A process for the synthesis of pregnenolone

Abstract

The application relates to the technical field of organic synthesis, and particularly discloses a synthesis process of high-purity pregnenolone, which comprises the following steps: S1, esterification reaction of progesterone and an acylation reagent to obtain product 1; S2, ketalization reaction of the product 1, diol and a dehydrating agent in the presence of a catalyst to obtain product 2; S3, reduction reaction of the product 2 and a reducing agent to obtain product 3; and hydrolysis reaction of the product 3 and an acidic compound to obtain pregnenolone. The synthesized pregnenolone has high purity and yield.

Description

Technical Field

[0001] This application relates to the field of organic synthesis technology, and more specifically, to a process for synthesizing high-purity pregnenolone. Background Technology

[0002] Pregnenolone, as a key precursor compound in the biosynthetic pathway of steroid hormones, holds an irreplaceable position in the pharmaceutical and chemical fields. Its molecular structure contains the basic skeleton of the steroid nucleus (a tetracyclic structure of A, B, C, and D rings) and features functional groups such as Δ5 double bonds, 3β-hydroxyl groups, and 20-keto groups. It can be converted into various physiologically active steroid hormones such as progesterone, testosterone, and estradiol through reactions such as hydroxyl oxidation, double bond reduction, and side chain modification. It is used in the research and development and production of contraceptive drugs, anti-inflammatory drugs, and sex hormone replacement therapy drugs.

[0003] Currently, the synthesis processes of pregnenolone are mainly divided into three categories: chemical synthesis using natural sterols as raw materials, total chemical synthesis, and biosynthesis. For example, patent application CN109970835A discloses a method for preparing pregnenolone. This method uses pregnenolone acetate as the starting material and obtains high-purity pregnenolone through hydrogenation reduction reaction, preliminary separation, hydrolysis and purification, and refining steps. However, when using Reinhold nickel and hydrogen for hydrogenation, the Reinhold nickel catalytic selectivity is insufficient, which easily leads to over-reduction of non-target double bonds on the steroid nucleus or side reactions of functional groups, generating structurally similar steroidal byproducts. At the same time, small fluctuations in hydrogen reaction conditions (temperature, pressure, purity, etc.) can exacerbate the problem of incomplete reduction of raw materials or over-hydrogenation, resulting in fluctuations in the content of unreacted raw materials and byproducts. In addition, Reinhold nickel is easy to remain due to its small particle size, and its degradation products can also introduce impurities. These factors together make it difficult to stably control the types and contents of impurities in the product, directly affecting the purity and yield of pregnenolone.

[0004] Therefore, researching a synthetic process for pregnenolone with fewer side reactions, higher purity, and higher yield has significant practical implications and application value. Summary of the Invention

[0005] In order to provide a synthetic process for pregnenolone with fewer side reactions and higher product purity and yield, this application provides a synthetic process for high-purity pregnenolone.

[0006] The synthesis process for high-purity pregnenolone provided in this application adopts the following technical solution:

[0007] In a first aspect, this application provides a process for synthesizing high-purity pregnenolone, employing the following technical solution:

[0008] A process for synthesizing high-purity pregnenolone includes the following steps:

[0009] S1, Progesterone is esterified with an acylation reagent to obtain product 1;

[0010] S2, the product 1, diol and dehydrating agent are subjected to a ketalization reaction in the presence of a catalyst to obtain product 2;

[0011] S3, the product 2 is reduced with a reducing agent to obtain product 3; the product 3 is hydrolyzed with an acidic compound to obtain pregnenolone.

[0012] By adopting the above technical solution, this process uses progesterone as the starting material and proceeds through four steps: esterification, ketal protection, reduction, and hydrolysis. This process has few side reactions and yields high purity and high yield of pregnenolone. At the same time, the conditions of each step are mild and the operation is simple. The raw materials used are readily available and low in cost. The post-processing is simple and can effectively remove impurities, making it suitable for large-scale production of pharmaceutical intermediates.

[0013] Preferably, in S1, the esterification reaction is carried out using a method of mother liquor recovery and reuse with the addition of reagents.

[0014] By adopting the above technical solution, the residual acylation reagent in the mother liquor can be recovered and an appropriate amount of reagent can be added to maintain its effective concentration, reducing material waste and costs; at the same time, waste emissions are reduced, which is in line with the concept of green chemistry, and the economic efficiency and sustainability of the process can be improved by cyclically stabilizing the reaction system.

[0015] Preferably, in S1, the acylation reagent is a mixture of acetyl chloride and acetic anhydride in a molar ratio of (5-9):(3-6); the molar ratio of progesterone to the acylation reagent is (1-4):(8-15).

[0016] By adopting the above technical solution, the acylation reagent is a mixture of acetyl chloride and acetic anhydride. Acetyl chloride has high reactivity, can quickly provide acetyl groups and maintain the acidity of the system by generating hydrochloric acid, and activates the carbonyl group of acetic anhydride to accelerate the reaction, especially in recycling to compensate for reagent loss. Acetic anhydride has a mild reaction and its byproducts are easy to handle, so as the main acylation reagent, it ensures the stable progress of the reaction. The synergistic effect of the two not only improves the reaction rate and raw material conversion rate, but also meets the reagent replenishment needs in the recycling process, reduces side reactions, and balances efficiency and operability.

[0017] By optimizing the molar ratio of progesterone to acylation reagent, adding an appropriate amount of excess acid anhydride can both promote the reversible reaction in the forward direction and ensure the full conversion of progesterone, while avoiding the waste of raw materials, increased side reactions, and post-processing burden caused by excess acid anhydride.

[0018] Preferably, in S2, the diol is one or more of ethylene glycol, 1,3-propanediol, and 2,2-dimethyl-1,3-propanediol, more preferably ethylene glycol; the dehydrating agent is one or more of trimethyl orthoformate, triethyl orthoformate, trimethyl orthoacetate, and triethyl orthoacetate, more preferably trimethyl orthoformate; the catalyst is one or two of p-toluenesulfonic acid and sulfuric acid, more preferably p-toluenesulfonic acid.

[0019] By adopting the above technical solution, the two hydroxyl groups in the ethylene glycol molecule are adjacent and have small steric hindrance, which can quickly undergo ketalization reaction with the carbonyl group that needs to be protected in product 1 to form a stable five-membered ring ketal structure. At the same time, it is widely available, inexpensive, and has good miscibility with common reaction solvents such as toluene, which is beneficial to the homogeneity of the reaction system and can promote the efficient progress of the reaction.

[0020] The three methoxy groups in the trimethyl orthoformate molecule can react with the water produced in the reaction, driving the ketalization equilibrium to the right by consuming water. This results in high dehydration efficiency and a mild reaction. Meanwhile, the reaction byproducts are formic acid and methanol, both of which are readily soluble in organic solvents and do not form solid residues. Trimethyl orthoformate also has a certain catalytic effect, which can help activate the carbonyl group and synergistically increase the reaction rate with the catalyst. Furthermore, its moderate boiling point facilitates subsequent separation from the system by distillation, improving dehydration efficiency and simplifying post-processing.

[0021] p-Toluenesulfonic acid, as a strong organic acid, effectively donates protons, combining with the carbonyl group in product 1 to form a protonated carbonyl group. This significantly enhances the electrophilicity of the carbonyl carbon, thereby accelerating the nucleophilic attack of the diol and promoting the rapid progress of the ketalization reaction, greatly shortening the time to reach equilibrium. p-Toluenesulfonic acid not only boasts the advantages of high activation activity and low dosage, ensuring efficient reaction and reducing raw material costs, but also exhibits chemical stability, resisting decomposition under reaction conditions such as toluene reflux. Furthermore, it does not undergo side reactions with the diol or dehydrating agent in the system, avoiding the introduction of impurities. In addition, its acidity requirements are highly compatible with the ketalization reaction, activating the carbonyl group without causing side reactions such as decomposition of product 1 or the diol due to excessive acidity.

[0022] Preferably, the molar ratio of product 1, ethylene glycol, trimethyl orthoformate and p-toluenesulfonic acid is 1:(10-15):(7-8):(0.005-0.02).

[0023] By adopting the above technical solution, as the core reactant of ketalization, excess ethylene glycol can ensure that the carbonyl group to be protected in product 1 reacts fully; when ethylene glycol is insufficient, the carbonyl group conversion is incomplete, and the residual raw material will lead to a decrease in the selectivity of the subsequent reduction reaction; when there is too much excess ethylene glycol, the unreacted ethylene glycol will increase the difficulty of post-processing and may form hydrogen bonds with product 2, affecting the purity of crystallization.

[0024] Trimethyl orthoformate acts as a dehydrating agent, driving the equilibrium forward by reacting with the water generated in the reaction. If the proportion is insufficient, the high water content in the system will cause the ketal hydrolysis to proceed in reverse, reducing the yield of product 2. If the proportion is too high, excessive reagent residue will form an azeotrope with product 2 during purification, increasing the difficulty of separation.

[0025] p-Toluenesulfonic acid acts as an acidic catalyst, accelerating the reaction by proton-activated carbonyl groups. If the proportion is too low, the catalytic activity will be insufficient, the reaction time will be prolonged, and the conversion will be incomplete. If the proportion is too high, the acidity will be too strong, triggering side reactions such as ester hydrolysis and intermolecular dehydration of ethylene glycol in product 1, generating impurities and reducing the purity of product 2.

[0026] In summary, by optimizing the molar ratio of product 1, ethylene glycol, trimethyl orthoformate, and p-toluenesulfonic acid, high selectivity and high yield of the ketalization reaction were achieved, providing a high-purity intermediate for the subsequent reduction step.

[0027] Preferably, in S3, the reducing agent is a borohydride salt, specifically one or both of sodium borohydride and potassium borohydride; the molar ratio of product 2 to potassium borohydride is 1:(3-5).

[0028] By adopting the above technical solution, potassium borohydride has a slightly lower solubility in water than sodium borohydride. In mixed solvent systems such as methanol-tetrahydrofuran, the reaction rate can be adjusted by controlling the feeding method and stirring intensity, reducing the risk of local over-reduction. Secondly, it has good chemical stability, lower requirements for storage and transportation conditions, and high operational safety. Excess potassium borohydride during post-processing can be quenched with water to form water-soluble potassium borate, which can be easily removed by separation or filtration. It also has better compatibility with the reaction system and process adaptability.

[0029] If the proportion of borohydride is too low, insufficient hydride anions will lead to incomplete reduction of product 3, with residual raw materials mixed into the product, reducing the purity of subsequent hydrolysis reactions. Conversely, if there is an excess, the excess borohydride will react with the reaction solvent or water to generate hydrogen gas and borate, which not only wastes raw materials but may also pose safety risks due to localized exothermic reactions, while increasing the difficulty of separation in post-processing. Therefore, a reasonable molar ratio ensures the complete conversion of product 3 while avoiding economic losses caused by excessive reagents, and reduces the generation of by-products, providing a high-purity intermediate for the subsequent hydrolysis reaction of S4.

[0030] Preferably, in S3, the acidic compound is one or more of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, and formic acid, and the molar ratio of product 2 to hydrochloric acid is 1:(1-2).

[0031] By employing the above technical solution, the acidic compound completely ionizes into hydrogen ions in aqueous solution, which can efficiently protonate the oxygen atom of the ketal protecting group in product 3, weakening the stability of the CO bond and promoting the rapid hydrolysis of the ketal into a carbonyl group and ethylene glycol. Simultaneously, the hydrogen ions can activate the carbonyl group of the ester group, accelerating its nucleophilic reaction with water molecules to generate the corresponding carboxylic acid and alcohol, achieving simultaneous cleavage of the ester group and satisfying the structural requirements of pregnenolone. The acidic compound of this application, by using hydrochloric acid, has the following advantages: the hydrochloric acid has moderate and controllable acidity, ensuring both hydrolysis... The reaction proceeds efficiently under mild conditions, avoiding side reactions such as double bond displacement and dehydration of the steroid skeleton caused by excessive acidity. Secondly, excess hydrochloric acid can be neutralized by adding inexpensive bases such as sodium carbonate or sodium hydroxide to generate water-soluble sodium chloride, which can be separated from the organic phase by liquid-liquid separation or filtration, simplifying post-processing. Furthermore, hydrochloric acid is miscible with solvents such as water and methanol, resulting in a reaction system with good compatibility, ensuring reaction homogeneity, reducing impurities caused by excessively high local concentrations, and ultimately providing a stable hydrolysis environment for the generation of high-purity pregnenolone.

[0032] If the hydrochloric acid ratio is too low, insufficient hydrogen ion concentration will lead to incomplete hydrolysis of the ester group, and residual protecting groups will mix into the pregnenolone product, reducing purity. Simultaneously, the reaction rate will be significantly slowed, requiring extended reaction time and affecting production efficiency. Conversely, if the hydrochloric acid ratio is too high, the strongly acidic environment will cause side effects. On the one hand, excess hydrogen ions may cause double bond isomerization or hydroxyl dehydration of the pregnenolone steroid skeleton, generating impurities that are difficult to separate. On the other hand, high concentrations of hydrochloric acid will increase the corrosiveness to equipment, and subsequent neutralization requires more alkali, increasing raw material costs and wastewater treatment load. Therefore, by optimizing the molar ratio of product 2 to hydrochloric acid, both raw material residue due to insufficient acid and side reactions caused by excessive acid can be avoided, ultimately providing a stable reaction environment for the production of high-purity pregnenolone.

[0033] Preferably, the method further includes the following step: S4, adding the pregnenolone obtained in S3 to a mixed solvent and purifying it by recrystallization to obtain the refined pregnenolone.

[0034] By adopting the above technical solution, the difference in solubility of pregnenolone and impurities in the mixed solvent can be used to effectively remove unreacted raw materials, by-products and other impurities, thereby improving product purity.

[0035] Preferably, the mixed solvent is a mixture of petroleum ether and ethyl acetate in a volume ratio of (3-5):1.

[0036] By adopting the above technical solution, petroleum ether and ethyl acetate are non-polar and moderately polar solvents, respectively, which can precisely match the amphiphilic structure of pregnenolone and synergistically achieve selective dissolution of the target product that is easily soluble while impurities are difficult to dissolve; moreover, the solubility of pregnenolone in it changes significantly with temperature, and it can be completely dissolved under high-temperature reflux, and high-purity crystals are rapidly precipitated at room temperature; at the same time, the two have similar boiling points, are homogeneous, inexpensive, widely available, low in toxicity and recyclable, and are safe to operate, making them suitable for large-scale industrial purification.

[0037] If the crude product contains a large amount of fat-soluble impurities, the inhibition effect on fat-soluble impurities can be enhanced by increasing the proportion of petroleum ether. If it contains a small amount of polar impurities, the content of ethyl acetate can be increased to ensure that pregnenolone is fully dissolved and to avoid the residue of the target product due to insufficient solvent polarity. Therefore, by optimizing the volume ratio of petroleum ether and ethyl acetate, the dissolution efficiency and selectivity can be better balanced to ensure complete dissolution at high temperature and efficient precipitation at low temperature, thereby improving the purity of pregnenolone.

[0038] Preferably, the pregnenolone concentrate is added to methanol, heated to reflux and stirred, cooled and filtered to obtain high-purity pregnenolone; the mass-to-volume ratio of the pregnenolone concentrate to methanol is 1:(3-5) g / mL.

[0039] By adopting the above technical solution, methanol, as a polar solvent, significantly changes the solubility of pregnenolone with temperature. That is, pregnenolone is easily soluble in methanol at high temperatures, and its solubility decreases significantly after cooling, thus precipitating out in a more regular crystal form. Through this step, any possible residual trace impurities can be further removed, thereby improving the purity of pregnenolone and making the crystal state more stable.

[0040] The mass-volume ratio of pregnenolone concentrate to methanol ensures that the crude product is fully dissolved during reflux, and the target product is efficiently precipitated after cooling, reducing impurity residue and product loss; an improper ratio may lead to insufficient dissolution, decreased crystallization purity, or reduced yield.

[0041] In summary, this application has the following beneficial effects:

[0042] 1. This application uses progesterone as the starting material and synthesizes high-purity, high-yield pregnenolone products through a four-step reaction involving esterification, ketal protection, reduction, and hydrolysis.

[0043] 2. The esterification reaction in this application adopts the mode of mother liquor recovery and reagent replenishment. By recovering the residual acylation reagent in the mother liquor and adding an appropriate amount of reagent, its effective concentration can be maintained, reducing material waste and cost; at the same time, it reduces waste emissions, which is in line with the concept of green chemistry, and can also improve the economic efficiency and sustainability of the process by stabilizing the reaction system through circulation.

[0044] 3. This application reduces the occurrence of side reactions and improves the purity and yield of the prepared pregnenolone by precisely controlling the reaction conditions and purification steps. Attached Figure Description

[0045] Figure 1 The HPLC chromatogram of the high-purity pregnenolone prepared in Example 1. Detailed Implementation

[0046] The present application will be further described in detail below with reference to the embodiments.

[0047] Unless otherwise specified, the raw materials used in the embodiments and comparative examples of this application are all commercially available.

[0048] Example

[0049] Example 1

[0050] This embodiment discloses a synthesis process for high-purity pregnenolone, specifically including the following steps:

[0051] S1, Esterification: Add 100g progesterone to a 500mL three-necked flask, followed by 97.5g acetic anhydride and 124.9g acetyl chloride. Maintain the temperature at 30℃ for 6-7 hours, monitoring the reaction with TLC. After the starting material is completely converted, cool to 0-5℃. A large amount of solid precipitates. Filter quickly; the filter cake is the esterification product. Recover the filtrate and add another 100g progesterone, followed by 20g acetyl chloride and 16.2g acetic anhydride. Continue to maintain the temperature at 30℃ for 6 hours, monitoring the reaction with TLC. After the starting material is completely converted, cool to 0-5℃. A large amount of solid will precipitate. Filter quickly; the filter cake is the esterification product. Recover the filtrate and add another 100g progesterone, followed by 30g acetyl chloride and 32.5g acetic anhydride. The acetic anhydride was kept at 30°C for 6 hours, and the reaction was monitored by TLC. After the raw material conversion was complete, the mixture was cooled to 0-5°C, and a large amount of solid precipitated. This solid was quickly filtered, and the filter cake was the esterification product. After recovering the filtrate, 100g of progesterone, 50g of acetyl chloride, and 48.6g of acetic anhydride were added, and the mixture was kept at 30°C for 6 hours, and the reaction was monitored by TLC. After the raw material conversion was complete, the mixture was cooled to 0-5°C, and a large amount of solid precipitated. This solid was quickly filtered, and the filter cake was the esterification product. All the filter cakes obtained were collected, and acetonitrile (V acetonitrile: m filter cake = 2:1) was added to the filter cakes. The mixture was slurried at room temperature for 1 hour, then cooled to 0-5°C, stirred for 2 hours, and quickly filtered. The product was the filter cake, and the filtrate was collected for later use.

[0052] The reaction equation for process S1 is as follows:

[0053] ;

[0054] S2, carbonyl protection to form a ketal: Under nitrogen protection, 35.6 g of the above product was added to a 500 mL three-necked flask, followed by 130 mL of toluene, 80.6 g of ethylene glycol, 79.6 g of trimethyl orthoformate, and 215 mg of p-toluenesulfonic acid. The mixture was heated to reflux at 70 °C and reacted for 1 h. The reaction was monitored by TLC. After the reaction, toluene was recovered under reduced pressure, and a solid precipitated. 200 mL of deionized water was added to a round-bottom flask, and the mixture was stirred to disperse the solid and remove any residual ethylene glycol. After drying, a white solid product was obtained and directly proceeded to the next step of the reaction.

[0055] The reaction equation for process S2 is as follows:

[0056]

[0057] S3, Reduction of ketal: Add 40g of the above white solid product to a 500mL three-necked flask, then add 140mL of tetrahydrofuran and 140mL of methanol. Cool to 0-5℃ in an ice-water bath, then add a total of 21.58g of potassium borohydride in 5 portions, ensuring the reaction system temperature is below 10℃. After the potassium borohydride is added, maintain the temperature at 0-5℃ and continue the reaction for 0.5h. Slowly raise the temperature to room temperature and continue the reaction for 8h. Monitor the reaction with TLC. After the reaction is complete, quench the reaction with 3M hydrochloric acid, adjust the pH of the system to 6, and recover the methanol and tetrahydrofuran solvent under reduced pressure. A large amount of solid precipitates. Add 200mL of deionized water to a round-bottom flask, then extract with dichloromethane and combine the organic phases.

[0058] The reaction equation for process S3 is as follows:

[0059]

[0060] S4, Synthesis of pregnenolone: ​​50 mL of 3 M hydrochloric acid was added to the above organic phase, and the reaction was carried out at room temperature for 1.5 h. The reaction was monitored by TLC. After the reaction was completed, the phase was allowed to stand and separate into layers. The organic phase was washed with saturated sodium bicarbonate and water until neutral, dried with anhydrous sodium sulfate, and concentrated to obtain crude pregnenolone.

[0061] The reaction equation for process S4 is as follows:

[0062]

[0063] S5, Purification of Pregnenolone: ​​40 g of crude pregnenolone was added to a 500 mL round-bottom flask, followed by 120 mL of petroleum ether and 30 mL of ethyl acetate. The mixture was heated to reflux and stirred for 4 hours. After cooling to room temperature, the mixture was filtered to obtain a white solid. The mother liquor could be recycled multiple times. The same 40 g white solid was added to a 250 mL round-bottom flask, followed by 160 mL of methanol. The mixture was heated to reflux and stirred for 4 hours. After cooling to 40°C, the mixture was filtered while hot to obtain a white solid and dried. The mother liquor could be recycled. The product purity was 98.4% as determined by HPLC. The yield, calculated based on progesterone, was 69.6%, and the HPLC chromatogram is shown below. Figure 1 As shown.

[0064] Example 2

[0065] This embodiment is basically the same as Example 1, except that in S1, 100g of progesterone is added to a 500mL three-necked flask, followed by 97.5g of acetic anhydride and 124.9g of acetyl chloride. The mixture is kept at 30°C and reacted for 6-7 hours. The reaction is monitored by TLC. After the raw material is completely converted, the mixture is cooled to 0-5°C, and a large amount of solid precipitates. The mixture is quickly filtered, and the filter cake is collected. Acetonitrile (V acetonitrile: m filter cake = 2:1) is added to the filter cake. The mixture is stirred at room temperature for 1 hour, then cooled to 0-5°C, stirred for 2 hours, and quickly filtered. The product is the filter cake, and the filtrate is collected for later use.

[0066] The other steps were the same as in Example 1. The final product was analyzed by HPLC and the purity was 98.2%; the yield was 67.2% based on progesterone.

[0067] Example 3

[0068] This embodiment is basically the same as Example 1, except that in S2, specifically: carbonyl protection to form a ketal: under nitrogen protection, 35.6g of the above product was added to a 500mL three-necked flask, followed by 130mL of toluene, 62g of ethylene glycol, 74.3g of trimethyl orthoformate, and 108mg of p-toluenesulfonic acid. The mixture was heated to reflux at 70°C and reacted for 1 hour. The reaction was monitored by TLC. After the reaction, toluene was recovered under reduced pressure, and a solid precipitated. 200mL of deionized water was added to a round-bottom flask, stirred and dispersed to remove residual ethylene glycol. After drying, a white solid product was obtained and directly proceeded to the next step of the reaction.

[0069] The other steps were the same as in Example 1. The final product was analyzed by HPLC and the purity was 97.8%; the yield was 65.3% based on progesterone.

[0070] Example 4

[0071] The examples are basically the same as Example 1, except that in S2, specifically: carbonyl protection to form a ketal: under nitrogen protection, 35.6g of the above product was added to a 500mL three-necked flask, followed by 130mL of toluene, 93g of ethylene glycol, 84.9g of trimethyl orthoformate, and 430mg of p-toluenesulfonic acid. The mixture was heated to reflux at 70°C and reacted for 1 hour. The reaction was monitored by TLC. After the reaction, toluene was recovered under reduced pressure, and a solid precipitated. 200mL of deionized water was added to a round-bottom flask, stirred and dispersed to remove residual ethylene glycol. After drying, a white solid product was obtained and directly proceeded to the next step of the reaction.

[0072] The other steps were the same as in Example 1. The final product was analyzed by HPLC and the purity was 98.0%; the yield was 66.2% based on progesterone.

[0073] Example 5

[0074] The examples are basically the same as Example 1, except that in S3, the reduction of the ketal is as follows: 40g of the white solid product was added to a 500mL three-necked flask, along with 140mL of tetrahydrofuran and 140mL of methanol. The mixture was cooled to 0-5°C in an ice-water bath, and then 16.19g of potassium borohydride was added in 5 portions, ensuring that the temperature of the reaction system was below 10°C. After the potassium borohydride was added, the mixture was kept at 0-5°C for 0.5h and then slowly heated to room temperature for 8h. The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched with 3M hydrochloric acid, the pH of the system was adjusted to 6, and the methanol and tetrahydrofuran solvents were recovered under reduced pressure. A large amount of solid precipitated. 200mL of deionized water was added to a round-bottom flask, and the mixture was extracted with dichloromethane. The organic phases were combined.

[0075] The other steps were the same as in Example 1. The final product was detected by HPLC and the purity was 97.9%; the yield was 65.8% based on progesterone.

[0076] Example 6

[0077] The examples are basically the same as Example 1, except that in S3, the reduction of the ketal is as follows: 40g of the white solid product was added to a 500mL three-necked flask, along with 140mL of tetrahydrofuran and 140mL of methanol. The mixture was cooled to 0-5°C in an ice-water bath, and then 32.37g of potassium borohydride was added in 5 portions, ensuring that the reaction system temperature was below 10°C. After the potassium borohydride was added, the mixture was kept at 0-5°C for 0.5h, and then slowly heated to room temperature for 8h. The reaction was monitored by TLC. After the reaction was completed, the reaction was quenched with 3M hydrochloric acid, the pH of the system was adjusted to 6, and the methanol and tetrahydrofuran solvents were recovered under reduced pressure. A large amount of solid precipitated. 200mL of deionized water was added to a round-bottom flask, and the mixture was extracted with dichloromethane. The organic phases were combined.

[0078] The other steps were the same as in Example 1. The final product was detected by HPLC and the purity was 98.1%; the yield was 66.7% based on progesterone.

[0079] Example 7

[0080] The examples are basically the same as those in Example 1, except that in S4, specifically: Synthesis of pregnenolone: ​​33.3 mL of 3M hydrochloric acid was added to the above organic phase, and the reaction was carried out at room temperature for 1.5 h. The reaction was monitored by TLC. After the reaction was completed, the phase was allowed to stand and separate into layers. The organic phase was washed with saturated sodium bicarbonate and water until neutral, dried with anhydrous sodium sulfate, and concentrated to obtain crude pregnenolone.

[0081] The other steps were the same as in Example 1. The final product was analyzed by HPLC and the purity was 97.8%; the yield was 66.3% based on progesterone.

[0082] Example 8

[0083] The examples are basically the same as those in Example 1, except that in S4, specifically: Synthesis of pregnenolone: ​​66.7 mL of 3M hydrochloric acid was added to the above organic phase, and the reaction was carried out at room temperature for 1.5 h. The reaction was monitored by TLC. After the reaction was completed, the phase was allowed to stand and separate into layers. The organic phase was washed with saturated sodium bicarbonate and water until neutral, dried with anhydrous sodium sulfate, and concentrated to obtain crude pregnenolone.

[0084] The other steps were the same as in Example 1. The final product was analyzed by HPLC and the purity was 98.3%; the yield was 65.8% based on progesterone.

[0085] Example 9

[0086] This embodiment is basically the same as Example 1, except that in S5, the purification of pregnenolone: ​​40g of crude pregnenolone was added to a 500mL round-bottom flask, followed by 112.5mL of petroleum ether and 37.5mL of ethyl acetate. The mixture was heated to reflux and stirred for 4 hours. After cooling to room temperature, the mixture was filtered to obtain a white solid. The mother liquor could be recovered and reused multiple times. The above 40g of white solid was added to a 250mL round-bottom flask, followed by 160mL of methanol. The mixture was heated to reflux and stirred for 4 hours. After cooling to 40°C, the mixture was filtered while hot to obtain a white solid and dried. The mother liquor could be recycled. The purity of the product was 98.2% as determined by HPLC. The yield, calculated based on progesterone, was 69.5%.

[0087] Example 10

[0088] This embodiment is basically the same as Example 1, except that in S5, the purification of pregnenolone: ​​40g of crude pregnenolone was added to a 500mL round-bottom flask, followed by 125mL of petroleum ether and 25mL of ethyl acetate. The mixture was heated to reflux and stirred for 4 hours. After cooling to room temperature, the mixture was filtered to obtain a white solid. The mother liquor could be recovered and reused multiple times. The above 40g of white solid was added to a 250mL round-bottom flask, followed by 160mL of methanol. The mixture was heated to reflux and stirred for 4 hours. After cooling to 40°C, the mixture was filtered while hot to obtain a white solid and dried. The mother liquor could be recycled. The purity of the product was 98.1% as determined by HPLC. The yield, calculated based on progesterone, was 69.7%.

[0089] Example 11

[0090] This embodiment is basically the same as Example 1, except that in S5, the purification of pregnenolone: ​​40g of crude pregnenolone was added to a 500mL round-bottom flask, followed by 120mL of petroleum ether and 30mL of ethyl acetate. The mixture was heated to reflux and stirred for 4 hours. After cooling to room temperature, the mixture was filtered to obtain a white solid. The mother liquor could be recovered and reused multiple times. The above 40g of white solid was added to a 250mL round-bottom flask, followed by 120mL of methanol. The mixture was heated to reflux and stirred for 4 hours. After cooling to 40°C, the mixture was filtered while hot to obtain a white solid and dried. The mother liquor could be recycled. The purity of the product was 98.2% as determined by HPLC. The yield, calculated based on progesterone, was 69.6%.

[0091] Example 12

[0092] This embodiment is basically the same as Example 1, except that in S5, the purification of pregnenolone: ​​40g of crude pregnenolone was added to a 500mL round-bottom flask, followed by 112.5mL of petroleum ether and 37.5mL of ethyl acetate. The mixture was heated to reflux and stirred for 4 hours. After cooling to room temperature, the mixture was filtered to obtain a white solid. The mother liquor could be recovered and reused multiple times. The above 40g of white solid was added to a 250mL round-bottom flask, followed by 200mL of methanol. The mixture was heated to reflux and stirred for 4 hours. After cooling to 40°C, the mixture was filtered while hot to obtain a white solid and dried. The mother liquor could be recycled. The purity of the product was 98.5% as determined by HPLC. The yield, calculated based on progesterone, was 69.1%.

[0093] Example 13

[0094] This embodiment discloses a synthesis process for high-purity pregnenolone, specifically including the following steps:

[0095] S1, Esterification: Add 100g progesterone to a 500mL three-necked flask, followed by 97.5g acetic anhydride and 124.9g acetyl chloride. Maintain the temperature at 30℃ for 6-7 hours, monitoring the reaction with TLC. After the starting material is completely converted, cool to 0-5℃. A large amount of solid precipitates. Filter quickly; the filter cake is the esterification product. Recover the filtrate and add another 100g progesterone, followed by 20g acetyl chloride and 16.2g acetic anhydride. Continue to maintain the temperature at 30℃ for 6 hours, monitoring the reaction with TLC. After the starting material is completely converted, cool to 0-5℃. A large amount of solid will precipitate. Filter quickly; the filter cake is the esterification product. Recover the filtrate and add another 100g progesterone, followed by 30g acetyl chloride and 32.5g acetic anhydride. The acetic anhydride was kept at 30°C for 6 hours, and the reaction was monitored by TLC. After the raw material conversion was complete, the mixture was cooled to 0-5°C, and a large amount of solid precipitated. This solid was quickly filtered, and the filter cake was the esterification product. After recovering the filtrate, 100g of progesterone, 50g of acetyl chloride, and 48.6g of acetic anhydride were added, and the mixture was kept at 30°C for 6 hours, and the reaction was monitored by TLC. After the raw material conversion was complete, the mixture was cooled to 0-5°C, and a large amount of solid precipitated. This solid was quickly filtered, and the filter cake was the esterification product. All the filter cakes obtained were collected, and acetonitrile (V acetonitrile: m filter cake = 2:1) was added to the filter cakes. The mixture was slurried at room temperature for 1 hour, then cooled to 0-5°C, stirred for 2 hours, and quickly filtered. The product was the filter cake, and the filtrate was collected for later use.

[0096] S2, carbonyl protection to form a ketal: Under nitrogen protection, 35.6 g of the above product was added to a 500 mL three-necked flask, followed by 130 mL of toluene, 80.6 g of ethylene glycol, 79.6 g of trimethyl orthoformate, and 215 mg of p-toluenesulfonic acid. The mixture was heated to reflux at 70 °C and reacted for 1 h. The reaction was monitored by TLC. After the reaction, toluene was recovered under reduced pressure, and a solid precipitated. 200 mL of deionized water was added to a round-bottom flask, and the mixture was stirred to disperse the solid and remove any residual ethylene glycol. After drying, a white solid product was obtained and directly proceeded to the next step of the reaction.

[0097] S3, Reduction of ketal: Add 40g of the above white solid product to a 500mL three-necked flask, then add 140mL of tetrahydrofuran and 140mL of methanol. Cool to 0-5℃ in an ice-water bath, then add a total of 21.58g of potassium borohydride in 5 portions, ensuring the reaction system temperature is below 10℃. After the potassium borohydride is added, maintain the temperature at 0-5℃ and continue the reaction for 0.5h. Slowly raise the temperature to room temperature and continue the reaction for 8h. Monitor the reaction with TLC. After the reaction is complete, quench the reaction with 3M hydrochloric acid, adjust the pH of the system to 6, and recover the methanol and tetrahydrofuran solvent under reduced pressure. A large amount of solid precipitates. Add 200mL of deionized water to a round-bottom flask, then extract with dichloromethane and combine the organic phases.

[0098] S4, Synthesis of pregnenolone: ​​50 mL of 3M hydrochloric acid was added to the above organic phase, and the reaction was carried out at room temperature for 1.5 h. The reaction was monitored by TLC. After the reaction was completed, the phase was allowed to stand and separate into layers. The organic phase was washed with saturated sodium bicarbonate and water until neutral, dried with anhydrous sodium sulfate, and concentrated to obtain pregnenolone. The purity was 91.5% as determined by HPLC. The yield was 76.2% based on progesterone.

[0099] Example 14

[0100] This embodiment discloses a synthesis process for high-purity pregnenolone, specifically including the following steps:

[0101] S1, Esterification: Add 100g progesterone to a 500mL three-necked flask, followed by 97.5g acetic anhydride and 124.9g acetyl chloride. Maintain the temperature at 30℃ for 6-7 hours, monitoring the reaction with TLC. After the starting material is completely converted, cool to 0-5℃. A large amount of solid precipitates. Filter quickly; the filter cake is the esterification product. Recover the filtrate and add another 100g progesterone, followed by 20g acetyl chloride and 16.2g acetic anhydride. Continue to maintain the temperature at 30℃ for 6 hours, monitoring the reaction with TLC. After the starting material is completely converted, cool to 0-5℃. A large amount of solid will precipitate. Filter quickly; the filter cake is the esterification product. Recover the filtrate and add another 100g progesterone, followed by 30g acetyl chloride and 32.5g acetic anhydride. The acetic anhydride was kept at 30°C for 6 hours, and the reaction was monitored by TLC. After the raw material conversion was complete, the mixture was cooled to 0-5°C, and a large amount of solid precipitated. This solid was quickly filtered, and the filter cake was the esterification product. After recovering the filtrate, 100g of progesterone, 50g of acetyl chloride, and 48.6g of acetic anhydride were added, and the mixture was kept at 30°C for 6 hours, and the reaction was monitored by TLC. After the raw material conversion was complete, the mixture was cooled to 0-5°C, and a large amount of solid precipitated. This solid was quickly filtered, and the filter cake was the esterification product. All the filter cakes obtained were collected, and acetonitrile (V acetonitrile: m filter cake = 2:1) was added to the filter cakes. The mixture was slurried at room temperature for 1 hour, then cooled to 0-5°C, stirred for 2 hours, and quickly filtered. The product was the filter cake, and the filtrate was collected for later use.

[0102] S2, carbonyl protection to form a ketal: Under nitrogen protection, 35.6 g of the above product was added to a 500 mL three-necked flask, followed by 130 mL of toluene, 80.6 g of ethylene glycol, 79.6 g of trimethyl orthoformate, and 215 mg of p-toluenesulfonic acid. The mixture was heated to reflux at 70 °C and reacted for 1 h. The reaction was monitored by TLC. After the reaction, toluene was recovered under reduced pressure, and a solid precipitated. 200 mL of deionized water was added to a round-bottom flask, and the mixture was stirred to disperse the solid and remove any residual ethylene glycol. After drying, a white solid product was obtained and directly proceeded to the next step of the reaction.

[0103] S3, Reduction of ketal: Add 40g of the above white solid product to a 500mL three-necked flask, then add 140mL of tetrahydrofuran and 140mL of methanol. Cool to 0-5℃ in an ice-water bath, then add a total of 21.58g of potassium borohydride in 5 portions, ensuring the reaction system temperature is below 10℃. After the potassium borohydride is added, maintain the temperature at 0-5℃ and continue the reaction for 0.5h. Slowly raise the temperature to room temperature and continue the reaction for 8h. Monitor the reaction with TLC. After the reaction is complete, quench the reaction with 3M hydrochloric acid, adjust the pH of the system to 6, and recover the methanol and tetrahydrofuran solvent under reduced pressure. A large amount of solid precipitates. Add 200mL of deionized water to a round-bottom flask, then extract with dichloromethane and combine the organic phases.

[0104] S4, Synthesis of pregnenolone: ​​50 mL of 3 M hydrochloric acid was added to the above organic phase, and the reaction was carried out at room temperature for 1.5 h. The reaction was monitored by TLC. After the reaction was completed, the phase was allowed to stand and separate into layers. The organic phase was washed with saturated sodium bicarbonate and water until neutral, dried with anhydrous sodium sulfate, and concentrated to obtain pregnenolone.

[0105] S5, Purification of pregnenolone: ​​40 g of crude pregnenolone was added to a 500 mL round-bottom flask, followed by 120 mL of petroleum ether and 30 mL of ethyl acetate. The mixture was heated to reflux and stirred for 4 h. After cooling to room temperature, the mixture was filtered to obtain a white solid and dried. The mother liquor could be recycled. The purity of the product was 96.7% as determined by HPLC. The yield was 73.1% based on progesterone.

[0106] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A process for synthesizing pregnenolone, characterized in that, Includes the following steps: S1, Progesterone is esterified with an acylation reagent, cooled to 0-5℃, filtered, acetonitrile is added to the filter cake and slurryed at room temperature, then cooled to 0-5℃, stirred, filtered, to obtain product 1; S2, the product 1, ethylene glycol, and the dehydrating agent trimethyl orthoformate are subjected to a ketalization reaction in the presence of the catalyst p-toluenesulfonic acid to obtain product 2; the molar ratio of the product 1, ethylene glycol, trimethyl orthoformate, and p-toluenesulfonic acid is 1:(10-15):(7-8):(0.005-0.02). S3, the product 2 is reduced with a reducing agent to obtain product 3; the product 3 is hydrolyzed with hydrochloric acid to obtain pregnenolone; S4, the pregnenolone obtained in S3 is added to a mixed solvent and purified by recrystallization to obtain a high-purity pregnenolone; the high-purity pregnenolone is added to methanol, heated to reflux and stirred, cooled and filtered to obtain a high-purity pregnenolone; the mixed solvent is a mixture of petroleum ether and ethyl acetate with a volume ratio of (3-5):1; the mass-volume ratio of the high-purity pregnenolone to methanol is 1:(3-5) g / mL; The esterification reaction is carried out by recycling the mother liquor and adding reagents. The acylation reagent is a mixture of acetyl chloride and acetic anhydride in a molar ratio of (5-9):(3-6); the molar ratio of progesterone to the acylation reagent is (1-4):(8-15). The structural formula of product 1 is as follows: The product 2 has the following structural formula: The structural formula of product 3 is: .

2. The synthesis process of pregnenolone according to claim 1, characterized in that, In S3, the reducing agent is potassium borohydride, and the molar ratio of product 2 to potassium borohydride is 1:(3-5).

3. The synthesis process of pregnenolone according to claim 1, characterized in that, In S3, the molar ratio of product 2 to hydrochloric acid is 1:(1-2).

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