An improved synthesis method of 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione

Abstract

The invention discloses an improved synthesis method of 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione. The steps are: 1) under inert atmosphere protection, 17α-hydroxyprogesterone, acid and dichlorodicyanobenzoquinone react at 0-10 DEG C, wherein dichlorodicyanobenzoquinone is added after the reaction system is cooled to 0-10 DEG C, and the reaction is complete; 2) the reaction solution obtained in step 1) is warmed to 30-40 DEG C, dichlorodicyanobenzoquinone is added, and the temperature is continued to be raised to reflux, and the reflux reaction is carried out until the reaction is complete; 3) post-treatment obtains 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione. The synthetic method has high yield and high purity, and is prepared by a one-pot method, is easy to operate, has high production efficiency, and is green and environmentally friendly.

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of steroid hormone pharmaceutical intermediates, and particularly relates to an improved synthesis method of 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione. Background Art

[0002] 17α-Hydroxy-1,4,6-pregnanetriene-3,20-dione is an intermediate in the synthesis of the steroid hormone drug cyproterone acetate. Its structural formula is shown below.

[0003]

[0004] Cyproterone acetate, also known as cyproterone acetate, is an androgen antagonist with strong anti-androgenic effects and progestogenic activity. It can directly inhibit androgen production at the cellular level without altering follicle-stimulating hormone (FSH) and luteinizing hormone (ICSH) levels. Developed by Schering, Germany, and marketed as Androcur, it is the first anti-androgen drug used clinically. It is used to treat male sexual desire disorder, benign prostatic hyperplasia (BPH), and inoperable prostate cancer. Its combination with ethinyl estradiol can be used for short-term contraception and to treat acne, seborrhea, androgenic alopecia, and mild hirsutism caused by androgen excess in women. Currently, cyproterone acetate preparations are marketed in over 80 countries worldwide.

[0005] The industrial production of 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione in China mostly uses a synthesis process reported by the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. Specifically, 17α-hydroxyprogesterone (Formula 1) is used as the starting material. The product is then dehydrogenated with chloroquinone in ethyl acetate under reflux, concentrated, cooled and crystallized, filtered, washed with alkali to remove hydroquinone, and then filtered and dried to obtain Formula 2. The resulting Formula 2 is then dehydrogenated with dichlorodicyanoquinone (DDQ) under reflux in dioxane, concentrated, cooled and crystallized, filtered, washed with alkali to remove hydroquinone, and then filtered and dried to obtain Formula 3.

[0006]

[0007] This process uses a large amount of solvent and has a low yield of only 42%. Post-processing is complex, labor-intensive, and production efficiency is low. It also produces large amounts of wastewater, making environmentally friendly disposal difficult.

[0008] Chinese patent ZL 201310087408.2 reports a method of using 17α-hydroxyprogesterone, a compound of formula 1, as a starting material, and carrying out a 3-position etherification reaction in anhydrous ethanol and triethyl orthoformate using pyridinium p-toluenesulfonate as a catalyst. After the reaction, the reaction is neutralized with triethylamine to obtain a solution containing (compound 4); toluene is then added, and the mixture is protected under N2 and dehydrogenated with (DDQ). After the reaction, the mixture is filtered, washed with water, concentrated, and washed with alkali to remove hydroquinone, and then filtered and dried to obtain the compound of formula 3.

[0009]

[0010] This synthesis process uses a one-pot method with a yield of 80-83%. However, various solvents are mixed during the reaction, making it difficult to recycle and treat, and the wastewater contains toxic substances such as triethyl orthoformate, making environmentally friendly treatment difficult.

[0011] Chinese patent CN 109651477 A discloses a conventional method for producing alclomethasone dipropionate, which uses dexamethasone defluoroacetate as a raw material and uses DDQ for dehydrogenation at the 6-position. Dehydrogenation at the 6.7-position is performed using DDQ in the presence of dioxane and HCl.

[0012]

[0013] The patent does not mention specific reaction conditions, such as reaction temperature, DDQ dosage, HCl dosage, post-treatment method, product purity, process yield, and other key parameters. Furthermore, the raw material dexamethasone defluoroacetate used in the patent is a 1,2-dehydrogenated compound, which is more conducive to 6,7-position dehydrogenation than non-dehydrogenated 1,2-position compounds.

[0014] In addition, Wang Zhonglin et al. from the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, reported a biofermentation + chemical synthesis method. Using 17α-hydroxyprogesterone (1) as the starting material, they first fermented and dehydrogenated it with Arthrobacter to obtain the compound of formula 5, which was then brominated with N-bromosuccinimide (NBS) in chloroform and dehydrobrominated with calcium carbonate to obtain the compound of formula 3.

[0015]

[0016] This process, which uses bio-fermentation dehydrogenation raw materials, struggles to fully react, resulting in a low yield of only 47.5%. Furthermore, the process uses bromine-containing compounds, and the wastewater contains chloroform and bromine, making environmentally friendly disposal difficult. Summary of the Invention

[0017] To address the problems of the prior art, the present invention aims to provide an improved synthesis method for 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione. This method offers high yield and purity, utilizes a one-pot process, is simple to operate, has high production efficiency, and is environmentally friendly.

[0018] In order to solve the above technical problems, the technical solutions adopted by the present invention are as follows:

[0019] An improved synthesis method of 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione, the synthesis route is as follows:

[0020]

[0021] The specific steps of the improved synthesis method are as follows:

[0022] 1) Under inert atmosphere, the compound of formula 1, 17α-hydroxyprogesterone, an acid, and dichlorodicyanobenzoquinone (DDQ) are reacted at 0-10° C., wherein DDQ is added after the reaction system is cooled to 0-10° C., and the reaction is completed to obtain a reaction solution containing the compound of formula 2;

[0023] 2) heating the reaction solution obtained in step 1) to 30-40° C., adding DDQ, and continuing to heat to reflux, and reflux to react until the reaction is complete;

[0024] 3) Post-treatment to obtain the compound of formula 3, 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione.

[0025] The present invention uses 17α-hydroxyprogesterone as a raw material, reacts it with DDQ at 0-10°C under acid catalysis, and performs a highly selective dehydrogenation reaction at the 6,7 position, providing a prerequisite for further synthesis of the target product; after the first step reaction, DDQ is directly added for a reflux reaction to selectively remove the 1,2 hydrogens to synthesize the target product, ultimately effectively improving the reaction yield and purity of the target product. Specifically, in the first step, DDQ is added after cooling, which can avoid the impurities that consume DDQ under acidic conditions due to excessively high temperatures, while also causing incomplete reaction of the raw materials. By regulating the reaction addition sequence, the amount of acid used, and the reaction temperature, the first step reaction is carried out with high selectivity at the 6,7 position, achieving a highly selective dehydrogenation reaction at the 6,7 position, which also lays a good foundation for the high yield and high purity of the overall reaction. DDQ is then added for a reflux reaction to prepare the target product, with high product yield and high purity. The one-pot preparation method is simple to operate, highly efficient, and environmentally friendly.

[0026] According to the above scheme, in step 1), the acid is one of HCl gas, formic acid, p-toluenesulfonic acid, oxalic acid, aminosulfonic acid, etc.

[0027] According to the above scheme, in step 1), the reaction solvent used is one of dioxane, ethyl acetate, toluene, tert-butanol, etc.

[0028] According to the above scheme, in step 1), the mass ratio of 17α-hydroxyprogesterone to the reaction solvent is 1:2-10.

[0029] According to the above scheme, in step 1), the mass ratio of 17α-hydroxyprogesterone to acid is 1:0.01-0.05.

[0030] According to the above scheme, in step 1), the mass ratio of 17α-hydroxyprogesterone to DDQ is 1:0.69-0.70.

[0031] According to the above scheme, in step 1), the completion of the reaction is confirmed by TLC; preferably, the TLC developing solvent is: dichloromethane:acetone = 10:1.

[0032] According to the above scheme, in step 1), the reaction time is 1-2 hours.

[0033] According to the above scheme, the mass ratio of 17α-hydroxyprogesterone in step 1) to DDQ in step 2) is 1:0.69-0.70.

[0034] According to the above scheme, in step 2), the completion of the reaction is confirmed by TLC. Preferably, the TLC developing solvent is: dichloromethane:acetone = 10:1.

[0035] According to the above scheme, in step 2), the reaction time is 3-5h.

[0036] According to the above scheme, in step 3), the post-treatment process is to cool to 50-60°C, filter to obtain a hydroquinone filter cake, and wash the hydroquinone filter cake with a 50-60°C solvent, combine the filtrates, concentrate the filtrates under negative pressure to near dryness, add methanol and stir evenly, cool to 0-5°C to crystallize for 2-4 hours, filter, and dry to obtain the compound of formula 3.

[0037] Preferably, the solvent is a recovered solvent obtained when the filtrate is concentrated under negative pressure.

[0038] Preferably, the solvent is the same solvent used in step 1).

[0039] Preferably, the filtrate is concentrated under negative pressure to obtain a recovered solvent, which is recycled for washing the hydroquinone filter cake.

[0040] Preferably, the mass ratio of the solvent to the raw material 17α-hydroxyprogesterone is 2-4:1.

[0041] The beneficial effects of the present invention are as follows:

[0042] 1. The present invention provides an improved synthesis method for 17α-hydroxy-1,4,6-pregnatriene-3,20-dione. Using 17α-hydroxyprogesterone as a raw material, DDQ is first used at 0-10°C under acid catalysis to highly selectively remove hydrogen at the 6 and 7 positions. After the reaction is complete, DDQ is then used in a reflux reaction to selectively remove hydrogen at the 1 and 2 positions. 17α-hydroxy-1,4,6-pregnatriene-3,20-dione is synthesized in a one-pot process, effectively improving the reaction yield and purity. The product yield reaches 85-90%, and the HPLC purity is ≥98.5%. The method has important industrial application prospects.

[0043] 2. The solvent used in the synthesis method of the present invention is single and recyclable; the recovered hydroquinone can be used to prepare DDQ for reuse; there is basically no wastewater discharge, and a small amount of waste liquid (including methanol mother liquor) is entrusted to a qualified enterprise for harmless incineration.

[0044] 3. The present invention adopts a one-pot method to synthesize 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione, which makes industrial production have the advantages of simple operation, short production cycle, low labor intensity, and green environmental protection. DETAILED DESCRIPTION

[0045] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0046] Example 1

[0047] Provided is an improved synthesis method of 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione, the synthesis route of which is as follows:

[0048] 50 g of 17a-hydroxyprogesterone and 200 g of dioxane were added to the reaction flask in sequence. Under nitrogen protection, the temperature was cooled to 0-5°C with stirring. 2 g of HCl (gas) was introduced, and 34.5 g of DDQ was added. The temperature was kept at 0-5°C for 1 hour. The reaction was confirmed to be complete by TLC (developing solvent: dichloromethane: acetone = 10:1).

[0049] Raise the temperature to 30-40°C, add 34.5g of DDQ to the reaction flask, continue heating to reflux, and reflux for 3 hours. TLC confirms the reaction is complete (developing solvent: dichloromethane:acetone = 10:1). HCl (gas) will be emitted during the reaction heating process. This can be collected in another reaction apparatus to achieve continuous operation. At the same time, be sure to absorb the exhaust gas with 10% NaOH solution.

[0050] The reaction solution was cooled to 50-60°C in a water bath and filtered. The filter cake (hydroquinone) was washed with 100 g of dioxane at 50-60°C. The filtrate and washings were combined and concentrated under reduced pressure to near dryness to recover dioxane. 50 g of methanol was added to the solid obtained by concentration, stirred evenly, cooled to 0-5°C for crystallization for 2 hours, filtered, washed with a small amount of methanol, and dried at 70-80°C for 6 hours to obtain 43.8 g of a light yellow sandy solid. The recovered dioxane can be used for washing the filter cake (hydroquinone). The recovered hydroquinone can also be reused in the preparation of DDQ.

[0051] The yield of the product (17α-hydroxy-1,4,6-pregnanetriene-3,20-dione) in Example 1 was 87.6% (based on the weight of 17α-hydroxyprogesterone) and the purity was 98.8% (HPLC).

[0052] Example 2

[0053] Provided is an improved synthesis method of 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione, the synthesis route of which is as follows:

[0054] 50 g of 17a-hydroxyprogesterone, 400 g of toluene, and 1 g of p-toluenesulfonic acid were added to the reaction flask in sequence. Under nitrogen protection, the temperature was cooled to 5-10°C with stirring. 34.5 g of DDQ was added and the temperature was kept at 5-10°C for 2 hours. The reaction was confirmed to be complete by TLC (developing solvent: dichloromethane: acetone = 10:1).

[0055] The temperature was raised to 30-40°C, and 34.5 g of DDQ was added to the reaction flask. The temperature was raised to reflux, and the mixture was refluxed for 4 hours. The reaction was confirmed to be complete by TLC (developing solvent: dichloromethane: acetone = 10:1).

[0056] The reaction solution was cooled to 50-60°C in a water bath, filtered, and the filter cake (hydroquinone) was washed with 200g of 50-60°C toluene. The filtrate and washings were combined and concentrated under negative pressure to near dryness to obtain recovered toluene. 50g of methanol was added to the concentrated solid, stirred evenly, cooled to 0-5°C for crystallization for 2 hours, filtered, washed with a small amount of methanol, and dried at 70-80°C for 6 hours to obtain 45.0g of a light yellow sandy solid. The recovered toluene can be used for washing the filter cake (hydroquinone), and the recovered hydroquinone can also be reused in the preparation of DDQ.

[0057] The yield of the product (17α-hydroxy-1,4,6-pregnanetriene-3,20-dione) in Example 2 was 90.0% (based on the weight of 17α-hydroxyprogesterone) and the purity was 98.5% (HPLC).

[0058] Example 3

[0059] Provided is an improved synthesis method of 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione, the synthesis route of which is as follows:

[0060] 50 g of 17a-hydroxyprogesterone, 500 g of ethyl acetate, and 2.5 g of formic acid were added to the reaction flask in sequence. Under nitrogen protection, the temperature was cooled to 0-5°C with stirring. 34.5 g of DDQ was added and the temperature was kept at 0-5°C for 1.5 hours. The reaction was confirmed to be complete by TLC (developing solvent: dichloromethane: acetone = 10:1).

[0061] The temperature was raised to 30-40°C, and 34.5 g of DDQ was added to the reaction flask. The temperature was raised to reflux, and the mixture was refluxed for 5 hours. The reaction was confirmed to be complete by TLC (developing solvent: dichloromethane: acetone = 10:1).

[0062] The reaction solution was cooled to 50-60°C in a water bath and filtered. The filter cake (hydroquinone) was washed with 200g of 50-60°C ethyl acetate. The filtrate and washings were combined and concentrated under reduced pressure to near dryness to obtain recovered ethyl acetate. 50g of methanol was added to the concentrated solid, stirred evenly, cooled to 0-5°C to crystallize for 2 hours, filtered, washed with a small amount of methanol, and dried at 70-80°C for 6 hours to obtain 43.3g of a light yellow sandy solid. The recovered ethyl acetate can be used to wash the filter cake (hydroquinone), and the recovered hydroquinone can also be reused in the preparation of DDQ.

[0063] The yield of the product (17α-hydroxy-1,4,6-pregnanetriene-3,20-dione) in Example 3 was 86.6% (based on the weight of 17α-hydroxyprogesterone) and the purity was 98.7% (HPLC).

[0064] Example 4

[0065] Provided is an improved synthesis method of 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione, the synthesis route of which is as follows:

[0066] 50 g of 17a-hydroxyprogesterone, 100 g of tert-butanol, and 1 g of aminosulfonic acid were added to the reaction flask in sequence. Under nitrogen protection, the temperature was cooled to 5-10°C with stirring. 34.5 g of DDQ was added and the temperature was kept at 5-10°C for 2 hours. The reaction was confirmed to be complete by TLC (developing solvent: dichloromethane: acetone = 10:1).

[0067] The temperature was raised to 30-40°C, and 34.5 g of DDQ was added to the reaction flask. The temperature was raised to reflux, and the mixture was refluxed for 5 hours. The reaction was confirmed to be complete by TLC (developing solvent: dichloromethane: acetone = 10:1).

[0068] The reaction solution was cooled to 50-60°C in a water bath and filtered. The filter cake (hydroquinone) was washed with 50 g of 50-60°C tert-butanol. The filtrate and washings were combined and concentrated under negative pressure to near dryness to obtain recovered tert-butanol. 50 g of methanol was added to the concentrated solid, stirred evenly, cooled to 0-5°C to crystallize for 2 hours, filtered, washed with a small amount of methanol, and dried at 70-80°C for 6 hours to obtain 42.5 g of a light yellow sandy solid. The recovered tert-butanol can be used to wash the filter cake (hydroquinone), and the recovered hydroquinone can also be reused in the preparation of DDQ.

[0069] The yield of the product (17α-hydroxy-1,4,6-pregnanetriene-3,20-dione) in Example 4 was 85.0% (based on the weight of 17α-hydroxyprogesterone) and the purity was 99.2% (HPLC).

Claims

1. An improved synthesis method of 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione, characterized in that: The synthetic route is as follows: The improved synthesis method specifically comprises the following steps: 1) Under inert atmosphere, the compound of formula 1, 17α-hydroxyprogesterone, an acid, and dichlorodicyanobenzoquinone are reacted at 0-10°C, wherein the dichlorodicyanobenzoquinone is added after the reaction system is cooled to 0-10°C, and the reaction is completed to obtain a reaction solution containing the compound of formula 2; wherein the acid is one of HCl gas, formic acid, p-toluenesulfonic acid, and aminosulfonic acid; 2) The reaction solution obtained in step 1) was heated to 30-40°C, dichlorodicyanobenzoquinone was added, and the temperature was continued to be raised to reflux, and the reaction was refluxed until the reaction was complete; 3) Post-treatment to obtain the compound 17α-hydroxy-1,4,6-pregnanetriene-3,20-dione of formula 3.

2. The improved synthesis method according to claim 1, characterized in that In the step 1), the reaction solvent used is one of dioxane, ethyl acetate, toluene, and tert-butanol.

3. The improved synthesis method according to claim 1, characterized in that In the step 1), the mass ratio of 17α-hydroxyprogesterone to acid is 1:0.01-0.

05.

4. The improved synthesis method according to claim 1, characterized in that In the step 1), the mass ratio of 17α-hydroxyprogesterone to dichlorodicyanobenzoquinone is 1:0.69-0.

70.

5. The improved synthesis method according to claim 1, characterized in that In the step 1), the reaction time is 1-2 hours.

6. The improved synthesis method according to claim 1, characterized in that The mass ratio of 17α-hydroxyprogesterone in step 1) to dichlorodicyanobenzoquinone in step 2) is 1:0.69-0.

70.

7. The improved synthesis method according to claim 1, characterized in that In the step 2), the reaction time is 3-5 hours.

8. The improved synthesis method according to claim 1, characterized in that In the step 3), the post-treatment process is to cool to 50-60°C, filter to obtain a hydroquinone filter cake, and wash the hydroquinone filter cake with a 50-60°C solvent, combine the filtrates, concentrate the filtrates under negative pressure to near dryness, add methanol and stir evenly, cool to 0-5°C to crystallize for 2-4 hours, filter, and dry to obtain the compound of formula 3.

9. The improved synthesis method according to claim 8, characterized in that The filtrate is concentrated under negative pressure to obtain a recovered solvent, which is recycled for washing the hydroquinone filter cake.

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