Preparation method of pregnanolone

Abstract

The invention provides a preparation method of pregnanolone, which comprises the following steps: 1) under the action of a first catalyst, progesterone and anhydride react to obtain a compound as shown in a formula (I); 2) under the action of a dehydrating agent and a second catalyst, diol reacts with the compound shown in the formula (I), and a compound shown in a formula (II) is obtained after deprotection; 3) under the action of a ligand and a third catalyst, selectively reducing the compound as shown in the formula (II) by hydrogen to obtain a compound as shown in a formula (III); and 4) reacting the compound as shown in the formula (III) with a reducing agent, and deprotecting to obtain pregnanolone. According to the present invention, progesterone is adopted as the starting material, enol esterification reaction, ketal protection, ester group hydrolysis, hydrogenation and reduction hydrolysis are performed to obtain pregnanolone, the method has characteristics of mild condition, conventional reagent, simple operation and suitableness for industrialization, the obtained product has characteristics of good quality, purity of more than 99.0%, and total yield of about 90.0%.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, and in particular to a method for preparing pregnanolone. Background Art

[0002] Pregnanolone (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. Figdor et al. first discovered its anesthetic effect through animal experiments in 1957. Pregnanolone has the characteristics of rapid anesthetic onset, short duration of action, stable hemodynamics, non-toxicity, non-accumulation, and few adverse reactions. In recent years, it has been used clinically for the induction and maintenance of anesthesia, as well as outpatient surgical anesthesia.

[0003] The prior art publicly reports a variety of synthesis methods of pregnaneolone. For example:

[0004] In 1961, Kupfer, D et al. reported in Tetrahedron, 1961, 15, 193-6 that pregnanolone was synthesized 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 disadvantages: 1) poor selectivity; 2) low yield;

[0005]

[0006] In 2012, Singh, Chandan et al. reported in Journal of Medicinal Chemistry, 2012, 55, 10662-10673 that pregnanolone was synthesized by eight steps using lithocholic acid as the starting material:

[0007]

[0008] This route has the following disadvantages: 1) This route has a long process, a low yield, and lithocholic acid is expensive; 2) This route uses genotoxic benzene; 3) This route also uses lead tetraacetate, which is highly toxic. 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 pregnanolone, and the method provided in the present application has high yield and high selectivity.

[0010] The present application provides a method for preparing pregnaneolone, comprising the following steps:

[0011] Step 1) under the action of a first catalyst, progesterone and anhydride react to obtain a compound represented by formula (I);

[0012]

[0013] In formula (I), R is the residue after the carboxyl group is removed after hydrolysis of anhydride;

[0014] Step 2) reacting the diol with the compound represented by formula (I) under the action of a dehydrating agent and a second catalyst, and obtaining the compound represented by formula (II) after deprotection;

[0015]

[0016] Step 3) Under the action of the ligand and the third catalyst, the compound represented by formula (II) is selectively reduced by hydrogen to obtain the compound represented by formula (III);

[0017]

[0018] Step 4) The compound represented by formula (III) reacts with a reducing agent and then undergoes deprotection to obtain pregnanolone.

[0019] The present invention uses progesterone as the starting material, and obtains pregnanolone through enol esterification reaction, ketal protection, ester hydrolysis, hydrogenation, and reductive hydrolysis. The method has mild conditions, conventional reagents, simple operation, and is suitable for industrialization. The obtained product has good quality, HPLC purity of more than 99.0%, high yield, and a total yield of about 90.0%. The reaction route is as follows:

[0020]

[0021] The present application uses progesterone as a raw material, and reacts with an anhydride under the action of a first catalyst to obtain a 3-carbonyl protected enol ester, i.e., compound I shown in formula (I). In some specific implementations, the 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 anhydride is a combination of multiple substances, the present application has no special restrictions on the proportion of each specific substance. The anhydride is preferably acetic anhydride. In some specific implementations, the weight ratio of the anhydride to progesterone is 1 to 5.4:1, for example, it can be 1:1, 2:1, 3:1, 4:1, 5:1, 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, etc., and can be one or more thereof. When the first catalyst is a combination of multiple substances, the present application has no 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 to 0.4:1, for example 0.1:1, 0.2:1, 0.3:1, 0.4:1.

[0023] Specifically, the present application first dissolves progesterone, then adds the first catalyst and anhydride to react, concentrates and removes the solvent after the reaction is complete, and then precipitates the material to obtain a compound shown in formula (I). In formula (I), R is the residue of the carboxyl group removed after the anhydride is hydrolyzed, for example, when the anhydride is acetic anhydride, R is ethyl, and when the anhydride is propionic anhydride, R is propyl, etc. Correspondingly, the R is selected from ethyl, propyl, butyl, benzyl, etc., preferably ethyl. In some specific implementations, the solvent of the reaction includes but is not limited to dichloromethane, chloroform, etc., which can be one or more thereof. When the solvent is a combination of multiple substances, the present application has no special restrictions on the usage ratio of each specific substance. The solvent is preferably dichloromethane. In some specific implementations, the volume 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 to 60°C, and the reaction time is 1.5 to 6.0h. It can be understood that in the present 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.; 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 diol under the action of a dehydrating agent and a second catalyst to obtain a ketal protected by the carbonyl group at position 20, and then the 3rd position is deprotected to obtain a compound shown in formula (II). In some specific implementations, in the 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 them. When the second catalyst is a combination of multiple substances, the application has no special restrictions on its specific proportion. 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, etc., and can be one or more thereof. When the dehydrating agent is a combination of multiple substances, the present application has no special restrictions on the specific proportions of each substance. The dehydrating agent is preferably triethyl orthoformate. In some specific implementations, the volume mass ratio of the dehydrating agent to the compound represented by 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-propylene glycol and 2,2-dimethyl-1,3-propylene glycol, etc., and can be one or more thereof. When the diol is a combination of multiple substances, the present application has no special restrictions on the proportion of each specific substance. The diol is preferably ethylene glycol. In some specific implementations, the volume mass ratio of the diol to the compound represented by 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, for example 4L:1kg, 4.5L:1kg, 5L:1kg, 5.6L:1kg, etc.

[0027] Specifically, after obtaining the compound shown in formula (I), the present application dissolves it, then adds a second catalyst, a diol and a dehydrating agent to react, and after the reaction is completed, the obtained 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., which can be one or more of them. When the solvent is a combination of multiple substances, the present application has no special restrictions on the dosage ratio of each specific substance. The solvent is preferably dichloromethane. In some specific implementations, the volume 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 the step 2), the reaction temperature is 15°C to 50°C, for example, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 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] In the step 2), the deprotection is performed using a base, and specifically comprises the following steps:

[0029] The resulting mixture is mixed with a base to react and 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, such as 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, the present application will react the mixture obtained by the reaction with a base and methanol, the reaction temperature is preferably room temperature, the time is preferably 0.5h to 2h, and after the reaction is completed, it is concentrated, preferably concentrated under reduced pressure to remove part of the solvent, and 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 the ligand and the 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, in the 4-substituted pyridine, the substituents include but are not limited to C1-4 alkyl or C1-4 alkoxy, 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 them. When the ligand is a combination of multiple substances, the present application has no special restrictions 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, it can be: 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 carbon, etc., and can be one or more of them; when the third catalyst is a combination of multiple substances, the present application has no special restrictions on the usage ratio of each substance. The third catalyst is preferably palladium carbon. In some specific implementations, the weight ratio of the third catalyst to the compound represented by formula (II) is preferably 0.01 to 1:1, more preferably 0.05 to 0.3:1, for example, it can be: 0.05:1, 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.3:1, etc.

[0033] Specifically, the present application first dissolves the compound shown in formula (II), then adds the third catalyst and the ligand, passes hydrogen to react, quenches the reaction with acid after the reaction is completed, filters, concentrates and removes 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., which can be one or more of them. When the solvent is a combination of multiple substances, the present application has no special restrictions on the ratio of each specific substance. The solvent is preferably methanol. In some specific implementations, the volume ratio mass ratio of the solvent to the compound shown in formula (II) is 5L~20L:1kg, for example, it can be 5L:1kg, 10L:1kg, 15L:1kg, 20L:1kg, etc. In some specific implementations, in step 3), the reduction temperature is 20°C to 40°C, for example, 20°C, 25°C, 30°C, 35°C, 40°C, etc.; the reaction time is 4.0h to 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 reacted with a reducing agent and then deprotected to obtain pregnane alcohol ketone. In some specific implementations, the reducing agent is a borohydride salt, including but not limited to sodium borohydride, potassium borohydride, etc., and can be one or more thereof, 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, the present application first dissolves the compound shown in formula (III), then mixes with a reducing agent for reaction, and after the reaction is completed, the obtained reaction product is deprotected to obtain pregnane alcohol 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., which can be one or more of them, preferably a mixed solvent of methanol or ethanol and dichloromethane. In some specific implementations, the volume ratio of the methanol or ethanol to dichloromethane is preferably 3 to 5:5 to 10, more preferably 3:6. In a specific example, the reaction temperature of step 4) is 0 to 40°C, such as 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 to 6.0h, such as 1.0h, 2.0h, 3.0h, 4.0h, 5.0h, 6.0h, etc.

[0036] After the reaction is completed, the obtained reaction product is mixed with an acidic compound, the carbonyl protecting group at position 20 is removed, part of the solvent is concentrated to remove, dichloromethane is used for extraction, the solvent is concentrated to remove, and pregnane alcohol ketone is obtained by drying. In some specific implementations, the acidic compound includes but is not limited to hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc., and can be one or more thereof, preferably hydrochloric acid. In some specific implementations, the volume mass ratio of the acidic compound to the compound represented by formula (III) is preferably 1L to 11.8L:1kg, for example, it can be 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] The present invention uses progesterone as the starting material, and obtains pregnanolone through enol esterification reaction, ketal protection, ester hydrolysis, hydrogenation, and reductive hydrolysis. The method can effectively meet the current resource form and avoid the limitation of fermentation process. The conditions are mild, the reagents are conventional, the operation is simple, and it is suitable for industrialization. The obtained product has good quality, HPLC purity is above 99.0%, the yield is high, and the total yield is about 90.0%. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 is the hydrogen spectrum of pregnanolone synthesized in Example 7;

[0039] Figure 2 This is the carbon spectrum of pregnanolone synthesized in Example 7;

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

[0041] Figure 4 This is the MS spectrum of pregnanolone synthesized in Example 7;

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

[0043] Figure 6 is the IR spectrum of pregnanolone synthesized in Example 7;

[0044] Figure 7 This is the HPLC spectrum of pregnanolone synthesized in Example 7. DETAILED DESCRIPTION

[0045] The present invention provides a method for preparing pregnaneolone, and those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the method and application of this article without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0046] The present invention uses progesterone as the starting material, and obtains pregnanolone through enol esterification reaction, ketal protection, ester hydrolysis, hydrogenation, and reductive hydrolysis. The method has mild conditions, conventional reagents, simple operation, and is suitable for industrialization. The obtained product has good quality, HPLC purity of more than 99.0%, high yield, and a total yield of about 90.0%. The reaction route is as follows:

[0047]

[0048] The preparation method of pregnanolone provided in the present application is further described below in conjunction with examples.

[0049] Example 1

[0050] Add 1kg of progesterone, 0.2kg of p-toluenesulfonic acid, 5L of acetic anhydride and 0.4L of dichloromethane to the reaction flask in sequence and stir until dissolved. React at room temperature for 1.5 to 2h, concentrate under reduced pressure to remove dichloromethane, slowly pour the liquid into 10L of water, stir for 0.5h, filter, rinse the filter cake with 5L of water, and discharge. Dry in an oven at 40°C for 5h or more to obtain compound I (where R is ethyl) of formula (I), with a yield of 105±3% and a purity of about 98%;

[0051]

[0052] Example 2

[0053] Add 1kg of compound I prepared in Example 1, 20g of p-toluenesulfonic acid and 4L of dichloromethane to the reaction flask in sequence, stir until dissolved, add 5L of ethylene glycol and 2.5L of triethyl orthoformate, and keep warm at 36±2℃ for 1.5-2h. Cool to 20±5℃, add 2L of sodium hydroxide solution (8%) and 1L of methanol, and stir for 1h. Concentrate under reduced pressure at 50℃ until the volume of the liquid is about 6L, add 5L of water, stir for 1h, filter, and rinse with water until the filtrate is neutral, collect the material, and dry it in an oven at 55℃ for 5h or more to obtain compound II shown in formula (II), with a yield of 94±3% and a purity of about 92%.

[0054]

[0055] Example 3

[0056] Add 1kg of compound II prepared in Example 2, 0.1kg of 4-methoxypyridine, 0.1kg of palladium carbon, and 15L of methanol to the reaction bottle in sequence, and stir until dissolved. Replace with nitrogen 3 times, replace with hydrogen 3 times, react at 25±5°C for 6h, filter, recover the filtrate and concentrate. Add 4L of water to the system, extract with 4L of dichloromethane 3 times, and combine the organic phases. Concentrate to dryness and discharge. Dry in an oven at 40°C for 5h or more to obtain a crude compound III with a yield of 92±3% and a purity of about 90%.

[0057] Add crude compound III, 4 L of dichloromethane and 2 L of methanol into a reaction tank, stir until dissolved, and 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 represented by formula (III) with a yield of 93±5% and a purity greater than 99%.

[0058]

[0059] Example 4

[0060] Add 1kg of compound II prepared in Example 2, 0.3kg of 4-methoxypyridine, 0.05kg of palladium carbon, and 20L of methanol to the reaction bottle in sequence, and stir until dissolved. Replace with nitrogen 3 times, replace with hydrogen 3 times, react at 20±5°C for 5h, filter, recover the filtrate and concentrate. Add 4L of water to the system, extract with 4L of dichloromethane 3 times, and combine the organic phases. Concentrate to dryness and discharge. Dry in an oven at 40°C for 5h or more to obtain a crude compound III with a yield of 93±3% and a purity of about 86%.

[0061] Add crude compound III, 4 L of dichloromethane and 2 L of methanol into a reaction tank, stir until dissolved, and 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 94±5% and a purity of about 96%.

[0062]

[0063] Example 5

[0064] Add 1kg of compound II prepared in Example 2, 0.3kg of pyridine, 0.10kg of Raney nickel, and 15L of methanol to the reaction bottle in sequence, and stir until dissolved. Replace with nitrogen 3 times, replace with hydrogen 3 times, react at 25±5°C for 5h, filter, recover the filtrate and concentrate. Add 4L of water to the system, extract with 4L of dichloromethane 3 times, and combine the organic phases. Concentrate to dryness and discharge. Dry in an oven at 40°C for 5h or more to obtain a crude compound III with a yield of 92±3% and a purity of about 85%.

[0065] Add crude compound III, 4 L of dichloromethane and 2 L of methanol into a reaction tank, stir until dissolved, and 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 93±5% and a purity of about 87%.

[0066]

[0067] Example 6

[0068] Add 1kg of compound II prepared in Example 2, 0.5kg of 4-methoxypyridine, 0.3kg of palladium carbon, and 5L of methanol to the reaction bottle in sequence, and stir until dissolved. Replace with nitrogen 3 times, replace with hydrogen 3 times, react at 40±5°C for 4h, filter, recover the filtrate and concentrate. Add 4L of water to the system, extract with 4L of dichloromethane 3 times, and combine the organic phases. Concentrate to dryness and discharge. Dry in an oven at 40°C for 5h or more to obtain a crude compound III with a yield of 90±3% and a purity of about 78%.

[0069] Add crude compound III, 4 L of dichloromethane and 2 L of methanol into a reaction tank, stir until dissolved, and 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 about 90%.

[0070]

[0071] Example 7

[0072] Add 1kg of compound III prepared in Example 3, 3L of methanol and 5L of dichloromethane to the reaction flask in sequence and stir until dissolved. Then add 0.3kg of potassium borohydride in batches, and react at 25±5°C for 3h after addition. After the reaction is completed, cool to below 20°C and slowly add aqueous hydrochloric acid solution (10L of 37% hydrochloric acid / 20L of water). After the addition is complete, continue to keep warm at 25-30°C for 1h, concentrate under reduced pressure to remove the solvent, extract 3 times with 12L of dichloromethane, combine the organic phases, add 3L of water to wash the organic phase, concentrate to dryness, and discharge. Dry at 50°C for 5h or more to obtain crude pregnanolone. The yield is 95±3% and the purity is about 95%.

[0073] Add crude pregnanolone, 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°C for precipitation, filter to obtain pregnanolone, dry at 65°C for 5h or more, the yield is 95±2%, the purity is greater than 99.5%, and a single impurity is less than 0.1%.

[0074] The pregnanolone was subjected to NMR analysis, single crystal diffraction analysis, MS analysis, UV analysis, IR analysis and HPLC analysis, and the results are shown in Figure 1 to Figure 7 , Figure 1 is the hydrogen spectrum of pregnanolone synthesized in Example 7; Figure 2 This is the carbon spectrum of pregnanolone synthesized in Example 7; Figure 3 is the single crystal diffraction pattern of pregnanolone synthesized in Example 7; Figure 4 This is the MS spectrum of pregnanolone synthesized in Example 7; Figure 5 This is the UV spectrum of pregnanolone synthesized in Example 7; Figure 6 is the IR spectrum of pregnanolone synthesized in Example 7; Figure 7 This is the HPLC spectrum of pregnanolone synthesized in Example 7. Figures 1 to 7 It can be seen that the method provided in this application prepared pregnanolone.

[0075] Example 8

[0076] Add 1kg of compound III prepared in Example 2, 6L of methanol and 10L of dichloromethane to the reaction flask in sequence and stir until dissolved. Then add 0.1kg of potassium borohydride in batches, and react at 20±5°C for 6h after addition. After the reaction is completed, cool to below 20°C and slowly add aqueous hydrochloric acid solution (11L of 37% hydrochloric acid / 22L of water). After the addition is complete, continue to keep warm at 25-30°C for 1h, concentrate under reduced pressure to remove the solvent, extract 3 times with 12L of dichloromethane, combine the organic phases, add 3L of water to wash the organic phase, concentrate to dryness, and discharge. Dry at 50°C for 5h or more to obtain crude pregnane alcohol ketone. The yield is 93±3% and the purity is about 92%.

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

[0078] Example 9

[0079] Add 1kg of compound III, 3L of ethanol and 5L of dichloromethane to the reaction bottle in sequence, and stir until dissolved. Then add 0.5kg of sodium borohydride in batches, and react at 40±5℃ for 2h after addition. After the reaction is completed, cool to below 20℃ and slowly add hydrochloric acid aqueous solution (5L hydrochloric acid / 10L water). After the addition is complete, continue to keep warm at 25-30℃ for 1h, concentrate under reduced pressure to remove the solvent, extract 3 times with 12L of dichloromethane, combine the organic phases, add 3L of water to wash the organic phase, concentrate to dryness, and discharge. Dry at 50℃ for 5h or more to obtain crude pregnanolone. The yield is 95±3% and the purity is about 87%.

[0080] Add crude pregnanolone, 4L of dichloromethane and 2L of methanol into a reaction flask, stir until dissolved, concentrate under reduced pressure to 1L of solvent, slowly cool to 0±5°C to precipitate, filter to obtain pregnanolone, dry at 65°C for more than 5h, the yield is 93±2%, and the purity is about 89%.

[0081] The above are only preferred embodiments of the present invention. It should be pointed out that, for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing pregnanolone, comprising the following steps: Step 1) under the action of a first catalyst, progesterone and anhydride react to obtain a compound represented by formula (I); In formula (I), R is the residue after the carboxyl group is removed after hydrolysis of anhydride; Step 2) reacting the diol with the compound represented by formula (I) under the action of a dehydrating agent and a second catalyst, and obtaining the compound represented by formula (II) after deprotection; Step 3) Under the action of the ligand and the third catalyst, the compound represented by formula (II) is selectively reduced by hydrogen to obtain the compound represented by formula (III); Step 4) The compound represented by formula (III) reacts with a reducing agent and then undergoes deprotection to obtain pregnanolone.

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

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

4. The preparation method according to claim 1, characterized in that: In the step 2), the second catalyst is selected from an acid; The dehydrating agent is selected from one or more of triethyl orthoformate, trimethyl orthoacetate and triethyl orthoacetate; The diol is selected from one or more of ethylene glycol, 1,3-propylene glycol and 2,2-dimethyl-1,3-propylene glycol.

5. The preparation method according to claim 4, characterized in that: In the step 2), the reaction temperature is 15°C to 50°C and the reaction time is 1h to 5h; The deprotection is carried out using a base.

6. The preparation method according to claim 1, characterized in that: In the step 3), the ligand is selected from one or more of quinoline, pyridine and 4-substituted pyridine, wherein the substituent in the 4-substituted pyridine 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 represented by formula (II) is 0.1-1:0.01-1:

1.

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

8. The preparation method according to claim 1, characterized in that: In the step 4), the reducing agent is selected from one or more of potassium borohydride and sodium borohydride; The weight ratio of the reducing agent to the compound represented by formula (III) is 0.3 to 1:

1.

9. The preparation method according to claim 8, characterized in that: In the step 4), the reaction temperature is 0°C to 40°C, and the reaction time is 3.0h to 4.0h; The deprotection is carried out using an acid.

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

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