Preparation method of epiandrosterone

Abstract

The invention discloses a preparation method of epiandrosterone, which comprises the following step: in a closed reactor and in a hydrogen atmosphere, reacting a mixture containing dehydroepiandrosterone, a catalyst and a solvent to obtain the epiandrosterone. The method for preparing the Pd-based catalyst comprises the following steps: soaking the carrier in an alkaline solution of which the pH value is adjusted to 8-9, stirring for a certain time, carrying out suction filtration after stirring, and drying in a drying oven. Stirring for a period of time, dispersing the carrier in ultrapure water, slowly dropwise adding a mixed solution of a precursor and auxiliary metal ions, stirring for a certain period of time, carrying out suction filtration on the catalyst, drying in a drying oven, and reducing palladium metal; and washing the catalyst after reduction, and drying in a drying oven for a certain time to obtain the catalyst. The catalyst disclosed by the invention is used for preparing epiandrosterone, the conversion rate of a dehydroepiandrosterone raw material is greater than 99.9%, the selectivity of a target product epiandrosterone is greater than 96%, and the selectivity of a byproduct dienedione is less than 4%.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediates, and particularly relates to a method for preparing epiandrosterone. Background Art

[0002] Epiandrosterone is an important pharmaceutical intermediate that can be used in the synthesis of a variety of drugs. The synthesis of epiandrosterone can be achieved through a variety of pathways, including starting from precursor compounds such as cholesterol, phytosterols, dehydroepiandrosterone (DHEA) or androstenedione. The latter two are currently the main products on the market. The synthesis route using androstenedione as the raw material has a wide source of raw materials and relatively lower costs, but the current production process is relatively cumbersome and the product yield is low. The synthesis route using dehydroepiandrosterone as the raw material for hydrogenation generally uses high-content precious metal catalysts in the prior art, and the reaction conditions are harsh and the reaction time is long. Patent Publication No. CN118530293A, after synthesizing DHEA through an improved process, uses a nickel catalyst for catalysis, and its catalyst cost is low, but the product yield is also relatively low. Patent Publication No. CN114409718A provides a method for synthesizing epiandrosterone by a new reactor reaction, but it requires a customized microchannel reactor, which restricts the development of this route. Patent publication number CN106582757A provides a method for preparing a palladium metal catalyst for hydrogenation of dehydroepiandrosterone, but the catalyst has a high noble metal content, a long reaction time, and a correspondingly increased impurity content. Therefore, a method for preparing epiandrosterone under low pressure and with a short reaction time is required. Summary of the invention

[0003] The purpose of the present invention is to provide a preparation method for preparing epiandrosterone by hydrogenating dehydroepiandrosterone raw materials and a green and safe catalytic technology to realize low-pressure catalytic hydrogenation.

[0004] According to one aspect of the present invention, the present invention provides a method for preparing epiandrosterone, the preparation method comprising: reacting a mixture containing dehydroepiandrosterone, a catalyst, and a solvent in a closed reactor in a hydrogen atmosphere to obtain the epiandrosterone; The catalyst comprises a carrier, an active component and a metal promoter component; The active component is Pd, and the auxiliary metal ion in the auxiliary metal component is selected from Fe 3+ 、Ru 3+ , Cu 2+ , Pt 4+ 、In 3 + 、Ce 3+ 、Bi 3+ At least one of; In the catalyst, the mass percentage of the active component is 2wt.%~3wt.%, and the mass percentage of the auxiliary metal component is 0.3wt.%~0.4wt.%; The support is selected from alumina and / or silica.

[0005] Optionally, the method for preparing the catalyst comprises the following steps: Step S1: treating the carrier with alkali, stirring for 1, and drying for 1 to obtain the carrier after alkali treatment; Step S2: immersing the alkali-treated support in a precursor solution, stirring II, adding an alkaline solution, stirring III, and drying II to obtain a pretreated catalyst; Step S3: reducing the pretreated catalyst, sintering, solvent washing, and drying III to obtain the catalyst; The precursor solution includes a Pd precursor solution and an auxiliary metal ion precursor solution.

[0006] Optionally, in step S1, the alkali-treated solution is selected from at least one of sodium hydroxide, potassium hydroxide and sodium carbonate.

[0007] Optionally, the pH value of the alkali treatment is 8-9.

[0008] Optionally, the stirring time I is 4 to 6 hours.

[0009] Optionally, the temperature of the drying I is 80-110° C., and the time of the drying I is 12-18 hours.

[0010] Optionally, in step S2, the Pd precursor solution is selected from palladium dichloride and / or chloropalladic acid.

[0011] Optionally, the mass percentage of Pd in ​​the Pd precursor solution is 2wt.%~3wt.%.

[0012] Optionally, the auxiliary metal ion precursor solution is selected from at least one of chloroplatinic acid, indium nitrate, cerium nitrate, ferric chloride, cupric chloride, ruthenium chloride, and bismuth nitrate.

[0013] Optionally, in step S2, the stirring time of II is 5 to 10 hours.

[0014] Optionally, the alkaline solution is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate and hydrazine hydrate.

[0015] Optionally, the stirring time of III is 4h~6h.

[0016] Optionally, the temperature of the drying II is 80-110° C., and the time of the drying II is 12-18 hours.

[0017] Optionally, in step S3, the reducing atmosphere is hydrogen or a hydrogen-argon mixture.

[0018] Optionally, the sintering temperature is 120-220° C., and the sintering time is 3-8 hours.

[0019] Optionally, in step S3, the solvent used in the solvent washing is selected from ethanol and / or water.

[0020] Optionally, the temperature of the drying III is 80-110° C., and the time of the drying III is 12-18 hours.

[0021] Optionally, the water content of the pretreatment catalyst is 3% to 4%.

[0022] Optionally, the mass ratio of dehydroepiandrosterone to catalyst is 1:5%-10%.

[0023] Optionally, the mass ratio of the dehydroepiandrosterone to the solvent is (30-50): (100-200) g.

[0024] Optionally, the reaction temperature is 40-45° C., and the reaction time is 2 h-5 h.

[0025] Optionally, the reaction temperature is independently selected from any value of 40°C, 41°C, 42°C, 43°C, 44°C, 45°C or a range between any two of the above values.

[0026] Optionally, the reaction time is independently selected from any value among 2h, 3h, 5h or a range between any two of the above.

[0027] Optionally, the pressure of the hydrogen is 0.05~0.08MPa.

[0028] Optionally, the pressure of the hydrogen is independently selected from any value among 0.05 MPa, 0.06 MPa, 0.07 MPa, 0.08 MPa or a range between any two of the above values.

[0029] Optionally, the solvent is selected from ethanol and / or water.

[0030] As an optional implementation mode, the present invention is implemented by the following technical solution: 1. A process for preparing a catalyst, comprising the following steps: 1) Place the alumina or silica carrier in an alkaline solution adjusted to pH 8-9 and stir for a certain period of time; 2) After soaking, the solid-liquid separation and filtration of the carrier are completed, and the carrier is placed in an oven to dry for a certain period of time; 3) Disperse the Pd precursor in ultrapure water and stir for a certain period of time; 4) Adding metal ions including Fe 3+ 、Ru 3+ , Cu 2+ , Pt 4+ 、In 3+ 、Ce 3+ 、Bi 3+ One or more of the above, stirring for a certain period of time; 5) Disperse the carrier in ultrapure water, slowly add the mixed solution of the precursor and the auxiliary metal ion, and stir for a certain period of time; 6) Add alkaline solution and stir for a certain period of time; 7) After filtering the catalyst, place it in an oven to dry for a certain period of time, and take it out after it is dried to below a certain water content; 8) Place the catalyst in a tubular furnace and reduce it with gas; 9) The reduced catalyst is washed in a solvent, filtered and dried in an oven for a period of time to obtain a catalyst for dehydroepiandrosterone hydrogenation.

[0031] 2. The catalyst is applied to the hydrogenation process of epiandrosterone, comprising the following steps: 1) dissolving a dehydroepiandrosterone raw material in a solvent and adding the palladium catalyst prepared in claim 1; 2) Stirring for a certain period of time under appropriate reaction conditions; 3) Separate the product from the catalyst to obtain epiandrosterone.

[0032] The beneficial effects that the present invention can produce include: The preparation method of epiandrosterone provided by the present invention can realize hydrogenation at a low dosage of 5%-10% of the catalyst and a low pressure of 0.05-0.08MPa of hydrogen by preparing a Pd-based catalyst, and realize complete conversion of the dehydroepiandrosterone raw material, and the selectivity of the finally prepared epiandrosterone is greater than 96.0%, and the selectivity of the by-product diene dione is less than 4%. DETAILED DESCRIPTION

[0033] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0034] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0035] Conversion rate of dehydroepiandrosterone = (1-content percentage of dehydroepiandrosterone) × 100%.

[0036] Selectivity of epiandrosterone = percentage of epiandrosterone content ÷ conversion rate of dehydroepiandrosterone × 100%.

[0037] Selectivity of by-product diene dione = percentage of diene dione content ÷ conversion rate of dehydroepiandrosterone × 100%.

[0038] Example 1 The alumina carrier was placed in a sodium hydroxide solution adjusted to pH 8 and stirred for 6 hours, the carrier was filtered out by solid-liquid separation, and dried at 110°C for 12 hours; the Pd precursor was dispersed in ultrapure water (3% palladium mass fraction), and the auxiliary metal ion precursors chloroplatinic acid and copper nitrate were added, with a metal mass ratio of Pd:Pt:Cu=10:1:1, and stirred for 5 hours; the carrier was dispersed in ultrapure water, and a mixed solution of the precursor and the auxiliary metal ion was slowly added dropwise, and stirred for 5 hours; 2 ml of hydrazine hydrate was slowly added dropwise to the carrier solution of the adsorbed precursor, stirred for 5 hours, and dried at 80°C for 12 hours to obtain a pretreated catalyst with a water content of 3%; the pretreated catalyst was reduced in hydrogen for 3 hours, sintered at 120°C for 8 hours, and washed in ethanol solvent; the catalyst was filtered and dried in an oven at 80°C for 18 hours to obtain catalyst product A, i.e., dehydroepiandrosterone hydrogenation catalyst.

[0039] 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A were weighed and placed in a reactor. Hydrogen was introduced. The reaction time was 3 h at 40 ° C and 0.08 MPa pressure. The raw material conversion rate was 99.99%, the selectivity of the target product epiandrosterone was 96.7%, and the selectivity of the by-product diene dione was 3%.

[0040] Example 2 The alumina carrier was placed in a sodium hydroxide solution adjusted to pH 9 and stirred for 4 hours, the carrier was filtered out by solid-liquid separation, and dried at 110°C for 12 hours; the Pd precursor was dispersed in ultrapure water (3% palladium mass fraction), and the auxiliary metal ion precursors ferric chloride and ruthenium chloride were added, with a metal mass ratio of Pd:Fe:Ru=10:1:1, and stirred for 5 hours; the carrier was dispersed in ultrapure water, and the mixed solution of the precursor and the auxiliary metal ion was slowly added dropwise, and stirred for 5 hours; 1 ml of hydrazine hydrate was slowly added dropwise to the carrier solution of the adsorbed precursor, stirred for 4 hours, and dried at 80°C for 12 hours to obtain a pretreated catalyst with a water content of 3%; the pretreated catalyst was reduced in hydrogen for 3 hours, sintered at 120°C for 8 hours, and washed in ethanol solvent; the catalyst was filtered and dried in an oven at 80°C for 18 hours to obtain catalyst product B, i.e., dehydroepiandrosterone hydrogenation catalyst.

[0041] 30 g of dehydroepiandrosterone raw material, 100 g of 95% ethanol, and 1.5 g of catalyst product B were weighed and placed in a reactor. Hydrogen was introduced. The reaction time was 3 h at 45 ° C and 0.05 MPa pressure. The raw material conversion rate was 99.99%, the selectivity of the target product epiandrosterone was 96.6%, and the selectivity of the by-product diene dione was 3.2%.

[0042] Example 3 The alumina carrier was placed in a sodium carbonate solution adjusted to pH 8 and stirred for 6 hours. The carrier was filtered out by solid-liquid separation and dried at 110°C for 12 hours. The Pd precursor was dispersed in ultrapure water (palladium mass fraction 2%), and the auxiliary metal ion precursors cerium nitrate and bismuth nitrate were added, with a metal mass ratio of Pd:Ce:Bi=10:2:3, and stirred for 3 hours. The carrier was dispersed in ultrapure water, and a mixed solution of the precursor and the auxiliary metal ion was slowly added dropwise, and stirred for 3 hours. 2 ml of sodium hydroxide was slowly added dropwise to the carrier solution of the adsorbed precursor, stirred for 4 hours, and dried at 80°C for 12 hours to obtain a pretreated catalyst with a water content of 3%; the pretreated catalyst was reduced in hydrogen for 3 hours, sintered at 120°C for 8 hours, and washed in ethanol solvent; the catalyst was filtered and dried in an oven at 80°C for 18 hours to obtain catalyst product C.

[0043] 30 g of dehydroepiandrosterone raw material, 100 g of anhydrous ethanol, and 1.5 g of catalyst product C were weighed and placed in a reactor. Hydrogen was introduced. The reaction time was 2 h at 42 ° C and 0.06 MPa pressure. The raw material conversion rate was 99.99%, the selectivity of the target product epiandrosterone was 96.3%, and the selectivity of the by-product diene dione was 3.4%.

[0044] Example 4 The silica carrier was placed in a sodium hydroxide solution adjusted to pH 8 and stirred for 6 hours. The carrier was filtered out by solid-liquid separation and dried at 110°C for 12 hours. The Pd precursor was dispersed in ultrapure water (palladium mass fraction 2%), and the auxiliary metal ion precursors cerium nitrate and copper nitrate were added, with a metal mass ratio of Pd:Ce:Cu=10:1:2, and stirred for 5 hours. The carrier was dispersed in ultrapure water, and a mixed solution of the precursor and the auxiliary metal ion was slowly added dropwise, and stirred for 3 hours. 3 ml of potassium hydroxide was slowly added dropwise to the carrier solution of the adsorbed precursor, stirred for 5 hours, and dried at 80°C for 12 hours to obtain a pretreated catalyst with a water content of 3%; the pretreated catalyst was reduced in hydrogen for 3 hours, sintered at 110°C for 10 hours, washed in ethanol solvent, and the catalyst was filtered and dried in an oven at 80°C for 18 hours to obtain catalyst product D.

[0045] 30 g of dehydroepiandrosterone raw material, 100 g of 95% ethanol, and 1.5 g of catalyst product D were weighed and placed in a reactor. The reaction temperature was 42 ° C and 0.08 MPa. The reaction time was 3 h, and the raw material conversion rate was 99.99%, the selectivity of the target product epiandrosterone was 96.5%, and the selectivity of the by-product diene dione was 2.9%.

[0046] Example 5 The alumina carrier was placed in a sodium hydroxide solution adjusted to pH 9 and stirred for 4 hours, the carrier was filtered out by solid-liquid separation, and dried at 80°C for 18 hours; the Pd precursor was dispersed in ultrapure water (palladium mass fraction 2%), and the auxiliary metal ion precursors chloroplatinic acid and copper nitrate were added, the metal mass ratio Pd:Pt:Cu=10:1:1, and stirred for 5 hours; the carrier was dispersed in ultrapure water, and the mixed solution of the precursor and the auxiliary metal ion was slowly added dropwise, and stirred for 10 hours; 2 ml of sodium hydroxide was slowly added dropwise to the carrier solution of the adsorbed precursor, stirred for 6 hours, and dried at 110°C for 12 hours to obtain a pretreated catalyst with a water content of 4%; the pretreated catalyst was reduced in hydrogen for 3 hours, sintered at 220°C for 3 hours, and washed in ethanol solvent; the catalyst was filtered and dried in an oven at 110°C for 12 hours to obtain catalyst product E, i.e., dehydroepiandrosterone hydrogenation catalyst.

[0047] Weigh 50g of dehydroepiandrosterone raw material, 200g of ultrapure water, and 5g of catalyst product E, place them in a reactor, introduce hydrogen, and react at 45°C, 0.05MPa pressure, and for 5h to achieve a raw material conversion rate of 99.99%, a selectivity for the target product epiandrosterone of 96%, and a selectivity for the by-product dienedione of 3.7%.

[0048] Example 6 The amount of catalyst product A in Example 1 was replaced with 3 g, and the remaining preparation steps were consistent with those in Example 1, achieving a raw material conversion rate of 99.9%, a target product epiandrosterone selectivity of 97.5%, and a by-product diene dione selectivity of 2.3%.

[0049] Comparative Example 1 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A were weighed and placed in a reactor. Hydrogen was introduced. The reaction time was 3 h at 30 ° C and 0.08 MPa pressure. The raw material conversion rate was 89%, the selectivity of the target product epiandrosterone was 96.5%, and the selectivity of the by-product diene dione was 3.1%.

[0050] Comparative Example 2 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A were weighed and placed in a reactor. Hydrogen was introduced. The reaction time was 3 h at 50 ° C and 0.08 MPa pressure. The raw material conversion rate was 99.9%, the selectivity of the target product epiandrosterone was 89%, and the selectivity of the by-product diene dione was 10.5%.

[0051] Comparative Example 3 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A were weighed and placed in a reactor. Hydrogen was introduced. The reaction time was 3 h at 40 ° C and 0.02 MPa pressure. The raw material conversion rate was 66.3%, the selectivity of the target product epiandrosterone was 81.9%, and the selectivity of the by-product diene dione was 15.3%.

[0052] Comparative Example 4 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A were weighed and placed in a reactor. Hydrogen was introduced. The reaction time was 3 h at 40 ° C and 0.10 MPa pressure. The raw material conversion rate was 99.9%, the selectivity of the target product epiandrosterone was 90.1%, and the selectivity of the by-product diene dione was 9.5%.

[0053] Comparative Example 5 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A were weighed and placed in a reactor. Hydrogen was introduced. The reaction time was 1 h at 40 ° C and 0.08 MPa pressure. The raw material conversion rate was 75.2%, the selectivity of the target product epiandrosterone was 98.2%, and the selectivity of the by-product dienedione was 1.6%.

[0054] Comparative Example 6 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A were weighed and placed in a reactor. Hydrogen was introduced. The reaction time was 6 h at 40 ° C and 0.08 MPa pressure. The raw material conversion rate was 99.9%, the selectivity of the target product epiandrosterone was 95.9%, and the selectivity of the by-product diene dione was 3.9%.

[0055] Comparative Example 7 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product C were weighed and placed in a reactor. Hydrogen was introduced. The reaction time was 3 h at 40 ° C and 0.08 MPa pressure. The raw material conversion rate was 99.5%, the selectivity of the target product epiandrosterone was 96.8%, and the selectivity of the by-product diene dione was 3%.

[0056] Comparative Example 8 The amount of catalyst product A in Example 1 was replaced with 1 g, and the remaining preparation steps were consistent with those in Example 1, achieving a raw material conversion rate of 71.5%, a target product epiandrosterone selectivity of 98.3%, and a by-product diene dione selectivity of 1.1%.

[0057] Comparative Example 9 The amount of catalyst product A in Example 1 was replaced with 4 g, and the remaining preparation steps were consistent with those in Example 1, achieving a raw material conversion rate of 99.9%, a target product epiandrosterone selectivity of 96%, and a by-product diene dione selectivity of 3.6%.

[0058] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A method for preparing epiandrosterone, characterized in that: The preparation method comprises: reacting a mixture containing dehydroepiandrosterone, a catalyst and a solvent in a closed reactor in a hydrogen atmosphere to obtain the epiandrosterone; The catalyst comprises a carrier, an active component and a metal promoter component; The active component is Pd, and the auxiliary metal ion in the auxiliary metal component is selected from Fe 3+ 、Ru 3+ , Cu 2+ , Pt 4+ 、In 3+ 、Ce 3 + 、Bi 3+ At least one of; In the catalyst, the mass percentage of the active component is 2wt.%~3wt.%, and the mass percentage of the auxiliary metal component is 0.3wt.%~0.4wt.%; The support is selected from alumina and / or silica.

2. The preparation method according to claim 1, characterized in that: The preparation method of the catalyst comprises the following steps: Step S1: treating the carrier with alkali, stirring for 1, and drying for 1 to obtain the carrier after alkali treatment; Step S2: immersing the alkali-treated support in a precursor solution, stirring II, adding an alkaline solution, stirring III, and drying II to obtain a pretreated catalyst; Step S3: reducing the pretreated catalyst, sintering, solvent washing, and drying III to obtain the catalyst; The precursor solution includes a Pd precursor solution and an auxiliary metal ion precursor solution.

3. The preparation method according to claim 2, characterized in that: In step S1, the alkali-treated solution is selected from at least one of sodium hydroxide, potassium hydroxide, and sodium carbonate; Preferably, the pH value of the alkali treatment is 8-9; Preferably, the stirring time is 4 to 6 hours; Preferably, the temperature of the drying I is 80-110° C., and the time of the drying I is 12-18 hours.

4. The preparation method according to claim 2, characterized in that: In the step S2, the Pd precursor solution is selected from palladium dichloride and / or chloropalladic acid; Preferably, the mass percentage of Pd in ​​the Pd precursor solution is 2wt.%~3wt.%; Preferably, the auxiliary metal ion precursor solution is selected from at least one of chloroplatinic acid, indium nitrate, cerium nitrate, ferric chloride, cupric chloride, ruthenium chloride and bismuth nitrate.

5. The preparation method according to claim 2, characterized in that: In the step S2, the stirring time of II is 5 to 10 hours; Preferably, the alkaline solution is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate and hydrazine hydrate; Preferably, the stirring time of III is 4h~6h; Preferably, the temperature of the drying II is 80-110° C., and the time of the drying II is 12-18 hours.

6. The preparation method according to claim 2, characterized in that: In step S3, the reducing atmosphere is hydrogen or a hydrogen-argon mixture; Preferably, the sintering temperature is 120-220° C., and the sintering time is 3-8 hours.

7. The preparation method according to claim 2, characterized in that: In step S3, the solvent used in the solvent washing is selected from ethanol and / or water; Preferably, the temperature of drying III is 80-110° C., and the time of drying III is 12-18 hours; Preferably, the water content of the pretreatment catalyst is 3% to 4%.

8. The preparation method according to claim 1, characterized in that: The mass ratio of dehydroepiandrosterone to the catalyst is 1:5%-10%; Preferably, the mass ratio of the dehydroepiandrosterone to the solvent is (30-50):(100-200) g.

9. The preparation method according to claim 1, characterized in that: The reaction temperature is 40-45°C and the reaction time is 2h-5h; Preferably, the pressure of the hydrogen is 0.05-0.08 MPa.

10. The preparation method according to claim 1, characterized in that: The solvent is selected from ethanol and / or water.