Preparation method for tegoprazan key intermediate, and novel intermediates using thereof

Abstract

The present invention relates to a novel preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan, and a novel intermediate used therein. The preparation method of the present invention may utilize a novel intermediate to prepare 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide with a few steps and without post-treatment, thereby achieving low raw material costs and shortened process times to provide excellent efficiency and cost-effectiveness. Furthermore, the 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide prepared by the preparation method of the present invention has excellent yield and purity, and the preparation method of the present invention is highly reproducible. Thus, the preparation method of the present invention may be usefully applied to the industrial scale production of tegoprazan (in particular, its key intermediate 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide).

Description

PREPARATION METHOD FOR TEGOPRAZAN KEY INTERMEDIATE, AND NOVEL INTERMEDIATES USING THEREOF

[0001] The present invention relates to a preparation method for a tegoprazan intermediate and a novel intermediate used therein. Specifically, the present invention relates to a novel preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan, and a novel intermediate used therein.

[0002] Tegoprazan is a potassium-competitive acid blocker (P-CAB) indicated for the prevention or treatment of diseases mediated by acid pump antagonist activity, such as gastrointestinal diseases including gastroesophageal disease, gastroesophageal reflux disease, peptic ulcer, gastroesophageal disease, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, non-erosive reflux disease (NERD), visceral referred pain, heartburn, nausea, esophagitis, dysphagia, sialorrhea, airway lesion, and asthma.

[0003] In addition, tegoprazan (4-[(5,7-difluoro-3,4-dihydro-2H-chromen-4-yl)oxy]-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide) exhibits a structure where a benzimidazole moiety is linked to a 3,4-dihydrochromene moiety, as shown in the following Chemical Formula I:

[0004] [Chemical Formula I]

[0005] .

[0006] A preparation method for tegoprazan is disclosed in International Publication WO 2007 / 072146 and may be prepared according to the following Reaction Scheme A and Example 1:

[0007] [Reaction Scheme A]

[0008] .

[0009] In other words, it may be appreciated that the key intermediates in the preparation of tegoprazan are the benzimidazole moiety intermediate 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide and the 3,4-dihydrochromene moiety intermediate 5,7-difluoro-3,4-dihydro-2H-chromen-4-ol.

[0010] However, according to the preparation methods disclosed in the above document, the preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide represented by Chemical Formula Ia below requires many processes, which is inefficient, has a high risk of environmental pollution, and is not suitable for mass production due to expensive raw materials:

[0011] [Chemical Formula Ia]

[0012] .

[0013] Therefore, there is a growing need to develop a novel preparation method capable of preparing tegoprazan, especially its key intermediate, in a more efficient manner while overcoming the above challenges.

[0014] An object of the present invention is to provide a novel preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan, with the use of inexpensive reagents, high yield, low difficulty in post-processing, and high purity product.

[0015] Another object of the present invention is to provide a novel intermediate capable of being used in the above preparation method.

[0016] In order to achieve the above purpose, the present inventors have made research efforts, and as a result, completed the present invention by developing a novel preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, which is a tegoprazan intermediate, and a novel intermediate capable of being usefully employed therefor.

[0017] Preparation method (A) of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide

[0018] The present invention provides a preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate used in the preparation of tegoprazan.

[0019] According to an embodiment of the present invention, the preparation method may comprise Steps (A-1) to (A-5) below:

[0020] (A-1) preparing a compound represented by the following Chemical Formula A2 from a compound represented by the following Chemical Formula A1;

[0021] (A-2) preparing a compound represented by the following Chemical Formula A3 from the compound represented by Chemical Formula A2;

[0022] (A-3) preparing a compound represented by the following Chemical Formula A4 from the compound represented by Chemical Formula A3;

[0023] (A-4) preparing a compound represented by the following Chemical Formula A5 from the compound represented by Chemical Formula A4; and

[0024] (A-5) preparing a compound represented by the following Chemical Formula Ia from the compound represented by Chemical Formula A5:

[0025] [Chemical Formula A1]

[0026]

[0027] [Chemical Formula A2]

[0028]

[0029] [Chemical Formula A3]

[0030]

[0031] [Chemical Formula A4]

[0032]

[0033] [Chemical Formula A5]

[0034]

[0035] [Chemical Formula Ia]

[0036] .

[0037] Hereinafter, Steps (A-1) to (A-5) will be specifically described.

[0038] Step (A-1)

[0039] Step (A-1) of the present invention is a step of preparing the compound represented by Chemical Formula A2 by acetylating the compound represented by Chemical Formula A1.

[0040] Specifically, Step (A-1) may be performed by reacting 4-aminobenzoic acid represented by Chemical Formula A1 with an acetylating reagent. The acetylating reagent may be an acid anhydride or an acyl halide. For example, acetic anhydride or acetyl chloride may be used. However, the present invention is not limited thereto.

[0041] In addition, Step (A-1) may be performed by adding, as an acid or dehydrating agent, at least one selected from the group consisting of sulfuric acid, acetic acid, acetic anhydride, or a combination thereof, together with the acetylating reagent. However, the present invention is not limited thereto.

[0042] Further, Step (A-1) may be performed by adding a reactant under ice bath conditions, heating the reaction solution to about 15℃ to about 30℃, followed by stirring the reaction solution under reflux at about 120℃ to about 140℃. Specifically, a temperature during the heating may be room temperature or ambient temperature, and for example, may be raised to a range of one lower limit and one upper limit selected from the group consisting of about 15℃, about 20℃, about 25℃, and about 30℃. Further, the stirring under reflux may be performed in a range of one lower limit and one upper limit selected from the group consisting of about 120℃, about 125℃, about 130℃, about 135℃, and about 140℃.

[0043] In addition, Step (A-1) may be performed in a non-alcoholic polar solvent. For example, Step (A-1) may be performed in a solvent selected from the group consisting of dichloromethane (DCM), chloroform, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and acetonitrile. However, the present invention is not limited thereto.

[0044] According to an embodiment of the present invention, Step (A-1) may be performed in a continuous flow process.

[0045] Step (A-2)

[0046] Step (A-2) of the present invention is a step of preparing the compound represented by Chemical Formula A3 by subjecting the compound represented by Chemical Formula A2 to an amide coupling reaction.

[0047] Specifically, Step (A-2) may be performed by reacting the compound represented by Chemical Formula A2 with dimethyl amine.

[0048] More specifically, Step (A-2) may be performed by first reacting the compound represented by Chemical Formula A2 with pivaloyl chloride and then reacting it with dimethyl amine.

[0049] In addition, Step (A-2) may be performed in the presence of a base. The base may be an inorganic base, an amine base, or a heterocyclic base. For example, the base may be sodium hydroxide, calcium hydroxide, sodium bicarbonate, triethylamine, or pyridine. However, the present invention is not limited thereto.

[0050] Further, Step (A-2) may be performed by heating to about 15℃ to about 30℃ after cooling and stirring. Specifically, a temperature during the heating may be room temperature or ambient temperature, and for example, may be raised to a range of one lower limit and one upper limit selected from the group consisting of about 15℃, about 20℃, about 25℃, and about 30℃.

[0051] In addition, Step (A-2) may be performed in a non-alcoholic polar solvent. For example, Step (A-2) may be performed in a solvent selected from the group consisting of dichloromethane (DCM), chloroform, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and acetonitrile. However, the present invention is not limited thereto.

[0052] According to an embodiment of the present invention, Step (A-2) may be performed in a continuous flow process.

[0053] Step (A-3)

[0054] Step (A-3) of the present invention is a step of preparing the compound represented by Chemical Formula A4 by subjecting the compound represented by Chemical Formula A3 to a nitration reaction.

[0055] Specifically, Step (A-3) may be conducted by reacting the compound represented by Chemical Formula A3 with nitric acid or nitrate to perform a dinitration reaction. The nitrate may be potassium nitrate (KNO3). However, the present invention is not limited thereto.

[0056] In addition, Step (A-3) may be performed by adding, as an acid or dehydrating agent, at least one selected from the group consisting of sulfuric acid, acetic acid, acetic anhydride, or a combination thereof, together with nitric acid or nitrate. However, the present invention is not limited thereto.

[0057] Further, Step (A-3) may be performed at about 40℃ to about 90℃. Specifically, Step (A-3) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 40℃, about 45℃, about 50℃, about 55℃, about 60℃, about 65℃, about 70℃, about 75℃, about 80℃, about 85℃, and about 90℃.

[0058] In addition, Step (A-3) may be performed in a non-alcoholic polar solvent. For example, Step (A-3) may be performed in a solvent selected from the group consisting of dichloromethane (DCM), chloroform, dimethylformamide (DMF), tetrahydrofuran (THF), and acetonitrile. However, the present invention is not limited thereto.

[0059] According to an embodiment of the present invention, Step (A-3) may be performed in a continuous flow process. Specifically, Step (A-3) may be performed by reacting the compound represented by Chemical Formula A3, which is a reactant of Step (A-3), with nitric acid or nitrate, via a continuous flow process.

[0060] According to an embodiment of the present invention, fluids containing the reactants in Step (A-3) above may be supplied to different pumps, respectively, and mixed in a T-shaped connector to perform the reaction. More specifically, Step (A-3) may comprise reacting a fluid a1 containing the compound represented by Chemical Formula A3; and a fluid a2 containing the nitric acid or nitrate.

[0061] According to an embodiment of the present invention, a flow velocity ratio of the fluid a1 and the fluid a2 may be from about 2 : 1 to about 4 : 1.

[0062] Step (A-4)

[0063] Step (A-4) of the present invention is a step of preparing the compound represented by Chemical Formula A5 by hydrogenating the compound represented by Chemical Formula A4. Specifically, Step (A-4) may be performed by adding hydrogen to the reaction in the presence of a metal catalyst.

[0064] The metal catalyst may be at least one selected from the group consisting of Raney-Ni, Pd(OAc)2, Pd / C, Pt / C, PdO, and Fe powder. However, the present invention is not limited thereto.

[0065] Further, Step (A-4) may be performed at about 40℃ to about 80℃. Specifically, Step (A-4) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 40℃, about 45℃, about 50℃, about 55℃, about 60℃, about 65℃, about 70℃, about 75℃, and about 80℃.

[0066] In addition, Step (A-4) may be performed in an alcoholic solvent. For example, Step (A-4) may be performed in a solvent selected from the group consisting of methanol, ethanol, isopropanol, and butanol. However, the present invention is not limited thereto.

[0067] According to an embodiment of the present invention, Step (A-4) may be performed in a continuous flow process. Specifically, Step (A-4) may be performed by reacting the compound represented by Chemical Formula A4, which is a reactant of Step (A-4), with hydrogen gas, via a continuous flow process.

[0068] According to an embodiment of the present invention, fluids containing the reactants in Step (A-4) above may be supplied to different pumps, respectively, and mixed in a T-shaped connector, followed by performing the reaction while passing through a column filled with a metal catalyst. More specifically, Step (A-4) may comprise reacting a fluid a3 containing the compound represented by Chemical Formula A4; and a fluid a4 containing the hydrogen.

[0069] According to an embodiment of the present invention, a flow velocity ratio of the fluid a3 and the fluid a4 may be from about 1 : 4 to about 1 : 8.

[0070] The reaction may be performed under conditions where the internal pressure of the pump transporting the fluid is between about 2 bar and about 10 bar. Specifically, the internal pressure of the pump may be in a range of one lower limit and one upper limit selected from the group consisting of about 2 bar, about 3 bar, about 4 bar, about 5 bar, about 6 bar, about 7 bar, about 8 bar, about 9 bar, and about 10 bar.

[0071] Step (A-5)

[0072] Step (A-5) of the present invention is a step of preparing the compound represented by Chemical Formula Ia from the compound represented by Chemical Formula A5. Specifically, Step (A-5) may be performed by the Sandmeyer reaction.

[0073] More specifically, Step (A-5) may be performed by reacting the compound represented by Chemical Formula A5 with sodium nitrite (NaNO2) in the presence of acid to form an unstable intermediate, a diazonium compound, while simultaneously reacting it with a copper salt. The above copper salt may be Cu2O, Cu(NO3)2·3H2O, CuSO4, or a combination thereof. However, the present invention is not limited thereto.

[0074] Step (A-5) may be performed at about 0℃ to about 70℃. Specifically, Step (A-5) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 0℃, about 5℃, about 10℃, about 15℃, about 20℃, about 25℃, about 30℃, about 35℃, about 40℃, about 45℃, about 50℃, about 55℃, about 60℃, about 65℃, and about 70℃.

[0075] According to an embodiment of the present invention, Step (A-5) may be performed in a continuous flow process. Specifically, Step (A-5) may be performed by reacting the compound represented by Chemical Formula A5, which is a reactant of Step (A-5), with sodium nitrite and a copper salt, via a continuous flow process.

[0076] According to an embodiment of the present invention, fluids containing the reactants in Step (A-5) above may be supplied to different pumps, respectively, and mixed in a T-shaped connector to perform the reaction. More specifically, Step (A-5) may comprise reacting a fluid a5 containing the compound represented by Chemical Formula A5; and a fluid a6 containing sodium nitrite and a copper salt.

[0077] The preparation method of the present invention may prepare 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide with a few steps and without post-treatment, thereby shortening the process time to provide excellent efficiency and cost-effectiveness.

[0078] In addition, the preparation method of the present invention may reduce the amount of reagents or solvents, making it environmentally friendly, and also may be performed in a small space and safely as all processes are system-controlled.

[0079] Furthermore, the 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide prepared by the preparation method of the present invention has excellent yield and purity, and the preparation method of the present invention is highly reproducible.

[0080] In addition, the present invention provides a novel intermediate capable of being used in preparing 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan. Specifically, the novel intermediate is a compound represented by the following Chemical Formula A4 or a salt thereof:

[0081] [Chemical Formula A4]

[0082] .

[0083] The novel intermediate of the present invention enables the preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan, by a novel synthesis pathway. The above synthesis pathway is a very simple process that can significantly reduce process time, resulting in overall excellent efficiency and cost-effectiveness. Thus, the novel intermediate of the present invention may be usefully employed as a key intermediate in the preparation method of the present invention capable of being usefully applied to industrial scale production.

[0084] In addition, the present invention provides a preparation method for 4-acetamido-N,N-dimethyl-3,5-dinitrobenzamide, a novel intermediate used in the preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide.

[0085] Specifically, the preparation method comprises the following Steps (A-1) to (A-3):

[0086] (A-1) preparing a compound represented by the following Chemical Formula A2 from a compound represented by the following Chemical Formula A1;

[0087] (A-2) preparing a compound represented by the following Chemical Formula A3 from the compound represented by Chemical Formula A2; and

[0088] (A-3) preparing a compound represented by the following Chemical Formula A4 from the compound represented by Chemical Formula A3:

[0089] [Chemical Formula A1]

[0090]

[0091] [Chemical Formula A2]

[0092]

[0093] [Chemical Formula A3]

[0094]

[0095] [Chemical Formula A4]

[0096] .

[0097] The description of Steps (A-1) to (A-3) above is as provided above.

[0098] Preparation method (B) of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide

[0099] The present invention provides a preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate used in the preparation of tegoprazan.

[0100] According to an embodiment of the present invention, the preparation method may comprise the following Steps (B-1) to (B-6):

[0101] (B-1) preparing a compound represented by the following Chemical Formula B2 from a compound represented by the following Chemical Formula B1;

[0102] (B-2) preparing a compound represented by the following Chemical Formula B3 from the compound represented by Chemical Formula B2;

[0103] (B-3) preparing a compound represented by the following Chemical Formula B4 from the compound represented by Chemical Formula B3;

[0104] (B-4) preparing a compound represented by the following Chemical Formula B5 from the compound represented by Chemical Formula B4;

[0105] (B-5) preparing a compound represented by the following Chemical Formula B6 from the compound represented by Chemical Formula B5; and

[0106] (B-6) preparing a compound represented by the following Chemical Formula Ia from the compound represented by Chemical Formula B6:

[0107] [Chemical Formula B1]

[0108]

[0109] [Chemical Formula B2]

[0110]

[0111] [Chemical Formula B3]

[0112]

[0113] [Chemical Formula B4]

[0114]

[0115] [Chemical Formula B5]

[0116]

[0117] [Chemical Formula B6]

[0118]

[0119] [Chemical Formula Ia]

[0120] .

[0121] Hereinafter, Steps (B-1) to (B-6) will be described in detail.

[0122] Step (B-1)

[0123] Step (B-1) of the present invention is a step of preparing the compound represented by Chemical Formula B2 by subjecting the compound represented by Chemical Formula B1 to a nitration reaction.

[0124] Specifically, Step (B-1) may be performed by adding nitric acid or nitrate to the 4-chlorobenzoic acid represented by Chemical Formula B1 to perform a dinitration reaction. The nitrate may be potassium nitrate (KNO3). However, the present invention is not limited thereto.

[0125] In addition, Step (B-1) may be performed by adding, as an acid or dehydrating agent, at least one selected from the group consisting of sulfuric acid, acetic acid, acetic anhydride, or a combination thereof, together with nitric acid or nitrate. However, the present invention is not limited thereto.

[0126] Further, Step (B-1) may be performed at about 20℃ to about 180℃. Specifically, Step (B-1) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 20℃, about 30℃, about 40℃, about 50℃, about 60℃, about 70℃, about 80℃, about 90℃, about 100℃, about 110℃, about 120℃, about 130℃, about 140℃, about 150℃, about 160℃, about 170℃, and about 180℃.

[0127] According to an embodiment of the present invention, Step (B-1) may be performed in a continuous flow process.

[0128] Step (B-2)

[0129] Step (B-2) of the present invention is a step of preparing the compound represented by Chemical Formula B3 by replacing -Cl in the compound represented by Chemical Formula B2 with -NH2. Specifically, Step (B-2) may be performed by adding aqueous ammonia to the compound represented by Chemical Formula B2.

[0130] Further, Step (B-2) may be performed at about 40℃ to about 80℃. Specifically, Step (B-2) may be performed in a range of one lower limit and one upper limit selected from the group consisting of about 40℃, about 50℃, about 60℃, about 70℃, and about 80℃.

[0131] In addition, Step (B-2) may be performed in an alcoholic solvent. For example, Step (B-2) may be performed in a solvent selected from the group consisting of methanol, ethanol, isopropanol, and butanol. However, the present invention is not limited thereto.

[0132] According to an embodiment of the present invention, Step (B-2) may be performed in a continuous flow process.

[0133] Step (B-3)

[0134] Step (B-3) of the present invention is a step of preparing the compound represented by Chemical Formula B4 by subjecting the compound represented by Chemical Formula B3 to an acetylation reaction.

[0135] Specifically, Step (B-3) may be performed by reacting an acetylating reagent with the compound represented by Chemical Formula B3. The acetylating reagent may be an acid anhydride or an acyl halide. For example, acetic anhydride or acetyl chloride may be used. However, the present invention is not limited thereto.

[0136] In addition, Step (B-3) may be performed by adding, as an acid or dehydrating agent, at least one selected from the group consisting of sulfuric acid, acetic acid, acetic anhydride, or a combination thereof, together with the acetylating reagent. However, the present invention is not limited thereto.

[0137] Further, Step (B-3) may be performed at about 20℃ to about 85℃. Specifically, Step (B-3) may be performed in a range of one lower limit and one upper limit selected from the group consisting of about 20℃, about 30℃, about 40℃, about 50℃, about 60℃, about 70℃, about 80℃, and about 85℃.

[0138] In addition, Step (B-3) may be performed in a non-alcoholic polar solvent. For example, Step (B-3) may be performed in a solvent selected from the group consisting of dichloromethane (DCM), chloroform, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and acetonitrile. However, the present invention is not limited thereto.

[0139] According to an embodiment of the present invention, Step (B-3) may be performed in a continuous flow process.

[0140] Step (B-4)

[0141] Step (B-4) of the present invention is a step of preparing the compound represented by Chemical Formula B5 by hydrogenating the compound represented by Chemical Formula B4. Specifically, Step (B-4) may be performed by adding hydrogen to the reaction in the presence of a metal catalyst.

[0142] The metal catalyst may be at least one selected from the group consisting of Raney-Ni, Pd(OAc)2, Pd / C, Pt / C, PdO, and Fe powder. However, the present invention is not limited thereto.

[0143] Further, Step (B-4) may be performed at about 40℃ to about 80℃. Specifically, Step (B-4) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 40℃, about 45℃, about 50℃, about 55℃, about 60℃, about 65℃, about 70℃, about 75℃, and about 80℃.

[0144] In addition, Step (B-4) may be performed in an alcoholic solvent. For example, Step (B-4) may be performed in a solvent selected from the group consisting of methanol, ethanol, isopropanol, and butanol. However, the present invention is not limited thereto.

[0145] According to an embodiment of the present invention, Step (B-4) may be performed in a continuous flow process. Specifically, Step (B-4) may be performed by reacting the compound represented by Chemical Formula B4, which is a reactant of Step (B-4), with hydrogen gas, via a continuous flow process.

[0146] According to an embodiment of the present invention, fluids containing the reactants in Step (B-4) above may be supplied to different pumps, respectively, and mixed in a T-shaped connector, followed by performing the reaction while passing through a column filled with a metal catalyst. More specifically, Step (B-4) may comprise reacting a fluid b1 containing the compound represented by Chemical Formula B4; and a fluid b2 containing the hydrogen.

[0147] According to an embodiment of the present invention, a flow velocity ratio of the fluid b1 and the fluid b2 may be from about 1 : 2 to about 1 : 8.

[0148] The reaction may be performed under conditions where the internal pressure of the pump transporting the fluid is between about 2 bar and about 10 bar. Specifically, the internal pressure of the pump may be in a range of one lower limit and one upper limit selected from the group consisting of about 2 bar, about 3 bar, about 4 bar, about 5 bar, about 6 bar, about 7 bar, about 8 bar, about 9 bar, and about 10 bar.

[0149] Step (B-5)

[0150] Step (B-5) of the present invention is a step of preparing the compound represented by Chemical Formula B6 by subjecting the compound represented by Chemical Formula B5 to an amide coupling reaction.

[0151] Specifically, Step (B-5) may be performed by reacting the compound represented by Chemical Formula B5 with dimethyl amine.

[0152] More specifically, Step (B-5) may be performed by first reacting the compound represented by Chemical Formula B5 with pivaloyl chloride and then reacting it with dimethyl amine.

[0153] In addition, Step (B-5) may be performed in the presence of a base. The base may be an inorganic base, an amine base, or a heterocyclic base. For example, the base may be sodium hydroxide, calcium hydroxide, sodium bicarbonate, triethylamine, or pyridine. However, the present invention is not limited thereto.

[0154] Further, Step (B-5) may be performed by heating to about 15℃ to about 30℃ after cooling and stirring. Specifically, a temperature during the heating may be room temperature or ambient temperature, and for example, may be raised to a range of one lower limit and one upper limit selected from the group consisting of about 15℃, about 20℃, about 25℃, and about 30℃.

[0155] In addition, Step (B-5) may be performed in a non-alcoholic polar solvent. For example, Step (B-5) may be performed in a solvent selected from the group consisting of dichloromethane (DCM), chloroform, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and acetonitrile. However, the present invention is not limited thereto.

[0156] According to an embodiment of the present invention, Step (B-5) may be performed in a continuous flow process.

[0157] Step (B-6)

[0158] Step (B-6) of the present invention is a step of preparing the compound represented by Chemical Formula Ia from the compound represented by Chemical Formula B6. Specifically, Step (B-6) may be performed by the Sandmeyer reaction.

[0159] More specifically, Step (B-6) may be performed by reacting the compound represented by Chemical Formula B6 with sodium nitrite (NaNO2) in the presence of acid to form an unstable intermediate, a diazonium compound, while simultaneously reacting it with a copper salt. The above copper salt may be Cu2O, Cu(NO3)2·3H2O, CuSO4, or a combination thereof. However, the present invention is not limited thereto.

[0160] Further, Step (B-6) may be performed at about 0℃ to about 70℃. Specifically, Step (B-6) may be performed at a range of one lower limit and one upper limit selected from the group consisting of about 0℃, about 5℃, about 10℃, about 15℃, about 20℃, about 25℃, about 30℃, about 35℃, about 40℃, about 45℃, about 50℃, about 55℃, about 60℃, about 65℃, and about 70℃.

[0161] According to an embodiment of the present invention, Step (B-6) may be performed in a continuous flow process. Specifically, Step (B-6) may be performed by reacting the compound represented by Chemical Formula B6, which is a reactant of Step (B-6), with sodium nitrite and a copper salt, via a continuous flow process.

[0162] According to an embodiment of the present invention, fluids containing the reactants in Step (B-6) above may be supplied to different pumps, respectively, and mixed in a T-shaped connector to perform the reaction. More specifically, Step (B-6) may comprise reacting a fluid b3 containing the compound represented by Chemical Formula B6; and a fluid b4 containing sodium nitrite and a copper salt.

[0163] The preparation method of the present invention may prepare 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide with a few steps and without post-treatment, thereby shortening the process time to provide excellent efficiency and cost-effectiveness.

[0164] In addition, the preparation method of the present invention may reduce the amount of reagents or solvents, making it environmentally friendly, and also may be performed in a small space and safely as all processes are system-controlled.

[0165] Furthermore, the 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide prepared by the preparation method of the present invention has excellent yield and purity, and the preparation method of the present invention is highly reproducible.

[0166] In addition, the present invention provides a novel intermediate capable of being used in preparing 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan. Specifically, the novel intermediate is a compound represented by the following Chemical Formula B4 or a salt thereof:

[0167] [Chemical Formula B4]

[0168] .

[0169] The novel intermediate of the present invention enables the preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide, a key intermediate of tegoprazan, by a novel synthesis pathway. The above synthesis pathway is a very simple process that can significantly reduce process time, resulting in overall excellent efficiency and cost-effectiveness. Thus, the novel intermediate of the present invention may be usefully employed as a key intermediate in the preparation method of the present invention capable of being usefully applied to industrial scale production.

[0170] In addition, the present invention provides a preparation method for 4-acetamido-3,5-dinitrobenzoic acid, a novel intermediate used in the preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide.

[0171] Specifically, the preparation method comprises the following Steps (B-1) to (B-3):

[0172] (B-1) preparing a compound represented by the following Chemical Formula B2 from a compound represented by the following Chemical Formula B1;

[0173] (B-2) preparing a compound represented by the following Chemical Formula B3 from the compound represented by Chemical Formula B2; and

[0174] (B-3) preparing a compound represented by the following Chemical Formula B4 from the compound represented by Chemical Formula B3:

[0175] [Chemical Formula B1]

[0176]

[0177] [Chemical Formula B2]

[0178]

[0179] [Chemical Formula B3]

[0180]

[0181] [Chemical Formula B4]

[0182] .

[0183] The description of Steps (B-1) to (B-3) above is as provided above.

[0184] The preparation method of the present invention may utilize a novel intermediate to prepare 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide with a few steps and without post-treatment, thereby shortening the process time to provide excellent efficiency and cost-effectiveness. In addition, the preparation method of the present invention may reduce the amount of reagents or solvents, making it environmentally friendly, and also may be performed in a small space and safely as all processes are system-controlled. Furthermore, the 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide prepared by the preparation method of the present invention has excellent yield and purity, and the preparation method of the present invention is highly reproducible. Thus, the preparation method of the present invention may be usefully applied to the industrial scale production of tegoprazan (in particular, its key intermediate 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide).

[0185] FIG. 1 is a schematic diagram of Step A-3 of Example 1 according to the present invention.

[0186] FIG. 2 is a schematic diagram of Step A-4 of Example 1 according to the present invention.

[0187] FIG. 3 is a schematic diagram of Step A-5 of Example 1 according to the present invention.

[0188] FIG. 4 is a schematic diagram of Step B-4 of Example 2 according to the present invention.

[0189] FIG. 5 is a schematic diagram of Step B-6 of Example 2 according to the present invention.

[0190] Hereinafter, the present invention will be described in more detail through Examples. However, the following Examples are only provided to illustrate the present invention, and the scope of the present invention is not limited thereto.

[0191] Example 1. Synthesis of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (Preparation method A)

[0192]

[0193] Step A-1: Synthesis of 4-acetamidobenzoic acid (Chemical Formula A2)

[0194] Acetic acid (50 mL) and acetic anhydride (50 mL) were added to a 500 mL round-bottom flask, and an ice bath was set up. 4-Aminobenzoic acid (Chemical Formula A1, 20 g) was added and heated to room temperature and the reaction solution was stirred at reflux at 120 to 140℃ for 15 minutes. The reaction product was cooled to room temperature and then added to ice water (250 mL) under stirring. The reaction product was filtered and washed with water (700 mL). The filtered solid was dried in a 40℃ oven for 24 hours to obtain the title compound (20.8 g, 80% yield).

[0195] 1H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 9.83 (s, 1H), 8.01 - 7.94 (m, 2H), 7.86 - 7.79 (m, 2H), 2.14 (s, 3H).

[0196] 13C NMR (100 MHz, DMSO-d6) δ 169.14, 167.83, 140.63, 131.33, 125.57, 119.74, 24.07.

[0197] MS (ESI) m / z: 180.07 (M+H)+.

[0198] Step A-2: Synthesis of 4-acetamido-N,N-dimethylbenzamide (Chemical Formula A3)

[0199] To a 250 mL round-bottom flask, DCM (100 mL) was added and the 4-acetamidobenzoic acid (10 g) prepared in Step A-1 was added, followed by the addition of triethylamine (10 mL). The reaction solution was cooled to below 5℃, and then pivaloyl chloride (8.8 mL) was added dropwise. A 50% solution of dimethylamine (17 mL) was added to another 500 mL round-bottom flask, and cooled to below 5℃, and the previously prepared reaction solution was added dropwise. After the addition was completed, the reaction solution was cooled and stirred for 30 minutes, and then heated to room temperature and stirred for 30 minutes. After the reaction was completed, water (200 mL) was added to extract the organic layer, followed by washing twice with water (100 mL). The organic layer was then concentrated under reduced pressure at 40℃. The obtained concentrate was crystallized with ethyl acetate (EA) to obtain the title compound (8.7 g, yield 76%).

[0200] 1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 7.79 - 7.68 (m, 5H), 2.98 (s, 6H), 2.17 (s, 3H).

[0201] 13C NMR (100 MHz, CDCl3) δ 170.18, 169.31, 139.21, 133.14, 129.08, 119.79, 36.80, 24.11.

[0202] MS (ESI) m / z: 207.11 (M+H)+.

[0203] Step A-3: Synthesis of 4-acetamido-N,N-dimethyl-3,5-dinitrobenzamide (Chemical Formula A4)

[0204] The 4-acetamido-N,N-dimethylbenzamide (10 g) prepared in Step A-2 was dissolved in THF (20 mL) and connected to pump A. 60% nitric acid was connected to pump B. Pump A transported the solution at a flow rate of 0.6 mL / min, and pump B transported the solution at a flow rate of 0.2 mL / min. A T-shaped connector was connected and the mixing point was heated to 55℃. The transported reaction product was poured into water, and then DCM (30 mL) was added to extract the organic layer. The organic layer was washed twice with ice water (100 mL). The organic layer was concentrated under reduced pressure at 40℃ to obtain the title compound (12.5 g, yield 87%).

[0205] 1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.47 (s, 2H), 3.01 (s, 6H), 2.24 (s, 3H).

[0206] 13C NMR (100 MHz, CDCl3) δ 169.71, 169.11, 138.26, 133.75, 129.01, 128.60, 36.24, 23.50.

[0207] MS (ESI) m / z: 297.08 (M+H)+.

[0208] Step A-4: Synthesis of 4-amino-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (Chemical Formula A5)

[0209] A Raney-Ni catalyst was loaded into a catalyst column with a diameter of 1 cm and a length of 5 cm. The 4-acetamido-N,N-dimethyl-3,5-dinitrobenzamide (5 g) prepared in Step A-3 was dissolved in methanol (100 mL) and connected to a pump. A T-shaped connector was attached to the top of the column to connect both hydrogen gas and the compound solution prepared in Step A-3. Hydrogen gas was transported at a flow rate of 3 mL / min and the compound solution was transported at a flow rate of 0.5 mL / min, while the internal pressure was maintained at 3 bar. The pump was operated, and after 8 minutes, the liquid was collected from the gas-liquid separator. The liquid was transferred to a flask and heated while stirring. After reacting for 2 hours, the reaction product was concentrated under reduced pressure at 40℃ to obtain the title compound (3.3 g, yield 90%).

[0210] 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 7.60 (d,J= 1.6 Hz, 1H), 7.17 (d,J= 1.4 Hz, 1H), 5.83 (d,J= 8.1 Hz, 1H), 5.66 (d,J= 8.1 Hz, 1H), 3.01 (s, 6H), 2.33 (s, 3H).

[0211] 13C NMR (100 MHz, CDCl3) δ 170.55, 149.24, 138.11, 136.28, 135.53, 134.82, 110.64, 105.53, 36.44, 14.14.

[0212] MS (ESI) m / z: 219.12 (M+H)+.

[0213] Step A-5: Synthesis of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (Chemical Formula Ia)

[0214] The 4-amino-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (5 g) prepared in Step A-4 was dissolved in sulfuric acid (10 mL) and connected to pump A. Sodium nitrite (1.9 g) was dissolved in water (20 mL), and Cu(NO3)2·3H2O (6.5 g) and Cu2O (3 g) were added and connected to pump B. A T-shaped connector was connected to transport the solution at a flow rate of 0.5 mL / min. The liquid was collected in a flask, and DCM (50 mL) was added to extract the organic layer. The organic layer was washed twice with water (50 mL). The organic layer was concentrated under reduced pressure at 40℃ to obtain the title compound (4.7 g, yield 95%).

[0215] 1H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 9.31 (s, 1H), 7.69 (d,J= 1.6 Hz, 1H), 7.27 (d,J= 1.4 Hz, 1H), 3.01 (s, 6H), 2.34 (s, 3H).

[0216] 13C NMR (100 MHz, CDCl3) δ 170.65, 150.45, 149.07, 139.65, 134.36, 134.04, 108.51, 106.06, 36.44, 14.14.

[0217] MS (ESI) m / z: 220.11 (M+H)+.

[0218] Example 2. Synthesis of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (Preparation method B)

[0219]

[0220] Step B-1: Synthesis of 4-chloro-3,5-dinitrobenzoic acid (Chemical Formula B2)

[0221] To a 1000 mL round-bottom flask, sulfuric acid (200 mL) was added, and 4-chlorobenzoic acid (Chemical Formula B1, 20 g) was added and dissolved. Potassium nitrate (32.3 g) was added in small portions, and the reaction temperature was kept below 40℃ when added. After the addition was completed, the reaction solution was stirred at 135℃ for 3 hours. The reaction solution was cooled to room temperature and then added to ice water (250 mL) under stirring. The reaction product was filtered and washed with water (100 mL). The filtered solid was dried in a 40℃ oven for 24 hours to obtain the title compound (28 g, 89% yield).

[0222] 1H NMR (400 MHz, DMSO-d6) δ 13.17 (s, 0H), 8.66 (s, 1H).

[0223] 13C NMR (100 MHz, DMSO-d6) δ 166.65, 147.89, 129.92, 128.53, 126.61.

[0224] MS (ESI) m / z: 246.98 (M+H)+.

[0225] Step B-2: Synthesis of 4-amino-3,5-dinitrobenzoic acid (Chemical Formula B3)

[0226] To a 500 mL round-bottom flask, methanol (50 mL) was added, and the 4-chloro-3,5-dinitrobenzoic acid (10 g) prepared in Step B-1 was added and dissolved. 25% ammonia water (60 mL) was added dropwise, and the reaction solution was stirred under reflux for 1 hour and cooled to room temperature. The reaction solution was concentrated, and water (500 mL) was added to the residue and stirred. The reaction solution was adjusted to pH 7 with 2M HCl solution and then filtered. The filtered solid was dried in a 40℃ oven for 24 hours to obtain the title compound (8 g, 87% yield).

[0227] 1H NMR (400 MHz, Acetone-d6) δ 13.11 (s, 3H), 8.60 (s, 6H), 7.03 (d,J= 8.0 Hz, 4H), 6.88 (d,J= 8.1 Hz, 4H).

[0228] 13C NMR (100 MHz, Acetone-d6) δ 167.17, 144.38, 135.05, 128.88, 118.97.

[0229] MS (ESI) m / z: 228.03 (M+H)+.

[0230] Step B-3: Synthesis of 4-acetamido-3,5-dinitrobenzoic acid (Chemical Formula B4)

[0231] The 4-amino-3,5-dinitrobenzoic acid (5 g) prepared in Step B-2 was added to acetic anhydride (31 mL). Sulfuric acid (0.1 mL) was added to the reaction solution. The reaction solution was stirred under reflux for 15 minutes. The reaction temperature was lowered to room temperature, and the reaction product was filtered and washed with diethyl ether. The filtrate was poured into ice water and stirred, and the obtained solid was filtered. The filtered solid was dried in a 40℃ oven for 24 hours to obtain the title compound (5.3 g, 89% yield).

[0232] 1H NMR (400 MHz, DMSO-d6) δ 13.28 (s, 1H), 10.25 (s, 1H), 8.63 (s, 2H), 2.18 (s, 3H).

[0233] 13C NMR (100 MHz, DMSO-d6) δ 169.25, 167.06, 139.44, 136.68, 128.67, 122.37, 23.39.

[0234] MS (ESI) m / z: 270.04 (M+H)+.

[0235] Step B-4: Synthesis of 4-amino-2-methyl-1H-benzo[d]imidazole-6-carboxylic acid (Chemical Formula B5)

[0236] A Raney-Ni catalyst was loaded into a catalyst column with a diameter of 1 cm and a length of 5 cm. The 4-acetamido-3,5-dinitrobenzoic acid (5 g) prepared in Step B-3 was dissolved in methanol (100 mL) and connected to a pump. A T-shaped connector was connected to the top of the column to connect both hydrogen gas and the compound solution prepared in Step B-3. Hydrogen gas was transported at a flow rate of 3 mL / min and the compound solution at a flow rate of 0.5 mL / min, while the internal pressure was maintained at 3 bar. The pump was operated, and after 8 minutes, the liquid was collected from the gas-liquid separator. The liquid was transferred to a flask and heated while stirring. After reacting for 2 hours, the reaction product was concentrated under reduced pressure at 40℃ to obtain the title compound (3.2 g, yield 90%).

[0237] 1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 10.49 (s, 1H), 7.57 (dd,J= 12.1, 1.5 Hz, 3H), 5.88 (s, 2H), 2.33 (s, 3H).

[0238] 13C NMR (100 MHz, DMSO-d6) δ 168.00, 149.51, 138.01, 136.26, 133.61, 129.79, 110.67, 105.14, 14.14.

[0239] MS (ESI) m / z: 192.08 (M+H)+.

[0240] Step B-5: Synthesis of 4-amino-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (Chemical Formula B6)

[0241] To a 100 mL round-bottom flask, DCM (30 mL) was added and the 4-amino-2-methyl-1H-benzo[d]imidazole-6-carboxylic acid (3 g) prepared in Step B-4 was added, and then triethylamine (2.8 mL) was added. The reaction solution was cooled to below 5℃, and pivaloyl chloride (2.5 mL) was added dropwise. A 50% solution of dimethylamine (5.2 mL) was added to another 100 mL round-bottom flask, and cooled to below 5℃, and the previously prepared reaction solution was added dropwise. After the addition was completed, the reaction solution was cooled and stirred for 30 minutes, and then heated to room temperature and stirred for 30 minutes. After the reaction was completed, water (30 mL) was added to extract the organic layer, followed by washing twice with water (30 mL). The organic layer was then concentrated under reduced pressure at 40℃. The obtained concentrate was crystallized with ethyl acetate (EA) to obtain the title compound (2.7 g, yield 80%).

[0242] 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 7.59 (d,J= 1.6 Hz, 1H), 7.42 (d,J= 1.6 Hz, 1H), 5.97 (s, 2H), 2.99 (s, 6H), 2.34 (s, 3H).

[0243] 13C NMR (100 MHz, DMSO-d6) δ 170.82, 149.65, 138.12, 136.10, 135.23, 135.07, 110.09, 105.51, 36.49, 14.15.

[0244] MS (ESI) m / z: 219.12 (M+H)+.

[0245] Step B-6: Synthesis of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (Chemical Formula Ia)

[0246] The 4-amino-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (2 g) prepared in Step B-5 was dissolved in sulfuric acid (4 mL) and connected to pump A. Sodium nitrite (0.76 g) was dissolved in water (8 mL), and Cu(NO3)2·3H2O (2.6 g) and Cu2O (1.2 g) were added and connected to pump B. A T-shaped connector was connected to transport the solution at a flow rate of 0.5 mL / min. The liquid was collected in a flask, and DCM (20 mL) was added to extract the organic layer. The organic layer was washed twice with water (20 mL). The organic layer was concentrated under reduced pressure at 40℃ to obtain the title compound (1.9 g, yield 95%).

[0247] 1H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 9.31 (s, 1H), 7.69 (d,J= 1.6 Hz, 1H), 7.27 (d,J= 1.4 Hz, 1H), 3.01 (s, 6H), 2.34 (s, 3H).

[0248] 13C NMR (100 MHz, CDCl3) δ 170.65, 150.45, 149.07, 139.65, 134.36, 134.04, 108.51, 106.06, 36.44, 14.14.

[0249] MS (ESI) m / z: 220.11 (M+H)+.

[0250] As described above, the present invention has been described in detail through preferred Examples, but the scope of the present invention is not limited to the specific Examples and should be interpreted by the claims. Further, those skilled in the art should understand that many modifications and variations can be made without departing from the scope of the present invention.

Claims

1.A preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide comprising:(A-1) preparing a compound represented by the following Chemical Formula A2 from a compound represented by the following Chemical Formula A1;(A-2) preparing a compound represented by the following Chemical Formula A3 from the compound represented by Chemical Formula A2;(A-3) preparing a compound represented by the following Chemical Formula A4 from the compound represented by Chemical Formula A3;(A-4) preparing a compound represented by the following Chemical Formula A5 from the compound represented by Chemical Formula A4; and(A-5) preparing a compound represented by the following Chemical Formula Ia from the compound represented by Chemical Formula A5:[Chemical Formula A1][Chemical Formula A2][Chemical Formula A3][Chemical Formula A4][Chemical Formula A5][Chemical Formula Ia].2.The preparation method of claim 1, wherein Step (A-3) comprises reacting with nitric acid or nitrate.3.The preparation method of claim 2, wherein Step (A-3) is performed in a continuous flow process.4.The preparation method of claim 3, wherein Step (A-3) comprises reacting a fluid a1 and a fluid a2:the fluid a1 containing the compound represented by Chemical Formula A3; andthe fluid a2 containing the nitric acid or nitrate.5.The preparation method of claim 4, wherein a flow velocity ratio of the fluid a1 and the fluid a2 is from 2 : 1 to 4 : 1.6.The preparation method of claim 1, wherein Step (A-4) is performed by adding hydrogen in the presence of a metal catalyst.7.The preparation method of claim 6, wherein Step (A-4) is performed under conditions where the internal pressure is between 2 and 10 bar.8.The preparation method of claim 6, wherein Step (A-4) is performed in a continuous flow process.9.The preparation method of claim 8, wherein Step (A-4) comprises reacting a fluid a3 and a fluid a4:the fluid a3 containing the compound represented by Chemical Formula A4; andthe fluid a4 containing the hydrogen.10.The preparation method of claim 9, wherein a flow velocity ratio of the fluid a3 and the fluid a4 is from 1 : 4 to 1 : 8.11.The preparation method of claim 1, wherein Step (A-5) is performed by the Sandmeyer reaction.12.The preparation method of claim 11, wherein Step (A-5) is performed in a continuous flow process.13.The preparation method of claim 12, wherein Step (A-5) comprises reacting a fluid a5 and a fluid a6:the fluid a5 containing the compound represented by Chemical Formula A5; andthe fluid a6 containing sodium nitrite and a copper salt.14.A preparation method for 4-acetamido-N,N-dimethyl-3,5-dinitrobenzamide comprising:(A-1) preparing a compound represented by the following Chemical Formula A2 from a compound represented by the following Chemical Formula A1;(A-2) preparing a compound represented by the following Chemical Formula A3 from the compound represented by Chemical Formula A2; and(A-3) preparing a compound represented by the following Chemical Formula A4 from the compound represented by Chemical Formula A3:[Chemical Formula A1][Chemical Formula A2][Chemical Formula A3][Chemical Formula A4].15.A compound represented by the following Chemical Formula A4 or a salt thereof:[Chemical Formula A4].16.The compound or the salt thereof of claim 15, wherein the compound or the salt thereof is used in the preparation of tegoprazan represented by the following Chemical Formula I:[Chemical Formula I].17.The compound or the salt thereof of claim 15, wherein the compound or the salt thereof is used in the preparation of a tegoprazan intermediate represented by the following Chemical Formula Ia:[Chemical Formula Ia].18.The compound or the salt thereof of claim 15, wherein the compound or the salt thereof is prepared by the preparation method of claim 14.19.A preparation method for 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide comprising:(B-1) preparing a compound represented by the following Chemical Formula B2 from a compound represented by the following Chemical Formula B1;(B-2) preparing a compound represented by the following Chemical Formula B3 from the compound represented by Chemical Formula B2;(B-3) preparing a compound represented by the following Chemical Formula B4 from the compound represented by Chemical Formula B3;(B-4) preparing a compound represented by the following Chemical Formula B5 from the compound represented by Chemical Formula B4;(B-5) preparing a compound represented by the following Chemical Formula B6 from the compound represented by Chemical Formula B5; and(B-6) preparing a compound represented by the following Chemical Formula Ia from the compound represented by Chemical Formula B6:[Chemical Formula B1][Chemical Formula B2][Chemical Formula B3][Chemical Formula B4][Chemical Formula B5][Chemical Formula B6][Chemical Formula Ia].20.The preparation method of claim 19, wherein Step (B-1) comprises reacting with nitric acid or nitrate.21.The preparation method of claim 20, wherein Step (B-1) is performed in a continuous flow process.22.The preparation method of claim 19, wherein Step (B-2) comprises reacting with ammonia.23.The preparation method of claim 19, wherein Step (B-3) comprises reacting with acetic anhydride or acetyl halide.24.The preparation method of claim 19, wherein Step (B-4) is performed by adding hydrogen under a metal catalyst.25.The preparation method of claim 24, wherein Step (B-4) is performed under conditions where the internal pressure is between 2 and 10 bar.26.The preparation method of claim 24, wherein Step (B-4) is performed in a continuous flow process.27.The preparation method of claim 26, wherein Step (B-4) comprises reacting a fluid b1 and a fluid b2:the fluid b1 containing the compound represented by Chemical Formula B4; andthe fluid b2 containing the hydrogen.28.The preparation method of claim 27, wherein a flow velocity ratio of the fluid b1 and the fluid b2 is from 1 : 2 to 1 : 8.29.The preparation method of claim 19, wherein Step (B-5) comprises reacting with dimethylamine.30.The preparation method of claim 19, wherein Step (B-6) is performed by the Sandmeyer reaction.31.The preparation method of claim 30, wherein Step (B-6) is performed in a continuous flow process.32.The preparation method of claim 31, wherein Step (B-6) comprises reacting a fluid b3 and a fluid b4:the fluid b3 containing the compound represented by Chemical Formula B6; andthe fluid b4 containing sodium nitrite and a copper salt.33.A preparation method for 4-acetamido-3,5-dinitrobenzoic acid comprising:(B-1) preparing a compound represented by the following Chemical Formula B2 from a compound represented by the following Chemical Formula B1;(B-2) preparing a compound represented by the following Chemical Formula B3 from the compound represented by Chemical Formula B2; and(B-3) preparing a compound represented by the following Chemical Formula B4 from the compound represented by Chemical Formula B3:[Chemical Formula B1][Chemical Formula B2][Chemical Formula B3][Chemical Formula B4].

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