Catalytic hydrogenation synthesis method of chiral finasterin intermediate

Abstract

The invention relates to the technical field of catalytic hydrogenation, and particularly discloses a catalytic hydrogenation synthesis method of a chiral finasterin intermediate. The process for preparing the N-tert-butyl-3-oxo-4-aza-5 alpha-androstane-17 beta-amide through hydrogenation of the finasterin intermediate N-tert-butyl-3-oxo-4-aza-5 alpha-androstane-17 beta-amide has the restriction bottleneck of the synthesis yield of the finasterin, the yield requirement is met, and the requirement for the enantiomeric quantity of a target chiral compound is also met. The existing catalyst adopts palladium carbon with high loading capacity for catalytic hydrogenation, the production cost is always high, the yield is low, in order to increase the chiral yield of the reaction, the reaction technical route generally adopts an acidic environment, and the activity of the catalyst is greatly influenced. The invention provides a high-selectivity and high-efficiency chiral finasterin intermediate catalytic hydrogenation synthesis method by modifying the catalyst, and the catalyst has the advantages of low noble metal loading capacity and low cost.

Description

Technical Field

[0001] The present invention relates to the technical field of catalytic hydrogenation, and specifically discloses a method for catalytic hydrogenation synthesis of a chiral finasteride intermediate. Background Art

[0002] The master's thesis of Jilin University, "Synthesis Research of Finasteride", combined with the analysis of domestic and foreign synthesis routes, used platinum dioxide to catalyze hydrogenation under normal temperature, normal pressure and acidic environment to hydrogenate the intermediate N-tert-butyl-3-oxo-4-aza-5α-androstene-17β-carboxamide to obtain N-tert-butyl-3-oxo-4-aza-5α-androstan-17β-carboxamide.

[0003] The master's thesis of Henan Normal University, "Research on the Synthesis Process of Finasteride", in the research on the synthesis process route of finasteride, used ethanol as a solvent and carried out a catalytic hydrogenation reaction with 10% palladium on carbon under high temperature and high pressure conditions to produce N-tert-butyl-3-oxo-4-aza-5α-androstan-17β-carboxamide, and the catalyst dosage reached 10%. However, after testing, at a lower catalyst feeding amount, even when the pressure was increased, the reaction yield and the selectivity of intermediate D still decreased significantly, and the recycling times of this 10% palladium on carbon catalyst were not high and it needed to be activated frequently.

[0004] Patent CN108752415A adopted a catalytic hydrogenation system of diamide, 5% palladium on carbon, p-toluenesulfonic acid and glacial acetic acid, and reacted at 60 °C for 8 h under a hydrogen atmosphere, and the filtrate was concentrated under reduced pressure to dryness to obtain 5β-chiral hydride. By sampling and testing, the main peak content of the chiral hydride was 28.8%, and the final mass yield was 22.7%.

[0005] In the process of hydrogenating the finasteride intermediate N-tert-butyl-3-oxo-4-aza-5α-androstene-17β-carboxamide to prepare N-tert-butyl-3-oxo-4-aza-5α-androstan-17β-carboxamide, the catalyst generally uses PtO 2 , or high-content palladium on carbon for catalytic hydrogenation, resulting in high production costs. In order to increase the chiral yield of the reaction, the reaction technical route generally adopts an acidic environment, which will have a greater impact on the catalyst activity, and it is necessary to use a larger dosage to achieve better conversion and selectivity. The enantiomeric excess value of the isomers of the hydrogenation product in this step and the hydrogenation yield directly restrict the yield of finasteride. Summary of the Invention

[0006] In order to solve the problems of large noble metal feeding amount, low yield under low hydrogen pressure and easy deactivation of the catalyst under acidic conditions in the catalytic hydrogenation synthesis of chiral finasteride intermediates, the first aspect of the present invention proposes a method for catalytic hydrogenation synthesis of chiral finasteride intermediates, including: Mix substrate I, organic solvent, and catalyst Cat, heat up the temperature, and apply pressure under a hydrogen atmosphere to obtain the α-configured chiral finasteride intermediate.

[0007] In some specific embodiments of the first aspect of the present invention, the catalyst Cat uses carbon as a carrier and is loaded with the active component palladium and the promoter metal component magnesium.

[0008] In some specific embodiments of the first aspect of the present invention, the heating up is to heat up to 70 - 80 °C, and in some embodiments, it is 75 °C.

[0009] In some specific embodiments of the first aspect of the present invention, the hydrogen pressure is greater than 0.3 Mpa, and in some embodiments, it is 0.4 Mpa, in some embodiments, it is 0.5 Mpa, and in some embodiments, it is 0.6 Mpa.

[0010] In some specific embodiments of the first aspect of the present invention, the organic solvent is selected from alcohols.

[0011] In some specific embodiments of the first aspect of the present invention, the alcohol is selected from methanol, ethanol, and isopropanol.

[0012] In some specific embodiments of the first aspect of the present invention, the feeding mass ratio of the catalyst Cat to substrate I is (1 - 2):60, and in some embodiments, it is 1.2:60, in some embodiments, it is 1.4:60, and in some embodiments, it is 1.6:60.

[0013] In some specific embodiments of the first aspect of the present invention, in every 1 L of the organic solvent, 100 - 140 g of substrate I is fed, and in some embodiments, 110 g of substrate I is fed, in some embodiments, 120 g of substrate I is fed, and in some embodiments, 130 g of substrate I is fed.

[0014] In some specific embodiments of the first aspect of the present invention, the preparation method of the catalyst Cat includes: S1: Mix the palladium salt solution and the magnesium compound to prepare a metal precursor solution; S2: Disperse the carrier carbon in water to obtain a first dispersion system, and then drop the metal precursor solution into the first dispersion system to obtain a second dispersion system; S3: Under the stirring state of the second dispersion system, add an alkali and a reducing agent, and perform solid-liquid separation to obtain the catalyst Cat loaded with the active component palladium and the promoter metal component magnesium.

[0015] In some specific embodiments of the first aspect of the present invention, in S1, the palladium salt is selected from any one or combination of palladium chloride, chloropalladic acid, sodium chloropalladate, ammonium chloropalladate, potassium chloropalladate, and palladium powder.

[0016] In some specific embodiments of the first aspect of the present invention, the magnesium compound in S1 is selected from any one or a combination of magnesium hydroxide, magnesium chloride, magnesium sulfate, and magnesium sulfite.

[0017] In some specific embodiments of the first aspect of the present invention, the palladium salt solution in S1 is an aqueous solution of a palladium salt.

[0018] In some specific embodiments of the first aspect of the present invention, the molar concentration of the palladium salt in S1 is 0.08 - 0.12 mol / L. In some embodiments, the molar concentration of the palladium salt is 0.09 mol / L. In some embodiments, the molar concentration of the palladium salt is 0.10 mol / L. In some embodiments, the molar concentration of the palladium salt is 0.11 mol / L.

[0019] In some specific embodiments of the first aspect of the present invention, the support carbon in S2 is selected from any one or a combination of graphite carbon, activated carbon, and carbon nanotubes.

[0020] In some specific embodiments of the first aspect of the present invention, in the first dispersion system of S2, 125 - 250 g of support carbon is added per 1 L of water.

[0021] In some specific embodiments of the first aspect of the present invention, the stirring speed of the second dispersion system in S3 is 200 - 400 rpm.

[0022] In some specific embodiments of the first aspect of the present invention, the base in S3 is selected from any one or a combination of ethylenediamine, potassium hydroxide, sodium hydroxide, and cesium hydroxide.

[0023] In some specific embodiments of the first aspect of the present invention, the reducing agent in S3 is selected from any one or a combination of NaBH 4 、KBH 4 、hydrazine hydrate, formic acid, citric acid, formaldehyde, and / or, in S3, the method of adding the base and the reducing agent is dropwise addition.

[0024] In some specific embodiments of the first aspect of the present invention, during the dropwise addition of the base and the reducing agent in S3, the pH of the second dispersion system is controlled between 10 and 12. In some embodiments, the pH is controlled to be 11.

[0025] In some specific embodiments of the first aspect of the present invention, in S3, the method of solid - liquid separation is suction filtration.

[0026] The catalyst composition includes: the active component palladium, the promoter metal magnesium, and the support carbon.

[0027] The active component is Pd: The Pd metal precursor can be selected from one of palladium chloride, chloropalladic acid, sodium chloropalladate, ammonium chloropalladate, potassium chloropalladate, and palladium powder.

[0028] The catalyst preparation method is as follows.

[0029] Solution Preparation (1)0.1mol / L H 2 PdCl 4 Solution (chloropalladic acid solution): Weigh 3.55g of PdCl 2 solid, add 4.05ml of 36% hydrochloric acid and 50ml of ultrapure water, heat until the solid is completely dissolved, then cool and make up the volume to 200ml; (2)0.5mol / L NaBH 4 Aqueous solution: Weigh 3.78g of NaBH 4 , add 200ml of ultrapure water, stir until the solid sample is dissolved clearly, and prepare it for immediate use.

[0030] In the present invention, e.e is defined as the enantiomeric excess value.

[0031] In the present invention, the raw material conversion rate is defined as: the yield of the substrate raw material converted into the mixture of α and β enantiomers.

[0032] All the reagents used in the present invention are purchased from the open and legal market and are not further purified.

[0033] Advantages of the present invention: The process of hydrogenating finasteride intermediate N-tert-butyl-3-oxo-4-aza-5α-androstene-17β-carboxamide to N-tert-butyl-3-oxo-4-aza-5α-androstan-17β-carboxamide is the bottleneck restricting the synthesis yield of finasteride. By modifying the catalyst and adding co-metal magnesium in the present invention, compared with the prior art technical scheme of hydrogenating to prepare N-tert-butyl-3-oxo-4-aza-5α-androstan-17β-carboxamide, the feeding amount of this 3% supported catalyst is significantly reduced, and under an alcohol solvent, a relatively low hydrogen pressure (0.4MPa) and temperature (70 - 80°C), good yield and the requirement of the chiral enantiomeric amount of the target compound can be achieved without adding acid. Moreover, adding co-metal can significantly increase the number of reuse activities and reduce the required activation times, having great cost advantages. Specific Examples The following will clearly and completely describe the technical solutions in the embodiments of the present application in combination with the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art based on the present application belong to the scope protected by the present application.

[0035] The technical solution of the present invention is as follows:

[0036] Charge the raw material intermediate compound I, alcohol, and catalyst Cat into the reaction kettle. Control the temperature of the reaction kettle to rise to a predetermined temperature, introduce hydrogen for pressurized reaction, and the reaction duration is 4 - 5 h. After opening the kettle, take a sample for liquid chromatography analysis.

[0037] Preparation method of catalyst Cat: Weigh activated carbon and disperse it in water. Separately, take a solution of chloropalladic acid and mix it with one of magnesium dichloride or magnesium hydroxide to prepare a metal precursor solution, and mix evenly. Drop the metal precursor solution into the aqueous solution of activated carbon using a burette funnel, and continue stirring and dispersing after the dropping is completed.

[0038] After the stirring and dispersing is completed, simultaneously dropwise add NaOH and NaBH 4 solution, adjust and maintain the pH of the solution at 10. After all the dropping is completed, continue stirring for 3 h. Subsequently, filter by suction to separate the catalyst cake, and wash it until neutral to obtain the catalyst Cat loaded with 3% palladium.

[0039] Charge raw material I, alcohol, and catalyst Cat into the reaction kettle, control the temperature of the reaction kettle, and start pressurized reaction with hydrogen. After opening the kettle, take a sample for liquid chromatography analysis (Daicel CHIRALPAK IA, n - hexane / isopropanol = 90 / 10, 0.9 mL / min, λ = 254 nm), and calculate the raw material conversion rate and the e.e. value of the α - configuration product (product II).

[0040] Example 1 Step (1): Weigh 50 g of activated carbon and disperse it in 200 ml of ultrapure water. Separately, take 141 ml of a 0.1 mol / L solution of chloropalladic acid and 0.60 g of magnesium hydroxide to prepare a metal precursor solution, and mix evenly. At a rotation speed of 300 rpm, drop the metal precursor solution into the aqueous solution of activated carbon using a burette funnel, and continue stirring and dispersing for 8 h after the dropping is completed.

[0041] Step (2): Add 0.5 mol / L NaOH to 56.5 ml of 0.5 mol / L NaBH 4 solution to adjust and maintain the pH of the solution at 10.

[0042] Step (3): After all the NaBH 4 solution is dropped, continue stirring at 300 rpm for 3 h. Subsequently, filter by suction to separate the catalyst cake, and wash it until neutral to obtain the wet product of the 3% palladium - loaded catalyst Cat with a water content of 65.8%.

[0043] Step (4) The reaction was carried out in a 500 ml reactor. 12 g of raw material intermediate compound I, 100 ml of ethanol, and 0.2 g of catalyst Cat in dry basis were charged into the reactor. The reactor was heated to 70 °C, and 0.3 MPa of hydrogen was introduced to start the reaction for 4 h. After opening the reactor, a sample was taken for liquid chromatography analysis. In the obtained hydrogenation product, the conversion rate of the raw material was 98.2%, and the e.e. value of the α-configured product was 95.7%.

[0044] Example 2 Step (1) 25 g of activated carbon was weighed and dispersed in 200 ml of ultrapure water. A metal precursor solution was prepared by mixing 70.5 ml of 0.1 mol / L chloropalladic acid and 1.95 g of magnesium chloride. After mixing evenly, the metal precursor solution was added dropwise to the activated carbon aqueous solution using a burette funnel at a rotation speed of 300 rpm. After the addition was completed, stirring and dispersion were continued for 8 h.

[0045] Step (2) 0.5 mol / L NaOH was added to 28.3 ml of 0.5 mol / L KBH 4 to adjust and maintain the solution pH at 12.

[0046] Step (3) After all the NaBH 4 solution was added dropwise, stirring was continued at 300 rpm for 2 h. Subsequently, the catalyst cake was separated by suction filtration and washed to neutrality to obtain a wet catalyst Cat-1 with 3% palladium and a water content of 65.0%.

[0047] Step (4) The reaction was carried out in a 500 ml reactor. 12 g of raw material intermediate compound I, 100 ml of isopropanol as the solvent, and 0.3 g of catalyst Cat-1 in dry basis were charged into the reactor. The reactor was heated to 80 °C, and 0.4 MPa of hydrogen was introduced to start the reaction for 5 h. After opening the reactor, a sample was taken for liquid chromatography analysis. In the obtained hydrogenation product, the conversion rate of the raw material was 97.2%, and the e.e. value of the α-configured product was 96.8%.

[0048] Comparative Example 1 The difference between Comparative Example 1 and Example 1 is that in step (1) of Comparative Example 1, 0.36 g of cobalt hydroxide was also added in the preparation of the metal precursor solution to obtain catalyst Cat-2.

[0049] Comparative Example 2 The difference between Comparative Example 2 and Example 1 is that in step (1) of Comparative Example 2, 0.25 g of iron hydroxide was also added in the preparation of the metal precursor solution to obtain catalyst Cat-3.

[0050] Comparative Example 3 The difference between Comparative Example 3 and Example 1 lies in that in Comparative Example 3, when preparing the metal precursor solution in step (1), magnesium hydroxide is not added, and a catalyst Cat-4 loaded with 3% palladium is obtained.

[0051] Example 3 12 g of raw material intermediate compound I, 100 ml of ethanol, and 0.3 g of the catalyst shown in Table 1 were added into a 500 ml reaction kettle. The reaction kettle was controlled to be heated to 80 °C, and 0.3 MPa of hydrogen was introduced to start the reaction for 4 h. After opening the kettle, a sample was taken for liquid chromatography analysis to test the raw material conversion rate and the e.e. value of the α-configured product, and Table 1 was obtained.

[0052] Table 1 Example 4 12 g of raw material intermediate compound I was added into a 500 ml reaction kettle, and then 100 ml of the solvent shown in Table 2 and 0.2 g of the catalyst on dry basis were added. The reaction kettle was controlled to be heated and pressurized to the predetermined temperature (°C) and hydrogen pressure (MPa) shown in Table 2 to start the reaction for 4 h. After opening the kettle, a sample was taken for liquid chromatography analysis to test the raw material conversion rate and the e.e. value of the α-configured product, and Table 2 was obtained.

[0053] Table 2 Example 5 12 g of raw material intermediate compound I, 100 ml of ethanol, and 0.2 g of the catalyst shown in Table 3 on dry basis were added into a 500 ml reaction kettle. The reaction kettle was controlled to be heated to 80 °C, and 0.3 MPa of hydrogen was introduced to start the reaction for 4 h. After opening the kettle, a sample was taken for liquid chromatography analysis. Each time, the raw material conversion rate and the ee value of the α-configured product were tested. After multiple recycles, if the conversion rate of the current time was lower than 90% of the first product yield value, or the e.e. value of the α-configured product of the current time was lower than 90% of the e.e. value of the first α-configured product, the reaction was stopped, and the number of recycles was recorded as N90%_init.

[0054] It should be noted that although the above embodiments have been described in this article, the patent protection scope of the present invention is not limited thereby. Therefore, based on the innovative concept of the present invention, any changes and modifications made to the embodiments described in this article, or any equivalent structural or equivalent process transformations made using the content of the specification of the present invention, and directly or indirectly applying the above technical solutions to other related technical fields, are all included in the patent protection scope of the present invention.

Claims

1. A catalytic hydrogenation synthesis method of a chiral finasteride intermediate, comprising: Substrate I, an organic solvent, and a catalyst Cat are mixed, heated, and pressurized under a hydrogen atmosphere to obtain product II, i.e., an α-configuration chiral finasteride intermediate; 。 2. The catalytic hydrogenation synthesis method of the chiral finasteride intermediate according to claim 1, characterized in that: The catalyst Cat uses carbon as a carrier and is loaded with an active component of palladium and a metal promoter component of magnesium.

3. The catalytic hydrogenation synthesis method of the chiral finasteride intermediate according to any one of claims 1 or 2, characterized in that: The temperature is raised to 70-80° C., and / or the hydrogen pressure is greater than 0.3 Mpa, preferably 0.3-0.4 Mpa.

4. The catalytic hydrogenation synthesis method of the chiral finasteride intermediate according to any one of claims 1 to 3, characterized in that: The organic solvent is selected from alcohol, and / or the organic solvent is selected from methanol, ethanol, isopropanol.

5. The catalytic hydrogenation synthesis method of the chiral finasteride intermediate according to any one of claims 1 to 4, characterized in that: The mass ratio of the catalyst Cat to the substrate I is (1-2):60, and / or, 100-140 g of the substrate I is added to every 1 L of the organic solvent.

6. The catalytic hydrogenation synthesis method of the chiral finasteride intermediate according to any one of claims 1 to 5, characterized in that: The preparation method of the catalyst Cat includes: S1: mixing a palladium salt solution and a magnesium compound to prepare a metal precursor solution; S2: The carrier carbon is dispersed in water to obtain a first dispersion system, and then the metal precursor solution is added dropwise to the first dispersion system to obtain a second dispersion system; S3: while the second dispersed system is being stirred, alkali and a reducing agent are added to separate the solid and the liquid, thereby obtaining a catalyst Cat loaded with an active component of palladium and a metal promoter component of magnesium.

7. The catalytic hydrogenation synthesis method of the chiral finasteride intermediate according to claims 1 to 6, characterized in that: The palladium salt in S1 is selected from any one or a combination of palladium chloride, chloropalladic acid, sodium chloropalladate, ammonium chloropalladate, potassium chloropalladate, and palladium powder, and / or the magnesium compound in S1 is selected from any one or a combination of magnesium hydroxide, magnesium chloride, magnesium sulfate, and magnesium sulfate, and / or the palladium salt solution in S1 is an aqueous solution of palladium salt, and / or the molar concentration of the palladium salt in S1 is 0.08-0.12 mol / L.

8. The catalytic hydrogenation synthesis method of the chiral finasteride intermediate according to any one of claims 6 or 7, characterized in that: The carrier carbon in S2 is selected from any one or a combination of graphite carbon, activated carbon, and carbon nanotubes, and / or, in the first dispersion system of S2, 125-250 g of the carrier carbon is added per 1 L of water.

9. The catalytic hydrogenation synthesis method of the chiral finasteride intermediate according to any one of claims 6 to 8, characterized in that: The stirring speed of the second dispersed system in S3 is 200-400 rpm, and / or the base in S3 is selected from any one or a combination of ethylenediamine, potassium hydroxide, sodium hydroxide and cesium hydroxide.

10. The catalytic hydrogenation synthesis method of the chiral finasteride intermediate according to any one of claims 6 to 9, characterized in that: The reducing agent in S3 is selected from any one or a combination of NaBH4, KBH4, hydrazine hydrate, formic acid, citric acid, and formaldehyde, and / or, in S3, the alkali and the reducing agent are added by dropwise addition, and / or, during the dropwise addition of the alkali and the reducing agent in S3, the pH of the second dispersion is controlled between 10 and 12, and / or, in S3, the solid-liquid separation is performed by suction filtration.

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