A process for the preparation of epiandrosterone

Abstract

The application discloses a preparation method of epiandrosterone, and the preparation method comprises the following steps: in a closed reactor, a mixture containing dehydroepiandrosterone, a catalyst and a solvent is reacted in a hydrogen atmosphere to obtain the epiandrosterone. The method for preparing a Pd-based catalyst comprises the following steps: a carrier is soaked in an alkaline solution with a pH value of 8-9 and stirred for a certain period of time, then the carrier is filtered and dried in an oven. The carrier is dispersed in ultrapure water, a mixed solution of a precursor and an auxiliary metal ion is slowly added dropwise, and the mixture is stirred for a certain period of time, then the catalyst is filtered and dried in an oven, and the palladium metal is reduced. After reduction, the catalyst is washed and dried in an oven for a certain period of time, so the catalyst is obtained. The catalyst disclosed by the application is used for preparing epiandrosterone, the conversion rate of dehydroepiandrosterone raw material is greater than 99.9%, the selectivity of the target product epiandrosterone is greater than 96%, and the selectivity of the by-product dienedione is less than 4%.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of pharmaceutical intermediates, and particularly relates to a preparation method of epiandrosterone. BACKGROUND

[0002] Epiandrosterone is an important pharmaceutical intermediate and can be used for the synthesis of various drugs. The synthesis of epiandrosterone can be achieved through various routes, including starting from precursor compounds such as cholesterol, phytosterol, dehydroepiandrosterone (DHEA) or androstenedione, among which the latter two are currently dominant in the market. The synthesis route using androstenedione as the raw material has a wide source of raw materials and relatively lower cost, 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 noble metal catalysts in the prior art, and the reaction conditions are harsh and the reaction time is long. Patent Publication No. CN118530293A, after improving the process to synthesize DHEA, uses a nickel catalyst for catalysis, which has a lower catalyst cost, but the product yield is also relatively low. Patent Publication No. CN114409718A provides a method for synthesizing epiandrosterone by using a new type of reactor, but it needs to customize a micro-channel reactor, which restricts the development of this route. Patent Publication No. CN106582757A provides a method for preparing a palladium metal catalyst for dehydroepiandrosterone hydrogenation, but the noble metal content is high, the reaction time is long, and the impurity content is correspondingly increased. Therefore, a preparation method for preparing epiandrosterone under low pressure and short reaction time is needed. SUMMARY

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

[0004] According to one aspect of the present application, the present application provides a preparation method of epiandrosterone, comprising: reacting a mixture containing dehydroepiandrosterone, a catalyst, and a solvent in a hydrogen atmosphere in a closed reactor to obtain the epiandrosterone;

[0005] The catalyst comprises a carrier, an active component, and an auxiliary metal component;

[0006] The active component is Pd, and the auxiliary metal ions in the auxiliary metal component are selected from at least one of Fe 3+ , Ru 3+ , Cu 2+ , Pt 4+ , In 3 + , Ce 3+ , Bi 3+ ;

[0007] The active component has a mass percentage of 2wt.%-3wt.% in the catalyst, and the auxiliary metal component has a mass percentage of 0.3wt.%-0.4wt.%.

[0008] The carrier is selected from alumina and / or silica.

[0009] Optionally, the preparation method of the catalyst comprises the following steps:

[0010] Step S1: alkali treatment of the carrier, stirring I, drying I, to obtain an alkali-treated carrier;

[0011] Step S2: impregnation of the alkali-treated carrier in a precursor solution, stirring II, addition of an alkaline solution, stirring III, drying II, to obtain a pretreated catalyst;

[0012] Step S3: reduction of the pretreated catalyst, sintering, solvent cleaning, drying III, to obtain the catalyst;

[0013] The precursor solution comprises a Pd precursor solution and an auxiliary metal ion precursor solution.

[0014] Optionally, in the step S1, the alkali treatment solution is selected from at least one of sodium hydroxide, potassium hydroxide, and sodium carbonate.

[0015] Optionally, the pH value of the alkali treatment is 8-9.

[0016] Optionally, the stirring I time is 4-6h.

[0017] Optionally, the drying I temperature is 80-110℃, and the drying I time is 12-18h.

[0018] Optionally, in the step S2, the Pd precursor solution is selected from palladium dichloride and / or chloropalladic acid.

[0019] Optionally, the mass percentage of Pd in the Pd precursor solution is 2wt.%-3wt.%.

[0020] Optionally, the auxiliary metal ion precursor solution is selected from at least one of chloroplatinic acid, indium nitrate, cerium nitrate, iron chloride, copper chloride, ruthenium chloride, and bismuth nitrate.

[0021] Optionally, in the step S2, the stirring II time is 5-10h.

[0022] Optionally, the alkaline solution is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, and hydrazine hydrate.

[0023] Optionally, the stirring III time is 4h-6h.

[0024] Optionally, the temperature of the drying II is 80-110℃, and the time of the drying II is 12-18h.

[0025] Optionally, in the step S3, the atmosphere of the reduction is hydrogen or hydrogen-argon mixed gas.

[0026] Optionally, the temperature of the sintering is 120-220℃, and the time of the sintering is 3-8h.

[0027] Optionally, in the step S3, the solvent used in the solvent cleaning is selected from ethanol and / or water.

[0028] Optionally, the temperature of the drying III is 80-110℃, and the time of the drying III is 12-18h.

[0029] Optionally, the water content of the pretreated catalyst is 3%-4%.

[0030] Optionally, the mass ratio of the dehydroepiandrosterone to the catalyst is 1:5%-10%.

[0031] Optionally, the mass ratio of the dehydroepiandrosterone to the solvent is (30-50):(100-200) g.

[0032] Optionally, the temperature of the reaction is 40-45℃, and the time of the reaction is 2h-5h.

[0033] Optionally, the temperature of the reaction is independently selected from any value or a range between any two values of 40℃, 41℃, 42℃, 43℃, 44℃, 45℃.

[0034] Optionally, the time of the reaction is independently selected from any value or a range between any two values of 2h, 3h, 5h.

[0035] Optionally, the pressure of the hydrogen is 0.05-0.08MPa.

[0036] Optionally, the pressure of the hydrogen is independently selected from any value or a range between any two values of 0.05MPa, 0.06MPa, 0.07MPa, 0.08MPa.

[0037] Optionally, the solvent is selected from ethanol and / or water.

[0038] As an optional embodiment, the present application is implemented by the following technical solutions:

[0039] 1. A preparation process of a catalyst, comprising the following steps:

[0040] 1) Put the alumina or silica carrier into an alkaline solution with pH adjusted to 8-9 and stir for a certain time;

[0041] 2) After the end of the soaking, solid-liquid separation is performed to extract the carrier by suction filtration and the carrier is placed in an oven for drying for a certain time;

[0042] 3) The precursor of Pd is dispersed in ultrapure water and stirred for a certain time;

[0043] 4) One or more of the assistant metal ions including Fe 3+ , Ru 3+ , Cu 2+ , Pt 4+ , In 3+ , Ce 3+ , Bi 3+ is added and stirred for a certain time;

[0044] 5) The carrier is dispersed in ultrapure water, and the mixed solution of the precursor and the assistant metal ion is slowly added dropwise, and stirred for a certain time;

[0045] 6) An alkaline solution is added and stirred for a certain time;

[0046] 7) After suction filtration of the catalyst, the catalyst is placed in an oven for drying for a certain time, and is taken out after drying to a certain water content;

[0047] 8) The catalyst is placed in a tube furnace and reduced by a gas;

[0048] 9) The reduced catalyst is placed in a solvent for cleaning, suction filtration and drying in an oven for a period of time to obtain a catalyst for the hydrogenation of dehydroepiandrosterone.

[0049] 2. The catalyst is applied to the hydrogenation process of epiandrosterone, comprising the following steps:

[0050] 1) The dehydroepiandrosterone raw material is dissolved in a solvent and put into the Pd catalyst prepared in claim 1;

[0051] 2) Stirring for a certain time under appropriate reaction conditions;

[0052] 3) The product is separated from the catalyst to obtain epiandrosterone.

[0053] The beneficial effects that can be produced by the present application include:

[0054] The preparation method of epiandrosterone provided by the present application can realize hydrogenation at a low catalyst dosage of 5%-10% and a low hydrogen pressure of 0.05-0.08 MPa by preparing a Pd-based catalyst, and can realize complete conversion of the dehydroepiandrosterone raw material, and the selectivity of the finally prepared epiandrosterone is >96.0%, and the selectivity of the byproduct dienedione is less than 4%. DETAILED DESCRIPTION

[0055] The application will be described in greater detail below with reference to the embodiments. However, the application is not limited to these embodiments.

[0056] The raw materials in the embodiments of the application are commercially available unless otherwise specified.

[0057] Conversion rate of dehydroepiandrosterone = (1 - percentage of dehydroepiandrosterone content) x 100%.

[0058] Selectivity of epiandrosterone = percentage of epiandrosterone content ÷ conversion rate of dehydroepiandrosterone x 100%.

[0059] Selectivity of by-product dien-dione = percentage of dien-dione content ÷ conversion rate of dehydroepiandrosterone x 100%.

[0060] Example 1

[0061] The alumina carrier was stirred in a sodium hydroxide solution with a pH adjusted to 8 for 6 h, the carrier was separated by suction filtration and dried at 110°C for 12 h; the precursor of Pd was dispersed in ultrapure water (mass fraction of Pd 3%), and the precursor of auxiliary metal ions chloroplatinic acid and copper nitrate were added, the mass ratio of metals Pd: Pt: Cu = 10: 1: 1, and stirred for 5 h; the carrier was dispersed in ultrapure water, and the mixed solution of the precursor and the auxiliary metal ions was slowly added dropwise, and stirred for 5 h; 2 ml of hydrazine hydrate was slowly added dropwise to the carrier solution adsorbing the precursor, and stirred for 5 h, and dried at 80°C for 12 h to obtain a pretreated catalyst with a water content of 3%; after the pretreated catalyst was reduced in hydrogen for 3 h, it was sintered at 120°C for 8 h, and then washed in an ethanol solvent; after the catalyst was suction filtered, it was dried in an oven at 80°C for 18 h to obtain catalyst product A, i.e. a dehydroepiandrosterone hydrogenation catalyst.

[0062] 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 reaction kettle, hydrogen was introduced, and the reaction was carried out at 40°C and a pressure of 0.08 MPa for 3 h, achieving a raw material conversion rate of 99.99%, a target product epiandrosterone selectivity of 96.7%, and a by-product dien-dione selectivity of 3%.

[0063] Example 2

[0064] The alumina carrier is placed in a sodium hydroxide solution with pH adjusted to 9 and stirred for 4 h, the carrier is separated by filtration and dried at 110°C for 12 h; the precursor of Pd is dispersed in ultrapure water (palladium mass fraction 3%), and the precursor of auxiliary metal ions, iron chloride and ruthenium chloride, is added, and the metal mass ratio of Pd:Fe:Ru is 10:1:1, and stirred for 5 h; the carrier is dispersed in ultrapure water, and the mixed solution of the precursor and the auxiliary metal ions is slowly added dropwise, and stirred for 5 h; 1 ml of hydrazine hydrate is slowly added dropwise to the carrier solution adsorbed with the precursor, and stirred for 4 h, and dried at 80°C for 12 h to obtain a pretreated catalyst with a water content of 3%; after the pretreated catalyst is reduced in hydrogen for 3 h, it is sintered at 120°C for 8 h, and then washed in an ethanol solvent; after the catalyst is filtered, it is dried in an oven at 80°C for 18 h to obtain catalyst product B, i.e. a dehydroepiandrosterone hydrogenation catalyst.

[0065] 30 g of dehydroepiandrosterone raw material, 100 g of 95% ethanol, and 1.5 g of catalyst product B are weighed and placed in a reaction kettle, hydrogen is introduced, and the reaction is carried out at 45°C and 0.05 MPa for 3 h, achieving a raw material conversion rate of 99.99%, a target product epiandrosterone selectivity of 96.6%, and a by-product dien-dione selectivity of 3.2%.

[0066] Example 3

[0067] The alumina carrier is placed in a sodium carbonate solution with pH adjusted to 8 and stirred for 6 h, the carrier is separated by filtration and dried at 110°C for 12 h; the precursor of Pd is dispersed in ultrapure water (palladium mass fraction 2%), and the precursor of auxiliary metal ions, cerium nitrate and bismuth nitrate, is added, and the metal mass ratio of Pd:Ce:Bi is 10:2:3, and stirred for 3 h; the carrier is dispersed in ultrapure water, and the mixed solution of the precursor and the auxiliary metal ions is slowly added dropwise, and stirred for 3 h; 2 ml of sodium hydroxide is slowly added dropwise to the carrier solution adsorbed with the precursor, and stirred for 4 h, and dried at 80°C for 12 h to obtain a pretreated catalyst with a water content of 3%; after the pretreated catalyst is reduced in hydrogen for 3 h, it is sintered at 120°C for 8 h, and then washed in an ethanol solvent; after the catalyst is filtered, it is dried in an oven at 80°C for 18 h to obtain catalyst product C.

[0068] 30 g of dehydroepiandrosterone raw material, 100 g of anhydrous ethanol, and 1.5 g of catalyst product C are weighed and placed in a reaction kettle, hydrogen is introduced, and the reaction is carried out at 42°C and 0.06 MPa for 2 h, achieving a raw material conversion rate of 99.99%, a target product epiandrosterone selectivity of 96.3%, and a by-product dien-dione selectivity of 3.4%.

[0069] Example 4

[0070] The silicon oxide carrier is placed in a sodium hydroxide solution with pH adjusted to 8 and stirred for 6 h, the carrier is separated by filtration and dried at 110°C for 12 h; the precursor of Pd is dispersed in ultrapure water (2% by mass of Pd), and the precursor of the auxiliary metal ion cerium nitrate and copper nitrate is added, and the metal mass ratio of Pd:Ce:Cu is 10:1:2, and stirred for 5 h; the carrier is dispersed in ultrapure water, and the mixed solution of the precursor and the auxiliary metal ion is slowly added dropwise, and stirred for 3 h; 3 ml of potassium hydroxide is slowly added dropwise to the carrier solution adsorbed with the precursor, and stirred for 5 h, and dried at 80°C for 12 h to obtain a pretreated catalyst with a water content of 3%; after the pretreated catalyst is reduced in hydrogen for 3 h, it is sintered at 110°C for 10 h, washed in an ethanol solvent, and dried at 80°C for 18 h in an oven after the catalyst is filtered to obtain a catalyst product D.

[0071] 30 g of dehydroepiandrosterone raw material, 100 g of 95% ethanol, and 1.5 g of the catalyst product D are weighed and placed in a reaction kettle, and the reaction is carried out at 42°C and 0.08 MPa for 3 h, achieving a raw material conversion rate of 99.99%, a target product epiandrosterone selectivity of 96.5%, and a by-product dien-dione selectivity of 2.9%.

[0072] Example 5

[0073] The aluminum oxide carrier is placed in a sodium hydroxide solution with pH adjusted to 9 and stirred for 4 h, the carrier is separated by filtration, and dried at 80°C for 18 h; the precursor of Pd is dispersed in ultrapure water (2% by mass of Pd), and the precursor of the auxiliary metal ion chloroplatinic acid and copper nitrate is added, and the metal mass ratio of Pd:Pt:Cu is 10:1:1, and stirred for 5 h; the carrier is dispersed in ultrapure water, and the mixed solution of the precursor and the auxiliary metal ion is slowly added dropwise, and stirred for 10 h; 2 ml of sodium hydroxide is slowly added dropwise to the carrier solution adsorbed with the precursor, and stirred for 6 h, and dried at 110°C for 12 h to obtain a pretreated catalyst with a water content of 4%; after the pretreated catalyst is reduced in hydrogen for 3 h, it is sintered at 220°C for 3 h, washed in an ethanol solvent; the catalyst is filtered and dried at 110°C for 12 h in an oven to obtain a catalyst product E, i.e., a dehydroepiandrosterone hydrogenation catalyst.

[0074] 50 g of dehydroepiandrosterone raw material, 200 g of ultrapure water, and 5 g of the catalyst product E are weighed and placed in a reaction kettle, and hydrogen is introduced, and the reaction is carried out at 45°C and 0.05 MPa for 5 h, achieving a raw material conversion rate of 99.99%, a target product epiandrosterone selectivity of 96%, and a by-product dien-dione selectivity of 3.7%.

[0075] Example 6

[0076] The amount of catalyst product A in Example 1 is replaced with 3 g, and the remaining preparation steps are consistent with those in Example 1, achieving a raw material conversion rate of 99.9%, a target product androstenedione selectivity of 97.5%, and a by-product dien-dione selectivity of 2.3%.

[0077] Comparative Example 1

[0078] 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A are weighed and placed in a reaction kettle, hydrogen is introduced, and the reaction is carried out at 30°C and 0.08 MPa for 3 h, achieving a raw material conversion rate of 89%, a target product androstenedione selectivity of 96.5%, and a by-product dien-dione selectivity of 3.1%.

[0079] Comparative Example 2

[0080] 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A are weighed and placed in a reaction kettle, hydrogen is introduced, and the reaction is carried out at 50°C and 0.08 MPa for 3 h, achieving a raw material conversion rate of 99.9%, a target product androstenedione selectivity of 89%, and a by-product dien-dione selectivity of 10.5%.

[0081] Comparative Example 3

[0082] 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A are weighed and placed in a reaction kettle, hydrogen is introduced, and the reaction is carried out at 40°C and 0.02 MPa for 3 h, achieving a raw material conversion rate of 66.3%, a target product androstenedione selectivity of 81.9%, and a by-product dien-dione selectivity of 15.3%.

[0083] Comparative Example 4

[0084] 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A are weighed and placed in a reaction kettle, hydrogen is introduced, and the reaction is carried out at 40°C and 0.10 MPa for 3 h, achieving a raw material conversion rate of 99.9%, a target product androstenedione selectivity of 90.1%, and a by-product dien-dione selectivity of 9.5%.

[0085] Comparative Example 5

[0086] 30 g of dehydroepiandrosterone raw material, 100 g of ultrapure water, and 1.5 g of catalyst product A are weighed and placed in a reaction kettle, hydrogen is introduced, and the reaction is carried out at 40°C and 0.08 MPa for 1 h, achieving a raw material conversion rate of 75.2%, a target product androstenedione selectivity of 98.2%, and a by-product dien-dione selectivity of 1.6%.

[0087] Comparative Example 6

[0088] Take 30g dehydroepiandrosterone raw material, 100g ultrapure water, 1.5g catalyst product A, place in the reaction kettle, hydrogen is introduced, at 40℃, 0.08MPa pressure, reaction time 6h, the raw material conversion rate is 99.9%, the target product androstenedione selectivity is 95.9%, the by-product diene dione selectivity is 3.9%.

[0089] Comparative example 7

[0090] Take 30g dehydroepiandrosterone raw material, 100g ultrapure water, 1.5g catalyst product C, place in the reaction kettle, hydrogen is introduced, at 40℃, 0.08MPa pressure, reaction time 3h, the raw material conversion rate is 99.5%, the target product androstenedione selectivity is 96.8%, the by-product diene dione selectivity is 3%.

[0091] Comparative example 8

[0092] The amount of catalyst product A in example 1 is replaced by 1g, and the remaining preparation steps are consistent with those in example 1, the raw material conversion rate is 71.5%, the target product androstenedione selectivity is 98.3%, and the by-product diene dione selectivity is 1.1%.

[0093] Comparative example 9

[0094] The amount of catalyst product A in example 1 is replaced by 4g, and the remaining preparation steps are consistent with those in example 1, the raw material conversion rate is 99.9%, the target product androstenedione selectivity is 96%, and the by-product diene dione selectivity is 3.6%.

[0095] The above is only a few embodiments of the present application, not any form of limitation on the present application, although the preferred embodiments are disclosed as above, however, not to limit the present application, any skilled in the art, within the scope of the technical scheme of the present application, use the above disclosed technical content to make some changes or modifications are equivalent to equivalent embodiments, all belong to the scope of the technical scheme.

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 co-metal 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 2 wt.% to 3 wt.%, and the mass percentage of the metal-promoting component is 0.3 wt.% to 0.4 wt.%; The carrier is selected from alumina and / or silica; The preparation method of the catalyst comprises the following steps: Step S1: treating the carrier with alkali, stirring for 1 hour, and drying for 1 hour to obtain the alkali-treated carrier; 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; In step S2, the Pd precursor solution is selected from palladium dichloride and / or chloropalladic acid; The auxiliary metal ion precursor solution is selected from at least one of chloroplatinic acid, indium nitrate, cerium nitrate, ferric chloride, copper chloride, ruthenium chloride, and bismuth nitrate; The pressure of the hydrogen is 0.05-0.08 MPa.

2. The preparation method according to claim 1, characterized in that In step S1, the alkali-treated solution is selected from at least one of sodium hydroxide, potassium hydroxide, and sodium carbonate.

3. The preparation method according to claim 1, characterized in that The pH value of the alkali treatment is 8-9.

4. The preparation method according to claim 1, characterized in that The stirring time is 4 to 6 hours.

5. The preparation method according to claim 1, characterized in that The temperature of the drying process is 80-110° C., and the time of the drying process is 12-18 hours.

6. The preparation method according to claim 1, characterized in that The mass percentage of Pd in ​​the Pd precursor solution is 2 wt.% to 3 wt.%.

7. The preparation method according to claim 1, characterized in that In the step S2, the stirring time of II is 5 to 10 hours.

8. The preparation method according to claim 1, characterized in that The alkaline solution is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate and hydrazine hydrate.

9. The preparation method according to claim 1, characterized in that The stirring time of III is 4h~6h.

10. The preparation method according to claim 1, characterized in that The temperature of the drying II is 80-110° C., and the time of the drying II is 12-18 hours.

11. The preparation method according to claim 1, characterized in that In step S3, the reducing atmosphere is hydrogen or a hydrogen-argon mixture.

12. The preparation method according to claim 1, characterized in that The sintering temperature is 120-220° C., and the sintering time is 3-8 hours.

13. The preparation method according to claim 1, characterized in that In step S3, the solvent used in the solvent washing is selected from ethanol and / or water.

14. The preparation method according to claim 1, characterized in that The temperature of the drying step III is 80-110° C., and the time of the drying step III is 12-18 hours.

15. The preparation method according to claim 1, characterized in that The water content of the pretreatment catalyst is 3% to 4%.

16. The preparation method according to claim 1, characterized in that The mass ratio of the dehydroepiandrosterone to the catalyst is 1:5%-10%.

17. The preparation method according to claim 1, characterized in that The mass ratio of the dehydroepiandrosterone to the solvent is (30-50): (100-200) g.

18. The preparation method according to claim 1, characterized in that The reaction temperature is 40-45° C., and the reaction time is 2-5 hours.

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