Preparation method of finasteride

Abstract

According to the preparation method, sodium perborate tetrahydrate is selected as an oxidizing agent, the requirement for preparing the finasteride through an oxidation elimination reaction is met by accurately controlling reaction conditions, the impurity amount is small, a reagent which easily generates a large amount of waste solids or waste liquid is avoided, operation is easy, and the method is suitable for industrial production. Waste liquid generated by post-treatment is easy to treat. Meanwhile, side reactions are reduced, tedious refining steps are avoided, and the yield of the product is increased.

Description

Technical Field

[0001] This invention relates to the field of drug synthesis technology, specifically a method for preparing finasteride. Background Technology

[0002] Finasteride, chemically named N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-amide, marketed as Proscar and Propecia, is an effective drug for treating benign prostatic hyperplasia (BPH) and male pattern baldness in men. It is widely used both domestically and internationally, with a large market demand and excellent application prospects and development potential. The pathogenesis of this type of disease is closely related to dihydrotestosterone (DHT). Finasteride is a specific inhibitor of type II 5α-reductase, an intracellular enzyme involved in the metabolism of testosterone to DHT. It can very effectively reduce DHT levels in the blood and prostate, thereby reducing prostate volume, improving symptoms, increasing urine flow rate, and preventing benign prostatic hyperplasia (BPH) by inhibiting the conversion of testosterone to DHT.

[0003] Several synthetic methods for finasteride have been published in the literature: Method 1: International patent document WO2005075497A uses compound 1 as a raw material to synthesize finasteride using the benzene selenite anhydride method. This method uses expensive and highly toxic benzene selenite anhydride in the reaction process, and the resulting finasteride product is difficult to purify, requiring column chromatography separation. It does not meet the requirements of green chemical synthesis and has a low yield of only about 50%, which is not conducive to industrial production.

[0004] Method 2: US Patent document US20070167477A1 describes the method using compound 1 as a starting material and oxidizing it with DDQ / BSTFA (i.e., 3,3-difluoro-5,6-dicyanobenzoquinone / bis(trimethylsilyl)trifluoroacetamide). This method uses environmentally unfriendly DDQ-BSTFA reagents in the reaction process, leaving behind quinone toxins that are difficult to degrade, and producing fluoride-containing wastewater that is difficult to treat.

[0005]

[0006] Method 3: For example, in international patent document WO2008101308A, finasteride is synthesized from compound 1 using the phenyl sulfide oxidation method. This method uses expensive and difficult-to-obtain synthetic reagents such as lithium bis(trimethylsilylamino)amine, di-tert-butyl carbonate, and diphenyl disulfide compounds. The diphenyl sulfide reaction is carried out under harsh conditions of low temperature, anhydrous and oxygen-free environment. The reaction has many steps, is complicated, has high energy consumption, and has a low yield. The total yield of the two steps is only 60%.

[0007]

[0008] Method 4: As described in Chinese patent documents CN105646641A and CN108203455A, compound 1 is first prepared into the corresponding α-iodide compound 2, which is then reacted with potassium persulfate (trade name: Oxone) and perdisulfate to obtain finasteride. This process generates a large amount of difficult-to-treat sulfur-containing solid waste salts or waste liquids, limiting the scale-up of the process to some extent. Furthermore, the aforementioned oxidative deiodination conditions produce significant unknown impurities, often requiring cumbersome and lengthy purification processes to obtain the target product, resulting in less than ideal yields.

[0009]

[0010] In summary, the existing methods for preparing finasteride have the following main problems: the reagents used are highly toxic, the environment is not friendly, wastewater is difficult to treat, and the operation is complicated. In addition, the yield and purity are not ideal. Summary of the Invention

[0011] This invention provides a method for preparing finasteride, thereby addressing at least one of the many problems associated with existing preparation methods.

[0012] In view of this, the solution of the present invention is as follows: A method for preparing finasteride involves adding dihydrofinasteride iodide to a solvent, adjusting the pH to 1-3, adding excess sodium perborate, and reacting at 10-30°C for 6-8 hours to obtain finasteride. The solvent comprises water and a water-miscible organic solvent in a volume ratio of (1.8-2.0):1. The structural formula of the dihydrofinasteride iodide is shown in Formula I. .

[0013] Furthermore, the molar ratio of sodium perborate to dihydrofinasteride iodide is (2~3):1.

[0014] Preferably, the molar ratio of sodium perborate to dihydrofinasteride iodide is 2.5:1.

[0015] Furthermore, the organic solvent is selected from at least one of methanol, ethanol, tetrahydrofuran, and acetone.

[0016] Furthermore, the pH adjustment process uses an organic acid, with a volume ratio of organic acid to water of (0.1~0.25):1; the organic acid is preferably a monocarboxylic acid, preferably at least one of acetic acid and propionic acid, with a volume ratio of organic acid to water of (0.20~0.25):1.

[0017] Furthermore, the sodium perborate is added in batches, with each addition being 20-50%; preferably, it is added in 4-6 batches. The sodium perborate can be a common sodium perborate hydrate, such as at least one selected from sodium perborate tetrahydrate, sodium perborate trihydrate, and sodium perborate monohydrate.

[0018] Furthermore, the reaction temperature is 20~25℃.

[0019] Furthermore, based on the above, a method for preparing the dihydrofinasteride iodinated derivative is also provided, comprising the steps of: dissolving dihydrofinasteride, adding an acid-binding agent, and reacting it with an activating reagent and iodine under nitrogen protection; the structural formula of the dihydrofinasteride is shown in Formula II: .

[0020] Furthermore, in the preparation of dihydrofinasteride iodide, the reaction temperature is 10~20℃, the reaction time is 0.5~1.5h, preferably 1h.

[0021] Furthermore, in the preparation of dihydrofinasteride iodide, the acid-binding agent is selected from at least one of triethylamine, tetramethylethylenediamine, and diisopropylethylamine. And / or, the activating agent is selected from at least one of trimethylchlorosilane and triethylchlorosilane.

[0022] Furthermore, in the preparation of dihydrofinasteride iodinated derivatives, the molar ratio of the acid-binding agent to dihydrofinasteride is (3~4):1; and / or, the molar ratio of the activator to dihydrofinasteride is (2~3):1.

[0023] Compared with the prior art, the present invention has the following beneficial effects: The preparation method described in this invention selects sodium perborate as the oxidant. By precisely controlling the reaction conditions, it meets the requirements for the preparation of finasteride via oxidative elimination reaction. It results in fewer impurities, avoids the use of reagents that easily generate large amounts of waste solids or liquids, simplifies the operation, and facilitates the treatment of waste liquid generated during post-processing. Simultaneously, it reduces the generation of side reactions, avoids cumbersome purification steps, and improves the product yield. Detailed Implementation

[0024] The technical solution of the present invention will now be clearly and completely described in conjunction with preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0025] In one embodiment, a method for preparing finasteride is proposed, which involves first preparing a dihydrofinasteride iodide derivative (compound I) from dihydrofinasteride (compound II), and then obtaining finasteride through an oxidative elimination reaction. The specific process is as follows:

[0026] In the above embodiments, when using potassium peroxymonosulfate or perdisulfate in the prior art for the oxidative elimination reaction, a large amount of difficult-to-treat sulfur-containing solid waste salt or waste liquid is generated during the post-processing, limiting the scale-up of the process. Simultaneously, the oxidative deiodination conditions produce significant unknown impurities, often requiring cumbersome and lengthy purification processes to obtain the target product, resulting in unsatisfactory yields. Therefore, this invention attempts to replace the oxidant; however, simply replacing the oxidant without changing the reaction conditions does not yield the expected product finasteride.

[0027] To address the problems described in the above embodiments, this invention provides a novel oxidation method. By selecting sodium perborate as the oxidant, an oxidation-elimination reaction is completed under suitable solvent and pH conditions, which can reduce the impurity content. The specific reaction conditions are as follows: sodium perborate is dissolved in a solvent, the pH is adjusted to 1-3, excess sodium perborate is added in batches, and the reaction is carried out at 10-30°C for 6-8 hours to obtain finasteride; the solvent includes water and a water-miscible organic solvent, with a volume ratio of (1.8-2.0):1.

[0028] In the above embodiments, by controlling the reaction conditions, the inherent instability of sodium perborate is avoided, while selective oxidation reaction can be carried out to obtain the target product. The reaction yield is above 96%, with few reaction impurities, simple post-processing, and no need for cumbersome purification steps, making it suitable for industrial production.

[0029] In the above embodiments, the inventors found that the oxidizing power of sodium perborate is greatly affected by pH. If the system is too alkaline, the target product cannot be obtained, and if the system is too acidic, there will be more impurities in the reaction. It is necessary to precisely control the pH value to 1~3, preferably to adjust it to a pH value of 2.0~2.5.

[0030] In the above embodiments, the post-processing of the reaction product is as follows: a solvent is added to the reaction product, and after filtration, an aqueous solution of a reducing compound is added to the filtrate. After separation, the organic layer is washed with water, the solvent is removed, the solution is dissolved, water is added to crystallize, and the product is filtered and dried.

[0031] In a preferred embodiment, the adjustment process uses an organic acid, with a volume ratio of organic acid to water of (0.1~0.25):1; the organic acid is preferably a monocarboxylic acid, preferably at least one of acetic acid and propionic acid, with a volume ratio of organic acid to water of (0.20~0.25):1.

[0032] In a preferred embodiment, the molar ratio of sodium perborate to dihydrofinasteride iodide is (2~3):1, preferably 2.5:1. The sodium perborate is added in batches, with each addition being 20~50%; preferably, it is added in 3~5 equal batches.

[0033] In a preferred embodiment, the organic solvent is selected from at least one of methanol, ethanol, tetrahydrofuran, and acetone.

[0034] In the above embodiments, sodium perborate was chosen as the oxidant because, on the one hand, it has less toxicity compared to traditional oxidants such as potassium peroxymonosulfate and potassium perdisulfate, and on the other hand, sodium perborate has less impact on subsequent water treatment, its waste is easier to handle, and it is more suitable for industrial production.

[0035] Example 1 1. Dissolve 100 g of compound II in 1000 mL of toluene, add 120 mL of tetramethylethylenediamine, purge with nitrogen, add 68 mL of trimethylchlorosilane dropwise, and react at 20 °C for 1 h. Divide the mixture into three equal portions, adding 120 g of iodine in each portion at 20-minute intervals. After the addition is complete, react at 25 °C for 4 h. After the reaction is complete, add 500 mL of 10% sodium bisulfite aqueous solution, quench and stir until homogeneous. Separate the aqueous layer, wash the organic layer once with 500 mL of 10% sodium bisulfite aqueous solution, separate the aqueous layer, wash the organic layer with 500 mL of water, distill off 800 mL of solvent from the organic layer under negative pressure, add 500 mL of cyclohexane, stir until homogeneous, filter, and dry to obtain 127.0 g of off-white solid compound I, yield 95.06%, HPLC purity 97.6%. 2. Take 127g of compound I from step 1, add 1000mL of methanol, 438mL of acetic acid and 1.9L of water, stir well and measure the pH value to be 2.2. Weigh 97.5g of sodium perborate tetrahydrate and divide it into four batches to add to the above reaction solution. Keep the temperature below 30℃, then keep it at 22℃ for 7h. After the reaction is complete, add 1300mL of dichloromethane, filter, wash the filter cake, wash the filtrate with 650mL of 10% sodium bisulfite aqueous solution, separate the aqueous layer, wash the organic layer with 500mL of water, evaporate the solvent from the organic layer under negative pressure, add 250mL of ethanol to dissolve, add 1300mL of water dropwise and stir to precipitate crystals, filter and dry to obtain 91.5g of white solid finasteride, yield 96.8%, HPLC purity 99.801%.

[0036] Example 2 1. Dissolve 100g of compound II in 1000mL of toluene, add 120mL of tetramethylethylenediamine, replace with nitrogen, add 68mL of trimethylchlorosilane dropwise, and react at 22℃ for 1h. Divide the mixture into three equal batches, adding 120g of iodine in each batch at 20-minute intervals, and react at 20℃ for 5h. After the reaction is complete, add 500mL of 10% sodium bisulfite aqueous solution, quench and stir until homogeneous, separate the aqueous layer, wash the organic layer once with 500mL of 10% sodium bisulfite aqueous solution, separate the aqueous layer, wash the organic layer with 500mL of water, distill off 800-900mL of solvent from the organic layer under negative pressure, add 500mL of cyclohexane, stir until homogeneous, filter, and dry to obtain 127.3g of off-white solid compound I, yield 95.28%, HPLC purity 99.084%; 2. Take 127g of compound I from step 1, add 1000mL of ethanol, 365mL of propionic acid and 1.8L of water, stir well and measure the pH value to be 2.5. Weigh 117g of sodium perborate tetrahydrate and add it to the above reaction solution in three equal batches. Keep the temperature below 30℃, and then keep it at 20℃ for 8 hours. After the reaction is complete, add 1300mL of dichloromethane, filter, wash the filter cake, wash the filtrate with 650mL of 10% sodium bisulfite aqueous solution, separate the aqueous layer, wash the organic layer with 500mL of water, evaporate the solvent from the organic layer under negative pressure, add 250mL of ethanol to dissolve, add 1300mL of water dropwise and stir to precipitate crystals, filter and dry to obtain 91.0g of white solid finasteride, yield 96.3%, HPLC purity 99.413%.

[0037] Example 3 1. Dissolve 1 kg of compound II in 10 L of toluene, add 1.2 L of tetramethylethylenediamine, purge with nitrogen, add 680 mL of trimethylchlorosilane dropwise, and react at 23 °C for 1 h. Divide the mixture into three equal batches, adding 1.2 kg of iodine at 20-minute intervals, and react at 25 °C for 5 h. After the reaction is complete, add 5 L of 10% sodium bisulfite aqueous solution, quench and stir until homogeneous, separate the aqueous layer, wash the organic layer once with 5 L of 10% sodium bisulfite aqueous solution, separate the aqueous layer, wash the organic layer with 5 L of water, distill off 9 L of solvent from the organic layer under negative pressure, add 5 L of cyclohexane, stir until homogeneous, filter, and dry to obtain 1295 g of off-white solid compound I, yield 96.9%, HPLC purity 98.285%; 2. Take 1.29 kg of compound I from step 1, add 10.3 L of methanol, 4.45 L of acetic acid, and 19 L of water. After stirring evenly, the pH value is measured to be 2.0. Weigh 1.51 kg of sodium perborate tetrahydrate and divide it into five equal portions, adding them to the above reaction solution. Keep the temperature below 30℃, and then keep it at 25℃ for 6.5 h. After the reaction is complete, add 13 L of dichloromethane, filter, wash the filter cake, wash the filtrate with 6.5 L of 10% sodium bisulfite aqueous solution, separate the aqueous layer, wash the organic layer with 6.5 L of water, evaporate the solvent from the organic layer under negative pressure, add 2.5 L of ethanol to dissolve, add 13 L of water dropwise, stir to precipitate crystals, filter and dry to obtain 922.8 g of white solid finasteride, yield 96.1%, HPLC purity 99.813%.

[0038] Comparative Example 1 Finasteride was prepared from compound I obtained in Example 2, except that propionic acid was not added for pH adjustment, while the amounts of other reagents and reaction conditions were the same as in Example 2. Sampling and testing showed that no target product was generated.

[0039] Comparative Example 2 Dissolve 26.6 g of the compound in 130 mL of acetone, then add 12.6 g of sodium bicarbonate solid. Prepare a potassium persulfate solution (18.4 g of potassium persulfate dissolved in 73 mL of water) and add it dropwise to the above reaction mixture over 2 hours, ensuring the temperature does not exceed 30°C during the addition. Stir overnight at 20-25°C. Evaporate the acetone under reduced pressure, extract the remaining solid with 50 mL of dichloromethane, wash the resulting organic phase with 20 mL of 10% sodium sulfite solution, and dry with anhydrous sodium sulfate. After removing the solvent under reduced pressure, recrystallize the crude product from 10 mL of ethanol and 20 mL of water to obtain white crystals. Filter, rinse with 5 mL of water, filter again, and repeat the recrystallization process once more. Dry under vacuum at 60°C to obtain 4.5 g of the final product, with a yield of 85% and an HPLC purity of 99.402%.

[0040] It is evident from the above examples that the oxidation and digestion of dihydrofinasteride iodinated derivatives using sodium perborate tetrahydrate to form double bonds at the 1,2 positions yields finasteride with high conversion rates and simple post-processing. In Comparative Example 1, when pH adjustment was not performed with added acid, the higher pH actually hindered the formation of the target product. In Comparative Example 2, the product yield was significantly reduced when using the traditional oxidant potassium persulfate.

[0041] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing finasteride, characterized in that, Dihydrofinasteride iodide was added to a solvent, the pH was adjusted to 1-3, excess sodium perborate was added, and the reaction was carried out at 10-30℃ for 6-8 hours to obtain finasteride; the solvent included water and an organic solvent miscible with water, with a volume ratio of (1.8-2.0):1; the structural formula of the dihydrofinasteride iodide is shown in Formula I: 。 2. The preparation method according to claim 1, characterized in that, The molar ratio of sodium perborate to dihydrofinasteride iodide is (2~3):

1.

3. The preparation method according to claim 2, characterized in that, The molar ratio of sodium perborate to dihydrofinasteride iodide is 2.5:

1.

4. The preparation method according to claim 1, characterized in that, The organic solvent is selected from at least one of methanol, ethanol, tetrahydrofuran, and acetone.

5. The preparation method according to claim 1, characterized in that, The pH adjustment process uses organic acids.

6. The preparation method according to claim 1, characterized in that, The sodium perborate is added in batches, with each batch containing 20-50%.

7. The preparation method according to claim 1, characterized in that, The reaction temperature is 20~25℃.

8. The preparation method according to claim 1, characterized in that, The dihydrofinasteride iodinated derivative is obtained by the following preparation method: dihydrofinasteride is dissolved, an acid-binding agent is added, and under nitrogen protection, an activating reagent and iodine are added to react and the product is obtained. The structural formula of the dihydrofinasteride is shown in Formula II.

9. The preparation method according to claim 8, characterized in that, In the preparation of dihydrofinasteride iodinated derivative, the reaction temperature is 10~20℃ and the reaction time is 0.5~1.5h.

10. The preparation method according to claim 8, characterized in that, In the preparation of dihydrofinasteride iodinated derivatives, the acid-binding agent is selected from at least one of triethylamine, tetramethylethylenediamine, and diisopropylethylamine; And / or, the activating agent is selected from at least one of trimethylchlorosilane and triethylchlorosilane; And / or, the molar ratio of the acid-binding agent to dihydrofinasteride is (3~4):1; and / or, the molar ratio of the activator to dihydrofinasteride is (2~3):1.

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