A method for preparing pregnanediolone

Abstract

This application provides a method for preparing pregnanelonone, comprising the following steps: Step 1) under the action of a first catalyst, progesterone reacts with an acid anhydride to obtain the compound shown in formula (I); Step 2) under the action of a dehydrating agent and a second catalyst, a diol reacts with the compound shown in formula (I), and after deprotection, the compound shown in formula (II) is obtained; Step 3) under the action of a ligand and a third catalyst, the compound shown in formula (II) is selectively reduced by hydrogen to obtain the compound shown in formula (III); Step 4) the compound shown in formula (III) reacts with a reducing agent and is then deprotected to obtain pregnanelonone. This application uses progesterone as the starting material, and obtains pregnanelonone through enol esterification, ketal protection, ester hydrolysis, hydrogenation, and reductive hydrolysis. This method is mild, uses conventional reagents, is simple to operate, suitable for industrialization, and yields a high-quality product with a purity of over 99.0% and an overall yield of approximately 90.0%.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a method for preparing pregnanediolone. Background Technology

[0002] Pregnanedolone (CAS: 128-20-1) is a natural metabolite of progesterone, with no hormonal activity. It was first isolated from the urine of pregnant women in 1973, and its anesthetic effect was first discovered by Figdor et al. in animal experiments in 1957. Pregnanedolone is characterized by rapid onset of action, short duration of action, hemodynamic stability, non-toxicity, non-cumulation, and few adverse reactions. In recent years, it has been used clinically for the induction and maintenance of anesthesia, as well as for outpatient surgical anesthesia.

[0003] Existing technologies have publicly reported various methods for synthesizing pregnanelonones. For example:

[0004] In 1961, Kupfer, D. et al. reported in Tetrahedron, 1961, 15, 193-6, the synthesis of pregnaneloids with a total yield of 60% using progesterone as the starting material, sodium borohydride as the reducing agent, and pyridine as the solvent. This route has the following drawbacks: 1) poor selectivity; 2) low yield.

[0005]

[0006] In 2012, Singh, Chandan, et al. reported in the Journal of Medicinal Chemistry, 2012, 55, 10662-10673, on the synthesis of pregnaneloids from lithocholic acid via an eight-step reaction:

[0007]

[0008] The following shortcomings exist in this route: 1) The route has a long procedure, low yield, and expensive lithocholic acid; 2) Benzene, which is genotoxic, is used in this route; 3) Lead tetraacetate, which is highly toxic, is also used in this route. Summary of the Invention

[0009] In view of this, the technical problem to be solved by the present invention is to provide a method for preparing pregnanelonone, and the method provided in this application has high yield and high selectivity.

[0010] This application provides a method for preparing pregnanelonone, comprising the following steps:

[0011] Step 1) Under the action of the first catalyst, progesterone and acid anhydride react to obtain the compound shown in formula (I);

[0012]

[0013] In formula (I), R is the residue that has been decarboxylated after hydrolysis of the acid anhydride;

[0014] Step 2) Under the action of a dehydrating agent and a second catalyst, the diol reacts with the compound shown in formula (I) and after deprotection, the compound shown in formula (II) is obtained.

[0015]

[0016] Step 3) Under the action of ligands and a third catalyst, the compound shown in formula (II) is selectively reduced by hydrogen to obtain the compound shown in formula (III).

[0017]

[0018] Step 4) The compound shown in formula (III) reacts with a reducing agent to deprotect it, yielding pregnane-1,4-ketone.

[0019] This application uses progesterone as the starting material and proceeds through enol esterification, ketal protection, ester hydrolysis, hydrogenation, and reductive hydrolysis to obtain pregnanetanolone. This method is mild, uses common reagents, is simple to operate, and is suitable for industrialization. The product obtained is of high quality, with an HPLC purity of over 99.0% and a high yield, with an overall yield of approximately 90.0%. The reaction route is as follows:

[0020]

[0021] This application uses progesterone as a raw material, reacting it with an acid anhydride under the action of a first catalyst to obtain an enol ester with a carbonyl group protected at the 3-position, namely compound I shown in formula (I). In some specific implementations, the acid anhydride is selected from one or more of alkyl anhydrides and phenyl-substituted alkyl anhydrides, including but not limited to acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride, etc., and can be one or more of them. When the acid anhydride is a combination of multiple substances, this application does not have a special limitation on the proportion of each specific substance. The acid anhydride is preferably acetic anhydride. In some specific implementations, the weight ratio of the acid anhydride to progesterone is 1 to 5.4:1, for example, it can be 1:1, 2:1, 3:1, 4:1, 5:1, or 5.4:1.

[0022] In some specific implementations, the first catalyst is an acid catalyst, including but not limited to sulfuric acid, glacial acetic acid, p-toluenesulfonic acid, or trifluoroacetic acid, and may be one or more of these. When the first catalyst is a combination of multiple substances, this application does not impose any special restrictions on the proportion of each specific substance. The first catalyst is preferably p-toluenesulfonic acid. In some specific implementations, the mass ratio of the first catalyst to progesterone is 0.1–0.4:1, for example, 0.1:1, 0.2:1, 0.3:1, or 0.4:1.

[0023] Specifically, this application first dissolves progesterone, then adds a first catalyst and an acid anhydride to react. After the reaction is complete, the solvent is removed by concentration, and then the mixture is separated by water to obtain the compound shown in formula (I). In formula (I), R is a residue after the acid anhydride is hydrolyzed and the carboxyl group is removed. For example, when the acid anhydride is acetic anhydride, R is ethyl; when the acid anhydride is propionic anhydride, R is propyl, etc. Accordingly, R is selected from ethyl, propyl, butyl, benzyl, etc., preferably ethyl. In some specific implementations, the solvent for the reaction includes, but is not limited to, dichloromethane, chloroform, etc., and can be one or more of them. When the solvent is a combination of multiple substances, this application does not have a special limitation on the proportion of each specific substance. The solvent is preferably dichloromethane. In some specific implementations, the volume-to-mass ratio of the solvent to progesterone is 0.4L to 2L:1kg, for example, 0.4L:1kg, 0.6L:1kg, 0.8L:1kg, 1L:1kg, 1.2L:1kg, 1.4L:1kg, 1.6L:1kg, 1.8L:1kg, 2L:1kg, etc. In some specific implementations, the reaction temperature is 0–60°C, and the reaction time is 1.5–6.0h. It is understood that in this invention, the reaction temperature of step 1) includes, but is not limited to, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, etc.; and the reaction time of step 1) includes, but is not limited to, 1.5h, 2.0h, 2.5h, 3.0h, 3.5h, 4.0h, 4.5h, 5.0h, 5.5h, 6.0h, etc.

[0024] After obtaining the compound shown in formula (I), it is reacted with a diol under the action of a dehydrating agent and a second catalyst to obtain a ketal with a carbonyl group protected at position 20. Then, the protection at position 3 is removed to obtain the compound shown in formula (II). In some specific implementations, in step 2), the second catalyst is selected from acids, including but not limited to sulfuric acid, p-toluenesulfonic acid, etc., and can be one or more of these. When the second catalyst is a combination of multiple substances, this application does not have any special restrictions on its specific ratio. The second catalyst is preferably p-toluenesulfonic acid. In some specific implementations, the weight ratio of the second catalyst to the compound shown in formula (I) is 0.01 to 0.05:1, for example, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1, etc.

[0025] In some specific implementations, the dehydrating agent includes, but is not limited to, triethyl orthoformate, trimethyl orthoacetate, and triethyl orthoacetate, and may be one or more of these. When the dehydrating agent is a combination of multiple substances, this application does not impose any special restrictions on the specific proportions of each substance. The dehydrating agent is preferably triethyl orthoformate. In some specific implementations, the volume-to-mass ratio of the dehydrating agent to the compound shown in formula (I) is 1L to 3L:1kg, including but not limited to 1L:1kg, 1.5L:1kg, 2L:1kg, 2.5L:1kg, 3L:1kg, etc.

[0026] In some specific implementations, the diol includes, but is not limited to, ethylene glycol, 1,3-propanediol, and 2,2-dimethyl-1,3-propanediol, and may be one or more of these. When the diol is a combination of multiple substances, this application does not impose any special restrictions on the proportion of each specific substance. The diol is preferably ethylene glycol. In some specific implementations, the volume-to-mass ratio of the diol to the compound shown in formula (I) is 1L to 5.6L:1kg, preferably 2L to 5.6L:1kg, more preferably 3L to 5.6L:1kg, and most preferably 4L to 5.6L:1kg, such as 4L:1kg, 4.5L:1kg, 5L:1kg, 5.6L:1kg, etc.

[0027] Specifically, after obtaining the compound shown in formula (I), this application dissolves it, then adds a second catalyst, a diol, and a dehydrating agent to react. After the reaction is complete, the resulting reaction product is deprotected to obtain the compound shown in formula (II). In some specific implementations, the solvent used in step 2) includes, but is not limited to, dichloromethane, chloroform, methanol, etc., and can be one or more of these. When the solvent is a combination of multiple substances, this application does not have any special restrictions on the proportion of each specific substance. The solvent is preferably dichloromethane. In some specific implementations, the volume-to-mass ratio of the solvent to the compound shown in formula (I) is 1L to 6L:1kg, for example, 1L:1kg, 2L:1kg, 3L:1kg, 4L:1kg, 5L:1kg, 6L:1kg, etc. In some specific implementations, in step 2), the reaction temperature is 15℃ to 50℃, for example, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, etc.; the reaction time is 1h to 5h, for example, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h, 3.5h, 4.0h, 4.5h, 5.0h, etc.

[0028] Step 2), the deprotection process, involves using an alkali base, and specifically includes the following steps:

[0029] The mixture obtained from the reaction is mixed with a base to deprotect the 3-position.

[0030] In some specific implementations, the base is selected from sodium hydroxide. In some specific implementations, the weight ratio of the base to the compound shown in formula (I) is 0.16 to 1:1, for example, 0.16:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, etc. Specifically, this application reacts the mixture obtained from the reaction with a base and methanol. The reaction temperature is preferably room temperature, the reaction time is preferably 0.5h to 2h, and after the reaction is completed, the mixture is concentrated, preferably under reduced pressure, to remove part of the solvent. Then, water is added, stirred, filtered, washed with water, and dried to obtain the compound shown in formula (II).

[0031] After obtaining the compound shown in formula (II), it is selectively reduced by hydrogen under the action of a ligand and a third catalyst to obtain the compound shown in formula (III). In some specific implementations, the ligand includes, but is not limited to, one or more of quinoline, pyridine, and 4-substituted pyridine, wherein the substituents in the 4-substituted pyridine include, but are not limited to, C1-4 alkyl or C1-4 alkoxy groups, such as methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc. In some specific implementations, the ligand can be one or more of these, and when the ligand is a combination of multiple substances, this application does not have a special limitation on the proportion of each specific substance. The ligand is preferably pyridine or 4-substituted pyridine, more preferably 4-methoxypyridine. In some specific implementations, the weight ratio of the ligand to the compound shown in formula (II) is preferably 0.1 to 0.5:1, for example, 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, etc.

[0032] In some specific implementations, the third catalyst includes, but is not limited to, Raney nickel and palladium on carbon, and may be one or more of these. When the third catalyst is combined with multiple substances, this application does not impose any special restrictions on the proportion of each substance. The third catalyst is preferably palladium on carbon. In some specific implementations, the weight ratio of the third catalyst to the compound shown in formula (II) is preferably 0.01 to 1:1, more preferably 0.05 to 0.3:1, for example, 0.05:1, 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.3:1, etc.

[0033] Specifically, this application first dissolves the compound shown in formula (II), then adds a third catalyst and ligand, introduces hydrogen gas to carry out the reaction, quenches the reaction with acid after the reaction is complete, filters, concentrates to remove part of the solvent, adds water, extracts with dichloromethane, concentrates the organic phase to remove the solvent, and dries to obtain the compound shown in formula (III). In some specific implementations, the solvent used to dissolve the compound shown in formula (II) includes, but is not limited to, methanol, dichloromethane, ethanol, ethyl acetate, tetrahydrofuran, etc., and can be one or more of these. When the solvent is a combination of multiple substances, this application does not have a special limitation on the proportion of each specific substance. The solvent is preferably methanol. In some specific implementations, the volume-to-mass ratio of the solvent to the compound shown in formula (II) is 5L to 20L:1kg, for example, 5L:1kg, 10L:1kg, 15L:1kg, 20L:1kg, etc. In some specific implementations, in step 3), the reduction temperature is 20℃~40℃, for example 20℃, 25℃, 30℃, 35℃, 40℃, etc.; the reaction time is 4.0h~6.0h, for example 4.0h, 4.5h, 5.0h, 5.5h, 6.0h, etc.

[0034] After obtaining the compound shown in formula (III), it is deprotected by reacting it with a reducing agent to obtain a pregnane ketone. In some specific implementations, the reducing agent is a borohydride salt, including but not limited to sodium borohydride, potassium borohydride, etc., and may be one or more of them, preferably potassium borohydride. In some specific implementations, the weight ratio of the reducing agent to the compound shown in formula (III) is 0.1 to 0.5:1:1, for example, 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, etc.

[0035] Specifically, this application first dissolves the compound shown in formula (III), then mixes it with a reducing agent to react. After the reaction is complete, the resulting reaction product is deprotected to obtain a pregnane ketone. In some specific implementations, the solvent for dissolving the compound shown in formula (III) includes, but is not limited to, methanol, dichloromethane, ethanol, etc., and can be one or more of these, preferably methanol or a mixture of ethanol and dichloromethane. In some specific implementations, the volume ratio of methanol or ethanol to dichloromethane is preferably 3-5:5-10, more preferably 3:6. In a specific example, the reaction temperature of step 4) is 0-40°C, for example 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc., and the reaction time of step 4) is 1.0-6.0h, for example 1.0h, 2.0h, 3.0h, 4.0h, 5.0h, 6.0h, etc.

[0036] After the reaction is complete, the resulting reaction product is mixed with an acidic compound to remove the carbonyl protecting group at position 20. The mixture is then concentrated to remove some of the solvent, extracted with dichloromethane, concentrated again to remove the solvent, and dried to obtain pregnane-1,3-dimethylol ketone. In some specific implementations, the acidic compound includes, but is not limited to, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc., and may be one or more of these, preferably hydrochloric acid. In some specific implementations, the volume-to-mass ratio of the acidic compound to the compound shown in formula (III) is preferably 1L to 11.8L:1kg, for example, 1L:1kg, 2L:1kg, 3L:1kg, 4L:1kg, 5L:1kg, 6L:1kg, 7L:1kg, 8L:1kg, 9L:1kg, 10L:1kg, 11L:1kg, 11.8L:1kg, etc.

[0037] This application uses progesterone as a starting material, and proceeds through enol esterification, ketal protection, ester hydrolysis, hydrogenation, and reductive hydrolysis to obtain pregnanetanolone. This method effectively utilizes current resource availability, avoids the limitations of fermentation processes, employs mild conditions and common reagents, is simple to operate, is suitable for industrialization, and yields high-quality products with an HPLC purity of over 99.0% and a high yield, with an overall yield of approximately 90.0%. Attached Figure Description

[0038] Figure 1 This is the proton NMR spectrum of the pregnane-1,000 ketone synthesized in Example 7;

[0039] Figure 2 This is the carbon spectrum of the pregnane-1,3-carbon synthesized in Example 7;

[0040] Figure 3 This is the single-crystal diffraction pattern of the pregnaneolone synthesized in Example 7;

[0041] Figure 4 This is the MS spectrum of the pregnane-1, synthesized in Example 7;

[0042] Figure 5 This is the UV spectrum of the pregnanelotone synthesized in Example 7;

[0043] Figure 6 This is the IR spectrum of the pregnane-1, synthesized in Example 7;

[0044] Figure 7 This is the HPLC chromatogram of the pregnane-1, synthesized in Example 7. Detailed Implementation

[0045] This invention provides a method for preparing pregnanelotones. Those skilled in the art can refer to this document and appropriately modify the process parameters to achieve the desired result. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in this invention. The methods and applications of this invention have been described through preferred embodiments. Those skilled in the art can clearly modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0046] This application uses progesterone as the starting material and proceeds through enol esterification, ketal protection, ester hydrolysis, hydrogenation, and reductive hydrolysis to obtain pregnanetanolone. This method is mild, uses common reagents, is simple to operate, and is suitable for industrialization. The product obtained is of high quality, with an HPLC purity of over 99.0% and a high yield, with an overall yield of approximately 90.0%. The reaction route is as follows:

[0047]

[0048] The preparation method of pregnanelotone provided in this application will be further described below with reference to the embodiments.

[0049] Example 1

[0050] 1 kg of progesterone, 0.2 kg of p-toluenesulfonic acid, 5 L of acetic anhydride, and 0.4 L of dichloromethane were added sequentially to a reaction flask and stirred until dissolved. The reaction was carried out at room temperature for 1.5–2 h. The dichloromethane was removed by concentration under reduced pressure. The solution was slowly poured into 10 L of water and stirred for 0.5 h. The mixture was filtered, and the filter cake was washed with 5 L of water. The product was then discharged. The product was dried in an oven at 40 °C for 5 h or more to obtain compound I (where R is ethyl) as shown in formula (I), with a yield of 105 ± 3% and a purity of approximately 98%.

[0051]

[0052] Example 2

[0053] In a reaction flask, 1 kg of compound I prepared in Example 1, 20 g of p-toluenesulfonic acid, and 4 L of dichloromethane were added sequentially and stirred until dissolved. Then, 5 L of ethylene glycol and 2.5 L of triethyl orthoformate were added, and the reaction was maintained at 36 ± 2 °C for 1.5–2 h. The temperature was lowered to 20 ± 5 °C, and 2 L of sodium hydroxide solution (8%) and 1 L of methanol were added. The mixture was stirred for 1 h. The mixture was concentrated under reduced pressure at 50 °C to a volume of approximately 6 L. Then, 5 L of water was added, and the mixture was stirred for 1 h. The mixture was then filtered, and the filtrate was washed with water until neutral. The filtrate was collected and dried in an oven at 55 °C for 5 h or more to obtain compound II as shown in formula (II), with a yield of 94 ± 3% and a purity of approximately 92%.

[0054]

[0055] Example 3

[0056] In a reaction flask, 1 kg of compound II prepared in Example 2, 0.1 kg of 4-methoxypyridine, 0.1 kg of palladium on carbon, and 15 L of methanol were added sequentially, and the mixture was stirred until dissolved. The mixture was purged with nitrogen three times and then with hydrogen three times, and reacted at 25 ± 5 °C for 6 h. The mixture was filtered, and the filtrate was recovered and concentrated. 4 L of water was added to the system, and the mixture was extracted three times with 4 L of dichloromethane. The organic phases were combined. The mixture was concentrated to dryness and discharged. It was dried in an oven at 40 °C for 5 h or more to obtain crude compound III, with a yield of 92 ± 3% and a purity of approximately 90%.

[0057] Add crude compound III, 4 L of dichloromethane, and 2 L of methanol to a reaction vessel. Stir until dissolved, then concentrate under reduced pressure to 1 L of solvent. Slowly cool to 20 ± 5 °C to precipitate the material. Filter to obtain compound III as shown in formula (III), with a yield of 93 ± 5% and a purity greater than 99%.

[0058]

[0059] Example 4

[0060] In a reaction flask, 1 kg of compound II prepared in Example 2, 0.3 kg of 4-methoxypyridine, 0.05 kg of palladium on carbon, and 20 L of methanol were added sequentially, and the mixture was stirred until dissolved. The mixture was purged with nitrogen three times and then with hydrogen three times, and reacted at 20 ± 5 °C for 5 h. The mixture was filtered, and the filtrate was recovered and concentrated. 4 L of water was added to the system, and the mixture was extracted three times with 4 L of dichloromethane. The organic phases were combined. The mixture was concentrated to dryness and discharged. It was dried in an oven at 40 °C for 5 h or more to obtain crude compound III, with a yield of 93 ± 3% and a purity of approximately 86%.

[0061] Add crude compound III, 4 L of dichloromethane, and 2 L of methanol to a reaction vessel. Stir until dissolved, then concentrate under reduced pressure to 1 L of solvent. Slowly cool to 20 ± 5 °C to precipitate the material. Filter to obtain compound III with a yield of 94 ± 5% and a purity of approximately 96%.

[0062]

[0063] Example 5

[0064] In a reaction flask, 1 kg of compound II prepared in Example 2, 0.3 kg of pyridine, 0.10 kg of Raney nickel, and 15 L of methanol were added sequentially, and the mixture was stirred until dissolved. The mixture was purged with nitrogen three times and then with hydrogen three times, and reacted at 25 ± 5 °C for 5 h. The mixture was filtered, and the filtrate was recovered and concentrated. 4 L of water was added to the system, and the mixture was extracted three times with 4 L of dichloromethane. The organic phases were combined. The mixture was concentrated to dryness and discharged. It was dried in an oven at 40 °C for 5 h or more to obtain crude compound III, with a yield of 92 ± 3% and a purity of approximately 85%.

[0065] Add crude compound III, 4 L of dichloromethane, and 2 L of methanol to a reaction vessel. Stir until dissolved, then concentrate under reduced pressure to 1 L of solvent. Slowly cool to 20 ± 5 °C to precipitate the material. Filter to obtain compound III with a yield of 93 ± 5% and a purity of approximately 87%.

[0066]

[0067] Example 6

[0068] In a reaction flask, 1 kg of compound II prepared in Example 2, 0.5 kg of 4-methoxypyridine, 0.3 kg of palladium on carbon, and 5 L of methanol were added sequentially, and the mixture was stirred until dissolved. The mixture was purged with nitrogen three times and then with hydrogen three times, and reacted at 40 ± 5 °C for 4 h. The mixture was filtered, and the filtrate was recovered and concentrated. 4 L of water was added to the system, and the mixture was extracted three times with 4 L of dichloromethane. The organic phases were combined. The mixture was concentrated to dryness and discharged. It was dried in an oven at 40 °C for 5 h or more to obtain crude compound III, with a yield of 90 ± 3% and a purity of approximately 78%.

[0069] Add crude compound III, 4 L of dichloromethane, and 2 L of methanol to a reaction vessel. Stir until dissolved, then concentrate under reduced pressure to 1 L of solvent. Slowly cool to 20 ± 5 °C to precipitate the material, filter, and obtain compound III with a yield of 92 ± 5% and a purity of approximately 90%.

[0070]

[0071] Example 7

[0072] In a reaction flask, 1 kg of compound III prepared in Example 3, 3 L of methanol, and 5 L of dichloromethane were added sequentially, and the mixture was stirred until dissolved. Then, 0.3 kg of potassium borohydride was added in portions, and the reaction was carried out at 25 ± 5 °C for 3 h. After the reaction was completed, the temperature was lowered to below 20 °C, and hydrochloric acid aqueous solution (10 L of 37% hydrochloric acid / 20 L of water) was slowly added dropwise. After the addition was completed, the reaction was continued at 25–30 °C for 1 h. The solvent was removed by concentration under reduced pressure, and the mixture was extracted three times with 12 L of dichloromethane. The organic phases were combined, washed with 3 L of water, concentrated to dryness, and discharged. The product was dried at 50 °C for 5 h or more to obtain crude pregnanelonone. The yield was 95 ± 3%, and the purity was approximately 95%.

[0073] Add crude pregnane, 4 L of dichloromethane, and 2 L of methanol to a reaction flask, stir until dissolved, concentrate under reduced pressure to 1 L of solvent, slowly cool to 0 ± 5 °C to precipitate, filter, and obtain pregnane. Dry the material at 65 °C for 5 hours or more, with a yield of 95 ± 2%, a purity greater than 99.5%, and a single impurity of less than 0.1%.

[0074] The pregnane-1,3-acetone was analyzed by NMR, single-crystal diffraction, MS, UV, IR and HPLC, respectively. The results are shown in [reference needed]. Figures 1 to 7 , Figure 1 This is the proton NMR spectrum of the pregnane-1,000 ketone synthesized in Example 7; Figure 2 This is the carbon spectrum of the pregnane-1,3-carbon synthesized in Example 7; Figure 3 This is the single-crystal diffraction pattern of the pregnaneolone synthesized in Example 7; Figure 4 This is the MS spectrum of the pregnane-1, synthesized in Example 7; Figure 5 This is the UV spectrum of the pregnanelotone synthesized in Example 7; Figure 6 This is the IR spectrum of the pregnane-1, synthesized in Example 7; Figure 7 This is the HPLC chromatogram of the pregnanelotone synthesized in Example 7. (From...) Figures 1 to 7 It is known that the method provided in this application has yielded pregnane-1,4-diolone.

[0075] Example 8

[0076] In a reaction flask, 1 kg of compound III prepared in Example 2, 6 L of methanol, and 10 L of dichloromethane were added sequentially, and the mixture was stirred until dissolved. Then, 0.1 kg of potassium borohydride was added in portions. After the addition was complete, the reaction was carried out at 20 ± 5 °C for 6 h. After the reaction was completed, the temperature was lowered to below 20 °C, and hydrochloric acid aqueous solution (11 L of 37% hydrochloric acid / 22 L of water) was slowly added dropwise. After the addition was complete, the reaction was continued at 25–30 °C for 1 h. The solvent was removed by concentration under reduced pressure, and the mixture was extracted three times with 12 L of dichloromethane. The organic phases were combined, washed with 3 L of water, concentrated to dryness, and discharged. The product was dried at 50 °C for 5 h or more to obtain crude pregnanelonone. The yield was 93 ± 3%, and the purity was approximately 92%.

[0077] Add crude pregnane, 4L of dichloromethane and 2L of methanol to a reaction flask, stir until dissolved, concentrate under reduced pressure to 1L of solvent, slowly cool to 0±5℃ to precipitate, filter to obtain pregnane, dry at 65℃ for more than 5 hours, yield 92±2%, purity about 94%.

[0078] Example 9

[0079] In a reaction flask, 1 kg of compound III, 3 L of ethanol, and 5 L of dichloromethane were added sequentially, and the mixture was stirred until dissolved. Then, 0.5 kg of sodium borohydride was added in portions. After the addition was complete, the reaction was carried out at 40 ± 5 °C for 2 h. After the reaction was completed, the temperature was lowered to below 20 °C, and hydrochloric acid aqueous solution (5 L hydrochloric acid / 10 L water) was slowly added dropwise. After the addition was complete, the reaction was continued at 25–30 °C for 1 h. The solvent was removed by concentration under reduced pressure, and the mixture was extracted three times with 12 L of dichloromethane. The organic phases were combined, washed with 3 L of water, concentrated to dryness, and discharged. The product was dried at 50 °C for 5 h or more to obtain crude pregnanelonone. The yield was 95 ± 3%, and the purity was approximately 87%.

[0080] Add crude pregnane, 4L of dichloromethane and 2L of methanol to a reaction flask, stir until dissolved, concentrate under reduced pressure to 1L of solvent, slowly cool to 0±5℃ to precipitate, filter to obtain pregnane. Dry at 65℃ for more than 5 hours, yield 93±2%, purity about 89%.

[0081] The above are merely preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing pregnanelonone, comprising the following steps: Step 1) Under the action of the first catalyst, progesterone and acid anhydride react to obtain the compound shown in formula (I); Formula (I); In formula (I), R is the residue after the acid anhydride is hydrolyzed and the carboxyl group is removed; Step 2) Under the action of a dehydrating agent and a second catalyst, ethylene glycol reacts with the compound shown in formula (I) to obtain the compound shown in formula (II) after deprotection. Formula (II); Step 3) Under the action of ligands and a third catalyst, the compound shown in formula (II) is selectively reduced by hydrogen to obtain the compound shown in formula (III); Formula (III); Step 4) The compound shown in formula (III) is reacted with a reducing agent to deprotect it, yielding a pregnane ketone; the reducing agent is selected from one or more of potassium borohydride and sodium borohydride; the deprotection is performed using an acid.

2. The preparation method according to claim 1, characterized in that, In step 1), the acid anhydride is selected from one or more of alkyl acid anhydrides and phenyl-substituted alkyl acid anhydrides; The weight ratio of the acid anhydride to progesterone is 1~5.4:1; The first catalyst is selected from acids.

3. The preparation method according to claim 2, characterized in that, In step 1), the reaction temperature is 0~60℃ and the time is 1.5~6.0h.

4. The preparation method according to claim 1, characterized in that, In step 2), the second catalyst is selected from acids; The dehydrating agent is selected from one or more of triethyl orthoformate, trimethyl orthoacetate, and triethyl orthoacetate.

5. The preparation method according to claim 4, characterized in that, In step 2), the reaction temperature is 15℃~50℃ and the time is 1h~5h; The deprotection is performed using an alkali.

6. The preparation method according to claim 1, characterized in that, In step 3), the ligand is selected from one or more of quinoline, pyridine and 4-substituted pyridine, wherein in the 4-substituted pyridine, the substituent is selected from C1-4 alkyl or C1-4 alkoxy. The third catalyst is selected from one or more of Raney nickel and palladium on carbon; The weight ratio of the ligand, the third catalyst, and the compound shown in formula (II) is 0.1~1:0.01~1:

1.

7. The preparation method according to claim 6, characterized in that, In step 3), the reduction temperature is 20℃~40℃, and the reaction time is 4.0h~6.0h.

8. The preparation method according to claim 1, characterized in that, In step 4), the weight ratio of the reducing agent to the compound shown in formula (III) is 0.3 to 1:

1.

9. The preparation method according to claim 8, characterized in that, In step 4), the reaction temperature is 0℃~40℃ and the reaction time is 3.0h~4.0h.

10. The preparation method according to any one of claims 1 to 9, characterized in that, In step 1), the solvent used in the reaction is selected from one or more of dichloromethane and chloroform; In step 2), the solvent used in the reaction is selected from one or more of dichloromethane, chloroform, and methanol; In step 3), the solvent used in the reaction is selected from one or more of methanol, dichloromethane, ethanol, ethyl acetate, and tetrahydrofuran; In step 4), the solvent used in the reaction is selected from one or more of methanol, ethanol and dichloromethane.

Images