Method for preparing intermediates of 6-methoxypyridine-3-YL derivatives

Abstract

The present invention relates to a method for preparing intermediates of 6-methoxypyridin-3-yl derivatives. The preparation method according to the present invention has the advantage of utilizing low-cost substances and performing the reaction under conditions suitable for mass production. Furthermore, it has the advantage of shortening the preparation process, thereby securing process convenience while simultaneously increasing yield and purity. Therefore, there is provided a method for preparing intermediates of 6-methoxypyridin-3-yl derivatives useful for industrial mass production.

Description

METHOD FOR PREPARING INTERMEDIATES OF 6-METHOXYPYRIDINE-3-YL DERIVATIVES

[0001] The present invention relates to a method for preparing intermediates of 6-methoxypyridin-3-yl derivatives.

[0002] Potassium-competitive acid blockers (P-CABs) are emerging to improve on the shortcomings of proton pump inhibitors (PPIs). Potassium-competitive acid blockers inhibit acid secretion powerfully and rapidly by binding to the proton pump (H+ / K+-ATPase), which is an enzyme involved in the final stage of acid secretion in gastric wall cells, in a reversible and competitive manner to K+ ions. These P-CAB agents show strong inhibition compared to PPI agents at normal stomach acidity (pH 1-3). However, the above P-CAB agents require pharmacologic activity that decreases the inhibitory ability with increasing pH, and some P-CAB agents show pharmacologic activity that is maintained even with increasing pH, and some adverse effects have been reported in association with this. In addition, because P-CAB agents are mainly metabolized through the CYP3A4 enzyme, the differences in drug efficacy between individuals are relatively small, and concerns about interactions with drugs metabolized by the CYP2C19 enzyme are relatively low.

[0003] International Patent Publication WO2019 / 013310 A1 discloses vonoprazan as a potassium-competitive acid blocker. However, vonoprazan was found to cause severe hypergastrinemia compared to the conventional PPI drug lansoprazole. This hypergastrinemia may lead to problems such as enterochromaffin-like (ECL)-cell overgrowth; parietal cell hyperplasia; fundic gland polyps; bone loss, damaged bone mass, fractures, and the like. In fact, in mouse and rat carcinogenicity tests, vonoprazan has been reported to be associated with the development of neuroendocrine cell tumors of the stomach. However, discontinuation of administration of P-CABs or PPIs based drugs such as vonoprazan is not easily accomplished despite the above concerns since the discontinuation of administration of these medications restores excess stomach acid, causes indigestion, and the like.

[0004] Against this background, many attempts are being made to develop novel P-CAB drugs. For example, Korean Patent Registration No. 10-2432523 discloses a novel P-CAB inhibitor that exhibits excellent acid secretion inhibition effect. Specifically, Korean Patent No. 10-2432523 discloses a method for producing a novel P-CAB drug comprising: Step (I) introduction of an appropriate heteroarylsulfonyl group into the starting material using a base in the presence of an inert solvent; Step (II) reduction using a reducing agent in the presence of an inert solvent; Step (III) oxidation using an oxidizing agent in the presence of an inert solvent; and Step (IV), which is a reductive amination process using an appropriate amine and reducing agent. However, the production methods disclosed in the patents have the disadvantages that the manufacturing process is very long, production yield and purity are low, and temperature conditions are not suitable for mass production. In particular, substances such as NaH, DIBAL-H, and DMP have high unit costs and have problems with temperature control due to severe heat generation during reaction, resulting in very difficult drug development.

[0005] Under this background, attempts are needed to improve the production method disclosed in No. 10-2432523 above. To address these issues, the present inventors have secured a manufacturing method and an appropriate intermediate thereof capable of significantly increasing the production level of the target material while shortening the manufacturing process to suit mass production and ensuring process convenience while maximizing yield. Therefore, the present inventors have completed the present invention by providing a process for preparing intermediates of novel 6-methoxypyridin-3-yl derivatives.

[0006] The present invention aims to provide a method for preparing intermediates of 6-methoxypyridin-3-yl derivatives.

[0007] An object of the present invention is to provide a method for preparing intermediates of 6-methoxypyridin-3-yl derivatives, comprising:

[0008] 1) hydrolyzing a compound represented by the following Chemical Formula 2 to prepare a compound represented by the following Chemical Formula 3;

[0009] 2) reacting the compound represented by the following Chemical Formula 3 with an acid activator and then adding a reducing agent to prepare a compound represented by the following Chemical Formula 4; and

[0010] 3) oxidizing the compound represented by the following Chemical Formula 4 to prepare a compound represented by the following Chemical Formula 5, followed by reacting with a deprotection reagent to prepare a compound represented by the following Chemical Formula 1:

[0011] [Chemical Formula 1]

[0012]

[0013] [Chemical Formula 2]

[0014]

[0015] [Chemical Formula 3]

[0016]

[0017] [Chemical Formula 4]

[0018]

[0019] [Chemical Formula 5]

[0020] .

[0021] Further, another object of the present invention is to provide a compound represented by the following Chemical Formula 6, or a pharmaceutically acceptable salt thereof:

[0022] [Chemical Formula 6]

[0023] .

[0024] In one general aspect, a preparation method is provided as shown in Reaction Scheme 1 below:

[0025] [Reaction Scheme 1]

[0026]

[0027] Specifically, the present invention provides a method for preparing a compound represented by Chemical Formula 1, comprising steps 1 to 3 below:

[0028] 1) hydrolyzing a compound represented by Chemical Formula 2 to prepare a compound represented by Chemical Formula 3;

[0029] 2) reacting the compound represented by Chemical Formula 3 with an acid activator and then adding a reducing agent to prepare a compound represented by Chemical Formula 4; and

[0030] 3) oxidizing the compound represented by Chemical Formula 4 to prepare a compound represented by Chemical Formula 5, followed by reacting with a deprotection reagent to prepare the compound represented by Chemical Formula 1.

[0031] In Chemical Formulas 4 and 5 above, R1may be selected from the group consisting of C(=O)-Ra, S(=O)2-Rb, and Rc.

[0032] Here, Ramay be any one selected from the group consisting of methyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, di-tertbutoxy, phenoxy, benzyloxy, and 1-imidazolyl.

[0033] Rbmay be methyl or 4-methylphenyl.

[0034] Rcmay be any one selected from the group consisting ofN,N'-dicyclohexylcarbodiimide,N,N'-diisopropylcarbodiimide, 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide, benzotriazolyl, azabenzotriazolyl, tris(dimethylamino)phosphonium, tris(pyrrolidine)phosphonium, tetramethyluronium, dimethylamino-N-methylmethanaminium, 3,5-dichlorotriazine, 3,5-dimethoxy-triazine, 4-methoxybenzyl, and benzyl.

[0035] Hereinafter, an embodiment of the present invention will be described in detail for each of the above steps. As described below, it is also possible to control the quality of the final material by adjusting the process temperature and performance time of each step above.

[0036] [Step 1]

[0037] Step 1 is a step of hydrolyzing the compound represented by Chemical Formula 2 to prepare the compound represented by Chemical Formula 3.

[0038] The hydrolyzing in Step 1 may be performed in the presence of a metal salt.

[0039] In Step 1 above, the metal salt may be a sodium salt, potassium salt, or lithium salt. Specifically, the metal salt may be any one or more sodium salts selected from the group consisting of sodium hydroxide, sodium bromide, and sodium iodide. Specifically, the metal salt may be any one or more potassium salts selected from the group consisting of potassium hydroxide, potassium chloride, potassium bromide, and potassium iodide. Specifically, the metal salt may be any one or more lithium salts selected from the group consisting of lithium hydroxide, lithium chloride, lithium bromide, lithium iodide, lithium sulfate (Li2SO4), lithium nitrate (LiNO3), lithium tetrafluoroborate (LiBF4), lithium trifluoroacetate (CF3CO2Li), lithium trifluoromethane sulfonate (CF3SO3Li), and lithium p-toluenesulfonate (C7H7LiO3S). Preferably, sodium salt or lithium salt may be used. More preferably, sodium hydroxide or lithium hydroxide may be used.

[0040] In the reaction in Step 1, a reaction solvent may be any one or more selected from the group consisting of water, acetonitrile, tetrahydrofuran, dichloromethane, methanol, ethanol, propanol, iso-propanol, butanol, tert-butanol,N,N-dimethylformamide,N-dimethylacetamide,N-methylpyrrolidone, and dimethylsulfoxide. Specifically, methanol may be used as the reaction solvent in Step 1 above.

[0041] The reaction of Step 1 may be performed at 60 to 90℃. Specifically, the reaction within the reaction temperature range of Step 1 above may contribute to increasing a conversion rate of Step 1 and reducing a content of related substances in the final material.

[0042] The reaction of Step 1 above may be performed for 1 hour to 24 hours. When the reaction time is less than 1 hour, the reaction does not proceed sufficiently, resulting in lower production yield, and when the reaction time exceeds 24 hours, the production yield does not substantially increase.

[0043] After completion of the reaction, as needed, a step of purifying the compound represented by Chemical Formula 3 may be further included. The purifying step may be performed by concentrating or not concentrating a reaction solution upon completion of the reaction, dissolving, and washing the reaction solution as is in water, followed by adding an acidic aqueous solution to the water layer to crystallize the compound represented by Chemical Formula 3.

[0044] For the washing, any solvent may be used without limitation as long as it is immiscible with water and is able to separate layers, specifically, may be any one or more organic solvents selected from the group consisting of dichloromethane, butanol, tert-butanol, ethyl acetate, isopropyl acetate, ethyl ether, and methyl tertiary butyl ether. Preferably, dichloromethane may be used.

[0045] The acidic aqueous solution may be an inorganic acid or an organic acid. Specifically, the acidic aqueous solution may be any one or more inorganic acids selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. Specifically, the acidic aqueous solution may be any one or more organic acids selected from the group consisting of acetic acid, citric acid, tartaric acid, glutamic acid, malonic acid, succinic acid, oxalic acid, fumaric acid, and methanesulfonic acid. Preferably, an aqueous hydrochloric acid solution may be used.

[0046] The purification process may be effective in removing metal salts in residual solvents, such as sodium hydroxide or lithium hydroxide.

[0047] After purifying the compound represented by Chemical Formula 3 through the above steps, the compound may be dried at 30 to 45℃ for 12 hours or more to reduce the moisture content contained in the compound. This may increase the conversion rate for the next step.

[0048] A washing step using a solvent used after completion of the reaction in each step may be further included.

[0049] [Step 2]

[0050] Step 2 is a step of reacting the compound represented by Chemical Formula 3 with an acid activator and then adding a reducing agent to prepare the compound represented by Chemical Formula 4.

[0051] More specifically, in Step 2, the compound represented by Chemical Formula 3 may be reacted with an acid activator to prepare an intermediate in an activated acid form, thereby facilitating the reduction reaction, while simultaneously introducing a protecting group that protects the nitrogen of the pyrrole via the R1group in a subsequent reaction. Step 2 above may simultaneously perform the acid activation and the introduction of the protecting group to thereby simplify the process, resulting in higher productivity and improved yields.

[0052] Step 2 may comprise Step 2-1 of reacting an acid activator and Step 2-2 of adding a reducing agent.

[0053] [Reaction Scheme 2]

[0054]

[0055] With respect to Reaction Scheme 2 above, the preparation method is as follows:

[0056] 2-1) reacting the compound represented by Chemical Formula 3 with an acid activator to prepare an intermediate represented by the following Chemical Formula 3-1; and

[0057] 2-2) adding a reducing agent to the activated intermediate compound to perform conversion to the compound represented by Chemical Formula 4;

[0058] [Chemical Formula 3-1]

[0059]

[0060] in Chemical Formula 3-1 above, R1may be selected from the group consisting of C(=O)-Ra, S(=O)2-Rb, and Rc.

[0061] Here, Ramay be any one selected from the group consisting of methyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, di-tertbutoxy, phenoxy, benzyloxy, and 1-imidazolyl.

[0062] Rbmay be methyl or 4-methylphenyl.

[0063] Rcmay be any one selected from the group consisting ofN,N'-dicyclohexylcarbodiimide,N,N'-diisopropylcarbodiimide, 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide, benzotriazolyl, azabenzotriazolyl, tris(dimethylamino)phosphonium, tris(pyrrolidine)phosphonium, tetramethyluronium, dimethylamino-N-methylmethanaminium, 3,5-dichlorotriazine, 3,5-dimethoxy-triazine, 4-methoxybenzyl, and benzyl.

[0064] As shown in Chemical Formula 3-1 above, the intermediate may form an acid anhydride, a sulfonate-based mixed anhydride, or an ester through substitution at the R1position, and thus it is possible to improve the yield of the reaction by subsequent treatment with a reducing agent, and maintain the reaction conditions at room temperature, while simultaneously protecting the nitrogen of the pyrrole via the R1group in a subsequent reaction. Step 2-1 above may simultaneously perform the acid activation and the introduction of the protecting group to thereby simplify the process, resulting in higher productivity and improved yields.

[0065] In Step 2-1, the acid activator refers to a compound for preparing an intermediate in the form of an activated acid. More specifically, the acid activator is any compound capable of providing a compound structure in the activated acid form, such as an acid anhydride, a sulfonate-based mixed anhydride, or an ester.

[0066] This acid activator is not limited, but may be any one selected from the group consisting of an anhydride former, a sulfonate-based mixed anhydride former, and an ester former.

[0067] More specifically, the anhydride former may be any one selected from the group consisting of acetic anhydride (Ac2O), pivaloyl chloride (PivCl), 1,1'-carbonyldiimidazole (CDI), methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, n-propylchloroformate, butylchloroformate, iso-butylchloroformate, phenylchloroformate, di-tert-butyldicarbonate (Boc), benzylchloroformate (Cbz), and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ).

[0068] The sulfonate-based mixed anhydride former may be methanesulfonyl chloride (MsCl) or p-toluenesulfonyl chloride (TsCl).

[0069] The ester former may be any one selected from the group consisting ofN,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(pyrrolidine)phosphonium hexafluorophosphate (PyBOP),N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU),N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HATU),N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborateN-oxide (TBTU), 2-(2-oxo-1(2H)-pyridyl-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), O-[(cyano(ethoxycarbonyl)methyleneamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TOTU), cyanuric acid 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.

[0070] According to a preferred embodiment of the present invention, the acid activator may be an anhydride former, which is any one selected from the group consisting of isopropyl chloroformate, ethyl chloroformate, iso-butyl chloroformate, and di-tert-butyldicarbonate (Boc).

[0071] Further, the acid activator may be a sulfonate-based mixed anhydride former such as methanesulfonyl chloride (MsCl) or p-toluenesulfonyl chloride (TsCl).

[0072] Alternatively, the acid activator may be an ester former such as 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) or 1-hydroxybenzotriazole (HOBt).

[0073] More preferably, the acid activator may be ethylchloroformate.

[0074] In an embodiment, when Steps 2-1 and 2-2 are performed using ethyl chloroformate as the acid activator in Step 2, the compound represented by Chemical Formula 4 may be a compound represented by the following Chemical Formula 6:

[0075] [Chemical Formula 6]

[0076] .

[0077] In Step 2-1 above, a molar ratio between the compound represented by Chemical Formula 3 and the acid activator may be 10 : 1 to 1 : 10, and more preferably 5 : 1 to 1 : 5.

[0078] The treatment with the acid activator in Step 2-1 may be performed in any one or more organic solvents selected from the group consisting of triethylamine, tetrahydrofuran, dimethylacetamide, dimethyl sulfoxide, toluene, methanol, ethanol, dichloromethane, ethyl acetate, acetonitrile, propanol, iso-propanol, butanol, tert-butanol, 2-methyl tetrahydrofuran,N,N-dimethylformamide, andN-methylpyrrolidone. Specifically, the treatment with the acid activator may be performed using tetrahydrofuran, triethylamine, or both as solvents.

[0079] The reaction of Step 2-1 may be performed at 0 to 35℃. Specifically, the compound represented by Chemical Formula 3 and the solvent may be stirred in a reactor at room temperature, an internal temperature of the reactor may be lowered to 0 to 10℃, and the triethylamine and ethyl chloroformate may be added, followed by stirring at 20 to 30℃, and then a solid precipitated during the reaction may be filtered.

[0080] In Step 2-1, the reaction between the compound represented by Chemical Formula 3 and the acid activator may be performed for 30 minutes to 8 hours. When the reaction time is less than 30 minutes, the reaction does not proceed sufficiently, resulting in lower production yield, and when the reaction time exceeds 8 hours, the production yield does not substantially increase. More specifically, the reaction may be performed for 1 hour to 5 hours.

[0081] Step 2-2 above is the step of adding a reducing agent to the activated intermediate compound in Step 2-1 to perform conversion to the compound represented by Chemical Formula 4. The reducing agent may be any one or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. Preferably, sodium borohydride may be used. The use of the above reducing agents has the advantage of eliminating the use of hazardous reagents and environmentally polluting reagents.

[0082] In Step 2-2 above, a molar ratio between the compound represented by Chemical Formula 3 and the reducing agent may be 10 : 1 to 1 : 10, and more preferably 5 : 1 to 1 : 5.

[0083] The treatment with the reducing agent in Step 2-2 above may be performed in any one solvent selected from the group consisting of water, triethylamine, tetrahydrofuran, dimethylacetamide, dimethyl sulfoxide, toluene, methanol, ethanol, dichloromethane, ethyl acetate, acetonitrile, propanol, iso-propanol, butanol, tert-butanol, 2-methyl tetrahydrofuran,N,N-dimethylformamide, andN-methylpyrrolidone.

[0084] The reaction of Step 2-2 may be performed at 0 to 35℃. Specifically, a filtrate in Step 2-1 above may be lowered to 0 to 10℃ and sodium borohydride, a reducing agent, may be added. This process has the advantage that the reaction is able to be performed by stirring in the range of 0 to 10℃ without increasing the internal temperature, and the reaction is performed under mild conditions close to room temperature compared to previously known conditions.

[0085] In Step 2-2 above, the reaction between the compound represented by Chemical Formula 3 and the sodium borohydride may be performed for 30 minutes to 8 hours. When the reaction time is less than 30 minutes, the reaction does not proceed sufficiently, resulting in lower production yield, and when the reaction time exceeds 8 hours, the production yield does not substantially increase. More specifically, the reaction may be performed for 1 hour to 5 hours.

[0086] Thereafter, extraction may be performed 1 to 3 times using an organic solvent to obtain an organic layer. A desiccant may be added to the organic layer, stirred, and then filtered under reduced pressure. Then, the filtrate may be washed and concentrated under reduced pressure.

[0087] For the extraction, an organic solvent may be used which is water, methyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, diethyl ether, dimethyl ether, diisopropyl ether, methyl tertiary butyl ether, isopropanol, 1-butanol, dichloromethane, acetone, or a mixture of two or more thereof. Preferably, ethyl acetate alone or a mixed solvent containing ethyl acetate may be used.

[0088] If necessary, a basic aqueous solution may be used together during extraction. The basic aqueous solution may be any one or more selected from the group consisting of ammonia water, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium methylate, potassium butyrate, and cesium carbonate. Preferably, an aqueous solution of sodium carbonate or sodium bicarbonate may be used. This process may be effective in removing by-products generated during the reaction.

[0089] [Step 3]

[0090] Step 3 is a step of oxidizing the compound represented by Chemical Formula 4 to prepare the compound represented by Chemical Formula 5, followed by reacting with a deprotection reagent to prepare the compound represented by Chemical Formula 1.

[0091] More specifically, Step 3 may comprise Step 3-1 of oxidizing the compound represented by Chemical Formula 4 to prepare the compound represented by Chemical Formula 5 and Step 3-2 of deprotecting the compound represented by Chemical Formula 5 to prepare the compound represented by Chemical Formula 1. Here, to perform Steps 3-1 and 3-2 above in situ, a deprotection reagent may be added to the reaction solution after Step 3-1.

[0092] In Step 3-1 above, the oxidation of the alcohol group of the compound represented by Chemical Formula 4 may proceed in the presence of a copper catalyst, a metal catalyst ligand, and a cocatalyst.

[0093] 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) triflate toluene complex, copper(I) iodide, copper(II) iodide, copper(I) iodide tetrabutylammonium iodide complex, tetrakis(acetonitrile)copper(I) hexafluorophosphate, copper(I) iodide triethylphosphite complex, copper(I) bromide triphenylphosphine complex, copper(I) oxide, and copper(II) oxide.

[0094] The metal catalyst ligand may be any one or more selected from the group consisting ofN,N'-dimethylethane-1,2-diamine, trans-N,N'-dimethylcyclohexane-1,2-diamine, ethane-1,2-diol, propane-1,3-diol, 2-acetylcyclohexanone, acetoacetonate, 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, picolinic acid, glyoxal bis(phenylhydrazone), 2,6-dimethylanilino(oxo)acetic acid, 2,6-difluoroanilino(oxo)acetic acid, 2,6-dimethyloxyanilino(oxo)acetic acid, 2,3,4,5,6-pentafluoroanilino(oxo)acetic acid, 3,5-bis(trifluoromethyl)anilino(oxo)acetic acid, 2-fluoro-6-(piperidine-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.

[0095] The cocatalyst may be any one or more selected from the group consisting of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO), di-tert-butyl azodicarboxylate (DBAD), 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-methacryloyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-oxo-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-carboxy-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl benzoate, 4-(2-iodoacetamido)-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-maleimido-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-isothiocyanato-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy, and 4-phosphonooxy-2,2,6,6-tetramethyl-1-piperidinyloxy.

[0096] In the reaction of Step 3-1 above, a base may be used together to improve yield, and the base may be any one or more selected from the group consisting ofN-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 methylate, potassium butyrate, and cesium carbonate.

[0097] The oxidizing step according to the present invention employs a copper catalyst, a metal catalyst ligand, and a cocatalyst system to specifically oxidize alcohol. This catalyst system enables selective oxidation to aldehydes rather than carboxylic acids and allows the reaction to proceed with high yield in aliphatic systems. In addition, this catalyst system has the advantage of greatly improving practicality in that oxygen in the air is used as an oxidizing agent instead of adding a separate oxidizing agent, a general organic solvent is used, and the reaction is possible to occur at room temperature.

[0098] The reaction of Step 3-1 according to the present invention may be performed by preferably using copper(I) iodide (CuI) as a copper catalyst, 2,2'-bipyridine (bpy) as a metal catalyst ligand, 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) as a cocatalyst, andN-methylimidazole (NMI) as a base.

[0099] In Step 3-1 above, the copper catalyst, metal catalyst ligand, and cocatalyst may each be used in an amount of 0.01 to 1 equivalent relative to the compound represented by Chemical Formula 4. Preferably, the copper catalyst, metal catalyst ligand, and cocatalyst may each be used in amounts of 0.05 to 0.5 equivalents. When the amount of the copper catalyst, metal catalyst ligand, cocatalyst, and base used is less than the lower limit, the reaction rate and yield may decrease, and when the amount thereof exceeds the upper limit, the economic effect during production may be reduced.

[0100] In order to maximize the yield of the Step 3-1 reaction, a ratio in the catalyst system, i.e., a ratio between the copper catalyst, metal catalyst ligand, and cocatalyst, preferably has a molar ratio of 1 to 5 : 1 to 5 : 0.5 to 2.5. More specifically, the ratio may be any range between approximately 1 : 0.5 : 0.5 and 1 : 2.5 : 2.5.

[0101] It is desirable to maintain the above range because when the molar ratio is deviated from the above range, the stability of the catalyst is reduced, the catalyst lifetime is shortened, or it is difficult to exert catalytic activity or perform selective oxidization to aldehydes.

[0102] The type of reaction solvent capable of being used in Step 3-1 above is not particularly limited, and organic solvents commonly used in alcohol oxidation reactions may be used. For example, the solvent may be 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, and specifically, dimethyl sulfoxide.

[0103] A reaction temperature of Step 3-1 above may be 10 to 35℃. When the reaction temperature is lower than 10℃, there is a problem that the production yield is lowered, and when the reaction temperature is higher than 35℃, the production yield does not substantially increase. More specifically, the reaction may be performed at 20 to 30℃.

[0104] The reaction of Step 3-1 above may be performed for 10 hours to 20 hours. When the reaction time is less than 10 hours, the reaction does not proceed sufficiently, resulting in lower production yield, and when the reaction time exceeds 20 hours, the production yield does not substantially increase. More specifically, the reaction may be performed for 15 hours to 20 hours.

[0105] Step 3-2 is a step of reacting the compound represented by Chemical Formula 5 with a deprotection reagent to remove a protecting group, thereby preparing the compound represented by Chemical Formula 1.

[0106] The deprotection reagent refers to various compounds used in the art to remove protecting groups, and may include, for example, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, amines or acids.

[0107] Specifically, the alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate or alkaline earth metal carbonate may be any one selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, and lithium carbonate.

[0108] Specifically, the amine may be any one selected from the group consisting of methylamine, ethylamine, benzylamine, and ethanol amine.

[0109] In detail, the acid may be trifluoroacetic acid or hydrochloric acid.

[0110] Preferably, potassium carbonate may be used as the deprotection reagent.

[0111] In Step 3-2 above, a molar ratio between the compound represented by Chemical Formula 5 and the deprotection reagent may be 10 : 1 to 1 : 10, more preferably 5 : 1 to 1 : 5, and more preferably 3 : 1 to 1 : 3.

[0112] The type of reaction solvent capable of being used in Step 3-2 above is not particularly limited, and organic solvents commonly used in alcohol oxidation reactions may be used. For example, the solvent may be 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, and specifically, dimethyl sulfoxide. Here, to perform Steps 3-1 and 3-2 above in situ, a deprotection reagent may be added to the reaction solution after Step 3-1.

[0113] The reaction of Step 3-2 may be performed at 10 to 60℃. It is not desirable that when the reaction temperature is lower than 10℃, there is a problem that the production yield is lowered, and when the reaction temperature is higher than 60℃, side reactions may occur. The reaction within the reaction temperature range of Step 3-2 above has the advantage that it increases a conversion rate of Step 3-2 above, and the reaction is performed under mild conditions close to room temperature compared to previously known conditions.

[0114] The reaction of Step 3-2 above may be performed for 1 hour to 24 hours. When the reaction time is less than 1 hour, the reaction does not proceed sufficiently, resulting in lower production yield, and when the reaction time exceeds 24 hours, the production yield does not substantially increase. More specifically, the reaction may be performed for 1 hour to 10 hours.

[0115] After completion of the reaction, as needed, a step of purifying the compound represented by Chemical Formula 1 may be further included. The purifying step may be performed by crystallizing the compound represented by Chemical Formula 1 from the reaction product of Step 3 (including Steps 3-1 and 3-2).

[0116] As a solvent for crystallizing the compound represented by Chemical Formula 1 from the reaction product of Step 3 above, a mixture of ether and alkane may be used. Specifically, the ether may be any one selected from the group consisting of dimethyl ether, diethyl ether, tetrahydrofuran, and methyl tertiary butyl ether (MTBE). More specifically, the alkane may be any one selected from the group consisting of hexane, heptane, octane, nonane, and decane.

[0117] Preferably, the crystallization solvent may be a mixture of methyl tertiary butyl ether (MTBE) and n-hexane or a mixture of methyl tertiary butyl ether (MTBE) and n-heptane. For example, methyl tertiary butyl ether (MTBE) and n-hexane may be added to the reaction product of Step 3 at a temperature range of 20 to 30℃ and stirred for 12 hours or more.

[0118] After purifying the compound represented by Chemical Formula 1, the purified compound may be dried to lower the moisture content contained in the compound represented by Chemical Formula 1. For example, the moisture content of the compound represented by Chemical Formula 1 may be significantly lowered by drying for 12 hours or more at a temperature range of 35 to 45℃.

[0119] Further, the present invention provides a compound represented by the following Chemical Formula 6, or a pharmaceutically acceptable salt thereof:

[0120] [Chemical Formula 6]

[0121] .

[0122] The compound or a pharmaceutically acceptable salt thereof according to the present invention is highly likely to be used as an intermediate compound for preparing the compound of Chemical Formula 1.

[0123] The preparation method according to the present invention has the advantage of utilizing low-cost substances and performing the reaction under conditions suitable for mass production. Furthermore, it has the advantage of shortening the preparation process, thereby securing process convenience while simultaneously increasing yield and purity. This provides a large amount of intermediates of 6-methoxypyridin-3-yl derivatives that are useful for industrial scale mass production and may be utilized in subsequent preparation methods.

[0124] Hereinafter, the present invention will be described in more detail through the following Examples. However, the following Examples are only provided to illustrate the present invention, and the content of the present invention is not limited to these Examples.

[0125] The preparation process according to an embodiment of the present invention is schematically described in Reaction Scheme 3 below:

[0126] [Reaction Scheme 3]

[0127]

[0128] Example 1. Preparation of 5-(2-fluorophenyl)-4-methoxy-1H-pyrrole-3-carbaldehyde (Chemical Formula 1)

[0129] (Step 1) Synthesis of 5-(2-fluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid (Chemical Formula 3)

[0130]

[0131] In an embodiment of the present invention, 50.0 g of methyl 5-(2-fluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylate (Chemical Formula 2), 84.2 g of lithium hydroxide hydrate, and 396.0 g of methanol were added and stirred at 70℃ to 75℃ for 16 hours to complete the reaction. The reaction solution was concentrated under reduced pressure, 500.0 g of raw water was added to dissolve the concentrate, and the aqueous layer was washed twice using 133.0 g of dichloromethane. To the separated water layer, 500.0 g of 3.0 N aqueous hydrogen chloride solution was added to adjust the pH to the range of 4 to 5, followed by precipitation as crystals. The suspension was further stirred at 20℃ to 30℃ for 2 hours, the crystals were filtered, and the filtrate was washed with 100.0 g of raw water. The washed filtrate was dried at 35℃ to 45℃ for 12 hours or more to obtain 42.44 g of the compound represented by Chemical Formula 3 (yield 93.3%).

[0132] (Step 1) Synthesis of 5-(2-fluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid (Chemical Formula 3)

[0133]

[0134] In another embodiment of the present invention, 100.0 g of methyl 5-(2-fluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylate (Chemical Formula 2), 80.2 g of sodium hydroxide, 237.6 g of methanol, and 300.0 g of water were added and stirred at 75℃ to 85℃ for 1.5 hours to complete the reaction. After confirming completion of the reaction, the reaction solution was washed once using 665.0 g of dichloromethane and the aqueous layer was separated. To the separated water layer, 350.0 g of 6.0 N aqueous hydrogen chloride solution was added to adjust the pH to the range of 1 to 2, followed by precipitation as crystals. The suspension was further stirred at 20℃ to 30℃ for 1.5 hours, the crystals were filtered, and the filtrate was washed with 500.0 g of raw water. The washed filtrate was dried at 35 to 45℃ for 12 hours or more to obtain 93.26 g of the compound represented by Chemical Formula 3 (yield 98.8%).

[0135] (Step 2) Synthesis of ethyl 2-(2-fluorophenyl)-4-(hydroxymethyl)-3-methoxy-1H-pyrrole-1-carboxylate (Chemical Formula 6)

[0136]

[0137] 20.0 g of 5-(2-fluorophenyl)-4-methoxy-1H-pyrrole-3-carboxylic acid (Chemical Formula 3) and 177.6 g of tetrahydrofuran were added and dissolved by stirring. The resulting mixture was cooled to an internal temperature of 0℃ to 10℃, and 25.8 g of triethylamine and 27.7 g of ethyl chloroformate were added and stirred at 20℃ to 30℃ for 3 hours to complete the reaction. The solid precipitated during the reaction was filtered and the filtrate was washed with 88.8 g of tetrahydrofuran. Then, the filtrate was cooled to an internal temperature of 0℃ to 10℃, 40.0 g of raw water was added, and 9.7 g of sodium borohydride was added in three portions. Once the addition was complete, the reaction was completed by stirring for 2 hours at an internal temperature of 0℃ to 10℃. The solid precipitated during the reaction was filtered and the filtrate was washed with 180.4 g of ethyl acetate. The filtrate was washed twice with 200.0 g of 1.0 N sodium bicarbonate, and the separated organic layer was further washed once with 200.0 g of 10% aqueous sodium chloride solution. Next, 6.0 g of magnesium sulfate was added to the separated organic layer, stirred for 30 minutes, and filtered. Then, the filtrate was washed with 18.0 g of ethyl acetate and concentrated under reduced pressure to obtain the compound of Chemical Formula 6 in a liquid state.

[0138] (Step 3) Synthesis of 5-(2-fluorophenyl)-4-methoxy-1H-pyrrole-3-carbaldehyde (Chemical Formula 1)

[0139]

[0140] To the concentrated residue according to Step 2, 137.1 g of dimethyl sulfoxide was added and stirred. When the resulting solution was completely dissolved, 3.2 g of copper(I) iodide, 1.3 g of 2,2'-bipyridine, 1.4 g of 2-methylimidazole, 1.3 g of 2,2,6,6-tetramethylpiperidine-1-oxyl were added and stirred at 20℃ to 30℃ for 16 hours or more to complete the reaction. When the reaction was completed, an aqueous potassium carbonate solution (5.9 g of potassium carbonate + 100.0 g of raw water) was added to the reaction solution and stirred at 45℃ to 55℃ for 2 hours or more to complete the reaction. When the reaction was completed, 224.8 g of ethyl acetate and 254.2 g of 0.1 M aqueous ethylenediaminetetraacetic acid solution were added, stirred for 30 minutes, and the organic layer was separated. Next, 112.4 g of ethyl acetate was added to the separated aqueous layer, and additional extraction was performed once. The organic layer was separated and combined with the previously separated organic layer, and then the organic layer was washed twice using 249.2 g of raw water. The organic layer was then further washed using 249.2 g of 10% aqueous sodium chloride solution. Then, to the separated organic layer, 7.2 g of magnesium sulfate was added, stirred for 30 minutes, and filtered, and then the filtrate was washed with 22.5 g of ethyl acetate. The filtrate was then concentrated under reduced pressure, 44.4 g of methyl tertiary butyl ether and 39.7 g of n-hexane were added to the concentrate, and the mixture was stirred at 20℃ to 30℃ for 12 hours or more to precipitate crystals. Then, the crystals were cooled to an internal temperature of 0℃ to 5℃, aged for 1 hour, and filtered under reduced pressure. The filtrate was washed with 20.0 g of a mixture of methyl tertiary butyl ether and n-hexane, and the washed filtrate was dried at a temperature range of 35℃ to 45℃ for 12 hours or more to obtain 11.0 g of the compound represented by Chemical Formula 1 (Yield: 59.1% / Purity 99.7%).

Claims

1.A method for preparing a compound represented by the following Chemical Formula 1:1) hydrolyzing a compound represented by the following Chemical Formula 2 to prepare a compound represented by the following Chemical Formula 3;2) reacting the compound represented by the following Chemical Formula 3 with an acid activator and then adding a reducing agent to prepare a compound represented by the following Chemical Formula 4; and3) oxidizing the compound represented by the following Chemical Formula 4 to prepare a compound represented by the following Chemical Formula 5, followed by reacting with a deprotection reagent to prepare the compound represented by the following Chemical Formula 1;[Chemical Formula 1][Chemical Formula 2][Chemical Formula 3][Chemical Formula 4][Chemical Formula 5]in Chemical Formulas 4 and 5 above, R1is C(=O)-Ra, S(=O)2-Rb, or Rc,wherein Rais methyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, di-tertbutoxy, phenoxy, benzyloxy or 1-imidazolyl;Rbis methyl or 4-methylphenyl; andRcis N,N'-dicyclohexylcarbodiimide,N,N'-diisopropylcarbodiimide, 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide, benzotriazolyl, azabenzotriazolyl, tris(dimethylamino)phosphonium, tris(pyrrolidine)phosphonium, tetramethyluronium, dimethylamino-N-methylmethanaminium, 3,5-dichlorotriazine, 3,5-dimethoxy-triazine, 4-methoxybenzyl or benzyl.2.The method of claim 1, wherein the hydrolyzing in Step 1 is performed in the presence of a metal salt.3.The method of claim 2, wherein the metal salt is any one or more selected from the group consisting of sodium hydroxide, sodium bromide, sodium iodide, potassium hydroxide, potassium chloride, potassium bromide, potassium iodide, lithium hydroxide, lithium chloride, lithium bromide, lithium iodide, lithium sulfate (Li2SO4), lithium nitrate (LiNO3), lithium tetrafluoroborate (LiBF4), lithium trifluoroacetate (CF3CO2Li), lithium trifluoromethanesulfonate (CF3SO3Li), and lithium p-toluenesulfonate (C7H7LiO3S).4.The method of claim 2, wherein the metal salt is a sodium salt or a lithium salt.5.The method of claim 2, wherein the metal salt is sodium hydroxide or lithium hydroxide.6.The method of claim 1, wherein the acid activator in Step 2 is any one or more selected from the group consisting of an anhydride former, a sulfonate-based mixed anhydride former, and an ester former.7.The method of claim 6, wherein the acid activator is any one selected from the group consisting of isopropyl chloroformate, ethyl chloroformate, iso-butyl chloroformate, di-tert-butyldicarbonate (Boc), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), 1-ethyl-3-(3'-dimethylaminopropyl)-carbodiimide hydrochloride (EDC), and 1-hydroxybenzotriazole (HOBt).8.The method of claim 1, wherein the reducing agent in Step 2 is any one or more selected from the group consisting of sodium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.9.The method of claim 1, wherein the oxidizing in Step 3 is performed in the presence of a copper catalyst, a metal catalyst ligand, and a cocatalyst.10.The method of claim 9, wherein the copper catalyst is 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) triflate toluene complex, copper(I) iodide, copper(II) iodide, copper(I) iodide tetrabutylammonium iodide complex, tetrakis(acetonitrile)copper(I) hexafluorophosphate, copper(I) iodide triethylphosphite complex, copper(I) bromide triphenylphosphine complex, copper(I) oxide, and copper(II) oxide,the metal catalyst ligand is any one or more selected from the group consisting ofN,N'-dimethylethane-1,2-diamine, trans-N,N'-dimethylcyclohexane-1,2-diamine, ethane-1,2-diol, propane-1,3-diol, 2-acetylcyclohexanone, acetoacetonate, 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, picolinic acid, glyoxal bis(phenylhydrazone), 2,6-dimethylanilino(oxo)acetic acid, 2,6-difluoroanilino(oxo)acetic acid, 2,6-dimethyloxyanilino(oxo)acetic acid, 2,3,4,5,6-pentafluoroanilino(oxo)acetic acid, 3,5-bis(trifluoromethyl)anilino(oxo)acetic acid, 2-fluoro-6-(piperidine-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, andthe cocatalyst is any one or more selected from the group consisting of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO), di-tert-butyl azodicarboxylate (DBAD), 4-acetamido-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-methacryloyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-oxo-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-carboxy-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl benzoate, 4-(2-iodoacetamido)-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-maleimido-2,2,6,6-tetramethyl-1-piperidinyloxy, 4-isothiocyanato-2,2,6,6-tetramethylpiperidine 1-oxyl, 4-methoxy-2,2,6,6-tetramethyl-1-piperidinyloxy, and 4-phosphonooxy-2,2,6,6-tetramethyl-1-piperidinyloxy.11.The method of claim 10, wherein the copper catalyst is copper (I) iodide (CuI), the metal catalyst ligand is 2,2'-bipyridine (bpy), and the cocatalyst is 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO).12.The method of claim 1, wherein the deprotection reagent in Step 3 is any one or more selected from the group consisting of: sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, methylamine, ethylamine, benzylamine, ethanol amine, trifluoroacetic acid, and hydrochloric acid.13.A compound represented by the following Chemical Formula 6, or a pharmaceutically acceptable salt thereof:[Chemical Formula 6].

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