) Cool the solution to -5 to -15°C, Crystallize and separate to obtain the crystal form A of the steroid compound represented by formula (II). During the crystallization process of this preparation method, in order to achieve the purpose of sufficient crystallization, in addition to cooling the solution to -5 ~ -15°C and continuing to stir at this temperature for a period of time, a series of measures can also be taken by professionals in the technical field. Other measures are known and are within the scope of the present invention. After the crystallization is completed, the crystallized material can be separated by common methods, including but not limited to filtration and centrifugation. The organic solvent is selected from alcohol solvents containing 1 to 3 carbon atoms and/or ether solvents containing 3 to 5 carbon atoms.

In the present invention, the preparation method of the compound represented by formula (I) includes preparing the steroid compound represented by formula (II) or its crystal form A in an acidic solvent system with a pH of 2 to 6, more preferably 3 to 5. Hydrolysis. After the hydrolysis is completed (can be detected by conventional detection means in the field (such as HPLC or TLC), the reaction end point is when the content of the compound shown in (III) no longer changes), the reaction solution is treated as usual to obtain the target product. Concentrate, after recrystallization, the target product obtained is basically free of the 21-position monoester by-product (compound represented by formula (IV)) by high-performance liquid chromatography, and the purity is not less than 99.2% and can reach 99.8%. The yield is not less than 90%. Therefore, the invention provides a method for preparing 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3 represented by formula (I) using the crystal form A of the steroid compound represented by formula (II). , the 20-diketone method is particularly suitable for industrial large-scale production.

In the description of the present invention, "multiple" means two or more types.

In the present invention, drying is preferably vacuum drying, and vacuum drying can be performed in a conventional commercially available vacuum dryer. The vacuum degree is generally -0.1~-0.08MPa.

The present invention will be further described below in conjunction with specific examples. It should be understood that the following examples are only used to provide best practice modes of the present invention and should not be construed to limit the scope of the present invention. Experimental methods without specifying specific conditions in the following examples usually follow conventional operating methods and conditions, or conditions recommended by the manufacturer.

In the following examples, the hydrogen spectrum and carbon spectrum of the product were detected using a Bruker AV III 300 nuclear magnetic resonance spectrometer.

The X-ray powder diffraction pattern of Form A was detected using a Bruker D2PHASER X-ray diffractometer.

The DSC spectrum of Form A was detected using a Mettler Toledo DSC 1 differential scanning calorimeter.

Example 1: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml acetonitrile, 7.7g trimethyl orthopropionate, 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione and 0.14 g of pyridine-p-toluenesulfonate, insulated and stirred at 50°C for 3 hours. After the reaction, concentrate under reduced pressure, then add water, extract with dichloromethane, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 12.1g of concentrate. , dissolve the concentrate in 30 mL methanol, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 17,21-[(1-methoxy Propylene)bis(oxy)]pregnant-4-ene-3,20-dione 11.8g, crystal form A, yield 98%, purity 99.8%.

The XRPD pattern of Form A is shown in Figure 1, including the following diffraction peaks expressed at 2θ angles:

9.9±0.2°, 12.3±0.2°, 14.9±0.2°, 15.3±0.2°, 16.8±0.2°, 17.1±0.2°, 17.5±0.2°, 18.6±0.2°.

The DSC spectrum of Form A is shown in Figure 2. The DSC spectrum shows an endothermic peak with an Onset value of 191.99°C, which is a melting endothermic peak.

The mass spectrum of Form A is shown in Figure 3, HRMS (TOF ES ⁺ ): m/z calcd for C ₂₅ H ₃₆ O ₅ [(M+H) ⁺ ].417.57; found, 417.20.

The hydrogen spectrum of Form A is shown in Figure 4, ¹ H NMR (300MHz, CDCl ₃ ): δ = 0.66 (s, 3H, CH ₃ ), 0.95～1.05 (m, 3H, CH ₃ ), 1.10～1.16 (m, 3H,CH ₂ ),1.19(s,3H,CH ₃ ),1.24～1.30(m,2H,CH ₂ ),1.39～1.51(m,2H,CH ₂ ),1.58～1.64(m,1H,CH) ,1.68～1.72(m,2H,CH ₂ ),1.74～1.76(m,2H,CH ₂ ),1.78～1.81(m,2H,CH ₂ ),1.83～1.88(m,2H,CH ₂ ),1.95 ~2.08(m,2H,CH ₂ ),2.27~2.36(m,2H,CH ₂ ),2.38~2.44(m,2H,CH ₂ ),2.65~2.73(m,1H,CH),3.25(s, 3H,CH ₃ ), 3.92～4.19(m,2H,CH ₂ ), 5.74(s,1H,CH).

Example 2: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregest-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, add 100ml propionitrile, 9.7g trimethyl orthopropionate, 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione and 100ml propionitrile under magnetic stirring and nitrogen protection. 0.15g of pyridine-p-toluenesulfonate was stirred at 50°C for 3 hours. After the reaction, concentrate under reduced pressure, then add water, extract with methylene chloride, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 12.0g of concentrate. Dissolve the concentrate in 30 mL of ethanol, heat to reflux to dissolve, stir and cool to -10°C, stir for 6 hours, filter, and store the wet product at 50°C. After air drying for 12 hours, 11.2g of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A was obtained, with a yield of 93%. , purity 99.7%.

Example 3: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml butyronitrile, 7.8g trimethyl orthopropionate, 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione and 0.15g of pyridine-p-toluenesulfonate was stirred at 55°C for 3 hours. After the reaction was completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 11.8g of concentrate. substance, dissolve the concentrate in 30 mL of methyl tert-butyl ether, heat to reflux to dissolve, stir and cool to -12°C, stir for 6 hours, filter, and dry the wet product in vacuum at 50°C for 12 hours to obtain 17,21- [(1-Methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A 11.0g, yield 92%, purity 99.8%.

Example 4: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml methanol, 5.8g trimethyl orthopropionate, 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione and 0.22 g pyridine-p-toluenesulfonate, stirred at 45°C for 5 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 11.5g of concentrate. , dissolve the concentrate in 30 mL isopropyl alcohol, heat to reflux to dissolve, stir and cool to -8°C, stir for 5 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 17,21-[(1- Methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A 10.0g, yield 83%, purity 100%.

Example 5: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 120ml ethanol, 11.6g trimethyl orthopropionate, 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione and 0.18 g pyridine-p-toluenesulfonate, stirred at 55°C for 2.5 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 11.7g of concentrate. , dissolve the concentrate in 30 mL isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 17,21-[(1- Methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A 10.5g, yield 87%, purity 100%.

Example 6: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregest-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, add 120ml isopropyl alcohol, 6.5g trimethyl orthopropionate, and 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione under magnetic stirring and nitrogen protection. and 0.12g of pyridine-p-toluenesulfonate, and stirred at 55°C for 2.5 hours. After the reaction, concentrate under reduced pressure, then add water, extract with dichloromethane, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 11.4g. Concentrate, dissolve the concentrate in 30 mL methanol, heat to reflux to dissolve, stir and cool to -12°C, stir for 5 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 17,21-[(1- Methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A 10.2g, yield 85%, purity 100%.

Example 7: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, add 90ml isopropyl alcohol, 10.0g trimethyl orthopropionate, and 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione under magnetic stirring and nitrogen protection. and 0.18g of pyridine-p-toluenesulfonate. Keep stirring at 42°C for 3 hours. After the reaction is completed, concentrate under reduced pressure. Then add water and extract with dichloromethane. The layered organic phase is concentrated under reduced pressure to dryness to obtain about 11.1g. Concentrate, dissolve the concentrate in 26 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -14°C, stir for 6 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 17,21-[( 1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A 9.7g, yield 81%, purity 100%.

Example 8: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, add 150ml ethyl acetate, 8.0g trimethyl orthopropionate, and 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione under magnetic stirring and nitrogen protection. and 0.15g of pyridine-p-toluenesulfonate, and stirred at 45°C for 4 hours. After the reaction, concentrate under reduced pressure, then add water, extract with dichloromethane, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 11.0g. Concentrate, dissolve the concentrate in 24 mL of methanol, heat to reflux to dissolve, stir and cool to -6°C, stir for 4 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 17,21-[(1- Methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A 10.6g, yield 88%, purity 100%.

Example 9: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, add 110ml methyl acetate, 9.0g trimethyl orthopropionate, and 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione under magnetic stirring and nitrogen protection. and 0.19g of pyridine-p-toluenesulfonate. Keep stirring at 52°C for 3 hours. After the reaction is completed, concentrate under reduced pressure. Then add water and extract with dichloromethane. The layered organic phase is concentrated under reduced pressure to dryness to obtain about 12.0g. Concentrate, dissolve the concentrate in 30 mL methanol, heat to reflux to dissolve, stir and cool to -9°C, stir for 4.5 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 17,21-[(1- Methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A 10.3g, yield 86%, purity 100%.

Example 10: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 95ml isopropyl acetate, 9.2g trimethyl orthopropionate, 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-di Ketone and 0.21g pyridine-p-toluenesulfonate were heated and stirred at 43°C for 5 hours. After the reaction was completed, concentrated under reduced pressure, then added water, extracted with dichloromethane, and concentrated the layered organic phase to dryness under reduced pressure to obtain about 12.3 g concentrate, dissolve the concentrate in 40 mL methanol, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 17,21-[(1 -Methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A10.1g, yield 84%, purity 100%.

Example 11: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml tetrahydrofuran, 7.7g trimethyl orthopropionate, 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione and 0.14 g pyridine p-toluenesulfonate, stirred at 49°C for 4 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 11.7g of concentrate. , dissolve the concentrate in 28 mL of ethanol, heat to reflux to dissolve, stir and cool to -13°C, stir for 5 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 17,21-[(1-methoxy Propylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A 9.9g, yield 82%, purity 100%.

Example 12: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml 2-methyltetrahydrofuran, 8.8g trimethyl orthopropionate, 10g 17α,21-dihydroxy-pregnant-4-ene-3,20- Dione and 0.16g pyridine p-toluenesulfonate were heated and stirred at 55°C for 3 hours. After the reaction was completed, concentrated under reduced pressure, then added water, extracted with dichloromethane, and concentrated the layered organic phase to dryness under reduced pressure to obtain approximately 12.2g concentrate, dissolve the concentrate in 30 mL ethanol, heat to reflux to dissolve, stir and cool to -8°C, stir for 4 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 17,21-[( 1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A 10.2g, yield 85%, purity 100%.

Example 13: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

In a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml 2-methyltetrahydrofuran, 10.5g trimethyl orthopropionate, 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-di Ketone and 0.1g p-toluenesulfonic acid, keep stirring at 50°C for 3 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 12.8g of concentrated The concentrated product was dissolved in 35 mL of isopropyl ether, heated to reflux to dissolve, stirred and cooled to -10°C, stirred for 5 hours, filtered, and the wet product was vacuum dried at 50°C for 12 hours to obtain 17,21-[(1 -Methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A 10.3g, yield 86%, purity 100%.

Example 14: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 130ml methanol, 9.0g trimethyl orthopropionate, 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione and p- 0.12 p-toluenesulfonic acid, keep stirring at 53°C for 3 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 13.2g of concentrate, which is The concentrate was dissolved in 40 mL of ethanol, heated to reflux to dissolve, stirred and cooled to -10°C, stirred for 5 hours, filtered, and the wet product was vacuum dried at 50°C for 12 hours to obtain 17,21-[(1-methoxysubstituted Propyl)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A 9.4g, yield 78%, purity 99.8%.

Example 15: Preparation of 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A

In a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml methanol, 8.5g trimethyl orthopropionate, 10g 17α,21-dihydroxy-pregnant-4-ene-3,20-dione and 0.15g p-toluenesulfonic acid, insulated at 48℃ Stir for 3.5 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 13.5g of concentrate. Dissolve the concentrate in 40 mL of isopropyl alcohol. in, heat to reflux to dissolve, stir and cool to -12°C, stir for 5.5 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 17,21-[(1-methoxypropylene)bis(oxy) )] Pregnant-4-ene-3,20-dione crystal form A9.6g, yield 80%, purity 99.5%.

Example 16: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione (compound represented by formula (I))

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml methanol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20- For diketone crystal form A, use formic acid/sodium formate buffer to adjust the pH of the reaction system to about 4, and keep stirring at 64°C for 3 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and separate the separated organic phases. Concentrate to dryness under reduced pressure to obtain about 12.9g of concentrate. Dissolve the concentrate in 100 mL of methyl tert-butyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and wet product at 50 ℃ vacuum drying for 12 hours to obtain 9.4g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, with a yield of 97% and a purity of 99.5%.

The mass spectrum of the compound represented by formula (I) is shown in Figure 5.

HRMS(TOF ES ⁺ ): m/z calcd for C ₂₄ H ₃₄ O ₅ [(M+H) ⁺ ].403.54; found, 403.17.

The hydrogen spectrum of compound 1 is shown in Figure 6, ¹ H NMR (300MHz, CDCl ₃ ): δ = 0.69 (s, 3H, CH ₃ ), 0.98 ~ 1.06 (m, 1H, CH), 1.07 ~ 1.10 (m, 1H ,CH),1.12～1.17(m,3H,CH ₃ ),1.20(s,3H,CH ₃ ),1.35～1.50(m,2H,CH ₂ ),1.54～1.61(m,1H,CH),1.65 ~1.70(m,2H,CH ₂ ),1.73~1.79(m,2H,CH ₂ ),1.82~1.88(m,2H,CH ₂ ),1.90~1.97(m,2H,CH ₂ ),2.02~2.09 (m,1H,CH),2.28～2.33(m,2H,CH ₂ ),2.36～2.41(m,2H,CH ₂ ),2.43～2.45(m,2H,CH ₂ ),2.80～2.88(m, 1H,CH), 3.10～3.13(m,1H,CH), 4.19～4.34(m,2H,CH ₂ ), 5.75(s,1H,CH).

The carbon spectrum of compound 1 is shown in Figure 7.

¹³ C NMR (75MHz, CDCl ₃ ): δ=8.8, 14.2, 17.3, 20.4, 23.8, 27.7, 30.3, 30.7, 31.8, 32.6, 33.8, 35.4, 35.6, 38.4, 47.6, 50.8, 53.0, 66.8, 93.7, 124.0, 170.4, 174.0, 199.3, 206.2.

Example 17: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml ethanol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20- For diketone crystal form A, use acetic acid/sodium acetate buffer to adjust the pH of the reaction system to approximately 5.5, and insulate and stir at 78°C for 2.5 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and layer the organic The phase was concentrated to dryness under reduced pressure to obtain about 13.5g of concentrate. Dissolve the concentrate in 100mL of methyl tert-butyl ether, heat to reflux to dissolve, stir and cool to -15°C, stir for 6.5 hours, filter, and wet The product was vacuum dried at 50°C for 12 hours to obtain 9.2g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, with a yield of 95% and a purity of 99.7%.

Example 18: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-en-3,20-dione (compound 1)

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml isopropanol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3, For 20-diketone Form A, use citric acid/sodium citrate buffer to adjust the pH of the reaction system to about 4, and keep stirring at 82°C for 2 hours. After the reaction is completed, concentrate under reduced pressure, then add water, and extract with dichloromethane. The separated organic phase was concentrated to dryness under reduced pressure to obtain approximately 13.0 g of concentrate. Dissolve the concentrate in 100 mL of methyl tert-butyl ether, heat to reflux to dissolve, stir and cool to -9°C, and stir for 4 hours. , filtered, and the wet product was vacuum dried at 50°C for 12 hours to obtain 8.9g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-en-3,20-dione, with a yield of 92%. Purity 99.8%.

Example 19: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml methanol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20- For diketone crystal form A, use dilute sulfuric acid (for example, mass concentration is 50%) to adjust the pH of the reaction system to about 3.5, keep stirring at 64°C for 4 hours, after the reaction is completed, concentrate under reduced pressure, then add water, and extract with dichloromethane , the layered organic phase was concentrated to dryness under reduced pressure to obtain about 12.6g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, and filter. , the wet product was vacuum dried at 50°C for 12 hours to obtain 8.7g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, with a yield of 90% and a purity of 99.2 %.

Example 20: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml ethanol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20- For diketone crystal form A, use dilute phosphoric acid (for example, mass concentration is 40%) to adjust the pH of the reaction system to approximately 3.5. Keep stirring at 78°C for 4 hours. After the reaction is completed, concentrate under reduced pressure, then add water, and extract with dichloromethane. , the layered organic phase was concentrated to dryness under reduced pressure to obtain about 12.6g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, and filter. , the wet product was vacuum dried at 50°C for 12 hours to obtain 8.6g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, with a yield of 89% and a purity of 99.3 %, the 21-position monoester by-product (compound represented by formula (IV)) is 0.03%.

Example 21: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml isopropanol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3, For 20-diketone crystal form A, use dilute hydrochloric acid (for example, mass concentration is 15%) to adjust the pH of the reaction system to about 3. Keep stirring at 83°C for 3.5 hours. After the reaction is completed, concentrate under reduced pressure, then add water, and use methylene chloride. Extract, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 12.3g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours. Filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 8.5g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, yield 88%, purity 99.1%, and the 21-position monoester by-product (compound represented by formula (IV)) is 0.05%.

Example 22: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml isopropyl alcohol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3 , 20-diketone crystal form A, use dilute hydrochloric acid (for example, mass concentration is 18%) to adjust the pH of the reaction system to about 2, keep stirring at 83°C for 3.5 hours, after the reaction is completed, concentrate under reduced pressure, then add water, use dichloride Extract with methane, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 12.5g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, and stir for 5 hours. , filtered, and the wet product was vacuum dried at 50°C for 12 hours to obtain 7.5g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, with a yield of 78%. The purity is 96.5%, and the 21-position monoester by-product (compound represented by formula (IV)) is 3.23%.

Example 23: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, add 100ml isopropanol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3 under magnetic stirring and nitrogen protection. For 20-diketone crystal form A, use dilute hydrochloric acid (for example, mass concentration is 15%) to adjust the pH of the reaction system to about 2, and keep stirring at 83°C for 3 hours. After the reaction is completed, concentrate under reduced pressure, then add water, and use methylene chloride. Extract and concentrate the layered organic phase to dryness under reduced pressure to obtain about 11.5g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours. Filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 6.8g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, yield 70%, purity 95.5%, and the 21-position monoester by-product (compound represented by formula (IV)) is 4.26%.

Example 24: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, add 100ml acetone and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20- under magnetic stirring and nitrogen protection. For diketone crystal form A, use a citric acid solution (for example, a mass concentration of 48%) to adjust the pH of the reaction system to about 4. Keep stirring at 56°C for 4 hours. After the reaction is completed, concentrate under reduced pressure, then add water, and extract with dichloromethane. , the layered organic phase was concentrated to dryness under reduced pressure to obtain about 12.6g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, and filter. , the wet product was vacuum dried at 50°C for 12 hours to obtain 8.9g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, with a yield of 92% and a purity of 99.2 %, the 21-position monoester by-product (compound represented by formula (IV)) is 0.06%.

Example 25: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml acetonitrile and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20- For diketone crystal form A, use dilute sulfuric acid (for example, mass concentration is 30%) to adjust the pH of the reaction system to about 3, keep stirring at 81°C for 4.5 hours, after the reaction is completed, concentrate under reduced pressure, then add water, and extract with dichloromethane , the layered organic phase was concentrated to dryness under reduced pressure to obtain about 12.8g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, and filter. , the wet product was vacuum dried at 50°C for 12 hours to obtain 21-hydroxy 8.5g of base-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, yield 88%, purity 99.0%, monoester by-product at position 21 (formula (IV) compound) is 0.05%.

Example 26: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml tetrahydrofuran and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20- For diketone crystal form A, use phosphoric acid/potassium dihydrogen phosphate buffer to adjust the pH of the reaction system to about 4, keep stirring at 66°C for 4 hours, and after the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and separate layers. The organic phase was concentrated to dryness under reduced pressure to obtain about 12.0g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and obtain wet product. Dry under vacuum at 50°C for 12 hours to obtain 8.3g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, yield 86%, purity 99.4%, 21 The monoester by-product (compound represented by formula (IV)) is 0.03%.

Example 27: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, add 50ml methanol, 50ml acetonitrile, and 10g 17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3 under magnetic stirring and nitrogen protection. , 20-diketone crystal form A, use dilute sulfuric acid (for example, mass concentration is 20%) to adjust the pH of the reaction system to about 2.3, keep stirring at 64°C for 4 hours, after the reaction is completed, concentrate under reduced pressure, then add water, and use Extract with methyl chloride, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 11.6g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filtered, and the wet product was vacuum dried at 50°C for 12 hours to obtain 7.1g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, with a yield of 73%. , the purity is 97.2%, and the 21-position monoester by-product (compound represented by formula (IV)) is 2.04%.

Example 28: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml methanol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20- For diketone crystal form A, use formic acid/sodium formate buffer to adjust the pH of the reaction system to about 3.5, insulate and stir at 64°C for 4 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with methyl tert-butyl ether, and layer The organic phase was concentrated to dryness under reduced pressure to obtain about 12.0g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and wet product in After vacuum drying at 50°C for 12 hours, 8.7g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione was obtained. The yield was 90%, the purity was 99.5%, and the 21st position The monoester by-product (compound represented by formula (IV)) was 0.02%.

Example 29: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml methanol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20- Dione crystal form A, use formic acid to adjust the pH of the reaction system to about 6, keep stirring at 64°C for 10 hours, concentrate under reduced pressure, then add water, extract with isopropyl acetate, and concentrate the layered organic phase to dryness under reduced pressure to obtain About 12.4g of concentrate, dissolve the concentrate in Dissolve 300 mL in isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 21-hydroxy-17-(1-oxopropoxy base) Pregnant-4-ene-3,20-dione 9.3g, yield 96%, purity 70.5%, of which the 21-position monoester by-product (compound represented by formula (IV)) is 0.01%, and the raw material is about 28 %.

Example 30: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml methanol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20- Dione crystal form A, use dilute hydrochloric acid (for example, mass concentration is 20%) to adjust the pH of the reaction system to about 3.5, keep stirring at 64°C for 4 hours, after the reaction is completed, concentrate under reduced pressure, then add water, extract with toluene, and separate The organic phase of the layer was concentrated to dryness under reduced pressure to obtain about 11.5g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and wet The product was vacuum dried at 50°C for 12 hours to obtain 8.4g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, with a yield of 87% and a purity of 99.5%. The 21-position monoester by-product (compound represented by formula (IV)) was 0.03%.

Example 31: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck flask, add 100ml of methanol under magnetic stirring and nitrogen protection, use dilute hydrochloric acid (for example, mass concentration is 21%) to adjust the system pH to about 3, then add 10g of 17,21-[(1-methoxy Propylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A, insulated and stirred at 64°C for 4 hours. After the reaction is completed, concentrate under reduced pressure, then add water, and use methylene chloride Extract and concentrate the layered organic phase to dryness under reduced pressure to obtain about 12.5g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours. Filter, and dry the wet product under vacuum at 50°C for 12 hours to obtain 8.3g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, yield 86%, purity 98.9%, and the 21-position monoester by-product (compound represented by formula (IV)) is 0.07%.

Example 32: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

Into a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml of methanol, adjust the pH of the reaction system to about 2.2 with concentrated hydrochloric acid solution, and then add 10g of 17,21-[(1-methoxypropylene)bis(oxygen) base)] Pregnant-4-ene-3,20-dione crystal form A, keep stirring at 64°C for 4 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and separate the separated organic phases. Concentrate to dryness under reduced pressure to obtain about 12.5g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and store the wet product at 50°C. After vacuum drying for 12 hours, 8.3g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione was obtained, with a yield of 86% and a purity of 93%. The 21-position monoester The by-product (compound represented by formula (IV)) was 6.5%.

Example 33: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck flask, add 100ml methanol under magnetic stirring and nitrogen protection, use dilute sulfuric acid (for example, mass concentration is 30%) to adjust the pH of the reaction system to about 4.8, add 10g17,21-[(1-methyl Oxypropylene)bis(oxy)]pregnant-4-ene-3,20-dione crystal form A, stir at 64°C for 4 hours. After the reaction is completed, concentrate under reduced pressure, then add water, and use dimethyl Extract with methyl chloride, and concentrate the layered organic phase to dryness under reduced pressure to obtain about 12.5g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filtered, and the wet product was vacuum dried at 50°C for 12 hours to obtain 8.2g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, with a yield of 85% , the purity is 98.5%, and the 21-position monoester by-product (compound represented by formula (IV)) is 0.09%.

Example 34: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck flask, add 100ml of methanol under magnetic stirring and nitrogen protection. Use phosphoric acid with a mass concentration of about 20% to adjust the pH of the reaction system to about 4.8. Add 10g of 17,21-[(1-methoxypropylene) Bis(oxy)]pregnant-4-ene-3,20-dione crystal form A, incubate and stir at 64°C for 4 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and separate layers. The organic phase was concentrated to dryness under reduced pressure to obtain about 12.5g of concentrate. Dissolve the concentrate in 300mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and obtain wet product. Dry under vacuum at 50°C for 12 hours to obtain 8.4g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, yield 87%, purity 99.0%, 21 The monoester by-product (compound represented by formula (IV)) is 0.05%.

Example 35: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, under magnetic stirring and nitrogen protection, add 100ml methanol and 10g17,21-[(1-methoxypropylene)bis(oxy)]pregnant-4-ene-3,20- For diketone crystal form A, use formic acid to adjust the pH of the reaction system to about 4.0, and keep stirring at 64°C for 4 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and concentrate the layered organic phase under reduced pressure to Dry to obtain about 12.5g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and dry the wet product in vacuum at 50°C for 12 hours. , 9.0g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione was obtained, with a yield of 93%, a purity of 99.1%, and the 21-position monoester by-product (formula (IV) Compound) is 0.05%.

Example 36: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

Into a 1000ml four-neck flask, under magnetic stirring and nitrogen protection, add 100ml methanol, use citric acid (for example, the mass concentration is 51%) to adjust the pH of the reaction system to about 4.5, and add 10g of 17,21-[(1-methoxypropylene Bis(oxy)]pregnant-4-ene-3,20-dione crystal form A, insulated and stirred at 64°C for 4 hours. After the reaction, concentrate under reduced pressure, then add water, and extract with dichloromethane. The separated organic phase was concentrated to dryness under reduced pressure to obtain about 12.5g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, and filter. The wet product was vacuum dried at 50°C for 12 hours to obtain 8.7g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, with a yield of 90% and a purity of 99.1%. , the 21-position monoester by-product (compound represented by formula (IV)) is 0.04%.

Example 37: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, add 100ml of methanol under magnetic stirring and nitrogen protection, adjust the pH of the reaction system to about 4.8 using acetic acid/sodium acetate buffer, and add 10g of 17,21-[(1-methoxypropylene)bis( Oxygen)] Pregnant-4-ene-3,20-dione crystal form A, incubate and stir at 64°C for 4 hours. After the reaction is completed, concentrate under reduced pressure, then add water, extract with dichloromethane, and layer the organic The phase was concentrated to dryness under reduced pressure to obtain about 12.5g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and wet product at 50 ℃ vacuum drying for 12 hours, to obtain 8.9g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione, with a yield of 92%, a purity of 99.6%, and 21-unit unit The ester by-product (compound represented by formula (IV)) was 0.02%.

Example 38: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck flask, add 100ml of methanol under magnetic stirring and nitrogen protection, use acetic acid/potassium acetate buffer to adjust the reaction pH to about 5.0, then add 10g of 17,21-[(1-methoxypropylene)bis (oxy)] Pregnant-4-ene-3,20-dione crystal form A, insulated and stirred at 64°C for 4 hours. After the reaction was completed, concentrated under reduced pressure, then added water, extracted with dichloromethane, and separated into layers. The organic phase was concentrated to dryness under reduced pressure to obtain about 12.5g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and wet product in After vacuum drying at 50°C for 12 hours, 9.0 g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione was obtained. The yield was 93%, the purity was 99.4%, and the 21st position The monoester by-product (compound represented by formula (IV)) was 0.04%.

Example 39: Preparation of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione

To a 1000ml four-neck bottle, add 100ml of methanol under magnetic stirring and nitrogen protection, adjust the pH of the reaction system to about 3.0 using formic acid/sodium formate buffer, then add 10g of 17,21-[(1-methoxypropylene)bis (oxy)] Pregnant-4-ene-3,20-dione crystal form A, insulated and stirred at 64°C for 4 hours. After the reaction was completed, concentrated under reduced pressure, then added water, extracted with dichloromethane, and separated into layers. The organic phase was concentrated to dryness under reduced pressure to obtain about 12.5g of concentrate. Dissolve the concentrate in 300 mL of isopropyl ether, heat to reflux to dissolve, stir and cool to -10°C, stir for 5 hours, filter, and wet product in After vacuum drying at 50°C for 12 hours, 8.5g of 21-hydroxy-17-(1-oxopropoxy)pregnant-4-ene-3,20-dione was obtained, with a yield of 88% and a purity of 99.3%. The 21st position The monoester by-product (compound represented by formula (IV)) was 0.03%.

Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present invention and do not limit the protection scope of the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, it is not limited to those listed in the examples. , Those of ordinary skill in the art should understand that the technical solution of the present invention can be modified or equivalently substituted without departing from the essence and scope of the technical solution of the present invention.

Claims (12)

1. A steroidal compound, characterized in that its structure is shown in the following formula (II):
   
2. The preparation method of steroid compounds according to claim 1, characterized in that, the preparation method includes step (1): adding the compound shown in formula (III) and trimethyl orthopropionate in a reaction solvent under the influence of an acid catalyst. The reaction is carried out under the action of the formula (II) to obtain the steroid compound represented by the formula (II). The reaction formula is as follows:
   
3. The preparation method according to claim 2, characterized in that step (1) has one or more features selected from the following:

   (i) The reaction solvent is selected from the group consisting of nitrile solvents containing 2 to 4 carbon atoms, alcohol solvents containing 1 to 3 carbon atoms, ester solvents containing 3 to 5 carbon atoms, and ester solvents containing 4 to 5 carbon atoms. One or more ether solvents of atoms;

   (ii) the acid catalyst is selected from pyridine p-toluenesulfonate and/or p-toluenesulfonic acid;

   (iii) The molar ratio of the compound represented by formula (III) and the acid catalyst is 1:0.01~0.03, more preferably 1:0.015~0.02;

   (iv) The molar ratio of the compound represented by formula (III) and trimethyl orthopropionate is 1:1.0~3.0, more preferably 1:1.2~2.0;

   (v) The reaction temperature is 40 to 80°C, and the reaction time is 2 to 5 hours.
4. The preparation method according to claim 3, characterized in that:

   The nitrile solvent is selected from one or more of acetonitrile, propionitrile and butyronitrile, and/or

   The alcohol solvent is selected from one or more of methanol, ethanol and isopropyl alcohol, and/or

   The ester solvent is selected from one or more of ethyl acetate, methyl acetate and isopropyl acetate, and/or

   The ether solvent is selected from tetrahydrofuran and/or 2-methyltetrahydrofuran.
5. Crystalline form A of the steroid compound represented by formula (II) is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form A includes the following diffraction peaks expressed in 2θ angles:

   9.9±0.2°, 12.3±0.2°, 14.9±0.2°, 15.3±0.2°,
   
6. The crystalline form A according to claim 5, characterized in that the crystalline form A also has one or more characteristics selected from the following:

   (i) Cu-Kα radiation is used, and its X-ray powder diffraction pattern also includes one or more of the following diffraction peaks expressed in 2θ angles:

   8.8±0.2°, 10.3±0.2°, 11.0±0.2°, 12.7±0.2°, 15.7±0.2°, 16.8±0.2°, 17.1±0.2°, 17.5±0.2°, 18.6±0.2°, 18.9±0.2°, 19.5±0.2°, 20.9±0.2°, 21.2±0.2°, 22.4±0.2°, 22.8±0.2°, 23.7±0.2°, 25.8±0.2°, 26.2±0.2°, 27.2±0.2°, 27.9±0.2°, 29.0±0.2°, 30.3±0.2°, 31.0±0.2°, 31.6±0.2°, 32.2±0.2°, 33.2±0.2°, 34.2±0.2°, 34.7±0.2°, 35.5±0.2°, 36.1±0.2°, 36.7±0.2°, 37.1±0.2°, 37.9±0.2°, 39.4±0.2°, 39.8±0.2°;

   (ii) Its differential thermal analysis diagram shows an endothermic peak with an Onset value of 191.99°C, which is a melting endothermic peak.
7. The preparation method of crystalline form A according to any one of claims 5-6, characterized in that the preparation method includes the following steps:

   (1) Add the steroid compound represented by formula (II) or the steroid compound represented by formula (II) in the form of a residue to an organic solvent, and heat it to 20 to 120°C, so that the steroid compound represented by formula (II) The steroid compound represented by formula (II) in the form of a body compound or residue is completely dissolved;

   (2) Cool the solution to -5~-15°C, crystallize and separate the crystals to obtain the crystal form A,

   The organic solvent is selected from alcohol solvents containing 1 to 3 carbon atoms and/or ether solvents containing 3 to 5 carbon atoms.
8. The preparation method according to claim 7, characterized in that the alcohol solvent is selected from one or more of methanol, ethanol and isopropyl alcohol, and/or

   The ether solvent is selected from isopropyl ether and/or methyl tert-butyl ether, and/or

   In step (2), the crystallization process is carried out at -5 to -15°C under stirring conditions.
9. The preparation method according to claim 7, characterized in that the steroid compound represented by formula (II) in the form of a residue is prepared by the following step (1):

   The compound represented by formula (III) and trimethyl orthopropionate are reacted in a reaction solvent under the action of an acid catalyst, the reaction liquid is concentrated, the concentrate is added to water, and extracted with an organic solvent, and the layered organic phase Concentrate to dryness to obtain the steroid compound represented by formula (II) in the form of a residue:
   
10. The use of the steroidal compound represented by formula (II) according to claim 1 or the crystal form A described in any one of claims 5-6 for preparing the compound represented by formula (I),
    
11. The use according to claim 10, characterized in that the method for preparing the compound represented by formula (I) includes the following steps:

    (1) Hydrolyze the steroid compound represented by formula (II) or crystal form A in an acidic solvent system, and treat the reaction solution to obtain the residue of the compound represented by formula (I). The reaction formula is as follows:
    

    The pH of the acidic solvent system is 2 to 6, more preferably 3 to 5;

    (2) Add the residue of step (1) to an organic solvent and heat it to 50 to 120°C to completely dissolve the compound of formula (I) in the form of the residue, and cool the solution to -5 to -15°C. crystallize and separate crystals,

    The organic solvent is selected from methyl tert-butyl ether and/or isopropyl ether.
12. The use according to claim 11, characterized in that the acid used in the acidic solvent system is selected from inorganic acids, organic acids, or buffers formed by acids and their salts,

    The inorganic acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, or combinations thereof,

    The organic acid is a medium strength acid, selected from acetic acid, formic acid, citric acid, or a combination thereof; and/or

    The solvent in the acidic solvent system is selected from methanol, ethanol, isopropyl alcohol, acetone, tetrahydrofuran, acetonitrile, or combinations thereof; and/or

    The temperature at which hydrolysis is performed is 50 to 100°C, and more preferably 55 to 90°C.