Method for producing 4-methoxypyrrole derivatives

Abstract

The present invention relates to a method for producing a 4-methoxypyrrole derivative. According to one embodiment of the present invention, the production time is reduced by half, and the process efficiency and yield are improved, which is useful for industrial mass production of 4-methoxypyrrole derivatives.

Description

[Technical Field]

[0001] [CROSS-REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of priority based on Korean Patent Application No. 10-2023-0020155, filed February 15, 2023, and all contents disclosed in the documents of said Korean patent application are incorporated herein by reference.

[0002] The present invention relates to a method for producing a 4-methoxypyrrole derivative. [Background technology]

[0003] Gastrointestinal ulcers, gastritis, and reflux esophagitis occur when the balance between attacking factors (e.g., gastric acid, Helicobacter pepsin, stress, alcohol, and tobacco) and defensive factors (e.g., gastric mucosa, bicarbonate, prostaglandins, blood supply, etc.) is disrupted. Therefore, treatments for gastrointestinal damage such as gastrointestinal ulcers, gastritis, and reflux esophagitis are divided into drugs that suppress attacking factors and drugs that strengthen defensive factors.

[0004] On the other hand, it has been reported that gastrointestinal ulcers, gastritis, and reflux esophagitis can develop even without increased gastric acid secretion, and that a decrease in defensive factors due to pathological changes in the gastrointestinal mucosa plays an equally important role in the development of gastric ulcers as an increase in aggressive factors. Therefore, in addition to drugs that suppress aggressive factors, drugs that strengthen defensive factors are used to treat gastrointestinal ulcers and gastritis. Known drugs that strengthen defensive factors include mucosal protectants that bind to the ulcer site to form a physicochemical membrane, and drugs that promote mucus synthesis and secretion.

[0005] Meanwhile, Helicobacter pylori, a bacterium present in the gastrointestinal tract, is known to cause chronic gastritis, gastric ulcers, and duodenal ulcers, and many patients with gastrointestinal damage are infected with Helicobacter pylori (H. pylori). Therefore, such patients must take antibiotics such as clarithromycin, amoxicillin, metronidazole, and tetracycline along with antiulcer drugs such as proton pump inhibitors and gastric acid pump antagonists, which has led to various reported side effects.

[0006] Therefore, there is a need in the art for the development of anti-ulcer drugs that simultaneously inhibit gastric acid secretion (e.g., proton pump inhibitory activity), enhance defense factors (e.g., increase mucus secretion), and eradicate Helicobacter pylori (H. pylori).

[0007] Related Korean Patent Registration No. 10-1613245 reports that 4-methoxypyrrole derivatives or pharmaceutically acceptable salts thereof have excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.) and Helicobacter pylori (H. pylori) eradication activity, and are therefore useful for the prevention and treatment of gastrointestinal ulcers, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori.

[0008] Specifically, the above patent proposes the following compound as a type of 4-methoxypyrrole derivative. JPEG2026503148000001.jpg51146

[0009] According to the patent, the manufacturing process for the compound consists of a total of seven steps.

[0010] However, the manufacturing process of the patent has a low yield of 4.63%, and requires high-temperature reactions and expensive equipment, making it unsuitable for industrial mass production.

[0011] For this purpose, Korean Patent Registration No. 10-2233455 provides a method for preparing the following intermediate during the preparation of 4-methoxypyrrole derivatives: JPEG2026503148000002.jpg39153

[0012] According to the description in the patent, the manufacturing process of the intermediate compound consists of a total of six steps.

[0013] In addition, Korean Patent Registration No. 10-2126576 provides a method for producing a 4-methoxypyrrole derivative from the intermediate. According to the patent, the process for producing the intermediate compound consists of a total of four steps.

[0014] However, when 4-methoxypyrrole derivatives are produced by combining the manufacturing processes of the two patents, the total yield is low at 20.2% and the manufacturing steps consist of a total of 10 steps, which is still not suitable for industrial mass production.

[0015] Therefore, the inventors have constructed a manufacturing process of a total of six steps to obtain a 4-methoxypyrrole derivative, and have confirmed that the compound can be obtained in a higher yield than in the above patent, thereby completing the present invention. Summary of the Invention [Problem to be solved by the invention]

[0016] The present invention provides a method for producing a 4-methoxypyrrole derivative. [Means for solving the problem]

[0017] In order to solve the above problems, the present invention provides a production method as shown in the following Reaction Scheme 1: [Reaction Scheme 1] JPEG2026503148000003.jpg156167

[0018] Specifically, one embodiment of the present invention provides a method for preparing a compound represented by Chemical Formula 1, comprising the following steps 1 to 6: 1) reacting the compound represented by Formula 1-1 with p-toluenesulfinic acid and formamide in the presence of an acid catalyst to prepare the compound represented by Formula 1-2; 2) reacting the compound represented by Formula 1-2 with a dehydrating reagent to prepare the compound represented by Formula 1-3; 3) reacting the compound represented by the formula 1-3 with a cyclization reagent to prepare the compound represented by the formula 1-4; 4) reacting the compound represented by Formula 1-4 with 3-fluorobenzenesulfonyl chloride to prepare the compound represented by Formula 1-5; 5) reacting the compound represented by Formula 1-5 with sodium hydride to prepare a compound represented by Formula 1-6; and 6) reacting the compound represented by Formula 1-6 with methylamine to produce an intermediate, and then adding a reducing agent to convert the intermediate into the compound represented by Formula 1.

[0019] In the above-mentioned Korean Patent Registration Nos. 10-2233455 and 10-2126576, when the compound represented by Chemical Formula 1 is produced from the compound represented by Chemical Formula 1-1, many reaction steps must be passed through, resulting in low yields of the final substance and low process efficiency.

[0020] For example, in order to prepare a compound represented by Chemical Formula 1 from a compound represented by Chemical Formula 1-1 by combining Korean Patent Registration No. 10-2233455 and Korean Patent Registration No. 10-2126576, a total of 10 reaction steps must be performed, which reduces the yield of the final substance and process efficiency.

[0021] In contrast, in the overall embodiment, the reaction steps to be passed through are simplified, improving process efficiency and the yield of the final substance compared to the above patent, and reducing the number of days required for production by half, which is an advantage useful for industrial mass production of 4-methoxypyrrole derivatives.

[0022] Hereinafter, an embodiment of the present invention will be described in detail for each step. By adjusting the process temperature, execution time, etc. of each step, it is possible to control the quality of the final material.

[0023] (Stage 1) Step 1 is a step of preparing a compound represented by Chemical Formula 1-2 by reacting a compound represented by Chemical Formula 1-1 with sodium p-toluenesulfinate and formamide in the presence of an acid catalyst, and is a step of introducing a phenylsulfonyl group substituted with a formamide group into the compound represented by Chemical Formula 1-1.

[0024] First, step 1 may include preparing a p-toluenesulfinic acid (4-methylbenzenesulfinic acid) concentrate prior to the reaction with the compound represented by Formula 1-1, whereby the concentrated p-toluenesulfinic acid can be used in the reaction between the compound represented by Formula 1-1 and formamide.

[0025] The p-toluenesulfinic acid concentrate can be produced by mixing sodium p-toluenesulfinate with water and an organic solvent under acidic conditions, separating the organic layer from the mixture, and adding sodium sulfate to the organic layer to remove water and concentrate the mixture. Here, the p-toluenesulfinic acid concentrate may be concentrated to 10 mol % or more, more specifically, 50 to 500 mol %.

[0026] Preferably, the acid that can be used is hydrochloric acid, nitric acid, sulfuric acid, or phosphoric acid, and preferably, hydrochloric acid is used.

[0027] Preferably, the organic solvent is ethyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, tert-butyl methyl ether, or a mixture of two or more thereof. Preferably, the organic solvent is ethyl acetate.

[0028] Preferably, the method may further include the steps of separating an organic layer from the mixture of sodium p-toluenesulfinate, water, and ether before mixing the sodium sulfate, mixing a saturated sodium chloride solution with the organic layer, and then separating the organic layer again.

[0029] Preferably, the concentrating step may be a vacuum concentration step.

[0030] Next, the concentrated residue of the produced p-toluenesulfinic acid is mixed with the compound represented by Chemical Formula 1-1 (2,4-Difluorobenzaldehyde) and formamide in the presence of an acid catalyst to react with it, thereby producing a compound represented by Chemical Formula 1-2.

[0031] Preferably, the molar ratio of the compound represented by Chemical Formula 1-1 to formamide may be 10:1 to 1:10, specifically 5:1 to 1:5.

[0032] Preferably, the reaction may be carried out in the presence of an acid catalyst such as chlorotrimethylsilane (TMSCl), camphorsulfonic acid, trifluoromethanesulfonic acid (TfOH), trifluoroacetic acid, benzoic acid, nitrobenzoic acid, hydrochloric acid, calcium chloride, or a mixture of two or more thereof. The compound can be used as an acid catalyst for the Mannich reaction, which is the reaction in step 1. Preferably, the reaction may be carried out in the presence of chlorotrimethylsilane, trifluoromethanesulfonic acid, or a mixture thereof.

[0033] Preferably, the molar ratio of the compound represented by Chemical Formula 1-1 to the acid catalyst is 20:1 to 1:10, and more preferably 10:1 to 1:5.

[0034] Preferably, the reaction solvent is acetonitrile, tetrahydrofuran, methylene chloride, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, toluene, or a mixture of two or more thereof. Specifically, a mixture of toluene and acetonitrile can be used.

[0035] Preferably, the reaction is carried out at 0°C to 80°C, or more preferably at 10°C to 70°C or 20°C to 60°C. If the reaction temperature is too low, the yield of step 1 may be low, while if the reaction temperature is too high, side reactions may occur or the production cost may increase without a substantial increase in production yield. Preferably, the reaction temperature may be the internal temperature of the reactor.

[0036] Preferably, the second reaction is carried out for 1 to 36 hours, more preferably 5 to 30 hours. If the reaction time is too short, the reaction may not proceed sufficiently, resulting in a low production yield of Step 1. If the reaction time is too long, production costs may increase without a substantial increase in production yield.

[0037] After the reaction of Step 1 is completed, if necessary, the method may further include a step of concentrating and then purifying the compound represented by Formula 1-2. Preferably, the purification may be performed by crystallizing the compound represented by Formula 1-2 from the reaction product of Step 1.

[0038] The solvent for crystallizing the compound represented by Formula 1-2 from the reaction product of Step 1 can be an alcohol compound alone or a mixed solvent with water. Specific examples of the alcohol include methanol, ethanol, propanol, butanol, isopropyl alcohol, or a mixture of two or more of these. For example, the reaction product of Step 1 can be crystallized by adding methanol or isopropyl alcohol alone or a mixture of these with water at a temperature ranging from 0°C to 30°C, stirring for 10 minutes to 1 hour, filtering under reduced pressure, and then washing the filtrate. The filtrate can be washed with water or an alcohol compound, specifically, with methanol, isopropyl alcohol, or a mixture of these with water.

[0039] After purifying the compound represented by Chemical Formula 1-2, the water content of the compound represented by Chemical Formula 1-2 can be reduced by drying it at 40° C. to 80° C. for 12 to 48 hours. Specifically, the drying may be vacuum drying.

[0040] More specifically, by drying at 40 to 80°C, the water content of the compound represented by Formula 1-2 can be significantly reduced, thereby increasing the conversion rate in the next step (i.e., Step 2 below).

[0041] (Stage 2) Step 2 is a step of reacting the compound represented by Formula 1-2 with a dehydrating reagent to prepare the compound represented by Formula 1-3.

[0042] Preferably, step 2 is a step of converting the formamide group present in the compound represented by formula 1-2 into an isocyanide group to prepare a compound represented by formula 1-3.

[0043] Preferably, the dehydrating reagent includes phosphoryl chloride, trichloromethyl chloroformate, bis(trichloromethyl)carbonate, triphenylphosphine, thionyl chloride, p-toluenesulfonic acid, or a mixture of two or more thereof. The dehydrating reagent can convert a formamide group into an isocyanide group.

[0044] Preferably, the molar ratio of the compound represented by Chemical Formula 1-2 to the dehydrating reagent may be 20:1 to 1:10, more preferably 10:1 to 1:5.

[0045] Preferably, Step 2 may be carried out in the presence of a base. The base may be trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methylate, potassium butyrate, or cesium carbonate, and may preferably be triethylamine. Preferably, the molar ratio of the compound represented by Chemical Formula 1-2 to the base is 20:1 to 1:20, more preferably 10:1 to 1:10.

[0046] Preferably, the reaction solvent in Step 2 can include 1,2-dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl carbonate, acetonitrile, ethyl acetate, N,N-dimethylformamide, carbon tetrachloride, methylene chloride, or a mixture of two or more thereof. Specifically, the reaction solvent can be 1,2-dimethoxyethane.

[0047] Preferably, step 2 is carried out at a temperature range of -20°C to 20°C. Preferably, the reaction temperature may be -10°C to 10°C. If the reaction temperature is too low, the yield of step 2 may be low, and if the reaction temperature is too high, the yield may be low due to an increase in reaction by-products. Preferably, the reaction temperature may be the internal temperature of the reactor.

[0048] Preferably, the second reaction is carried out for 10 minutes to 10 hours, or more preferably 30 minutes to 8 hours, or 1 hour to 4 hours. If the reaction time is too short, the reaction may not proceed sufficiently, resulting in a low production yield of Step 1. If the reaction time is too long, production costs may increase without a substantial increase in production yield.

[0049] After the reaction of Step 2 is completed, the method may further include a step of purifying the compound represented by Formula 1-3, if necessary. Preferably, the purification may be carried out by crystallizing the compound represented by Formula 1-3 from the reaction product of Step 2.

[0050] The solvent for crystallizing the compound represented by Formula 1-3 from the reaction product of Step 2 can include ethyl acetate, butyl acetate, isopropyl acetate, n-hexane, n-heptane, methanol, water, or a mixture of two or more thereof. For example, the reaction product of Step 2 can be extracted with ethyl acetate and the organic layer can be concentrated. The concentrated residue can then be mixed with methanol and water sequentially, stirred for 10 minutes to 1 hour, filtered under reduced pressure, and the filtrate washed to perform crystallization. Furthermore, sodium bicarbonate can be used to wash the organic layer prior to crystallization in order to terminate the reaction and remove by-products.

[0051] After purifying the compound represented by Chemical Formula 1-3, the water content of the compound represented by Chemical Formula 1-3 can be reduced by drying it at 40°C to 80°C for 12 to 48 hours. Preferably, the drying may be vacuum drying.

[0052] More specifically, by drying at 40 to 60°C, the water content of the compound represented by Formula 1-3 can be significantly reduced, thereby increasing the conversion rate in the next step (i.e., Step 3 below).

[0053] (Stage 3) Step 3 is a step of reacting the compound represented by Formula 1-3 with a cyclization reagent to prepare the compound represented by Formula 1-4.

[0054] Specifically, the cyclization reagent includes ethyl (Z)-2-cyano-3-methoxyacrylate (CMA), methyl (Z)-2-cyano-3-methoxyacrylate, propyl (Z)-2-cyano-3-methoxyacrylate, or a mixture of two or more thereof.

[0055] Preferably, the molar ratio of the compound represented by Chemical Formula 1-3 to the cyclization reagent may be 10:1 to 1:10, more preferably 5:1 to 1:5.

[0056] The reaction solvent in step 3 can be acetonitrile, tetrahydrofuran, methylene chloride, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, toluene, or a mixture of two or more thereof. Specifically, methanol can be used.

[0057] Step 3 is preferably carried out in the presence of a base. Specifically, the base may be trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methylate, potassium butyrate, or cesium carbonate, and preferably potassium carbonate. Preferably, the molar ratio of the compound represented by Formula 1-3 to the base is 20:1 to 1:10, more preferably 10:1 to 1:5.

[0058] The reaction temperature in step 3 may be 50°C to 150°C based on the external temperature of the reactor. Preferably, the reaction temperature may be 50°C to 100°C. If the reaction temperature is too low, the production yield may be reduced, and if the reaction temperature is too high, the yield may be reduced due to an increase in reaction by-products.

[0059] Preferably, the second reaction is carried out for 30 minutes to 10 hours, more preferably 1 hour to 5 hours. If the reaction time is too short, the reaction may not proceed sufficiently, resulting in a low production yield of Step 3. If the reaction time is too long, production costs may increase without a substantial increase in production yield.

[0060] After the reaction of Step 3 is completed, the method may further include a step of purifying the compound represented by Formula 1-4, if necessary. Preferably, the purification may be carried out by crystallizing the compound represented by Formula 1-4 from the reaction product of Step 3.

[0061] Solvents for crystallizing the compound represented by Formula 1-4 from the reaction product of Step 3 may include ethyl acetate, butyl acetate, isopropyl acetate, n-hexane, n-heptane, or a mixture of two or more thereof. For example, after the reaction of Step 3 is completed, ethyl acetate and water are mixed, and the organic layer is separated. The separated organic layer can be washed sequentially with water and sodium chloride solution and concentrated under reduced pressure. An organic solvent such as methanol can then be added to the concentrated residue, followed by adding purified water, cooling, and stirring. The crystals can then be filtered under reduced pressure, and the filtrate can be washed to perform crystallization.

[0062] After purifying the compound represented by Chemical Formula 1-4, the compound can be dried at 40 to 80°C for 12 to 48 hours to reduce the water content of the compound represented by Chemical Formula 1-4. Preferably, the drying may be vacuum drying. More specifically, the drying temperature may be 40 to 60°C.

[0063] (Stage 4) Step 4 is a step of reacting the compound represented by Formula 1-4 with 3-fluorobenzenesulfonyl chloride to prepare the compound represented by Formula 1-5.

[0064] The method may further include dissolving the compound represented by Formula 1-4 in an organic solvent and a catalyst before reacting with 3-fluorobenzenesulfonyl chloride to prepare a composition containing the compound represented by Formula 1-4.

[0065] The catalyst may be a nucleophilic catalyst. More specifically, the catalyst may be one or more nucleophilic catalysts selected from the group consisting of 4-dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine (PPY), pyridine (PY), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD). Preferably, the catalyst may be 4-dimethylaminopyridine (DMAP).

[0066] Preferably, the molar ratio of the compound represented by Chemical Formula 1-4 to the catalyst may be 100:1 to 1:10, specifically 20:1 to 1:3.

[0067] The organic solvent may be acetonitrile, tetrahydrofuran, methylene chloride, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, toluene, or a mixture of two or more thereof. Specifically, acetonitrile may be used. Preferably, the solvent is used in an amount (mL / g) that is 1 to 10 times the weight of the compound represented by Chemical Formula 1-4.

[0068] Then, the compound represented by Chemical Formula 1-4 can be reacted with 3-fluorobenzenesulfonyl chloride under basic conditions.

[0069] The base may be trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methylate, potassium butyrate, or cesium carbonate, and preferably diisopropylethylamine is used. Preferably, the molar ratio of the compound represented by Chemical Formula 1-4 to the base may be 10:1 to 1:10, more specifically 5:1 to 1:5.

[0070] The molar ratio of the compound represented by Chemical Formula 1-4 to 3-fluorobenzenesulfonyl chloride in Step 4 may be 10:1 to 1:10, more specifically 5:1 to 1:5.

[0071] The reaction temperature in step 4 may be 0° C. to 60° C. Preferably, the reaction temperature may be 15° C. to 55° C. If the reaction temperature is too low, the production yield may be reduced, and if the reaction temperature is too high, side reactions may occur, resulting in increased production costs without a substantial increase in production yield.

[0072] Preferably, step 4 is carried out with stirring for 30 minutes to 10 hours, more preferably 1 hour to 5 hours. If the reaction time is too short, the reaction may not proceed sufficiently, resulting in a low production yield of step 4. If the reaction time is too long, production costs may increase without a substantial increase in production yield.

[0073] After the reaction of Step 4 is completed, if necessary, the method may further include purifying the reaction product with the compound represented by Formula 1-5. Preferably, the purification may be performed by crystallizing the compound represented by Formula 1-5 from the reaction product of Step 4.

[0074] Preferably, the reaction product of step 4 is mixed with ethyl acetate and water, followed by separation of the organic layer. The separated organic layer is then concentrated, mixed with methanol, and concentrated. Then, methanol is added again, and the mixture is stirred at a temperature of 40°C to 60°C, cooled to room temperature, and then mixed with water. The resulting crystals are filtered under reduced pressure, and the filtrate is washed to perform crystallization.

[0075] After purifying the compound represented by Chemical Formula 1-5, the water content in the compound represented by Chemical Formula 1-5 can be reduced by drying it at 40°C to 80°C for 12 to 48 hours.

[0076] More specifically, by drying at 40 to 60°C, the water content of the compound represented by Formula 1-5 can be significantly reduced, thereby increasing the conversion rate in the next step (i.e., Step 5 below).

[0077] (Stage 5) Step 5 is a step of reacting the compound represented by Formula 1-5 with sodium hydride to prepare a compound represented by Formula 1-6.

[0078] Preferably, step 5 is a step of converting an isocyanide group present in the compound represented by formula 1-5 into an aldehyde group to prepare a compound represented by formula 1-6.

[0079] Preferably, the molar ratio of the compound represented by Chemical Formula 1-5 to sodium hydride may be 20:1 to 1:10, and more preferably 10:1 to 1:5.

[0080] The sodium hydride may be used in the form of a dispersion in mineral oil. Specifically, it may be used in the form of a dispersion in liquid paraffin. By using sodium hydride dispersed in mineral oil, the sodium hydride is in a dry solid state, minimizing contact with air and reducing the risk of fire.

[0081] Preferably, in Step 5, acetonitrile, tetrahydrofuran, methylene chloride, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, toluene, or a mixture of two or more thereof can be used as a reaction solvent, and specifically, tetrahydrofuran (THF) can be used as the solvent.

[0082] Preferably, Step 5 may be carried out in the presence of zinc halide. The zinc halide may include zinc chloride, zinc bromide, zinc iodide, or a mixture of two or more thereof. The zinc halide controls the reactivity of the reduction reaction with sodium hydride in Step 5, thereby reducing side reactions and promoting the production of the compound represented by Formula 1-6. The presence of zinc halide can improve the reaction efficiency of Step 5.

[0083] Here, the molar ratio of the compound represented by Chemical Formula 1-5 to the zinc halide may be 10:1 to 1:10, and more specifically, 5:1 to 1:5.

[0084] The reaction temperature in step 5 may be 20° C. to 80° C. Preferably, the reaction temperature may be 40° C. to 60° C. If the reaction temperature is too low, the production yield may be reduced, and if the reaction temperature is too high, the yield may be reduced due to an increase in reaction by-products.

[0085] Preferably, step 5 is carried out with stirring for 1 to 36 hours, more preferably 5 to 24 hours. If the reaction time is too short, the reaction may not proceed sufficiently, resulting in a low production yield of step 5. If the reaction time is too long, production costs may increase without a substantial increase in production yield.

[0086] Specifically, the compound represented by Chemical Formula 1-5 and the solvent are stirred in a reactor at room temperature, and then the zinc chloride and sodium hydride are added, followed by stirring at 40°C to 60°C for 5 to 24 hours to proceed with Step 5.

[0087] Hydrogen and heat can be generated by the reaction of the compound represented by Formula 1-5 and the sodium hydride, and after completion of the reaction in Step 5, the reactor can be cooled until the internal temperature reaches −5° C. to 5° C. For example, when the reactor is cooled until the internal temperature reaches −5° C. to 5° C., safety at a production scale can be improved.

[0088] After cooling the internal temperature of the reactor, a step of purifying the compound represented by Formula 1-6 may be included, if necessary. More specifically, the purification may be carried out by crystallizing the compound represented by Formula 1-6 from the reaction product of Step 5.

[0089] Specifically, after cooling the reaction product of step 5, ethyl acetate, butyl acetate, isopropyl acetate, or a mixture of two or more thereof, is mixed with water, and the resulting mixture is adjusted to a pH of 1.0 to 2.0 to form an acid solution, and the organic layer is separated. Thereafter, sodium sulfate is mixed with the organic layer, and the mixture is filtered and concentrated under reduced pressure.

[0090] The concentrated residue can then be mixed with a crystallization solvent such as methanol, ethanol, propanol, butanol, isopropyl alcohol, ethyl acetate, butyl acetate, isopropyl acetate, n-hexane, n-heptane, or a mixture of two or more of these, either alone or with water, and stirred for 10 minutes to 1 hour. The resulting mixture is then filtered under reduced pressure, washed, and vacuum-dried at 40°C to 80°C for 12 to 48 hours to reduce the water content of the compound represented by Chemical Formula 1-6.

[0091] (Stage 6) Step 6 is a step of converting the compound represented by Formula 1-6 into the compound represented by Formula 1 using a reductive amination reaction.

[0092] Specifically, in step 6, the compound represented by Chemical Formula 1-6 generates an imine compound by an imine-forming reaction with methylamine. Since this imine compound corresponds to an intermediate with an unstable structure, it can be easily converted to the compound represented by Chemical Formula 1 by a reduction reaction.

[0093] The reductive imination reaction of step 6 may be carried out in a reaction solvent that is methanol, ethanol, isopropanol, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl ether, acetonitrile, or a mixture of two or more thereof.

[0094] More specifically, the compound represented by Formula 1-6 and methanol are added to a reactor separate from Step 6, cooled to 10°C to 15°C, and then methylamine is added and stirred at 10°C to 30°C for 20 minutes to 2 hours, so that the compound represented by Formula 1-6 and the methylamine can react in a state where they are fully dissolved in the solvent to produce an imine compound.

[0095] At this time, the stirring time and temperature can be adjusted taking into consideration that the lower the solubility of the compound represented by Chemical Formula 1-6, the more related substances may be contained in the final product. For example, stirring at 10°C to 15°C for 30 minutes to 1 hour will allow the compound represented by Chemical Formula 1-6 to be fully dissolved, and if the reaction is allowed to proceed under these conditions, the content of related substances in the final product can be reduced.

[0096] Meanwhile, the reduction of the intermediate (i.e., imine compound) generated by the reaction of the compound represented by Formula 1-6 with methylamine is more stable at low temperatures.

[0097] In consideration of this, after the reaction of the compound represented by Chemical Formula 1-6 with methylamine is completed, the reactor temperature may be cooled to a range of −10° C. to 0° C., for example, −10° C. to −5° C., and then the reducing agent may be added within the cooled temperature range, followed by stirring while maintaining the reactor temperature at −5° C. to 10° C., for example, −5° C. to 0° C. At such a low temperature range, the intermediate (i.e., imine compound) can stably react with the reducing agent and be converted to the compound represented by Chemical Formula 1.

[0098] Here, the reducing agent may include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or a mixture of two or more thereof, and the molar ratio of the compound represented by Chemical Formula 6 to the methylamine may be 10:1 to 1:10, and the molar ratio of the compound represented by Chemical Formula 6 to the reducing agent may be 10:1 to 1:10. Specifically, the respective molar ratios may be 5:1 to 1:5, and more specifically, 3:1 to 1:3.

[0099] After the intermediate (i.e., the imine compound) has been sufficiently reacted with the reducing agent, in order to complete the reaction (work-up), an acidic aqueous solution containing hydrochloric acid, glutamic acid, malonic acid, succinic acid, tartaric acid, oxalic acid, fumaric acid, phosphoric acid, methanesulfonic acid, or a mixture of two or more thereof can be supplied to adjust the pH. For example, a 5 to 7 N hydrochloric acid aqueous solution can be supplied to adjust the pH to 6.5 to 7.5, more specifically, to 7.0 to 7.5.

[0100] The organic layer is then extracted 1 to 3 times with an organic solvent to obtain an organic layer. To remove acidic related substances, which are decomposition products generated during the process, the organic layer is washed with an aqueous base solution, followed by stirring with the addition of a drying agent and filtration under reduced pressure. The filtrate is washed, and the pH of the filtrate is adjusted to 6.0 to 6.5, after which the filtrate is concentrated under reduced pressure. Adjusting the pH of the filtrate to 6.0 to 6.5 before concentration under reduced pressure increases the efficiency of removing unknown related substances during crystallization, allowing the product represented by Chemical Formula 1 to be obtained in high purity without an additional purification step.

[0101] During the extraction, an organic solvent such as ethyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, or a mixture of two or more thereof can be used.

[0102] The base used to prepare the aqueous base solution may be potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methylate, potassium butyrate, or cesium carbonate, and preferably sodium bicarbonate.

[0103] Furthermore, drying agents used after the extraction include magnesium sulfate, sodium sulfate, and the like.

[0104] The acid or its mixed solution with an organic solvent used to adjust the pH of the filtrate obtained after drying may be hydrochloric acid, glutamic acid, malonic acid, succinic acid, tartaric acid, oxalic acid, fumaric acid, phosphoric acid, methanesulfonic acid, or a mixture of two or more of these or a mixed solution with an organic solvent, and the organic solvent in the mixed solution can be selected from the organic solvents listed above. For example, a mixed solution in which hydrochloric acid is dissolved in ethyl acetate, diethyl ether, or a mixture of these as the organic solvent to a concentration of 0.5 to 2.0 M can be used to adjust the pH.

[0105] (Additional Step - Preparation of Acid Addition Salt) The compound represented by Chemical Formula 1 may be in the form of a pharmaceutically acceptable salt. The salt includes common acid addition salts, such as salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid, and salts derived from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanedisulfonic acid, ethanedisulfonic acid, oxalic acid, or trifluoroacetic acid. Preferably, the salt may be a hydrochloride or fumarate salt.

[0106] To provide the compound represented by Chemical Formula 1 in the form of a pharmaceutically acceptable salt, the method may further include, after Step 6, adding an acid to the compound represented by Chemical Formula 1 to obtain a pharmaceutically acceptable acid salt represented by Chemical Formula 1-1: [Chemical formula 1-1] JPEG2026503148000004.jpg42152

[0107] Specifically, the additional step may include supplying an organic solvent to the compound represented by Chemical Formula 1, and then supplying an acid or a mixed solution thereof with the organic solvent to crystallize the acid salt represented by Chemical Formula 1-1.

[0108] More specifically, an organic solvent may be supplied to the concentrated residue of Step 6 containing the compound represented by Formula 1. The organic solvent supplied may be ethyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropyl alcohol, acetonitrile, dichloromethane, n-hexane, or a mixture of two or more thereof, such as ethyl acetate.

[0109] After the organic solvent is supplied to the concentrated residue of Step 6 containing the compound represented by Chemical Formula 1 and stirred, the internal temperature of the reactor is adjusted to 0°C to 5°C, and the acid or a mixed solution thereof with the organic solvent is supplied, followed by stirring at 18°C ​​to 22°C, thereby crystallizing the acid salt represented by Chemical Formula 1-1.

[0110] The acid or its mixed solution with an organic solvent used to crystallize the acid salt represented by Chemical Formula 1-1 may be hydrochloric acid, glutamic acid, malonic acid, succinic acid, tartaric acid, oxalic acid, fumaric acid, phosphoric acid, methanesulfonic acid, or a mixture of two or more thereof; or a mixed solution with an organic solvent, and the organic solvent in the mixed solution can be selected from the organic solvents listed above. For example, a mixed solution in which hydrochloric acid is dissolved in ethyl acetate, diethyl ether, or a mixture thereof to a concentration of 0.5 to 2.0 M can be used to crystallize the acid salt represented by Chemical Formula 1-1.

[0111] Regarding the temperature range of 18°C ​​to 22°C for crystallization of the acid salt represented by Chemical Formula 1-1, if the reaction temperature is less than 18°C, the solubility of impurities decreases, resulting in a decrease in the purity of the acid salt represented by Chemical Formula 1-1, whereas if the reaction temperature is more than 22°C, there may be a problem that the production cost increases without a substantial increase in production yield.

[0112] In addition, for crystallization, the acid salt represented by Chemical Formula 1-1 is stirred for at least 1 hour after supplying the acid or its mixed solution with an organic solvent, and the stirring time can be controlled to 12 hours or less to prevent precipitation of related substances during stirring.

[0113] Compared with the prior art, the present disclosure has the advantage that the same level of quality can be obtained despite the acid salt being crystallized only once.

[0114] Meanwhile, the present invention provides a pharmaceutical composition for preventing or treating gastrointestinal ulcer, gastritis, reflux esophagitis, or gastrointestinal damage caused by Helicobacter pylori (H. pylori), comprising the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0115] The present invention also provides a pharmaceutical composition for preventing or treating a 5-HT receptor- or muscarinic acetylcholine receptor-mediated disease, comprising the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. In this case, the 5-HT receptor- or muscarinic acetylcholine receptor-mediated disease may be depression, bipolar disorder, schizophrenia, autism, obsessive-compulsive disorder, anxiety disorder, migraine, hypertension, eating disorder, irritable bowel syndrome (IBS), peptic ulcer, diabetic neuropathy, asthma, or overactive bladder.

[0116] The pharmaceutical composition may contain pharmaceutically acceptable carriers such as commonly used excipients, disintegrants, sweeteners, lubricants, or flavoring agents, and may be formulated by a conventional method into oral preparations such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or parenteral preparations such as injections. The preparations may be formulated into various forms, for example, single-dose or multi-dose dosage forms.

[0117] The compositions can be administered orally or parenterally, including intravenously, intramuscularly, intraperitoneally, subcutaneously, rectally, and topically. The compositions are preferably orally administrable. Accordingly, the compositions can be formulated in a variety of forms, such as tablets, capsules, aqueous solutions, or suspensions. For oral tablets, carriers such as lactose or cornstarch and lubricants such as magnesium stearate may typically be added. For oral capsules, lactose and / or dried cornstarch can be used as diluents. When aqueous oral suspensions are required, the active ingredient can be combined with emulsifying and / or suspending agents. If necessary, specific sweeteners and / or flavoring agents can be added. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, sterile solutions of the active ingredient are typically prepared, and the pH of the solution should be suitably adjusted and buffered. For intravenous administration, the total concentration of solutes should be adjusted to render the formulation isotonic. The compositions of the present invention may also be in the form of an aqueous solution containing a pharmaceutically acceptable carrier, such as saline at pH 7.4. The solution can be introduced into a patient's intramuscular blood stream by local bolus injection.

[0118] In this case, the pharmaceutical composition may be administered in a therapeutically effective amount. Thus, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition may be administered to a patient in an effective amount of about 0.01 mg / kg to about 100 mg / kg per day. Of course, the dosage may vary depending on the age, weight, sensitivity, and symptoms of the patient, or the efficacy of the compound. [Effects of the Invention]

[0119] As described above, according to one embodiment of the present invention, the process efficiency and yield are improved, which is useful for industrial mass production of 4-methoxypyrrole derivatives. DETAILED DESCRIPTION OF THE INVENTION

[0120] The present invention will be described in more detail with reference to the following examples, but the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0121] Analysis of the compounds prepared in the following examples was carried out as follows: nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker 400 MHz spectrometer, chemical shifts were reported in ppm, and column chromatography was carried out on silica gel (Merck, 70-230 mesh) (W.C. Still, J. Org. Chem., 1978(43), 2923-2925). [Example]

[0122] [Reaction Scheme 1-1] JPEG2026503148000005.jpg147160

[0123] A flask was charged with 24.0 g of sodium p-toluenesulfinate, 100.0 mL of purified water, 100 mL of ethyl acetate, and 12.0 mL of hydrochloric acid, and the mixture was stirred for 10 minutes. After allowing to stand for 10 minutes, the aqueous layer was discarded and the organic layer was separated. Then, 20.0 mL of saturated sodium chloride solution was added to the organic layer, and the mixture was stirred for 10 minutes. After allowing to stand for 10 minutes, the aqueous layer was discarded. 6.0 g of sodium sulfate was added to the organic layer, and the mixture was stirred for 5 minutes. The mixture was then filtered under reduced pressure and concentrated under reduced pressure at 40°C to 50°C to produce a p-toluenesulfinic acid concentrate concentrated to 150 mol%.

[0124] To the flask containing the concentrated residue obtained from the concentrate, 46.0 mL of toluene, 46.0 mL of acetonitrile, 12.2 g of the compound represented by Chemical Formula 1-1 (2,4-difluorobenzaldehyde), 9.9 g of formamide, and 10.2 g of chlorotrimethylsilane (TMSCl) were added, and the mixture was stirred at 30° C. for 18 hours.

[0125] The solvent was then removed by concentration at an external temperature of 40°C. 73.2 mL of methanol was added to the concentrated residue and stirred at 50°C for 30 minutes, then cooled to room temperature and stirred for an additional hour. The resulting crystals were filtered under reduced pressure, and the filtrate was washed with 24.4 mL of methanol. The washed filtrate was placed in a dryer and vacuum dried at 50-60°C for 12 hours or more, yielding 25.8 g of the compound represented by formula 1-2 (yield 92.3%). 1 H NMR (500 MHz, DMSO): δ 9.93 (d, 1H), 8.02 (d, 1H), 7.73 (td, 1H), 7.67 (d, 2H), 7.45 (d, 2H), 7.39 - 7.33 (m, 1H), 7.29 (td, 1H), 6.51 (d, 1H), 2.42 (s, 3H)

[0126] (Stage 2) 10.1 g of the compound represented by chemical formula 1-2 and 60.0 mL of 1,2-dimethoxyethane were placed in a flask, cooled to 0° C. to 5° C., and stirred. 11.5 g of phosphoryl chloride was gradually added to the flask over 5 minutes.

[0127] A mixed solution of 15.5 mL of 1,2-dimethoxyethane and 15.6 g of triethylamine was gradually added to the flask over 10 minutes, and the mixture was stirred for 1 hour while maintaining the temperature at -5°C to 0°C.

[0128] Next, 10.0 g of sodium bicarbonate was dissolved in 150.0 mL of purified water, and the solution was slowly added and vigorously stirred for 10 minutes. 150.0 mL of ethyl acetate was added to the stirred mixture, stirred for 5 minutes, and then allowed to stand. The aqueous layer was discarded, and the organic layer was concentrated at an external temperature of 40°C. 50.0 mL of methanol was added to the resulting concentrated residue and stirred, and then 50.0 mL of purified water was slowly added dropwise. After stirring at room temperature for 20 minutes, the resulting crystals were filtered under reduced pressure. The filtered product was placed in a dryer and vacuum dried at 50-60°C for at least 12 hours to obtain 7.1 g of the compound represented by formula 1-3 (yield: 74.4%). 1H NMR (500 MHz, DMSO): δ 7.70 (d, 2H), 7.54 (d, 2H), 7.47 - 7.39 (m, 2H), 7.26 (td, 1H), 7.10 (s, 1H), 2.46 (s, 3H)

[0129] (Stage 3) A flask was charged with 8.0 g of the compound represented by chemical formula 1-3, 4.0 g of ethyl (Z)-2-cyano-3-methoxyacrylate (CMA), 7.2 g of potassium carbonate (K2CO3), and 160.0 mL of methanol, and the mixture was refluxed and stirred at an external temperature of 80°C for 2 hours.

[0130] The reaction mixture was concentrated under reduced pressure at a temperature of 40°C to 45°C. 160.0 mL of ethyl acetate (EA) and 160.0 mL of purified water were added to the concentrated residue in the flask and stirred for 10 minutes. After standing for 10 minutes, the aqueous layer was discarded. The organic layer was washed with 80.0 mL of purified water and 40.0 mL of saturated sodium chloride solution. The organic layer was concentrated under reduced pressure at an external temperature of 40°C. 60.0 mL of methanol was added to the concentrated residue and stirred to dissolve it. 30.0 mL of purified water was gradually added, and the mixture was cooled to 0 to 5°C and stirred for 1 hour.

[0131] The resulting crystals were filtered under reduced pressure and washed with a mixture of 20.0 mL of methanol and 10.0 mL of purified water. The filtered product was placed in a dryer and vacuum dried at 50-60°C for 12 hours or more to obtain 4.7 g of the compound represented by formula 1-4 (yield 76.8%). 1 H NMR (500 MHz, CDCl3): δ 8.93 (s, 1H), 8.00 (td, 1H), 7.15 (d, 1H), 6.96 (dddd, 1H), 6.89 (ddd, 1H), 4.04 (s, 3H)

[0132] (Stage 4) 7.5 g of the compound represented by Chemical Formula 1-4, 0.8 g of 4-dimethylaminopyridine (DMAP), and 37.5 mL of acetonitrile were placed in a flask and dissolved by stirring.

[0133] 7.5 g of 3-fluorobenzenesulfonyl chloride and 5.0 g of N,N-diisopropylethylamine (DIPEA) were added to the mixture, and the mixture was stirred at 35°C to 40°C for 2 hours to complete the reaction.

[0134] Next, 37.5 mL of purified water and 37.5 mL of ethyl acetate (EA) were added, stirred for 10 minutes, and allowed to stand for 10 minutes, after which the aqueous layer was discarded. After concentrating the organic layer, 15.0 mL of methanol was added to the concentrated residue, stirred at room temperature to dissolve, and then concentrated again. 37.5 mL of methanol was added to the concentrated residue, stirred at 50-60°C to dissolve, and then cooled to room temperature. 22.5 mL of purified water was added to the flask over 10 minutes and stirred for 1 hour. The resulting crystals were filtered under reduced pressure, and the filtrate was washed with 15.0 mL of purified water. The washed filtrate was placed in a dryer and vacuum dried at 50-60°C for at least 12 hours to obtain 11.4 g of the compound represented by chemical formula 1-5 (yield 90.7%). 1 H NMR (500 MHz, CDCl3): δ 7.84 (s, 1H), 7.45 (td, 1H), 7.40 - 7.30 (m, 1H), 7.22 (dt, 1H), 7.18 (td, 1H), 7.04 (dt, 1H), 6.94 (td, 1H), 6.77 (td, 1H), 3.73 (s, 3H)

[0135] (Stage 5) 10.0 g of the compound represented by Chemical Formula 1-5 and 100.0 mL of tetrahydrofuran (THF) are placed in a flask and stirred at room temperature for 10 minutes.

[0136] Thereafter, 5.2 g of zinc chloride and 3.1 g of sodium hydride (60%, dispersion in liquid paraffin) are added, and the mixture is stirred at a temperature of 45°C to 55°C for 15 hours.

[0137] The reaction mixture was cooled to 0-5°C, and 50.0 mL of purified water and 50.0 mL of ethyl acetate (EA) were added and stirred. The pH was adjusted to 1.0-2.0 with 6N HCl solution, followed by stirring for 10 minutes and standing for 10 minutes. The aqueous layer was then discarded. 10.0 g of sodium sulfate was added to the organic layer, followed by stirring for 10 minutes, filtration under reduced pressure, and concentration. 40.0 mL of ethanol and 10.0 mL of water were added to the concentrated residue, and the mixture was stirred at room temperature for 1 hour.

[0138] The resulting crystals were filtered under reduced pressure and washed with 20.0 mL of a mixed solution of ethanol and water. The filtered product was placed in a dryer and vacuum dried at 40-50°C for 12 hours or more to obtain 7.5 g of the compound represented by chemical formula 1-6 (yield 74.4%). 1 H NMR (500 MHz, CDCl3): δ 9.89 (s, 1H), 7.99 (s, 1H), 7.44 (td, 1H), 7.33 (tdd, 1H), 7.24 (dt, 1H), 7.18 (td, 1H), 7.06 (dt, 1H), 6.97 - 6.89 (m, 1H), 6.77 (td, 1H), 3.63 (s, 3H)

[0139] (Stage 6) 100.0 g of the compound represented by Formula 1-6 obtained in Step 5 and 396.0 g of methanol were placed in a flask and cooled to 10 to 15°C. Then, 42.7 g of methylamine was added and the mixture was stirred at 10 to 15°C for 1 hour.

[0140] Thereafter, the internal temperature was cooled to -10°C to -5°C, and 4.8 g of sodium borohydride was added in portions while maintaining the temperature range of -5°C to 0°C, followed by stirring at -5°C to 0°C for 30 minutes to complete the reaction.

[0141] After the reaction was completed, 1,000 g of purified water was gradually added while maintaining the internal temperature at 10° C. to 25° C., followed by adding 902.0 g of ethyl acetate. Next, while maintaining the internal temperature at 10° C. to 25° C., the pH was adjusted to 7.0 to 7.5 using a 6N aqueous hydrochloric acid solution.

[0142] After stirring for 10 minutes, the mixture was allowed to stand for 30 minutes to separate the layers, and the organic layer was stored. 451.0 g of ethyl acetate was added to the aqueous layer, which was then stirred for 10 minutes and allowed to stand for 10 minutes. After this, the layers were separated, and the organic layer was combined with the previously obtained organic layer, and the same re-extraction process was carried out once again.

[0143] Thereafter, 1,026.6 g of an aqueous sodium hydrogencarbonate solution (26.6 g of sodium hydrogencarbonate, 1,000.0 g of purified water) was added to the combined organic layers, followed by stirring for 10 minutes and leaving to stand for 10 minutes to allow the layers to separate, after which the aqueous layer was discarded.

[0144] 200.0 g of sodium sulfate was added to the organic layer, and the mixture was stirred for 10 minutes while maintaining the internal temperature at 20°C to 30°C, followed by filtration under reduced pressure. The residue was washed with 270.6 g of ethyl acetate, and the pH of the filtrate was adjusted to 6.0 to 6.5 using a 1.0 M solution of hydrochloric acid in ethyl acetate. The filtrate was then concentrated under reduced pressure at 38°C to 42°C.

[0145] (Additional Step - Preparation of Acid Addition Salts) 90.2 g of ethyl acetate was added to the concentrated residue and stirred until it became relatively homogeneous. Then, 460.5 g of a 1.0 M hydrochloric acid ethyl acetate solution was gradually added at an internal temperature of 0 to 5°C, and the mixture was stirred at 18 to 22°C for 1 hour to crystallize the compound represented by chemical formula 1-1.

[0146] The resulting crystals were filtered under reduced pressure, and the filtrate was washed with 90.2 g of ethyl acetate. The filtrate was placed in a dryer and vacuum dried at 40 to 50°C for 12 hours or more, finally obtaining 95.7 g of the compound represented by Chemical Formula 1-1 (yield: 84.7%). 1 H-NMR (500 MHz, MeOD): 7.69(s, 1H), 7.58-7.53(m, 1H), 7.45(t, 1H), 7.30(d, 1H), 7.20-7.15(m, 2H), 7.02-6.94(m, 2H), 4.07(d, 2H), 3.46(s, 3H), 2.71(s, 3H)

[0147] Comparative Example The comparative example proceeded according to the following reaction formula. JPEG2026503148000006.jpg239156

[0148] (Stage 1) A flask was charged with 35.8 g of ammonium chloride and 26.9 g of sodium cyanide, followed by 716.0 mL of ammonium hydroxide (25-28%) and stirring for 10 minutes. The mixture was cooled to 0-5°C and stirred for 10 minutes, then warmed to room temperature and stirred for 15 minutes. After cooling to 0-5°C, another flask was charged with 100.0 g of the prepared 2,4-difluorobenzaldehyde (formula A-1) and 770.0 mL of methanol over 15-20 minutes. The mixture was warmed to room temperature and stirred for 22 hours to complete the first reaction. The mixture was concentrated under reduced pressure at 50°C, followed by 983.0 mL of acetic acid and 983.0 mL of concentrated HCl, and refluxed at an internal temperature of 100-105°C for 5 hours to complete the second reaction. The solvent was removed by concentration under reduced pressure at 75°C until a solid precipitated. Purified water was added and the mixture was stirred to precipitate crystals. The pH was adjusted to 6.5 using 5M NaOH solution at an internal temperature of 25°C or less. Ethanol was added and the mixture was stirred at 10°C to 15°C for 1 hour. After filtration under reduced pressure, the residue was washed with ethanol. The resulting solid was dried under reduced pressure to obtain 78.4 g of the compound represented by chemical formula A-2 (yield: 59.5%).

[0149] (Stage 2) A flask was charged with 100.0 g of the compound represented by formula A-2 prepared in step 1, 1.5 L of THF, and 1.5 L of purified water, and stirred at room temperature for 10 minutes. The internal temperature was cooled to 0-5°C, and 134.6 g of sodium bicarbonate and 139.5 g of di-tert-butyl dicarbonate were added. The reaction was completed by stirring at an internal temperature of 20-30°C for 12 hours, and then concentrated under reduced pressure at 45°C. Ethyl acetate was added, and the internal temperature was cooled to below 10°C. The pH was adjusted to 2.5 using 6N HCl. The organic layer was separated, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure at 45°C, yielding 151.2 g of the compound represented by formula A-3 (yield: 98.5%). 1 H-NMR (500 MHz, CDCl3): 8.13-8.14 (d, 1H), 7.37-7.42 (m, 1H), 6.82-6.89 (m, 2H), 5.46-5.47 (d, 1H), 1.23 (s, 9H)

[0150] (Stage 3) 100.0 g of the compound represented by Formula A-3 prepared in Step 2, 61.9 g of carbonyldiimidazole, and 1.0 L of acetonitrile were added to a flask and stirred at room temperature for 1 hour. 59.8 g of methyl potassium malonate, 36.4 g of anhydrous magnesium chloride, 1.0 L of acetonitrile, and 38.8 g of triethylamine were added to another flask and stirred at 20-30°C for 1 hour. The reactants in the two flasks were mixed and refluxed at an external temperature of 80°C for 1 hour to complete the reaction. After cooling to room temperature, purified water was added. After cooling to an internal temperature of 5-10°C, the mixture was stirred for 1 hour. The resulting solid was filtered under reduced pressure and washed with purified water. Since the resulting crystals were magnesium salts, the salt dissociation process was carried out.

[0151] The magnesium salt, 1.5 L of ethyl acetate, and 1.0 L of purified water were added to a flask and stirred for 10 minutes. The pH was adjusted to 7.0 using 6N-HCl. The organic layer was extracted, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at 45°C to produce 97.3 g of the compound represented by formula A-4 (yield: 81.4%). 1 H-NMR (500 MHz, CDCl3): 7.26-7.30 (m, 1H), 6.85-6.92 (m, 2H), 5.83 (s, 1H), 5.64-5.65 (d, 1H), 3.67 (s, 3H), 3.38-3.52 (dd, 2H), 1.41 (s, 9H)

[0152] (Stage 4) A flask was charged with 100.0 g of the compound represented by formula A-4 prepared in step 3 and 2.0 L of toluene, and the mixture was stirred at room temperature for 10 minutes. 104.1 g of N,N-dimethylformamide dimethyl acetal was added, and the mixture was stirred at 40°C for 4 hours to complete the reaction. After concentrating under reduced pressure at 45°C, ethyl acetate and purified water were added to the concentrated residue, and the mixture was stirred for 10 minutes. The pH was adjusted to 7.0 using 1N HCl. The organic layer was extracted, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure at 45°C to produce 79.2 g of the compound represented by formula 1-5 (yield: 77.0%). However, since the compound represented by formula A-5 was unstable (e.g., aerial oxidation occurred), the following step 5 was carried out in situ. 1 H-NMR (500 MHz, CDCl3): 7.73 (s, 1H), 7.48 (s, 1H), 7.38-7.43 (q, 1H), 6.83-6.95 (tt, 2H), 3.90 (s, 3H), 1.39 (s, 9H)

[0153] (Stage 5) A flask was charged with 100.0 g of the compound represented by formula A-5 prepared in step 4 and 1.5 L of acetone, followed by stirring at room temperature for 10 minutes. 78.2 g of potassium carbonate and 42.9 g of dimethyl sulfate were added, and the mixture was stirred at 40°C for 6 hours to complete the reaction. After cooling to room temperature, purified water and ethyl acetate were added and stirred for 10 minutes. The pH was adjusted to 7.0 using 6N-HCl. The organic layer was extracted, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at 45°C to produce 90.6 g of the compound represented by formula A-6 (yield: 87.1%). Next, the following step 6 was carried out in situ without any additional purification steps. 1 H-NMR (500 MHz, CDCl3): 7.87 (s, 1H), 7.31-7.36 (q, 1H), 6.84-6.95 (tt, 2H), 3.86 (s, 3H), 3.68 (s, 3H), 1.38 (s, 9H)

[0154] (Stage 6) A flask was charged with 100.0 g of the compound represented by Formula A-6 in Step 5 and 500.0 mL of methylene chloride, and the mixture was stirred at room temperature for 10 minutes. 310.4 g of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 6 hours to complete the reaction. After cooling to 0-5°C, purified water was slowly added at 15°C or below. The pH was adjusted to 7.0 using 50.0% NaOH solution at 15°C or below. Ethyl acetate was added, and the mixture was stirred for 10 minutes. The organic layer was extracted and dried over anhydrous magnesium sulfate. The organic layer was filtered under reduced pressure through a filter placed on Celite washed with ethyl acetate, and then concentrated under reduced pressure at 45°C. Ethyl acetate was added to the concentrated residue, and the mixture was stirred to form a suspension. n-Hexane was added, and the internal temperature was cooled to 0-5°C, and the mixture was stirred for 1 hour. The resulting solid was filtered under reduced pressure, and the filtrate was washed with n-hexane. The resulting solid was dried under reduced pressure to obtain 65.5 g of the compound represented by Formula B (yield: 90.0%). 1H-NMR (500 MHz, CDCl3): 8.78 (s, 1H), 8.12 (m, 1H), 7.30 (d, 1H), 6.95 (t, 1H), 6.88 (t, 1H), 3.87 (s, 3H), 3.85 (s, 3H)

[0155] (Stage 7) A flask was charged with 100.0 g of methyl 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylate (chemical formula B), 9.2 g of 4-(dimethylamino)-pyridine, and 393.0 g of acetonitrile, and stirred at room temperature for 10 minutes. After the internal temperature of the flask was cooled to 5-10°C, 80.1 g of 3-fluorobenzenesulfonyl chloride (chemical formula B-1) and 53.2 g of N,N-diisopropylethylamine were charged, and the mixture was stirred at a temperature range of 20-30°C for 2 hours to complete the reaction.

[0156] Next, 500.0 g of purified water and 451.0 g of ethyl acetate were added, and the mixture was stirred for 10 minutes, allowed to stand for 10 minutes, and then the aqueous layer was discarded.

[0157] Thereafter, 500.0 g of purified water was added to the organic layer, and a 1N aqueous solution of hydrochloric acid was gradually added within a temperature range of 20°C to 30°C to adjust the pH to 3.5 to 5.0. The mixture was then stirred for 10 minutes and allowed to stand for 10 minutes, and the aqueous layer generated here was discarded.

[0158] The organic layer was then concentrated under reduced pressure at 50-55°C, and 158.4 g of methanol was added at an internal temperature of 20-30°C, followed by stirring for 10 minutes. The organic layer was then concentrated under reduced pressure at 50-55°C, and 396.0 g of methanol was added at an internal temperature of 20-30°C, followed by stirring for 1 hour. While maintaining the internal temperature at 20-30°C, 300.0 g of purified water was added over 20 minutes, followed by stirring for 1 hour. The resulting crystals were filtered under reduced pressure, and the filtrate was washed with 200.0 g of purified water.

[0159] The washed residue was placed in a dryer and vacuum dried at a temperature of 40°C to 45°C for 12 hours or more to obtain 154.4 g of the compound represented by chemical formula B-2 (yield: 97.0%). 1 H-NMR (500 MHz, MeOD): 7.98 (s, 1H), 7.43-7.39 (m, 1H), 7.30 (t, 1H), 7.23 (d, 1H), 7.15 (q, 1H), 7.67 (q, 1H), 6.91 (t, 1H), 6.77 (t, 1H), 3.87 (s, 3H), 3.61 (s, 3H)

[0160] (Step 8) Into a new flask, 100.0 g of the compound represented by formula B-2 obtained in Step 1 and 444.5 g of tetrahydrofuran were added and stirred at 20 to 30° C. for 10 minutes, and then the internal temperature was cooled to −10 to −5° C. To the resulting reaction solution, 32.1 g of zinc chloride was added over 5 minutes and stirred for 10 minutes, and then 28.5 g of N,N-dimethylaniline was added and stirred.

[0161] Thereafter, 8.9 g of sodium borohydride was added in three divided portions over 5 minutes while maintaining the internal temperature within the range of -10°C to 0°C, and stirring for 10 minutes was repeated three times.

[0162] Thereafter, the mixture was stirred at an internal temperature of 60° C. to 65° C. for 20 hours to complete the reaction, and then the internal temperature was cooled to 0° C. to 5° C. Through this reaction, a compound represented by the above chemical formula B-3 was produced.

[0163] Subsequently, 200.0 g of purified water was gradually added while the internal temperature was kept between 0 and 15°C, and 451.0 g of ethyl acetate was added while the internal temperature was kept between 20 and 30°C. Next, 87.2 g of 6N aqueous hydrochloric acid was added, and the mixture was stirred for 30 minutes. After allowing to stand for 10 minutes (maintaining the internal temperature between 20 and 30°C), the layers were separated and the aqueous layer was discarded. The organic layer was then washed with 300.0 g of purified water and 10.9 g of 6N aqueous hydrochloric acid (repeated twice while maintaining the internal temperature between 20 and 30°C). The layers were separated and the aqueous layer was discarded. 50.0 g of magnesium sulfate was added to the organic layer, stirred for 10 minutes, filtered under reduced pressure, and the filtrate was concentrated under reduced pressure at 50 to 55°C. Next, 265.3 g of methylene chloride was added, and the mixture was stirred for 10 minutes and then concentrated under reduced pressure at 50 to 55°C.

[0164] (Step 9) To the concentrated residue from Step 2, 6.9 g of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, 86.1 g of (diacetoxyiodo)benzene, and 1,171.1 g of dichloromethane were added and stirred at an internal temperature of 20°C to 30°C for 2 hours to complete the reaction, after which 882.8 g of purified water was added. Then, 679.7 g of saturated aqueous sodium bicarbonate solution (61.8 g of sodium bicarbonate, 617.9 g of purified water) was gradually added and stirred for 10 minutes. The mixture was then allowed to stand for 10 minutes to separate the layers, and the aqueous layer was discarded. 17.7 g of magnesium sulfate was added to the organic layer, stirred for 10 minutes, and filtered under reduced pressure.

[0165] Thereafter, the mixture was concentrated under reduced pressure at 38°C to 42°C, and then 513.6 g of an aqueous ethanol solution (390.0 g of ethanol, 123.6 g of purified water) was added, followed by stirring at an internal temperature of 20°C to 30°C for 1 hour to cause crystallization.

[0166] The resulting crystals were filtered under reduced pressure, and the filtrate was washed with 174.3 g of an ethanol aqueous solution (132.3 g of ethanol, 41.9 g of purified water). The washed filtrate was placed in a dryer and vacuum dried at 40 to 45°C for 12 hours or more to obtain 83.9 g of the compound represented by chemical formula B-4 (yield: 90.0%). 1 H-NMR (500 MHz, MeOD): 9.89 (s, 1H), 7.99 (s, 1H), 7.45-7.41 (m, 1H), 7.33 (s, 1H), 7.25 (d, 1H), 7.18 (q, 1H), 7.05 (s, 1H), 6.92 (t, 1H), 6.77 (t, 1H), 3.63 (s, 3H)

[0167] (Step 10) Into a new flask, 100.0 g of the compound represented by formula B-4 obtained in Step 3, 396.0 g of methanol, and 48.5 g of methylamine (9.8 M in methanol) were added, and the internal temperature was adjusted to 20°C to 30°C, followed by stirring for 30 minutes.

[0168] Thereafter, the internal temperature was cooled to -5°C to 0°C, and 4.8 g of sodium borohydride was added in portions while maintaining the temperature range of -5°C to 10°C, followed by stirring at -5°C to 10°C for 30 minutes to complete the reaction.

[0169] After the reaction was completed, 1,000 g of purified water was gradually added while maintaining the internal temperature at 10 to 15° C., followed by 902.0 g of ethyl acetate. Next, while maintaining the internal temperature at 10 to 15° C., the pH was adjusted to 6.7 to 7.3 using a 6N aqueous hydrochloric acid solution.

[0170] After stirring for 10 minutes, the mixture was allowed to stand for 30 minutes to separate the layers, and the organic layer was stored. 451.0 g of ethyl acetate was added to the aqueous layer, which was then stirred for 10 minutes and allowed to stand for 10 minutes. The organic layer was then combined with the previously obtained organic layer and the same re-extraction process was carried out once again.

[0171] Thereafter, 600.0 g of an aqueous sodium chloride solution (100.0 g of sodium chloride, 500.0 g of purified water) was added to the combined organic layers, and the mixture was stirred for 10 minutes, allowed to stand for 10 minutes to separate the layers, and the aqueous layer was discarded.

[0172] To the resulting organic layer, 100.0 g of magnesium sulfate was added, and the mixture was stirred for 10 minutes while maintaining the internal temperature at 10 to 15°C, and then filtered under reduced pressure. The residue was washed with 270.6 g of ethyl acetate, and the filtrate was concentrated under reduced pressure at 38 to 42°C.

[0173] 90.2 g of ethyl acetate was added to the concentrated residue and stirred until it became relatively homogeneous. Then, 460.5 g of a 1.0 M hydrochloric acid ethyl acetate solution was gradually added at an internal temperature of -5°C to 5°C, and the mixture was stirred at 0°C to 5°C for 12 hours to crystallize the compound represented by Chemical Formula 1.

[0174] (Refine stage) Next, the crystals obtained in step 10 were filtered under reduced pressure, and the filtrate was washed with 90.2 g of ethyl acetate. The filtrate and 815.4 g of ethyl acetate were added to a new flask, cooled to an internal temperature of 0°C to 15°C, and stirred for 10 minutes. Thereafter, 976.3 g of aqueous sodium bicarbonate solution (72.3 g of sodium bicarbonate, 904.0 g of purified water) was added at an internal temperature of 10°C to 15°C, stirred for 10 minutes, and then allowed to stand for 30 minutes. The layers were separated, and the organic layer was stored.

[0175] To the resulting aqueous layer, 407.7 g of ethyl acetate was added, and the mixture was stirred for 10 minutes. After standing for 10 minutes, the layers were separated, and the organic layer was combined with the previously obtained organic layer. The aqueous layer was re-extracted once more in the same manner and combined with the organic layer.

[0176] 90.4 g of magnesium sulfate was added to the organic layer, and the mixture was stirred for 10 minutes at an internal temperature of 10 to 15°C, and then filtered under reduced pressure. The residue was washed with 244.6 g of ethyl acetate, and the filtrate was concentrated under reduced pressure at 38 to 42°C.

[0177] To the concentrated residue, 81.5 g of ethyl acetate was added and stirred, and then 368.4 g of a 1.0 M hydrochloric acid ethyl acetate solution was gradually added at an internal temperature of -5°C to 5°C, followed by stirring at 0°C to 5°C for 12 hours to allow recrystallization.

[0178] The crystals were filtered under reduced pressure, and the filtrate was washed with 81.5 g of ethyl acetate. The filtrate was then placed in a dryer and vacuum dried at 20°C to 30°C for 12 hours, and then heated to 38°C to 42°C and further dried for 6 hours, finally obtaining 90.7 g of the compound represented by chemical formula 1-1 (yield: 80.2%). 1 H-NMR (500 MHz, MeOD): 7.69(s, 1H), 7.58-7.53(m, 1H), 7.45(t, 1H), 7.30(d, 1H), 7.20-7.15(m, 2H), 7.02-6.94(m, 2H), 4.07(d, 2H), 3.46(s, 3H), 2.71(s, 3H)

[0179] Comparison of Examples and Comparative Examples The yield, quality, etc. of the 4-methoxypyrrole derivatives obtained by the respective production methods of the Examples and Comparative Examples were evaluated as follows, and are shown in Table 1 below.

[0180] Yield of 4-methoxypyrrole derivative The weight of the 4-methoxypyrrole derivative (Chemical Formula 1) recovered after the reaction and the weight of methyl 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylate (Chemical Formula 2) before the reaction were each substituted into the following formula 1 to calculate: [Formula 1] Yield (%) of 4-methoxypyrrole derivative = 100% * {number of moles of 4-methoxypyrrole derivative (chemical formula 1) recovered after completion of reaction} / {number of moles of methyl 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylate (chemical formula 2) before reaction}

[0181] Purity of 4-methoxypyrrole derivatives and content of related substance B The purity of the 4-methoxypyrrole derivative (Chemical Formula 1) recovered after the reaction and the content of related substance B were measured using an HPLC (high performance liquid chromatography, manufactured by Waters, e2695 system) instrument.

[0182] Here, analogue B is 1-(5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine.

[0183] [Table 1]

[0184] From Table 1, it can be seen that the Example not only had improved process efficiency compared to the Comparative Example, but also had an overall yield that was about 1.5 times higher than the Comparative Example.

[0185] In addition, when the manufacturing methods of the Examples and Comparative Examples are applied to industrial production, the manufacturing method of the Comparative Examples takes 17 days to produce the final substance, while the Manufacturing Method of the Examples takes only 9 days. In other words, the manufacturing time of the Examples is reduced by half compared to the Comparative Examples, and therefore production efficiency is expected to double.

[0186] Furthermore, according to the above examples, it is expected that industrial mass production will be possible by ensuring a step-by-step crystallization process.

[0187] Specifically, the Examples and Comparative Examples use the same starting material (i.e., the compound represented by Chemical Formula 1-1) to produce the same final material (i.e., the 4-methoxypyrrole derivative represented by Chemical Formula 1). In addition, the Examples do not use dimethyl sulfate, a genotoxic substance used in the Comparative Examples, thereby reducing worker safety and potential risks to pharmaceuticals.

Claims

1. 1) reacting a compound represented by the following Formula 1-1 with p-toluenesulfinic acid and formamide in the presence of an acid catalyst to prepare a compound represented by the following Formula 1-2: 2) reacting a compound represented by the following formula 1-2 with a dehydrating reagent to prepare a compound represented by the following formula 1-3: 3) reacting a compound represented by the following formula 1-3 with a cyclization reagent to prepare a compound represented by the following formula 1-4: 4) reacting a compound represented by the following formula 1-4 with 3-fluorobenzenesulfonyl chloride to prepare a compound represented by the following formula 1-5: 5) reacting a compound represented by the following formula 1-5 with sodium hydride to prepare a compound represented by the following formula 1-6; and 6) reacting a compound represented by the following formula 1-6 with methylamine to produce an intermediate, and then adding a reducing agent to convert the intermediate into a compound represented by the following formula 1: Method for producing 4-methoxypyrrole derivatives: [Chemical formula 1-1] [Chemical formula 1-2] [Chemical formula 1-3] [Chemical formula 1-4] [Chemical formula 1-5] [Chemical formula 1-6] [Chemical formula 1]

2. 2. The method of claim 1, wherein step 1 is carried out in the presence of an acid catalyst selected from the group consisting of chlorotrimethylsilane (TMSCl), camphorsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, benzoic acid, nitrobenzoic acid, hydrochloric acid, calcium chloride, and mixtures of two or more thereof.

3. The method according to claim 1, wherein the molar ratio of the compound represented by Chemical Formula 1-1 to the acid catalyst is 20:1 to 1:

10.

4. The method according to claim 1, wherein the molar ratio of the compound represented by Chemical Formula 1-1 to formamide is 10:1 to 1:

10.

5. 2. The method according to claim 1, wherein in step 1, p-toluenesulfinic acid is a concentrate having a concentration of 10 mol % or more.

6. The method of claim 1, wherein the reaction temperature in step 1 is 0°C to 80°C.

7. 2. The method of claim 1, wherein the dehydration reagent in step 2 comprises phosphoryl chloride, trichloromethyl chloroformate, triphosgene (bis(trichloromethyl)carbonate), triphenylphosphine, thionyl chloride, p-toluenesulfonic acid, or a mixture of two or more thereof.

8. The method according to claim 1, wherein the molar ratio of the compound represented by Chemical Formula 1-2 to the dehydrating reagent is 20:1 to 1:

10.

9. Step 2 is carried out in the presence of a base, 2. The method of claim 1, wherein the molar ratio of the compound represented by Formula 1-2 to the base in Step 2 is 20:1 to 1:

20.

10. The method of claim 1, wherein the reaction temperature in step 2 is -20°C to 20°C.

11. 2. The method of claim 1, wherein the cyclization reagent in step 3 comprises ethyl (Z)-2-cyano-3-methoxyacrylate, methyl (Z)-2-cyano-3-methoxyacrylate, propyl (Z)-2-cyano-3-methoxyacrylate, or a mixture of two or more thereof.

12. 2. The method of claim 1, wherein in step 3, the molar ratio of the compound represented by Formula 1-4 to the cyclization reagent is 10:1 to 1:

10.

13. Step 3 is carried out in the presence of a base; 2. The method of claim 1, wherein the molar ratio of the compound represented by Formula 1-3 to the base in Step 3 is 20:1 to 1:

10.

14. The method of claim 1, wherein the reaction temperature in step 3 is 50 to 150°C.

15. The method of claim 1, further comprising, before step 4, dissolving the compound represented by Formula 1-4 in an organic solvent together with a catalyst to prepare a composition containing the compound represented by Formula 1-4.

16. 16. The process of claim 15, wherein the catalyst comprises 4-dimethylaminopyridine, 4-pyrrolidinylpyridine, pyridine, 1,5,7-triazabicyclo[4.4.0]dec-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene, 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene, or a mixture thereof.

17. 16. The method of claim 15, wherein in step 4, the molar ratio of the compound represented by Formula 1-4 to the catalyst is 100:1 to 1:

10.

18. 2. The method of claim 1, wherein in step 4, the molar ratio of the compound represented by Formula 1-4 to 3-fluorobenzenesulfonyl chloride is 10:1 to 1:

10.

19. Step 4 is carried out in the presence of a base; 2. The method of claim 1, wherein the molar ratio of the compound represented by Formula 1-4 to the base in Step 4 is 10:1 to 1:

10.

20. The method of claim 1, wherein the reaction temperature in step 4 is 0 to 60°C.

21. 10. The method of claim 1, wherein the sodium hydride of step 5 is a dispersion in mineral oil.

22. 2. The method of claim 1, wherein in step 5, the molar ratio of the compound represented by Formula 1-5 to sodium hydride is 20:1 to 1:

10.

23. 2. The method of claim 1, wherein step 5 is carried out in the presence of zinc halide.

24. 24. The method of claim 23, wherein the zinc halide comprises zinc chloride, zinc bromide, zinc iodide, or a mixture of two or more thereof.

25. 24. The method of claim 23, wherein in step 5, the molar ratio of the compound represented by Formula 1-5 to zinc halide is 10:1 to 1:

10.

26. The method of claim 1, wherein the reaction temperature in step 5 is 20 to 80°C.

27. 10. The method of claim 1, wherein in step 6, the reaction temperature of the compound represented by Formula 1-6 and methylamine is 10 to 30°C.

28. 10. The method of claim 1, wherein the reducing agent in step 6 comprises sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or a mixture of two or more thereof.

29. 2. The method of claim 1, wherein in step 6, the reaction temperature of the reducing agent and the intermediate is −5 to 10° C.

30. 2. The method of claim 1, wherein in step 6, a molar ratio of the compound represented by Formula 1-6 to the methylamine is 10:1 to 1:10, and a molar ratio of the compound represented by Formula 1-6 to the reducing agent is 10:1 to 1:

10.

31. 10. The method of claim 1, further comprising the step of washing the reaction product of step 6 with an aqueous base solution to adjust the pH to 6.0 to 6.

5.

32. After step 6, The method of claim 1 further comprising the additional step of adding an acid to the compound represented by Chemical Formula 1 to prepare an acid salt represented by Chemical Formula 1-1: [Chemical formula 1-1]

33. The method of claim 32, wherein the additional step comprises supplying an organic solvent to the compound represented by Chemical Formula 1, and then supplying an acid or a mixed solution thereof with the organic solvent to crystallize the acid salt represented by Chemical Formula 1-1.

Images