Preparation method of 6-methoxypyridine-3-yl derivative

Abstract

The invention relates to a preparation method of a 6-methoxy pyridine-3-yl derivative. The preparation method provided by the invention has the advantages that the preparation process is greatly shortened, and the reaction can be carried out under proper conditions for mass production. In addition, although the process described above is shortened, it has the advantages of improving process efficiency, simplifying a salt preparation process, minimizing the occurrence of related substances, and increasing yield through excellent yield. Therefore, useful benefits are brought to industrial mass production.

Description

Technical Field

[0001] The invention relates to a method for preparing a 6-methoxypyridin-3-yl derivative. Background Art

[0002] In order to improve the shortcomings of proton pump inhibitors (PPIs), potassium-competitive acid blockers (P-CABs) have attracted much attention. Potassium-competitive acid blockers inhibit the proton pump (H-P) of the enzyme involved in the final stage of gastric acid secretion in gastric parietal cells. + / K + -ATPase) and K + Ions reversibly and competitively bind to effectively and rapidly inhibit gastric acid secretion. Compared with PPI preparations, this type of P-CAB preparation shows a strong inhibitory effect in the general acidity of the stomach (pH 1 to 3). However, the pharmacological activity of gastric P-CAB preparations needs to decrease with the increase of pH value. Some P-CAB preparations show pharmacological activity, and the pharmacological activity remains unchanged even when the pH value increases. Some side effects related to them have been reported. In addition, since P-CAB preparations are mainly metabolized by CYP3A4 enzymes, the difference in efficacy between individuals is relatively insignificant, and the concern about interactions with drugs metabolized by CYP2C19 enzymes is relatively low.

[0003] International Patent Publication No. WO2019 / 013310A1 discloses vonoprazan as a potassium-competitive acid blocker.

[0004] However, it has been confirmed that vonoprazan induces severe hypergastrinemia compared to the existing PPI drug lansoprazole. This hypergastrinemia can cause problems such as enterochromaffin-like (ECL) cell hyperplasia, parietal cell hyperplasia, fundic gland polyp, bone loss, damaged bone and fractures. In fact, in carcinogenicity tests in mice and rats, vonoprazan has been reported to be associated with the occurrence of gastric neuroendocrine cell tumors. However, stopping the administration of P-CAB or PPI series drugs such as vonoprazan will restore hyperacidity and induce indigestion, etc. Therefore, even if the above problems exist, drug administration cannot be easily stopped.

[0005] In this context, many attempts are being made to develop novel P-CAB drugs. For example, in Korean Patent Registration No. 10-2432523, a novel P-CAB inhibitor showing excellent acid secretion inhibitory effect is disclosed. Specifically, Korean Patent Registration No. 10-2432523 discloses a method for preparing a novel P-CAB drug, comprising: step (I), introducing a suitable heteroarylsulfonyl group into a starting material using a base in the presence of an inert solvent; step (II), reducing using a reducing agent in the presence of an inert solvent; step (III), oxidizing using an oxidizing agent in the presence of an inert solvent; and step (IV), a reductive amination process using a suitable amine and a reducing agent.

[0006] However, the preparation method disclosed in the above patent has the disadvantages of very long preparation process and low production yield. In particular, the preparation process using substances such as DIBAL (diisobutyl aluminium hydride) is dangerous; the use of high-priced raw materials such as sulfone derivatives in the initial step of the reaction is not suitable for mass production and has the disadvantage of being difficult to carry out subsequent development as a salt.

[0007] In order to solve the above problems, the present inventors have developed a novel preparation process, which greatly improves the production level of the target substance while maximizing the yield in the preparation process, thereby completing the present invention. Summary of the invention

[0008] [Problems to be solved by the invention]

[0009] The present invention aims to provide a method for preparing a 6-methoxypyridin-3-yl derivative.

[0010] In order to solve the above-mentioned problem, one embodiment of the present invention is a method for preparing a 6-methoxypyridin-3-yl derivative, which comprises:

[0011] Step 1), reacting the compound represented by the following chemical formula 2 with the compound represented by the following chemical formula 3 to prepare the compound represented by the following chemical formula 4;

[0012] Step 2), 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;

[0013] [Chemical formula 1]

[0014]

[0015] [Chemical formula 2]

[0016]

[0017] [Chemical formula 3]

[0018]

[0019] [Chemical formula 4]

[0020]

[0021] [Technical means to solve the problem]

[0022] In order to solve the above problems, the present invention provides a preparation method as shown in the following reaction formula 1:

[0023] [Reaction 1]

[0024]

[0025] Specifically, as an embodiment of the present invention, the following steps 1 and 2 are included to prepare a compound represented by the following chemical formula 1.

[0026] Step 1), reacting a compound represented by the following chemical formula 2 with a compound represented by the following chemical formula 3 to prepare a compound represented by the following chemical formula 4; and

[0027] Step 2), 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.

[0028] Optionally, a method for preparing the compound represented by the following chemical formula 1-1 is provided, which further comprises the following step 3.

[0029] Step 1), reacting the compound represented by the following chemical formula 2 with the compound represented by the following chemical formula 3 to prepare the compound represented by the following chemical formula 4;

[0030] Step 2), 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; and

[0031] Step 3), adding an acid to the compound represented by the above chemical formula 1 to prepare an acid salt represented by the following chemical formula 1-1;

[0032] Hereinafter, an embodiment of the present invention will be described in detail according to the above steps. Referring to the following description, if the process temperature, execution time, etc. of the above steps are adjusted, the quality of the final product can also be controlled.

[0033] [Step 1]

[0034] Step 1 is a step of reacting the compound represented by Chemical Formula 2 with the compound represented by Chemical Formula 3 to prepare the compound represented by Chemical Formula 4, and is a step of introducing a substituted pyridinesulfonyl group into the pyrrol group of the compound represented by Chemical Formula 2.

[0035] The reaction in step 1 can be performed in the presence of 4-(dimethylamino)-pyridine, a base and an organic solvent. Here, as the base, N,N-diisopropylethylamine, triethylamine, diisopropylamine, diisopropylethylamine, 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 thereof can be used. Specifically, triethylamine can be used.

[0036] In the above step 1, a solvent that is conducive to dispersing the base and 4-(dimethylamino)-pyridine, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ether, methyl tert-butyl ether, toluene, xylene, heptane or a mixture of two or more thereof, can be used as a reaction solvent. Specifically, acetone can be used as the reaction solvent of the above step 1. In particular, under the above solvent, the base, such as triethylamine, etc., can be easily precipitated, thereby maximizing the reaction yield.

[0037] In the step 1, the molar ratio of the compound represented by the chemical formula 2 to the compound represented by the chemical formula 3 may be 10:1 to 1:10, specifically, 5:1 to 1:5, and more specifically, 3:1 to 1:3.

[0038] The reaction in step 1 may be performed at 10° C. to 35° C. Specifically, the reaction in the reaction temperature range of step 1 may increase the conversion rate of step 1 and help reduce the content of related substances in the final substance.

[0039] The reaction of step 1 can be performed for 30 minutes to 8 hours. When the reaction time is less than 30 minutes, there is a problem that the reaction is insufficient and the production yield is reduced; when the reaction time exceeds 8 hours, the production yield is not substantially increased. More specifically, the reaction can be performed for 1 hour to 5 hours.

[0040] If necessary, after the reaction is terminated, the process may further include a step of purifying the compound represented by Chemical Formula 4. Specifically, the compound represented by Chemical Formula 4 may be crystallized from the reaction product of Step 1.

[0041] As a solvent for crystallizing the compound represented by the above Chemical Formula 4 from the reaction product, for example, an alcohol having 1 to 4 carbon atoms may be used.

[0042] Here, the alcohol having a carbon number of 1 to 4 may be methanol, ethanol, propanol, 2-propanol, butanol, tert-butanol, or a mixture of two or more thereof. More specifically, 2-propanol may be used alone. For example, 2-propanol may be added and heated to 40°C to 80°C, cooled to 15°C to 35°C, and then stirred. Stirring may be performed by further cooling to 0°C to 10°C as required. Through this process, an excellent effect of removing the base on the residual solvent may be exhibited, such as triethylamine and 4-(dimethylamino)-pyridine.

[0043] After the compound represented by Chemical Formula 4 is refined through the above steps, the moisture content included in the compound represented by Chemical Formula 4 can be reduced by drying at 40° C. to 60° C. for 10 to 14 hours. Thus, the moisture content of the compound represented by Chemical Formula 4 can be significantly reduced, and the conversion rate of the next step can be improved.

[0044] The method may further include a washing step using the solvent used after the reaction in each of the above steps is completed.

[0045] [Step 2]

[0046] The step 2 is a step of reacting the compound represented by the chemical formula 4 with methylamine to generate an intermediate, and adding a reducing agent to convert the intermediate into the compound represented by the chemical formula 1.

[0047] The step 2 is a step of converting the compound represented by the chemical formula 4 into the compound represented by the chemical formula 1 by a reductive amination reaction.

[0048] Specifically, in the above step 2, the compound represented by the above chemical formula 4 undergoes an imine formation reaction with methylamine to generate an imine compound. This imine compound is an intermediate with an unstable structure and can be easily reduced to the compound represented by the above chemical formula 1.

[0049] The reductive imidization reaction of step 2 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 thereof. The solvent conditions according to the present invention are to use a solvent that can provide a reaction under moderate conditions, and in particular, there is an advantage that the reaction under solvent conditions does not cause restrictions by the Food and Drug Safety Administration and the like.

[0050] More specifically, after the compound represented by the above chemical formula 4 and the above methylamine are added together with the above reaction solvent, they are stirred at 15° C. to 35° C., 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.

[0051] At this time, considering that as the solubility of the compound represented by the above Chemical Formula 4 is lowered, the related substances included in the final substance may be increased, and thus the above stirring time and temperature may be adjusted.

[0052] In addition, the methylamine may be preferably methylamine dissolved in water. In particular, the reaction conditions have the advantage of reacting under moderate conditions close to room temperature conditions compared to the known conditions. In addition, the equivalent of methylamine is appropriately controlled to minimize the content of related substances. For example, by adding 1.5 to 2.5 eq of methylamine, the generation of related substances related to dimer formation is minimized compared to the known methods.

[0053] The reduction reaction (Reduction) of the intermediate (ie, the imine compound) generated by the reaction of the compound represented by the above Chemical Formula 4 with methylamine can be performed more stably at a lower temperature.

[0054] In view of this, after the reaction of the compound represented by the above chemical formula 4 and methylamine is completed, the reactor temperature may be cooled to a range of -5°C to 15°C, for example, 0°C to 10°C, and then the reducing agent is added in accordance with the cooling temperature range, and then the reactor temperature is maintained and stirred. 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.

[0055] Here, as the reducing agent, any one or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride can be used.

[0056] The molar ratio of the compound represented by Chemical Formula 4 to the methylamine may be 10:1 to 1:10, and the molar ratio of the compound represented by Chemical Formula 4 to 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.

[0057] Thereafter, extraction is performed 1 to 3 times using an organic solvent to obtain an organic layer, a desiccant is added to the organic layer, the mixture is stirred, and then filtered under reduced pressure. After washing the filtrate, the filtrate may be concentrated under reduced pressure.

[0058] In the above extraction, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, 2-propanol, 1-butanol, dichloromethane, acetone or an organic solvent of a mixture of two or more thereof can be used. Preferably, ethyl acetate can be used.

[0059] [Step 3]

[0060] After the above step 2, the following step 3 may be optionally further included.

[0061] The three-step process can be carried out through the following steps, and the preparation method also includes:

[0062] Step 3), adding an acid to the compound represented by the above chemical formula 1 to prepare an acid salt represented by the following chemical formula 1-1;

[0063] [Chemical formula 1-1]

[0064]

[0065] The above step 3 is a step for providing the compound represented by the above chemical formula 1 in the form of a pharmaceutically acceptable salt, and adding an acid to the compound represented by the above chemical formula 1 simultaneously with or after the above step 2 to obtain a pharmaceutically acceptable acidic salt represented by the above chemical formula 1-1.

[0066] Specifically, the step 3 may include the following steps: providing an organic solvent to the compound represented by the chemical formula 1, and then providing an acid or a mixed solution thereof in the organic solvent to crystallize the acid salt represented by the chemical formula 1-1.

[0067] More specifically, an organic solvent can be provided to the concentrated residue including the compound represented by the above chemical formula 1. The organic solvent provided at this time can be ethyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, methanol, ethanol, isopropanol, acetonitrile, dichloromethane, n-hexane, dimethyl sulfoxide or a mixture of two or more thereof. Preferably, it can be selected from the group consisting of a mixed solvent of ethanol and ethyl acetate, a mixed solvent of isopropanol and ethyl acetate, a mixed solvent of methanol and ethyl acetate, a mixed solvent of methanol and methyl tert-butyl ether, a mixed solvent of methanol and acetone, a mixed solvent of ethanol and acetone, a mixed solvent of ethanol and acetone, a mixed solvent of ethanol and methyl tert-butyl ether, dimethyl sulfoxide, ethanol and ethyl acetate. More preferably, it can be a mixed solvent of ethanol and ethyl acetate. In particular, by crystallization under the organic solvent conditions of the present invention, it has the advantages of minimizing the generation of related substances and generating the target salt without the need for additional refining processes.

[0068] After providing the above-mentioned organic solvent to the concentrated residue including the compound represented by the above-mentioned 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 provided and stirred, so that the acidic salt represented by the above-mentioned Chemical Formula 1-1 can be crystallized.

[0069] The acid used for crystallizing the acid 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.

[0070] The acid and the organic solvent may be provided as a mixed solution, and the organic solvent in the mixed solution may be selected from the organic solvents mentioned above.

[0071] In one embodiment, when the acid used for crystallization in the above Chemical Formula 1-1 is fumaric acid, the crystal has a chemical structure of the following Chemical Formula 1-2.

[0072] [Chemical formula 1-2]

[0073]

[0074] After the preparation of the salt, the salt is dried at 40 to 60° C. for 10 to 14 hours to reduce the moisture content included in the compound represented by Chemical Formula 4. Thus, the moisture content of the compound represented by Chemical Formula 4 can be significantly reduced, thereby maximizing the yield of the target compound.

[0075] In the above step 3, the crystallization of the acid salt represented by the above chemical formula 1-1 may be performed two or more times as necessary.

[0076] For example, after the acid salt represented by the above chemical formula 1-1 is crystallized, the acid 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 provided to recrystallize the acid salt represented by the above chemical formula 1-1.

[0077] In the above-mentioned recrystallization process, a base can be further used to dissociate the acidic salt. Here, as the base for dissociating the above-mentioned 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 thereof can be used. Specifically, potassium carbonate can be used, and its use method can be well known in the art.

[0078] The method may further include a washing step using the solvent used after the reaction in each of the above steps is completed.

[0079] When the above step 3 is selectively performed, it is performed together with step 2, and the above reaction can be performed in two steps instead of three steps. In this case, the present invention provides a preparation method as shown in the following reaction formula 2.

[0080] [Reaction 2]

[0081]

[0082] In the case of the above reaction formula 2, the preparation method is as follows:

[0083] Step 1), reacting a compound represented by the following chemical formula 2 with a compound represented by the following chemical formula 3 to prepare a compound represented by the following chemical formula 4; and

[0084] Step 2), the compound represented by the following chemical formula 4 reacts with methylamine to generate an intermediate, a reducing agent is added, and an acid is added to prepare an acid salt represented by the following chemical formula 1-1.

[0085] In one aspect, the present invention provides a pharmaceutical composition for preventing or treating gastrointestinal ulcers, gastrointestinal inflammatory diseases or gastric acid-related diseases, the composition comprising the compound of the above Chemical Formula 1 or a pharmaceutically acceptable salt thereof (preferably, Chemical Formula 1-1 or 1-2).

[0086] The present invention provides a compound of Formula 1 as defined in any of the embodiments described herein, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0087] The present invention provides a compound of Chemical Formula 1 as defined in any of the embodiments described herein, or a pharmaceutically acceptable salt thereof, for use in preventing or treating gastrointestinal ulcers, gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0088] The present invention provides a method for treating gastrointestinal ulcer, gastrointestinal inflammatory disease or gastric acid-related disease, 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 subject in need thereof.

[0089] The present invention provides the use of a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating a disease or symptom for which an acid secretion inhibitor is prescribed, such as gastrointestinal ulcer, gastrointestinal inflammatory disease or gastric acid-related disease.

[0090] The present invention provides a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof as defined in any of the embodiments described herein for use in treating a disease or symptom for which an acid secretion inhibitor is prescribed.

[0091] The present invention provides a compound of Chemical Formula 1 as defined in any embodiment described in the present invention or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof, which is used for treating a disease or symptom for which an acid secretion inhibitor is prescribed.

[0092] The present invention provides a gastric acid secretion inhibitor, which comprises a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0093] The above-mentioned gastrointestinal ulcer refers to an ulcer that occurs in the digestive tract including the stomach and intestines. For example, peptic ulcer, gastric ulcer, duodenal ulcer, ulcer induced by NSAID (non-steroidal anti-inflammatory drugs), acute stress ulcer, Zollinger-Ellison syndrome, etc., but not limited thereto. If the above-mentioned gastric ulcer is severe, it will lead to cancer. For example, as the above-mentioned gastric ulcer situation worsens, it may develop into gastric cancer.

[0094] In particular, the gastrointestinal ulcer may include gastric mucosal damage or small intestinal mucosal damage induced by drugs or alcohol, etc. In particular, it may be gastric mucosal damage or small intestinal mucosal damage induced by NSAID or alcohol.

[0095] The above-mentioned gastrointestinal inflammatory diseases refer to diseases caused by inflammation of the gastrointestinal tract.

[0096] For example, Helicobacter pylori infection, gastritis (eg, acute hemorrhagic gastritis, chronic superficial gastritis, chronic atrophic gastritis), inflammatory bowel disease, including gastric MALT lymphoma, etc., but not limited thereto.

[0097] The gastric acid-related disease refers to a disease caused by excessive secretion of gastric acid, for example, erosive esophagitis, non-erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, hyperacidity, upper gastrointestinal bleeding caused by invasive stress, etc., but is not limited thereto.

[0098] According to the present invention, the above-mentioned gastrointestinal ulcer, gastrointestinal inflammatory disease or gastric acid-related disease may include any one or more selected from the group consisting of peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, acute stress ulcer, Zollinger-Ellison 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.

[0099] The pharmaceutical composition may include the compound of the present invention and a pharmaceutically acceptable carrier. Other pharmacologically active ingredients may also be present. In the present invention, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic preparations and absorption delaying agents that are physiologically miscible.

[0100] The compositions of the present invention can be in various forms. They include, for example, liquid, semi-solid and solid administration forms, such as liquid solutions (e.g., injectable and injectable solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The above forms depend on the intended mode of administration and therapeutic use.

[0101] Typical compositions are in the form of compositions similar to injectable and infusible solutions. One route of administration is parenteral (eg, intravenous, subcutaneous, intraperitoneal, intramuscular).

[0102] Solid administration forms for oral administration, for example, can provide hard or soft capsules, pills, sachets, lozenges or tablets each containing a predetermined amount of one or more compounds of the present invention. In another embodiment, oral administration can be in the form of powder or granules.

[0103] In another embodiment, oral administration may be in the form of a liquid administration. Liquid administration forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, for example containing inactive diluents commonly used in the art (eg, water).

[0104] In another embodiment, the present invention includes non-oral administration forms. "Parenteral administration" includes, for example, subcutaneous injection, intravenous injection, intraperitoneal injection, intramuscular injection, intrasternal injection and infusion. Injectable preparations (i.e., sterile injectable aqueous or oily suspensions) can be formulated using suitable dispersants, wetting agents and / or suspending agents by published techniques.

[0105] Other carrier materials and administration methods known in the pharmaceutical technology field can also be used. The pharmaceutical compositions of the present invention can be prepared by any widely disclosed pharmaceutical technology (eg, effective dosage formulation and administration procedures).

[0106] Typically, the compounds of the present invention are administered at an effective dose for treating the symptoms described herein. The compounds of the present invention may be administered as the compounds themselves, or differently, as pharmaceutically acceptable salts. For administration and dosage purposes, the above compounds themselves or their pharmaceutically acceptable salts will be simply referred to as compounds of the present invention.

[0107] The compounds of the present invention are administered by any appropriate route, in the form of pharmaceutical compositions suitable for the above routes, and in an amount effective for the intended treatment. The compounds of the present invention can be administered orally, rectally, vaginally, parenterally or topically.

[0108] The compounds of the present invention are preferably administered orally. Oral administration may be accompanied by swallowing, so that the compound enters the gastrointestinal tract.

[0109] In another embodiment, the compounds of the invention may also be administered directly into the bloodstream, muscle or internal organs. Suitable methods for parenteral administration include: intravenous, intraarterial, intraperitoneal, intramuscular and subcutaneous.

[0110] The administration therapy of the compounds of the present invention and / or compositions containing the above compounds is based on various factors, including the type, age, weight, sex and medical symptoms of the patient; the severity of the symptoms; the route of administration; and the activity of the specific compound used. Therefore, there may be wide differences in the administration therapy. In one embodiment, typically, for the treatment of the proposed symptoms discussed in the present invention, the total daily administration amount of the compound of the present invention is about 0.001 mg / kg to about 100 mg / kg (i.e., mg of the compound of the present invention per kg of body weight).

[0111] [Effects of the Invention]

[0112] The preparation method of the present invention has the advantages of greatly shortening the preparation process and being able to perform the reaction under the appropriate conditions of mass production. In addition, although the process as described above is shortened, it has the advantages of improving process efficiency and simplifying the preparation process of the salt, minimizing the occurrence of related substances and improving the yield through excellent yield. Therefore, it brings useful benefits for industrial mass production. DETAILED DESCRIPTION

[0113] Hereinafter, the present invention will be described in more detail by the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited to these examples.

[0114] Example 1. Preparation of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine fumarate

[0115] (Step 1) Synthesis of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carbaldehyde (compound of Chemical Formula 4)

[0116]

[0117] 700.0 g of 5-(2-fluorophenyl)-4-methoxy-1H-pyrrole-3-carboxaldehyde (compound of Chemical Formula 2), 795.6 g of 6-methoxypyridine-3-sulfonyl chloride (compound of Chemical Formula 3), 78.0 g of 4-(dimethylamino)-pyridine and 5488 g of acetone were added, and stirred for 10 minutes at an internal temperature of 20 to 30°C. 387.7 g of triethylamine was added, and stirred for 4 hours at an internal temperature of 20 to 30°C to complete the reaction. Next, the precipitated solid was filtered, and the filtrate was washed with 1,646 g of acetone. Thereafter, the filtrate was concentrated under reduced pressure at 35 to 45°C, and then 3851 g of 2-propanol was added to the concentrated solution, and the internal temperature was raised to 60 to 70°C and stirred for 10 minutes. Then, the internal temperature was cooled to 20 to 30°C and stirred for 12 hours. Next, the internal temperature was cooled to 0-5°C and stirred for 1 hour. After the stirring was completed, the generated crystals were filtered under reduced pressure and the filtrate was washed with 1650 g of 2-propanol. The washed filtrate was dried at a temperature range of 45-55°C for more than 12 hours to obtain 1145.8 g of the compound represented by Chemical Formula 4. (Yield: 91.9% / Purity 99.9%)

[0118] Through the above-mentioned preparation process, the compound represented by Chemical Formula 4 was produced in large quantities with a yield of 91% or more.

[0119] 1 H-NMR (Nuclear Magnetic Resonance) (400 MHz, CDCl3) 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)

[0120] (Step 2 and Step 3) Synthesis of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethylamine fumarate (compound of Chemical Formula 1-2)

[0121]

[0122] Step 2, add 30.0g of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxaldehyde (compound of chemical formula 4) and 119g of methanol, and stir at room temperature for 10 minutes. Add 9.5g of methylamine (12M in water) and stir for 1 hour at an internal temperature of 20 to 30°C. Then, cool the internal temperature to 0 to 10°C, add 1.4g of sodium borohydride, raise the internal temperature to 20 to 30°C and stir for 2 hours to complete the reaction. After the reaction is completed, keep the internal temperature at 0 to 10°C, add 271g of ethyl acetate, add 300g of 10% sodium chloride aqueous solution and stir at room temperature for 10 minutes. Then, separate the organic layer of the mixture, add 300g of purified water to the separated organic layer and stir for 10 minutes. Thereafter, the organic layer was 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 stirred at room temperature for 10 minutes. Next, the organic layer of the mixture was separated, 5 g of magnesium sulfate was added, stirred for 30 minutes and filtered, and the filtrate was washed with 54 g of ethyl acetate.

[0123] Step 3, the filtrate is concentrated under reduced pressure at 35-45°C, 71g of ethanol, 189g of ethyl acetate and 8.9g of fumaric acid are added to the concentrate, and stirred for more than 12 hours at an internal temperature range of 20-30°C. After the stirring is completed, the generated crystals are filtered under reduced pressure, and the filtrate is washed with 54g of ethyl acetate. The washed filtrate is dried at a temperature range of 45-55°C for more than 12 hours to obtain 36.6g of the compound represented by chemical formula 1-2. (Yield: 91.3% / purity 99.7%)

[0124] Through the above-mentioned preparation process, the compound represented by Chemical Formula 1-2 was produced in large quantities with a yield of 91% or more.

[0125] 1H-NMR (400MHz, 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) ,7.16~7.12(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)

[0126] Experimental Example 1, confirming the influence of organic solvent in the preparation of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carbaldehyde (compound of chemical formula 4)

[0127] In order to confirm the influence of organic solvent in step 1) when preparing 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl))-N-methylmethanamine fumarate, acetonitrile was used instead of acetone organic solvent to prepare 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carbaldehyde.

[0128] Specifically, the preparation is carried out under the conditions of 4-(dimethylamino)-pyridine, triethylamine and acetonitrile solvent.

[0129] Then, the content of triethylamine remaining in the solvent was confirmed by NMR.

[0130] The results are shown in Table 1 below.

[0131] [Table 1]

[0132] Residual triethylamine acetone 38,784ppm Acetonitrile 132,189ppm

[0133] As described above, it was confirmed that when acetonitrile was used, the residual amount of triethylamine was very high, and therefore a further purification process was required.

[0134] This confirms the importance of selecting a suitable organic solvent in the preparation process of step 1 according to the present invention.

[0135] On the other hand, the above embodiment is only an example of the above embodiment, which can not only improve the yield and process efficiency of the final material, but also control the quality.

[0136] With reference to the above embodiment, by adjusting the process temperature, execution time, etc. of each step within the scope of the above embodiment, the quality can be controlled while improving the yield and process efficiency of the final material.

Claims

1. A method for preparing a 6-methoxypyridin-3-yl derivative, characterized in that: It includes: Step 1), reacting the compound represented by the following chemical formula 2 with the compound represented by the following chemical formula 3 to prepare the compound represented by the following chemical formula 4; Step 2), reacting the compound represented by Chemical Formula 4 with methylamine to generate an intermediate, and adding a reducing agent to convert the intermediate into a compound represented by the following Chemical Formula 1; [Chemical formula 1] [Chemical formula 2] [Chemical formula 3] [Chemical formula 4] 2. The preparation method according to claim 1, characterized in that The step 1 is carried out in the presence of a base, 4-(dimethylamino)-pyridine and an organic solvent.

3. The preparation method according to claim 2, characterized in that: 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 preparation method according to claim 2, characterized in that: 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 tert-butyl ether, toluene, xylene and heptane.

5. The preparation method according to claim 1, characterized in that: In the step 1, 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 preparation method according to claim 1, characterized in that: The reaction temperature of step 1 is 10°C to 35°C.

7. The preparation method according to claim 1, characterized in that: The reaction solvent of step 2 is selected from any one or more of the group consisting of water, methanol, ethanol, isopropanol, dichloromethane, dichloroethane, tetrahydrofuran, ethyl acetate, dimethyl ether and acetonitrile.

8. The preparation method according to claim 1, characterized in that: In the step 2, the reaction temperature of the compound represented by Chemical Formula 4 and the methylamine is 15° C. to 35° C.

9. The preparation method according to claim 1, characterized in that: The reducing agent in step 2 is selected from any one or more of the group consisting of sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.

10. The preparation method according to claim 1, characterized in that: In the step 2, the reaction temperature of the reducing agent and the intermediate is -5°C to 15°C.

11. The preparation method according to claim 1, characterized in that: In the step 2, 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 preparation method according to claim 1, characterized in that: After step 2, the method further includes: Step 3), adding an acid to the compound represented by the chemical formula 1 to prepare an acid salt represented by the following chemical formula 1-1; [Chemical formula 1-1] 13. The preparation method according to claim 12, characterized in that: 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.

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