TW202411216A - Method for preparation of 6-methoxypyridine-3-yl derivatives - Google Patents

Abstract

The present invention relates to a method for producing a 6-methoxypyridine-3-yl derivative. The production method of the present invention has the advantage of performing the reaction under appropriate conditions that enable mass production. In addition, it has the following advantages: using salt to simplify the production process, minimize the generation of soft substances, and thereby produce high-purity compounds with high yields. This will bring useful benefits to mass production in the industry.

Description

Preparation method of 6-methoxypyridin-3-yl derivatives

The present invention relates to a method for preparing a 6-methoxypyridin-3-yl derivative.

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 reversibly and competitively bind to K ⁺ ions on the proton pump (H ⁺ /K ⁺ -ATPase) of the enzyme involved in the final stage of gastric acid secretion in the gastric wall cells, effectively and quickly inhibiting gastric acid secretion. Compared with PPI preparations, this P-CAB preparation shows a strong inhibitory effect in the normal acidity (pH1-3) in the stomach. However, the pharmacological activity required for gastric P-CAB preparations decreases with increasing pH. Some P-CAB preparations show pharmacological activity, and even if the pH value increases, the pharmacological activity remains unchanged. 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 drug interactions with drugs metabolized by CYP2C19 enzymes is relatively low.

International Patent Publication WO2019/013310A1 discloses vonolazan as a potassium-competitive acid retardant.

However, it has been confirmed that vonoprazan induces severe hypergastrinemia compared to the existing PPI drug lansoprazole. This hypergastrinemia can cause problems such as intestinal chromaffin-like (ECL)-cell hyperplasia, parietal cell hyperplasia, fundic gland polyps, bone loss, damaged bone and fractures. In fact, vonoprazan has been reported to be associated with the occurrence of gastric neuroendocrine cell tumors in mouse and rat carcinogenicity tests. 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, the drug administration cannot be easily stopped.

In this context, many attempts are being made to develop new P-CAB drugs. For example, Korean Patent Registration No. 10-2432523 discloses a new P-CAB inhibitor that exhibits excellent acid secretion inhibition effects. Specifically, Korean Patent Registration No. 10-2432523 discloses a method for preparing a novel P-CAB drug, comprising the steps of introducing a suitable heteroarylsulfonyl group into a starting material using a base in the presence of an inert solvent (I); performing reduction using a reducing agent in the presence of an inert solvent (II); performing oxidation using an oxidizing agent in the presence of an inert solvent (III); and performing a reductive amination process using a suitable amine and a reducing agent (IV).

However, the manufacturing method disclosed in the above patent has the disadvantages of a very long manufacturing process, low production yield and purity, and temperature conditions that are not suitable for mass production. In particular, substances such as NaH, DIBAL-H and DMP have problems such as high unit price, severe heat generation during the reaction, and difficulty in controlling the temperature, so the development of drugs related to them is very difficult.

In order to solve the above problems, the inventors have developed a new manufacturing process that maximizes the yield in the manufacturing process and significantly improves the production level of the target substance, thereby completing the present invention.

[The problem the invention is trying to solve]

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

In order to solve the above problems, the object of the present invention is to provide a method for preparing a 6-methoxypyridin-3-yl derivative, which comprises:

1) a step of reacting a compound represented by the following chemical formula 2 with a compound represented by the following chemical formula 3 to produce a compound represented by the following chemical formula 4;

2) a step of hydrolyzing the compound represented by the following chemical formula 4 to produce the compound represented by the following chemical formula 5;

3) reacting the acid activator with the compound represented by the following chemical formula 5, and adding a reducing agent to produce the compound represented by the following chemical formula 6;

4) a step of oxidizing the compound represented by the following chemical formula 6 to produce the compound represented by the following chemical formula 7; and

5) a step of reacting the compound represented by the following chemical formula 7 with methylamine and adding a reducing agent to produce the compound represented by the following chemical formula 1;

[Chemical formula 1]

[Chemical formula 2]

[Chemical formula 3]

[Chemical formula 4]

[Chemical formula 5]

[Chemical formula 6]

[Chemical formula 7] . [Technical means to solve the problem]

In order to solve the above problem, the present invention provides a production method as shown in the following reaction formula 1:

[Reaction 1]

Specifically, as an embodiment of the present invention, the compound represented by the following chemical formula 1 is prepared by comprising the following steps 1 and 5.

1) a step of reacting a compound represented by the following chemical formula 2 with a compound represented by the following chemical formula 3 to produce a compound represented by the following chemical formula 4;

2) a step of hydrolyzing the compound represented by the following chemical formula 4 to produce the compound represented by the following chemical formula 5;

3) reacting the acid activator with the compound represented by the following chemical formula 5, and adding a reducing agent to produce the compound represented by the following chemical formula 6;

4) oxidizing the compound represented by the following chemical formula 6 to produce the compound represented by the following chemical formula 7; and

5) A step of reacting the compound represented by the following chemical formula 7 with methylamine and adding a reducing agent to produce the compound represented by the following chemical formula 1.

Alternatively, the present invention provides a method for preparing the compound represented by the following chemical formula 1-1, further comprising the following step 6.

1) a step of reacting a compound represented by the following chemical formula 2 with a compound represented by the following chemical formula 3 to produce a compound represented by the following chemical formula 4;

2) a step of hydrolyzing the compound represented by the following chemical formula 4 to produce the compound represented by the following chemical formula 5;

3) reacting the acid activator with the compound represented by the following chemical formula 5, and adding a reducing agent to produce the compound represented by the following chemical formula 6;

4) a step of oxidizing the compound represented by the following chemical formula 6 to produce the compound represented by the following chemical formula 7;

5) a step of reacting the compound represented by the following chemical formula 7 with methylamine and adding a reducing agent to produce the compound represented by the following chemical formula 1; and

6) A step of adding an acid to the compound represented by the above Chemical Formula 1 to prepare an acidic salt represented by the following Chemical Formula 1-1.

In the following, an embodiment of the present invention is 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.

[Step 1]

The step 1 is a step of reacting the compound represented by the chemical formula 2 with the compound represented by the chemical formula 3 to produce the compound represented by the chemical formula 4, which is a step of introducing a substituted pyridinesulfonyl group into the pyrrolyl group of the compound represented by the chemical formula 2.

The reaction of step 1 can be performed in the presence of an alkali, 4-(dimethylamino)-pyridine and an organic solvent. Here, as the alkali, triethylamine, N,N-diisopropylethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, 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.

In the above step 1, a favorable solvent for dispersing the above alkali and 4-(dimethylamino)-pyridine can be used. For example, any one or more selected from the group consisting of dichloromethane, acetonitrile, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, acetone, ethyl acetate, 2-methyltetrahydrofuran, N,N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide can be used. Specifically, dichloromethane can be used as the reaction solvent of the above step 1. In particular, under the above solvent, a higher reaction conversion rate is shown, the extraction process is simple, and triethylamine and the like are easily removed, thereby maximizing the yield.

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, more preferably 1:1 to 1:10, and even more preferably 1:1 to 1:3.

The reaction in step 1 can be performed at 10°C to 35°C, preferably at room temperature. Specifically, the reaction in the reaction temperature range of step 1 is a reaction under moderate conditions, suitable for mass production, and can be easily applied to the process, while showing a higher conversion rate and helping to reduce the content of soft substances in the final material.

The reaction of step 1 can be performed for 30 minutes to 8 hours. If the reaction time is less than 30 minutes, the reaction is insufficient and the production yield is reduced. If the reaction time exceeds 8 hours, the production yield will not be substantially increased. More specifically, the reaction can be performed for 1 hour to 5 hours.

If necessary, after the reaction is completed, the step of purifying the compound represented by Chemical Formula 4 may be further included. Specifically, the compound represented by Chemical Formula 4 may be crystallized from the reaction product of Step 1.

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 can be used.

Here, the alcohol with carbon number of 1 to 4 can be methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or a mixture of two or more thereof. More specifically, a mixed solvent of ethanol and water can be used. For example, ethanol is added and stirred at a temperature of 20°C to 30°C for 30 minutes, and then purified water is added and stirred at a temperature of 20°C to 30°C for 12 hours. This process can show an excellent effect of removing the alkali group on the residual solvent, such as triethylamine and 4-(dimethylamino)-pyridine.

After the compound represented by Chemical Formula 4 is purified by the above steps, it is dried at 35° C. to 45° C. for more than 12 hours to reduce the water content of the compound represented by Chemical Formula 4. In this way, the water content of the compound represented by Chemical Formula 4 can be significantly reduced, and the conversion rate of the next step can be improved.

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

[Step 2]

The step 2 is a step of hydrolyzing the compound represented by the chemical formula 4 to produce the compound represented by the chemical formula 5.

The hydrolysis in step 2 can be performed in the presence of a metal salt and an alkaline group.

In the above step 2, the metal salt may be a sodium salt, a potassium salt or a lithium salt. Specifically, it may be a sodium salt of sodium bromide or sodium iodide. Specifically, it may be any one or more potassium salts selected from the group consisting of potassium chloride, potassium bromide and potassium iodide. Specifically, any one or more lithium salts selected from the group consisting of lithium chloride, lithium bromide, lithium iodide, lithium sulfate (Li ₂ SO ₄ ), lithium nitrate (LiNO ₃ ), lithium tetrafluoroborate (LiBH ₄ ), lithium trifluoroacetate (CF ₃ CO ₂ Li), sodium trifluoromethanesulfonate (CF ₃ SO ₃ Li) and lithium p-toluenesulfonate (C ₇ H ₇ LiO ₃ S) may be used. Preferably, lithium bromide can be used.

In the above step 2, the alkali group can be any one or more selected from the group consisting of triethylamine (TEA), N,N-diisopropylethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate and cesium carbonate. Specifically, triethylamine can be used.

In the above step 2, the molar ratio of the compound represented by the above chemical formula 4 to the above metal salt and the alkali group can be 10:1 to 1:20, respectively. In other words, the molar ratio of the compound represented by the above chemical formula 4 to the above metal salt satisfies 5:1 to 1:15, and the molar ratio of the compound represented by the above chemical formula 4 to the above alkali group satisfies 3:1 to 1:12, which can be used for the reaction of the above step 2. The above molar ratios can preferably be 1:1 to 1:10.

In the reaction of step 2, any one or more selected from the group consisting of water, acetonitrile, tetrahydrofuran, dichloromethane, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, N,N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide can be used as a reaction solvent. Specifically, acetonitrile can be used as the reaction solvent of step 2.

The reaction of step 2 can be performed at 10° C. to 35° C. Specifically, the reaction within the reaction temperature range of step 2 can improve the conversion rate of step 2, which helps to reduce the content of soft substances in the final material. In addition, compared with the known conditions, the reaction conditions have the advantage of being able to react under moderate conditions close to room temperature.

The reaction of step 2 can be performed for 10 to 24 hours. If the reaction time is less than 10 hours, the reaction is insufficient and the production yield is reduced. If the reaction time exceeds 24 hours, the production yield will not be substantially increased. More specifically, the reaction can be performed for 14 to 20 hours.

If necessary, after the above reaction is completed, an acidic aqueous solution can be used in the extraction process to wash the compound represented by Chemical Formula 5. The above acidic aqueous solution can be an inorganic acid or an organic acid. Specifically, it can be any one or more inorganic acids selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and nitric acid. Specifically, it can be any one or more organic acids from the group consisting of acetic acid, citric acid, tartaric acid, glutamine, malonic acid, succinic acid, oxalic acid, fumaric acid and methanesulfonic acid. Preferably, an aqueous hydrochloric acid solution can be used. By this process, excellent effects can be achieved in removing metal salts and alkalines in residual solvents, such as lithium bromide and triethylamine.

As a solvent for crystallizing the compound represented by the above Chemical Formula 5 from the reaction product, for example, an alcohol having 1 to 4 carbon atoms can be used.

The alcohol having 1 to 4 carbon atoms here may be methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or a mixture of two or more thereof. More specifically, a mixed solvent of isopropanol and water may be used.

After the compound represented by Chemical Formula 5 is purified by the above steps, it is dried at 30°C to 45°C for more than 12 hours to reduce the water content of the compound represented by Chemical Formula 5. In this way, the water content of the compound represented by Chemical Formula 5 can be significantly reduced, thereby increasing the conversion rate of the next step.

After the reaction of the above steps is completed, a washing step using a solvent may be further included.

[Step 3]

The step 3 is a step of reacting the acid activator with the compound represented by the chemical formula 5 to generate an intermediate, and then adding a reducing agent to convert it into the compound represented by the chemical formula 6.

More specifically, the reduction step of step 3 is to produce an intermediate in the form of an activated acid before the reducing agent treatment to make the reduction reaction smoother. The step 3 can be composed of step 3-1 of treating the acid activator and step 3-2 of adding the reducing agent.

[Reaction 2]

In the case of the above reaction formula 2, the production method is as follows.

3-1) a step of reacting an acid activator with the compound represented by the above chemical formula 5 to generate an intermediate represented by the following chemical formula 5-1;

3-2) adding a reducing agent to the activated intermediate compound to convert it into the compound represented by the above chemical formula 6;

[Chemical formula 5-1]

In the above chemical formula 5-1, R ₁ may be selected from the group consisting of Cl, OC(=O)-R _a , OS(=O) ₂ -R _b , OP(=O)-R _c1 (OR _c2 ) and OR _d .

The _Ra can be any one or more selected from the group consisting of methyl, ethyl, ethoxy, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, tert-butyl, benzoyl and 1-imidazoline.

The above R _b may be a methyl group or a 4-methylphenyl group.

The above R _c1 or R _c2 may be any one of the group consisting of methyl, ethyl and propyl.

The above R _d is any one of the group consisting of N,N'-dicyclohexylcarbodiimide, N,N'-diisopropylcarbodiimide, 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide, benzotriazolyl, azabenzotriazolyl, tris(dimethylamino)phosphonium, tris(pyrrolidino)phosphonium, tetramethylurea, dimethylamino-N-methylmethaneammonium, 3,5-dichlorotriazine, 3,5-dimethoxy-triazine, 4-methoxybenzyl, and benzyl.

As shown in the above chemical formula 5-1, the intermediate improves the yield of the subsequent reaction treated with a reducing agent by forming an acid chloride, an acid anhydride, a sulfonic acid alkali mixed anhydride, a phosphate alkali mixed anhydride or an ester, and allows the reaction conditions to be sustained at room temperature.

In the above step 3-1, the acid activator refers to a compound used to prepare an intermediate in the form of an activated acid. More specifically, it is any compound that can provide a compound structure in the form of an activated acid, such as a chloride, an acid anhydride, a sulfonic acid alkali mixed anhydride, a phosphate alkali mixed anhydride or an ester.

The acid activator is not limited thereto, but may be any one selected from the group consisting of a chlorinating agent, an anhydride former, a sulfonate-based mixed anhydride former, a phosphorus-based mixed anhydride former, and an ester former.

More specifically, the chlorinating agent may be any one selected from the group consisting of mercaptan chloride (SOCl ₂ ), phosphorus trichloride (PCl ₃ ), phosphorus chloride (PCl ₅ ), phosphorus oxychloride (POCl ₃ ), oxalyl chloride, and Vilsmeier reagent.

The anhydride forming agent may be any one selected from the group consisting of anhydrous acetic acid (Ac ₂ O), pyrrole chloride (PivCl), 1,1'-dichlorophenylimidazole (CDI), methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, n-propyl chloroformate, butyl chloroformate, isobutyl chloroformate, phenyl chloroformate, di-tert-butyl dicarbonate (Boc), benzyl chloroformate (Cbz) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ).

The sulfonate mixed anhydride forming agent may be methylsulfonyl chloride (MsCl) or p-toluenesulfonyl chloride (TsCl).

The phosphoric acid-based mixed anhydride forming agent may be n-propanesulfonic anhydride (T3P) or ethylmethylphosphonic anhydride (EMPA).

The ester forming agent may be selected from N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), (benzotriazol-1-yloxy)tris-(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-1-yloxy)tris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP), N,N,N',N'-tetramethyl 1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU), N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylformammonium hexafluorophosphate N-oxide (HATU), N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylformammonium tetrafluoroborate N-oxide (TBTU), 2-(2-oxo-1(2H)-pyridinyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), Any one of the group consisting of O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), cyanuric chloride (1,3,5-trichlorotriazine), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMTMM), 4-methoxybenzyl chloride (PMB) and benzyl chloride.

According to a preferred embodiment of the present invention, the acid activator can be an anhydride forming agent selected from the group consisting of isopropyl chloroformate, ethyl chloroformate, isobutyl chloroformate and di-tert-butyl dicarbonate (Boc).

Alternatively, the acid activator may be any chlorinating agent selected from the group consisting of mercaptan chloride (SOCl ₂ ), phosphorus trichloride (PCl ₃ ) and phosphorus oxychloride (POCl ₃ ).

Alternatively, the acid activator may be 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) or 1-hydroxybenzotriazole (HOBt) ester forming agent.

More preferably, the acid activator is isopropyl chloroformate.

In the step 3-1, the molar ratio of the compound represented by the chemical formula 5 to the acid activator may be 10:1 to 1:10, more preferably 5:1 to 1:5, and even more preferably 3:1 to 1:3.

The acid activator treatment in step 3-1 is carried out in any organic solvent selected from the group consisting of triethylamine, tetrahydrofuran, dimethylacetamide, dimethyl sulfoxide, toluene, methanol, ethanol, dichloromethane, ethyl acetate, acetonitrile, propanol, isopropanol, butanol, tert-butanol, 2-methyltetrahydrofuran, N,N-dimethylformamide and N-pyrrolidone, and specifically, tetrahydrofuran, triethylamine or any of them can be used as the solvent.

The reaction of step 3-1 can be performed at 0°C to 35°C. Specifically, after the compound represented by the chemical formula 5 and the solvent are stirred in a reactor at room temperature, the internal temperature of the reactor is lowered to 0°C to 10°C, the triethylamine and isopropyl chloroformate are added, and after stirring at 20°C to 30°C, the solid precipitated in the reaction is filtered.

In the above step 3-1, the reaction of the compound represented by Chemical Formula 5 and the above acid activator can be performed in a period of 30 minutes to 8 hours. When the above reaction time is less than 30 minutes, there is a problem that the reaction is not sufficient and the production yield is reduced. When the above reaction time exceeds 8 hours, the production yield will not actually increase. More specifically, the above reaction can be performed in a period of 1 hour to 5 hours.

The above step 3-2 is a step of adding a reducing agent to the activated intermediate compound in step 3-1 to convert it into the compound represented by the above chemical formula 6. The above reducing agent can be selected from any one or more of the group consisting of sodium borohydride, sodium cyanoborohydride and sodium triacetyloxyborohydride. Preferably, sodium borohydride can be used. By using the above reducing agent, the use of hazardous reagents and environmentally polluting reagents is eliminated, and there is an advantage that the concentrated residual solution of step 3 can be directly used to form the above step 4 in situ.

In the step 3-2, the molar ratio of the compound represented by the chemical formula 5 to the reducing agent may be 10:1 to 1:10, preferably 5:1 to 1:5, and even more preferably 3:1 to 1:3.

The reducing agent treatment in step 3-2 can be performed in any one or more organic solvents selected from the group consisting of water, triethylamine, tetrahydrofuran, dimethylacetamide, dimethyl sulfoxide, toluene, methanol, ethanol, dichloromethane, ethyl acetate, acetonitrile, propanol, isopropanol, butanol, tert-butanol, 2-methyltetrahydrofuran, N,N-dimethylformamide and N-pyrrolidone, and specifically, tetrahydrofuran, triethylamine or any of them can be used as the solvent.

The reaction of step 3-2 can be performed at 0°C to 35°C. Specifically, the filtered solution of step 3-1 is lowered to 0°C to 5°C, and a reducing agent, sodium borohydride, is added. This process can be carried out without increasing the internal temperature and stirring within the range of 0°C to 5°C, which has the advantage of reacting under moderate conditions close to room temperature compared to known conditions.

In the above step 3-2, the reaction of the compound represented by the above chemical formula 5 and the above sodium borohydride can be performed for 30 minutes to 8 hours. When the above reaction time is less than 30 minutes, there is a problem that the reaction is not sufficient and the production yield is reduced. When the above reaction time exceeds 8 hours, the production yield will not actually increase. More specifically, the above reaction can be performed for 1 hour to 5 hours.

Thereafter, an organic solvent is used for extraction 1 to 3 times to obtain an organic layer, and a desiccant is added to the organic layer, the mixture is stirred, and then filtered under reduced pressure. After washing the filtrate, the filtrate can be concentrated by reducing pressure.

For the above extraction, water, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, ethyl ether, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, isopropanol, 1-butanol, dichloromethane and acetone, or a mixture of two or more of these organic solvents can be used. Preferably, a mixed solvent of ethyl acetate and water can be used.

If necessary, an alkaline aqueous solution may be used in combination with the extraction. The alkaline aqueous solution may be selected from any one or more of the group consisting of ammonia water, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium methoxide, potassium butyrate and cesium carbonate. Preferably, sodium carbonate or sodium bicarbonate aqueous solution may be used. This process can achieve excellent results in removing byproducts generated during the reaction.

[Step 4]

The step 4 is a step of oxidizing the compound represented by Chemical Formula 6 to produce the compound represented by Chemical Formula 7. Here, a catalyst, an organic base and a solvent may be added to the concentrated residue obtained by the step 3, so that the steps 3 and 4 may be performed in situ.

In the above step 4, the oxidation of the alcohol group of the compound represented by Chemical Formula 6 can be carried out in the presence of a copper catalyst, a metal catalytic ligand and a co-catalyst.

For example, the copper catalyst may be any one or more selected from the group consisting of copper (I) acetate, copper (II) acetate, copper (I) chloride, copper (II) chloride, copper (I) bromide, copper (II) bromide, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate toluene complex, copper (I) iodide, copper (II) iodide, copper (I) iodide tetrabutylammonium iodide complex, copper (I) hexafluorophosphate tetraacetonitrile, copper (I) iodide triethyl phosphite complex, copper (I) bromide triphenylphosphine complex, copper (I) oxide, and copper (II) oxide.

The metal catalyst ligand may be selected from N,N'-dimethylethane-1,2-diimine and trans-N,N'-dimethyl-cyclohexane-1,2-diimine, ethane-1,2-diol, propane-1,3-diol, 2-acetylcyclohexanone, acetylacetonate, 2,2,6,6-tetramethylheptane-3,5-dione, N-methylglycine, N,N-dimethylglycine, ethyl 2-oxocyclohexanecarboxylate, ethylene glycol, pyridine, 2,2'-bipyridine, 1,10-phenanthroline, neocuproine, 8-hydroxyquinoline, pyridine acid, glyoxal bis(phenyl) any one or more of the group consisting of 2,6-dimethylanilino(oxo)acetic acid, 2,6-difluoroanilino(oxo)acetic acid, 2,6-dimethoxyanilino(oxo)acetic acid, 2,3,4,5,6-pentafluoroanilino(oxo)acetic acid, 3,5-bis(trifluoromethyl)anilino(oxo)acetic acid, 2-fluoro-6-(piperidin-1-sulfonyl)anilino(oxo)acetic acid, N1,N2-di([1,1'-biphenyl]-2-yl)oxalamide, N1,N2-bis(2-phenoxyphenyl)oxalamide and thiophene-2-carboxylic acid.

The above-mentioned catalytic agent can be selected from 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), di-tert-butyl azodicarboxylate (DBAD), 4-acetamido-2,2,6,6-tetramethylpiperidinyl-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidinyl-1-oxyl, 4-methylacryloxy-2,2,6,6-tetramethylpiperidinyl-1-oxyl, 4-oxy-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-amino-2,2,6,6-tetramethylpiperidinyl-1-oxyl, 4-carboxyl- any one or more of 2,2,6,6-tetramethylpiperidinyl 1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidinyl 1-oxybenzoate, 4-(2-iodoacetylamino)-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-maleimide-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-isothiocyanato-2,2,6,6-tetramethylpiperidinyl 1-oxyl, 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy, and 4-phosphoxy-2,2,6,6-tetramethyl-1-piperidinyloxy.

In the reaction of step 4, in order to improve the yield, a base group can be used together, and the base group can be selected from any one or more of the group consisting of N-methylimidazole (NMI), potassium tert-butoxide (KOtBu), 4-dimethylaminopyridine, pyridine, triethylamine (TEA), N,N-diisopropylethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate and cesium carbonate.

The oxidation step of the present invention uses a copper catalyst, a metal catalyst ligand and a co-catalyst system to specifically oxidize alcohols. This catalytic system allows selective oxidation to aldehydes rather than carboxylic acids, and can react with high yields in aliphatic systems. In addition, the catalytic system has the advantages of using oxygen in the air as an oxidant instead of adding a separate oxidant, using a common organic solvent, and reacting at room temperature, which greatly improves practicality.

The method of the present invention preferably uses copper (I) hydrogen iodide (CuI) as a copper catalyst, 2,2'-bipyridine (bpy) as a metal catalyst ligand, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a co-catalyst, and N-methylimidazole (NMI) as a base.

In the above step 4, the copper catalyst, metal catalyst ligand and co-catalyst can be used in 0.01 to 1 equivalents, respectively, compared to the compound represented by the above chemical formula 6. Preferably, the copper catalyst, metal catalyst ligand and co-catalyst can be used in 0.05 to 0.5 equivalents, respectively. When the usage of the copper catalyst, metal catalyst ligand, co-catalyst and base does not reach the lower limit, the reaction rate and yield may decrease, and if it exceeds the upper limit, the economic benefit during production may decrease.

In order to maximize the yield of the reaction in step 4, the ratio in the catalytic system, i.e., the ratio between the copper catalyst, the metal catalyst ligand and the co-catalyst, preferably has a molar ratio of 1:1.5:0.5 to 1:2.5:1.5. If the molar ratio is deviated from the above, the stability of the catalyst will decrease, thereby shortening the life of the catalyst, or it will be difficult to selectively oxidize to catalytic activity or aldehyde, so it is better to maintain the above range.

The type of reaction solvent that can be used in the above step 4 is not particularly limited, and an organic solvent commonly used in alcohol oxidation reaction can be used. For example, the reaction can be carried out in any one or more organic solvents selected from the group consisting of dimethyl sulfoxide, acetonitrile, dichloromethane, dichloroethane, ethyl acetate, methanol, toluene, dimethylformamide, tetrahydrofuran and trifluorotoluene. Specifically, dimethyl sulfoxide can be used.

The reaction temperature of step 4 may be 10° C. to 35° C. When the reaction temperature is less than 10° C., the production yield may be reduced. When the reaction temperature is more than 35° C., the production yield may not be increased. More specifically, the reaction may be performed at 20° C. to 30° C.

The reaction of step 4 can be performed in a period of 10 to 20 hours. If the reaction time is less than 10 hours, the reaction is not sufficient, resulting in a decrease in production yield. If the reaction time exceeds 20 hours, the production yield will not actually increase. More specifically, the reaction can be performed in a period of 10 to 15 hours.

After the reaction is completed, a step of purifying the compound represented by the above chemical formula 6 may be further included as needed. The above purification may be performed by crystallizing the compound represented by the chemical formula 6 from the reaction product of the above step 4.

From the reaction product of step 4, the compound represented by the chemical formula 6 can be used as a crystallization solvent by mixing an alcohol having 1 to 4 carbon atoms with water. Here, the alcohol having 1 to 4 carbon atoms can be methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, or a mixture of two or more thereof. Specifically, isopropanol can be used. For example, the reaction product of step 4 can be stirred for more than 3 hours by adding isopropanol at a temperature range of 20°C to 30°C.

After the compound represented by the above chemical formula 6 is purified, it can be dried to reduce the water content included in the compound represented by the above chemical formula 6. For example, drying at a temperature range of 35° C. to 45° C. for more than 12 hours can significantly reduce the water content of the compound represented by the above chemical formula 6 and improve the reactivity of the next step (i.e., the following step 5) of the reduction amination reaction.

[Step 5]

The step 5 is a step of reacting the compound represented by the chemical formula 7 with methylamine to generate an intermediate, and adding a reducing agent to convert the intermediate into the compound represented by the chemical formula 1.

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.

Specifically, in the above step 5, the compound represented by the above chemical formula 7 is converted into an imine compound by an imine formation reaction with methylamine. Since this imine compound corresponds to an intermediate with an unstable structure, it can be easily reduced and converted into the compound represented by the above chemical formula 1.

The reductive imidization reaction of step 5 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 invented by the present invention are to use a solvent that can provide a reaction under appropriate conditions. In particular, the reaction has the advantage that the reaction under solvent conditions will not cause restrictions from the Food and Drug Safety Administration and the like.

More specifically, after adding the compound represented by the above chemical formula 7 and the above methylamine together with the above reaction solvent, stirring is carried out 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 7 and the above methylamine are fully dissolved in the above solvent and react to generate an imine compound.

At this time, considering that as the solubility of the compound represented by the above chemical formula 7 decreases, the amount of soft substances included in the final substance can increase, the above stirring time and temperature can be adjusted.

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

The reduction reaction of the intermediate (i.e., imine compound) generated by the reaction of the compound represented by the above chemical formula 7 with methylamine can be carried out more stably at a lower temperature.

Taking this into consideration, after the reaction of the compound represented by the above chemical formula 7 and methylamine is completed, the temperature of the above reactor may be cooled to a range of -5°C to 15°C, for example, 0°C to 10°C, and then the above reducing agent may be added within the cooling temperature range, and then the reactor temperature may be maintained and stirred. Within the above temperature range, the above intermediate (i.e., the imine compound) reacts stably with the above reducing agent and may be converted into the compound represented by the above chemical formula 1.

Here, as the reducing agent, at least one selected from the group consisting of sodium borohydride, sodium cyanoborohydride, and sodium triacetyloxyborohydride can be used.

In the above step 5, the molar ratio of the compound represented by the above chemical formula 7 to the above methylamine and the reducing agent can be 10:1 to 1:10, respectively. In other words, the molar ratio of the compound represented by the above chemical formula 7 to the above methylamine satisfies 10:1 to 1:10, and the molar ratio of the compound represented by the above chemical formula 7 to the above reducing agent satisfies 10:1 to 1:10, which can be used for the reaction of the above step 5.

Subsequently, the organic layer is extracted 1 to 3 times with an organic solvent, and a desiccant is added to the organic layer, the mixture is stirred, and then filtered under reduced pressure. After washing the filtrate, the filtrate can be concentrated under reduced pressure.

In the above extraction, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tert-butyl ether, isopropanol, 1-butanol, dichloromethane, acetone or a mixture of two or more of these organic solvents can be used. Preferably, ethyl acetate can be used.

[Step 6]

After the above step 5, the following step 6 may be optionally further included.

The six-step process may be performed through the following steps, and the manufacturing method further includes:

6) adding an acid to the compound represented by the above chemical formula 1 to prepare an acidic salt represented by the following chemical formula 1-1;

[Chemical formula 1-1]

The step 6 is a step for providing the compound represented by the chemical formula 1 in the form of a pharmaceutically acceptable salt, and simultaneously with or after the step 5, adding an acid to the compound represented by the chemical formula 1 to obtain a pharmaceutically acceptable acidic salt represented by the chemical formula 1-1.

Specifically, the step 6 may include: supplying an organic solvent to the compound represented by the chemical formula 1, and then supplying a mixed solution of an acid or its organic solvent to crystallize the acidic salt represented by the chemical formula 1-1.

More specifically, an organic solvent may be supplied to the concentrated residue including the compound represented by the above Chemical Formula 1. The organic solvent supplied at this time may 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 any one of the mixed solvents 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, and a mixed solvent of 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 soft substances and generating the target salt without the need for additional refining processes.

The above-mentioned organic solvent is supplied to the concentrated residue including the compound represented by the above-mentioned chemical formula 1 and the internal temperature of the reactor is adjusted to 15°C to 35°C, preferably between 20°C and 30°C, and the mixed solution of the acid and the organic solvent is stirred to crystallize the acidic salt represented by the above-mentioned chemical formula 1-1.

The acid used for crystallizing the acidic salt represented by the above chemical formula 1-1 may be, for example, one or more selected from the group consisting of hydrochloric acid, glutamine, malonic acid, succinic acid, tartaric acid, oxalic acid, fumaric acid, phosphoric acid and methanesulfonic acid.

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.

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

[Chemical formula 1-2]

After the salt is prepared, the salt is dried at 45° C. to 55° C. for 12 hours to reduce the water content included in the compound represented by Chemical Formula 7. In this way, the water content of the compound represented by Chemical Formula 7 can be significantly reduced, thereby maximizing the yield of the target compound.

If necessary, in the above step 6, the crystallization of the acidic salt represented by the above chemical formula 1-1 can be performed more than twice.

For example, after the acidic salt represented by the above chemical formula 1-1 is crystallized, the acidic salt represented by the above chemical formula 1-1 is extracted using the above organic solvent, and then a mixed solution with 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-mentioned recrystallization process, an alkali may be further used to dissociate the acid salt. Here, as the alkali for dissociating the above-mentioned acid 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 may be used. Specifically, potassium carbonate may be used, and the method of using the alkali may be well known in the art.

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

When the step 6 is selectively performed, the reaction can be performed together with the step 5, and the reaction can be performed as a 6-step reaction instead of a 5-step reaction. In this case, the present invention provides a production method as shown in the following reaction formula 3.

[Reaction 3]

In the case of the above reaction formula 3, the production method is as follows.

1) a step of reacting a compound represented by the following chemical formula 2 with a compound represented by the following chemical formula 3 to produce a compound represented by the following chemical formula 4;

2) a step of hydrolyzing the compound represented by the following chemical formula 4 to produce the compound represented by the following chemical formula 5;

3) reacting an acid activator with a compound represented by the following chemical formula 5, and adding a reducing agent to produce a compound represented by the following chemical formula 6;

4) oxidizing the compound represented by the following chemical formula 6 to produce the compound represented by the following chemical formula 7; and

5) A step of reacting the compound represented by the following chemical formula 7 with methylamine, adding a reducing agent, and adding an acid to produce an acid salt represented by the following chemical formula 1-1.

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

The present invention provides a compound of formula 1 defined in any embodiment of the present invention, or a pharmaceutically acceptable salt thereof, for use as a medicament.

The present invention provides a compound of formula 1 defined in any embodiment of the present invention, or a pharmaceutically acceptable salt thereof, for preventing or treating gastrointestinal ulcers, gastrointestinal inflammatory diseases or gastric acid-related diseases.

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 strip in need of the salt.

The present invention provides the use of a compound of Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of 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.

The present invention provides a compound of formula 1 defined in any embodiment of the present invention, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition for which an acid secretion inhibitor is prescribed.

The present invention provides a pharmaceutical composition for treating diseases or symptoms for which the acid secretion inhibitor is prescribed, comprising a compound of formula 1 defined in any embodiment of the present invention, or a pharmaceutically acceptable salt thereof.

The present invention provides a gastric acid secretion inhibitor comprising a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

The above-mentioned gastrointestinal ulcer refers to an ulcer that occurs in the digestive tract including the stomach and intestines. For example, digestive ulcer, gastric ulcer, duodenal ulcer, NSAID (non-steroidal anti-inflammatory drugs) induced ulcer, acute stress ulcer, Zollinger-Ellison syndrome, etc., but not limited thereto. If the above-mentioned gastric ulcer is severe, it may lead to cancer. For example, if the above-mentioned gastric ulcer is in a serious condition, it may develop into gastric cancer as the disease progresses.

In particular, gastrointestinal ulcers may include gastric mucosal damage or small intestinal mucosal damage induced by drugs or alcohol, etc. In particular, gastric mucosal damage or small intestinal mucosal damage may be induced by NSAIDs or alcohol.

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

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.

The above-mentioned gastric acid-related diseases refer to diseases caused by excessive secretion of gastric acid, such as erosive esophagitis, non-erosive esophagitis, reflux esophagitis, symptomatic gastroesophageal reflux disease (symptomatic GERD), functional dyspepsia, hyperacidity, upper gastrointestinal bleeding caused by aggressive stress, etc., but are not limited thereto.

According to the present invention, the 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-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 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 agents and absorption delaying agents that are physiologically miscible.

The compositions of the present invention may be in a variety of forms. Examples include liquid, semisolid and solid administration 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 mode of administration and therapeutic use.

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).

Solid administration forms for oral administration, for example, can provide hard or soft capsules, pills, bases, slag 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.

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

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 water suspensions or suspensions) can be formulated using appropriate dispersants, wetting agents and/or suspending agents by published techniques.

Other carrier materials and administration methods disclosed in the pharmaceutical technology field can also be used. The pharmaceutical composition of the present invention can be manufactured by any widely disclosed pharmaceutical technology, such as effective dosage form and administration procedures.

Typically, the compounds of the present invention are administered in an effective dose for treating the symptoms described herein. The compounds of the present invention may be administered as the compound itself, or alternatively, as a pharmaceutically acceptable salt. For administration and dosage purposes, the above compounds themselves or their pharmaceutically acceptable salts will be simply referred to as the compounds of the present invention.

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

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.

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

The dosing regimen of the compounds of the present invention or compositions containing the compounds is based on various factors, including the type, age, weight, sex and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the specific compound used. Therefore, the dosing regimen may vary widely. In one embodiment, the total daily dose of the compounds of the present invention is typically about 0.001 mg/kg to about 100 mg/kg (i.e., mg of the compounds of the present invention per kg of body weight) for the treatment of the proposed condition discussed herein. [Effects of the Invention]

The manufacturing method of the present invention has the advantage of performing the reaction under appropriate conditions suitable for mass production. In addition, the process efficiency is improved by excellent yield, and the salt manufacturing process is simplified, so that the production of soft materials is minimized and the yield and purity are improved. This brings useful benefits to industrial mass production.

Hereinafter, the present invention will be described in more detail by the following embodiments. However, the following embodiments are only examples to illustrate the present invention, and the scope of the present invention is not limited to them.

The manufacturing process according to the embodiment of the present invention is roughly described as shown in the following reaction formula 4.

[Reaction 4]

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

(Step 1) Synthesis of methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxylate

40.0 g of methyl 5-(2-fluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylate, 40.0 g of 6-methoxypyridine-3-sulfonyl chloride, 3.9 g of 4-(dimethylamino)-pyridine and 266.0 g of dichloromethane were added respectively, and stirred at an internal temperature of 20-30°C for 10 minutes. 32.5 g of triethylamine was added, and stirred at an internal temperature of 20-30°C for more than 3 hours to complete the reaction. After the reaction was completed, 200 g of purified water was added and stirred at room temperature for 10 minutes. Then the organic layer of the mixture was separated, and 200 g of 10% sodium chloride aqueous solution was added and stirred for 10 minutes. Then the organic layer was separated, and 200 g of purified water was added and stirred for 10 minutes. Then, the organic layer was separated, and 12 g of magnesium sulfate was added, and the mixture was filtered by stirring for 30 minutes, and the filtrate was washed with 133.0 g of dichloromethane. The filtrate was concentrated under reduced pressure, and 94.7 g of ethanol was added to the concentrate, and the mixture was stirred for 30 minutes at an internal temperature of 20 to 30°C to precipitate crystals. Then, 400 g of purified water was added, and the mixture was stirred for 12 hours at an internal temperature of 20 to 30°C. After the stirring was completed, the generated crystals were filtered, and the filtrate was washed with 100 g of purified water. The washed filtrate was dried at a temperature of 35 to 45°C for more than 12 hours to obtain 65.5 g of the compound. (Yield: 97.0%/Purity 99.2%)

¹ H-NMR (Nuclear Magnetic Resonance) (400 MHz, DMSO) 8.17 (s, 1H), 8.03 (s, 1H), 7.81 (d, 1H), 7.59-7.53 (m, 1H), 7.27-7.16 (m, 3H), 6.99 (d, 1H), 3.94 (s, 3H), 3.80 (s, 3H), 3.53 (s, 3H)

Through the above-mentioned manufacturing process, the compound represented by Chemical Formula 4 was produced in large quantities with a yield of 97%.

(Step 2) Synthesis of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxylic acid

20.0 g of methyl 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxylate, 33.1 g of lithium bromide, 9.6 g of triethylamine, 6.0 g of purified water and 127.2 g of acetonitrile were added respectively, and the reaction was stirred at 20-30°C for 15 hours to complete. The reaction solution was concentrated under reduced pressure, and 221.7 g of ethyl acetate and 200.0 g of 0.5N aqueous hydrogen chloride solution were added to the concentrated solution, and stirred at room temperature for 10 minutes. The organic layer was separated, and 100.0 g of 0.5N aqueous hydrogen chloride solution was added to the separated organic layer and stirred for 10 minutes. Then, the organic layer was separated, and 200 g of 10% sodium chloride aqueous solution was added and stirred for 10 minutes. Then, the organic layer was separated, 6 g of magnesium sulfate was added, and then the mixture was stirred for 30 minutes and filtered, and the filtrate was washed with 45.1 g of ethyl acetate. The filtrate was concentrated under reduced pressure, and 47.2 g of isopropanol was added to the concentrated solution, and the temperature was raised to an internal temperature of 80-85°C. After confirming the dissolution, the temperature was cooled to a range of 20-30°C to precipitate crystals. Then, 200.0 g of purified water was added dropwise, and the mixture was stirred for 12 hours at an internal temperature of 20-30°C. After the stirring was completed, the generated crystals were filtered, and the filtrate was washed with 100.0 g of purified water. The washed filtrate was dried at a temperature range of 35-40°C for more than 12 hours to obtain 18.5 g of the compound. (Yield: 95.8%/Purity 95.0%)

¹ H-NMR (400 MHz, DMSO) 12.78 (s, 1H), 8.16 (s, 1H), 7.95 (s, 1H), 7.82 (d, 1H), 7.58-7.53 (m, 2H), 7.33-7.16 (m, 3H), 6.99 (d, 1H), 6.49 (s, 2H), 3.96 (s, 3H), 3.53 (s, 3H)

(Step 3) Synthesis of 5-(2-fluorophenyl)-4-methoxy-1-(((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)methanol

Add 20.0 g of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carboxylic acid and 177.6 g of tetrahydrofuran, and stir to dissolve. Cool to an internal temperature of 0-10°C, add 7.5 g of triethylamine and 36.9 ml of isopropyl chloroformate (2M in toluene), and stir for 1 hour at 20-30°C to complete the reaction. Filter the solid precipitated during the reaction, and wash the filtrate with 88.8 g of tetrahydrofuran. Then cool the filtrate to an internal temperature of 0-5°C, add 5.6 g of sodium borohydride, and slowly drop 40 g of purified water into the reaction solution. Stir for 1 hour at an internal temperature of 0 to 5°C to complete the reaction. Add 180.4 g of ethyl acetate and 200.0 g of purified water and stir. Use 1.0N hydrochloric acid aqueous solution to adjust the pH range to 5 to 6, separate the organic layer of the mixture, and add 200.0 g of 1.0N sodium carbonate aqueous solution and stir. Then separate the organic layer, and the same process is carried out twice. Then add 6 g of magnesium sulfate to the separated organic layer, filter while stirring for 30 minutes, and wash the filtrate with 45.1 g of ethyl acetate, and then reduce the pressure and concentrate the filtrate.

¹ H-NMR (400 MHz, DMSO) 8.13 (dd, 1H), 7.69 (dd, 1H), 7.53-7.47 (m, 1H), 7.35 (d, 1H), 7.25-7.13 (m, 3H), 6.97 (dd, 1H), 5.08 (t, 1H), 4.36 (d, 2H), 3.92 (s, 3H), 3.46 (s, 3H)

(Step 4) Synthesis of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrole-3-carbaldehyde

106.2 g of dimethyl sulfoxide was added to the concentrated residue of step 3 and stirred. After the dissolution was complete, 1.2 g of cuprous iodide, 1.0 g of 2,2'-bipyridine, 1.1 g of 2-methylimidazole, and 1.0 g of 2,2,6,6-tetramethylpiperidin-1-oxyl were added, and the reaction was stirred at 20-30°C for more than 16 hours to complete the reaction. After the reaction was completed, 174.2 g of ethyl acetate was added and stirred for 10 minutes, and 193.12 ml of 0.1M ethylenediaminetetraacetic acid aqueous solution was added and stirred for 10 minutes. Then, the organic layer of the mixture was separated into the aqueous layer, and 87.1 g of ethyl acetate was added to the separated aqueous layer and stirred for 10 minutes. The organic layer was then separated and combined with the previously separated organic layer, and then washed with 193 g of purified water. The separated organic layer was then further washed with 193.0 g of 10% sodium chloride aqueous solution. After 6 g of magnesium sulfate was injected into the separated organic layer, the mixture was stirred for 30 minutes to filter, and the filtrate was washed with 52.2 g of ethyl acetate. The filtrate was then concentrated under reduced pressure, and 151.7 g of isopropanol was added, and the mixture was stirred for more than 12 hours at a temperature of 20 to 30°C to precipitate crystals. The mixture was cooled to an internal temperature of 0 to 5°C, and the crystals were fermented for 1 hour, and then filtered under reduced pressure. The filtrate was washed with 30.3 g of isopropanol and dried at 35-45°C for more than 12 hours to obtain 16.9 g. (Yield: 87.7%/Purity 98.8%)

¹ H-NMR (400 MHz, DMSO) 9.84 (s, 1H), 8.42 (s, 1H), 8.15 (dd, 1H), 7.79 (dd, 1H), 7.59-7.53 (m, 1H), 7.27-7.16 (m, 3H), 7.00 (dd, 1H), 3.94 (s, 3H), 3.57 (s, 3H)

(Step 5) Synthesis of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine

Add 20.0 g of 5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridine-3-d)sulfonyl)-1H-pyrrole-3-carboxaldehyde and 79.2 g of methanol, and stir at room temperature for 10 minutes. Add 9.1 g of methylamine (12M in water), and stir at an internal temperature of 20 to 30°C for 1 hour. Then cool to an internal temperature of 0 to 10°C, add 1.0 g of sodium borohydride, and then stir at an internal temperature of 0 to 10°C for 1 hour to complete the reaction. After the reaction is completed, keep the internal temperature at 0 to 10°C, add 126.3 g of ethyl acetate, and then add 140.0 g of 10% sodium chloride aqueous solution, and stir at room temperature for 10 minutes. The organic layer of the mixture was separated, and 140.0 g of purified water was added to the separated organic layer and stirred for 10 minutes. The organic layer was then separated, and 140.0 g of a 10% sodium chloride aqueous solution was added and stirred at room temperature for 10 minutes. The organic layer of the mixture was separated, and 6 g of magnesium sulfate was added to the separated organic layer, and then the mixture was filtered after stirring for 30 minutes, and the filtrate was washed with 18 g of ethyl acetate.

(Step 6) Synthesis of 1-(5-(2-fluorophenyl)-4-methoxy-1-((6-methoxypyridin-3-yl)sulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine fumarate

The filtrate obtained in step 5 was concentrated under reduced pressure, and 15.8 g of ethanol, 144.3 g of ethyl acetate, and 5.9 g of fumaric acid were added to the concentrate, and the internal temperature was stirred at 20-30°C for 12 hours. After the stirring was completed, the resulting crystals were filtered under reduced pressure, and the filtrate was washed with 18 g of ethyl acetate. The washed filtrate was dried at a temperature range of 45-55°C for more than 12 hours to obtain 23.8 g of the compound. (Yield: 88.9%/purity 99.5%)

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), 7.16-7.12 (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)

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.

With reference to the above-mentioned embodiments, by adjusting the process temperature, execution time, etc. of each step within the scope of the above-mentioned embodiment, the yield and process efficiency of the final material can be improved while controlling the quality.

Claims (17)

A method for preparing a 6-methoxypyridin-3-yl derivative, comprising: 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; 2) hydrolyzing the compound represented by the following chemical formula 4 to prepare a compound represented by the following chemical formula 5; 3) reacting an acid activator with the compound represented by the following chemical formula 5, adding a reducing agent to prepare a compound represented by the following chemical formula 6; 4) oxidizing the compound represented by the following chemical formula 6 to prepare a compound represented by the following chemical formula 7; and 5) reacting the compound represented by the following chemical formula 7 with methylamine, adding a reducing agent to prepare a compound represented by the following chemical formula 1; [Chemical Formula 1] [Chemical formula 2] [Chemical formula 3] [Chemical formula 4] [Chemical formula 5] [Chemical formula 6] [Chemical formula 7] . The production method of claim 1, wherein the step 1 is performed in the presence of an alkali, 4-(dimethylamino)-pyridine and an organic solvent. The production method of claim 2, wherein the base group in step 1 is selected from any one or more of the group consisting of triethylamine (TEA), N,N-diisopropylethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate and cesium carbonate. The production method of claim 2, wherein the organic solvent in step 1 is selected from any one or more of the group consisting of dichloromethane (DCM), acetonitrile, tetrahydrofuran, methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, acetone, ethyl acetate, 2-methyltetrahydrofuran, N,N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dimethyl sulfoxide. The production method of claim 1, wherein the hydrolysis in step 2 is performed in the presence of a metal salt and an alkaline base. The production method of claim 5, wherein the metal salt is selected from any one or more of the group consisting of sodium bromide, sodium iodide, potassium chloride, potassium bromide, potassium iodide, lithium chloride, lithium bromide, lithium iodide, lithium sulfate (Li ₂ SO ₄ ), lithium nitrate (LiNO ₃ ), lithium tetrafluoroborate (LiBH ₄ ), lithium trifluoroacetate (CF ₃ CO ₂ Li), lithium trifluoromethanesulfonate (CF ₃ SO ₃ Li) and lithium p-toluenesulfonate (C ₇ H ₇ LiO ₃ S). The manufacturing method of claim 5, wherein the metal salt is a lithium salt. The production method of claim 5, wherein the alkali group is selected from any one or more of the group consisting of triethylamine (TEA), N,N-diisopropylethylamine, diisopropylamine, diisopropylethylamine, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium butyrate and cesium carbonate. The production method of claim 1, wherein the acid activator in step 3 is selected from any one or more of the group consisting of a chlorinating agent, an anhydride forming agent, a sulfonate mixed anhydride forming agent, a phosphorus mixed anhydride forming agent and an ester forming agent. A production method as claimed in claim 9, wherein the acid activator is selected from any one or more of the group consisting of isopropyl chloroformate, ethyl chloroformate, isobutyl chloroformate, di-tert-butyl dicarbonate (Boc), sulfinyl chloride (SOCl2), phosphorus trichloride (PCl3), phosphorus oxychloride (POCl3), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and 1-hydroxybenzotriazole (HOBt). The production method of claim 1, wherein the reducing agent in step 3 is selected from any one or more of the group consisting of sodium borohydride, sodium cyanoborohydride and sodium triacetyloxyborohydride. The manufacturing method of claim 1, wherein the oxidation in step 4 is carried out in the presence of a copper catalyst, a metal catalyst ligand and a co-catalyst. The manufacturing method of claim 12, wherein the copper catalyst is selected from the group consisting of copper (I) acetate, copper (II) acetate, copper (I) chloride, copper (II) chloride, copper (I) bromide, copper (II) bromide, copper (I) bromide dimethyl sulfide complex, copper (I) trifluoromethanesulfonate toluene complex, copper (I) iodide, copper (II) iodide, copper (I) iodide tetrabutylammonium iodide complex, copper (I) hexafluorophosphate tetraacetonitrile, copper (I) iodide triethyl phosphite complex, copper (I) bromide triphenylphosphine complex, copper (I) oxide and copper (II) oxide. The metal catalyst ligand is selected from N,N'-dimethylethane-1,2-diimine and trans-N,N'-dimethyl-cyclohexane-1,2-diimine, ethane-1,2-diol, propane-1,3-diol, 2-acetylcyclohexanone, acetylacetonate, 2,2,6,6-tetramethylheptane-3,5-dione, N-methylglycine, N,N-dimethylglycine, 2-oxocyclohexanecarboxylic acid ethyl ester, ethylene glycol, pyridine, 2,2'-bipyridine, 1,10-phenanthroline, neocuproine, 8-hydroxyquinoline, pyridine acid, glyoxal bis(phenylhydrazone) , 2,6-dimethylanilino(oxo)acetic acid, 2,6-difluoroanilino(oxo)acetic acid, 2,6-dimethoxyanilino(oxo)acetic acid, 2,3,4,5,6-pentafluoroanilino(oxo)acetic acid, 3,5-bis(trifluoromethyl)anilino(oxo)acetic acid, 2-fluoro-6-(piperidin-1-sulfonyl)anilino(oxo)acetic acid, N1,N2-di([1,1'-biphenyl]-2-yl)oxalamide, N1,N2-bis(2-phenoxyphenyl)oxalamide and thiophene-2-carboxylic acid, any one or more thereof, The above-mentioned catalytic agent is selected from 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), di-tert-butyl azodicarboxylate (DBAD), 4-acetamido-2,2,6,6-tetramethylpiperidinyl-1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidinyl-1-oxyl, 4-methylacryloxy-2,2,6,6-tetramethylpiperidinyl-1-oxyl, 4-oxy-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-amino-2,2,6,6-tetramethylpiperidinyl-1-oxyl, 4-carboxyl-2, Any one or more of 2,6,6-tetramethylpiperidinyl 1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidinyl 1-oxybenzoate, 4-(2-iodoacetylamide)-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-maleimide-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-isothiocyanato-2,2,6,6-tetramethylpiperidinyl 1-oxyl, 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy, and 4-phosphoxy-2,2,6,6-tetramethyl-1-piperidinyloxy. The production method of claim 1, wherein the reducing agent in step 5 is selected from any one or more of the group consisting of sodium borohydride, sodium cyanoborohydride and sodium triacetyloxyborohydride. The method of claim 1, wherein after step 5, further comprising the step 6) adding an acid to the compound represented by the chemical formula 1 to produce an acidic salt represented by the following chemical formula 1-1, [Chemical formula 1-1] . The production method of claim 15, wherein the acid is selected from any one or more of the group consisting of hydrochloric acid, glutamine, malonic acid, succinic acid, tartaric acid, oxalic acid, fumaric acid, phosphoric acid, and methanesulfonic acid. A manufacturing method as claimed in claim 15, wherein the acid is fumaric acid.