Process for preparing benzimidazole derivatives

Abstract

The present invention relates to a process for the preparation of benzimidazole derivatives and to compounds prepared by said process.

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of benzimidazole derivatives and to compounds prepared by said process. [Background technology]

[0002] Benzimidazole is known as a very important pharmacophore in the fields of medicine and chemistry. This compound has a chemical structure in which a benzene ring and an imidazole ring are fused together, and it has been found to have many pharmaceutical properties. In the 1990s, many benzimidazole derivatives with substituents such as fluoro and propylene were synthesized, and they were shown to have stability, bioavailability, and biological activity.

[0003] For example, among benzimidazole derivatives, oxidazole-1H-benzimidazole is known to have antibacterial activity and has been reported to have inhibitory activity against fungi, while tetrahydro-imidazole[4,5,1-jk][1,4]-benzodiazepine-2(1H)-one and N-alkoxy-2-alkyl-benzimidazole are also being developed as HIV inhibitors. In addition, benzimidazole derivatives with sulfoxide or methylene groups are known to inhibit gastric acid secretion by inhibiting the proton pump and to have a gastric mucosa protective function. In addition, benzimidazole derivatives are known to have antiviral and antihypertensive effects.

[0004] Benzimidazole derivatives are also very useful in the textile industry, and are known to be used primarily as dye dispersants and fabric softeners.

[0005] As mentioned above, benzimidazole is a pharmacophore with extremely high applicability in the fields of medicine and chemistry, and its synthetic methods have been developed by many researchers and proposed through various literature.

[0006] International Patent Publication WO2004 / 054984 describes a preparation method using 2-amino-3-nitrophenol. However, the preparation method described in this patent uses expensive intermediates and reagents in the amidation reaction, and also uses a metal catalyst that is difficult to remove, making purification difficult. Therefore, the preparation cost is high, and silica gel is used to separate some intermediates, so it is not suitable for general mass synthesis processes. In addition, there is a drawback in that the use of a metal catalyst that may cause fire or explosion means that it can only be produced in special equipment.

[0007] Furthermore, International Patent Publication WO2007 / 072146 describes a method of using carbon monoxide in the step of introducing a carbonyl group for the amidation reaction. However, this reaction requires a separate reaction apparatus and involves a risk factor due to exposure to carbon monoxide gas during the process. In addition, the preparation cost is high due to the use of expensive reagents, and silica gel is used to separate some intermediates, making it unsuitable for general mass synthesis processes.

[0008] The present inventors have therefore confirmed a method for industrially mass-producing benzimidazole, which is known as an extremely important pharmacophore in the fields of medicine and chemistry, in high yields while using commercially available reagents and solvents at low preparation costs, thereby completing the present invention. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Patent Publication WO2004 / 054984 [Patent Document 2] International Patent Publication WO2007 / 072146 Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention can provide a method for preparing a benzimidazole derivative.

[0011] The present invention can provide a compound prepared by the above-mentioned preparation method. [Means for solving the problem]

[0012] This will be described in detail below. Each description and embodiment disclosed in the present invention may be applied to other descriptions and embodiments. In other words, all combinations of various elements disclosed in the present invention are included in the scope of the present invention. In addition, the scope of the present invention is not limited to the specific description described below.

[0013] The present invention may provide a method for preparing a benzimidazole derivative, the method comprising: 1) a step of reacting a compound represented by the following formula 3 with a monovalent copper catalyst in the presence of a ligand represented by the following formula 4 or a stereoisomer thereof to prepare a compound represented by the following formula 2: 2) reacting a compound represented by the following formula 2 to prepare a compound represented by the following formula 5; and 3) reacting a compound represented by the following formula 5 with acetyl chloride and a compound represented by the following formula 6 in the presence of a base to prepare a compound represented by the following formula 1: [Formula 1] JPEG2025500545000001.jpg48160[Formula 2] JPEG2025500545000002.jpg34160[Formula 3] JPEG2025500545000003.jpg35160[Formula 4] JPEG2025500545000004.jpg23161[Formula 5] JPEG2025500545000005.jpg35160[Formula 6] JPEG2025500545000006.jpg19160, where R1 is C 1-4 alkyl or phenyl, in which case, 1-4At least one H of alkyl and phenyl is halogen or C 1-4 may be substituted with alkyl; R2 is H, C 1-4 alkyl, or acetyl, in which at least one H of the acetyl may be replaced by halogen; R3 and R4 are each independently H, C 1-4 Alkyl and C 3-7 cycloalkyl, or may be taken together to form a 3- to 7-membered alicyclic ring, in which case C 1-4 Alkyl, C 3-7 At least one H in the cycloalkyl and the 3- to 7-membered alicyclic ring formed may be substituted with halogen; and R5 is H, C 1-4 may be alkyl or acetyl; Includes.

[0014] The process for the preparation of benzimidazole derivatives further comprises: 4) adjusting the pH of the compound represented by the above formula 1 to prepare a compound represented by the following formula 1-1: [Formula 1-1] JPEG2025500545000007.jpg39161, where R1 may be the same as in formula 1 above. may include:

[0015] In one embodiment, R1 may be methyl, trifluoromethyl, or tolyl.

[0016] The present invention may provide a method for preparing a benzimidazole derivative, the method comprising: 1) a step of reacting a compound represented by the following formula 3 with a monovalent copper catalyst in the presence of a ligand represented by the following formula 4 or a stereoisomer thereof to prepare a compound represented by the following formula 2: 2) reacting a compound represented by the following formula 2 to prepare a compound represented by the following formula 5: 3) reacting a compound represented by the following formula 5 with acetyl chloride and a compound represented by the following formula 6 in the presence of a base to prepare a compound represented by the following formula 1; and 4) adjusting the pH of a compound represented by the following formula 1 to prepare a compound represented by the following formula 1-1: [Formula 1-1] JPEG2025500545000008.jpg39161[Formula 1] JPEG2025500545000009.jpg48160[Formula 2] JPEG2025500545000010.jpg34160[Formula 3] JPEG2025500545000011.jpg35160[Formula 4] JPEG2025500545000012.jpg23161[Formula 5] JPEG2025500545000013.jpg35160[Formula 6] JPEG2025500545000014.jpg19160, where R1 is C 1-4 alkyl or phenyl, in which case, 1-4 At least one H of alkyl and phenyl is halogen or C 1-4 may be substituted with alkyl; R2 is H, C 1-4 alkyl, or acetyl, in which at least one H of the acetyl may be replaced by halogen; R3 and R4 are each independently H, C 1-4 Alkyl, and C 3-7 cycloalkyl, or may be taken together to form a 3- to 7-membered alicyclic ring, in which case C 1-4 Alkyl, C 3-7 At least one H in the cycloalkyl and the 3- to 7-membered alicyclic ring formed may be substituted with halogen; and R5 is H, C 1-4 may be alkyl or acetyl; Includes.

[0017] In one embodiment, in the above formula: R1 is C 1-4 alkyl or phenyl, in which case, 1-4 At least one H of the alkyl may be substituted with halogen, and at least one H of the phenyl is C 1-4 may be substituted with alkyl; R2 may be H or acetyl, in which case at least one H of the acetyl may be substituted with halogen; R3 and R4 are C 1-4 may be alkyl or may be taken together to form a 3- to 7-membered alicyclic ring; and R5 is H or C 1-4 It may be alkyl.

[0018] In one embodiment, in the above formula: R1 is C 1-4 alkyl or phenyl, in which case, 1-4 At least one H of the alkyl may be substituted with fluoro (F), and at least one H of the phenyl may be substituted with methyl; R2 may be H or acetyl, in which case at least one H of the acetyl may be replaced with fluoro (F); R3 and R4 are C 1-4 may be alkyl or may be taken together to form a 3- to 7-membered alicyclic ring; and R5 is H or C 1-4 It may be alkyl.

[0019] In one embodiment, in the above formula: R1 may be methyl, trifluoromethyl, or tolyl; R2 may be H, acetyl, or trifluoroacetyl; R3 and R4 may be methyl or may join together to form a 6-membered alicyclic ring; and R5 may be H or methyl.

[0020] In the present invention, the compound represented by the above formula 4 may contain one or more stereocenters and may therefore exist as a racemate, a single enantiomer, a mixture of diastereomers or a mixture of single diastereomers.

[0021] The method for preparing the benzimidazole derivative of the present invention may include: 1) reacting a compound represented by the above formula 3 with a monovalent copper catalyst in the presence of a ligand represented by formula 4 or a stereoisomer thereof to prepare a compound represented by the above formula 2.

[0022] The monovalent copper catalyst in 1) above may be one selected from the group consisting of cuprous chloride, copper bromide, copper iodide, and cuprous oxide, and may in particular be copper bromide, but is not limited thereto.

[0023] In the above 1), the molar ratio of the compound represented by the above formula 3, the monovalent copper catalyst, and the ligand represented by the above formula 4 or its stereoisomer may be, but is not limited to, 10:2:4 to 10:0.5:0.5.

[0024] The above 1) may be carried out in at least one solvent selected from the group consisting of water, acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, and 1,4-dioxane, and may be particularly carried out in water and dimethylsulfoxide, but is not limited thereto.

[0025] The above 1) may be carried out by adjusting the temperature to between 37° C. and 60° C. and stirring for 10 to 60 minutes, but is not limited thereto.

[0026] The method for preparing the benzimidazole derivative according to the present invention may include: 2) reacting a compound represented by the above formula 2 to prepare a compound represented by the above formula 5.

[0027] The above 2) may be to prepare a compound represented by the above formula 5 by subjecting a compound represented by the above formula 2 to a reductive cyclization reaction.

[0028] The reductive cyclization in 2) above may be carried out by adding a reducing agent, or a reducing agent and an acetyl source.

[0029] The reductive cyclization in 2) above may include nitro reduction using a reducing agent, or nitro reduction using a reducing agent and cyclization with an acetyl source.

[0030] In the above 2), the reducing agent may be at least one selected from the group consisting of H2 / 10% palladium on carbon, reduced iron, and sodium dithionate, but is not limited thereto.

[0031] In the above 2), the acetyl source may be at least one selected from the group consisting of triethyl orthoacetate and acetylacetone, but is not limited thereto.

[0032] The above 2) may be carried out by reacting the compound represented by the above formula 2 with H2 / 10% palladium carbon and triethyl orthoacetate, or by reacting reduced iron and triethyl orthoacetate, or sodium dithionate, but is not limited thereto.

[0033] The method for preparing a benzimidazole derivative according to the present invention may include: 3) preparing a compound represented by the above formula 1 by reacting a compound represented by the above formula 5, acetyl chloride, and a compound represented by the above formula 6 in the presence of a base.

[0034] The base 3) above may be at least one selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, aqueous ammonia, and pyridine, and may be particularly potassium carbonate and pyridine, but is not limited thereto.

[0035] In the above 3), the molar ratio of the compound represented by the above formula 5 to the compound represented by the above formula 6 may be, but is not limited to, 1:1 to 1:2.5.

[0036] In the above 3), the molar ratio of the acetyl chloride to the base may be, but is not limited to, 1:2 to 1:4.

[0037] In the above 3), the molar ratio of the compound represented by the above formula 5 to the acetyl chloride may be, but is not limited to, 1:1 to 1:1.5.

[0038] In the above 3), the molar ratio of the compound represented by the above formula 6 to the base may be, but is not limited to, 1:1 to 1:4.

[0039] The above step 3) may be carried out in at least one solvent selected from the group consisting of acetone, methyl ethyl ketone, ethyl acetate, methylene chloride, chloroform, and acetonitrile, and may be carried out in methylene chloride, but is not limited thereto.

[0040] The above 3) is a) adding the compound represented by formula 5 and acetyl chloride to a solvent; and b) adding a compound represented by the above formula 6 in the presence of a base.

[0041] The compound represented by the above formula 5 may be added in an amount of 5% (w / v) to 33% (w / v) relative to the solvent, but is not limited thereto.

[0042] The above step a) may be carried out by adjusting the temperature to between 3° C. and 40° C. and stirring for 30 to 120 minutes, but is not limited thereto.

[0043] The above b) may be carried out by adjusting the temperature to between 27° C. and 40° C. and stirring for 10 to 180 minutes, but is not limited thereto.

[0044] The method for preparing a benzimidazole derivative according to the present invention may include the step of: 4) adjusting the pH of the compound represented by the above formula 1 to prepare a compound represented by the above formula 1-1.

[0045] The above 4) may be, but is not limited to, adjusting the pH to between 8 and 12.

[0046] The above 4) may be carried out by adjusting the temperature to between 3°C and 10°C, but is not limited thereto.

[0047] The method for preparing the benzimidazole derivative according to the present invention may involve carrying out the above steps 3) and 4) in situ.

[0048] The present invention relates to a compound represented by the following formula 1: [Formula 1] JPEG2025500545000015.jpg48160, where R1 is C 1-4 alkyl or phenyl, in which case 1-4 At least one H of alkyl and phenyl is halogen or C 1-4 may be substituted with alkyl; can be provided.

[0049] In one embodiment, in the above formula: R1 is C 1-4 alkyl or phenyl, in which case, 1-4 At least one H of the alkyl may be substituted with halogen, and at least one H of the phenyl is C 1-4 may be substituted with alkyl;

[0050] In one embodiment, in the above formula: R1 is C 1-4 alkyl or phenyl, in which case, 1-4At least one H of the alkyl may be substituted with fluoro (F), and at least one H of the phenyl may be substituted with methyl;

[0051] In one embodiment, R1 may be methyl, trifluoromethyl, or tolyl.

[0052] The compound represented by the above formula 1 is Acetic acid 6-(dimethylcarbamoyl)-2-methyl-1-tosyl-1H-benzo[d]imidazol-4-yl; Acetic acid 6-(dimethylcarbamoyl)-2-methyl-1-(trifluoromethyl)sulfonyl)-1H-benzo[d]imidazol-4-yl; and Acetic acid 6-(dimethylcarbamoyl)-2-methyl-1-methylsulfonyl-1H-benzo[d]imidazol-4-yl, may be selected from the group consisting of:

[0053] The present invention can provide the following methods (1) to (28): (1) A process for preparing a benzimidazole derivative, the process comprising: 1) a step of reacting a compound represented by the following formula 3 with a monovalent copper catalyst in the presence of a ligand represented by the following formula 4 or a stereoisomer thereof to prepare a compound represented by the following formula 2: 2) reacting a compound represented by the following formula 2 to prepare a compound represented by the following formula 5; and 3) reacting a compound represented by the following formula 5 with acetyl chloride and a compound represented by the following formula 6 in the presence of a base to prepare a compound represented by the following formula 1: [Formula 1] JPEG2025500545000016.jpg48160[Formula 2] JPEG2025500545000017.jpg34160[Formula 3] JPEG2025500545000018.jpg35160[Formula 4] JPEG2025500545000019.jpg23161[Formula 5] JPEG2025500545000020.jpg35160[Formula 6] JPEG2025500545000021.jpg19160, where R1 is C 1-4 alkyl or phenyl, in which case, 1-4 At least one H of alkyl and phenyl is halogen or C 1-4 may be substituted with alkyl; R2 is H, C 1-4 alkyl, or acetyl, in which at least one H of the acetyl may be replaced by halogen; R3 and R4 are each independently H, C 1-4 Alkyl, and C 3-7 cycloalkyl, or may be taken together to form a 3- to 7-membered alicyclic ring, in which case C 1-4 Alkyl, C 3-7 At least one H in the cycloalkyl and the 3- to 7-membered alicyclic ring formed may be substituted with halogen; and R5 is H, C 1-4 may be alkyl or acetyl; Includes.

[0054] (2) The method of (1) above further comprises: 4) adjusting the pH of the compound represented by the above formula 1 to prepare a compound represented by the following formula 1-1; [Formula 1-1] JPEG2025500545000022.jpg39161, where R1 may be the same as formula 1 above, may include:

[0055] (3) A process for preparing a benzimidazole derivative, the process comprising: 1) a step of reacting a compound represented by the following formula 3 with a monovalent copper catalyst in the presence of a ligand represented by the following formula 4 or a stereoisomer thereof to prepare a compound represented by the following formula 2: 2) reacting a compound represented by the following formula 2 to prepare a compound represented by the following formula 5: 3) reacting a compound represented by the following formula 5 with acetyl chloride and a compound represented by the following formula 6 in the presence of a base to prepare a compound represented by the following formula 1; and 4) adjusting the pH of a compound represented by the following formula 1 to prepare a compound represented by the following formula 1-1: [Formula 1-1] JPEG2025500545000023.jpg39161[Formula 1] JPEG2025500545000024.jpg48160[Formula 2] JPEG2025500545000025.jpg34160[Formula 3] JPEG2025500545000026.jpg35160[Formula 4] JPEG2025500545000027.jpg23161[Formula 5] JPEG2025500545000028.jpg35160[Formula 6] JPEG2025500545000029.jpg19160, where R1 is C 1-4 alkyl or phenyl, in which case, 1-4 At least one H of alkyl and phenyl is halogen or C 1-4 may be substituted with alkyl; R2 is H, C 1-4 alkyl, or acetyl, in which at least one H of the acetyl may be replaced by halogen; R3 and R4 are each independently H, C 1-4 Alkyl, and C 3-7 cycloalkyl, or may be taken together to form a 3- to 7-membered alicyclic ring, in which case C 1-4 Alkyl, C 3-7 At least one H in the cycloalkyl and the 3- to 7-membered alicyclic ring formed may be substituted with halogen; and R5 is H, C 1-4 may be alkyl or acetyl; Includes.

[0056] (4) R1 is C 1-4 alkyl or phenyl, in which case, 1-4 At least one H of the alkyl may be substituted with halogen, and at least one H of the phenyl is C 1-4 may be substituted with alkyl; R2 may be H or acetyl, in which case at least one H of the acetyl may be substituted with halogen; R3 and R4 are C 1-4 may be alkyl or may be taken together to form a 3- to 7-membered alicyclic ring; and R5 is H or C 1-4 The method according to (1), (2), or (3), wherein the alkyl group may be alkyl.

[0057] (5) R1 is C 1-4 alkyl or phenyl, in which case, 1-4 At least one H of the alkyl may be substituted with fluoro (F), and at least one H of the phenyl may be substituted with methyl; R2 may be H or acetyl, in which case at least one H of the acetyl may be replaced with fluoro (F); R3 and R4 are C 1-4 may be alkyl or may be taken together to form a 3- to 7-membered alicyclic ring; and R5 is H or C 1-4 The method according to (1), (2), (3), or (4), wherein the alkyl group is an alkyl group.

[0058] (6) R1 may be methyl, trifluoromethyl, or tolyl; R2 may be H, acetyl, or trifluoroacetyl; R3 and R4 may be methyl or may join together to form a 6-membered alicyclic ring; and The method according to (1), (2), (3), (4), or (5), wherein R5 may be H or methyl.

[0059] (7) The method according to (1), (2), (3), or (4) above, wherein R1 may be methyl, trifluoromethyl, or tolyl.

[0060] (8) The method according to (1), (2), (3), (4), (5), (6), or (7), wherein the monovalent copper catalyst of 1) above may be one selected from the group consisting of cuprous chloride, copper bromide, copper iodide, and cuprous oxide.

[0061] (9) The method according to (1), (2), (3), (4), (5), (6), (7), or (8), wherein in 1), the molar ratio of the compound represented by formula 3, the monovalent copper catalyst, and the ligand represented by formula 4 or a stereoisomer thereof may be 10:2:4 to 10:0.5:0.5.

[0062] (10) The method according to (1), (2), (3), (4), (5), (6), (7), (8), or (9), wherein the step 1) may be carried out in at least one solvent selected from the group consisting of water, acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, and 1,4-dioxane.

[0063] (11) The method according to (1), (2), (3), (4), (5), (6), (7), (8), (9), or (10), wherein the step 1) above may be carried out by adjusting the temperature to between 37°C and 60°C and stirring for 10 to 60 minutes.

[0064] (12) The method according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), or (11), wherein the step 2) above is subjecting the compound represented by the formula 2 above to a reductive cyclization reaction to prepare the compound represented by the formula 5 above.

[0065] (13) The method according to (12) above, wherein the reductive cyclization in 2) above may be carried out by adding a reducing agent, or a reducing agent and an acetyl source.

[0066] (14) The method according to (13) above, wherein the reducing agent is at least one selected from the group consisting of H2 / 10% palladium on carbon, reduced iron, and sodium dithionate.

[0067] (15) The method according to (13) or (14) above, wherein the acetyl source is at least one selected from the group consisting of triethyl orthoacetate and acetylacetone.

[0068] (16) The method according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), or (15) above, wherein the base in 3) above may be at least one selected from potassium carbonate, sodium carbonate, cesium carbonate, aqueous ammonia, and pyridine.

[0069] (17) The method according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), or (16), wherein in 3) above, the molar ratio of the compound represented by formula 5 to the compound represented by formula 6 may be 1:1 to 1:2.5.

[0070] (18) The method according to any one of (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), and (17), wherein in 3), a molar ratio of the acetyl chloride to the base may be from 1:2 to 1:4.

[0071] (19) The method according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), or (18) above, wherein in 3) above, the molar ratio of the compound represented by 5 above to the acetyl chloride may be 1:1 to 1:1.5.

[0072] (20) The method according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), or (19) above, wherein in 3) above, the molar ratio of the compound represented by formula 6 to the base may be 1:1 to 1:4.

[0073] (21) The method according to (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), or (20), wherein the step 3) above may be carried out in at least one solvent selected from the group consisting of acetone, methyl ethyl ketone, ethyl acetate, methylene chloride, chloroform, and acetonitrile.

[0074] (22) The above item 3) is a) adding the compound represented by formula 5 and acetyl chloride to a solvent; and b) adding a compound represented by formula 6 in the presence of a base; Method (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), or (21) above.

[0075] (23) The method according to (22), wherein in the above a), the compound represented by the above formula 5 may be added in an amount of 5% (w / v) to 33% (w / v) relative to the solvent.

[0076] (24) The method according to (22) or (23), wherein the step a) may be carried out by adjusting the temperature to between 3° C. and 40° C. and stirring for 30 to 120 minutes.

[0077] (25) The method according to (22), (23), or (24), wherein the step (b) may be carried out by adjusting the temperature to between 27° C. and 40° C. and stirring for 10 to 180 minutes.

[0078] (26) The method according to (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), or (25) above, wherein 4) above is adjusting the pH to between 8 and 12.

[0079] (27) The method according to (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), or (26), wherein the step 4) above may be carried out by adjusting the temperature to between 3° C. and 10° C.

[0080] (28) The method according to (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22), (23), (24), (25), (26), or (27), wherein steps 3) and 4) are carried out in situ.

[0081] The present invention can provide the following compounds (1) to (5): (1) A compound represented by the following formula 1: [Formula 1] JPEG2025500545000030.jpg48160, where R1 is C 1-4 alkyl or phenyl, in which case1-4 At least one H of alkyl and phenyl is halogen or C 1-4 It may be substituted with alkyl.

[0082] (2) R1 is C 1-4 alkyl or phenyl, in which case, 1-4 At least one H of the alkyl may be substituted with halogen, and at least one H of the phenyl is C 1-4 The compound of (1) above, which may be substituted with alkyl.

[0083] (3) R1 is C 1-4 alkyl or phenyl, in which case, 1-4 The compound of (1) or (2) above, wherein at least one H of the alkyl is optionally substituted with fluoro (F) and at least one H of the phenyl is optionally substituted with methyl.

[0084] (4) The compound of (1), (2), or (3) above, wherein R1 may be methyl, trifluoromethyl, or tolyl.

[0085] (5) The compound is Acetic acid 6-(dimethylcarbamoyl)-2-methyl-1-tosyl-1H-benzo[d]imidazol-4-yl; Acetic acid 6-(dimethylcarbamoyl)-2-methyl-1-(trifluoromethyl)sulfonyl)-1H-benzo[d]imidazol-4-yl; and Acetic acid 6-(dimethylcarbamoyl)-2-methyl-1-methylsulfonyl-1H-benzo[d]imidazol-4-yl, The compound according to (1), (2), (3), or (4), which may be selected from the group consisting of: Effect of the Invention

[0086] The preparation method of the benzimidazole derivative of the present invention has low preparation cost, does not require a chromatography step in the preparation process, and does not use high-risk and high-cost reagents, so it is advantageous for mass production and can be prepared with high yield.

[0087] In addition, the compounds prepared by the above-mentioned preparation method can be effectively used to prepare other compounds having a benzimidazole structure, particularly as intermediates for the preparation of compounds usable as antibacterial agents, antiulcer agents, and anti-inflammatory agents. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0088] The present invention will be described in detail below through the embodiments. These exemplary embodiments are provided only for the purpose of illustrating the present invention. Therefore, it will be apparent to those skilled in the art that the scope of the present invention is not limited thereto.

[0089] [Example 1] Step 1) [Example 1-1] Preparation of 4-acetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide 1034.8g of purified water, 701.9g of dimethyl sulfoxide, and 144.4g of potassium carbonate were added to the reactor in sequence. The resulting solution was stirred for 30 minutes while raising the internal temperature to 37°C. 3.8g of copper (I) bromide, 7.4g of trans-N,N-dimethylcyclohexane-1,2-diamine, and 344.9g of purified water were added and stirred while maintaining the internal temperature at 37°C. Then, a solution obtained by dissolving 172.5g of 4-acetamido-3-bromo-N,N-dimethyl-5-nitrobenzamide in 38.5g of dimethyl sulfoxide was added to the reactor. The reaction solution was stirred for 60 minutes while maintaining the temperature at 37°C, and the reaction was completed. 345.0g of distilled water was added, and the internal temperature was cooled to 10-15°C using an ice bath, and the resulting mixture was stirred for 12 hours to crystallize. The resulting crystals were filtered and washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 128.4 g (yield: 92%) of 4-acetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide.

[0090] 1 H-NMR (400MHz, DMSO-d6): 10.9(s, 1H), 9.8(s, 1H), 7.3(d, 1H), 7.2(d, 1H), 3.0(s, 6H), 2.0(s, 3H)

[0091] [Example 1-2] Preparation of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide 899.8g of purified water, 610.3g of dimethyl sulfoxide, and 125.6g of potassium carbonate were added to the reactor in sequence. The resulting solution was stirred for 30 minutes while raising the internal temperature to 60°C. 15.5g of copper(I) bromide, 6.4g of trans-N,N-dimethylcyclohexane-1,2-diamine, and 299.9g of purified water were added and stirred while maintaining the internal temperature at 60°C. Then, a solution obtained by dissolving 155.2g of 4-amino-3-bromo-N,N-dimethyl-5-nitrobenzamide in 33.5g of dimethyl sulfoxide was added to the reactor. The reaction solution was stirred for 10 minutes while maintaining the temperature at 60°C to complete the reaction. 300.0g of distilled water was added, and the internal temperature was cooled to 10-15°C using an ice bath, and the resulting mixture was stirred for 12 hours to crystallize. The crystals were filtered and washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 109.2 g (yield: 90%) of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide.

[0092] 1 H-NMR (400MHz, DMSO-d6): 10.7(s, 1H), 7.6(d, 1H), 7.1(s, 2H), 7.0(s, 1H), 3.0(s, 6H)

[0093] [Example 1-3] Preparation of 4-trifluoroacetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide 1010.8g of purified water, 685.6g of dimethyl sulfoxide, and 141.1g of potassium carbonate were added to the reactor in sequence. The resulting solution was stirred for 90 minutes while raising the internal temperature to 45°C. 3.7g of copper(I) bromide, 7.2g of trans-N,N-dimethylcyclohexane-1,2-diamine, and 336.9g of purified water were added and stirred while maintaining the internal temperature at 45°C. Then, a solution obtained by dissolving 163.0g of 4-trifluoroacetamido-3-bromo-N,N-dimethyl-5-nitrobenzamide in 37.6g of dimethyl sulfoxide was added to the reactor. The reaction solution was stirred for 60 minutes while maintaining the temperature at 45°C, and the reaction was completed. 337.0g of distilled water was added, and the internal temperature was cooled to 10-15°C using an ice bath, and the resulting mixture was stirred for 12 hours to crystallize. The resulting crystals were filtered and washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 117.2 g (yield: 86%) of 4-trifluoroacetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide.

[0094] 1 H-NMR (400MHz, DMSO-d6): 10.9(s, 1H), 9.8(s, 1H), 7.3(d, 1H), 7.2(d, 1H), 3.0(s, 6H)

[0095] [Examples 1-4] Preparation of 4-acetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide 1034.8g of purified water, 701.9g of dimethyl sulfoxide, and 144.4g of potassium carbonate were added to the reactor in sequence. The resulting solution was stirred for 30 minutes while raising the internal temperature to 37°C. 3.8g of copper(I) bromide, 5.9g of trans-1,2-diaminocyclohexane, and 344.9g of purified water were added and stirred while maintaining the internal temperature at 37°C. Then, a solution obtained by dissolving 172.5g of 4-acetamido-3-bromo-N,N-dimethyl-5-nitrobenzamide in 38.5g of dimethyl sulfoxide was added to the reactor. The reaction solution was stirred for 60 minutes while maintaining the temperature at 37°C, and the reaction was completed. 345.0g of distilled water was added, and the internal temperature was cooled to 10-15°C using an ice bath, and the resulting mixture was stirred for 12 hours to crystallize. The resulting crystals were filtered and washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 125.6 g (yield: 90%) of 4-acetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide.

[0096] 1 H-NMR (400MHz, DMSO-d6): 10.9(s, 1H), 9.8(s, 1H), 7.3(d, 1H), 7.2(d, 1H), 3.0(s, 6H), 2.0(s, 3H)

[0097] [Examples 1-5] Preparation of 4-amido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide 899.8g of purified water, 610.3g of dimethyl sulfoxide, and 125.6g of potassium carbonate were added to the reactor in sequence. The resulting solution was stirred for 30 minutes while raising the internal temperature to 60°C. 15.5g of copper(I) bromide, 5.1g of trans-1,2-diaminocyclohexane, and 299.9g of purified water were added and stirred while maintaining the internal temperature at 60°C. Then, a solution obtained by dissolving 155.2g of 4-amino-3-bromo-N,N-dimethyl-5-nitrobenzamide in 33.5g of dimethyl sulfoxide was added to the reactor. The reaction solution was stirred for 10 minutes while maintaining the temperature at 60°C to complete the reaction. 300.0g of distilled water was added, and the internal temperature was cooled to 10-15°C using an ice bath, and the resulting mixture was stirred for 12 hours to crystallize. The crystals were filtered and washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 104.3 g (yield: 86%) of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide.

[0098] 1 H-NMR (400MHz, DMSO-d6): 10.7(s, 1H), 7.6(d, 1H), 7.1(s, 2H), 7.0(s, 1H), 3.0(s, 6H)

[0099] [Examples 1-6] Preparation of 4-trifluoroacetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide 1010.8g of purified water, 685.6g of dimethyl sulfoxide, and 141.1g of potassium carbonate were added to the reactor in sequence. The resulting solution was stirred for 90 minutes while raising the internal temperature to 45°C. 3.7g of copper(I) bromide, 5.8g of trans-1,2-diaminocyclohexane, and 336.9g of purified water were added and stirred while maintaining the internal temperature at 45°C. Then, a solution obtained by dissolving 163.0g of 4-trifluoroacetamido-3-bromo-N,N-dimethyl-5-nitrobenzamide in 37.6g of dimethyl sulfoxide was added to the reactor. The reaction solution was stirred for 60 minutes while maintaining the temperature at 45°C, and the reaction was completed. 337.0g of distilled water was added, and the internal temperature was cooled to 10-15°C using an ice bath, and the resulting mixture was stirred for 12 hours to crystallize. The resulting crystals were filtered and washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 117.2 g (yield: 86%) of 4-trifluoroacetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide.

[0100] 1 H-NMR (400MHz, DMSO-d6): 10.9(s, 1H), 9.8(s, 1H), 7.3(d, 1H), 7.2(d, 1H), 3.0(s, 6H)

[0101] [Examples 1-7] Preparation of 4-acetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide 1034.8g of purified water, 701.9g of dimethyl sulfoxide, and 144.4g of potassium carbonate were added to the reactor in sequence. The resulting solution was stirred for 30 minutes while raising the internal temperature to 37°C. 3.8g of copper(I) bromide, 4.6g of 1,2-dimethylethylenediamine, and 344.9g of purified water were added and stirred while maintaining the internal temperature at 37°C. Then, a solution obtained by dissolving 172.5g of 4-acetamido-3-bromo-N,N-dimethyl-5-nitrobenzamide in 38.5g of dimethyl sulfoxide was added to the reactor. The reaction solution was stirred for 60 minutes while maintaining the temperature at 37°C, and the reaction was completed. 345.0g of distilled water was added, and the internal temperature was cooled to 10-15°C using an ice bath, and the resulting mixture was stirred for 12 hours to crystallize. The resulting crystals were filtered and washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 132.6 g (yield: 95%) of 4-acetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide.

[0102] 1 H-NMR (400MHz, DMSO-d6): 10.9(s, 1H), 9.8(s, 1H), 7.3(d, 1H), 7.2(d, 1H), 3.0(s, 6H), 2.0(s, 3H)

[0103] [Examples 1-8] Preparation of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide 899.8g of purified water, 610.3g of dimethyl sulfoxide, and 125.6g of potassium carbonate were added to the reactor in sequence. The resulting solution was stirred for 30 minutes while raising the internal temperature to 60°C. 15.5g of copper(I) bromide, 4.0g of 1,2-dimethylethylenediamine, and 299.9g of purified water were added and stirred while maintaining the internal temperature at 60°C. Then, a solution obtained by dissolving 155.2g of 4-amino-3-bromo-N,N-dimethyl-5-nitrobenzamide in 33.5g of dimethyl sulfoxide was added to the reactor. The reaction solution was stirred for 10 minutes while maintaining the temperature at 60°C to complete the reaction. 300.0g of distilled water was added, and the internal temperature was cooled to 10-15°C using an ice bath, and the resulting mixture was stirred for 12 hours to crystallize. The crystals were filtered and washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 117.7 g (yield: 97%) of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide.

[0104] 1 H-NMR (400MHz, DMSO-d6): 10.7(s, 1H), 7.6(d, 1H), 7.1(s, 2H), 7.0(s, 1H), 3.0(s, 6H)

[0105] [Examples 1-9] Preparation of 4-trifluoroacetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide 1010.8g of purified water, 685.6g of dimethyl sulfoxide, and 141.1g of potassium carbonate were added to the reactor in sequence. The resulting solution was stirred for 90 minutes while raising the internal temperature to 45°C. 3.7g of copper(I) bromide, 4.5g of 1,2-dimethylethylenediamine, and 336.9g of purified water were added and stirred while maintaining the internal temperature at 45°C. Then, a solution obtained by dissolving 163.0g of 4-trifluoroacetamido-3-bromo-N,N-dimethyl-5-nitrobenzamide in 37.6g of dimethyl sulfoxide was added to the reactor. The reaction solution was stirred for 60 minutes while maintaining the temperature at 45°C, and the reaction was completed. 337.0g of distilled water was added, and the internal temperature was cooled to 10-15°C using an ice bath, and the resulting mixture was stirred for 12 hours to crystallize. The resulting crystals were filtered and washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 122.7 g (yield: 90%) of 4-trifluoroacetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide.

[0106] 1 H-NMR (400MHz, DMSO-d6): 10.9(s, 1H), 9.8(s, 1H), 7.3(d, 1H), 7.2(d, 1H), 3.0(s, 6H)

[0107] [Example 2] Step 2) [Example 2-1] Preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide Methanol (994.8 g) and 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide (104.3 g) were added to the reactor in sequence. The resulting solution was stirred at 20-30°C to dissolve all solids, and then 10% palladium carbon (2.6 g) was added and the internal temperature was raised to 40°C. After the inside of the reactor was replaced with hydrogen gas, the resulting mixture was stirred for 30 minutes under a hydrogen pressure of 0.2 MPa. The internal temperature of the reactor was gradually cooled to 20-30°C, and then 225.4 g of triethyl orthoacetate was added and stirred for 12 hours to complete the reaction. The reaction solution was concentrated under vacuum at 40°C to remove methanol, and then 1564.5 g of purified water was added. The resulting mixture was stirred at 20-30°C for 12 hours to ripen the crystals, which were then filtered and washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 96.5 g (yield: 95%) of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide.

[0108] 1 H-NMR (400MHz, DMSO-d6): 12.3, 12.2(d, 1H), 10.0, 9.8(d, 1H), 7.0, 6.9(d, 1H), 6.6, 6.5(d, 1H), 2.9(s, 6H), 2.5(s, 3H)

[0109] [Example 2-2] Preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide 548.2g of methanol, 138.4g of 4-trifluoroacetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide, and 45.8g of triethylamine were added to the reactor in sequence. The resulting solution was stirred at 20-30°C to dissolve all solids, and then 3.1g of 10% palladium carbon was added and the internal temperature was raised to 40°C. After the inside of the reactor was replaced with hydrogen gas, the resulting mixture was stirred for 30 minutes under a hydrogen pressure of 0.2MPa. After the internal temperature of the reactor was gradually cooled to 20-30°C, 185.9g of triethyl orthoacetate was added and stirred for 12 hours to complete the reaction. The reaction solution was concentrated under vacuum at 40°C to remove methanol, and then 1840.5g of purified water was added. The resulting mixture was stirred at 20-30°C for 12 hours to mature the crystals, which were then filtered and washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 73.7 g (yield: 88%) of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide.

[0110] 1 H-NMR (400MHz, DMSO-d6): 12.3, 12.2(d, 1H), 10.0, 9.8(d, 1H), 7.0, 6.9(d, 1H), 6.6, 6.5(d, 1H), 2.9(s, 6H), 2.5(s, 3H)

[0111] [Example 2-3] Preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide 1458.6g of dimethyl sulfoxide, 1046.2g of ethanol, 132.6g of 4-acetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide, and 432.0g of sodium dithionate were added to the reactor in sequence. The resulting solution was stirred for 24 hours while increasing the internal temperature to 90°C, and the reaction was completed. The reaction solution was concentrated under vacuum at 40°C to remove ethanol, and then 1989.0g of purified water was added. The resulting mixture was stirred at 20-30°C for 12 hours to mature the crystals, which were then filtered and washed with purified water. The resulting solid was vacuum dried at 40°C to obtain 87.0g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (yield: 80%).

[0112] 1 H-NMR (400MHz, DMSO-d6): 12.3, 12.2(d, 1H), 10.0, 9.8(d, 1H), 7.0, 6.9(d, 1H), 6.6, 6.5(d, 1H), 2.9(s, 6H), 2.5(s, 3H)

[0113] [Example 2-4] Preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide 1387.7g of acetic acid and 132.2g of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide were added to the reactor in sequence. 65.6g of powdered reduced iron was added while stirring at 20-30°C, and the resulting mixture was stirred for 12 hours while raising the internal temperature to 70°C. After the internal temperature of the reactor was gradually cooled to 20-30°C, the reaction solution was passed through Celite filter paper to remove residual solids. Then, 285.6g of triethyl orthoacetate was added, and the reaction was completed by stirring for 12 hours. 1982.5g of purified water was added to the reaction solution, the pH of the solution was adjusted to 7-8, and the resulting solution was stirred at 20-30°C for 12 hours to mature the crystals, which were then filtered out. Then, it was washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 96.5 g (yield: 75%) of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide.

[0114] 1 H-NMR (400MHz, DMSO-d6): 12.3, 12.2(d, 1H), 10.0, 9.8(d, 1H), 7.0, 6.9(d, 1H), 6.6, 6.5(d, 1H), 2.9(s, 6H), 2.5(s, 3H)

[0115] [Example 2-5] Preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide 548.2g of methanol, 138.4g of 4-trifluoroacetamido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide, and 45.8g of triethylamine were added to the reactor in sequence. The resulting solution was stirred at 20-30°C for 1 hour and concentrated under vacuum at 40°C to remove methanol. 1453.6g of acetic acid was added to the resulting concentrate, and then 48.1g of powdered reduced iron was added, and the resulting mixture was stirred for 12 hours while increasing the internal temperature to 70°C. After the internal temperature of the reactor was gradually cooled to 20-30°C, the reaction solution was passed through Celite filter paper to remove residual solids. Then, 129.5g of triethyl orthoacetate was added, and the reaction was completed by stirring for 12 hours. 2076.0g of purified water was added to the reaction solution, the pH of the solution was adjusted to 7-8, and the resulting solution was stirred at 20-30°C for 12 hours to mature the crystals, which were then filtered out. Then, it was washed with purified water. The obtained solid was dried in vacuum at 40° C. to obtain 73.7 g (yield: 78%) of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide.

[0116] 1 H-NMR (400MHz, DMSO-d6): 12.3, 12.2(d, 1H), 10.0, 9.8(d, 1H), 7.0, 6.9(d, 1H), 6.6, 6.5(d, 1H), 2.9(s, 6H), 2.5(s, 3H)

[0117] [Example 3] Step 3) [Example 3-1] Preparation of 6-(dimethylcarbamoyl)-2-methyl-1-tosyl-1H-benzo[d]imidazol-4-yl acetate A mixed solution of 887.1 g of methylene chloride and 65.0 g of pyridine was charged into a reactor. After cooling the solution to 3-5°C, 66.7 g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide and 23.9 g of acetyl chloride were added in sequence while slowly stirring, and the mixture was stirred at 3-5°C for 2 hours. After confirming that the solids in the reaction solution were completely dissolved and reprecipitated, the temperature of the reaction solution was raised to 20-30°C, 42.0 g of potassium carbonate and 58.0 g of p-toluenesulfonyl chloride were added in sequence, and the mixture was stirred for another 30 minutes. The internal temperature was gradually cooled to 3-5°C using an ice bath, and 333.5 g of purified water was added to complete the reaction. The solution was stirred for 1 hour while heating to 20-30°C. The organic layer was separated and concentrated under vacuum at 40°C to remove the reaction solvent, after which 157.3g of acetonitrile and 200.1g of purified water were added and stirred to crystallize. The obtained crystals were filtered and washed with a mixed solution of acetonitrile and purified water. The obtained solid was dried in vacuum at 40°C to obtain 116.3g (yield: 92%) of 6-(dimethylcarbamoyl)-2-methyl-1-tosyl-1H-benzo[d]imidazol-4-yl acetate.

[0118] 1 H-NMR (400MHz, DMSO-d6): 8.0, 7.9(d, 2H), 7.5, 7.4(d, 2H), 7.3(s, 1H), 6.7(s, 1H), 3.0, 2.9(d, 6H), 2.8(s, 3H), 2.4(s, 3H), 2.0(s, 3H)

[0119] [Example 3-2] Preparation of 6-(dimethylcarbamoyl)-2-methyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazol-4-yl acetate A mixed solution of 691.6 g of methylene chloride and 37.5 g of pyridine was charged into a reactor. While slowly stirring the solution, 52.0 g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide and 18.6 g of acetyl chloride were added in sequence, the temperature was raised to 20-30 ° C, and the mixture was stirred at 20-30 ° C for 1 hour. After confirming that the solid had completely dissolved in the reaction solution and reprecipitated, 32.8 g of potassium carbonate and 40.0 g of triflyl chloride were added in sequence and the mixture was stirred for another 3 hours. The internal temperature was gradually cooled to 3-5 ° C using an ice bath, and 260.0 g of purified water was added to complete the reaction. The solution was stirred for 1 hour while heating to 20-30 ° C. The organic layer was separated and concentrated under vacuum at 40 ° C to remove the reaction solvent, after which 312.0 g of purified water was added and stirred to crystallize. The obtained crystals were filtered and washed with methanol. The obtained solid was dried in vacuum at 40° C. to obtain 76.5 g (yield: 82%) of 6-(dimethylcarbamoyl)-2-methyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazol-4-yl acetate.

[0120] 1 H-NMR (400MHz, DMSO-d6): 7.3(s, 1H), 6.7(s, 1H), 3.0, 2.9(d, 6H), 2.8(s, 3H), 2.0(s, 3H)

[0121] [Example 3-3] Preparation of 6-(dimethylcarbamoyl)-2-methyl-1-(methylsulfonyl)-1H-benzo[d]imidazol-4-yl acetate A mixed solution of 980.2g of methylene chloride and 26.6g of pyridine was charged into a reactor. After the solution was heated to 35-40°C, 73.7g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide and 26.4g of acetyl chloride were added in sequence while slowly stirring, and the mixture was stirred at 40°C for 30 minutes. After confirming that the solids were completely dissolved and reprecipitated in the reaction solution, the internal temperature was cooled to 20-30°C, 46.5g of potassium carbonate and 38.5g of methanesulfonyl chloride were added in sequence, and the mixture was stirred for another 3 hours. The internal temperature was gradually cooled to 3-5°C using an ice bath, and 368.5g of purified water was added to complete the reaction. The solution was stirred for 1 hour while heating to 20-30°C. The organic layer was separated and concentrated under vacuum at 40°C to remove the reaction solvent, after which 291.9g of methanol was added and stirred to crystallize. The obtained crystals were filtered and washed with methanol. The obtained solid was dried in vacuum at 40° C. to obtain 91.3 g (yield 80%) of 6-(dimethylcarbamoyl)-2-methyl-1-(methylsulfonyl)-1H-benzo[d]imidazol-4-yl acetate.

[0122] 1 H-NMR (400MHz, DMSO-d6): 7.3(s, 1H), 6.7(s, 1H), 3.0, 2.9(d, 6H), 2.8(s, 3H), 2.4(s, 3H), 2.0(s, 3H)

[0123] [Example 4] Step 4) [Example 4-1] Preparation of 4-hydroxy-N,N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide A mixed solution of 213.8 g of methanol and 270.0 g of purified water was charged into a reactor. While slowly stirring this solution at 20-30°C, 90.0 g of 6-(dimethylcarbamoyl)-2-methyl-1-tosyl-1H-benzo[d]imidazol-4-yl acetate was added. The internal temperature was gradually cooled to 3-5°C using an ice bath, and the pH of the reaction solution was adjusted to 10.0-10.2 with 30-35% ammonia water. The reaction solution was further stirred at 3-5°C for 16 hours while maintaining the pH of the reaction solution. The obtained crystals were filtered and washed with a mixed solution of methanol and purified water. The obtained solid was vacuum dried at 40°C to obtain 76.8 g of 4-hydroxy-N,N,2-trimethyl-1-tosyl-1H-benzo[d]imidazol-6-carboxamide (yield: 95%).

[0124] 1 H-NMR (400MHz, DMSO-d6): 10.4(s, 1H), 8.0, 7.9(d, 2H), 7.5, 7.4(d, 2H), 7.3(s, 1H), 6.7(s, 1H), 3.0, 2.9(d, 6H), 2.8(s, 3H), 2.4(s, 3H)

[0125] [Example 4-2] Preparation of 4-hydroxy-N,N,2-trimethyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazole-6-carboxamide A mixed solution of 130.8 g of methanol and 165.1 g of purified water was charged into a reactor. While slowly stirring this solution at 20-30°C, 55.0 g of 6-(dimethylcarbamoyl)-2-methyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazol-4-yl acetate was added. The internal temperature was gradually cooled to 3-5°C using an ice bath, and the pH of the reaction solution was adjusted to 8.0-8.2 with 30-35% ammonia water. After adding 330.2 g of purified water, the reaction solution was stirred at 3-5°C for 16 hours while maintaining the pH of the reaction solution. The obtained crystals were filtered and washed with a mixed solution of methanol and purified water. The resulting solid was dried in vacuum at 40° C. to obtain 46.2 g of 4-hydroxy-N,N,2-trimethyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazole-6-carboxamide (yield: 94%).

[0126] 1 H-NMR (400MHz, DMSO-d6): 10.4(s, 1H), 7.3(s, 1H), 6.7(s, 1H), 3.0, 2.9(d, 6H), 2.8(s, 3H)

[0127] [Example 4-3] Preparation of 4-hydroxy-N,N,2-trimethyl-1-(methylsulfonyl)-1H-benzo[d]imidazole-6-carboxamide A mixed solution of 171.1 g of methanol and 216.0 g of purified water was charged into a reactor. While slowly stirring this solution at 20-30 ° C, 72.0 g of 6-(dimethylcarbamoyl)-2-methyl-1-(methylsulfonyl)-1H-benzo[d]imidazol-4-yl acetate was added. The internal temperature was gradually cooled to 3-5 ° C using an ice bath, and the pH of the reaction solution was adjusted to 10.0-10.5 with 30-35% ammonia water. After adding 216.0 g of purified water, the reaction solution was stirred at 3-5 ° C for 16 hours while maintaining the pH of the reaction solution. The obtained crystals were filtered and washed with a mixed solution of methanol and purified water. The obtained solid was vacuum dried at 40 ° C to obtain 59.3 g of 4-hydroxy-N,N,2-trimethyl-1-(methylsulfonyl)-1H-benzo[d]imidazol-6-carboxamide (yield: 94%).

[0128] 1 H-NMR (400MHz, DMSO-d6): 10.4(s, 1H), 7.3(s, 1H), 6.7(s, 1H), 3.0, 2.9(d, 6H), 2.8(s, 3H), 2.4(s, 3H)

[0129] [Example 5] Step 3) + Step 4) In situ [Example 5-1] Preparation of 4-hydroxy-N,N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide A mixed solution of 663.7 g of methylene chloride and 48.7 g of pyridine was charged into a reactor. After cooling the solution to 3-5°C, 50.0 g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide and 17.9 g of acetyl chloride were added in sequence while slowly stirring, and the mixture was stirred at 3-5°C for 2 hours. After confirming that the solids in the reaction solution were completely dissolved and reprecipitated, the temperature of the reaction solution was raised to 20-30°C, 31.5 g of potassium carbonate and 87.0 g of p-toluenesulfonyl chloride were added in sequence, and the mixture was stirred for another 30 minutes. The internal temperature was gradually cooled to 3-5°C using an ice bath, and 50.0 g of purified water and 7.4 g of tetra-n-butylammonium bromide were added. While vigorously stirring the reaction solution, 157.6 g of potassium carbonate was added, and the reaction was continued for 16 hours. The reaction was terminated by adding 250.0 g of purified water and adjusting the pH of the reaction solution to 5-7. The reaction solution was stirred for 1 hour while being heated to 20-30°C. The organic layer was separated and concentrated under vacuum at 40°C to remove the reaction solvent, after which 118.8 g of methanol and 150.0 g of purified water were added and stirred to crystallize. The obtained crystals were filtered and washed with a mixed solution of methanol and purified water. The obtained solid was vacuum dried at 40°C to obtain 76.7 g of 4-hydroxy-N,N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide (yield: 90%).

[0130] 1H-NMR (400MHz, DMSO-d6): 10.4(s, 1H), 8.0, 7.9(d, 2H), 7.5, 7.4(d, 2H), 7.3(s, 1H), 6.7(s, 1H), 3.0, 2.9(d, 6H), 2.8(s, 3H), 2.4(s, 3H)

[0131] [Example 5-2] Preparation of 4-hydroxy-N,N,2-trimethyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazole-6-carboxamide A mixed solution of 663.6 g of methylene chloride and 36.1 g of pyridine was charged into a reactor. While slowly stirring the solution, 50.0 g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide and 17.9 g of acetyl chloride were added in sequence, the temperature was raised to 20-30 ° C, and the mixture was stirred at 20-30 ° C for 1 hour. After confirming that the solids in the reaction solution were completely dissolved and reprecipitated, 31.5 g of potassium carbonate and 76.9 g of triflyl chloride were added in sequence and the mixture was stirred for another 3 hours. The internal temperature was gradually cooled to 3-5 ° C using an ice bath, and 50.0 g of purified water and 7.4 g of tetra-n-butylammonium bromide were added. While vigorously stirring the reaction solution, 44.0 g of 30-35% ammonia water was added and the reaction was continued for 16 hours. 250.0 g of purified water was added, and the pH of the reaction solution was adjusted to 5-7 to terminate the reaction. The reaction solution was stirred for 1 hour while heating to 20-30°C. The organic layer was separated and concentrated under vacuum at 40°C to remove the reaction solvent, after which 118.8 g of methanol and 450.0 g of purified water were added and stirred to crystallize. The obtained crystals were filtered and washed with a mixed solution of methanol and purified water. The obtained solid was dried in vacuum at 40°C to obtain 64.1 g of 4-hydroxy-N,N,2-trimethyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazole-6-carboxamide (yield: 80%).

[0132] 1 H-NMR (400MHz, DMSO-d6): 10.4(s, 1H), 7.3(s, 1H), 6.7(s, 1H), 3.0, 2.9(d, 6H), 2.8(s, 3H)

[0133] [Example 5-3] Preparation of 4-hydroxy-N,N,2-trimethyl-1-(methylsulfonyl)-1H-benzo[d]imidazole-6-carboxamide A mixed solution of 663.5g of methylene chloride and 18.0g of pyridine was charged into a reactor. After the solution was heated to 35-40°C, 50.0g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide and 17.9g of acetyl chloride were added in sequence while slowly stirring, and the mixture was stirred at 40°C for 30 minutes. After confirming that the solids in the reaction solution were completely dissolved and reprecipitated, the internal temperature was cooled to 20-30°C, 31.5g of potassium carbonate and 52.2g of methanesulfonyl chloride were added in sequence, and the mixture was stirred for another 3 hours. The internal temperature was gradually cooled to 3-5°C using an ice bath, and 50.0g of purified water and 7.4g of tetra-n-butylammonium bromide were added. While vigorously stirring the reaction solution, 88.0g of 30-35% ammonia water was added, and the reaction was continued for 16 hours. The reaction was terminated by adding 250.0 g of purified water and adjusting the pH of the reaction solution to 5-7. The reaction solution was stirred for 1 hour while being heated to 20-30°C. The organic layer was separated and concentrated under vacuum at 40°C to remove the reaction solvent, after which 118.8 g of methanol and 300.0 g of purified water were added and stirred to crystallize. The obtained crystals were filtered and washed with a mixed solution of methanol and purified water. The obtained solid was dried in vacuum at 40°C to obtain 53.6 g of 4-hydroxy-N,N,2-trimethyl-1-(methylsulfonyl)-1H-benzo[d]imidazole-6-carboxamide (yield: 80%).

[0134] 1 H-NMR (400MHz, DMSO-d6): 10.4(s, 1H), 7.3(s, 1H), 6.7(s, 1H), 3.0, 2.9(d, 6H), 2.8(s, 3H), 2.4(s, 3H)

[0135] Although specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that such detailed description is provided only to explain exemplary embodiments and is not to be construed as limiting the scope of the present invention. Therefore, it should be understood that the substantial scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A process for preparing a benzimidazole derivative comprising the steps of: 1) preparing a compound represented by the following formula 2 by reacting a compound represented by the following formula 3 with a monovalent copper catalyst in the presence of a ligand represented by the following formula 4 or a stereoisomer thereof; 2) reacting a compound represented by the following formula 2 to prepare a compound represented by the following formula 5; and 3) reacting a compound represented by the following formula 5 with acetyl chloride and a compound represented by the following formula 6 in the presence of a base to prepare a compound represented by the following formula 1: [Formula 1] [Formula 2] [Formula 3] [Formula 4] [Formula 5] [Formula 6] Where: R 1 is C 1-4 alkyl or phenyl, in which case 1-4 At least one H of alkyl and phenyl is halogen or C 1-4 may be substituted with alkyl; R 2 is H, C 1-4 alkyl or acetyl, in which at least one H of the acetyl may be replaced by halogen; R 3 and R 4 are independently H, C 1-4 Alkyl, and C 3-7 cycloalkyl, or taken together form a 3- to 7-membered alicyclic ring, wherein said C 1-4 Alkyl, C 3-7 At least one H in the cycloalkyl and the 3- to 7-membered alicyclic ring formed may be replaced with a halogen; and R 5 , H, C 1-4 alkyl, or acetyl; The method includes:

2. 2. The method of claim 1, R 1 is methyl, trifluoromethyl, or tolyl; R 2 is H, acetyl, or trifluoroacetyl; R 3 and R 4 are methyl or together form a 6-membered alicyclic ring; and R 5 is H or methyl.

3. The method of claim 1, further comprising: 4) adjusting the pH of the compound represented by the above formula 1 to prepare a compound represented by the following formula 1-1; [Formula 1-1] Where: R 1 is the same as the above formula 1 in claim 1; The method includes:

4. R 1 2. The method of claim 1, wherein is methyl, trifluoromethyl, or tolyl.

5. 2. The method according to claim 1, wherein the monovalent copper catalyst 1) is one selected from the group consisting of cuprous chloride, copper bromide, copper iodide, and cuprous oxide.

6. The method according to claim 1, wherein in the above 1), the molar ratio of the compound represented by formula 3, the monovalent copper catalyst, and the ligand represented by formula 4 or a stereoisomer thereof is 10:2:4 to 10:0.5:0.

5.

7. 2. The method of claim 1, wherein 1) is carried out in at least one solvent selected from the group consisting of water, acetonitrile, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, and 1,4-dioxane.

8. 2. The method of claim 1, wherein the step 1) is carried out by adjusting the temperature to between 37°C and 60°C and stirring for 10 to 60 minutes.

9. The method according to claim 1, wherein the step 2) is to prepare a compound represented by formula 5 by subjecting a compound represented by formula 2 to a reductive cyclization reaction.

10. The method according to claim 9, wherein the reductive cyclization in 2) above is carried out by adding a reducing agent, or a reducing agent and an acetyl source.

11. The reducing agent is H 2 11. The method of claim 10, wherein the catalyst is at least one selected from the group consisting of 10% palladium on carbon, reduced iron, and sodium dithionate.

12. 11. The method of claim 10, wherein the acetyl source is at least one selected from the group consisting of triethyl orthoacetate and acetylacetone.

13. The method according to claim 1, wherein the base in 3) is at least one selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, aqueous ammonia, and pyridine.

14. The method according to claim 1, wherein in 3), the molar ratio of the compound represented by the above formula 5 to the compound represented by the above formula 6 is 1:1 to 1:2.

5.

15. The method according to claim 1, wherein in 3), the molar ratio of the acetyl chloride to the base is 1:2 to 1:

4.

16. The method according to claim 1, wherein in 3), the molar ratio of the compound represented by the above formula 5 to the acetyl chloride is 1:1 to 1:1.

5.

17. The method according to claim 1, wherein in 3), the molar ratio of the compound represented by the above formula 6 to the base is 1:1 to 1:

4.

18. The method according to claim 1, wherein 3) is carried out in at least one solvent selected from the group consisting of acetone, methyl ethyl ketone, ethyl acetate, methylene chloride, chloroform, and acetonitrile.

19. 3) is a) a step of adding the compound represented by the above formula 5 and acetyl chloride to a solvent; and b) a step of adding the compound represented by the above formula 6 in the presence of a base, the method according to claim 18.

20. The method according to claim 19, wherein the compound represented by the above formula 5 in a) is added in an amount of 5% (w / v) to 33% (w / v) with respect to the solvent.

21. The method according to claim 19, wherein a) is carried out by adjusting the temperature to between 3 °C and 40 °C and stirring for 30 to 120 minutes.

22. The method according to claim 19, wherein b) is carried out by adjusting the temperature to between 27 °C and 40 °C and stirring for 10 to 180 minutes.

23. The method according to claim 3, wherein 4) is characterized by adjusting the pH to between 8 and 12.

24. The method according to claim 3, wherein 4) is carried out by adjusting the temperature to between 3 °C and 10 °C.

25. The method according to claim 3, wherein 3) and 4) are carried out in situ.

26. A compound represented by the following formula 1: [Formula 1] where R 1 is C 1-4 alkyl or phenyl, in which case 1-4 At least one H of alkyl and phenyl is halogen or C 1-4 It may be substituted with alkyl.

27. R 1 27. The compound of claim 26, wherein is methyl, trifluoromethyl, or tolyl.

28. The compound represented by the above formula 1 is 6-(dimethylcarbamoyl)-2-methyl-1-tosyl-1H-benzo[d]imidazol-4-yl acetate; Acetic acid 6-(dimethylcarbamoyl)-2-methyl-1-(trifluoromethyl)sulfonyl)-1H-benzo[d]imidazol-4-yl; and Acetic acid 6-(dimethylcarbamoyl)-2-methyl-1-methylsulfonyl-1H-benzo[d]imidazol-4-yl, 27. The compound of claim 26, selected from the group consisting of:

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