A synthetic method of iguratimod

Abstract

The present invention discloses a new preparation method of iguratimod. The method uses N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide and N-phthaloylglycyl chloride as raw materials, and obtains iguratimod through acylation, demethylation, cyclization, deprotection and formylation. This method has a high yield, the intermediates are easy to separate and purify, and the final product obtained has a high purity and a high yield.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a preparation method of the drug Iguratimod. Background Art

[0002] Iguratimod is a new disease-modifying anti-rheumatic drug jointly developed by Toyama Chemical Co., Ltd. and Eisai Co., Ltd. in Japan for the treatment of rheumatoid arthritis and osteoarthritis. Its characteristic is that it has a rapid onset compared with other drugs, and its efficacy is equivalent to that of high-potency anti-rheumatic drugs, but it has lower toxicity.

[0003] Iguratimod was originally developed by Toyama Chemical in Japan as a new drug for the treatment of rheumatoid arthritis and osteoarthritis. Subsequently, Toyama Chemical and Eisai Co., Ltd. conducted clinical trial development and commercialization of Iguratimod. They submitted a marketing application in Japan in 2003 and obtained approval from the PMDA for marketing in August 2012. Subsequently, the patent WO1994023714A1 applied by Toyama Chemical in 1994 first related to the treatment of rheumatoid arthritis with Iguratimod, and this patent was authorized in countries or regions such as Japan, Europe, and the United States. On January 11, 2008, Simcere Pharmaceutical Group completed clinical research and submitted an NDA to the National Medical Products Administration. On August 23, 2011, Iguratimod tablets were approved for marketing by the NMPA under the trade name Aidixin for the treatment of active rheumatoid arthritis. Since 2017, it has successively been included in the medical insurance in various places and entered the national Class B medical insurance catalog in 2019.

[0004] The chemical name of Iguratimod is N-[3-(formamido)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]methanesulfonamide. There are two main synthetic methods reported in the literature, which are described in detail in Chemical and Pharmaceutical Bulletin, 2000, vol. 48. The first one is to use N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide (Compound 1) as an intermediate and obtain Iguratimod through six steps of reactions including acetylation, cyclization, hydrogenation, bromination, azidation, and formylation. This method has a long route, high production cost, and uses sodium azide, a reagent with potential safety hazards, and is not suitable for industrial production.

[0005] Article 2 also uses N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide (Compound 1) as an intermediate, and obtains iguratimod through four steps of acylation, formylation, demethylation, and cyclization. This method is the current mainstream production method, but there are the following three problems with this method. First, in this route, the acylation reaction step requires the use of nitrobenzene and nitromethane to achieve a better yield of this reaction. Due to the high toxicity of nitrobenzene and nitromethane, it poses a very great threat to the environment and personnel. Second, aluminum trichloride is used twice in this route, and this compound also causes great environmental pollution. Third, the yield in this route is not high, resulting in low economic value. Summary of the Invention

[0006] To solve the above problems, the inventors of the present invention have developed a method with high conversion rate, high purity, and suitable for industrial production to prepare iguratimod. The selectivity of the reaction is improved, the conversion rate is increased, the obtained product has high purity, and it is more conducive to industrial production. Specifically, it includes the following steps:

[0007] 1) Compound 1 and N-phthaloylglycyl chloride (Compound 2) are condensed in dichloromethane under the catalysis of ferric trichloride to obtain Compound 3;

[0008] 2) Compound 3 reacts with aluminum trichloride and sodium iodide in a solvent to remove the methyl group to obtain Compound 4;

[0009] 3) Compound 4 reacts with triethyl orthoformate to cyclize to obtain Compound 5;

[0010] 4) Compound 5 reacts with aqueous methylamine solution to remove the dibenzoyl protecting group to obtain Compound 6;

[0011] 5) Compound 6 reacts with formic acid and acetic anhydride to obtain iguratimod.

[0012] Compared with the prior art, the present invention avoids the use of nitrobenzene or nitromethane, reduces the dosage of aluminum trichloride, the intermediate is easily separated and purified, the yield of each step of the reaction is very high, and the purity is also very high, with high economic value.

[0013] Specific Embodiments

[0014] Add 30 g of N-(5-methoxy-2-phenoxyphenyl)methanesulfonamide and 200 ml of dichloroethane to a 500-ml three-necked flask, stir and dissolve until clear, then add 23 g of N-phthaloylglycyl chloride and 2.5 g of ferric trichloride, heat the reaction solution to 45 - 50 °C, and keep stirring for 5 - 6 hours. After the reaction is completed, cool the reaction solution to room temperature, add 200 ml of water for washing and separating layers, then wash the organic layer with 100 ml of water. Concentrate and evaporate the dichloroethane layer to dryness, add 150 ml of isopropyl ether to the residue and stir for crystallization, filter by suction, and dry at normal pressure at 60 - 70 °C to obtain 43.5 g of solid Compound 3.

[0015] Add 43 g of solid compound 3 and 200 ml of acetonitrile into a 500-ml three-necked flask, then add 30 g of sodium iodide. While stirring, maintain the internal temperature below 25°C and add 40 g of aluminum trichloride. Stir and react at an internal temperature of 15 - 25°C for 5 hours. After the reaction is completed, pour the reaction solution into 400 ml of water and stir for 1 hour. Filter by suction and dry at normal pressure at 60 - 70°C to obtain 31.1 g of solid compound 3.

[0016] Add 31 g of solid compound 3, 120 ml of trimethyl orthoformate and 5 ml of concentrated sulfuric acid into a 250-ml three-necked flask, heat to an internal temperature of 40 - 50°C and react for 3 hours. After the reaction is completed, pour the reaction solution into 350 ml of 5% sodium bicarbonate solution and stir for 1 hour. Filter by suction and dry at normal pressure at 60 - 70°C to obtain 32.2 g of solid compound 4.

[0017] Add 32 g of solid compound 4, 100 ml of methanol and 40% methylamine into a 250-ml three-necked flask, stir, and maintain the internal temperature at 40 - 50°C and react for 5 hours. After the reaction is completed, pour the reaction solution into 300 ml of clear water and stir for 1 hour. Filter by suction and dry at normal pressure at 60 - 70°C to obtain 25.6 g of solid compound 5.

[0018] Add 60 ml of anhydrous formic acid and 60 ml of acetic anhydride into a 250-ml three-necked flask, then heat the reaction solution to 40 - 45°C and react for 0.5 hour. Then add 25.0 g of solid 5 to the reaction solution, and then maintain the temperature at 40 - 45°C and react for 3 hours. After the reaction is completed, pour the reaction solution into 500 ml of clear water and stir for 1 hour. Filter by suction and dry at normal pressure at 60 - 70°C to obtain 22.5 g of solid iguratimod, with a content greater than 99.65%. mp 236 - 238°C.

Claims

1. A method for synthesizing iguratimod, characterized in that Using the following synthetic route, compound 1 and compound 2 undergo Friedel-Crafts acylation reaction to form compound 3, compound 3 is de-methylated to form compound 4, then compound 4 and triethyl orthoformate are cyclized to obtain compound 5, compound 5 is de-protected in aqueous methylamine solution to obtain compound 6, and finally compound 6 reacts with formic acid and acetic anhydride to prepare iguratimod: 。 2. The preparation method according to claim 1, characterized in that: This method specifically includes the following steps: 1) Compound 1 and compound 2 are condensed in dichloromethane under the catalysis of ferric chloride to obtain compound 3; 2) Compound 3 reacts with aluminum trichloride and sodium iodide in a solvent to remove the methyl group to obtain compound 4; 3) Compound 4 reacts with triethyl orthoformate to undergo cyclization to obtain compound 5; 4) Compound 5 reacts with aqueous methylamine solution to remove the dibenzoyl protecting group to obtain compound 6; 5) Compound 6 reacts with formic acid and acetic anhydride to obtain iguratimod.

3. The preparation method according to step 1 of claim 2, characterized in that: Using N-phthaloylglycyl chloride as the starting material and ferric chloride as the catalyst to react to obtain compound 3.

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