Method for producing 4-methoxypyrrole derivative

Abstract

The invention relates to a preparation method of a 4-methoxy pyrrole derivative. The preparation method according to one embodiment of the present invention has the following advantages that the number of production days is reduced by half, the process efficiency and yield can be improved, the 4-methoxypyrrole derivative can be effectively obtained, and the preparation method is suitable for industrial large-scale production.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of Korean Patent Application No. 10-2023-0020155 filed on February 15, 2023, in the Korean Intellectual Property Office, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to a method for preparing a 4-methoxypyrrole derivative. Background Art

[0004] When the balance between aggressive factors (e.g., gastric acid, Helicobacter pylori, pepsin, stress, alcohol, tobacco, etc.) and defensive factors (e.g., gastric mucosa, bicarbonate, prostaglandins, blood supply, etc.) is disrupted, gastrointestinal ulcers, gastritis, and reflux esophagitis may occur. Therefore, therapeutic agents for treating gastrointestinal lesions such as gastrointestinal ulcers, gastritis, and reflux esophagitis are divided into drugs for suppressing aggressive factors and drugs for enhancing defensive factors.

[0005] On the other hand, it is reported that even without gastric acid secretion, gastrointestinal ulcer, gastritis and reflux esophagitis also can ulcer.Therefore, along with the increase of aggressive factors, the defensive factors caused by the pathological changes of gastric mucosa reduce and are considered to play an important role in the generation of gastric ulcer.Therefore, except being used to suppress the medicine of aggressive factors, also use the medicine that is used to strengthen defensive factors to treat gastrointestinal ulcer and gastritis.As the medicine that is used to strengthen defensive factors, known have the mucosal protective medicine that is attached to the ulcer site to form physicochemical film and the medicine that promotes mucus synthesis and secretion.

[0006] On the other hand, Helicobacter pylori (a bacterium that lives in the stomach) is known to cause chronic gastritis, gastric ulcer, duodenal ulcer, and similar diseases, and a large number of patients with gastrointestinal damage are infected with Helicobacter pylori. Therefore, these patients must take antibiotics (such as clarithromycin, amoxicillin, metronidazole, tetracycline) and antiulcer agents (such as proton pump inhibitors or acid pump antagonists). As a result, various side effects have been reported.

[0007] Therefore, there is a need to develop anti-ulcer drugs that inhibit gastric acid secretion (eg, proton pump inhibitory activity) and enhance defensive factors (eg, increase in mucus secretion) while having eradication activity against Helicobacter pylori.

[0008] In this regard, Korean Patent No. 10-1613245 discloses that a 4-methoxypyrrole derivative or a pharmaceutically acceptable salt thereof has excellent anti-ulcer activity (i.e., proton pump inhibitory activity, etc.) and eradication activity against Helicobacter pylori, and thus is effectively used for preventing and treating gastrointestinal damage caused by gastrointestinal ulcers, gastritis, reflux esophagitis, or Helicobacter pylori.

[0009] Specifically, the above-mentioned previous patent discloses the following compounds as a class of 4-methoxypyrrole derivatives.

[0010]

[0011] According to the description in the above-mentioned previous patent, the preparation process of the compound consists of seven steps in total.

[0012] However, the preparation process according to the above-mentioned previous patent has a low yield of 4.63%, requires a high temperature reaction, and requires expensive equipment, and is therefore not suitable for industrial mass production.

[0013] Therefore, Korean Patent No. 10-2233455 provides a method for producing the following intermediate for preparing a 4-methoxypyrrole derivative.

[0014]

[0015] According to the description in the above-mentioned previous patent, the preparation process of the intermediate compound consists of six steps in total.

[0016] In addition, Korean Patent No. 10-2126576 provides a method for producing a 4-methoxypyrrole derivative from the above intermediate. According to the description of this previous patent, the preparation process of the intermediate compound consists of four steps in total.

[0017] However, when 4-methoxypyrrole derivatives were produced by combining the preparation processes of the above two previous patents, the overall yield was as low as 20.2% and the preparation process consisted of ten steps in total, thus still not suitable for industrial mass production.

[0018] Thus, the present inventors have found a production method for obtaining a 4-methoxypyrrole derivative consisting of six steps in total, and the compound is obtained in a higher yield than that of the above-mentioned previous patents, thereby completing the present invention. Summary of the Invention

[0019] [Technical Issues]

[0020] An object of the present invention is to provide a method for producing a 4-methoxypyrrole derivative.

[0021] [Technical solution]

[0022] To achieve the above objectives, this article provides a preparation method shown in the following reaction scheme 1:

[0023] [Reaction Scheme 1]

[0024]

[0025] Specifically, in one embodiment of the present invention, a method for producing a compound represented by Chemical Formula 1 is provided, comprising the following steps 1 to 6:

[0026] 1) reacting the compound represented by Chemical Formula 1-1 with p-toluenesulfinic acid and formamide in the presence of an acid catalyst to prepare the compound represented by Chemical Formula 1-2;

[0027] 2) reacting the compound represented by Chemical Formula 1-2 with a dehydrating agent to prepare a compound represented by Chemical Formula 1-3;

[0028] 3) reacting the compound represented by Chemical Formula 1-3 with a cyclization reagent to prepare a compound represented by Chemical Formula 1-4;

[0029] 4) reacting the compound represented by Chemical Formula 1-4 with 3-fluorobenzenesulfonyl chloride to prepare the compound represented by Chemical Formula 1-5;

[0030] 5) reacting the compound represented by Chemical Formula 1-5 with sodium hydride to prepare the compound represented by Chemical Formula 1-6; and

[0031] 6) reacting the compound represented by Chemical Formula 1-6 with methylamine to form an intermediate, and then adding a reducing agent to convert the intermediate into the compound represented by Chemical Formula 1.

[0032] In Korean Patent No. 10-2233455 and Korean Patent No. 10-2126576 discussed previously, when preparing the compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 1-1, many reaction steps must be performed, and the yield of the final material and process efficiency are low.

[0033] For example, by combining Korean Patent No. 10-2233455 and Korean Patent No. 10-2126576, in order to prepare the compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 1-1, a total of 10 reaction steps must be performed, which is a factor that reduces the yield of the final material and process efficiency.

[0034] On the other hand, the above embodiment of the present invention has the following advantages: the required reaction steps are simplified, the process efficiency and the yield of the final material are improved compared with the above-mentioned previous patents, and the production days are reduced by half, which makes it suitable for industrial large-scale production of 4-methoxypyrrole derivatives.

[0035] Next, the embodiments of the present invention will be described in detail for each of the above steps. Referring to the following description, the quality of the final material can also be controlled by adjusting the process temperature, process time, etc. of each of the above steps.

[0036] (Step 1)

[0037] Step 1 is a step of reacting the compound represented by Chemical Formula 1-1 with p-toluenesulfinic acid and formamide in the presence of an acid catalyst to prepare the compound represented by Chemical Formula 1-2, which is a step of introducing a formamide group and a substituted phenylsulfonyl group into the compound represented by Chemical Formula 1-1.

[0038] First, step 1 may include preparing a p-toluenesulfinic acid (4-methylbenzenesulfinic acid) concentrate before reacting with the compound represented by Chemical Formula 1-1. Thus, the concentrated p-toluenesulfinic acid can be used for the reaction between the compound represented by Chemical Formula 1-1 and formamide.

[0039] A p-toluenesulfinic acid concentrate can be prepared by mixing sodium p-toluenesulfinic acid with water and an organic solvent under acidic conditions, separating an organic layer from the mixture, mixing the organic layer with sodium sulfate, and removing and concentrating the water. The p-toluenesulfinic acid concentrate can be concentrated to 10 mol% or higher, more specifically 50 to 500 mol%.

[0040] Preferably, the acid that can be used includes hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid, and more preferably, hydrochloric acid is used.

[0041] Preferably, the organic solvent that can be used includes ethyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, tert-butyl methyl ether or a mixture of two or more thereof. Preferably, the organic solvent can be ethyl acetate.

[0042] Preferably, before mixing with sodium sulfate, the method may further comprise the steps of separating an organic layer of the mixture of sodium p-toluenesulfinate, water and ether, mixing the organic layer with a saturated sodium chloride solution, and then separating the organic layer again.

[0043] Preferably, the concentration step may be a reduced pressure concentration step.

[0044] Next, the prepared concentrated residue of p-toluenesulfinic acid is mixed with the compound represented by Chemical Formula 1-1 (2,4-difluorobenzaldehyde) and formamide and reacted in the presence of an acid catalyst to prepare a compound represented by Chemical Formula 1-2.

[0045] Preferably, the molar ratio between the compound represented by Chemical Formula 1-1 and formamide may be 10:1 to 1:10, specifically, 5:1 to 1:5.

[0046] Preferably, the reaction can be carried out in the presence of trimethylchlorosilane (TMSCl), camphorsulfonic acid, trifluoromethanesulfonic acid (TfOH), trifluoroacetic acid, benzoic acid, nitrobenzoic acid, hydrochloric acid, calcium chloride, or a mixture of two or more thereof as an acid catalyst. The above compounds can be used as acid catalysts for the Mannich reaction, which is the reaction of step 1. Preferably, the reaction can be carried out in the presence of trimethylchlorosilane, trifluoromethanesulfonic acid, or a mixture thereof.

[0047] Preferably, the molar ratio between the compound represented by Chemical Formula 1-1 and the acid catalyst may be 20:1 to 1:10, and more preferably 10:1 to 1:5.

[0048] Preferably, acetonitrile, tetrahydrofuran, dichloromethane, methanol, ethanol, propanol, isopropanol, butanol, tert-butyl alcohol, toluene or a mixture of two or more thereof can be used as the reaction solvent. Specifically, a mixture of toluene and acetonitrile can be used.

[0049] The reaction is preferably carried out at 0°C to 80°C. Preferably, the reaction is carried out 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 reduced, while if the reaction temperature is too high, side reactions may occur or the reaction may only incur production costs without significantly improving production yield. Preferably, the reaction temperature may be the internal temperature of the reactor.

[0050] Preferably, the second reaction is carried out for 1 to 36 hours. Preferably, the reaction is carried out for 5 to 30 hours. If the reaction time is too short, there is a problem that the reaction does not proceed sufficiently and the manufacturing yield of step 1 is reduced. If the reaction time is too long, there may be a problem that only the manufacturing cost is borne without significantly improving the manufacturing yield.

[0051] After the reaction of step 1 is completed, the method may further include the steps of concentrating and purifying the compound represented by Chemical Formula 1-2, if necessary. Preferably, the purification can be performed by crystallizing the compound represented by Chemical Formula 1-2 from the reaction product of step 1.

[0052] As a solvent for crystallizing the compound represented by Chemical Formula 1-2 from the reaction product of step 1, a single alcohol compound or a mixed solvent thereof with water can be used. Specific examples of alcohols may include methanol, ethanol, propanol, butanol, isopropanol, or a mixture of two or more thereof. For example, the reaction product of step 1 can be crystallized by adding methanol alone, isopropanol alone, or a mixture thereof with water at a temperature ranging from 0°C to 30°C, stirring the mixture 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, isopropanol, or a mixture thereof with water.

[0053] After the compound represented by Chemical Formula 1-2 is purified, it may be dried at 40° C. to 80° C. for 12 to 48 hours to reduce the moisture content contained in the compound represented by Chemical Formula 1-2. Specifically, the drying may be vacuum drying.

[0054] More specifically, if the moisture content in the compound represented by Formula 1-2 is significantly reduced by drying at 40° C. to 80° C., the conversion rate of the next step (ie, Step 2 below) may be improved.

[0055] (Step 2)

[0056] Step 2 is a step of reacting the compound represented by Chemical Formula 1-2 with a dehydrating agent to prepare a compound represented by Chemical Formula 1-3.

[0057] Preferably, step 2 is a step of converting a formamide group present in the compound represented by Chemical Formula 1-2 into an isonitrile group to prepare a compound represented by Chemical Formula 1-3.

[0058] Preferably, the dehydrating agent comprises phosphorus oxychloride, trichloromethyl chloroformate, bis(trichloromethyl)carbonate, triphenylphosphine, thionyl chloride, p-toluenesulfonic acid or a mixture of two or more thereof. The dehydrating agent can convert the formamide group into an isonitrile group.

[0059] Preferably, the molar ratio between the compound represented by Chemical Formula 1-2 and the dehydrating agent is 20:1 to 1:10, and more preferably 10:1 to 1:5.

[0060] Preferably, step 2 can be carried out in the presence of a base. Preferably, the base can be trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate or cesium carbonate, and preferably triethylamine. Preferably, the molar ratio between the compound represented by Chemical Formula 1-2 and the base is 20:1 to 1:20, and more preferably 10:1 to 1:10.

[0061] Preferably, the reaction solvent of step 2 may include 1,2-dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl carbonate, acetonitrile, ethyl acetate, N,N-dimethylformamide, carbon tetrachloride, dichloromethane or a mixture of two or more thereof. Specifically, 1,2-dimethoxyethane may be used as the reaction solvent.

[0062] 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 reduced, while if the reaction temperature is too high, the yield may be reduced due to an increase in reaction by-products. Preferably, the reaction temperature may be the internal temperature of the reactor.

[0063] Preferably, the secondary reaction is carried out for 10 minutes to 10 hours. Preferably, the reaction is carried out for 30 minutes to 8 hours, or 1 hour to 4 hours. If the reaction time is too short, the reaction cannot be fully carried out and the manufacturing yield of step 1 is reduced. If the reaction time is too long, there may be a problem that only the manufacturing cost is borne without significantly improving the manufacturing yield.

[0064] After the reaction of step 2 is completed, the method may further include the step of purifying the compound represented by Chemical Formula 1-3, if necessary. Preferably, the purification can be performed by crystallizing the compound represented by Chemical Formula 1-3 from the reaction product of step 2.

[0065] The solvent used to crystallize the compound represented by Chemical Formula 1-3 from the reaction product of step 2 may 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 crystallized by adding ethyl acetate to extract the organic layer, concentrating the organic layer, sequentially mixing methanol and water with the concentrated residue, stirring the mixture for 10 minutes to 1 hour, filtering under reduced pressure, and then washing the filtrate. In addition, sodium bicarbonate may be used before crystallization and during washing of the organic layer to complete the reaction and remove by-products.

[0066] The compound represented by Chemical Formula 1-3 is purified and then dried at 40° C. to 80° C. for 12 to 48 hours, so that the moisture content contained in the compound represented by Chemical Formula 1-3 can be reduced. Preferably, the drying may be vacuum drying.

[0067] More specifically, if the moisture content of the compound represented by Formula 1-3 is significantly reduced by drying at 40° C. to 60° C., the conversion rate in the next step (ie, Step 3 below) may be improved.

[0068] (Step 3)

[0069] Step 3 is a step of reacting the compound represented by Chemical Formula 1-3 with a cyclizing agent to prepare a compound represented by Chemical Formula 1-4.

[0070] 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.

[0071] Preferably, the molar ratio between the compound represented by Chemical Formula 1-3 and the cyclization reagent may be 10:1 to 1:10, and more preferably 5:1 to 1:5.

[0072] The reaction solvent of step 3 may include acetonitrile, tetrahydrofuran, dichloromethane, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, toluene or a mixture of two or more thereof. Specifically, methanol may be used.

[0073] Step 3 is preferably carried out in the presence of a base. Specifically, the base can be trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, potassium butyrate or cesium carbonate, and more preferably, potassium carbonate is used. Preferably, the molar ratio between the compound represented by Chemical Formula 1-3 and the base is 20:1 to 1:10, and more preferably 10:1 to 1:5.

[0074] 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, there is a problem of reduced production yield, while if the reaction temperature is too high, there may be a problem of reduced yield due to an increase in reaction by-products.

[0075] Preferably, the secondary reaction is carried out for 30 minutes to 10 hours. Preferably, the reaction is carried out for 1 hour to 5 hours. If the reaction time is too short, the reaction may not proceed sufficiently, resulting in a problem of reduced production yield in step 3. If the reaction time is too long, there may be a problem of only bearing the production cost without significantly improving the production yield.

[0076] After the reaction of step 3 is completed, the method may further include the step of purifying the compound represented by Chemical Formula 1-4, if necessary. Preferably, the purification can be performed by crystallizing the compound represented by Chemical Formula 1-4 from the reaction product of step 3.

[0077] The solvent for crystallizing the compound represented by Chemical 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 in step 3 is completed, ethyl acetate is mixed with water, the organic layer is separated, and the separated organic layer can then be washed with water and sodium chloride solution in sequence and concentrated under reduced pressure. An organic solvent (such as methanol) can then be added to the concentrated residue, purified water can be added, cooled, and then stirred. Crystallization can then be performed by filtering the crystals under reduced pressure and then washing the filtrate.

[0078] The compound represented by Chemical Formula 1-4 is purified and then dried at 40°C to 80°C for 12 to 48 hours to reduce the moisture content of the compound represented by Chemical Formula 1-4. Preferably, the drying is performed by vacuum drying. More specifically, the drying temperature may be 40°C to 60°C.

[0079] (Step 4)

[0080] Step 4 is a step of reacting the compound represented by Chemical Formula 1-4 with 3-fluorobenzenesulfonyl chloride to prepare a compound represented by Chemical Formula 1-5.

[0081] Before reacting the compound represented by Chemical Formula 1-4 with 3-fluorobenzenesulfonyl chloride, the method may further include a step of dissolving the compound together with a catalyst in an organic solvent to prepare a composition containing the compound represented by Chemical Formula 1-4.

[0082] The catalyst may be a nucleophilic catalyst. More specifically, the catalyst includes 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).

[0083] Preferably, the molar ratio between the compound represented by Chemical Formula 1-4 and the catalyst may be 100:1 to 1:10, specifically 20:1 to 1:3.

[0084] The organic solvent can be acetonitrile, tetrahydrofuran, dichloromethane, methanol, ethanol, propanol, isopropanol, butanol, tert-butyl alcohol, toluene or a mixture of two or more thereof. Specifically, acetonitrile can be used. Preferably, the solvent can be used in a volume (mL / g) of 1 to 10 times the weight of the compound represented by Chemical Formula 1-4.

[0085] Subsequently, the compound represented by Chemical Formula 1-4 and 3-fluorobenzenesulfonyl chloride may react under basic conditions.

[0086] The base may include trimethylamine, triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, potassium butyrate or cesium carbonate. Preferably, diisopropylethylamine is used.

[0087] Preferably, the molar ratio between the compound represented by Chemical Formula 1-4 and the base may be 10:1 to 1:10, more specifically 5:1 to 1:5.

[0088] In step 4, a molar ratio between the compound represented by Chemical Formula 1-4 and 3-fluorobenzenesulfonyl chloride may be 10:1 to 1:10, more specifically 5:1 to 1:5.

[0089] 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, there is a problem of reduced production yield, while if the reaction temperature is too high, side reactions may occur, and only production costs are incurred without significantly improving production yield.

[0090] Preferably, step 4 is carried out by stirring for 30 minutes to 10 hours. Preferably, it is carried out for 1 hour to 5 hours. If the reaction time is too short, there is a problem that the reaction cannot be fully carried out and the production yield in step 4 is reduced. If the reaction time is too long, there may be a problem that only the production cost is incurred without significantly improving the production yield.

[0091] After the reaction in step 4 is completed, the method may further include, if necessary, a step of purifying the reaction product containing the compound represented by Chemical Formula 1-5. Preferably, the purification can be performed by crystallizing the compound represented by Chemical Formula 1-5 from the reaction product of step 4.

[0092] Preferably, the reaction product of step 4 is mixed with ethyl acetate and water, and the organic layer is then separated. Next, the separated organic layer is concentrated, mixed with methanol and concentrated, and 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. Crystallization can be performed by filtering the resulting crystals under reduced pressure and then washing the filtrate.

[0093] The compound represented by Chemical Formula 1-5 is purified and then dried at 40° C. to 80° C. for 12 to 48 hours, so that the moisture content contained in the compound represented by Chemical Formula 1-5 can be reduced.

[0094] More specifically, if the moisture content in the compound represented by Formula 1-5 is significantly reduced by drying at 40° C. to 60° C., the conversion rate in the next step (ie, Step 5 below) may be improved.

[0095] (Step 5)

[0096] Step 5 is a step of reacting the compound represented by Chemical Formula 1-5 with sodium hydride to prepare the compound represented by Chemical Formula 1-6.

[0097] Preferably, step 5 is a step of converting an isonitrile group present in the compound represented by Chemical Formula 1-5 into an aldehyde group to prepare a compound represented by Chemical Formula 1-6.

[0098] Preferably, the molar ratio between the compound represented by Chemical Formula 1-5 and sodium hydride is 20:1 to 1:10, and more preferably 10:1 to 1:5.

[0099] Sodium hydride can be used in the form of a dispersion in mineral oil. Specifically, a dispersion in liquid paraffin can be used. By using the sodium hydride dispersed in mineral oil, sodium hydride is a dry solid state, thereby minimizing contact with air and reducing fire risk.

[0100] Preferably, in step 5, acetonitrile, tetrahydrofuran, dichloromethane, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, toluene or a mixture of two or more thereof may be used as a reaction solvent, and specifically, tetrahydrofuran (THF) may be used as a solvent.

[0101] Preferably, step 5 can be carried out in the presence of a zinc halide. The zinc halide may include zinc chloride, zinc bromide, zinc iodide, or a mixture of two or more thereof. The zinc halide plays a role in adjusting the reactivity of the sodium hydride reduction reaction in step 5 to reduce side reactions, and assists in producing the compound represented by Chemical Formula 1-6. The presence of these effects can improve the reaction efficiency in step 5.

[0102] Here, a molar ratio between the compound represented by Chemical Formula 1-5 and the zinc halide may be 10:1 to 1:10, more specifically 5:1 to 1:5.

[0103] The reaction temperature of 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, there is a problem of reduced production yield, while if the reaction temperature is too high, there may be a problem of reduced yield due to increased reaction by-products.

[0104] Preferably, step 5 is carried out by stirring for 1 to 36 hours. Preferably, it is carried out for 5 to 24 hours. If the reaction time is too short, there is a problem that the reaction does not proceed sufficiently and the production yield in step 5 is reduced. If the reaction time is too long, there may be a problem that only the production cost is incurred without significantly improving the production yield.

[0105] Specifically, the compound represented by Chemical Formula 1-5 and a solvent are stirred in a reactor at room temperature, zinc chloride and sodium hydride are then added, and the mixture is stirred at 40° C. to 60° C. for 5 to 24 hours.

[0106] Due to the reaction between the compound represented by Chemical Formula 1-5 and sodium hydride, hydrogen and heat may be generated. Therefore, after the reaction in step 5 is completed, the reactor is 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 on a production scale may be improved.

[0107] After cooling the internal temperature of the reactor, the method may include, if necessary, a step of purifying the compound represented by Chemical Formula 1-6. More specifically, purification may be performed by crystallizing the compound represented by Chemical Formula 1-6 from the reaction product of step 5.

[0108] 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 then the pH is adjusted to 1.0 to 2.0 with an acid solution, and the organic layer can be separated. Subsequently, sodium sulfate is mixed with the organic layer, followed by filtration and concentration under reduced pressure.

[0109] Subsequently, the concentrated residue is mixed with methanol, ethanol, propanol, butanol, isopropanol, ethyl acetate, butyl acetate, isopropyl acetate, n-hexane, n-heptane, or a mixture of two or more thereof as a crystallization solvent, or a mixture thereof with water, and the mixture is stirred for 10 minutes to 1 hour. Subsequently, after reduced pressure filtration, the filtrate is washed and vacuum-dried at 40° C. to 80° C. for 12 to 48 hours to reduce the moisture content contained in the compound represented by Chemical Formula 1-6.

[0110] (Step 6)

[0111] Step 6 is a step of reacting the compound represented by Chemical Formula 1-6 with methylamine to form an intermediate, and then adding a reducing agent to convert the intermediate into the compound represented by Chemical Formula 1.

[0112] Specifically, in step 6, the compound represented by Chemical Formula 1-6 undergoes an imine-forming reaction with methylamine to form an imine compound. Since the imine compound corresponds to an intermediate having an unstable structure, it can be easily converted into the compound represented by Chemical Formula 1 through a reduction reaction.

[0113] The reductive imidization reaction in step 6 can be carried out in a reaction solvent, which is methanol, ethanol, isopropanol, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl ether, acetonitrile or a mixture of two or more thereof.

[0114] More specifically, the compound represented by Chemical Formula 1-6 and methanol are added to a reactor separate from step 6, and then cooled to 10° C. to 15° C. Methylamine is then added thereto, and stirred at 10° C. to 30° C. for 20 minutes to 2 hours. This allows the compound represented by Chemical Formula 1-6 and methylamine to react while being fully dissolved in the solvent, thereby generating an imine compound.

[0115] At this time, considering that the content of structurally variable substances in the final material may increase as the solubility of the compound represented by Chemical Formula 1-6 decreases, the stirring time and temperature may be adjusted. For example, when stirring at 10°C to 15°C for 30 minutes to 1 hour, the compound represented by Chemical Formula 1-6 can be fully dissolved. However, if the reaction is carried out in this state, the content of structurally variable substances in the final material will be reduced.

[0116] On the other hand, the reduction reaction of the intermediate (ie, imine compound) generated by the reaction between the compound represented by Chemical Formula 1-6 and methylamine may be performed more stably at low temperatures.

[0117] In view of this, after the reaction between the compound represented by Chemical Formula 1-6 and methylamine is completed, the reactor is cooled until the temperature reaches a range of -10°C to 0°C, for example, -10°C to -5°C, a reducing agent is added according to the cooled temperature range, and the mixture may be stirred while the reactor temperature is maintained at -5°C to 10°C, for example, -5°C to 0°C. Within this low temperature range, the intermediate (i.e., the imine compound) may stably react with the reducing agent and may be converted into the compound represented by Chemical Formula 1.

[0118] Here, the reducing agent may include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or a mixture of two or more thereof, and the molar ratio between the compound represented by Chemical Formula 6 and methylamine may be 10:1 to 1:10, and the molar ratio between the compound represented by Chemical Formula 6 and the reducing agent may be 10:1 to 1:10. Specifically, each molar ratio may be 5:1 to 1:5, more specifically 3:1 to 1:3.

[0119] After the intermediate (i.e., the imine compound) and the reducing agent have fully reacted, 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 may be supplied to adjust the pH to terminate the reaction (post-treatment). For example, the pH may be adjusted to 6.5 to 7.5, more specifically 7.0 to 7.5, by supplying a 5 to 7N aqueous hydrochloric acid solution.

[0120] Thereafter, an organic solvent may be used to perform 1 to 3 extractions to obtain an organic layer. The organic layer is washed with an aqueous alkaline solution to remove acidic related substances, which are decomposition products produced during the process. A desiccant may be added thereto, stirred, and then filtered under reduced pressure. Subsequently, the filtrate is washed, the pH value of the filtrate is adjusted to 6.0 to 6.5, and the filtrate may be concentrated under reduced pressure. The pH value of the filtrate is adjusted to 6.0 to 6.5 before concentration under reduced pressure, so that the efficiency of removing unknown related substances during crystallization is improved, and a high-purity product represented by Chemical Formula 1 can be obtained without any further purification steps.

[0121] 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 may be used.

[0122] As the base for preparing the aqueous alkaline solution, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, potassium butyrate, or cesium carbonate can be used, and preferably, sodium bicarbonate can be used.

[0123] In addition, examples of the drying agent used after the extraction may include magnesium sulfate, sodium sulfate, and the like.

[0124] In order to regulate the pH of the filtrate obtained after drying, the acid or its mixed solutions with an organic solvent can 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 solutions with an organic solvent. The organic solvent in the mixed solutions can be selected from organic solvents mentioned above. For example, ethyl acetate, ether or its mixture can be used as an organic solvent and hydrochloric acid is dissolved in a mixed solutions wherein with a concentration of 0.5 to 2.0 M for regulating pH.

[0125] (Additional step - step of preparing acid addition salt)

[0126] The compound represented by Chemical Formula 1 may be in the form of a pharmaceutically acceptable salt. The salt includes conventional acid addition salts, for example, 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, p-aminobenzenesulfonic 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 a fumarate.

[0127] In order to provide the compound represented by Chemical Formula 1 in the form of a pharmaceutically acceptable salt, after step 6, a step of adding an acid to the compound represented by Chemical Formula 1 to obtain a pharmaceutically acceptable acid salt represented by Chemical Formula 1-1 may be further included:

[0128] [Chemical Formula 1-1]

[0129]

[0130] Specifically, the additional step may include the step of 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.

[0131] More specifically, an organic solvent may be supplied to the concentrated residue containing the compound represented by Chemical Formula 1 in step 6. The supplied organic solvent 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. For example, it may be ethyl acetate.

[0132] After the organic solvent is supplied to the concentrated residue containing the compound represented by Chemical Formula 1 in step 6, stirring is performed, the temperature inside the reactor is adjusted to 0°C to 5°C, and an acid or a mixed solution thereof with an organic solvent is supplied. Thereafter, the acid salt represented by Chemical Formula 1-1 can be crystallized by stirring at 18°C ​​to 22°C.

[0133] The acid used to crystallize the acid salt represented by Chemical Formula 1-1 or its mixed solution with an organic solvent can 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 thereof with an organic solvent. The organic solvent in the mixed solution can be selected from the organic solvents mentioned above. For example, a mixed solution in which ethyl acetate, diethyl ether, or a mixture thereof is used as an organic solvent and hydrochloric acid is dissolved therein at a concentration of 0.5 to 2.0 M can be used to crystallize the acid salt represented by Chemical Formula 1-1.

[0134] Considering that when the reaction temperature is lower than 18°C, the solubility of impurities decreases and the purity of the acid salt represented by Chemical Formula 1-1 decreases, and when the reaction temperature exceeds 22°C, only the manufacturing cost is incurred without a significant improvement in manufacturing yield, the crystallization temperature range of the acid salt represented by Chemical Formula 1-1 is determined to be 18°C ​​to 22°C.

[0135] In addition, in order to crystallize the acid salt represented by Chemical Formula 1-1, the acid or a mixed solution thereof with an organic solvent is supplied and then stirred for at least 1 hour. Furthermore, the stirring time may be controlled to 12 hours or less to prevent precipitation of related substances during stirring.

[0136] Compared with the prior art, the present invention has the advantage that the same level of quality can be obtained even if the acid salt is crystallized only once.

[0137] Meanwhile, a pharmaceutical composition for preventing or treating gastrointestinal damage caused by gastrointestinal ulcer, gastritis, reflux esophagitis or Helicobacter pylori (H. pylori) is provided, which comprises a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0138] In addition, a pharmaceutical composition for preventing or treating a 5-HT receptor-mediated or muscarinic acetylcholine receptor-mediated disease is provided, comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof. In this case, the 5-HT receptor-mediated or muscarinic acetylcholine receptor-mediated disease may be depression, manic depression, schizophrenia, autism, obsessive-compulsive disorder, anxiety, migraine, hypertension, eating disorders, irritable bowel syndrome (IBS), peptic ulcer, diabetic neuropathy, asthma, or overactive bladder.

[0139] Pharmaceutical compositions may include commonly used pharmaceutically acceptable carriers, such as excipients, disintegrants, sweeteners, lubricants, or flavorings. Pharmaceutical compositions may be formulated into oral formulations, such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups, or parenteral formulations, such as injections, according to existing methods. The formulations may be formulated into various dosage forms, such as single-dose or multi-dose forms.

[0140] The pharmaceutical composition can be administered orally or non-orally. Non-oral administration may include, for example, intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical administration. Preferably, the composition can be administered orally. Therefore, the composition can be formulated into various dosage forms, such as tablets, capsules, aqueous solutions, or suspensions. In the case of tablets for oral administration, a carrier (such as lactose or corn starch) and a lubricant (such as magnesium stearate) can usually be added. In the case of capsules for oral administration, lactose and / or dry corn starch can be used as diluents. When an aqueous suspension is required for oral use, the active ingredient can be combined with an emulsion and / or suspension. If necessary, certain sweeteners and / or flavorings can be added. For intramuscular, intraperitoneal, subcutaneous, and intravenous administration, a sterile solution of the active ingredient is usually prepared, and the pH value of the solution should be appropriately adjusted and buffered. For intravenous administration, the total concentration of the solute should be controlled to make the preparation isotonic. The composition according to the present invention can be in the form of an aqueous solution containing a pharmaceutically acceptable carrier (such as saline with a pH value of 7.4). The solution may be introduced into the patient's intramuscular bloodstream by local bolus injection.

[0141] In this case, the pharmaceutical composition can be administered in a therapeutically effective amount. Therefore, the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition can be administered to an individual patient in an effective amount ranging from about 0.01 mg / kg to about 100 mg / kg per day. Of course, the dosage can be varied according to the patient's age, weight, susceptibility, symptoms, or efficacy of the compound.

[0142] [Beneficial Effects]

[0143] As described above, according to one embodiment of the present invention, process efficiency and yield are improved, which may be beneficial to the industrial mass production of 4-methoxypyrrole derivatives. DETAILED DESCRIPTION

[0144] Hereinafter, the present invention will be described in more detail with the aid of the following examples. However, the following examples are for illustrative purposes only, and the scope of the present invention is not limited thereto.

[0145] Analysis of the compounds prepared in the following examples was performed as follows: Nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker 400 MHz spectrometer, chemical shifts were analyzed in ppm, and column chromatography was performed on silica gel (Merck, 70 to 230 mesh) (WC Still, J. Org. Chem., 1978 (43), 2923-2925).

[0146] Example

[0147] [Reaction Scheme 1-1]

[0148]

[0149] 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 were added to a flask, stirred for 10 minutes, and allowed to stand for 10 minutes. The aqueous layer was then discarded and the organic layer separated. 20.0 mL of saturated sodium chloride solution was then added to the organic layer, stirred for 10 minutes, allowed to stand for 10 minutes, and the aqueous layer was then discarded. 6.0 g of sodium sulfate was added to the organic layer, stirred for 5 minutes, 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%.

[0150] 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 trimethylsilyl chloride (TMSCl) were added to the flask containing the concentrated residue obtained from the above concentrate, and stirred at 30°C for 18 hours.

[0151] Subsequently, the resulting mixture was concentrated at an external temperature of 40°C to remove the solvent. 73.2 mL of methanol was added to the concentrated residue, stirred at 50°C for 30 minutes, then cooled to room temperature, and further stirred for 1 hour. The resulting crystals were filtered under reduced pressure, and the filtrate was washed with 24.4 mL of methanol. The filtrate thus washed was placed in a desiccator and then vacuum-dried at a temperature of 50°C to 60°C for 12 hours or longer to obtain 25.8 g of the compound represented by Chemical Formula 1-2 (yield: 92.3%).

[0152] 1H NMR (500MHz, DMSO): δ9.93(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).

[0153] (Step 2)

[0154] 10.1 g of the compound represented by Chemical Formula 1-2 and 60.0 mL of 1,2-dimethoxyethane were added to the flask, and the mixture was cooled to 0 to 5° C. and stirred. 11.5 g of phosphorus oxychloride was gradually added to the flask over 5 minutes.

[0155] Subsequently, 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. Subsequently, the mixture was stirred for 1 hour while maintaining the temperature at -5°C to 0°C.

[0156] Subsequently, 10.0g of sodium bicarbonate was dissolved in 150.0mL of purified water, and this solution was then gradually added and vigorously stirred for 10 minutes. 150.0mL 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. 50.0mL of methanol was added to the concentrated residue obtained and stirred, followed by gradual dropwise addition of 50.0mL of purified water, stirred at room temperature for 20 minutes, and the resulting crystals were filtered under reduced pressure. The filtrate was placed in a desiccator and vacuum dried at a temperature of 50°C to 60°C for 12 hours or longer to obtain 7.1g of the compound represented by Chemical Formula 1-3 (yield: 74.4%).

[0157] 1 H NMR (500MHz, DMSO): δ7.70(d,2H),7.54(d,2H),7.47-7.39(m,2H),7.26(td,1H),7.10(s,1H),2.46(s,3H).

[0158] (Step 3)

[0159] 8.0 g of the compound represented by Chemical Formula 1-3, 4.0 g of (Z)-2-cyano-3-methoxyethyl acrylate (CMA), 7.2 g of potassium carbonate (K2CO3) and 160.0 mL of methanol were added to the flask and the mixture was stirred under reflux at an external temperature of the reactor of 80°C for 2 hours.

[0160] The reaction solution 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 the mixture was stirred for 10 minutes, allowed to stand for 10 minutes, and then 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, stirred and dissolved. 30.0 mL of purified water was gradually added thereto, then cooled to 0 to 5°C and stirred for 1 hour.

[0161] The resulting crystals were filtered under reduced pressure and washed with a mixed solution of 20.0 mL of methanol and 10.0 mL of purified water. The filtrate was placed in a desiccator and vacuum-dried at 50° C. to 60° C. for 12 hours or longer to obtain 4.7 g of the compound represented by Chemical Formula 1-4 (yield: 76.8%).

[0162] 1 H NMR (500MHz, CDCl3): δ8.93(s,1H),8.00(td,1H),7.15(d,1H),6.96(dddd,1H),6.89(ddd,1H),4.04(s,3H).

[0163] (Step 4)

[0164] 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 added to the flask, and the mixture was stirred and dissolved.

[0165] 7.5 g of 3-fluorobenzenesulfonyl chloride and 5.0 g of N,N-diisopropylethylamine (DIPEA) were added thereto, and stirred at 35 to 40° C. for 2 hours to complete the reaction.

[0166] Subsequently, 37.5mL of purified water and 37.5mL of ethyl acetate (EA) were added thereto, stirred for 10 minutes, and allowed to stand for 10 minutes, after which the aqueous layer was discarded. After concentrating the organic layer, 15.0mL of methanol was added to the concentrated residue, stirred at room temperature, dissolved, and then concentrated again. 37.5mL of methanol was added to the concentrated residue, stirred at 50°C to 60°C, dissolved, and then cooled to room temperature. 22.5mL of purified water was added to the flask within 10 minutes and stirred for 1 hour. The resulting crystals were filtered under reduced pressure, and the filtrate was washed with 15.0mL of purified water. The filtrate thus washed was placed in a desiccator and then vacuum dried at a temperature of 50°C to 60°C for 12 hours or longer to obtain 11.4g of the compound represented by Chemical Formula 1-5 (yield: 90.7%).

[0167] 1 H NMR (500MHz, CDCl3): δ7.84(s,1H),7.45(td,1H),7.40-7.30(m,1H),7.22(d t,1H),7.18(td,1H),7.04(dt,1H),6.94(td,1H),6.77(td,1H),3.73(s,3H).

[0168] (Step 5)

[0169] 10.0 g of the compound represented by Chemical Formula 1-5 and 100.0 mL of tetrahydrofuran (THF) were added to the flask and stirred at room temperature for 10 minutes.

[0170] 5.2 g of zinc chloride and 3.1 g of sodium hydride (60%, dispersion in liquid paraffin) were added thereto, and stirred at a temperature of 45° C. to 55° C. for 15 hours.

[0171] The reaction solution was cooled to 0°C to 5°C, and 50.0 mL of purified water and 50.0 mL of ethyl acetate (EA) were added. The mixture was stirred and the pH was adjusted to 1.0 to 2.0 with a 6N-HCl solution, followed by stirring for 10 minutes. The mixture was allowed to stand for 10 minutes, and the aqueous layer was discarded. 10.0 g of sodium sulfate was added to the organic layer, stirred for 10 minutes, filtered under reduced pressure, and then concentrated. 40.0 mL of ethanol and 10.0 mL of water were added to the concentrated residue and stirred at room temperature for 1 hour.

[0172] The resulting crystals were filtered under reduced pressure and washed with 20.0 mL of a mixed solution of ethanol and water. The filtrate was placed in a desiccator and vacuum-dried at 40° C. to 50° C. for 12 hours or longer to obtain 7.5 g of the compound represented by Chemical Formula 1-6 (yield: 74.4%).

[0173] 1 H NMR (500MHz, CDCl3): δ9.89(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).

[0174] (Step 6)

[0175] 100.0 g of the compound represented by Chemical Formula 1-6 obtained in step 5 and 396.0 g of methanol were added to a flask, cooled to 10 to 15° C., and then 42.7 g of methylamine was added thereto and stirred at 10 to 15° C. for 1 hour.

[0176] Subsequently, the internal temperature was cooled to -10° C. to -5° C. While maintaining the temperature range of -5° C. to 0° C., 4.8 g of sodium borohydride was added portionwise, followed by stirring at -5° C. to 0° C. for 30 minutes to complete the reaction.

[0177] 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., and then 902.0 g of ethyl acetate was added thereto. Subsequently, the internal temperature was maintained at 10° C. to 25° C., and the pH was adjusted to 7.0 to 7.5 using a 6N aqueous hydrochloric acid solution.

[0178] The mixture was then stirred for 10 minutes, allowed to stand for 30 minutes to separate the layers, and the organic layer was saved. 451.0 g of ethyl acetate was added to the resulting aqueous layer, stirred for 10 minutes, and then allowed to stand for 10 minutes. Thereafter, the layers were separated, the organic layer was combined with the previously obtained organic layer, and the same re-extraction process was performed again.

[0179] Next, 1,026.6 g of an aqueous sodium bicarbonate solution (26.6 g of sodium bicarbonate, 1,000.0 g of purified water) was added to the combined organic layers, stirred for 10 minutes and allowed to stand for 10 minutes to separate the layers, and then the aqueous layer was discarded.

[0180] 200.0 g of sodium sulfate was added to the organic layer, stirred for 10 minutes while maintaining the internal temperature at 20 to 30° C., and then filtered under reduced pressure. The filtrate was washed with 270.6 g of ethyl acetate, the pH of the filtrate was adjusted to 6.0 to 6.5 using a 1.0 M hydrochloric acid ethyl acetate solution, and then the filtrate was concentrated under reduced pressure at 38 to 42° C.

[0181] (Additional Step - Preparation of Acid Addition Salt)

[0182] 90.2g of ethyl acetate is added to the concentrated residue and stirred until a relatively uniform state. 460.5g of 1.0M hydrochloric acid ethyl acetate solution is gradually added at an internal temperature in the range of 0°C to 5°C and stirred at 18°C ​​to 22°C for 1 hour to crystallize the compound represented by Chemical Formula 1-1. The obtained crystals are filtered under reduced pressure and the filtrate is washed with 90.2g of ethyl acetate. The filtrate is placed in a desiccator and vacuum dried at 40°C to 50°C for 12 hours or longer to finally obtain 95.7g of the compound represented by Chemical Formula 1-1 (yield: 84.7%).

[0183] 1H-NMR(500MHz,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).

[0184] Comparative Examples

[0185] Comparative Examples were performed according to the following reaction scheme.

[0186]

[0187] (Step 1)

[0188] 35.8g of ammonium chloride and 26.9g of sodium cyanide are added to a flask, 716.0mL of ammonium hydroxide (25% to 28%) is added, and stirred for 10 minutes. The mixture is cooled to 0°C to 5°C, stirred for 10 minutes, then allowed to warm to room temperature and stirred for 15 minutes. After cooling to 0°C to 5°C, a solution containing 100.0g of 2,4-difluorobenzaldehyde (chemical formula A-1) and 770.0mL of methanol prepared in another flask is gradually added over 15 to 20 minutes. The temperature is raised to room temperature, and the mixture is stirred for 22 hours to complete the primary reaction. The mixture is concentrated under reduced pressure at 50°C, followed by addition of 983.0mL of acetic acid and 983.0mL of concentrated HCl, and refluxed for 5 hours at an internal temperature of 100°C to 105°C to complete the secondary reaction. The solvent is removed by concentrating under reduced pressure at 75°C until solid precipitation. Purified water is added and then stirred to precipitate crystals. The pH was adjusted to 6.5 using a 5M NaOH solution at an internal temperature of 25°C or lower. Ethanol was added and stirred at 10°C to 15°C for 1 hour. After filtration under reduced pressure, the filtrate 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%).

[0189] (Step 2)

[0190] 100.0 g of the compound represented by chemical formula A-2 prepared in step 1, 1.5 L of THF and 1.5 L of purified water were added to a flask, and the mixture was stirred at room temperature for 10 minutes. The internal temperature was cooled to 0° C. to 5° C., and 134.6 g of sodium bicarbonate and 139.5 g of di-tert-butyl dicarbonate were added. The mixture was stirred at an internal temperature of 20° C. to 30° C. for 12 hours to complete the reaction, and concentrated under reduced pressure at 45° C. Ethyl acetate was added and cooled to an internal temperature of 10° C. or less. The pH value was adjusted to 2.5 using 6N-HCl. The organic layer was separated, dehydrated over anhydrous magnesium sulfate, and then concentrated under reduced pressure at 45° C. to obtain 151.2 g of the compound represented by chemical formula A-3 (yield: 98.5%).

[0191] 1 H-NMR (500MHz, 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).

[0192] (Step 3)

[0193] 100.0g of the compound represented by chemical formula A-3 prepared in step 2, 61.9g of carbonyldiimidazole and 1.0L of acetonitrile were added to a flask, and the mixture was stirred at room temperature for 1 hour. 59.8g of potassium methylmalonate, 36.4g of anhydrous magnesium chloride, 1.0L of acetonitrile and 38.8g of triethylamine were added to another flask, and the mixture was stirred at 20°C to 30°C for 1 hour. The reaction substances 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. The mixture was cooled to an internal temperature of 5°C to 10°C and stirred for 1 hour. The obtained solid was filtered under reduced pressure and then washed with purified water. Since the obtained crystals are magnesium salts, the salt dissociation process is carried out as follows.

[0194] The magnesium salt prepared above, 1.5 L of ethyl acetate, and 1.0 L of purified water were added to a flask, and the mixture was 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 then concentrated under reduced pressure at 45°C to obtain 97.3 g of the compound represented by Chemical Formula A-4 (yield: 81.4%).

[0195] 1H-NMR (500MHz, 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).

[0196] (Step 4)

[0197] 100.0 g of the compound represented by chemical formula A-4 prepared in step 3 and 2.0 L of toluene were added to a flask, and the mixture was stirred at room temperature for 10 minutes. 104.1 g of N, N-dimethylformamide dimethyl acetal was added and stirred at 40 ° C for 4 hours to complete the reaction. The mixture was concentrated under reduced pressure at 45 ° C, ethyl acetate and purified water were added to the concentrated residue, and stirred for 10 minutes. The pH value was adjusted to 7.0 using 1N HCl. The organic layer was extracted, dehydrated with anhydrous magnesium sulfate, and then concentrated under reduced pressure at 45 ° C to prepare 79.2 g of the compound represented by chemical formula 1-5 (yield: 77.0%). At the same time, the compound represented by chemical formula A-5 is unstable (air oxidation occurs), and the following step 5 is continuously performed in situ.

[0198] 1 H-NMR (500MHz, 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).

[0199] (Step 5)

[0200] 100.0 g of the compound represented by chemical formula A-5 prepared in step 4 and 1.5 L of acetone were added to a flask, and the mixture was stirred at room temperature for 10 minutes. 78.2 g of potassium carbonate and 42.9 g of dimethyl sulfate were added and stirred at 40 ° C for 6 hours to complete the reaction. The mixture was cooled to room temperature, and purified water and ethyl acetate were added and stirred for 10 minutes. The pH value 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 obtain 90.6 g of the compound represented by chemical formula A-6 (yield: 87.1%). Next, the following step 6 was performed in situ without a separate purification step.

[0201] 1 H-NMR (500MHz, 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).

[0202] (Step 6)

[0203] 100.0g of the compound represented by chemical formula A-6 prepared in step 5 and 500.0mL of dichloromethane were added to a flask, and the mixture was stirred at room temperature for 10 minutes. 310.4g of trifluoroacetic acid was added and stirred at room temperature for 6 hours to complete the reaction. Subsequently, after cooling to 0°C to 5°C, purified water was gradually added at 15°C or below. The pH value was adjusted to 7.0 using 50.0% NaOH solution at 15°C or below. Ethyl acetate was added and stirred for 10 minutes. The organic layer was extracted and dehydrated over anhydrous magnesium sulfate. The diatomaceous earth washed with ethyl acetate was placed on a filter, and the organic layer was filtered under reduced pressure and then concentrated under reduced pressure at 45°C. Ethyl acetate was added to the concentrated residue, and the mixture was stirred and suspended. N-hexane was added, cooled to an internal temperature of 0°C to 5°C, and stirred for 1 hour. The obtained solid was filtered under reduced pressure, and the filtrate was then washed with n-hexane. The obtained product was dried under reduced pressure to obtain 65.5 g of the compound represented by Chemical Formula B (yield: 90.0%).

[0204] 1 H-NMR (500MHz, 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).

[0205] (Step 7)

[0206] 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 were added to a flask, and the mixture was stirred at room temperature for 10 minutes. The internal temperature of the flask was cooled to 5°C to 10°C, and 80.1 g of 3-fluorobenzenesulfonyl chloride (Chemical Formula B-1) and 53.2 g of N,N-diisopropylethylamine were added. The mixture was stirred at a temperature range of 20°C to 30°C for 2 hours to complete the reaction.

[0207] Next, 500.0 g of purified water and 451.0 g of ethyl acetate were added, stirred for 10 minutes and allowed to stand for 10 minutes, and then the aqueous layer was discarded.

[0208] Subsequently, 500.0 g of purified water was added to the organic layer, and 1N aqueous hydrochloric acid solution was gradually added at a temperature range of 20° C. to 30° C., and the pH was adjusted to 3.5 to 5.0. The mixture was stirred for 10 minutes, allowed to stand for 10 minutes, and the aqueous layer produced therefrom was discarded.

[0209] Next, the organic layer was concentrated under reduced pressure at 50°C to 55°C, 158.4 g of methanol was added at an internal temperature of 20°C to 30°C, and the mixture was stirred for 10 minutes. Subsequently, the organic layer was concentrated under reduced pressure at 50°C to 55°C, 396.0 g of methanol was added at an internal temperature of 20°C to 30°C, and the mixture was stirred for 1 hour. While maintaining the internal temperature at 20°C to 30°C, 300.0 g of purified water was added over 20 minutes, and the mixture was stirred for 1 hour. The resulting crystals were filtered under reduced pressure, and the filtrate was washed with 200.0 g of purified water.

[0210] The washed filtrate was placed in a desiccator and vacuum-dried at 40° C. to 45° C. for 12 hours or longer to obtain 154.4 g of the compound represented by Chemical Formula B-2 (yield: 97.0%).

[0211] 1 H-NMR(500MHz,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).

[0212] (Step 8)

[0213] 100.0 g of the compound represented by Chemical Formula B-2 obtained in Step 1 and 444.5 g of tetrahydrofuran were added to a new flask, and the mixture was stirred at 20°C to 30°C for 10 minutes and cooled to an internal temperature of -10°C to 5°C. 32.1 g of zinc chloride was added to the resulting reaction solution over 5 minutes and stirred for 10 minutes. 28.5 g of N,N-dimethylaniline was added, followed by stirring.

[0214] Subsequently, while maintaining the internal temperature in the temperature range of -10°C to 0°C, 8.9 g of sodium borohydride was divided into three portions and added over 5 minutes, followed by repeated stirring three times for 10 minutes each.

[0215] Next, the mixture was stirred at an internal temperature of 60° C. to 65° C. for 20 hours to complete the reaction, and then cooled to an internal temperature of 0° C. to 5° C. In this reaction, a compound represented by Chemical Formula B-3 was produced.

[0216] Subsequently, 200.0g of purified water was gradually added at an internal temperature in the range of 0°C to 15°C, and 451.0g of ethyl acetate was added at an internal temperature in the range of 20°C to 30°C. Subsequently, 87.2g of 6N hydrochloric acid aqueous solution was added, stirred for 30 minutes and allowed to stand for 10 minutes (in any case, the internal temperature was maintained at 20°C to 30°C). The layers were separated and the aqueous layer was discarded. Next, the organic layer was washed with 300.0g of purified water and 10.9g of 6N hydrochloric acid aqueous solution (in any case, this was repeated twice while the internal temperature was maintained at 20°C to 30°C). The layers were separated and the aqueous layer was discarded. 50.0g of magnesium sulfate was added to the organic layer, stirred for 10 minutes, and then filtered under reduced pressure. The filtrate was concentrated under reduced pressure at 50°C to 55°C. Subsequently, 265.3g of dichloromethane was added and stirred for 10 minutes, and the mixture was concentrated under reduced pressure at 50°C to 55°C.

[0217] (Step 9)

[0218] 6.9 g of (2,2,6,6-tetramethylpiperidin-1-yl)oxy, 86.1 g of (diacetoxyiodo)benzene, and 1,171.1 g of dichloromethane were added to the concentrated residue from step 2, and the mixture was stirred at an internal temperature of 20°C to 30°C for 2 hours to complete the reaction, followed by the addition of 882.8 g of purified water. Subsequently, 679.7 g of a saturated aqueous sodium bicarbonate solution (61.8 g of sodium bicarbonate, 617.9 g of purified water) was gradually added, followed by stirring for 10 minutes and allowing the layers to stand for 10 minutes to separate. Thereafter, the aqueous layer was discarded. 17.7 g of magnesium sulfate was added to the organic layer, stirred for 10 minutes, and then filtered under reduced pressure.

[0219] Subsequently, after concentration under reduced pressure at 38 to 42° C., 513.6 g of an ethanol aqueous solution (390.0 g of ethanol, 123.6 g of purified water) was added thereto, and stirred at an internal temperature of 20 to 30° C. for 1 hour for crystallization.

[0220] The resulting crystals were filtered under reduced pressure, and the filtrate was washed with 174.3 g of an aqueous ethanol solution (132.3 g of ethanol, 41.9 g of purified water). The washed filtrate was placed in a desiccator and vacuum-dried at 40° C. to 45° C. for 12 hours or longer to obtain 83.9 g of the compound represented by Chemical Formula B-4 (yield: 90.0%).

[0221] 1 H-NMR(500MHz,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).

[0222] (Step 10)

[0223] 100.0 g of the compound represented by Chemical Formula B-4 obtained in Step 3, 396.0 g of methanol, and 48.5 g of methylamine (9.8 M methanol solution) were added to a new flask, the internal temperature was adjusted to 20 to 30° C., and the mixture was stirred for 30 minutes.

[0224] Subsequently, the internal temperature was cooled to -5 to 0°C, 4.8 g of sodium borohydride was added portionwise while maintaining the temperature range of -5 to 10°C, and stirred at -5 to 10°C for 30 minutes to complete the reaction.

[0225] After the reaction was completed, 1,000 g of purified water and then 902.0 g of ethyl acetate were gradually added while maintaining the internal temperature at 10 to 15° C. Subsequently, the internal temperature was maintained at 10 to 15° C. and the pH was adjusted to 6.7 to 7.3 using a 6N hydrochloric acid aqueous solution.

[0226] The mixture was then stirred for 10 minutes, allowed to stand for 30 minutes to separate the layers, and the organic layer was saved. 451.0 g of ethyl acetate was added to the resulting aqueous layer, stirred for 10 minutes, and then allowed to stand for 10 minutes. The layers were then separated, and the organic layer was combined with the previously obtained organic layer and the same re-extraction process was repeated.

[0227] Next, 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, stirred for 10 minutes, allowed to stand for 10 minutes to separate the layers, and the aqueous layer was discarded.

[0228] 100.0 g of magnesium sulfate was added to the organic layer, stirred for 10 minutes while maintaining the internal temperature at 10 to 15° C., and then filtered under reduced pressure. The filtrate was washed with 270.6 g of ethyl acetate and then concentrated under reduced pressure at 38 to 42° C.

[0229] 90.2 g of ethyl acetate was added to the concentrated residue, stirred until a relatively homogeneous state, and 460.5 g of a 1.0 M hydrochloric acid ethyl acetate solution was gradually added at an internal temperature ranging from -5° C. to 5° C. The mixture was then stirred at 0° C. to 5° C. for 12 hours to crystallize the compound represented by Chemical Formula 1.

[0230] (Purification Step)

[0231] 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 then stirred for 10 minutes. Subsequently, 976.3 g of an 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 allowed to stand for 30 minutes to separate the layers, and the organic layer was saved.

[0232] 407.7 g of ethyl acetate was added to the resulting aqueous layer, stirred for 10 minutes, and then allowed to stand for 10 minutes to separate the layers. The organic layer was combined with the previously obtained organic layer, and the aqueous layer was extracted once more using the same procedure and combined with the organic layer.

[0233] 90.4 g of magnesium sulfate was added to the organic layer, stirred for 10 minutes at an internal temperature of 10 to 15° C., and then filtered under reduced pressure. The filtrate was washed with 244.6 g of ethyl acetate and then concentrated under reduced pressure at 38 to 42° C.

[0234] 81.5 g of ethyl acetate was added to the concentrated residue, stirred, and the mixture was stirred. 368.4 g of a 1.0 M hydrochloric acid ethyl acetate solution was gradually added at an internal temperature within the range of -5°C to 5°C, and stirred at 0°C to 5°C for 12 hours for recrystallization.

[0235] The obtained 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 desiccator and vacuum-dried at 20° C. to 30° C. for 12 hours, and further dried for 6 hours by heating to 38° C. to 42° C. to obtain 90.7 g of the compound represented by Chemical Formula 1-1 (yield: 80.2%).

[0236] 1 H-NMR(500MHz,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).

[0237] Comparison between Examples and Comparative Examples

[0238] The yield, quality, etc. of the 4-methoxypyrrole derivatives obtained according to the production method of each of Examples and Comparative Examples were evaluated as follows and shown in Table 1 below.

[0239] The yield of the 4-methoxypyrrole derivative was calculated by substituting the weight of the recovered 4-methoxypyrrole derivative (Chemical Formula 1) after the reaction and the weight of 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester (Chemical Formula 2) before the reaction into the following formula 1.

[0240] [Formula 1]

[0241] Yield (%) of 4-methoxypyrrole derivative = 100% * {the number of moles of 4-methoxypyrrole derivative (Chemical Formula 1) recovered after the reaction is completed} / {the number of moles of 5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid methyl ester (Chemical Formula 2) before the reaction}

[0242] Purity of 4-methoxypyrrole derivative and content of related substance B: The purity of the 4-methoxypyrrole derivative (Chemical Formula 1) and the content of related substance B recovered after the reaction were measured using high performance liquid chromatography (HPLC, manufacturer: Waters, e2695 system).

[0243] Herein, the related substance B is 1-(5-(2,4-difluorophenyl)-4-methoxy-1H-pyrrol-3-yl)-N-methylmethanamine.

[0244] [Table 1]

[0245]

[0246] Referring to Table 1, it was confirmed that the Examples not only improved the process efficiency compared with the Comparative Examples, but also the overall yield was improved by about 1.5 times compared with the Comparative Examples.

[0247] Furthermore, when the manufacturing methods of Examples and Comparative Examples were applied to industrial production, the manufacturing method of Comparative Example required 17 days to produce the final material, while that of Examples required 9 days. In other words, since the manufacturing time of Examples was halved compared to that of Comparative Example, it is expected that the production efficiency will be doubled.

[0248] Furthermore, according to the embodiment, it is expected that industrial mass production will become possible by ensuring a stepwise crystallization process.

[0249] Specifically, in Examples and Comparative Examples, the same final material (i.e., the 4-methoxypyrrole derivative represented by Chemical Formula 1) was prepared by using the same starting material (i.e., the compound represented by Chemical Formula 1-1). In addition, since the Examples do not use the genotoxic substance dimethyl sulfate used in the Comparative Examples, the safety of workers and the potential risks of drugs can be reduced.

Claims

1. A method for producing a 4-methoxypyrrole derivative, comprising the following steps: 1) reacting a compound represented by the following Chemical Formula 1-1 with p-toluenesulfinic acid and formamide in the presence of an acid catalyst to prepare a compound represented by the following Chemical Formula 1-2; 2) reacting the compound represented by the following Chemical Formula 1-2 with a dehydrating agent to prepare a compound represented by the following Chemical Formula 1-3; 3) reacting the compound represented by the following Chemical Formula 1-3 with a cyclization reagent to prepare a compound represented by the following Chemical Formula 1-4; 4) reacting a compound represented by the following Chemical Formula 1-4 with 3-fluorobenzenesulfonyl chloride to prepare a compound represented by the following Chemical Formula 1-5; 5) reacting a compound represented by the following Chemical Formula 1-5 with sodium hydride to prepare a compound represented by the following Chemical Formula 1-6; and 6) reacting a compound represented by the following Chemical Formula 1-6 with methylamine to form an intermediate, and then adding a reducing agent to convert the intermediate into a compound represented by the following Chemical Formula 1: [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. The manufacturing method according to claim 1, wherein Step 1 is carried out in the presence of trimethylchlorosilane (TMSCl), camphorsulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, benzoic acid, nitrobenzoic acid, hydrochloric acid, calcium chloride or a mixture of two or more thereof as an acid catalyst.

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

10.

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

10.

5. The manufacturing method according to claim 1, wherein The p-toluenesulfinic acid in step 1 is a concentrate concentrated to 10 mol % or higher.

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

7. The manufacturing method according to claim 1, wherein: The dehydrating agent in step 2 includes phosphorus oxychloride, trichloromethyl chloroformate, bis(trichloromethyl)carbonate, triphenylphosphine, thionyl chloride, p-toluenesulfonic acid or a mixture of two or more thereof.

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

10.

9. The manufacturing method according to claim 1, wherein: Step 2 is performed in the presence of a base, and a molar ratio between the compound represented by Chemical Formula 1-2 and the base in step 2 is 20:1 to 1:

20.

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

11. The manufacturing method according to claim 1, wherein: The cyclization reagent in step 3 includes 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. The manufacturing method according to claim 1, wherein: In step 3, the molar ratio between the compound represented by Chemical Formula 1-4 and the cyclization reagent is 10:1 to 1:

10.

13. The manufacturing method according to claim 1, wherein: Step 3 is performed in the presence of a base, and a molar ratio between the compound represented by Chemical Formula 1-3 and the base in step 3 is 20:1 to 1:

10.

14. The manufacturing method according to claim 1, wherein: The reaction temperature of step 3 is 50°C to 150°C.

15. The manufacturing method according to claim 1, wherein: The method further comprises dissolving the compound represented by Chemical Formula 1-4 together with a catalyst in an organic solvent before step 4 to prepare a composition containing the compound represented by Chemical Formula 1-4.

16. The manufacturing method according to claim 15, wherein: The catalyst includes 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. The manufacturing method according to claim 15, wherein: In step 4, the molar ratio between the compound represented by Chemical Formula 1-4 and the catalyst is 100:1 to 1:

10.

18. The manufacturing method according to claim 1, wherein: In step 4, the molar ratio between the compound represented by Chemical Formula 1-4 and 3-fluorobenzenesulfonyl chloride is 10:1 to 1:

10.

19. The manufacturing method according to claim 1, wherein: Step 4 is performed in the presence of a base, and a molar ratio between the compound represented by Chemical Formula 1-4 and the base in step 4 is 10:1 to 1:

10.

20. The manufacturing method according to claim 1, wherein: The reaction temperature of step 4 is 0°C to 60°C.

21. The manufacturing method according to claim 1, wherein The sodium hydride in step 5 is a dispersion in mineral oil.

22. The manufacturing method according to claim 1, wherein: In step 5, the molar ratio between the compound represented by Chemical Formula 1-5 and sodium hydride is 20:1 to 1:

10.

23. The manufacturing method according to claim 1, wherein: Step 5 is carried out in the presence of a zinc halide.

24. The manufacturing method according to claim 23, wherein: The zinc halide includes zinc chloride, zinc bromide, zinc iodide or a mixture of two or more thereof.

25. The manufacturing method according to claim 23, wherein: In step 5, the molar ratio between the compound represented by Chemical Formula 1-5 and the zinc halide is 10:1 to 1:

10.

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

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

28. The manufacturing method according to claim 1, wherein The reducing agent in step 6 includes sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride or a mixture of two or more thereof.

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

30. The manufacturing method according to claim 1, wherein: In step 6, the molar ratio between the compound represented by Chemical Formula 1-6 and methylamine is 10:1 to 1:10, and the molar ratio between the compound represented by Chemical Formula 1-6 and the reducing agent is 10:1 to 1:

10.

31. The manufacturing method according to claim 1, wherein The method further comprises washing the reaction product of step 6 with an aqueous alkaline solution to adjust the pH value to 6.0 to 6.

5.

32. The manufacturing method according to claim 1, wherein: Further comprising, after step 6, an additional step of adding an acid to the compound represented by Chemical Formula 1 to prepare an acid salt represented by the following Chemical Formula 1-1: [Chemical Formula 1-1] 33. The manufacturing method according to claim 32, wherein: The additional step includes supplying an organic solvent to the compound represented by Chemical Formula 1, and then supplying an acid or a mixed solution of the acid and the organic solvent to crystallize the acid salt represented by Chemical Formula 1-1.

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