A method for efficiently synthesizing a puquimafine intermediate

Abstract

This invention discloses a highly efficient method for synthesizing proxalutamide intermediates, belonging to the field of pharmaceutical synthesis technology. First, dimethyl malonate and 2-chloro-5-nitropyridine are used as raw materials, condensed in the presence of potassium carbonate to generate dimethyl 2-(5-nitropyridine-2-yl)malonate. This is then reacted with tert-butyl acrylate and acid-hydrolyzed to obtain 4-(5-nitropyridine-2-yl)butyric acid. After activation with N,N'-carbonyl diimidazole, it is coupled with aminoacetaldehyde dimethyl acetal to form N-(2,2-dimethoxyethyl)-4-(5-nitropyridine-2-yl)butyramide. Then, a cyclization reaction mediated by phosphorus pentoxide and methanesulfonic acid is used to generate crude 2-(3-(5-nitropyridine-2-yl)propyl)oxazole. After purification, the nitro group is reduced by catalytic hydrogenation, and finally, it reacts with 1,5-naphthalenedisulfonic acid to form a salt, yielding the proxalutamide intermediate. This method achieves highly efficient synthesis of proxalutamide intermediates.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for the efficient synthesis of proxalutamide intermediates. Background Technology

[0002] Proxalutamide intermediates are key intermediates in the synthesis of the anti-prostate cancer drug proxalutamide. They are generated from starting materials such as aromatic amines and halogenated hydrocarbons through multiple steps of reaction. The molecules contain chiral amine fragments, aromatic rings and other core drug skeletons, and are mostly chiral compounds (such as chiral amines, amides and substituted benzene rings). The integrity and purity of their structure directly determine the feasibility of subsequent drug-making reactions and the efficacy and safety of the final drug.

[0003] Its core functions include constructing the molecular skeleton of active drugs, regulating reaction efficiency, ensuring drug quality, and controlling synthesis costs. However, the current intermediates of this type have problems such as complex synthesis processes, low overall yield, difficulty in controlling chiral purity (low efficiency of traditional chemical resolution and many impurity residues), reliance on imported key raw materials, high cost and difficulty in recycling precious metal catalysts, harsh reaction conditions (high temperature and pressure, high energy consumption), environmental pressure brought by organic solvents and highly corrosive reagents, and difficulty in removing multi-step reaction byproducts and achieving a purity of more than 99.5% for pharmaceutical use.

[0004] Chinese invention patent application CN115286623A discloses a method for synthesizing proxalutamide and its intermediate. The key intermediate for preparing proxalutamide is prepared by a one-step copper-catalyzed CN coupling reaction. At 150°C, using DMF as solvent, cuprous oxide is used to catalyze the reaction of 5,5-dimethyl-2-thionimidazol-4-one with 2-trifluoromethyl-3-fluoro-4-iodobenzonitrile for 20 h. After the reaction, the solid is removed, the solvent is concentrated, and then ammonia is added to crystallize the product in an aqueous system. Finally, the intermediate is obtained by washing with water and drying.

[0005] However, under high temperature and copper catalysis, haloaromatics may undergo side reactions such as dehalogenation and Ullman self-coupling. The cyanide itself is also an active group and may participate in the reaction. These will produce impurities with similar structures that are difficult to separate. Summary of the Invention

[0006] The purpose of this invention is to provide a highly efficient method for synthesizing proxalutamide intermediates. This method abandons the "one-step high-temperature copper-catalyzed coupling" strategy used in patented methods to construct the key framework. Instead, it employs a multi-step, mild classical organic reaction to progressively construct the molecule, fundamentally avoiding the use of high temperatures and copper catalysts, and eliminating side reaction pathways such as dehalogenation and Ullmann self-coupling. Furthermore, by setting separation and purification points for key intermediates, impurities can be effectively removed at an early stage of formation, preventing their accumulation and transfer, and ensuring the high purity of the final product.

[0007] The objective of this invention can be achieved through the following technical solutions: A method for efficiently synthesizing proxalutamide intermediates includes the following steps: Step 1: Using dimethyl malonate and 2-chloro-5-nitropyridine as raw materials, condense them in the presence of potassium carbonate to generate dimethyl 2-(5-nitropyridine-2-yl)malonate, which then reacts with tert-butyl acrylate and is acid-hydrolyzed to obtain 4-(5-nitropyridine-2-yl)butyric acid.

[0008] Step 2: 4-(5-nitropyridin-2-yl)butyric acid is activated with N,N'-carbonyldiimidazole and then coupled with aminoacetaldehyde dimethyl acetal to form N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide.

[0009] Step 3: Then, phosphorus pentoxide and methanesulfonic acid mediate a cyclization reaction to promote the formation of crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole from N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide. After purification, the nitro group is reduced by catalytic hydrogenation, and finally reacted with 1,5-naphthalenedisulfonic acid to form a salt, yielding the proxalutamide intermediate.

[0010] The general structural formula of the proxalutamide intermediate is shown in Formula 1: Formula 1.

[0011] Furthermore, the specific preparation steps for dimethyl 2-(5-nitropyridin-2-yl)malonate are as follows: N,N-dimethylformamide was added to a reaction flask. Under nitrogen protection, dimethyl malonate, potassium carbonate, and 2-chloro-5-nitropyridine were added. The mixture was stirred and heated to 40-50°C, and the reaction was maintained at this temperature for 12-14 hours. The mixture was then filtered, and the filter cake was washed with N,N-dimethylformamide. The filtrate was collected, and the pH was adjusted to 5-6 with dilute hydrochloric acid. The mixture was then filtered again and dried under vacuum to constant weight to obtain dimethyl 2-(5-nitropyridine-2-yl)malonate. The reaction process is shown below: Furthermore, the mass ratio of N,N-dimethylformamide, dimethyl malonate, potassium carbonate, and 2-chloro-5-nitropyridine is 5.4-5.8:2-2.2:2.612-2.812:1.2-1.4.

[0012] Furthermore, the specific preparation steps for 4-(5-nitropyridin-2-yl)butyric acid are as follows: Methanol was added to a reaction flask. Under nitrogen protection, tert-butyl acrylate, dimethyl 2-(5-nitropyridin-2-yl)malonate, and sodium carbonate were added. The mixture was stirred and heated to 58-62℃ under slight reflux for 5-6 hours. The pH was adjusted to 5-6 with hydrochloric acid solution. The methanol was concentrated to dryness under reduced pressure, and then 3 mol / L hydrochloric acid solution was added. The temperature was raised to 65-75℃ and the reaction was maintained for 12 hours. The temperature was lowered to 20-30℃, and 32wt% liquid alkali and deionized water were added dropwise to adjust the pH to 8-9. Activated carbon was added, and the mixture was stirred at room temperature for 60-80 minutes. The mixture was filtered, and the filtrate was collected. Methyl tert-butyl ether was added to the filtrate, and the mixture was stirred for 30-40 minutes. After standing for 30-40 minutes, the layers separated, and the aqueous phase was collected. Concentrated hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 3.8-4.2. The mixture was filtered and dried under vacuum to constant weight to obtain 4-(5-nitropyridin-2-yl)butyric acid. The reaction process is shown below: Furthermore, the mass ratio of methanol, tert-butyl acrylate, dimethyl 2-(5-nitropyridin-2-yl)malonate, sodium carbonate, 3 mol / L hydrochloric acid solution, activated carbon, and tert-methyl ether is 2.12-2.32:0.308-0.328:0.47-0.49:0.022-0.026:2.8-3:0.023-0.029:1.5-2.

[0013] Furthermore, the specific preparation steps of N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide are as follows: Dichloromethane and 4-(5-nitropyridin-2-yl)butyric acid were added to a reaction flask, stirred, and cooled to 0-10℃. N,N'-carbonyldiimidazole was added, the temperature was slowly increased, and the reaction was maintained at this temperature for 3-4 hours. Then, aminoacetaldehyde dimethyl acetal was added, the temperature was slowly increased, and the reaction was maintained at this temperature for another 2-3 hours. The mixture was washed with an alkaline aqueous solution, activated carbon was added, and the mixture was stirred, filtered, and the filtrate was collected. The mixture was then washed with an alkaline aqueous solution, deionized water was added, and the mixture was allowed to stand for separation. The lower organic layer was collected, anhydrous magnesium sulfate was added, the mixture was stirred, filtered, and the filter cake was washed with dichloromethane. The filtrate was collected, and the organic layer was distilled under normal pressure, followed by vacuum distillation to obtain N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide. The reaction process is shown below: Furthermore, the mass ratio of dichloromethane, 4-(5-nitropyridin-2-yl)butyric acid, N,N'-carbonyldiimidazole, aminoacetaldehyde dimethyl acetal, activated carbon, deionized water, and anhydrous magnesium sulfate is 1440-1640:240-260:185.2-195.2:126-130:12-16:600-800:100-120.

[0014] Furthermore, the specific preparation steps of the crude product 2-(3-(5-nitropyridin-2-yl)propyl)oxazole are as follows: Phosphorus pentoxide and methanesulfonic acid were added to a reaction flask. Under nitrogen protection, the mixture was stirred and heated to 80-85°C until dissolved. Then, a dichloromethane solution containing N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide was added. The mixture was heated to 130-140°C and reacted for 4-5 hours. The temperature was then lowered to 20-35°C, and the mixture was slowly added to deionized water cooled to 0-10°C to quench the reaction. The reaction flask was rinsed with ice water at room temperature, and then liquid alkali was added dropwise to adjust the pH to 7.5-8.5. The mixture was filtered and dried under vacuum to constant weight to obtain the crude product 2-(3-(5-nitropyridin-2-yl)propyl)oxazole. The reaction process is shown below: Furthermore, the ratio of phosphorus pentoxide, methanesulfonic acid, N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide, dichloromethane solution, deionized water, and ice water is 270-300g: 2.7-2.8kg: 180-200g: 600-700mL: 2.7-2.9kg: 900-1000mL.

[0015] Furthermore, the specific preparation steps of the proxalutamide intermediate are as follows: 2-(3-(5-nitropyridin-2-yl)propyl)oxazole, methanol, and 5% palladium on carbon catalyst were added to a reaction vessel. The gas inside the vessel was replaced 3-5 times with hydrogen at a pressure of 0.2-0.4 MPa. The reaction was carried out at 45-55℃ and a hydrogen pressure of 0.4-0.6 MPa, with stirring started and the hydrogen pressure maintained at 0.2-0.4 MPa for hydrogen absorption. The reaction was maintained at this temperature and pressure until no more hydrogen was absorbed, then the temperature was maintained for another 2-3 hours. After cooling to room temperature, the hydrogen pressure inside the vessel was released, the product was discharged, and the reaction solution was filtered to remove Pd / C. A methanol solution of 1,5-naphthalenedisulfonic acid tetrahydrate was added dropwise at -10-0℃ for 2-2.4 hours, and the mixture was stirred for 1-2 hours. The mixture was then filtered and vacuum dried to constant weight to obtain the proxalutamide intermediate. The reaction process is shown below: Furthermore, the mass ratio of 2-(3-(5-nitropyridin-2-yl)propyl)oxazole, methanol, and 5% palladium on carbon catalyst is 40-50:240-260:0.8-1.

[0016] Furthermore, the specific preparation steps of 2-(3-(5-nitropyridin-2-yl)propyl)oxazole are as follows: Crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole and ethyl acetate were added to a reaction flask and stirred at 30-40°C to dissolve. Activated carbon was then added and stirred for 1-2 hours. The mixture was washed with 5wt% sodium bicarbonate solution, and the lower aqueous layer was separated. Deionized water was added, and the mixture was washed again and the lower aqueous layer was separated. The organic layer was concentrated under reduced pressure, and ethanol was added and heated until the solution was clear. The mixture was then cooled to -5-0°C to induce crystallization. The crystals were filtered and dried under reduced pressure at 50-60°C to obtain 2-(3-(5-nitropyridin-2-yl)propyl)oxazole.

[0017] Further, the mass ratio of crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole, ethyl acetate, activated carbon, 5wt% sodium bicarbonate solution, deionized water, organic layer and ethanol is 100-110:600-700:5-10:200-300:200-300:85-90:200-300.

[0018] The beneficial effects of this invention are: This invention fundamentally solves the core defects inherent in existing technologies (such as CN115286623A) that employ "one-step high-temperature copper-catalyzed coupling," namely, numerous side reactions, difficulty in separating impurities, and high levels of heavy metal residues, by designing a novel, non-copper-catalyzed, multi-step, mild synthetic route. This scheme abandons the high-temperature metal catalysis strategy, employing highly selective reactions in key steps: in S3, the mild conditions of N,N'-carbonyldiimidazole (CDI) activation / condensation are used to efficiently construct amide bonds, greatly reducing byproducts; in S4, a phosphorus pentoxide / methanesulfonic acid system is used for specific acid-catalyzed cyclization, resulting in a clear reaction pathway and avoiding multiple competing pathways. Simultaneously, the establishment and purification of multiple key intermediates such as S1, S3, and S5 enable stepwise control and early removal of impurities, effectively preventing impurity accumulation and propagation.

[0019] All major steps of this route are carried out at mild temperatures (40-140℃), with controllable conditions and robust processes. While ensuring the ultra-high chemical purity and safety of the product, it also has excellent atom economy and industrialization feasibility, providing a new route for the synthesis of proxalutamide intermediates with high purity, high safety and high efficiency. Detailed Implementation

[0020] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments in the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0021] Example 1: A method for efficiently synthesizing proxalutamide intermediates, comprising the following steps: S1: Add 4.2 kg of N,N-dimethylformamide to a reaction flask. Under nitrogen protection, add 2 kg of dimethyl malonate, 2.612 kg of potassium carbonate, and 1.2 kg of 2-chloro-5-nitropyridine. Stir and heat to 40 °C, and maintain the temperature for 12 h. Take a sample for HPLC control. After the reaction is complete, filter and wash the filter cake with 1.2 kg of N,N-dimethylformamide. Collect the filtrate, adjust the pH to 5 with dilute hydrochloric acid, filter, and dry at 50 °C to constant weight to obtain dimethyl 2-(5-nitropyridine-2-yl)malonate.

[0022] S2: Add 2.12 kg of methanol to a reaction flask. Under nitrogen protection, add 308 g of tert-butyl acrylate, 470 g of dimethyl 2-(5-nitropyridin-2-yl)malonate, and 22 g of sodium carbonate. Stir and heat to 58 °C under slight reflux, and maintain the temperature for 5 h. When the content of dimethyl 2-(5-nitropyridin-2-yl)malonate is ≤1% and the total content of P7 and P8 is ≥70%, the reaction is considered complete. Adjust the pH to 5 with 150 g of 3 mol / L hydrochloric acid solution, concentrate the methanol to dryness under reduced pressure, add 2.8 kg of 3 mol / L hydrochloric acid solution, heat to 65 °C, and maintain the temperature for 12 h. When the total content of P7 and P8 is <1% and the content of P9 is ≥70%, the reaction is considered complete. Lower the temperature to 20 °C and add 1050 g of sodium carbonate dropwise. The pH was adjusted to 8 with 32wt% alkali and 1050g deionized water, then 23g activated carbon was added. The mixture was stirred at room temperature for 60min, filtered, and the filtrate was collected. 1.5kg methyl ether was added to the filtrate, stirred for 30min, and allowed to stand for 30min. The mixture separated into layers, and the aqueous phase was collected. Concentrated hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 3.8. The mixture was then filtered and dried at 50℃ to constant weight to obtain 4-(5-nitropyridin-2-yl)butyric acid.

[0023] S3: Add 1440g of dichloromethane and 240g of 4-(5-nitropyridin-2-yl)butyric acid to a reaction flask, stir and cool to 0℃, then add 185.2g of... N,N'-carbonyldiimidazole was slowly heated to 20°C and reacted for 3 hours. Then, 126g of aminoacetaldehyde dimethyl acetal was added, and the temperature was slowly increased to 30°C and reacted for another 2 hours. The mixture was washed twice with alkaline aqueous solution, and then 12g of activated carbon was added. The mixture was stirred for 30 minutes, filtered, and the filtrate was collected. The mixture was then washed once with alkaline aqueous solution, and 600g of deionized water was added. The mixture was allowed to stand for 30 minutes to separate into layers. The lower organic layer was collected, and 100g of anhydrous magnesium sulfate was added. The mixture was stirred for 30 minutes. A sample was taken to test the purity (≥95%) and moisture content (≤0.20%). The mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was collected, and the organic layer was distilled under normal pressure and then under reduced pressure to obtain N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide.

[0024] The specific procedure for washing with alkaline aqueous solution is as follows: add 1200g of 10wt% glacial acetic acid solution, stir for 30min, let stand for 30min, separate into layers, and collect the lower organic layer.

[0025] S4: Add 270g of phosphorus pentoxide and 2.7kg of methanesulfonic acid to a reaction flask. Under nitrogen protection, stir and heat to 80℃. After stirring until dissolved, add 600mL of dichloromethane solution containing 180g of N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide. Heat to 130℃ and keep the reaction at this temperature for 4 hours. Then cool to 20℃ and slowly add to 2.7kg of deionized water cooled to 0℃ to quench the reaction. Rinse the reaction flask with 900mL of ice water at room temperature, then add liquid alkali to adjust the pH to 7.5. Filter and dry under vacuum at 50℃ to constant weight to obtain crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole.

[0026] S5: Add 100g of crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole and 600g of ethyl acetate to a reaction flask, stir and dissolve at 30℃, then add 5g of activated carbon, stir for 1h, wash with 200g of 5wt% sodium bicarbonate solution, separate the lower aqueous layer, add 200g of deionized water, wash, separate the lower aqueous layer, concentrate under reduced pressure to 85g of organic layer, add 200g of ethanol, heat to clear, cool to -5℃, crystallize, filter, dry under reduced pressure at 50℃ to obtain 2-(3-(5-nitropyridin-2-yl)propyl)oxazole.

[0027] S6: Add 40g of 2-(3-(5-nitropyridin-2-yl)propyl)oxazole, 240g of methanol, and 0.8g of 5% palladium on carbon catalyst to a reactor. Replace the gas in the reactor three times with hydrogen pressure of 0.2MPa. At 45℃ and hydrogen pressure of 0.4MPa, start stirring and maintain hydrogen pressure at 0.2MPa for hydrogen absorption reaction. After the reaction stops absorbing hydrogen, continue to keep it at the same temperature for 2 hours, cool to room temperature, release the hydrogen pressure in the reactor, discharge the product, filter the reaction solution, filter out Pd / C, add 1,5-naphthalenedisulfonic acid tetrahydrate methanol solution dropwise at -10℃ for 2 hours, keep stirring at the same temperature for 1 hour, filter, and dry under vacuum at 50℃ to constant weight to obtain proxalutamide intermediate.

[0028] The 1,5-naphthalenedisulfonic acid tetrahydrate methanol solution was prepared by mixing 28.9 g of 1,5-naphthalenedisulfonic acid tetrahydrate and 80 g of methanol.

[0029] Example 2: Example 1: A method for efficiently synthesizing proxalutamide intermediates, comprising the following steps: S1: Add 4.3 kg of N,N-dimethylformamide to a reaction flask. Under nitrogen protection, add 2.1 kg of dimethyl malonate, 2.712 kg of potassium carbonate, and 1.3 kg of 2-chloro-5-nitropyridine. Stir and heat to 45°C, and maintain the temperature for 13 h. Take a sample for HPLC control. After the reaction is complete, filter and wash the filter cake with 1.3 kg of N,N-dimethylformamide. Collect the filtrate, adjust the pH to 5.5 with dilute hydrochloric acid, filter, and dry at 55°C to constant weight to obtain dimethyl 2-(5-nitropyridine-2-yl)malonate.

[0030] S2: Add 2.22 kg of methanol to a reaction flask. Under nitrogen protection, add 318 g of tert-butyl acrylate, 480 g of dimethyl 2-(5-nitropyridin-2-yl)malonate, and 24 g of sodium carbonate. Stir and heat to 60 °C under slight reflux, and maintain the temperature for 5.5 h. The reaction is considered complete when the content of dimethyl 2-(5-nitropyridin-2-yl)malonate is ≤1% and the total content of P7 and P8 is ≥70%. Adjust the pH to 5.5 with 175 g of 3 mol / L hydrochloric acid solution, concentrate the methanol to dryness under reduced pressure, add 2.9 kg of 3 mol / L hydrochloric acid solution, heat to 70 °C, and maintain the temperature for 12 h. The reaction is considered complete when the total content of P7 and P8 is <1% and the content of P9 is ≥70%. Lower the temperature to 25 °C and add 1100 g of sodium carbonate dropwise. The pH was adjusted to 8.5 with 32wt% alkali and 1100g deionized water, then 26g activated carbon was added. The mixture was stirred at room temperature for 70min, filtered, and the filtrate was collected. 1.75kg methyl ether was added to the filtrate, and the mixture was stirred for 35min. After standing for 35min, the layers separated, and the aqueous phase was collected. Concentrated hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 4.0. The mixture was then filtered and dried at 55℃ to constant weight to obtain 4-(5-nitropyridin-2-yl)butyric acid.

[0031] S3: Add 1540g of dichloromethane and 250g of 4-(5-nitropyridin-2-yl)butyric acid to a reaction flask, stir and cool to 5℃, then add 190.2g of... N,N'-carbonyldiimidazole was slowly heated to 22.5℃ and reacted for 3.5 h. Then 128 g of aminoacetaldehyde dimethyl acetal was added, and the temperature was slowly raised to 32.5℃ and reacted for another 2.5 h. The mixture was washed three times with alkaline aqueous solution, then 14 g of activated carbon was added, and the mixture was stirred for 35 min. The mixture was filtered, and the filtrate was collected. The mixture was then washed twice with alkaline aqueous solution, and 700 g of deionized water was added. The mixture was allowed to stand for 35 min to separate into layers, and the lower organic layer was collected. 110 g of anhydrous magnesium sulfate was added, and the mixture was stirred for 35 min. The purity was measured to be ≥95% and the moisture content ≤0.20%. The mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was collected, and the organic layer was distilled under normal pressure and then under reduced pressure to obtain N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide.

[0032] The specific procedure for washing with alkaline aqueous solution is as follows: add 1200g of 10wt% glacial acetic acid solution, stir for 30min, let stand for 30min, separate into layers, and collect the lower organic layer.

[0033] S4: Add 285g of phosphorus pentoxide and 2.75kg of methanesulfonic acid to a reaction flask. Under nitrogen protection, stir and heat to 82.5℃. After stirring until dissolved, add 650mL of dichloromethane solution containing 190g of N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide. Heat to 135℃ and keep the reaction at this temperature for 4.5h. Then cool to 27.5℃ and slowly add to 2.8kg of deionized water cooled to 5℃ to quench. Rinse the reaction flask with 950mL of ice water at room temperature, then add liquid alkali to adjust the pH to 8.0. Filter and dry under vacuum at 55℃ to constant weight to obtain crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole.

[0034] S5: 105g of crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole and 650g of ethyl acetate were added to a reaction flask and stirred at 35°C to dissolve. Then 7.5g of activated carbon was added and stirred for 1.5h. The mixture was washed with 250g of 5wt% sodium bicarbonate solution, and the lower aqueous layer was separated. Then 250g of deionized water was added, washed, and the lower aqueous layer was separated. The mixture was concentrated under reduced pressure to 87.5g of organic layer. 250g of ethanol was added and the mixture was heated to clear. The mixture was cooled to -2.5°C to crystallize. The crystals were filtered and dried under reduced pressure at 55°C to obtain 2-(3-(5-nitropyridin-2-yl)propyl)oxazole.

[0035] S6: 45g of 2-(3-(5-nitropyridin-2-yl)propyl)oxazole, 250g of methanol, and 0.9g of 5% palladium on carbon catalyst were added to a reactor. The gas inside the reactor was replaced four times with hydrogen at a pressure of 0.3MPa. The reactor was stirred at 50℃ and 0.5MPa hydrogen pressure, and the hydrogen absorption reaction was carried out while maintaining the hydrogen pressure at 0.3MPa. The reaction was kept at the same temperature and pressure until no more hydrogen was absorbed. The temperature was then maintained for 2.5h, cooled to room temperature, and the hydrogen pressure inside the reactor was released. The product was discharged, the reaction solution was filtered, and Pd / C was removed. A methanol solution of 1,5-naphthalenedisulfonic acid tetrahydrate was added dropwise at -5℃ for 2.2h, and the mixture was stirred for 1.5h. The mixture was then filtered and dried under vacuum at 55℃ to constant weight to obtain the proxalutamide intermediate.

[0036] The 1,5-naphthalenedisulfonic acid tetrahydrate methanol solution was prepared by mixing 28.9 g of 1,5-naphthalenedisulfonic acid tetrahydrate and 80 g of methanol.

[0037] Example 3: Example 1: A method for efficiently synthesizing proxalutamide intermediates, comprising the following steps: S1: Add 4.4 kg of N,N-dimethylformamide to a reaction flask. Under nitrogen protection, add 2.2 kg of dimethyl malonate, 2.812 kg of potassium carbonate, and 1.4 kg of 2-chloro-5-nitropyridine. Stir and heat to 50 °C, and maintain the temperature for 14 h. Take a sample for HPLC control. After the reaction is complete, filter and wash the filter cake with 1.4 kg of N,N-dimethylformamide. Collect the filtrate, adjust the pH to 6 with dilute hydrochloric acid, filter, and dry at 60 °C to constant weight to obtain dimethyl 2-(5-nitropyridine-2-yl)malonate.

[0038] S2: Add 2.32 kg of methanol to a reaction flask. Under nitrogen protection, add 328 g of tert-butyl acrylate, 490 g of dimethyl 2-(5-nitropyridin-2-yl)malonate, and 26 g of sodium carbonate. Stir and heat to 62 °C under slight reflux, and maintain the reaction temperature for 6 h. When the content of dimethyl 2-(5-nitropyridin-2-yl)malonate is ≤1% and the total content of P7 and P8 is ≥70%, the reaction is considered complete. Adjust the pH to 6 with 200 g of 3 mol / L hydrochloric acid solution. Concentrate the methanol to dryness under reduced pressure, then add 3 kg of 3 mol / L hydrochloric acid solution. Heat to 75 °C and maintain the reaction temperature for 12 h. When the total content of P7 and P8 is <1% and the content of P9 is ≥70%, the reaction is considered complete. Reduce the temperature to 30 °C and add 1150 g of sodium carbonate dropwise. The pH was adjusted to 9 with 32wt% alkali and 1150g deionized water, and then 29g activated carbon was added. The mixture was stirred at room temperature for 80min, filtered, and the filtrate was collected. 2kg methyl ether was added to the filtrate, and the mixture was stirred for 40min. After standing for 40min, the layers separated, and the aqueous phase was collected. Concentrated hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 4.2. The mixture was then filtered and dried at 60℃ to constant weight to obtain 4-(5-nitropyridin-2-yl)butyric acid.

[0039] S3: Add 1640g of dichloromethane and 260g of 4-(5-nitropyridin-2-yl)butyric acid to a reaction flask, stir and cool to 10℃, then add 195.2g of... N,N'-carbonyldiimidazole was slowly heated to 25°C and reacted for 4 hours. Then, 130g of aminoacetaldehyde dimethyl acetal was added, and the temperature was slowly increased to 35°C and reacted for another 3 hours. The mixture was washed four times with alkaline aqueous solution, then 16g of activated carbon was added, and the mixture was stirred for 40 minutes. The mixture was filtered, and the filtrate was collected. The mixture was then washed three times with alkaline aqueous solution, and 800g of deionized water was added. The mixture was allowed to stand for 40 minutes to separate into layers. The lower organic layer was collected, and 120g of anhydrous magnesium sulfate was added. The mixture was stirred for 40 minutes. A sample was taken to test the purity (≥95%) and moisture content (≤0.20%). The mixture was filtered, and the filter cake was washed with dichloromethane. The filtrate was collected, and the organic layer was distilled under normal pressure and then under reduced pressure to obtain N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide.

[0040] The specific procedure for washing with alkaline aqueous solution is as follows: add 1200g of 10wt% glacial acetic acid solution, stir for 30min, let stand for 30min, separate into layers, and collect the lower organic layer.

[0041] S4: Add 300g of phosphorus pentoxide and 2.8kg of methanesulfonic acid to a reaction flask. Under nitrogen protection, stir and heat to 85℃. After stirring until dissolved, add 700mL of dichloromethane solution containing 200g of N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide. Heat to 140℃ and keep the reaction at this temperature for 5h. Then cool to 35℃ and slowly add to 2.9kg of deionized water cooled to 10℃ to quench the reaction. At room temperature, rinse the reaction flask with 1000mL of ice water and then add liquid alkali to adjust the pH to 8.5. Filter and dry under vacuum at 60℃ to constant weight to obtain crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole.

[0042] S5: 110g of crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole and 700g of ethyl acetate were added to a reaction flask and stirred at 40℃ to dissolve. Then 10g of activated carbon was added and stirred for 2h. The mixture was washed with 300g of 5wt% sodium bicarbonate solution, and the lower aqueous layer was separated. Then 300g of deionized water was added, and the mixture was washed again and the lower aqueous layer was separated. The mixture was concentrated under reduced pressure to 90g of organic layer. 300g of ethanol was added and the mixture was heated to clear the solution. The mixture was cooled to 0℃ to crystallize. The crystals were filtered and dried under reduced pressure at 60℃ to obtain 2-(3-(5-nitropyridin-2-yl)propyl)oxazole.

[0043] S6: Add 50g of 2-(3-(5-nitropyridin-2-yl)propyl)oxazole, 260g of methanol, and 1g of 5% palladium on carbon catalyst to a reactor. Replace the gas in the reactor with hydrogen at a pressure of 0.4MPa five times. At 55℃ and a hydrogen pressure of 0.6MPa, start stirring and maintain the hydrogen pressure at 0.4MPa for hydrogen absorption reaction. After the reaction stops absorbing hydrogen, continue to maintain the temperature for 3 hours, cool to room temperature, release the hydrogen pressure in the reactor, discharge the material, filter the reaction solution, filter out Pd / C, add 1,5-naphthalenedisulfonic acid tetrahydrate methanol solution dropwise at 0℃ for 2.4 hours, keep warm and stir for 2 hours, filter, and dry under vacuum at 60℃ to constant weight to obtain proxalutamide intermediate.

[0044] The 1,5-naphthalenedisulfonic acid tetrahydrate methanol solution was prepared by mixing 28.9 g of 1,5-naphthalenedisulfonic acid tetrahydrate and 80 g of methanol.

[0045] In Examples 1-3, the activated carbon was selected from Gongyi Shengxing Water Purification Materials Factory, with a mesh size of 325 and an iodine value of 400-1300 mg / g; the 5% palladium on carbon catalyst was selected from Wuhan Lanabai Pharmaceutical Chemical Co., Ltd., with CAS number 7440-05-3; the remaining raw materials were all commercially available products.

[0046] Comparative Example 1: The difference from Example 1 is that step S3 is changed to coupling 4-(5-nitropyridin-2-yl)butyric acid with aminoacetaldehyde dimethyl acetal in N,N-dimethylformamide at 150°C using cuprous iodide as a catalyst. The crude product obtained is used without purification to replace N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butamide in the original step S4. The remaining steps remain unchanged to prepare the proxalutamide intermediate.

[0047] Comparative Example 2: The difference from Example 1 is that 2-chloro-5-nitro-3-iodopyridine was used instead of 2-chloro-5-nitropyridine in step S1 of Example 1 as the starting material. The corresponding iodobutyramide derivative was prepared according to the method of steps S1 to S3 of Example 1. In step S4, the phosphorus pentoxide / methanesulfonic acid system was not used. Instead, intramolecular coupling cyclization was carried out at 150°C under the catalysis of cuprous iodide. Then, the crude cyclized product obtained in this step was used directly in step S6 without purification in step S5. The remaining steps remained unchanged to prepare the proxalutamide intermediate.

[0048] Comparative Example 3: The difference from Example 1 is that the crude amide obtained in Comparative Example 1 was used and its corresponding intermediate purification step was skipped, while the other steps remained unchanged to prepare the proxalutamide intermediate.

[0049] Comparative Example 4: The difference from Example 1 is that the crude oxazole compound obtained in Comparative Example 2 was used and its corresponding intermediate purification step was skipped, while the other steps remained unchanged to prepare the proxalutamide intermediate.

[0050] The proxalutamide intermediates prepared in Examples 1-3 and Comparative Examples 1-3 were subjected to high performance liquid chromatography, atomic absorption spectrometry, and molar yield calculations. The results are shown in Table 1. Table 1 Performance test results of proxalutamide intermediate As can be seen from Table 1, the final product of the proxalutamide intermediate prepared in Examples 1-3 has significantly better HPLC purity and total yield than that of Comparative Examples 1-4, and the copper residue is much lower than that of the comparative examples.

[0051] The HPLC purity and overall yield of the final product in Comparative Example 1 decreased significantly, and copper residue was severe. This may be due to the replacement of the mild and highly selective "CDI activation / condensation" system in step S3 with a "high-temperature copper-catalyzed CN coupling" system. Under high temperature of 150℃ and copper catalysis, the formation efficiency of the target amide bond was low, and the Ullmann self-coupling side reaction became dominant, generating difficult-to-separate dimer impurities. Furthermore, the high temperature may cause the nitropyridine structure to decompose or be reduced. In addition, the crude product was used directly in subsequent steps without purification, resulting in the introduction of the above-mentioned by-products and the heavy metal copper catalyst itself as impurities that run through the entire synthetic route and cannot be removed in post-processing.

[0052] In Comparative Example 2, the final product showed a significant decrease in HPLC purity and overall yield, with the highest copper residue. This may be due to the combination of "iodinated substrate" and "high-temperature copper-catalyzed cyclization." Under copper catalysis, the more reactive carbon-iodine bond readily undergoes reductive deiodination. This side reaction fiercely competes with the target cyclization reaction, generating a large amount of dehalogenated impurities. High-temperature conditions also exacerbate intermolecular Ullmann coupling, forming polymeric byproducts. Compared to the specific acid-catalyzed cyclization mechanism provided by the phosphorus pentoxide / methanesulfonic acid system in Example 1, the copper catalytic pathway is chaotic because this route generates a complex mixture of impurities from the source, which cannot be purified even with subsequent reduction.

[0053] The purity and yield of the final product in Comparative Example 3 were still low and the copper residue exceeded the standard. This may be because the crude amide obtained in Comparative Example 1, which was already contaminated by copper catalytic side reactions, was used directly, and the corresponding fine post-processing and purification steps in the examples were skipped. This caused all the Ullman coupling impurities, copper complexes and other byproducts generated in the early stage to be directly carried into the subsequent S4 cyclization and S6 reduction to salt steps. These impurities are chemically stable under the subsequent reaction conditions and are difficult to convert or remove. In the end, they remain in the final product in almost a quantitative manner, resulting in quality deterioration.

[0054] The purity and yield of the final product in Comparative Example 4 were significantly poor, and there was a large amount of copper residue. This may be because the crude oxazole compound prepared in Comparative Example 2 contained severe deiodination and coupling impurities, and the crucial recrystallization purification step was skipped. Step S5 recrystallization is a decisive purification node for removing structurally similar impurities, polymers, and inorganic salts generated in the ring-closing step. Skipping this step means that the extremely complex crude reaction product is directly hydrogenated and salted. The deiodination products and coupling byproducts generated in the early stage may remain unchanged or generate new impurities under hydrogenation conditions, and all of them will eventually enter the final product.

[0055] 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 variations can be made to these embodiments without departing from the principles and spirit of the invention.

Claims

1. A method for efficiently synthesizing proxalutamide intermediates, characterized in that, Includes the following steps: Step 1: Using dimethyl malonate and 2-chloro-5-nitropyridine as raw materials, condense them in the presence of potassium carbonate to generate dimethyl 2-(5-nitropyridine-2-yl)malonate, which then reacts with tert-butyl acrylate and is acid-hydrolyzed to obtain 4-(5-nitropyridine-2-yl)butyric acid. Step 2: 4-(5-nitropyridin-2-yl)butyric acid is activated with N,N'-carbonyldiimidazole and then coupled with aminoacetaldehyde dimethyl acetal to form N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide; Step 3: Then, phosphorus pentoxide and methanesulfonic acid mediate a cyclization reaction to promote the formation of crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole from N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide. After purification, the nitro group is reduced by catalytic hydrogenation, and finally reacted with 1,5-naphthalenedisulfonic acid to form a salt, yielding the proxalutamide intermediate.

2. The method for efficiently synthesizing proxalutamide intermediate according to claim 1, characterized in that, The specific preparation steps for the dimethyl 2-(5-nitropyridin-2-yl)malonate are as follows: N,N-dimethylformamide was added to a reaction flask. Under nitrogen protection, dimethyl malonate, potassium carbonate, and 2-chloro-5-nitropyridine were added. The mixture was stirred and heated to 40-50°C, and the reaction was maintained at this temperature for 12-14 hours. The mixture was then filtered, and the filter cake was washed with N,N-dimethylformamide. The filtrate was collected, and the pH was adjusted to 5-6 with dilute hydrochloric acid. The mixture was then filtered and dried under vacuum to constant weight to obtain dimethyl 2-(5-nitropyridine-2-yl)malonate. The mass ratio of N,N-dimethylformamide, dimethyl malonate, potassium carbonate, and 2-chloro-5-nitropyridine is 5.4-5.8:2-2.2:2.612-2.812:1.2-1.

4.

3. The method for efficiently synthesizing proxalutamide intermediate according to claim 1, characterized in that, The specific preparation steps for the 4-(5-nitropyridin-2-yl)butyric acid are as follows: Methanol was added to a reaction flask. Under nitrogen protection, tert-butyl acrylate, dimethyl 2-(5-nitropyridin-2-yl)malonate, and sodium carbonate were added. The mixture was stirred and heated to 58-62°C under slight reflux for 5-6 hours. The pH was adjusted to 5-6 with hydrochloric acid solution. The methanol was concentrated to dryness under reduced pressure. Then, 3 mol / L hydrochloric acid solution was added, and the temperature was raised to 65-75°C for 12 hours. The temperature was lowered to 20-30°C, and 32 wt% liquid alkali and deionized water were added dropwise to adjust the pH to 8-9. Activated carbon was added, and the mixture was stirred at room temperature for 60-80 minutes. The mixture was filtered, and the filtrate was collected. Methyl tert-butyl ether was added to the filtrate, and the mixture was stirred for 30-40 minutes. The mixture was allowed to stand for 30-40 minutes to separate into layers. The aqueous phase was collected, and concentrated hydrochloric acid was added dropwise to adjust the pH of the reaction solution to 3.8-4.

2. The mixture was filtered and dried under vacuum to constant weight to obtain 4-(5-nitropyridin-2-yl)butyric acid.

4. The method for efficiently synthesizing proxalutamide intermediate according to claim 3, characterized in that, The mass ratio of methanol, tert-butyl acrylate, dimethyl 2-(5-nitropyridin-2-yl)malonate, sodium carbonate, 3 mol / L hydrochloric acid solution, activated carbon, and methyl tert-butyl ether is 2.12-2.32:0.308-0.328:0.47-0.49:0.022-0.026:2.8-3:0.023-0.029:1.5-2.

5. The method for efficiently synthesizing proxalutamide intermediate according to claim 1, characterized in that, The specific preparation steps for the N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide are as follows: Dichloromethane and 4-(5-nitropyridin-2-yl)butyric acid were added to a reaction flask, stirred, and cooled to 0-10℃. N,N'-carbonyldiimidazole was added, the temperature was slowly increased, and the reaction was maintained for 3-4 hours. Then, aminoacetaldehyde dimethyl acetal was added, the temperature was slowly increased, and the reaction was maintained for 2-3 hours. The mixture was washed with an alkaline aqueous solution, activated carbon was added, and the mixture was stirred, filtered, and the filtrate was collected. The mixture was then washed with an alkaline aqueous solution, deionized water was added, and the mixture was allowed to stand for separation. The lower organic layer was collected, anhydrous magnesium sulfate was added, the mixture was stirred, filtered, and the filter cake was washed with dichloromethane. The filtrate was collected, the organic layer was distilled under normal pressure, and then distilled under reduced pressure to obtain N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide.

6. The method for efficiently synthesizing proxalutamide intermediate according to claim 5, characterized in that, The mass ratio of dichloromethane, 4-(5-nitropyridin-2-yl)butyric acid, N,N'-carbonyldiimidazole, aminoacetaldehyde dimethyl acetal, activated carbon, deionized water, and anhydrous magnesium sulfate is 1440-1640:240-260:185.2-195.2:126-130:12-16:600-800:100-120.

7. The method for efficiently synthesizing proxalutamide intermediate according to claim 1, characterized in that, The specific preparation steps for the crude product 2-(3-(5-nitropyridin-2-yl)propyl)oxazole are as follows: Phosphorus pentoxide and methanesulfonic acid were added to a reaction flask. Under nitrogen protection, the mixture was stirred and heated to 80-85°C. After stirring until the solution was clear, a dichloromethane solution containing N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide was added. The mixture was heated to 130-140°C and kept at this temperature for 4-5 hours. Then, the temperature was lowered to 20-35°C, and the mixture was slowly quenched in deionized water at 0-10°C. The reaction flask was rinsed with ice water at room temperature, and then liquid alkali was added dropwise to adjust the pH to 7.5-8.

5. The mixture was then filtered and dried under vacuum to constant weight to obtain crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole. The ratio of phosphorus pentoxide, methanesulfonic acid, N-(2,2-dimethoxyethyl)-4-(5-nitropyridin-2-yl)butyramide, dichloromethane solution, deionized water, and ice water is 270-300g: 2.7-2.8kg: 180-200g: 600-700mL: 2.7-2.9kg: 900-1000mL.

8. The method for efficiently synthesizing proxalutamide intermediate according to claim 1, characterized in that, The specific preparation steps of the proxalutamide intermediate are as follows: 2-(3-(5-nitropyridin-2-yl)propyl)oxazole, methanol, and 5% palladium on carbon catalyst were added to a reactor. The gas inside the reactor was replaced 3-5 times with hydrogen pressure of 0.2-0.4 MPa. The reactor was stirred at 45-55℃ and hydrogen pressure of 0.4-0.6 MPa to carry out the hydrogen absorption reaction. The reaction was maintained at 0.2-0.4 MPa until no more hydrogen was absorbed. The temperature was maintained for 2-3 hours, and the temperature was lowered to room temperature. The hydrogen pressure inside the reactor was released, the product was discharged, the reaction solution was filtered to remove Pd / C, and 1,5-naphthalenedisulfonic acid tetrahydrate methanol solution was added dropwise at -10-0℃ for 2-2.4 hours. The mixture was stirred for 1-2 hours, filtered, and vacuum dried to constant weight to obtain proxalutamide intermediate.

9. The method for efficiently synthesizing a proxalutamide intermediate according to claim 8, characterized in that, The mass ratio of the 2-(3-(5-nitropyridin-2-yl)propyl)oxazole, methanol and 5% palladium on carbon catalyst is 40-50:240-260:0.8-1.

10. The method for efficiently synthesizing proxalutamide intermediates according to claim 8, characterized in that, The specific preparation steps for 2-(3-(5-nitropyridin-2-yl)propyl)oxazole are as follows: Crude 2-(3-(5-nitropyridin-2-yl)propyl)oxazole and ethyl acetate were added to a reaction flask and stirred at 30-40℃ to dissolve. Activated carbon was then added and stirred for 1-2 hours. The mixture was washed with 5wt% sodium bicarbonate solution, and the lower aqueous layer was separated. Deionized water was added, and the mixture was washed again and the lower aqueous layer was separated. The organic layer was concentrated under reduced pressure, and ethanol was added and heated until the solution was clear. The mixture was then cooled to -5-0℃ to induce crystallization. The crystals were filtered and dried under reduced pressure at 50-60℃ to obtain 2-(3-(5-nitropyridin-2-yl)propyl)oxazole. The crude product, 2-(3-(5-nitropyridin-2-yl)propyl)oxazole, ethyl acetate, activated carbon, 5wt% sodium bicarbonate solution, deionized water, organic layer, and ethanol are present in a mass ratio of 100-110:600-700:5-10:200-300:200-300:85-90:200-300.

Images