Method for preparing finasteride by efficient deiodination of dihydrogenated finasteride iodide

Abstract

The invention provides a method for preparing finasteride through efficient deiodination of dihydrogenated finasteride iodide. The method specifically comprises the following steps: adding a catalyst into a solvent 1, introducing inert gas, stirring and dissolving, adding organic alkali, cooling to-10 DEG C to 10 DEG C, and stirring and dissolving to obtain a reaction solution; dissolving dihydrofinasteride iodide in a solvent 2, introducing inert gas, cooling to-10 DEG C to 10 DEG C, dropwise adding into the obtained reaction liquid, and carrying out heat preservation reaction at-10 DEG C to 10 DEG C for 1-2 hours; after the reaction is finished, adding a quenching agent, quenching until the system is neutral, and adding into a saline solution; and cooling to-10 DEG C to 10 DEG C, growing crystals, filtering and drying to obtain the product. The specific organic base and the specific catalyst are creatively combined for use, the problems that a traditional beta-elimination substrate is decomposed, low in purity and difficult to purify are solved, meanwhile, the DMF / ammonium chloride aqueous solution serves as a crystallization system, the problem that a traditional elutriation method is low in yield is solved, the purity of the obtained finasteride product can reach 99.80%, and the molar yield can reach 98.25%.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine preparation, and particularly relates to a method for preparing finasteride by efficiently deiodizing dihydrofinasteride iodide. BACKGROUND

[0002] Finasteride is a synthetic steroid, which is a specific inhibitor of intracellular enzyme (type II 5alpha-reductase) in the process of testosterone metabolism into dihydrotestosterone. It can effectively reduce the dihydrotestosterone in blood and prostate, that is, by inhibiting the conversion of testosterone into dihydrotestosterone (DHT), the prostate volume is reduced to improve symptoms, increase urine flow rate, and prevent benign prostatic hyperplasia (BPH). In the prior art, different dosage forms of finasteride have formed clear application scenarios in the clinic: 5mg tablets (Proscar) are used for treating benign prostatic hyperplasia; 1mg tablets (Propecia) were approved by FDA in 1997 and are used for treating male alopecia, which can promote hair growth and prevent further hair loss, and are also used in the treatment of female hirsutism and other diseases, and the whole shows a good market development prospect.

[0003] Since finasteride was approved for marketing in China in 2001, after many times of technical iteration and survival of the fittest, the main technical routes for domestic industrialization are mainly divided into the following two kinds:

[0004] The first kind is to use dihydrofinasteride as a raw material to directly prepare finasteride under the action of DDQ / BSTFA. This method has short steps and high efficiency, but the DDQ used has high toxicity, and the quinone degradation impurities generated in the reaction are difficult to handle, which not only pollutes the environment, but also brings high safety risk.

[0005] The second is to use dihydrofinasteride iodide as raw material, and to prepare finasteride by direct elimination under the action of strong alkali such as methanol lithium, ethanol lithium and tert-butyl alcohol lithium. This method avoids the use of toxic and harmful chemical raw materials, does not produce waste and waste residue, and the salt-containing waste liquid is easy to treat, which meets the safety production requirements of green chemistry. However, direct use of these strong bases for beta-elimination can lead to decomposition of the substrate, producing various impurities, and the structures of these impurities are highly similar to that of finasteride, so it is difficult to achieve effective purification by conventional separation methods. Although various impurity removal and decolorization methods have been derived subsequently, due to the extremely high quality standard requirements of finasteride on the international market, even if the product reaches the quality standard after refining, the yield is relatively low, ultimately resulting in a lack of market competitiveness of this technical route. In addition, there are also patents in the prior art that attempt to prepare finasteride by oxidative elimination and deiodination, but this method has obvious defects: the organic oxidizing agent used is explosive and has high safety risks; the inorganic oxidizing agent used, peroxodisulfate, is easy to precipitate during dropping, and the raw material is easy to be forced out of the crystal by salt water, resulting in incomplete reaction. Not only is the operation process difficult to control, but the yield is also relatively low, which is not conducive to large-scale industrial production.

[0006] Therefore, designing an efficient deiodination method for dihydrofinasteride iodide, optimizing the reaction process to reduce impurity generation and improve separation and purification efficiency, and thus reducing the preparation cost of finasteride and improving the product quality, are important issues that need to be addressed by those skilled in the art. SUMMARY

[0007] The purpose of the present application is to provide a method for efficiently deiodinating dihydrofinasteride iodide to prepare finasteride, which uses an organic base in combination with a catalyst to efficiently deiodinate and prepare high-quality finasteride by beta-elimination. The method provided by the present application solves the problems of substrate decomposition, low purity, low yield and difficult purification in traditional beta-elimination, and high-purity finasteride is prepared with high yield. The raw materials used are inexpensive, the operation is simple, no waste gas and waste residue are produced, only salt-containing wastewater is produced and it is easy to treat, which is very suitable for large-scale industrial production.

[0008] To achieve the above-mentioned purpose, the present application provides a method for deiodinating dihydrofinasteride iodide to prepare finasteride, which specifically comprises the following steps

[0009] The catalyst is added to solvent 1, inert gas is introduced, and after stirring and dissolving, the organic base is added, the temperature is lowered to -10℃ to 10℃, and stirring and dissolving are performed to obtain a reaction solution;

[0010] The dihydrofinasteride iodide is dissolved in solvent 2, inert gas is introduced, and the temperature is lowered to -10℃ to 10℃, then it is added dropwise to the obtained reaction solution, and the reaction is carried out at -10℃ to 10℃ for 1 to 2 hours;

[0011] After the reaction is complete, a quencher is added and the system is quenched until it is neutral. Then, it is added to a salt solution. The temperature is lowered to -10℃ to 10℃ to grow crystals, filtered, and dried to obtain white finasteride crystals.

[0012] In a preferred embodiment, the catalyst comprises one or more of dicyclohexylcarbodiimide (DCC), anhydrous magnesium sulfate, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC); more preferably, the catalyst is anhydrous magnesium sulfate, which is inexpensive and can be uniformly dispersed throughout the system, resulting in good dehydration. In addition, anhydrous magnesium sulfate is easy to process and does not cause environmental pressure, making it very suitable for industrial applications.

[0013] In a preferred embodiment, the mass ratio of the dihydrofinasteride iodide to the catalyst is 1:(0.1 to 0.5); more preferably, the mass ratio of the dihydrofinasteride iodide to the catalyst is 1:(0.1 to 0.3).

[0014] In a preferred embodiment, the solvent 1 includes one or more of acetone, ethanol, acetonitrile, N,N-dimethylformamide, and toluene; more preferably, the solvent 1 is N,N-dimethylformamide. Experiments have verified that N,N-dimethylformamide has very high solubility for specific organic bases and dihydrofinasteride iodides, and can achieve the solubility of the system under low temperature conditions with a small amount. It also has good water solubility and is easy to process.

[0015] In a preferred embodiment, the mass-to-volume ratio of the dihydrofinasteride iodide to solvent 1 is 1 g: (3-10) ml; more preferably, the mass-to-volume ratio of the dihydrofinasteride iodide to solvent 1 is 1 g: 5 ml.

[0016] In a preferred embodiment, the organic base includes one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lithium tert-butoxide, and lithium diisopropylamino (LDA, CAS No. 4111-54-0); more preferably, the organic base is lithium tert-butoxide, which is inexpensive, highly reactive, and exhibits high selectivity for the β-elimination of substrates. Furthermore, it is easily quenched with water, making it convenient to process, and the post-treatment product, potassium hydroxide, is readily soluble in water. In addition, lithium tert-butoxide does not cause pollution when it enters wastewater, and the other product, tert-butanol, can be recovered and reused by distillation with the solvent acetonitrile, making it very suitable for large-scale industrial production.

[0017] In a preferred embodiment, the mass ratio of the dihydrofinasteride iodide to the organic base is 1:(1-3); more preferably, the mass ratio of the dihydrofinasteride iodide to the organic base is 1:2.

[0018] In a preferred embodiment, the solvent 2 includes one or more of acetone, ethanol, acetonitrile, N,N-dimethylformamide, and toluene; more preferably, the solvent 2 is N,N-dimethylformamide.

[0019] In a preferred embodiment, the mass-to-volume ratio of the dihydrofinasteride iodide to solvent 2 is 1 g: (3-10) ml; more preferably, the mass-to-volume ratio of the dihydrofinasteride iodide to solvent 2 is 1 g: 5 ml.

[0020] In this invention, the inert gas includes argon or nitrogen.

[0021] In a preferred embodiment, the quenching agent includes one or more of dilute hydrochloric acid, glacial acetic acid, and citric acid monohydrate; more preferably, the concentration of the dilute hydrochloric acid is 0.5–2 mol / L, the concentration of the glacial acetic acid is 5–15 mol / L, and the concentration of the citric acid monohydrate is 0.1–1 mol / L; most preferably, the quenching agent includes one or more of 1 mol / L dilute hydrochloric acid, 10 mol / L glacial acetic acid, and 0.5 mol / L citric acid monohydrate.

[0022] In a preferred embodiment, the mass ratio of the dihydrofinasteride iodide to the quencher is 1:(2-5); more preferably, the mass ratio of the dihydrofinasteride iodide to the quencher is 1:(2-3).

[0023] In a preferred embodiment, the saline solution comprises one or more of a 10% ammonium chloride aqueous solution, a 10% sodium chloride aqueous solution, and a 10% potassium chloride aqueous solution; more preferably, the mass concentration of the ammonium chloride aqueous solution is 5-15%, the mass concentration of the sodium chloride aqueous solution is 5-15%, and the mass concentration of the potassium chloride aqueous solution is 5-15%; most preferably, the saline solution comprises one or more of a 10% ammonium chloride aqueous solution, a 10% sodium chloride aqueous solution, and a 10% potassium chloride aqueous solution.

[0024] In a preferred embodiment, the mass ratio of the dihydrofinasteride iodide to the saline solution is 1:(20-50); more preferably, the mass ratio of the dihydrofinasteride iodide to the saline solution is 1:(40-50).

[0025] In this invention, the cooling rate of the cooling treatment is 5 to 30°C / h; more preferably, the cooling rate is 20 to 30°C / h.

[0026] In a preferred embodiment, the crystal growth temperature is 0-5°C; more preferably, the crystal growth temperature is 3°C.

[0027] In a preferred embodiment, the crystal growth time is 1 to 3 hours; more preferably, the crystal growth time is 2 hours.

[0028] In a preferred embodiment, the drying can be carried out using conventional methods known to those skilled in the art, such as drying at 40–60°C for 2–6 hours.

[0029] In a preferred embodiment, the purity of the obtained finasteride white crystals can reach 99.80%; the molar yield of the product can reach 98.25%.

[0030] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0031] The technical solution adopted in this method is as follows: First, the organic base and the reaction system are pretreated with a catalyst to remove water and provide a high-concentration anhydrous strong base negative ion environment. Then, a dihydrofinasteride iodide solution is added dropwise to the reaction system to remove HI through efficient β-elimination. After the reaction is completed, the system is quenched to neutrality, and then the reaction solution is added to a salt solution. After cooling and crystallization, high-purity finasteride can be obtained.

[0032] Taking lithium tert-butoxide as an example, its mechanism for β-elimination of dihydrofinasteride iodide is as follows: Under alkaline conditions, lithium tert-butoxide loses a β-hydrogen atom to generate a tert-butene anion and lithium hydroxide. The tert-butene anion then undergoes a nucleophilic substitution reaction with dihydrofinasteride iodide to generate finasteride and lithium iodide. However, experiments have shown that using only lithium tert-butoxide to catalyze the β-elimination of dihydrofinasteride iodide (as in Comparative Example 1) results in an HPLC purity of only 71.88%, with numerous impurities that are difficult to separate and purify, and the product quality cannot meet market requirements.

[0033] Therefore, we conducted a detailed structural analysis of dihydrofinasteride iodide and found that multiple sites, including the iodine atom at position 5, the exoamide at position 17, and the lactam at position 4, are reactive. Although the β-elimination activity of the iodine at positions 1 and 2 is significantly higher than other reactions under ideal anhydrous strong alkaline conditions, most organic bases are highly hygroscopic, and solvents such as dimethylformamide, which can dissolve both iodides and organic bases, are also highly hygroscopic. Simply using an inert gas to protect the reaction system is clearly insufficient to create an ideal anhydrous environment. Residual moisture in the reaction system not only leads to various hydrolysis reactions of the amide groups in the substrate, but also causes organic bases such as lithium tert-butoxide to react violently with water to form lithium hydroxide and tert-butanol, resulting in loss of reactivity. Simultaneously, the concentration of tert-butene anions decreases, and the substrate inevitably comes into contact with other substances in the system, resulting in various impurities such as substitution, double elimination, hydrolysis, esterification, and ammonolysis.

[0034] Based on this, this method proposes using a specific catalyst in combination with a specific organic base to first create a relatively ideal high-concentration anhydrous strong base anion environment, and then adding the substrate dropwise to carry out the reaction. This efficiently catalyzes the β-elimination reaction at the 1,2 positions of ring A of dihydrofinasteride iodide, thus rapidly and conveniently preparing high-purity finasteride. Meanwhile, due to the high solubility of N,N-dimethylformamide in the product, its large dosage, and the interference of byproducts such as tert-butanol in the system, conventional water precipitation methods cannot completely expel the product from the N,N-dimethylformamide system. Through extensive experimental design and verification, the inventors have shown that using ammonium chloride aqueous solution as a poor solvent can yield finasteride products close to the theoretical amount.

[0035] Verification by actual test data shows that the purity of finasteride white crystals obtained by the method of this invention is above 99.58%; the molar yield of the product is above 96.09%. The method of this invention is simple, has low raw material cost, no special requirements for equipment and energy consumption, high production efficiency, and high product purity, and has broad application prospects and market competitiveness. Attached Figure Description

[0036] To more clearly illustrate the technical solutions in the specific embodiments of this application or the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this application. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0037] Figure 1 This is a schematic diagram of the reaction synthesis route of the present invention;

[0038] Figure 2 This is the HPLC chromatogram of finasteride prepared in Example 1 of the present invention;

[0039] Figure 3 The HPLC chromatogram of finasteride prepared in Example 2 of this invention;

[0040] Figure 4 The HPLC chromatogram of finasteride prepared in Example 3 of this invention;

[0041] Figure 5 This is the HPLC chromatogram of finasteride prepared in Example 4 of the present invention;

[0042] Figure 6 This is the HPLC chromatogram of finasteride prepared in Comparative Example 1 of this invention;

[0043] Figure 7 This is the HPLC chromatogram of finasteride prepared in Comparative Example 2 of this invention. Detailed Implementation

[0044] To enable those skilled in the art to better understand the present invention, the present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. However, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0045] This invention provides a method for preparing finasteride from dihydrofinasteride iodide by deiodination. Firstly, it innovatively combines a specific organic base with a specific catalyst, solving the problems of substrate decomposition, low purity, and difficult purification associated with traditional β-elimination methods, thus efficiently preparing finasteride products with a purity of over 99%. Simultaneously, it innovatively proposes a DMF / ammonium chloride aqueous solution crystallization system, overcoming the low yield problem of traditional water precipitation methods and obtaining finasteride products with yields close to the theoretical amount.

[0046] Using the method provided by this invention, the reaction product can achieve a purity of over 99% without further purification. At the same time, the reaction has no safety risks and no special restrictions on production equipment and reaction conditions, making it particularly suitable for large-scale industrial preparation.

[0047] The technical solution of this application will be described in detail below through specific embodiments:

[0048] Unless otherwise specified, the technical means used in this invention are conventional means well known to those skilled in the art. All raw materials, reagents, instruments, and equipment used in this invention can be purchased commercially or prepared using existing methods. Unless otherwise specified, all reagents used in this invention are of analytical grade. In the embodiments of this invention, the synthetic route for the dihydrofinasteride iodide used is prior art, specifically adopting the synthetic route of CN117285585A (a method for preparing finasteride iodide). In the embodiments of this invention, the dihydrofinasteride iodide used was prepared according to Example 1 of CN117285585A.

[0049] Example 1

[0050] A method for preparing finasteride from dihydrofinasteride iodide by deiodination includes the following steps:

[0051] S1. Add 30g of anhydrous magnesium sulfate to 300ml of N,N-dimethylformamide, purge with nitrogen, stir for 30 minutes until fully dissolved, then add 200g of lithium tert-butoxide, cool to -10℃ at a cooling rate of 25℃ / h, stir for 30 minutes until fully dissolved, and obtain the reaction solution.

[0052] S2 dissolves 100g of dihydrofinasteride iodide in 300ml of N,N-dimethylformamide, introduces nitrogen gas, cools to -10℃ at a rate of 25℃ / h, and adds it dropwise to the resulting reaction solution. The reaction is then maintained at -10℃ for 1h.

[0053] After the S3 reaction is completed, 250g of 10mol / L glacial acetic acid is added to quench the reaction. After quenching until the pH of the system is 7, it is added to 4500g of 10% ammonium chloride aqueous solution. The temperature is lowered to 3℃ at a rate of 25℃ / h, and crystals are grown for 2h. After filtration, the crystals are dried at 40℃ for 2h to obtain finasteride white crystals.

[0054] The obtained white finasteride crystals were weighed to obtain 73 g of finasteride (0.30% moisture). The calculation results showed that the molar yield was 98.25%.

[0055] The obtained finasteride was analyzed by HPLC, and the results are as follows: Figure 2 As shown, its purity is 99.80%.

[0056] Example 2

[0057] The only difference from Example 1 is that in S3, the 250g of 10mol / L glacial acetic acid used is replaced with 250g of 1mol / L hydrochloric acid for quenching, while the other raw materials, amounts and reaction conditions are the same as in Example 1.

[0058] The white finasteride crystals obtained in this example were weighed to obtain 71.6 g of finasteride (0.38% moisture). The calculation results showed that the yield was 96.3%.

[0059] The obtained finasteride was analyzed by HPLC, and the results are as follows: Figure 3 As shown, its purity is 99.71%.

[0060] Example 3

[0061] The only difference from Example 1 is that in S3, lithium tert-butoxide is replaced with lithium diisopropylamino, and the amount is the same as in Example 1. All other raw materials, amounts and reaction conditions are the same as in Example 1.

[0062] The white finasteride crystals obtained in this example were weighed to obtain 72g of finasteride (0.37% moisture). The calculation results showed that the molar yield was 96.90%.

[0063] The obtained finasteride was analyzed by HPLC, and the results are as follows: Figure 4 As shown, its purity is 99.58%.

[0064] Example 4

[0065] The only difference from Example 1 is that in S1, 30g of anhydrous magnesium sulfate was added to 300ml of acetonitrile, while the other raw materials, amounts and reaction conditions were the same as in Example 1.

[0066] The white finasteride crystals obtained in this example were weighed to obtain 71.4 g of finasteride (0.31% moisture). The calculation results showed that the molar yield was 96.09%.

[0067] The obtained finasteride was analyzed by HPLC, and the results are as follows: Figure 5 As shown, its purity is 99.79%.

[0068] Comparative Example 1

[0069] The only difference from Example 1 is that anhydrous magnesium sulfate is not used as a catalyst. Instead, 200g of lithium tert-butoxide is directly added to 300ml of N,N-dimethylformamide and cooled to -10°C at a cooling rate of 25°C / h. The mixture is stirred for 30 minutes until fully dissolved to obtain the reaction solution. All other raw materials, amounts, and reaction conditions are the same as in Example 1.

[0070] The white finasteride crystals obtained in this example were weighed to obtain 50g of finasteride (0.35% moisture). The calculation results showed that the yield was 67.29%.

[0071] The obtained finasteride was analyzed by HPLC, and the results are as follows: Figure 6 As shown, its purity is 71.88%.

[0072] Comparative Example 2

[0073] The only difference from Example 1 is that in S3, the 10% ammonium chloride aqueous solution used is replaced with purified water, and the amount used is the same as in Example 1. The other raw materials, amounts and reaction conditions are the same as in Example 1.

[0074] The white finasteride crystals obtained in this example were weighed to obtain 30g of finasteride (0.33% moisture). The calculation results showed that the molar yield was 40.37%.

[0075] The obtained finasteride was analyzed by HPLC, and the results are as follows: Figure 7 As shown, its purity is 92.24%.

[0076] The foregoing description of specific exemplary embodiments of the invention is for illustrative and explanatory purposes. These descriptions are not intended to limit the invention to the precise forms disclosed, and it will be apparent that many changes and variations can be made in accordance with the foregoing teachings. The exemplary embodiments were chosen and described in order to explain the specific principles of the invention and its practical application, thereby enabling those skilled in the art to implement and utilize various different exemplary embodiments of the invention, as well as various different choices and variations. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. A method for preparing finasteride from dihydrofinasteride iodide by deiodination, characterized in that, Includes the following steps: The catalyst was added to solvent 1, an inert gas was introduced, and the mixture was stirred to dissolve. Then an organic base was added, the temperature was lowered to -10℃ to 10℃, and the mixture was stirred to dissolve, thus obtaining the reaction solution. Dihydrofinasteride iodide was dissolved in solvent 2, an inert gas was introduced, the temperature was lowered to -10℃~10℃, and it was added dropwise to the resulting reaction solution. The reaction was kept at -10℃~10℃ for 1~2 hours. After the reaction is complete, a quencher is added and the system is quenched until it is neutral. Then, it is added to a salt solution. The temperature is lowered to -10℃ to 10℃ to grow crystals, filtered, and dried to obtain white finasteride crystals.

2. The method for preparing finasteride from dihydrofinasteride iodide as described in claim 1, characterized in that, The catalyst comprises one or more of dicyclohexylcarbodiimide, anhydrous magnesium sulfate, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide; The mass ratio of the dihydrofinasteride iodide to the catalyst is 1:(0.1-0.5).

3. The method for preparing finasteride from dihydrofinasteride iodide as described in claim 1, characterized in that, Solvent 1 includes one or more of acetone, ethanol, acetonitrile, N,N-dimethylformamide, and toluene; The mass-to-volume ratio of the dihydrofinasteride iodide to solvent 1 is 1 g: (3-10) ml.

4. The method for preparing finasteride from dihydrofinasteride iodide as described in claim 1, characterized in that, The organic base includes one or more of 1,8-diazabicyclo[5.4.0]undec-7-ene, lithium tert-butoxide, and lithium diisopropylamino. The mass ratio of the dihydrofinasteride iodide to the organic base is 1:(1-3).

5. The method for preparing finasteride from dihydrofinasteride iodide as described in claim 1, characterized in that, Solvent 2 includes one or more of acetone, ethanol, acetonitrile, N,N-dimethylformamide, and toluene; The mass-to-volume ratio of the dihydrofinasteride iodide to solvent 2 is 1 g: (3-10) ml.

6. The method for preparing finasteride from dihydrofinasteride iodide as described in claim 1, characterized in that, The quenching agent includes one or more of dilute hydrochloric acid, glacial acetic acid, and citric acid monohydrate; The mass ratio of the dihydrofinasteride iodide to the quencher is 1:(2-5).

7. The method for preparing finasteride from dihydrofinasteride iodide as described in claim 1, characterized in that, The brine solution includes one or more of ammonium chloride aqueous solution, sodium chloride aqueous solution, and potassium chloride aqueous solution; The mass ratio of the dihydrofinasteride iodide to the saline solution is 1:(20-50).

8. The method for preparing finasteride from dihydrofinasteride iodide as described in claim 1, characterized in that, The crystal growth temperature is 0–5°C, and the crystal growth time is 1–3 hours.

9. The method for preparing finasteride from dihydrofinasteride iodide as described in any one of claims 1-8, characterized in that, The obtained finasteride white crystals have a purity of 99.80% and a product molar yield of 98.25%.

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