A new process for the preparation of an intermediate of ibrexafacerpt

Abstract

The application discloses a new preparation method of an intermediate of imatinib, and relates to the technical fields of medicines and chemical industry. The intermediate of imatinib, i.e. a-amino-2-methoxy-4-methanesulfonamido-5-phenoxyphenylacetophenone, is synthesized by taking 3-methanesulfonamido-4-phenoxyanisole and chloroacetyl chloride as raw materials, perfluoro-tert-butyl alcohol as a solvent, and D72 strong-acid macroporous resin as a catalyst, and then reacting with ammonia after a-chloro-2-methoxy-4-methanesulfonamido-5-phenoxyphenylacetophenone is synthesized. The application greatly improves the yield and purity, overcomes the shortcomings of the prior art in safety production, environmental protection and clean production, has a simple route, high reaction safety, convenient post-treatment, and effectively reduces the production cost, and is suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the fields of pharmaceuticals and chemical engineering, and more specifically, to a novel method for preparing an aramod intermediate, namely α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone. Background Technology

[0002] Iguratimod is a nonsteroidal anti-inflammatory drug (NSAID) with the chemical name 3-formamido-7-methanesulfonamido-6-phenoxy-4H-1-benzopyran-4-one (CAS Registry Number: 123663-49-0). It is a novel disease-modifying drug (DMARD) jointly developed by Toyama Pharmaceutical Co., Ltd. and Eisai Pharmaceutical Co., Ltd. of Japan, and is generally used to treat rheumatoid arthritis (RA) and osteoarthritis (OA). α-Amino-2-methoxy-4-methanesulfonamido-5-phenoxyacetophenone is a key intermediate in the synthesis of igraatimod.

[0003] Traditional methods, such as the "Research on the Synthetic Process of Ailamod (T-614)" in Volume 14, Issue 3 of Jiangsu Pharmaceutical and Clinical Research in 2006, and the "Research on the Synthesis of Ailamod" in Volume 15, Issue 23 of Chinese Journal of New Drugs in 2006, disclose the preparation methods of α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone. These methods use 3-methanesulfonamide-4-phenoxyanisole and aminoacetonitrile hydrochloride as raw materials, aluminum trichloride as catalyst, nitrobenzene as solvent, and hydrogen chloride to carry out the Geitmann-Koch reaction, followed by hydrolysis in dilute hydrochloric acid solution. However, this method not only has a low yield, but also has many problems: First, it uses a large amount of aluminum trichloride and hydrogen chloride gas, which will generate a large amount of aluminum-containing acidic wastewater that is difficult to recycle, resulting in high production costs and serious environmental pollution; Second, nitrobenzene vapor mixed with air at temperatures above 80°C is explosive and is a highly toxic and explosive compound, posing a high safety risk to the reaction and causing great harm to the human body. Furthermore, using nitrobenzene as a solvent makes the reaction liquid viscous and difficult to centrifuge during post-processing, which is not conducive to the subsequent processing of the product and affects the final purity.

[0004] Existing technologies for the preparation of α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone, such as patent application CN107162942A (the method for preparing intermediate IV of Ailamod), all utilize nitromethane instead of nitrobenzene as the solvent for preparing α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone. This reduces environmental pollution and harm to human health to some extent, and improves product yield and purity. However, the reaction safety in existing technologies remains generally poor. For example, nitromethane is still an explosive compound. Furthermore, existing technologies still suffer from difficulties in recycling and high production costs due to the use of large amounts of aluminum trichloride and hydrogen chloride gas, hindering industrial application and offering limited improvement in environmental pollution.

[0005] Therefore, a new technical solution is needed to solve the above-mentioned technical problems. Summary of the Invention

[0006] The purpose of this invention is to provide a novel method for preparing the intermediate of aramod, namely α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone, to solve the technical problems mentioned in the background art, which, while improving yield and purity, still have general reaction safety, are difficult to recycle and reuse, have high production costs, are not conducive to industrial promotion and application, and have limited improvement on environmental pollution.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] A novel method for preparing an aramod intermediate involves using 3-methanesulfonamide-4-phenoxyanisole and chloroacetyl chloride as raw materials, perfluorotert-butanol as solvent, and D72 strong acid macroporous resin as catalyst at 0–20°C to synthesize α-chloro-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone. Following this synthesis, the intermediate is refluxed with ammonia to obtain the aramod intermediate, α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone. The reaction equation for this novel method is as follows:

[0009] , .

[0010] Furthermore, the reflux time is 5 to 10 hours, the mass ratio of 3-methanesulfonyl-4-phenoxyanisole to perfluorotert-butanol is 1:8.0 to 12, the molar ratio of 3-methanesulfonyl-4-phenoxyanisole to chloroacetyl chloride is 1:1.1 to 1.3, the mass ratio of 3-methanesulfonyl-4-phenoxyanisole to D72 strong acid macroporous resin is 1:0.01 to 0.05, and the mass ratio of 3-methanesulfonyl-4-phenoxyanisole to 10% ammonia in ethanol solvent is 1:5 to 10.

[0011] Compared with the prior art, the beneficial effects of the present invention are:

[0012] 1. This invention uses 3-methanesulfonamide-4-phenoxyanisole and chloroacetyl chloride as raw materials, perfluorotert-butanol as solvent, and D72 strong acid macroporous resin as catalyst to synthesize α-chloro-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone. α-chloro-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone is then reacted with ammonia to obtain α-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone. Throughout the process, chloroacetyl chloride is used to replace aminoacetonitrile hydrochloride in the Friedel-Crafts reaction, perfluorotert-butanol is used to replace nitrobenzene and nitromethane as solvent, and D72 strong acid macroporous resin is used as catalyst. This significantly improves the yield and purity while overcoming the shortcomings of existing processes in terms of safe production, environmental protection, and clean production. The route is simple, the reaction is highly safe, post-processing is convenient, and production costs are effectively reduced, making it suitable for large-scale production.

[0013] 2. In this invention, before the reaction of α-chloro-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone with ammonia, the catalyst D72 strong acid macroporous resin can be filtered out by conventional filtration. Then, the solvent perfluorotert-butanol can be evaporated out by atmospheric pressure. This makes the overall process simpler, the post-processing simpler, and facilitates the recycling of catalyst and solvent, further reducing production costs. Detailed Implementation

[0014] The following examples are used to further illustrate the content of the present invention and do not limit the application of the present invention. Example 1

[0015] 15g of 3-methanesulfonamide-4-phenoxyanisole, 180g of perfluorotert-butanol, and 0.8g of D72 strong acid macroporous resin were added to a 250ml tetrafluoro reaction flask. Under nitrogen protection, 7.4g of chloroacetyl chloride was slowly added dropwise at 0℃, with the addition completed in 1 hour. The reaction continued for 10 hours. The catalyst was filtered out, and the perfluorotert-butanol was distilled off from the filtrate under normal pressure. Then, 150g of 10% ammonia in ethanol solvent was added, and the mixture was refluxed for 5 hours. The solution was cooled to 0℃, filtered, and the resulting solid was dried under vacuum at 60℃ for 5 hours to obtain 16.7ga-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone with a purity of 98.3%, a yield of 95.4%, and a melting point of 167-169℃.

[0016] 1¹H NMR (CDCl₃, 500 MHz) 3.07 (3H, s, CH₃SO₂), 3.97 (3H, s, aromatic hydrogen), 4.30 (2H, d, COCH₂), 6.95-7.33 (5H, m, aromatic hydrogen), 7.39-7.54 (2H, s, aromatic hydrogen), 8.65 (2H, s, NH₂), 9.24 (1H, s, SO₂NH). Example 2

[0017] 15g of 3-methanesulfonamide-4-phenoxyanisole, 120g of perfluorotert-butanol, and 0.2g of D72 strong acid macroporous resin were added to a 250ml tetrafluoro flask. Under nitrogen protection, 6.2g of chloroacetyl chloride was slowly added dropwise at 0℃, with the addition completed in 1 hour. The reaction continued for 5 hours. The catalyst was filtered out, and the perfluorotert-butanol was distilled off from the filtrate under normal pressure. Then, 75g of 10% ammonia in ethanol solvent was added, and the mixture was refluxed for 5 hours. The solution was cooled to 0℃, filtered, and the resulting solid was dried under vacuum at 60℃ for 5 hours to obtain 16.6ga-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone with a purity of 98.5%, a yield of 95%, and a melting point of 167-169℃. Example 3

[0018] 15g of 3-methanesulfonamide-4-phenoxyanisole, 150g of perfluorotert-butanol, and 0.4g of D72 strong acid macroporous resin were added to a 250ml tetrafluoromethane reaction flask. Under nitrogen protection, 6.8g of chloroacetyl chloride was slowly added dropwise at 0℃, with the addition completed in 1 hour. The reaction continued for 10 hours. The catalyst was filtered out, and the perfluorotert-butanol was distilled off from the filtrate under normal pressure. Then, 112g of 10% ammonia in ethanol solvent was added, and the mixture was refluxed for 7.5 hours. The solution was cooled to 0℃, filtered, and the resulting solid was dried under vacuum at 60℃ for 5 hours to obtain 16.9ga-amino-2-methoxy-4-methanesulfonamide-5-phenoxyacetophenone with a purity of 98.9%, a yield of 96.6%, and a melting point of 167-169℃.

Claims

1. A method for preparing an ellamod intermediate, characterized in that, At 0–20°C, using 3-methanesulfonyl-4-phenoxyanisole and chloroacetyl chloride as raw materials, perfluorotert-butanol as solvent, and D72 strong acid macroporous resin as catalyst, α-chloro-2-methoxy-4-methanesulfonyl-5-phenoxyacetophenone was synthesized. The resulting product was then refluxed with 10% ammonia in ethanol solvent for 5–10 hours to obtain the α-amino-2-methoxy-4-methanesulfonyl-5-phenoxyacetophenone intermediate. The mass ratio of amino-4-phenoxyanisole to perfluorotert-butanol is 1:8.0-12; the molar ratio of 3-methanesulfonamide-4-phenoxyanisole to chloroacetyl chloride is 1:1.1-1.3; the mass ratio of 3-methanesulfonamide-4-phenoxyanisole to D72 strong acid macroporous resin is 1:0.01-0.05; and the mass ratio of 3-methanesulfonamide-4-phenoxyanisole to 10% ammonia in ethanol solvent is 1:5-10. The reaction equation is as follows: 。

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