Finasteride intermediate as well as preparation method and application thereof

Abstract

The invention discloses a finasteride intermediate as well as a preparation method and application thereof, and belongs to the technical field of medicine synthesis. The preparation method of the finasteride intermediate comprises the following steps: mixing progesterone and an organic solvent, continuously introducing ozone at-20 DEG C to-10 DEG C to obtain an intermediate state I, dropwise adding peroxide at-10 DEG C or below, dropwise adding a sodium hydroxide solution, heating to 15-25 DEG C, and reacting to obtain the finasteride intermediate. In addition, the invention also provides the finasteride intermediate which is prepared by the preparation method. In addition, the invention also provides an application of the finasteride intermediate in preparation of finasteride. According to the method, sodium periodate does not need to be used, 4-position double bonds can be cut off through oxidation by adding a small amount of peroxide and a sodium hydroxide solution, the finasteride intermediate is obtained, and the green chemical requirement is met.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of drug synthesis, in particular to a finasteride intermediate and a preparation method and application thereof. BACKGROUND

[0002] Benign prostatic hyperplasia (BPH) is the most common benign disease causing urinary obstruction in middle-aged and elderly men, and the main causes are age factors and imbalance of androgens in the body. The treatment drugs for benign prostatic hyperplasia are 5 alpha reductase inhibitors, alpha adrenergic receptor blockers, and plant preparations, among which the representative drugs of 5 alpha reductase inhibitors are finasteride and dutasteride.

[0003] The difference between finasteride and dutasteride lies in the difference of the 17-position side chain, and the synthesis process is basically the same: 1. First, construct the side chain, then modify the A and B rings with the side chain, 2. Modify the A and B rings, then construct the side chain. From the perspective of cost control, the current production mainly adopts method 2. In the two synthesis strategies, the modification of A and B rings: compound I (pregnenone) is oxidized to cut off the double bond at position 4 under the action of sodium periodate to obtain compound II (A-carbon loss-3, 5-cracking-3-carboxyl-5-oxo-androstane), compound II is reacted with ammonia and dehydrogenated to obtain compound III, and compound III is reacted with the corresponding side chain reagent to obtain finasteride or dutasteride.

[0004] The reaction formula is as follows:

[0005] In industrial production, when the A and B rings are modified, the double bond at position 4 is cut off: tert-butyl alcohol is used as the solvent, a catalytic amount of potassium permanganate and sodium carbonate is added, and 6-8 equivalents of sodium periodate is added dropwise at high temperature; the large amount of tert-butyl alcohol and sodium periodate used results in a large environmental burden and high cost, which does not meet the requirements of green chemistry. SUMMARY

[0006] The present application aims to overcome the above technical deficiencies, and provides a finasteride intermediate and a preparation method and application thereof, which solves the technical problem of large amount of sodium periodate used for oxidizing and cutting off the double bond at position 4 in the prior art, which does not meet the requirements of green chemistry.

[0007] In order to achieve the above technical purpose, the technical scheme of the present application provides a preparation method of a finasteride intermediate, comprising the following steps: mixing progesterone and an organic solvent, continuously introducing ozone at-20℃ to-10℃ to obtain an intermediate state I, then adding a peroxide dropwise at below-10℃, then adding a sodium hydroxide solution dropwise, and then heating to 15-25℃ to react to obtain the finasteride intermediate.

[0008] In any embodiment, the organic solvent is one or more of dichloromethane, acetone, methanol, and chloroform.

[0009] In any embodiment, the peroxide is one or more of hydrogen peroxide, benzoyl peroxide, tert-butanol peroxide, and potassium persulfate.

[0010] In any embodiment, the reaction time at 15-25°C is 2-3 hours.

[0011] In any embodiment, the sodium hydroxide solution has a mass concentration of 10-15%, and the amount of sodium hydroxide solution added is 3-4 times the mass of the progesterone.

[0012] In any embodiment, after the reaction at 15-25°C, the process further includes: quenching with sodium thiosulfate dropwise, adjusting the pH to 2-3 with concentrated hydrochloric acid, then concentrating the water under reduced pressure to precipitate the material, and drying to obtain the finasteride intermediate.

[0013] In addition, the present invention also proposes a finasteride intermediate, which is prepared by the above preparation method.

[0014] In any implementation, its structural formula is: .

[0015] Furthermore, the present invention also proposes the application of the above-mentioned finasteride intermediate in the preparation of finasteride.

[0016] In any implementation, the above application includes the following steps: S1. The above-mentioned finasteride intermediate, toluene and ammonium acetate are mixed and refluxed at 90~100℃ to obtain intermediate II-a; S2. Methanol, palladium on carbon and intermediate II-a are mixed and reacted at a temperature of 20℃~30℃ to obtain intermediate II-b; S3. Mix dioxane, water and sodium hydroxide, then cool to below 5°C, add bromine and stir, then add intermediate II-b and keep the reaction at the temperature to obtain intermediate III; S4. Mix dichloromethane and thionyl chloride and cool to below 5°C. Then add pyridine and intermediate III sequentially and react at 30-35°C to obtain intermediate IV. S5. Mix dichloromethane, triethylamine and intermediate IV and stir until dissolved. Then add trimethylchlorosilane and heat to reflux. Then cool to below 30°C and add iodine to keep the reaction warm to obtain solid wet product-1. S6. Mix the solid wet product-1 and THF and stir until dissolved. Then add potassium persulfate solution dropwise to obtain solid wet product-2. S7, solid wet product-2 and acetone are mixed and heated to reflux to obtain the finasteride.

[0017] In any embodiment, in step S1, the reflux reaction time is 6-7 hours; and / or, in step S4, the reaction time is 2-3 hours at 30-35°C.

[0018] Compared with the prior art, the beneficial effects of the present invention include: the preparation method of the finasteride intermediate proposed in the present invention includes the following steps: mixing progesterone and an organic solvent, continuously introducing ozone at -20℃ to -10℃ to obtain intermediate state I, then adding peroxide dropwise below -10℃, followed by adding sodium hydroxide solution dropwise, and then reacting at 15-25℃ to obtain the finasteride intermediate. Sodium periodate is not required. Intermediate state I is formed by ozone, and then a small amount of peroxide and sodium hydroxide solution are added to oxidize and cleave the double bond at position 4 to obtain the finasteride intermediate, which meets the requirements of green chemistry. Attached Figure Description

[0019] Figure 1 This is a high-performance liquid chromatogram of intermediate II obtained in Example 1 of the present invention.

[0020] Figure 2 This is a high-performance liquid chromatogram of intermediate II-a obtained in Example 2 of the present invention.

[0021] Figure 3 This is a high-performance liquid chromatogram of intermediate II-b obtained in Example 2 of the present invention.

[0022] Figure 4 This is a high-performance liquid chromatogram of intermediate III obtained in Example 2 of the present invention.

[0023] Figure 5 This is a high-performance liquid chromatogram of intermediate IV obtained in Example 2 of the present invention.

[0024] Figure 6 This is a high-performance liquid chromatogram of finasteride prepared in Example 2 of the present invention. Detailed Implementation

[0025] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60~120 and 80~110 are listed for a specific parameter, it is also expected that ranges of 60~110 and 80~120 are also included. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1~3, 1~4, 1~5, 2~3, 2~4, and 2~5. In this application, unless otherwise stated, the numerical range "a~b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0~5" indicates that all real numbers between "0~5" have been listed in this article; "0~5" is simply a shortened representation of these numerical combinations. Furthermore, when a parameter is stated as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc.

[0026] Unless otherwise specified, the terms "comprising" and "including" as used in this application can be open-ended or closed-ended. For example, "comprising" and "including" can mean that other components not listed may also be included, or that only the listed components may be included.

[0027] Unless otherwise specified, the term "or" is inclusive in this application. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, the condition "A or B" is satisfied by any of the following conditions: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); or both A and B are true (or exist).

[0028] This specific embodiment provides a method for preparing a finasteride intermediate, comprising the following steps: mixing progesterone and an organic solvent, continuously introducing ozone at -20℃ to -10℃ to obtain intermediate I, then adding a peroxide dropwise below -10℃, followed by adding a sodium hydroxide solution dropwise, then heating to 15-25℃ and reacting for 2-3 hours, quenching with sodium thiosulfate dropwise, adjusting the pH to 2-3 with concentrated hydrochloric acid, then concentrating the water under reduced pressure to precipitate the material, and drying to obtain the finasteride intermediate; wherein the organic solvent is one or more of dichloromethane, acetone, methanol, and chloroform; the peroxide is one or more of hydrogen peroxide, benzoyl peroxide, tert-butanol peroxide, and potassium persulfate; the mass concentration of the sodium hydroxide solution is 10-15%, and the amount of sodium hydroxide solution added is 3-4 times the mass of the progesterone.

[0029] This specific embodiment also proposes a finasteride intermediate, prepared by the above-described method, with the following structural formula: .

[0030] This specific embodiment also proposes an application of the above-mentioned finasteride intermediate in the preparation of finasteride.

[0031] In some embodiments, the application includes the following steps: S1. Mix the above finasteride intermediate, toluene and ammonium acetate and reflux at 90~100℃ for 6~7 hours to obtain intermediate II-a; S2. Methanol, palladium on carbon and intermediate II-a are mixed and reacted at a temperature of 20℃~30℃ to obtain intermediate II-b; S3. Mix dioxane, water and sodium hydroxide, then cool to below 5°C, add bromine and stir, then add intermediate II-b and keep the reaction at the temperature to obtain intermediate III; S4. Mix dichloromethane and thionyl chloride and cool to below 5°C. Then add pyridine and intermediate III sequentially and react at 30-35°C for 2-3 hours. Then add tert-butylamine and reflux the mixture to obtain intermediate IV. S5. Mix dichloromethane, triethylamine and intermediate IV and stir until dissolved. Then add trimethylchlorosilane and heat to reflux. Then cool to below 30°C and add iodine to keep the reaction warm to obtain solid wet product-1. S6. Mix the solid wet product-1 and THF and stir until dissolved. Then add potassium persulfate solution dropwise to obtain solid wet product-2. S7, solid wet product-2 and acetone are mixed and heated to reflux to obtain the finasteride.

[0032] The reaction formula is as follows:

[0033] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0034] In this invention, the terms "some embodiments," "this embodiment," and examples are used to describe a subset of all possible embodiments. However, it is understood that "some embodiments" can be the same subset or different subsets of all possible embodiments and can be combined with each other without conflict.

[0035] If the application documents contain similar descriptions such as "first / second", the following explanation shall be added: In the following description, the terms "first / second / third" are used only to distinguish similar objects and do not represent a specific ordering of objects. It is understood that "first / second / third" may be interchanged in a specific order or sequence where permitted, so that the embodiments described herein can be implemented in an order other than that illustrated or described herein.

[0036] In this embodiment, the term "and / or" is merely a description of the relationship between related objects, indicating that there can be three relationships. For example, object A and / or object B can represent three situations: object A exists alone, object A and object B exist simultaneously, and object B exists alone.

[0037] The following describes embodiments of this application. The embodiments described below are exemplary and are only used to explain this application, and should not be construed as limiting this application. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Reagents or instruments used, unless otherwise specified, are all conventional products that can be obtained commercially.

[0038] Example 1 This embodiment presents a finasteride intermediate, which is prepared by the following steps: Using progesterone as a raw material (50g), 5w dichloromethane solvent (250g), ozone was continuously introduced at -10~-20℃. TLC detection showed that after the progesterone disappeared (approximately 1 hour), ozone was stopped to obtain intermediate I. 0.3w 30% hydrogen peroxide (15g) was added dropwise while maintaining below -10℃, followed by 3w 10% sodium hydroxide solution (150g). After the addition was complete, the temperature was slowly raised to 20℃ and reacted for 2 hours. 0.1w sodium thiosulfate (5g) was added to quench the reaction. The pH was adjusted to 3 with concentrated hydrochloric acid, and the water was concentrated under reduced pressure to precipitate the product. Drying yielded 50g of intermediate II (i.e., finasteride intermediate). Figure 1 HPLC ≥ 97%.

[0039] Example 2 This embodiment proposes the application of a finasteride intermediate in the preparation of finasteride, including the following steps: S1, 90g toluene, 30g ammonium acetate, and 50g finasteride intermediate from Example 1 were added to a reaction flask. The mixture was refluxed at 90-100°C for 6 hours. Samples were taken and spotted onto a TLC plate until the reaction was complete. The developing solvent was dichloromethane:methanol = 25:1. After the reflux reaction was complete, 50g of drinking water was added, and the mixture was distilled at atmospheric pressure until no toluene was detected. After distillation, two more portions of drinking water were added to the reaction vessel, and the temperature was lowered to below 40°C. The pH of the 15g hydrochloric acid solution was adjusted to ≤4. The mixture was filtered, and the filter cake was washed with drinking water until neutral. It was then dried at 80-90°C until the loss on drying was ≤0.5%, yielding 45g of intermediate II-a. Figure 2 HPLC > 98%, yield 90%.

[0040] S2. Under nitrogen protection, 400g methanol, 2.0g (4% palladium on carbon), and 40g intermediate II-a are added to the reactor. Nitrogen is purged three times, and hydrogen is added until the pressure reaches P. H2 =0.2~0.25Mpa; After reacting at 25℃ for 16 hours, samples were taken for TLC monitoring. After the reaction was complete, the hydrogen in the reactor was slowly vented to atmospheric pressure, vacuum was drawn, and then nitrogen was purged. This process was repeated 3 times. The reaction solution was filtered, and the organic phase was concentrated under reduced pressure with heating. 150g of drinking water was added, followed by further concentration under reduced pressure. Another 150g of drinking water was added, and this process was repeated twice to concentrate to a small volume. The mixture was cooled, and 400g of drinking water was added to precipitate the precipitate. The temperature was then lowered to below 40℃. The mixture was centrifuged and dried at 90℃ until the loss on drying was ≤0.5%, yielding 40g of intermediate II-b. Figure 3 HPLC > 98%.

[0041] S3. Add 400g of dioxane and 200g of drinking water to the reaction flask, add 60g of sodium hydroxide, cool to below 5℃, add 40g of bromine, stir for 5 minutes, add 40g of intermediate II-b, control the temperature to below 35℃ for reaction, and continue the reaction at this temperature for 1 hour after the reaction system is completely dissolved. Take a sample for TLC analysis. After the reaction is complete, add 20g of sodium bisulfite to quench the reaction, and stir for 30 minutes. Then add 100g of hydrochloric acid, stir for 15 minutes after the addition, and measure the pH value, which should be ≤4. Concentrate under normal pressure, add 10 parts of drinking water to precipitate the product, and cool to below 40℃. Filter, dry at 90℃ until the loss on drying is ≤0.5%, to obtain 40g of intermediate III, combined with... Figure 4 HPLC > 98%.

[0042] S4. Add 400g of dichloromethane to the reaction flask, then add 28g of thionyl chloride, and cool to below 5°C. Add 10g of pyridine and 40g of intermediate III sequentially; maintain the reaction at 30°C for 2.5 hours. Add 50g of tert-butylamine, and after the addition is complete, reflux the reaction; maintain the reaction at 30°C for 2.5 hours. Add 500g of 4% sodium hydroxide solution dropwise, stir for 30 minutes, separate the liquids, concentrate the organic phase under reduced pressure, add 400g of water to precipitate the precipitate, cool to below 40°C, filter, and dry to obtain 44.5g of intermediate IV. Figure 5 HPLC > 98%.

[0043] S5. Add 400g of dichloromethane, then 55g of triethylamine and 40g of intermediate IV to the reaction flask, and stir until completely dissolved. Slowly add 20g of trimethylchlorosilane to the reaction flask. After the addition is complete, heat to reflux and stir for about 1 hour. Cool down to below 30°C, and add 40g of iodine at 30°C. After the addition is complete, maintain the temperature at 20°C for about 2 hours. Quench the reaction with 400g of 5% sodium thiosulfate solution, stir for about 15 minutes, and allow to stand for separation. Add 200g of drinking water to the organic layer and concentrate under reduced pressure to remove most of the dichloromethane. Add another 400g of drinking water and continue to concentrate under reduced pressure until the concentrated fraction is free of dichloromethane. Cool down to below 30°C, filter, and obtain solid wet product-1.

[0044] S6. Add the above solid wet product-1 to the reaction flask, then add 300g THF, stir until dissolved, then add 1000g of 18% potassium persulfate solution dropwise, keep the temperature ≤50℃, react for 2h after the addition is complete, concentrate the water under reduced pressure to precipitate the material, filter it to obtain solid wet product-2.

[0045] S7, solid wet product-2, and 200g of acetone were added to a reaction flask. The mixture was heated to reflux for 1 hour, then cooled to 10°C and stirred to crystallize for 1 hour. The mixture was filtered, and the solid was purified with acetone once more. After filtration, the solid was dried at 60°C to obtain 34.5g of finasteride. Figure 6 HPLC > 99%.

[0046] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing a finasteride intermediate, characterized in that, The process includes the following steps: mixing progesterone and an organic solvent, continuously introducing ozone at -20°C to -10°C to obtain intermediate I, then adding peroxide dropwise below -10°C, followed by adding sodium hydroxide solution dropwise, and then reacting at 15-25°C to obtain the finasteride intermediate.

2. The method for preparing the finasteride intermediate according to claim 1, characterized in that, The organic solvent is one or more of dichloromethane, acetone, methanol, and chloroform.

3. The method for preparing the finasteride intermediate according to claim 1, characterized in that, The peroxide is one or more of hydrogen peroxide, benzoyl peroxide, tert-butanol peroxide, and potassium persulfate.

4. The method for preparing the finasteride intermediate according to claim 1, characterized in that, The reaction time is 2-3 hours at 15-25℃.

5. The method for preparing the finasteride intermediate according to claim 1, characterized in that, The sodium hydroxide solution has a mass concentration of 10-15%, and the amount of sodium hydroxide solution added is 3-4 times the mass of progesterone.

6. The method for preparing the finasteride intermediate according to claim 1, characterized in that, The reaction at 15-25℃ includes: quenching with sodium thiosulfate dropwise, adjusting the pH to 2-3 with concentrated hydrochloric acid, then concentrating the water under reduced pressure to precipitate the material, and drying to obtain the finasteride intermediate.

7. A finasteride intermediate, characterized in that, It is prepared by the preparation method according to any one of claims 1-6.

8. The finasteride intermediate according to claim 7, characterized in that, Its structural formula is .

9. The use of the finasteride intermediate according to claim 7 or 8 in the preparation of finasteride.

10. The application according to claim 9, characterized in that, Includes the following steps: S1. The finasteride intermediate as described in claim 7 or 8, toluene and ammonium acetate are mixed and refluxed at 90-100°C to obtain intermediate II-a; S2. Methanol, palladium on carbon and intermediate II-a are mixed and reacted at a temperature of 20℃~30℃ to obtain intermediate II-b; S3. Mix dioxane, water and sodium hydroxide, then cool to below 5°C, add bromine and stir, then add intermediate II-b and keep the reaction at the temperature to obtain intermediate III; S4. Mix dichloromethane and thionyl chloride and cool to below 5°C. Then add pyridine and intermediate III sequentially and react at 30-35°C. Then add tert-butylamine and reflux to react and react at 30-35°C to obtain intermediate IV. S5. Mix dichloromethane, triethylamine and intermediate IV and stir until dissolved. Then add trimethylchlorosilane and heat to reflux. Then cool to below 30°C and add iodine to keep the reaction warm to obtain solid wet product-1. S6. Mix the solid wet product-1 and THF and stir until dissolved. Then add potassium persulfate solution dropwise to obtain solid wet product-2. S7, solid wet product-2 and acetone are mixed and heated to reflux to obtain the finasteride.

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