Method for preparation of 6-methoxypyridine-3-yl derivatives

Abstract

This invention relates to a method for manufacturing a 6-methoxypyridine-3-yl derivative. The manufacturing method of this invention has the advantages of significantly shortening the manufacturing process and carrying out the reaction under suitable conditions that enable mass production. Furthermore, it has the following advantages: even with the process shortened as described above, process efficiency is improved due to excellent yield; the use of salt simplifies the manufacturing process, minimizing the generation of flexible materials and increasing yield. This will bring useful benefits to mass production.

Description

Method for manufacturing 6-methoxypyridine-3-yl derivatives This invention relates to a method for manufacturing a 6-methoxypyridine-3-yl derivative. To address the drawbacks of proton pump inhibitors (PPIs), potassium-competitive acid blockers (P-CABs) have attracted considerable attention. P-CABs target the proton pump (PPI), an enzyme involved in the final stage of gastric acid secretion, within gastric parietal cells. + / K + -ATPase) on, with K + Ions reversibly and competitively bond, effectively and rapidly inhibiting gastric acid secretion. Compared to PPI formulations, this P-CAB formulation exhibits strong inhibitory effects at normal gastric acidity (pH 1–3). However, the pharmacological activity required for gastric P-CAB formulations decreases with increasing pH; some P-CAB formulations exhibit pharmacological activity that remains unchanged even with increasing pH, and some related side effects have been reported. Furthermore, since P-CAB formulations are primarily metabolized by the CYP3A4 enzyme, inter-individual differences in efficacy are relatively insignificant, and concerns about drug interactions with those metabolized by the CYP2C19 enzyme are relatively low. Wonorazan, a potassium-competitive acid blocker, is disclosed in International Patent Publication WO2019 / 013310A1. However, it has been confirmed that vonoprazan induces severe hypergastrinemia compared to existing PPI drugs like lansoprazole. This hypergastrinemia can cause problems such as enterochromaffin-like (ECL) cell proliferation, parietal cell hyperplasia, fundic gland polyps, bone loss, damaged bone, and fractures. In fact, vonoprazan has been reported to be associated with the development of neuroendocrine cell tumors of the stomach in carcinogenesis studies in mice and rats. However, discontinuing the administration of P-CABs or PPI series drugs such as vonoprazan will restore hyperacidity and induce indigestion; therefore, even with the above problems, drug administration should not be easily discontinued. Against this backdrop, numerous attempts are underway to develop novel P-CAB drugs. For example, Korean Patent Registration No. 10-2432523 discloses a novel P-CAB inhibitor exhibiting excellent acid secretion inhibition effects. Specifically, Korean Patent Registration No. 10-2432523 discloses a method for manufacturing a novel P-CAB drug by: (I) introducing a suitable heteroarylsulfonyl group into a starting material using a base in the presence of an inert solvent; (II) performing reduction using a reducing agent in the presence of an inert solvent; (III) performing oxidation using an oxidizing agent in the presence of an inert solvent; and (IV) a reductive amination process using a suitable amine and a reducing agent. However, the manufacturing method disclosed in the aforementioned patent has the disadvantages of a very long manufacturing process and low production yield. In particular, the use of substances such as DIBAL (diisobutyl aluminum hydride) as raw materials is dangerous and expensive, and the use of sulfone derivatives in the initial reaction steps is not suitable for mass production. Furthermore, the salt makes subsequent development difficult. To address the aforementioned problems, the inventors have developed a novel manufacturing process that maximizes yield while significantly improving the production level of the target material, thus completing this invention. [The problem the invention aims to solve] The present invention aims to provide a method for manufacturing 6-methoxypyridine-3-yl derivatives. One embodiment of the present invention for solving the problems described above is a method for manufacturing a 6-methoxypyridine-3-yl derivative, comprising: 1) The step of reacting the compound represented by chemical formula 2 with the compound represented by chemical formula 3 to produce the compound represented by chemical formula 4; 2) The step of reacting the compound represented by the following chemical formula 4 with methylamine to generate an intermediate, and adding a reducing agent to convert the intermediate into the compound represented by the following chemical formula 1; [Chemical Formula 1] [Chemical Formula 2] [Chemical Formula 3] [Chemical Formula 4] [Technical means to solve the problem] To address the aforementioned issues, the present invention provides a manufacturing method according to the following reaction formula 1: [Reaction Formula 1] Specifically, as one embodiment of the present invention, the compound represented by the following chemical formula 1 is produced by including the following steps 1 and 2. 1) The step of reacting the compound represented by chemical formula 2 with the compound represented by chemical formula 3 to produce the compound represented by chemical formula 4; and 2) The step of reacting the compound represented by the following chemical formula 4 with methylamine to generate an intermediate, and adding a reducing agent to convert the intermediate into the compound represented by the following chemical formula 1. Optionally, a method is provided that further includes step 3 below, which can also produce the compound represented by the following chemical formula 1-1. 1) The step of reacting the compound represented by chemical formula 2 with the compound represented by chemical formula 3 to produce the compound represented by chemical formula 4; and 2) The step of reacting the compound represented by chemical formula 4 with methylamine to generate an intermediate, and then adding a reducing agent to convert the intermediate into the compound represented by chemical formula 1; and 3) The step of adding an acid to the compound represented by the above chemical formula 1 to produce the acidic salt represented by the following chemical formula 1-1; Hereinafter, an embodiment of the present invention will be described in detail according to the steps described above. Referring to the following description, the quality of the final material can also be controlled by adjusting the process temperature, execution time, etc., of each of the above steps. [Step 1] Step 1 above is a step of reacting the compound represented by chemical formula 2 with the compound represented by chemical formula 3 to produce the compound represented by chemical formula 4. It is a step of introducing a substituted pyridine sulfonyl group into the pyrrole group of the compound represented by chemical formula 2. The reaction in step 1 above can be carried out in the presence of 4-(dimethylamino)-pyridine, a base, and an organic solvent. Here, the base can be N,N-diisopropylethylamine, triethylamine, diisopropylamine, potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate, cesium carbonate, or a mixture of two or more of these. Specifically, triethylamine can be used. In step 1 above, a solvent that facilitates the dispersion of the bases and 4-(dimethylamino)-pyridine can be used, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ether, methyl tributyl ether, toluene, xylene, heptane, or a mixture of two or more of these as the reaction solvent. Specifically, acetone can be used as the reaction solvent in step 1 above. In particular, bases, such as triethylamine, can be easily precipitated in the above solvent, thereby maximizing the reaction yield. In step 1 above, the molar ratio of the compound represented by chemical formula 2 to the compound represented by chemical formula 3 can be 10:1 to 1:10, specifically 5:1 to 1:5, and more specifically 3:1 to 1:3. The reaction in step 1 above can be carried out at temperatures between 10°C and 35°C. Specifically, the reaction within the temperature range of step 1 above can improve the conversion rate of step 1 above, which helps to reduce the content of flexible substances in the final product. The reaction in step 1 above can be carried out for 30 minutes to 8 hours. If the reaction time is less than 30 minutes, there is a problem of insufficient reaction and reduced production yield. If the reaction time exceeds 8 hours, the production yield does not increase substantially. More specifically, the reaction can be carried out for 1 hour to 5 hours. If necessary, after the above reaction is terminated, a step of purifying the compound represented by chemical formula 4 may be included. Specifically, the compound represented by chemical formula 4 may be crystallized from the reaction product of step 1. An alcohol having 1 to 4 carbon atoms can be used as a solvent to crystallize the self-reaction product of the compound represented by the above chemical formula 4. The alcohols with 1 to 4 carbon atoms here can be methanol, ethanol, propanol, 2-propanol, butanol, tributanol, or mixtures of two or more thereof. More specifically, 2-propanol can be used alone. For example, 2-propanol can be added, heated to 40°C to 80°C, cooled to 15°C to 35°C, and then stirred. If necessary, stirring can be performed by further cooling to 0°C to 10°C. This process can demonstrate excellent effectiveness in removing bases from residual solvents, such as triethylamine and 4-(dimethylamino)-pyridine. After purifying the compound represented by chemical formula 4 through the above steps, the moisture content of the compound represented by chemical formula 4 can be reduced by drying it at 40°C to 60°C for 10 to 14 hours. This significantly reduces the moisture content of the compound represented by chemical formula 4, thereby improving the conversion rate of the next step. This may further include a cleaning step using the solvents used after the reactions in the above steps are completed. [Step 2] Step 2 above consists of the following steps: reacting the compound represented by chemical formula 4 with methylamine to generate an intermediate, and adding a reducing agent to convert the intermediate into the compound represented by chemical formula 1. Step 2 above is the following step: using a reductive amination reaction, the compound represented by chemical formula 4 above is converted into the compound represented by chemical formula 1 above. Specifically, in step 2 above, the compound represented by chemical formula 4 reacts with methylamine to form an imine compound. This imine compound is equivalent to an unstable intermediate, and therefore can be easily reduced to the compound represented by chemical formula 1 above. The reductive imine reaction in step 2 above can be carried out in a reaction solvent of water, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl ether, acetonitrile, or a mixture of two or more of these. The solvent conditions of this invention utilize solvents that provide suitable conditions for the reaction, and in particular, have the advantage that the reaction does not raise restrictions imposed by the Food and Drug Administration, etc. More specifically, the compound represented by the above chemical formula 4 and the above methylamine are added together with the above reaction solvent, and stirred at 15°C to 35°C, or more preferably at 20°C to 30°C for 20 minutes to 2 hours, so that the compound represented by the above chemical formula 4 and the above methylamine are fully dissolved in the above solvent and react to generate an imine compound. At this point, considering that as the solubility of the compound represented by the above chemical formula 4 decreases, the amount of flexible material included in the final substance can increase, the stirring time and temperature can be adjusted. Furthermore, the aforementioned methylamine can preferably be methylamine dissolved in water. In particular, the above reaction conditions have the advantage of being performed under moderate conditions close to room temperature compared to existing known conditions. Also, it has the advantage of appropriately controlling the equivalent of methylamine to minimize the content of its flexible substances. For example, by adding it to an equivalent of 1.5 to 2.5 eq, compared to existing known methods, it has the advantage of minimizing the formation of flexible substances associated with dimer formation. The reduction reaction of the intermediate (i.e., the imine compound) generated by the reaction of the compound represented by the above chemical formula 4 with methylamine can be carried out more stably at a lower temperature. With this in mind, after the reaction of the compound represented by the above chemical formula 4 with methylamine is completed, the reactor temperature can be cooled to a range of -5°C to 15°C, for example, 0°C to 10°C. Then, following the cooling temperature range, the reducing agent is added, and the reactor temperature is maintained while stirring. Within the above temperature range, the intermediate (i.e., the imine compound) reacts stably with the reducing agent and can be converted into the compound represented by the above chemical formula 1. Here, as the reducing agent mentioned above, one or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, and sodium triethoxyborohydride can be used. The molar ratio of the compound represented by chemical formula 4 to the aforementioned methylamine can be from 10:1 to 1:10, and the molar ratio of the compound represented by chemical formula 4 to the aforementioned reducing agent can be from 10:1 to 1:10. Specifically, each molar ratio can be from 5:1 to 1:5, and more specifically, from 3:1 to 1:3. Subsequently, an organic layer is obtained by extracting with an organic solvent 1 to 3 times. A desiccant is added to the organic layer and stirred. The mixture is then filtered under reduced pressure and the filtrate is washed. The filtrate can then be concentrated under reduced pressure. For the above extraction, organic solvents such as methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tributyl ether, 2-propanol, 1-butanol, dichloromethane, acetone, or mixtures of two or more of these can be used. Ethyl acetate is preferred. [Step 3] Following step 2 above, step 3 may optionally be included. These three steps can be performed through the following steps, and the manufacturing method further includes: 3) The step of adding acid to the compound represented by the above chemical formula 1 to produce an acidic salt represented by the following chemical formula 1-1; [Chemical Formula 1-1] . Step 3 above is used to supply the compound represented by the above chemical formula 1 in the form of a pharmaceutically acceptable salt, and simultaneously or after step 2 above, to add acid to the compound represented by the above chemical formula 1 to obtain a pharmaceutically acceptable acidic salt represented by the above chemical formula 1-1. Specifically, step 3 may include: supplying an organic solvent to the compound represented by the above chemical formula 1, and then supplying a mixed solution of the acid or the organic solvent thereof, to crystallize the acidic salt represented by the above chemical formula 1-1. More specifically, an organic solvent can be supplied to the concentrated residue comprising the compound represented by Formula 1 above. The supplied organic solvent may be ethyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tributyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropanol, acetonitrile, dichloromethane, n-hexane, dimethyl sulfoxide, or a mixture of two or more of these. Preferably, it may be any mixture selected from the group consisting of a mixture of ethanol and ethyl acetate, a mixture of isopropanol and ethyl acetate, a mixture of methanol and ethyl acetate, a mixture of methanol and methyl tributyl ether, a mixture of methanol and acetone, a mixture of ethanol and acetone, a mixture of ethanol and methyl tributyl ether, dimethyl sulfoxide, and a mixture of ethanol and ethyl acetate. More preferably, it may be a mixture of ethanol and ethyl acetate. In particular, the crystallization under the organic solvent conditions of the present invention has the excellent advantage of minimizing the formation of flexible materials and generating the target salt without additional refining processes. After supplying the organic solvent to the concentrated residue containing the compound represented by the above chemical formula 1 and stirring, the internal temperature of the reactor is adjusted to 15°C to 35°C, preferably between 20°C and 30°C, and a mixed solution of acid and organic solvent is supplied and stirred, which can crystallize the acidic salt represented by the above chemical formula 1-1. The acid used to crystallize the acidic salt represented by the above chemical formula 1-1 may be, for example, hydrochloric acid, glutamic acid, malonic acid, succinic acid, tartaric acid, oxalic acid, fumaric acid, phosphoric acid and / or methanesulfonic acid. The acid and organic solvent can be provided as a mixed solution, and the organic solvent in the mixed solution can be selected from the organic solvents mentioned above. In one embodiment, when the acidic fumaric acid used for crystallization in the above chemical formula 1-1 is used, the crystal has the chemical structure of the following chemical formula 1-2. [Chemical Formula 1-2] After the salt is manufactured, it is dried at 40°C to 60°C for 10 to 14 hours, which reduces the water content of the compound represented by chemical formula 4. This significantly reduces the water content of the compound represented by chemical formula 4, thereby maximizing the yield of the target compound. If necessary, the crystallization of the acidic salt represented by the above chemical formula 1-1 can be performed more than twice in step 3 above. For example, after crystallizing the acidic salt represented by the above chemical formula 1-1, the acidic salt represented by the above chemical formula 1-1 is extracted using the above organic solvent, and then a mixed solution of the above acid or its organic solvent is supplied to recrystallize the acidic salt represented by the above chemical formula 1-1. In the above recrystallization process, a base can be further used to dissociate the acidic salt. Here, as the base used to dissociate the acidic salt, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate, or cesium carbonate, or a mixture of two or more of these, can be used. Specifically, potassium carbonate can be used, and its method of use is well known in the art. This may further include a cleaning step using the solvents used after the reactions in the above steps are completed. When step 3 is selectively performed, it is carried out together with step 2, and the reaction can be performed as a two-step reaction instead of a three-step reaction. In this case, the present invention provides a manufacturing method according to reaction formula 2 below. [Reaction 2] In the case of reaction formula 2 above, the manufacturing method is as follows: 1) The step of reacting a compound represented by chemical formula 2 with a compound represented by chemical formula 3 to produce a compound represented by chemical formula 4; and 2) The steps of reacting the compound represented by the following chemical formula 4 with methylamine to generate an intermediate, adding a reducing agent and acid to produce an acidic salt represented by the following chemical formula 1-1. On one hand, the present invention provides a pharmaceutical composition for the prevention or treatment of gastrointestinal ulcers, gastrointestinal inflammatory diseases or acid-related diseases, the composition comprising a compound of the above-mentioned chemical formula 1 or a pharmaceutically acceptable salt thereof (preferably chemical formula 1-1 or 1-2). The present invention provides a compound of chemical formula 1 as defined in any embodiment of the present invention, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical agent. This invention provides a compound of chemical formula 1 as defined in any embodiment of this invention, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of gastrointestinal ulcers, gastrointestinal inflammatory diseases, or acid-related diseases. The present invention provides a treatment for gastrointestinal ulcers, gastrointestinal inflammatory diseases or acid-related diseases, comprising the step of administering a therapeutically effective amount of a compound represented by chemical formula 1, or a pharmaceutically acceptable salt thereof, to a band of tissue in which the salt is required. This invention provides the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a prescribed acid secretion inhibitor for diseases or symptoms, such as gastrointestinal ulcers, inflammatory diseases of the gastrointestinal tract, or acid-related diseases. This invention provides a compound of chemical formula 1 as defined in any embodiment of this invention, or a pharmaceutically acceptable salt thereof, for treating diseases or symptoms caused by a prescribed acid secretion inhibitor. The present invention provides a compound of chemical formula 1 as defined in any embodiment of the present invention, or a pharmaceutical composition including a pharmaceutically acceptable salt thereof, for treating diseases or symptoms caused by a prescription acid secretion inhibitor. The present invention provides a gastric acid secretion inhibitor comprising a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof. The aforementioned gastrointestinal ulcers refer to ulcers occurring within the digestive tract, including the stomach and intestines. Examples include peptic ulcers, gastric ulcers, duodenal ulcers, NSAID-induced ulcers, acute stress ulcers, and Zollinger-Ellison syndrome, but are not limited to these categories. If the aforementioned gastric ulcers become severe, they can lead to cancer. For example, as the condition worsens, the aforementioned gastric ulcers may develop into stomach cancer. In particular, gastrointestinal ulcers can include damage to the gastric or small intestinal mucosa induced by drugs or alcohols. Specifically, damage to the gastric or small intestinal mucosa can be induced by NSAIDs or alcohols. The aforementioned gastrointestinal inflammatory diseases refer to diseases caused by inflammation of the gastrointestinal tract. Examples include Helicobacter pylori infection, gastritis (e.g., acute hemorrhagic gastritis, chronic superficial gastritis, chronic atrophic gastritis), and inflammatory bowel disease. This also includes gastric MALT lymphoma, but is not limited to these conditions. The aforementioned acid-related diseases refer to diseases caused by excessive secretion of gastric acid. Examples include erosive esophagitis, non-erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, hyperacidity, and upper gastrointestinal bleeding caused by invasive stress, but are not limited to these. By virtue of the present invention, the aforementioned gastrointestinal ulcers, gastrointestinal inflammatory diseases, or gastric acid-related diseases may include any one or more of the following groups: peptic ulcers, gastric ulcers, duodenal ulcers, NSAID-induced ulcers, acute stress ulcers, Zollinger-Elison syndrome, Helicobacter pylori infection, gastritis, erosive esophagitis, non-erosive esophagitis, reflux esophagitis, inflammatory bowel disease, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, gastric cancer, gastric MALT lymphoma, hyperacidity, and upper gastrointestinal bleeding caused by invasive stress. The above-described pharmaceutical compositions may include the compounds of this invention and pharmaceutically acceptable carriers. Other pharmacologically active ingredients may also be present. In this invention, "pharmaceutically acceptable carriers" include any and all physiologically miscible solvents, dispersion media, coatings, antimicrobial and antifungal agents, isotonic formulations, and absorption delay agents, etc. The compositions of the present invention can be in various forms. These include, for example, liquid, semi-solid, and solid delivery forms, such as liquid solutions (e.g., injectable and injectable solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The form depends on the intended manner of delivery and therapeutic use. Typical compositions are in the form of injectable and infusionable solutions. One route of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). Oral administration in solid form may, for example, be provided as hard or soft capsules, pills, pouches, slag, or tablets, each containing a predetermined amount of one or more compounds of the present invention. In another embodiment, oral administration may be in powder or granular form. In another embodiment, oral administration may be in liquid form. Liquid forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and emulsions, such as those containing inactive diluents commonly used in the art (e.g., water). In another embodiment, the invention includes non-oral administration. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection, and infusion. Injectable formulations (i.e., sterile injectable aqueous suspensions or maintenance suspensions) can be formulated using suitable dispersants, wetting agents, and / or suspending agents using published techniques. Other carrier materials and delivery methods disclosed in the pharmaceutical technology field can also be utilized. The pharmaceutical compositions of this invention can be manufactured using any widely disclosed pharmaceutical technology, such as effective dosage formation and delivery procedures. Typically, the compounds of the present invention are administered at an effective dose to treat the symptoms described herein. The compounds of the present invention may be administered as the compound itself, or, differently, as pharmaceutically acceptable salts. For the purposes of administration and dosage, the aforementioned compounds, either alone or as pharmaceutically acceptable salts, will simply be referred to as the compounds of the present invention. The compounds of this invention may be administered via any suitable route, in the form of a pharmaceutical composition suitable for the aforementioned route, and at an dosage that is expected to be effective for treatment. The compounds of this invention may be administered orally, rectally, vaginally, non-orally, or topically. The compounds of this invention are preferably administered orally. Oral administration may involve swallowing, allowing the compounds to enter the gastrointestinal tract. In another embodiment, the compounds of the present invention can also be administered directly into the bloodstream, muscles, or internal organs. Suitable methods for parenteral administration include intravenous, intra-arterial, intra-abdominal, intramuscular, and subcutaneous administration. The compounds of this invention and / or compositions containing such compounds are administered as therapies based on various factors, including patient type, age, weight, sex, and medical symptoms; severity of symptoms; route of administration; and the activity of the specific compound used. Therefore, administration therapies may vary widely. In one embodiment, the total daily dose of the compounds of this invention, typically used to treat the symptoms discussed herein, is from about 0.001 mg / kg to about 100 mg / kg (i.e., mg of the compounds of this invention per kg of body weight). [Effects of the Invention] The manufacturing method of this invention has the advantages of significantly shortening the manufacturing process while carrying out the reaction under suitable conditions for mass production. Furthermore, despite shortening the process as described above, it also improves process efficiency and simplifies the salt manufacturing process through excellent yield, minimizing the formation of flexible substances and increasing yield. This brings useful benefits to industrial mass production. The present invention will now be described in more detail by way of the following embodiments. However, the following embodiments are merely illustrative of the invention, and the scope of the invention is not limited to these embodiments. Example 1. Preparation of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrolo-3-yl)-N-methylmethylamine fumarate (Step 1) Synthesis of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxaldehyde (a compound of formula 4) 700.0 g of 5-(2-fluorophenyl)-4-methoxy-1-H-pyrrole-3-carboxaldehyde (compound of formula 2), 795.6 g of 6-methoxypyridine-3-sulfonyl chloride (compound of formula 3), 78.0 g of 4-(dimethylamino)-pyridine, and 5488 g of acetone were added, and the mixture was stirred at an internal temperature of 20–30°C for 10 minutes. Then, 387.7 g of triethylamine was added, and the mixture was stirred at an internal temperature of 20–30°C for 4 hours to complete the reaction. The precipitated solid was then filtered, and the filter was washed with 1,646 g of acetone. The filtrate was then concentrated under reduced pressure at 35–45°C. Next, 3,851 g of 2-propanol was added to the concentrate, and the internal temperature was raised to 60–70°C and stirred for 10 minutes. Finally, the internal temperature was cooled to 20–30°C and stirred for 12 hours. Next, the internal temperature was cooled to 0–5°C and stirred for 1 hour. After stirring, the resulting crystals were filtered under reduced pressure, and the filter media was washed with 1650 g of 2-propanol. The washed filter media was dried at a temperature of 45–55°C for at least 12 hours to obtain 1145.8 g of the compound represented by formula 4. (Yield: 91.9% / Purity: 99.9%) Using the above manufacturing process, compounds represented by chemical formula 4 were mass-produced with a yield of over 91%. 1 H-NMR (Nuclear Magnetic Resonance) (400 MHz, CDCl₂) 3)9.89(s,1H),8.09(s,1H),7.99(s,1H),7.50~7.44(m,2H),7.26~7.17(m,2H),7.01(t,1H),6.69(d,1H),3.98(s,3H),3.62(s,3H) (Steps 2 and 3) Synthesis of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrolo-3-yl)-N-methylmethylamine fumarate (compounds of formulas 1-2) Step 2. Add 30.0 g of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxaldehyde (a compound in Formula 4) and 119 g of methanol, and stir at room temperature for 10 minutes. Add 9.5 g of methylamine (12 M in water), and stir at an internal temperature of 20–30°C for 1 hour. Then, cool the internal temperature to 0–10°C, add 1.4 g of sodium borohydride, and then raise the internal temperature to 20–30°C and stir for 2 hours to complete the reaction. After the reaction is complete, maintain the internal temperature at 0–10°C, add 271 g of ethyl acetate, then add 300 g of 10% sodium chloride aqueous solution and stir at room temperature for 10 minutes. Next, separate the organic layer of the mixture, add 300 g of purified water to the separated organic layer and stir for 10 minutes. The organic layer was then separated, and the same process was repeated. Next, 300 g of a 10% sodium chloride aqueous solution was added to the separated organic layer, and the mixture was stirred at room temperature for 10 minutes. Then, the organic layer of the mixture was separated, 5 g of magnesium sulfate was added, and the mixture was stirred for 30 minutes before filtration. The filtrate was washed with 54 g of ethyl acetate. Step 3. Concentrate the filtrate under reduced pressure at 35–45°C. Add 71 g of ethanol, 189 g of ethyl acetate, and 8.9 g of fumaric acid to the concentrate, and stir at an internal temperature range of 20–30°C for at least 12 hours. After stirring, filter the resulting crystals under reduced pressure, and wash the filtrate with 54 g of ethyl acetate. Dry the washed filtrate at a temperature range of 45–55°C for at least 12 hours to obtain 36.6 g of the compound represented by chemical formula 1-2. (Yield: 91.3% / Purity: 99.7%) Using the above manufacturing process, compounds represented by chemical formulas 1-2 were mass-produced with a yield of over 91%. 1 H-NMR(400 MHz, DMSO) 8.11 (dd, 1H), 7.69 (dd, 1H), 7.58 (s, 1H), 7.56 ~ 7.50 (m, 1H), 7.25 ~ 7.20 (m, 2H), 7.1 6~7.12 (td, 1H), 6.97 (dd, 1H), 6.51 (s, 2H), 3.93 (s, 3H), 3.77 (s, 2H), 3.40 (s, 3H), 2.46 (s, 3H) Experimental Example 1. Confirmation of the effect of organic solvents on the manufacture of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxaldehyde (a compound of formula 4). To confirm the effect of organic solvents in step 1 during the manufacture of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-yl))-N-methylmethylamine fumarate, acetonitrile was used instead of acetone as the organic solvent to manufacture 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxaldehyde. Specifically, it is manufactured under conditions of 4-(dimethylamino)-pyridine, triethylamine, and acetonitrile solvent. Then, the content of residual triethylamine in the solvent was confirmed by NMR. The results are shown in Table 1 below. [Table 1] As mentioned above, it has been confirmed that when acetonitrile is used, the residual amount of triethylamine is very high, so further refining processes are necessary. This confirms the importance of selecting a suitable organic solvent in the manufacturing process of step 1 of the present invention. On the other hand, the above embodiments are merely examples of one embodiment, which can not only improve the yield and process efficiency of the final material, but also control the quality. Referring to the above embodiments, by adjusting the process temperature and execution time of each step within the scope of the above embodiments, the yield and process efficiency of the final material can be improved while controlling the quality.

Claims

1. A method for manufacturing a 6-methoxypyridine-3-yl derivative, comprising: 1) The step of reacting the compound represented by chemical formula 2 with the compound represented by chemical formula 3 to produce the compound represented by chemical formula 4; 2) The step of reacting the compound represented by chemical formula 4 with methylamine to generate an intermediate, and adding a reducing agent to convert the intermediate into the compound represented by chemical formula 1; [Chemical formula 1] [Chemical formula 2] [Chemical formula 3] [Chemical formula 4] .

2. The manufacturing method of claim 1, wherein step 1 is performed in the presence of a base, 4-(dimethylamino)-pyridine and an organic solvent.

3. The manufacturing method of claim 2, wherein the base in step 1 is selected from any one or more of the group consisting of N,N-diisopropylethylamine, triethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate, and cesium carbonate.

4. The manufacturing method of claim 2, wherein the organic solvent in step 1 is selected from any one or more of the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ether, methyl tributyl ether, toluene, xylene and heptane.

5. The manufacturing method of claim 1, wherein in step 1 above, the molar ratio of the compound represented by chemical formula 2 to the compound represented by chemical formula 3 is 10:1 to 1:

10.

6. The manufacturing method as claimed in claim 1, wherein the reaction temperature in step 1 above is 10°C to 35°C.

7. The manufacturing method of claim 1, wherein the reaction solvent in step 2 is selected from one or more of the group consisting of water, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl ether and acetonitrile.

8. The manufacturing method of claim 1, wherein in step 2 above, the reaction temperature of the compound represented by chemical formula 4 and the methylamine is 15°C to 35°C.

9. The manufacturing method of claim 1, wherein the reducing agent in step 2 is selected from any one or more of the group consisting of sodium borohydride, sodium cyanoborohydride and sodium triethoxyborohydride.

10. The manufacturing method of claim 1, wherein in step 2 above, the reaction temperature of the reducing agent and the intermediate is -5°C to 15°C.

11. The manufacturing method of claim 1, wherein in step 2 above, the molar ratio of the compound represented by chemical formula 4 to the methylamine is 10:1 to 1:10, and the molar ratio of the compound represented by chemical formula 4 to the reducing agent is 10:1 to 1:

10.

12. The manufacturing method of claim 1, wherein after step 2 above, it further includes step 3) adding an acid to the compound represented by the above chemical formula 1 to manufacture the acidic salt represented by the following chemical formula 1-1, [chemical formula 1-1].

13. The manufacturing method of claim 12, wherein the acid is selected from any one or more of the group consisting of hydrochloric acid, glutamic acid, malonic acid, succinic acid, tartaric acid, oxalic acid, fumaric acid, phosphoric acid, and methanesulfonic acid.