A process for the preparation of dehydroepiandrosterone

Abstract

This invention proposes a method for preparing dehydroepiandrosterone (DHEA), comprising the following steps: S1, dissolving 4-androstenedione in acetic anhydride to obtain a first material, which is then pumped separately into an acetylation microchannel reactor with quaternized GO-phosphotungstic acid catalyst supported on the inner wall for reaction with acetyl chloride; S2, mixing triethyl orthoformate with anhydrous ethanol to obtain a second material, which is then pumped separately into a ketal microchannel reactor with niobium oxide / γ-CD-phosphotungstic acid catalyst supported on the inner wall of the ketal microchannel reactor; S3, dehydrating the effluent from step S2 and adjusting the pH to 7-8, then pumping separately into a reduction microchannel reactor with an ethanol solution containing sodium borohydride for reduction reaction; S4, adding hydrochloric acid to the effluent from step S3 and adjusting the pH to 2-3 to obtain a hydrolysate; evaporating the solvent from the hydrolysate, filtering and drying to obtain DHEA. The supported heteropolyacid composite membrane used in this invention exhibits high catalytic efficiency, high yield, and excellent quality.

Description

Technical Field

[0001] This invention relates to the technical field of pharmaceutical intermediate preparation, and more particularly to a method for preparing dehydroepiandrosterone. Background Technology

[0002] Dehydroepiandrosterone (DHEA), chemically named 3β-hydroxy-androst-5-en-17-one, is a major adrenal hormone and a precursor to the synthesis of many hormones in the human body. It has anti-aging and protein anabolic effects.

[0003] Traditional methods for preparing DHEA mostly employ chemical synthesis, with the most common route using 4-androstenedione as a raw material through steps such as acetylation, ketalization, reduction, and hydrolysis.

[0004] A prior art method for preparing dehydroepiandrosterone (DHEA) using a microchannel reactor has been disclosed. By carrying out each reaction step within the microchannel, the small size effect of the microchannel enables efficient mixing of materials, thereby improving the reaction rate and selectivity. However, this existing process still has the following shortcomings: the metal chloride (ZnCl2, FeCl3, aluminum trichloride) catalyst supported on the inner wall of the reactor is essentially a soluble Lewis acid salt with strong hydrophilicity. When in contact with the reaction liquid in the microchannel reaction, it is prone to deliquescence and desorption, leading to the loss of the active catalyst components and rapid decay of catalytic activity, which cannot meet the requirements of continuous industrial production. Therefore, there is a need for a method for preparing dehydroepiandrosterone with high catalytic activity and stability. Summary of the Invention

[0005] In view of this, the present invention proposes a method for preparing dehydroepiandrosterone with high catalytic activity and stability.

[0006] The technical solution of this invention is achieved as follows: On one hand, this invention provides a method for preparing dehydroepiandrosterone, comprising the following steps: S1, Acetylation: 4-Androstenedione is dissolved in acetic anhydride to obtain the first material, which is then pumped into an acetylation microchannel reactor for reaction with acetyl chloride. The inner wall of the acetylation microchannel reactor is supported with a quaternized GO-phosphotungstic acid catalyst. Specifically, the high activity of quaternized GO-phosphotungstic acid catalysts for acetylation mainly stems from the coupling effect of efficient exposure of strong acid sites, stable immobilization, and low intramembrane mass transfer resistance: phosphotungstic acid provides a high density of strongly Brønsted acid sites, which is beneficial for the activation of carbonyl / acylated active species in acetylation; quaternized GO introduces permanent positively charged sites, forming ion-pair / ion-exchange type immobilization with phosphotungstic acid ions, making it difficult for heteropolyacids to migrate and bleed in the acetic anhydride / acetyl chloride system and maintaining high dispersion, avoiding the waste of acid sites caused by agglomeration. Meanwhile, the continuous inner wall membrane composed of GO (graphene oxide) sheets has a large specific surface area and short diffusion paths, with acid sites mostly distributed on or near the membrane surface. Under the high heat and mass transfer conditions of microchannels, higher apparent reaction rates and stability can be achieved in a shorter residence time.

[0007] S2, Ketal: Triethyl orthoformate is mixed with anhydrous ethanol to obtain a second material, which is pumped into a ketal microchannel reactor for reaction with the material discharged from step S1. The inner wall of the ketal microchannel reactor is supported with niobium oxide / γ-CD-phosphotungstic acid catalyst. When niobium oxide / γ-CD-phosphotungstic acid catalysts are used for ketaling, their high activity stems from the combined effects of Brønsted-Lewis dual-acid synergy, hydrophobic substrate enrichment / microenvironment regulation, and continuous flow removal of inhibitory factors. The niobium oxide surface provides Lewis acid sites and acts as an inorganic framework to promote phosphotungstic acid dispersion and anchoring, while phosphotungstic acid provides strong Brønsted acid sites. This synergy facilitates the activation and de-alcoholization of key ketaling steps. The organic network formed by cross-linked γ-CD, on the one hand, increases the local concentration of steroid substrates near acid sites and reduces mass transfer limitations through hydrophobic inclusion / enrichment effects; on the other hand, it improves membrane wetting and structural stability, thus achieving a high ketaling rate even under relatively mild conditions. Furthermore, the efficient mass transfer and continuous discharge characteristics of the microchannel membrane reaction (especially in water-sensitive reversible ketaling systems) further weaken the inhibition of acid sites and equilibrium by water, resulting in higher space-time yields and better operational consistency at shorter residence times.

[0008] S3, Reduction: Dehydrate the material discharged from step S2 and adjust the pH to 7-8. Pump it into the reduction microchannel reactor along with the ethanol solution containing sodium borohydride to carry out the reduction reaction. S4, hydrolysis and separation: add hydrochloric acid to the output of step S3, adjust the pH to 2-3, and obtain hydrolysate; evaporate the solvent in the hydrolysate, filter and dry the filter cake to obtain dehydroepiandrosterone.

[0009] Based on the above technical solution, preferably, the preparation method of the quaternized GO-phosphotungstic acid includes the following steps: S11, GO is dispersed in DMF, 3-aminopropyltrimethoxysilane is added and reacted, centrifuged after the reaction is completed, the precipitate is washed and dried to obtain aminated GO; aminated GO is dispersed in anhydrous ethanol, bromoethane is added and reacted, the solid is collected by centrifugation after the reaction is completed, washed and dried to obtain quaternized GO. S12, quaternized GO is dispersed in water, phosphotungstic acid aqueous solution is added and stirred for adsorption, then concentrated, dried and calcined to obtain quaternized GO-phosphotungstic acid.

[0010] Based on the above technical solutions, preferably, the mass ratio of GO to 3-aminopropyltrimethoxysilane in step S11 is 0.2-0.6:1, and the mass ratio of aminated GO to bromoethane is 1:0.65-1.35.

[0011] Based on the above technical solutions, preferably, in step S12, the mass ratio of quaternized GO to phosphotungstic acid is 1:5.8-8.6, the calcination temperature is 150-220℃, and the time is 1-3 h.

[0012] Based on the above technical solutions, preferably, the mass ratio of 3-chloropropyltrimethoxysilane to GO in step S11 is 0.5-20:1, the reaction temperature is 40-80℃, and the reaction time is 2-24 h.

[0013] Based on the above technical solutions, preferably, the mass ratio of quaternized GO to phosphotungstic acid in step S12 is 0.1-10:1, the reaction time is 0.5-12 h, the heat treatment temperature is 100-250℃, and the heat treatment time is 0.5-6 h.

[0014] Based on the above technical solutions, preferably, the preparation method of the niobium oxide / γ-CD-phosphotungstic acid includes the following steps: S21, γ-CD is dissolved in water, epichlorohydrin is added and reacted to form a gel, then washed until neutral and dried to obtain cross-linked γ-CD; S22, Niobium ammonium oxalate is dissolved in water, cross-linked γ-CD is added, the pH is adjusted to 4.5-7 after stirring, the temperature is raised to 40-60℃ and kept at the temperature for 1-3 hours, after which the mixture is filtered and the filter residue is washed, and then dried and heat-treated to obtain niobium oxide / γ-CD; S23, niobium oxide / γ-CD is impregnated in an aqueous solution of phosphotungstic acid, filtered and dried to obtain niobium oxide / γ-CD-phosphotungstic acid.

[0015] Based on the above technical solutions, preferably, the mass ratio of epichlorohydrin to γ-CD in step S21 is 1-5:1, the reaction temperature is 25-60℃, and the reaction time is 1-10 h.

[0016] Based on the above technical solutions, preferably, the concentration of the niobium oxalate ammonium solution in step S22 is 0.1-0.5 mol / L, the amount of crosslinked γ-CD is 2-10 g / 100 mL of niobium oxalate ammonium solution, the heat treatment temperature is 150-300℃, and the heat treatment time is 0.5-6 h.

[0017] Based on the above technical solutions, preferably, the concentration of the phosphotungstic acid aqueous solution in step S23 is 0.01-1 mol / L, and the immersion time is 0.5-12 h.

[0018] Based on the above technical solutions, preferably, the mass ratio of 4-androstenedione:acetic anhydride:acetyl chloride:triethyl orthoformate:sodium borohydride is 1:4-6:0.5-1.2:3-5:0.03-0.12.

[0019] Based on the above technical solutions, preferably, the reaction temperature in the acetylation microchannel reactor is 20-40℃ and the material residence time is 1-2 min; the reaction temperature in the ketal microchannel reactor is 40-50℃ and the material residence time is 10-30 s; and the reaction temperature in the reduction microchannel reactor is 20-30℃ and the material residence time is 0.5-1 min.

[0020] The method for preparing dehydroepiandrosterone of the present invention has the following advantages over the prior art: (1) In this invention, a strong acidic heteropoly acid (phosphotungstic acid) is immobilized on the inner wall of an acetylation microchannel reactor by quaternized GO ion pairing to form a stable inner wall catalytic membrane. This maintains the high-density Brønsted acid sites of phosphotungstic acid for the efficient activation of the acetylation reaction, and significantly reduces the loss of catalytic components and the aggregation of acid sites in the acetic anhydride / acetyl chloride system, thereby achieving higher conversion rate and more stable continuous operation with a shorter residence time.

[0021] (2) Simultaneously, this invention introduces a niobium oxide / γ-CD-phosphotungstic acid composite catalytic membrane into the inner wall of the ketal microchannel reactor. The synergistic effect of the Lewis acid sites provided by niobium oxide and the Brønsted acid sites of phosphotungstic acid promotes the key steps of ketalization. Furthermore, the hydrophobic inclusion / enrichment effect of cross-linked γ-CD increases the local concentration of steroid substrates near the acid sites and reduces mass transfer limitations. Combined with the excellent heat and mass transfer properties of the microchannel reactor and the weakening of water inhibition under continuous flow conditions, the ketalization reaction maintains a high reaction rate and selectivity even under mild conditions. Since both key reactions utilize an inner-wall supported catalytic system, the metal ion residues and post-processing burden of traditional homogeneous Lewis acid systems are avoided, reducing equipment corrosion risks, improving process safety and scalability, and facilitating continuous and automated production. Overall, this improves space-time yield, product quality consistency, and comprehensive economic efficiency. Detailed Implementation

[0022] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0023] The quaternized GO-phosphotungstic acid catalyst and the niobium oxide / γ-CD-phosphotungstic acid catalyst used in this invention are film-supported on the inner wall of a microchannel reactor. The specific loading method is as follows: The prepared quaternized GO-phosphotungstic acid or niobium oxide / γ-CD-phosphotungstic acid powder was dispersed in deionized water to prepare a catalytic coating slurry with a solid content of 10 wt%. 5% (by weight of the catalyst solids) of silica sol was added as a binder under stirring conditions, followed by ultrasonic dispersion for 10 min to ensure uniformity and degassing. The acetylated microchannel reactor was rinsed sequentially with ethanol and deionized water, dried at 100°C until no residual solvent remained, and then cooled to room temperature. The coating slurry was pumped into the reactor using a pouring method until all channels were filled. After standing for 10 min to allow the slurry to fully wet the inner wall, excess slurry was discharged, and the channels were purged with nitrogen air at low speed to form a uniform liquid film. The reactor was then placed at room temperature and allowed to stand and dry for 2 hours, followed by drying at 100°C for 4 hours to gel and solidify the silica sol. If necessary, the coating-blowing-drying-drying steps were repeated 1-3 times to adjust the loading and film thickness. Finally, a continuous, dense and erosion-resistant quaternized GO-phosphotungstic acid catalytic film or niobium oxide / γ-CD-phosphotungstic acid catalytic film was formed on the inner wall of the acetylated microchannel reactor. The film thickness was selected as 20 μm.

[0024] The ammonium niobate used in this invention is ammonium niobate oxalate hydrate, which was purchased from Shanghai Maclean Biochemical Technology Co., Ltd.

[0025] Example 1

[0026] This embodiment provides a method for preparing dehydroepiandrosterone, the steps of which are as follows: 1. Preparation of Quaternized GO-phosphotungstic acid catalyst 1.1 Weigh 1.0 g of graphene oxide (GO) and disperse it in 100 mL of N,N-dimethylformamide (DMF). Sonicate the mixture for 30 min until a homogeneous suspension is formed. Add 0.4 g of 3-aminopropyltriethoxysilane and heat the mixture to 80 °C under nitrogen protection. Stir the mixture for 6 h. After the reaction is complete, centrifuge the precipitate and wash it successively with DMF and anhydrous ethanol to remove unreacted silane coupling agent. Dry the precipitate under vacuum at 60 °C to obtain aminated GO.

[0027] 1.2 Disperse 1g of aminated GO in 80mL of anhydrous ethanol, add 1g of bromoethane, heat to 65℃ and stir for 3h. After the reaction is complete, centrifuge to collect the solid, wash with anhydrous ethanol until no chloride ions are detected in the filtrate, and then dry under vacuum at 70℃ for 6h to obtain aminated GO.

[0028] 1.3 Disperse 1 g of quaternized graphene oxide in 80 mL of deionized water and sonicate for 20 min; slowly add 20 mL of 0.12 mol / L phosphotungstic acid aqueous solution and stir at room temperature for 4 h for adsorption; then heat to 80 °C and stir to concentrate until the system is in paste form, dry at 105 °C for 12 h, and then calcine in a muffle furnace at 180 °C for 1.5 h to obtain quaternized GO supported silicotungstic acid catalyst powder.

[0029] 2. Acetylation reaction Take 10g of 4-androstenedione and dissolve it in 50.0g of acetic anhydride. Stir at room temperature for 30min until completely dissolved to obtain the first material. Separately take 8.5g of acetyl chloride as the acetylation reagent. Pump the first material and acetyl chloride into the acetylation microchannel reactor (with quaternized GO-phosphotungstic acid catalyst loaded on the inner wall) using dual metering pumps. Control the reaction temperature at 30℃, the material residence time at 1.5min, and the reaction pressure at 0.2MPa. Continuously discharge to obtain the acetylation reaction solution.

[0030] 3. Preparation of niobium oxide / γ-CD-phosphotungstic acid catalyst 3.1 Dissolve 1g of γ-CD in 100mL of water, add 3g of epichlorohydrin, and react at 45℃ for 6 h to form a gel; wash with water until neutral and dry under vacuum at 60℃ to obtain cross-linked γ-CD.

[0031] 3.2 Dissolve 6g of niobium ammonium oxalate in 100mL of deionized water to obtain a 0.3 mol / L niobium ammonium oxalate solution; add cross-linked γ-CD, with a liquid-to-solid ratio of 27.5 mL / g; stir and adjust the pH to the median value of 5, heat to 50℃ and maintain the temperature for 2h. After completion, filter, wash the filter residue with deionized water until the washing liquid is neutral to remove oxalate, then vacuum dry at 80℃ and heat-treat at 220℃ for 3h to obtain niobium oxide / γ-CD.

[0032] 3.3 Niobium oxide / γ-CD was immersed in an aqueous solution of 0.05 mol / L phosphotungstic acid for 6 h; then filtered and dried to obtain niobium oxide / γ-CD-phosphotungstic acid.

[0033] 4. Kettal reaction 40.0 g of triethyl orthoformate and 20.0 g of anhydrous ethanol were mixed and stirred until homogeneous to obtain the second material. The acetylation reaction solution from step 2 and the second material were pumped into a ketal microchannel reactor (with niobium oxide / γ-CD-phosphotungstic acid catalyst supported on the inner wall) using a dual metering pump. The reaction temperature was controlled at 45 °C, the material residence time at 20 s, and the reaction pressure at 0.3 MPa. The ketal reaction solution was continuously discharged.

[0034] 5. Reduction reaction Add 7 wt% sodium hydroxide ethanol solution dropwise to the ketal reaction solution discharged from step 4, maintain the system temperature at 18℃, adjust the pH to 7.5, and let stand for 12 min to separate and remove the aqueous layer. Dissolve 0.75 g of sodium borohydride in 50 mL of anhydrous ethanol and stir until dissolved to obtain an ethanol solution containing sodium borohydride. Pump the dehydrated ketal reaction solution and the sodium borohydride ethanol solution into a reduction microchannel reactor (without a supported catalyst, relying on homogeneous reaction of materials) using dual metering pumps, controlling the reaction temperature at 25℃, the material residence time at 40 s, and the reaction pressure at 0.15 MPa, continuously discharging to obtain the reduced reaction solution.

[0035] 6. Hydrolysis and separation Add 12.5 wt% hydrochloric acid aqueous solution dropwise to the reduction reaction solution from step 5, maintain the system temperature at 18℃, adjust the pH to 2.5, and continue stirring at a constant temperature for 17.5 min to obtain the hydrolysis reaction solution. Transfer the hydrolysis solution to a vacuum distillation apparatus, heat to 55℃, reflux under reduced pressure, recover the solvent, and stop heating when no obvious solvent distillation occurs. Cool to 2.5℃ and let stand at a constant temperature for 2.5 h to precipitate a white solid. Filter, wash the filter cake until neutral, and then vacuum dry the filter cake at 65℃ for 5 h to obtain the dehydroepiandrosterone product.

[0036] Example 2

[0037] This embodiment provides a method for preparing dehydroepiandrosterone, the steps of which are as follows: 1. Preparation of Quaternized GO-phosphotungstic acid catalyst 1.1 Weigh 1.0 g of graphene oxide (GO) and disperse it in 100 mL of N,N-dimethylformamide (DMF). Sonicate the mixture for 30 min until a homogeneous suspension is formed. Add 0.2 g of 3-aminopropyltriethoxysilane and heat the mixture to 80 °C under nitrogen protection. Stir the mixture for 6 h. After the reaction is complete, centrifuge the precipitate and wash it successively with DMF and anhydrous ethanol to remove unreacted silane coupling agent. Dry the precipitate under vacuum at 60 °C to obtain aminated GO.

[0038] 1.2 Disperse 1g of aminated GO in 80mL of anhydrous ethanol, add 0.65g of bromoethane, heat to 65℃ and stir for 3h. After the reaction is complete, centrifuge to collect the solid, wash with anhydrous ethanol until no chloride ions are detected in the filtrate, and then dry under vacuum at 70℃ for 6h to obtain aminated GO.

[0039] 1.3 Disperse 1 g of quaternized graphene oxide in 80 mL of deionized water and sonicate for 20 min; slowly add 20 mL of 0.1 mol / L phosphotungstic acid aqueous solution and stir at room temperature for 4 h for adsorption; then heat to 80 °C and stir to concentrate until the system is in paste form, dry at 105 °C for 12 h, and then calcine in a muffle furnace at 150 °C for 3 h to obtain quaternized GO supported silicotungstic acid catalyst powder.

[0040] 2. Acetylation reaction Take 10g of 4-androstenedione and dissolve it in 40g of acetic anhydride. Stir at room temperature for 30min until completely dissolved to obtain the first material. Take 5g of acetyl chloride as the acetylation reagent. Pump the first material and acetyl chloride into the acetylation microchannel reactor (with quaternized GO-phosphotungstic acid catalyst loaded on the inner wall) using a dual metering pump. Control the reaction temperature at 20℃, the material residence time at 2min, and the reaction pressure at 0.2MPa. Continuously discharge to obtain the acetylation reaction solution.

[0041] 3. Preparation of niobium oxide / γ-CD-phosphotungstic acid catalyst 3.1 Dissolve 1g of γ-CD in 100mL of water, add 1g of epichlorohydrin, and react at 25℃ for 10h to form a gel; wash with water until neutral and dry under vacuum at 60℃ to obtain cross-linked γ-CD.

[0042] 3.2 Dissolve 2g of niobium ammonium oxalate in 100mL of deionized water to obtain a 0.1mol / L niobium ammonium oxalate solution; add cross-linked γ-CD, with a liquid-to-solid ratio of 27.5 mL / g; stir and adjust the pH to 4.5; heat to 40℃ and maintain the temperature for 3h. After completion, filter, wash the filter residue with deionized water until the washing liquid is neutral to remove oxalate, then vacuum dry at 80℃ and heat-treat at 150℃ for 6h to obtain niobium oxide / γ-CD.

[0043] 3.3 Niobium oxide / γ-CD was immersed in an aqueous solution of 0.01 mol / L phosphotungstic acid for 12 h; then filtered and dried to obtain niobium oxide / γ-CD-phosphotungstic acid.

[0044] 4. Kettal reaction 30g of triethyl orthoformate and 20.0g of anhydrous ethanol were mixed and stirred until homogeneous to obtain the second material. The acetylation reaction solution from step 2 and the second material were pumped into a ketal microchannel reactor (with niobium oxide / γ-CD-phosphotungstic acid catalyst supported on the inner wall) using a dual metering pump. The reaction temperature was controlled at 40℃, the material residence time at 30s, and the reaction pressure at 0.3MPa. The ketal reaction solution was continuously discharged.

[0045] 5. Reduction reaction Add 7 wt% sodium hydroxide ethanol solution dropwise to the ketal reaction solution discharged from step 4, maintain the system temperature at 18℃, adjust the pH to 7, and let stand for 12 min to separate and remove the aqueous layer. Dissolve 0.3 g of sodium borohydride in 50 mL of anhydrous ethanol and stir until dissolved to obtain an ethanol solution containing sodium borohydride. Pump the dehydrated ketal reaction solution and the sodium borohydride ethanol solution into a reduction microchannel reactor (without a supported catalyst, relying on homogeneous reaction of materials) using dual metering pumps, controlling the reaction temperature at 20℃, the material residence time at 1 min, and the reaction pressure at 0.15 MPa, continuously discharging to obtain the reduced reaction solution.

[0046] 6. Hydrolysis and separation Add 12.5 wt% hydrochloric acid aqueous solution dropwise to the reduction reaction solution from step 5, maintain the system temperature at 18℃, adjust the pH to 2, and continue stirring at a constant temperature for 17.5 min to obtain the hydrolysis reaction solution. Transfer the hydrolysis solution to a vacuum distillation apparatus, heat to 55℃, reflux under reduced pressure, recover the solvent, and stop heating when no obvious solvent distillation occurs. Cool to 2.5℃ and let stand at a constant temperature for 2.5 h, precipitating a white solid. Filter, wash the filter cake until neutral, and then vacuum dry the filter cake at 65℃ for 5 h to obtain the dehydroepiandrosterone product.

[0047] Example 3

[0048] This embodiment provides a method for preparing dehydroepiandrosterone, the steps of which are as follows: 1. Preparation of Quaternized GO-phosphotungstic acid catalyst 1.1 Weigh 1.0 g of graphene oxide (GO) and disperse it in 100 mL of N,N-dimethylformamide (DMF). Sonicate the mixture for 30 min until a homogeneous suspension is formed. Add 0.6 g of 3-aminopropyltriethoxysilane and heat the mixture to 80 °C under nitrogen protection. Stir the mixture for 6 h. After the reaction is complete, centrifuge the precipitate and wash it successively with DMF and anhydrous ethanol to remove unreacted silane coupling agent. Dry the precipitate under vacuum at 60 °C to obtain aminated GO.

[0049] 1.2 Disperse 1g of aminated GO in 80mL of anhydrous ethanol, add 1.35g of bromoethane, heat to 65℃ and stir for 3h. After the reaction is complete, centrifuge to collect the solid, wash with anhydrous ethanol until no chloride ions are detected in the filtrate, and then dry under vacuum at 70℃ for 6h to obtain aminated GO.

[0050] 1.3 Disperse 1 g of quaternized graphene oxide in 80 mL of deionized water and sonicate for 20 min; slowly add 20 mL of 0.15 mol / L phosphotungstic acid aqueous solution and stir at room temperature for 4 h for adsorption; then heat to 80 °C and stir to concentrate until the system is in paste form, dry at 105 °C for 12 h, and then calcine in a muffle furnace at 220 °C for 1 h to obtain quaternized GO supported silicotungstic acid catalyst powder.

[0051] 2. Acetylation reaction Take 10g of 4-androstenedione and dissolve it in 60g of acetic anhydride. Stir at room temperature for 30min until completely dissolved to obtain the first material. Separately, take 12g of acetyl chloride as the acetylation reagent. Pump the first material and acetyl chloride into the acetylation microchannel reactor (with quaternized GO-phosphotungstic acid catalyst loaded on the inner wall) using dual metering pumps. Control the reaction temperature at 40℃, the material residence time at 1min, and the reaction pressure at 0.2MPa. Continuously discharge to obtain the acetylation reaction solution.

[0052] 3. Preparation of niobium oxide / γ-CD-phosphotungstic acid catalyst 3.1 Dissolve 1g of γ-CD in 100mL of water, add 5g of epichlorohydrin, and react at 60℃ for 1h to form a gel; wash with water until neutral and dry under vacuum at 60℃ to obtain cross-linked γ-CD.

[0053] 3.2 Dissolve 2-10 g of niobium ammonium oxalate in 100 mL of deionized water to obtain a 0.5 mol / L niobium ammonium oxalate solution; add cross-linked γ-CD, with a liquid-to-solid ratio of 27.5 mL / g; stir and adjust the pH to the median value of 7, then heat to 60℃ and maintain the temperature for 1 h. After completion, filter, wash the filter residue with deionized water until the washing liquid is neutral to remove oxalate, then vacuum dry at 80℃, and heat-treat at 300℃ for 0.5 h to obtain niobium oxide / γ-CD.

[0054] 3.3 Niobium oxide / γ-CD was immersed in a 1 mol / L aqueous solution of phosphotungstic acid for 0.5 h; then filtered and dried to obtain niobium oxide / γ-CD-phosphotungstic acid.

[0055] 4. Kettal reaction 50g of triethyl orthoformate and 20.0g of anhydrous ethanol were mixed and stirred until homogeneous to obtain the second material. The acetylation reaction solution from step 2 and the second material were pumped into a ketal microchannel reactor (with niobium oxide / γ-CD-phosphotungstic acid catalyst supported on the inner wall) using a dual metering pump. The reaction temperature was controlled at 50℃, the material residence time at 10s, and the reaction pressure at 0.3MPa. The ketal reaction solution was continuously discharged.

[0056] 5. Reduction reaction Add 7 wt% sodium hydroxide ethanol solution dropwise to the ketal reaction solution discharged from step 4, maintain the system temperature at 18℃, adjust the pH to 8, and let stand for 12 min to separate and remove the aqueous layer. Dissolve 1.2 g of sodium borohydride in 50 mL of anhydrous ethanol and stir until dissolved to obtain an ethanol solution containing sodium borohydride. Pump the dehydrated ketal reaction solution and the sodium borohydride ethanol solution into a reduction microchannel reactor (without a supported catalyst, relying on homogeneous reaction of materials) using dual metering pumps, controlling the reaction temperature at 30℃, the material residence time at 0.5 min, and the reaction pressure at 0.15 MPa, continuously discharging to obtain the reduced reaction solution.

[0057] 6. Hydrolysis and separation Add 12.5 wt% hydrochloric acid aqueous solution dropwise to the reduction reaction solution from step 5, maintain the system temperature at 18℃, adjust the pH to 3, and continue stirring at a constant temperature for 17.5 min to obtain the hydrolysis reaction solution. Transfer the hydrolysis solution to a vacuum distillation apparatus, heat to 55℃, reflux under reduced pressure, recover the solvent, and stop heating when no obvious solvent distillation occurs. Cool to 2.5℃ and let stand at a constant temperature for 2.5 h to precipitate a white solid. Filter, wash the filter cake until neutral, and then vacuum dry the filter cake at 65℃ for 5 h to obtain the dehydroepiandrosterone product.

[0058] Example 4

[0059] This embodiment provides a method for preparing dehydroepiandrosterone, the steps of which are as follows: 1. Preparation of Quaternized GO-phosphotungstic acid catalyst 1.1 Weigh 1.0 g of graphene oxide (GO) and disperse it in 100 mL of N,N-dimethylformamide (DMF). Sonicate the mixture for 30 min until a homogeneous suspension is formed. Add 0.5 g of 3-aminopropyltriethoxysilane and heat the mixture to 80 °C under nitrogen protection. Stir the mixture for 6 h. After the reaction is complete, centrifuge the precipitate and wash it successively with DMF and anhydrous ethanol to remove unreacted silane coupling agent. Dry the precipitate under vacuum at 60 °C to obtain aminated GO.

[0060] 1.2 Disperse 1g of aminated GO in 80mL of anhydrous ethanol, add 1.1g of bromoethane, heat to 65℃ and stir for 3h. After the reaction is complete, centrifuge to collect the solid, wash with anhydrous ethanol until no chloride ions are detected in the filtrate, and then dry under vacuum at 70℃ for 6h to obtain aminated GO.

[0061] 1.3 Disperse 1 g of quaternized graphene oxide in 80 mL of deionized water and sonicate for 20 min; slowly add 20 mL of 0.14 mol / L phosphotungstic acid aqueous solution and stir at room temperature for 4 h for adsorption; then heat to 80 °C and stir to concentrate until the system is in paste form, dry at 105 °C for 12 h, and then calcine in a muffle furnace at 200 °C for 2.5 h to obtain quaternized GO supported silicotungstic acid catalyst powder.

[0062] 2. Acetylation reaction Take 10g of 4-androstenedione and dissolve it in 45g of acetic anhydride. Stir at room temperature for 30min until completely dissolved to obtain the first material. Take 10g of acetyl chloride as the acetylation reagent. Pump the first material and acetyl chloride into the acetylation microchannel reactor (with quaternized GO-phosphotungstic acid catalyst loaded on the inner wall) using a dual metering pump. Control the reaction temperature at 25℃, the material residence time at 1min, and the reaction pressure at 0.2MPa. Continuously discharge the acetylation reaction solution.

[0063] 3. Preparation of niobium oxide / γ-CD-phosphotungstic acid catalyst 3.1 Dissolve 1g of γ-CD in 100mL of water, add 2g of epichlorohydrin, and react at 55℃ for 4h to form a gel; wash with water until neutral and dry under vacuum at 60℃ to obtain cross-linked γ-CD.

[0064] 3.2 Dissolve 2-10 g of niobium ammonium oxalate in 100 mL of deionized water to obtain a 0.2 mol / L niobium ammonium oxalate solution; add cross-linked γ-CD, with a liquid-to-solid ratio of 27.5 mL / g; stir and adjust the pH to the median value of 6, then heat to 45℃ and maintain the temperature for 2.5 h. After completion, filter, wash the filter residue with deionized water until the washing liquid is neutral to remove oxalate, then vacuum dry at 80℃, and heat-treat at 200℃ for 4 h to obtain niobium oxide / γ-CD.

[0065] 3.3 Niobium oxide / γ-CD was immersed in an aqueous solution of 0.08 mol / L phosphotungstic acid for 4 h; then filtered and dried to obtain niobium oxide / γ-CD-phosphotungstic acid.

[0066] 4. Kettal reaction 45g of triethyl orthoformate and 20.0g of anhydrous ethanol were mixed and stirred until homogeneous to obtain the second material. The acetylation reaction solution from step 2 and the second material were pumped into a ketal microchannel reactor (with niobium oxide / γ-CD-phosphotungstic acid catalyst supported on the inner wall) using a dual metering pump. The reaction temperature was controlled at 42℃, the material residence time at 15s, and the reaction pressure at 0.3MPa. The ketal reaction solution was continuously discharged.

[0067] 5. Reduction reaction Add 7 wt% sodium hydroxide ethanol solution dropwise to the ketal reaction solution discharged from step 4, maintain the system temperature at 18℃, adjust the pH to 7, and let stand for 12 min to separate the aqueous layer. Dissolve 1 g of sodium borohydride in 50 mL of anhydrous ethanol and stir until dissolved to obtain an ethanol solution containing sodium borohydride. Pump the dehydrated ketal reaction solution and the sodium borohydride ethanol solution into a reduction microchannel reactor (without a supported catalyst, relying on homogeneous reaction of materials) using dual metering pumps, controlling the reaction temperature at 20℃, the material residence time at 30 s, and the reaction pressure at 0.15 MPa, continuously discharging to obtain the reduced reaction solution.

[0068] 6. Hydrolysis and separation Add 12.5 wt% hydrochloric acid aqueous solution dropwise to the reduction reaction solution from step 5, maintain the system temperature at 18℃, adjust the pH to 2, and continue stirring at a constant temperature for 17.5 min to obtain the hydrolysis reaction solution. Transfer the hydrolysis solution to a vacuum distillation apparatus, heat to 55℃, reflux under reduced pressure, recover the solvent, and stop heating when no obvious solvent distillation occurs. Cool to 2.5℃ and let stand at a constant temperature for 2.5 h, precipitating a white solid. Filter, wash the filter cake until neutral, and then vacuum dry the filter cake at 65℃ for 5 h to obtain the dehydroepiandrosterone product.

[0069] Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that the quaternized GO-phosphotungstic acid catalyst was replaced with zinc chloride, and the niobium oxide / γ-CD-phosphotungstic acid catalyst was replaced with a mixture of aluminum trichloride and acidic alumina, with a mass ratio of aluminum trichloride to alumina of 1:0.2. The rest of the contents are the same as in Example 1.

[0070] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that the quaternized GO-phosphotungstic acid catalyst was replaced with GO-phosphotungstic acid, and the rest of the contents are the same as in Example 1.

[0071] The preparation method of GO-phosphotungstic acid is as follows: 1g of graphene oxide is dispersed in 80mL of deionized water and ultrasonically dispersed for 20min; 20mL of 0.1mol / L phosphotungstic acid aqueous solution is slowly added dropwise and stirred and adsorbed at room temperature for 4h; then the temperature is raised to 80℃ and stirred and concentrated until the system is in paste form, dried at 105℃ for 12h, and then placed in a muffle furnace and calcined at 150℃ for 3h to obtain GO-phosphotungstic acid catalyst powder.

[0072] Comparative Example 3 The difference between Comparative Example 3 and Example 1 is that the niobium oxide / γ-CD-phosphotungstic acid catalyst is replaced with niobium oxide / phosphotungstic acid, and the rest is the same as in Example 1.

[0073] The preparation method of niobium oxide / phosphotungstic acid is as follows: 6g of ammonium niobate oxalate was dissolved in 100mL of deionized water to obtain a 0.3 mol / L ammonium niobate oxalate solution; the pH was adjusted to 5 with dilute ammonia or NaOH solution, and the temperature was raised to 50℃ and held for 2h. After the process, the solution was filtered, and the filter residue was washed with deionized water until the washing liquid was neutral to remove oxalate. Subsequently, the solution was vacuum dried at 80℃ and heat-treated at 220℃ for 3h to obtain niobium oxide powder.

[0074] Niobium oxide powder was immersed in a 0.05 mol / L aqueous solution of phosphotungstic acid for 6 h; then filtered and dried to obtain niobium oxide / γ-CD-phosphotungstic acid.

[0075] The test results of the above embodiments and comparative examples are summarized in Table 1.

[0076] Table 1. Conversion, selectivity, and yield of dehydroepiandrosterone in the acetylation / copper acetylene reaction.

[0077] Examples 1–4 are superior to Comparative Example 1 overall: Quaternized GO-phosphotungstic acid is used for acetylation and niobium oxide / γ-CD-phosphotungstic acid is used for ketalization, which simultaneously improves the conversion and selectivity of the two key reactions, thereby increasing the yield of dehydroepiandrosterone from 85% in Comparative Example 1 to 89%–93.5%.

[0078] Comparative Examples 2 and 3 performed poorly: In Comparative Example 2, the unquaternized GO-phosphotungstic acid exhibited weaker stability on the membrane inner wall and lower accessibility to acidic sites, leading to increased acetylation side reactions, resulting in decreased conversion / selectivity and ultimately lower yield. In Comparative Example 3, the lack of the γ-CD structure in the ketal catalyst weakened substrate confinement / enrichment and microenvironment regulation, leading to decreased ketal selectivity, increased subsequent impurity burden, and a lower yield than in the examples.

[0079] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of dehydroepiandrosterone, characterized in that, The method comprises the following steps: S1, acetylation: 4-androstenedione is dissolved in acetic anhydride to obtain a first material, and the acetic anhydride and acetyl chloride are pumped into an acetylation micro-channel reactor, wherein the inner wall of the acetylation micro-channel reactor is loaded with a quaternary ammonium GO-phosphotungstic acid catalyst; S2, ketal: triethyl orthoformate and anhydrous ethanol are mixed to obtain a second material, and the second material and the material discharged from step S1 are pumped into a ketal micro-channel reactor for reaction, wherein the inner wall of the ketal micro-channel reactor is loaded with a niobium oxide / γ-CD-phosphotungstic acid catalyst; S3, reduction: the material discharged from step S2 is dehydrated and the pH is adjusted to 7-8, and then the material is pumped into a reduction micro-channel reactor together with an ethanol solution containing sodium borohydride for reduction reaction; S4, hydrolysis and separation: hydrochloric acid is added to the material discharged from step S3 to adjust the pH to 2-3 to obtain a hydrolysis liquid; the solvent in the hydrolysis liquid is evaporated, the filter cake is filtered and dried to obtain dehydroepiandrosterone.

2. The process for preparing dehydroepiandrosterone as claimed in claim 1, wherein, The preparation method of the quaternary ammonium GO-phosphotungstic acid comprises the following steps: S11, GO is dispersed in DMF, 3-aminopropyltrimethoxysilane is added, centrifuged after the reaction is completed, and the precipitate is washed and dried to obtain aminated GO; the aminated GO is dispersed in anhydrous ethanol, bromoethane is added, and the solid is collected by centrifugation after the reaction is completed, and then washed and dried to obtain quaternary ammonium GO; S12, the quaternary ammonium GO is dispersed in water, and phosphotungstic acid aqueous solution is added and stirred to be adsorbed, and then concentrated, dried and calcined to obtain quaternary ammonium GO-phosphotungstic acid.

3. The process for preparing dehydroepiandrosterone as claimed in claim 2, wherein, The mass ratio of GO to 3-aminopropyltrimethoxysilane in step S11 is 0.2-0.6:1, and the mass ratio of aminated GO to bromoethane is 1:0.65-1.

35.

4. The process for preparing dehydroepiandrosterone as claimed in claim 2, wherein, In step S12, the mass ratio of quaternary ammonium GO to phosphotungstic acid is 1:5.8-8.6, the calcination temperature is 150-220℃, and the time is 1-3 h.

5. The process for preparing dehydroepiandrosterone as claimed in claim 1, wherein, The preparation method of the niobium oxide / γ-CD-phosphotungstic acid comprises the following steps: S21, γ-CD is dissolved in water, epichlorohydrin is added and reacted to form a gel, and then washed to neutral and dried to obtain crosslinked γ-CD; S22, ammonium niobium oxalate is dissolved in water, crosslinked γ-CD is added, stirred, the pH is adjusted to 4.5-7, the temperature is raised to 40-60℃ and kept for 1-3 h, then the filter residue is filtered and washed, and then dried and heat treated to obtain niobium oxide / γ-CD; S23, the niobium oxide / γ-CD is immersed in phosphotungstic acid aqueous solution, filtered and dried to obtain niobium oxide / γ-CD-phosphotungstic acid.

6. The process for preparing dehydroepiandrosterone as claimed in claim 5, wherein, In step S21, the mass ratio of epichlorohydrin to γ-CD is 1-5:1, the reaction temperature is 25-60℃, and the reaction time is 1-10 h.

7. The process for preparing dehydroepiandrosterone as claimed in claim 5, wherein, In step S22, the concentration of the ammonium niobium oxalate solution is 0.1-0.5 mol / L, the amount of crosslinked γ-CD is 2-10 g / 100 mL of the ammonium niobium oxalate solution, the heat treatment temperature is 150-300℃, and the heat treatment time is 0.5-6 h.

8. The process for preparing dehydroepiandrosterone as claimed in claim 5, wherein, In step S23, the concentration of the phosphotungstic acid aqueous solution is 0.01-1 mol / L, and the immersion time is 0.5-12 h.

9. The process for preparing dehydroepiandrosterone as claimed in claim 1, wherein, The mass ratio of 4-androstenedione:acetic anhydride:acetyl chloride:triethyl orthoformate:sodium borohydride is 1:4-6:0.5-1.2:3-5:0.03-0.

12.

10. The process for preparing dehydroepiandrosterone as claimed in claim 1, wherein, The reaction temperature in the acetylation microchannel reactor is 20-40℃, and the material residence time is 1-2 min; the reaction temperature in the ketal microchannel reactor is 40-50℃, and the material residence time is 10-30 s; the reaction temperature in the reduction microchannel reactor is 20-30℃, and the material residence time is 0.5-1 min.

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