Method for preparing benzimidazole derivatives

Abstract

The present invention relates to a method for preparing a benzimidazole derivative and a compound prepared thereby.

Description

Technical Field

[0001] The present invention relates to a method for preparing a benzimidazole derivative and a compound prepared thereby. Background Art

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

[0003] For example, among the benzimidazole derivatives, oxadiazole-1H-benzimidazole is known to have antimicrobial activity and has been reported to have inhibitory activity against fungi, while tetrahydroimidazole [4,5,1-jk][1,4]-benzodiazepine -2(1H)-ketone and N-alkoxy-2-alkylbenzimidazole are also developed as HIV inhibitors. In addition, benzimidazole derivatives having sulfoxide and methylene groups are known to inhibit gastric acid secretion by inhibiting proton pumps and have gastric mucosal protective functions. In addition, benzimidazole derivatives are known to have antiviral and antihypertensive effects.

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

[0005] As described above, benzimidazole is a pharmacophore having very high applicability in the fields of medicine and chemistry, and its synthesis method has been developed by many researchers and proposed through various literatures.

[0006] International patent publication WO 2004 / 054984 has described a kind of preparation method using 2-amino-3-nitrophenol.But the preparation method described in the patent uses expensive intermediates and reagents in amidation reaction, and because of using the metal catalyst that is difficult to remove, therefore also has purification difficulty.Therefore, preparation cost is high, and because of using silica gel to separate some intermediates, so this preparation method is not suitable for general large-scale synthesis process.In addition, because of using the metal catalyst with fire or explosion possibility, therefore be difficult to produce only in special equipment.

[0007] In addition, International Patent Publication WO 2007 / 072146 describes a method for using carbon monoxide in a process for introducing a carbonyl group to carry out an amidation reaction. However, this reaction requires a separate reaction unit and involves risk factors due to exposure to carbon monoxide gas during this process. In addition, due to the use of expensive reagents, the preparation cost is high, and due to the use of silica gel to separate some intermediates, this preparation method is not suitable for general large-scale synthesis processes.

[0008] Thus, the present inventors have confirmed a method capable of industrially mass-producing benzimidamide, which is known as a very important pharmacophore in the fields of medicine and chemistry, with a high yield despite using commercially available reagents and solvents at a low preparation cost, thereby completing the present invention.

[0009] [Related technical references]

[0010] [Patent Document]

[0011] (Patent Document 1) International Patent Publication WO 2004 / 054984

[0012] (Patent Document 2) International Patent Publication WO 2007 / 072146 Summary of the invention

[0013] Technical issues

[0014] The present invention can provide a method for preparing benzimidazole derivatives.

[0015] The present invention can provide a compound prepared by the above preparation method.

[0016] Technical Solution

[0017] The specific description is as follows. Meanwhile, each description and embodiment disclosed in the present invention can be applied to other descriptions and embodiments respectively. In other words, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. In addition, it may not be seen that the scope of the present invention is limited to the specific description described below.

[0018] The present invention can provide a method for preparing a benzimidazole derivative, the method comprising:

[0019] 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:

[0020] 2) preparing a compound represented by the following Formula 5 by reacting a compound represented by the following Formula 2: and

[0021] 3) preparing a compound represented by the following Formula 1 by reacting a compound represented by the following Formula 5, acetyl chloride and a compound represented by the following Formula 65 in the presence of a base,

[0022] [Formula 1]

[0023]

[0024] [Formula 2]

[0025]

[0026] [Formula 3]

[0027]

[0028] [Formula 4]

[0029]

[0030] [Formula 5]

[0031]

[0032] [Formula 6]

[0033]

[0034] in,

[0035] R1 can be C 1-4 Alkyl or phenyl, wherein the C 1-4 At least one of the H groups of the alkyl and phenyl groups may be replaced by halogen or C 1-4 Alkyl substitution,

[0036] R2 can be H, C 1-4 an alkyl group or an acetyl group, wherein at least one H of the acetyl group may be substituted with a halogen,

[0037] R3 and R4 can be independently selected from H, C 1-4 Alkyl and C 3-7 or together form a 3- to 7-membered alicyclic ring, wherein the C 1-4 Alkyl, C 3-7 The cycloalkyl group and at least one H of the formed 3- to 7-membered alicyclic ring may be substituted with halogen, and

[0038] R5 can be H, C 1-4 Alkyl or acetyl.

[0039] The method for preparing a benzimidazole derivative may further include:

[0040] 4) preparing the following compound represented by Formula 1-1 by adjusting the pH of the compound represented by Formula 1 above,

[0041] [Formula 1-1]

[0042]

[0043] in,

[0044] R1 may be the same as in Formula 1 above.

[0045] In one embodiment, R1 may be methyl, trifluoromethyl or tolyl.

[0046] The present invention can provide a method for preparing a benzimidazole derivative, the method comprising:

[0047] 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:

[0048] 2) preparing a compound represented by the following Formula 5 by reacting a compound represented by the following Formula 2:

[0049] 3) preparing a compound represented by the following Formula 1 by reacting a compound represented by the following Formula 5, acetyl chloride, and a compound represented by the following Formula 6 in the presence of a base; and

[0050] 4) preparing a compound represented by Formula 1-1 by adjusting the pH of the compound represented by Formula 1,

[0051] [Formula 1-1]

[0052]

[0053] [Formula 1]

[0054]

[0055] [Formula 2]

[0056]

[0057] [Formula 3]

[0058]

[0059] [Formula 4]

[0060]

[0061] [Formula 5]

[0062]

[0063] [Formula 6]

[0064]

[0065] in,

[0066] R1 can be C 1-4 Alkyl or phenyl, wherein the C 1-4 At least one of the H groups of the alkyl and phenyl groups may be replaced by halogen or C 1-4 Alkyl substitution,

[0067] R2 can be H, C 1-4 an alkyl group or an acetyl group, wherein at least one H of the acetyl group may be substituted with a halogen,

[0068] R3 and R4 can be independently selected from H, C 1-4 Alkyl and C 3-7 or together form a 3- to 7-membered alicyclic ring, wherein the C 1-4 Alkyl, C 3-7 The cycloalkyl group and at least one H of the formed 3- to 7-membered alicyclic ring may be substituted with halogen, and

[0069] R5 can be H, C 1-4 Alkyl or acetyl.

[0070] In one embodiment, in the above formula,

[0071] R1 can be C 1-4 Alkyl or phenyl, where C 1-4 At least one H of the alkyl group may be substituted with halogen, and at least one H of the phenyl group may be substituted with C 1-4 Alkyl substitution,

[0072] R2 may be H or acetyl, wherein at least one H of the acetyl may be substituted by halogen,

[0073] R3 and R4 can be C 1-4 alkyl, or together form a 3- to 7-membered alicyclic ring, and

[0074] R5 can be H or C 1-4 alkyl.

[0075] In one embodiment, in the above formula,

[0076] R1 can be C 1-4 Alkyl or phenyl, where C 1-4 At least one H of the alkyl group may be substituted with fluorine (F), and at least one H of the phenyl group may be substituted with methyl,

[0077] R2 may be H or acetyl, wherein at least one H of the acetyl may be substituted by fluorine (F),

[0078] R3 and R4 can be C 1-4 alkyl, or together form a 3- to 7-membered alicyclic ring, and

[0079] R5 can be H or C 1-4 alkyl.

[0080] In one embodiment, in the above formula,

[0081] R1 can be methyl, trifluoromethyl or tolyl,

[0082] R2 may be H, acetyl or trifluoroacetyl,

[0083] R3 and R4 may be methyl, or together form a 6-membered alicyclic ring, and

[0084] R5 may be H or methyl.

[0085] In the present invention, the compound represented by Formula 4 above may contain one or more stereocenters and thus may exist as a mixture of enantiomers including a racemate, a single enantiomer, a mixture of diastereomers, or as a single diastereomer.

[0086] The method for preparing the benzimidazole derivative according to the present invention may include: 1) preparing a compound represented by the above Formula 2 by reacting a compound represented by the above Formula 3 with a monovalent copper catalyst in the presence of a ligand represented by the above Formula 4 or a stereoisomer thereof.

[0087] The monovalent copper catalyst of 1) above may be a catalyst selected from the group consisting of cuprous chloride, cupric bromide, cupric iodide, and cuprous oxide, and specifically, may be cupric bromide, but is not limited thereto.

[0088] 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 a stereoisomer thereof in 1) above may be 10:2:4 to 10:0.5:0.5, but is not limited thereto.

[0089] The above 1) may be performed in at least one solvent selected from the group consisting of water, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, and 1,4-dioxane, and may specifically be performed in water and dimethyl sulfoxide, but is not limited thereto.

[0090] The above 1) can be performed by adjusting the temperature between 37° C. and 60° C. and stirring for 10 to 60 minutes, but is not limited thereto.

[0091] The method for preparing the benzimidazole derivative according to the present invention may include: 2) preparing the compound represented by the above Formula 5 by reacting the compound represented by the above Formula 2.

[0092] The above 2) can prepare the compound represented by the above Formula 5 by subjecting the compound represented by the above Formula 2 to a reductive cyclization reaction.

[0093] The reductive cyclization of 2) above can be performed by adding a reducing agent or a reducing agent and an acetyl source.

[0094] The reductive cyclization of 2) above may include nitro reduction using a reducing agent or nitro reduction using a reducing agent and cyclization with an acetyl source.

[0095] The reducing agent in the above 2) may be at least one selected from the group consisting of H2 / 10% palladium carbon, reduced iron and sodium dithionate, but is not limited thereto.

[0096] The acetyl source in the above 2) may be at least one selected from the group consisting of triethyl orthoacetate and acetylacetone, but is not limited thereto.

[0097] The above 2) may be performed by reacting the compound represented by the above Formula 2 with H2 / 10% palladium carbon and triethyl orthoacetate; reduced iron and triethyl orthoacetate; or sodium dithionate, but is not limited thereto.

[0098] The method for preparing the benzimidazole derivative according to the present invention may include: 3) preparing the compound represented by the above Formula 1 by reacting the compound represented by the above Formula 5, acetyl chloride and the compound represented by the above Formula 6 in the presence of a base.

[0099] The base of 3) above may be at least one selected from the group consisting of cobalt-free potassium carbonate, sodium carbonate, cesium carbonate, aqueous ammonia, and pyridine, and may specifically be potassium carbonate and pyridine, but is not limited thereto.

[0100] The molar ratio of the compound represented by the above Formula 5 and the compound represented by the above Formula 6 in the above 3) may be 1:1 to 1:2.5, but is not limited thereto.

[0101] The molar ratio of acetyl chloride to the base in 3) above may be 1:2 to 1:4, but is not limited thereto.

[0102] The molar ratio of the compound represented by the above Formula 5 and acetyl chloride in the above 3) may be 1:1 to 1:1.5, but is not limited thereto.

[0103] The molar ratio of the compound represented by the above Formula 6 and the base in the above 3) may be 1:1 to 1:4, but is not limited thereto.

[0104] The above 3) may be performed in at least one solvent selected from the group consisting of acetone, methyl ethyl ketone, ethyl acetate, dichloromethane, chloroform, and acetonitrile, and may specifically be performed in dichloromethane, but is not limited thereto.

[0105] 3) above may include:

[0106] a) adding a compound represented by the above Formula 5 and acetyl chloride to a solvent; and

[0107] b) Adding the compound represented by the above Formula 6 in the presence of a base.

[0108] The addition amount of the compound represented by the above Formula 5 in the above a) may be 5% (w / v) to 33% (w / v) with respect to the solvent, but is not limited thereto.

[0109] The above a) can be performed by adjusting the temperature between 3° C. and 40° C. and stirring for 30 to 120 minutes, but is not limited thereto.

[0110] The above b) can be performed by adjusting the temperature between 27° C. and 40° C. and stirring for 10 to 180 minutes, but is not limited thereto.

[0111] The method for preparing the benzimidazole derivative according to the present invention may include: 4) preparing the compound represented by the above Formula 1-1 by adjusting the pH of the compound represented by the above Formula 1.

[0112] The pH in 4) above can be adjusted between 8 and 12, but is not limited thereto.

[0113] The above 4) can be achieved by adjusting the temperature between 3°C and 10°C, but is not limited thereto.

[0114] The process for preparing the benzimidazole derivatives according to the present invention can be carried out in situ in 3) and 4).

[0115] The present invention may provide a compound represented by the following Formula 1:

[0116] [Formula 1]

[0117]

[0118] in,

[0119] R1 can be C 1-4 Alkyl or phenyl, wherein the C 1-4 At least one of the H groups of the alkyl and phenyl groups may be replaced by halogen or C 1-4 Alkyl substitution.

[0120] In one embodiment, in the above formula,

[0121] R1 can be C 1-4 Alkyl or phenyl, where C 1-4 At least one H of the alkyl group may be substituted with halogen, and at least one H of the phenyl group may be substituted with C 1-4 Alkyl substitution.

[0122] In one embodiment, in the above formula,

[0123] R1 can be C 1-4 Alkyl or phenyl, where C 1-4 At least one H of the alkyl group may be substituted with fluorine (F), and at least one H of the phenyl group may be substituted with a methyl group.

[0124] In one embodiment, R1 may be methyl, trifluoromethyl or tolyl.

[0125] The compound represented by the above Formula 1 may be selected from the group consisting of:

[0126] 6-(Dimethylcarbamoyl)-2-methyl-1-tosyl-1H-benzo[d]imidazol-4-yl acetate;

[0127] 6-(dimethylcarbamoyl)-2-methyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazol-4-yl acetate; and

[0128] 6-(Dimethylcarbamoyl)-2-methyl-1-methylsulfonyl-1H-benzo[d]imidazol-4-yl acetate.

[0129] The present invention can provide the following methods (1) to (28):

[0130] (1) A method for preparing a benzimidazole derivative, the method comprising:

[0131] 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:

[0132] 2) preparing a compound represented by the following Formula 5 by reacting a compound represented by the following Formula 2: and

[0133] 3) preparing a compound represented by the following Formula 1 by reacting a compound represented by the following Formula 5, acetyl chloride and a compound represented by the following Formula 6 in the presence of a base,

[0134] [Formula 1]

[0135]

[0136] [Formula 2]

[0137]

[0138] [Formula 3]

[0139]

[0140] [Formula 4]

[0141]

[0142] [Formula 5]

[0143]

[0144] [Formula 6]

[0145]

[0146] in,

[0147] R1 can be C 1-4 Alkyl or phenyl, wherein the C 1-4 At least one of the H groups of the alkyl and phenyl groups may be replaced by halogen or C 1-4 Alkyl substitution,

[0148] R2 can be H, C 1-4 an alkyl group or an acetyl group, wherein at least one H of the acetyl group may be substituted with a halogen,

[0149] R3 and R4 can be independently selected from H, C 1-4 Alkyl and C 3-7 or together form a 3- to 7-membered alicyclic ring, wherein the C 1-4 Alkyl, C 3-7 The cycloalkyl group and at least one H of the formed 3- to 7-membered alicyclic ring may be substituted with halogen, and

[0150] R5 can be H, C 1-4 Alkyl or acetyl.

[0151] (2) The method of (1) above may further include:

[0152] 4) By adjusting the pH of the compound represented by the above formula 1, the following compound represented by formula 1-1 is prepared:

[0153] [Formula 1-1]

[0154]

[0155] in,

[0156] R1 may be the same as in Formula I above.

[0157] (3) A method for preparing a benzimidazole derivative, the method comprising:

[0158] 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:

[0159] 2) preparing a compound represented by the following Formula 5 by reacting a compound represented by the following Formula 2:

[0160] 3) preparing a compound represented by the following Formula 1 by reacting a compound represented by the following Formula 5, acetyl chloride, and a compound represented by the following Formula 6 in the presence of a base; and

[0161] 4) preparing a compound represented by Formula 1-1 by adjusting the pH of the compound represented by Formula 1,

[0162] [Formula 1-1]

[0163]

[0164] [Formula 1]

[0165]

[0166] [Formula 2]

[0167]

[0168] [Formula 3]

[0169]

[0170] [Formula 4]

[0171]

[0172] [Formula 5]

[0173]

[0174] [Formula 6]

[0175]

[0176] in,

[0177] R1 can be C 1-4 Alkyl or phenyl, wherein the C 1-4 At least one of the H groups of the alkyl and phenyl groups may be replaced by halogen or C 1-4 Alkyl substitution,

[0178] R2 can be H, C 1-4an alkyl group or an acetyl group, wherein at least one H of the acetyl group may be substituted with a halogen,

[0179] R3 and R4 can be independently selected from H, C 1-4 Alkyl and C 3-7 or together form a 3- to 7-membered alicyclic ring, wherein the C 1-4 Alkyl, C 3-7 The cycloalkyl group and at least one H of the formed 3- to 7-membered alicyclic ring may be substituted with halogen, and

[0180] R5 can be H, C 1-4 Alkyl or acetyl.

[0181] (4) The method of (1), (2) or (3) above, wherein:

[0182] R1 can be C 1-4 Alkyl or phenyl, where C 1-4 At least one H of the alkyl group may be substituted with halogen, and at least one H of the phenyl group may be substituted with C 1-4 Alkyl substitution,

[0183] R2 may be H or acetyl, wherein at least one H of the acetyl may be substituted by halogen,

[0184] R3 and R4 can be C 1-4 alkyl, or together form a 3- to 7-membered alicyclic ring, and

[0185] R5 can be H or C 1-4 alkyl.

[0186] (5) The method of (1), (2), (3) or (4) above, wherein:

[0187] R1 can be C 1-4 Alkyl or phenyl, where C 1-4 At least one H of the alkyl group may be substituted with fluorine (F), and at least one H of the phenyl group may be substituted with methyl,

[0188] R2 may be H or acetyl, wherein at least one H of the acetyl may be substituted by fluorine (F),

[0189] R3 and R4 can be C 1-4 alkyl, or together form a 3- to 7-membered alicyclic ring, and

[0190] R5 can be H or C 1-4 alkyl.

[0191] (6) The method of (1), (2), (3), (4) or (5) above, wherein:

[0192] R1 can be methyl, trifluoromethyl or tolyl,

[0193] R2 may be H, acetyl or trifluoroacetyl,

[0194] R3 and R4 may be methyl, or together form a 6-membered alicyclic ring, and

[0195] R5 may be H or methyl.

[0196] (7) The method of (1), (2), (3) or (4) above, wherein:

[0197] R1 may be methyl, trifluoromethyl or tolyl.

[0198] (8) The method of (1), (2), (3), (4), (5), (6) or (7) above, wherein the monovalent copper catalyst of 1) above may be a catalyst selected from the group consisting of cuprous chloride, cupric bromide, cupric iodide and cuprous oxide.

[0199] (9) The method of (1), (2), (3), (4), (5), (6), (7) or (8) above, wherein 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 in the above 1) can be 10:2:4 to 10:0.5:0.5.

[0200] (10) The method of (1), (2), (3), (4), (5), (6), (7), (8) or (9) above, wherein 1) above can be carried out in at least one solvent selected from the group consisting of: water, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide and 1,4-dioxane.

[0201] (11) The method of (1), (2), (3), (4), (5), (6), (7), (8), (9) or (10) above, wherein 1) above can be carried out by adjusting the temperature between 37°C and 60°C and stirring for 10 to 60 minutes.

[0202] (12) The method of (1), (2), (3), (4), (5), (6), (7), (8), (9), (10) or (11) above, wherein 2) above can prepare the compound represented by the above formula 5 by subjecting the compound represented by the above formula 2 to a reductive cyclization reaction.

[0203] (13) The method of the above (12), wherein the reductive cyclization of the above 2) can be performed by adding a reducing agent or a reducing agent and an acetyl source.

[0204] (14) The method of (13) above, wherein the reducing agent may be at least one selected from the group consisting of H2 / 10% palladium carbon, reduced iron and sodium dithionate.

[0205] (15) The method of (13) or (14) above, wherein the acetyl group source may be at least one selected from the group consisting of triethyl orthoacetate and acetylacetone.

[0206] (16) The method of (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14) or (15) above, wherein the base in (3) above can be at least one selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, aqueous ammonia and pyridine.

[0207] (17) The method of (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15) or (16) above, wherein the molar ratio of the compound represented by the above formula 5 and the compound represented by the above formula 6 in the above 3) can be 1:1 to 1:2.5.

[0208] (18) The method of (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16) or (17) above, wherein the molar ratio of acetyl chloride to the base in 3) above can be 1:2 to 1:4.

[0209] (19) The method of (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17) or (18) above, wherein the molar ratio of the compound represented by the above formula 5 and acetyl chloride in the above 3) can be 1:1 to 1:1.5.

[0210] (20) The method of (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18) or (19) above, wherein the molar ratio of the compound represented by the above formula 6 and the base in the above 3) can be 1:1 to 1:4.

[0211] (21) The method of (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19) or (20) above, wherein the above 3) can be carried out in at least one solvent selected from the group consisting of acetone, methyl ethyl ketone, ethyl acetate, dichloromethane, chloroform and acetonitrile.

[0212] (22) The method of (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20) or (21) above, wherein 3) above may include:

[0213] a) adding a compound represented by the above Formula 5 and acetyl chloride to a solvent; and

[0214] b) Adding the compound represented by the above Formula 6 in the presence of a base.

[0215] (23) The method of (22) above, wherein the addition amount of the compound represented by the above Formula 5 in the above a) may be 5% (w / v) to 33% (w / v) relative to the solvent.

[0216] (24) The method of (22) or (23) above, wherein a) above can be performed by adjusting the temperature between 3°C and 40°C and stirring for 30 to 120 minutes.

[0217] (25) The method of (22), (23) or (24) above, wherein b) above can be performed by adjusting the temperature between 27°C and 40°C and stirring for 10 to 180 minutes.

[0218] (26) The method of (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 can adjust the pH to between 8 and 12.

[0219] (27) The method of (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) above, wherein 4) above can be carried out by adjusting the temperature between 3°C and 10°C.

[0220] (28) The method of (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) above, wherein 3) and 4) above are performed in situ.

[0221] The present invention can provide the following compounds (1) to (5):

[0222] (1) A compound represented by the following formula 1:

[0223] [Formula 1]

[0224]

[0225] in,

[0226] R1 is C 1-4 Alkyl or phenyl, wherein the C 1-4 At least one of the H groups of the alkyl and phenyl groups may be replaced by halogen or C 1-4 Alkyl substitution.

[0227] (2) The compound of (1) above, wherein R1 can be C 1-4 Alkyl or phenyl, where C 1-4 At least one H of the alkyl group may be substituted with halogen, and at least one H of the phenyl group may be substituted with C 1-4 Alkyl substitution.

[0228] (3) The compound of (1) or (2) above, wherein R1 can be C 1-4 Alkyl or phenyl, where C 1-4 At least one H of the alkyl group may be substituted with fluorine (F), and at least one H of the phenyl group may be substituted with a methyl group.

[0229] (4) The compound of (1), (2) or (3) above, wherein R1 may be methyl, trifluoromethyl or tolyl.

[0230] (5) The compound of (1), (2), (3) or (4) above, wherein the compound may be selected from the group consisting of:

[0231] 6-(Dimethylcarbamoyl)-2-methyl-1-tosyl-1H-benzo[d]imidazol-4-yl acetate;

[0232] 6-(dimethylcarbamoyl)-2-methyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazol-4-yl acetate; and

[0233] 6-(Dimethylcarbamoyl)-2-methyl-1-methylsulfonyl-1H-benzo[d]imidazol-4-yl acetate.

[0234] Beneficial Effects

[0235] The method for preparing the benzimidazole derivative according to the present invention has low preparation cost, does not require a chromatography process during the preparation process, and does not use high-risk and high-cost reagents, and thus can be advantageous for large-scale production and can be prepared in high yield.

[0236] Furthermore, the compound prepared by the above preparation method can be used to efficiently prepare other compounds having a benzimidazole structure, and specifically, can be used as an intermediate for preparing compounds useful as antibacterial agents, antiulcer agents and anti-inflammatory agents. DETAILED DESCRIPTION

[0237] Hereinafter, the present invention will be described in more detail through exemplary embodiments. These exemplary embodiments are provided only for the purpose of illustrating the present invention, and therefore it is obvious to those skilled in the art that the scope of the present invention is not limited thereto.

[0238] Example 1. Step 1)

[0239] Example 1-1. Preparation of 4-acetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide

[0240] 1034.8g purified water, 701.9g dimethyl sulfoxide and 144.4g potassium carbonate are added to the reactor in sequence. The resulting solution is stirred for 30 minutes while the internal temperature is raised to 37°C. 3.8g copper bromide (I), 7.4g trans-N, N-dimethylcyclohexane-1,2-diamine and 344.9g purified water are added and stirred while maintaining the internal temperature at 37°C. Then, a solution obtained by dissolving 172.5g 4-acetylamino-3-bromo-N, N-dimethyl-5-nitrobenzamide in 38.5g dimethyl sulfoxide is added to the reactor. The reaction solution is stirred for 60 minutes while being maintained at 37°C to complete the reaction. 345.0g distilled water is added and the internal temperature is cooled to 10-15°C by using an ice bath, after which the resulting mixture is stirred for 12 hours and crystallized. The resulting crystals are filtered and the filtrate is washed with pure water. The obtained solid was vacuum dried at 40° C. to give 128.4 g of 4-acetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide (yield: 92%).

[0241] 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)

[0242] Example 1-2. Preparation of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide

[0243] 899.8g purified water, 610.3g dimethyl sulfoxide and 125.6g potassium carbonate are added to the reactor in sequence. The resulting solution is stirred for 30 minutes while the internal temperature is raised to 60°C. 15.5g copper bromide (I), 6.4g trans-N, N-dimethylcyclohexane-1,2-diamine and 299.9g purified water are added and stirred while maintaining the internal temperature at 60°C. Then, a solution obtained by dissolving 155.2g 4-amino-3-bromo-N, N-dimethyl-5-nitrobenzamide in 33.5g dimethyl sulfoxide is added to the reactor. The reaction solution is stirred for 10 minutes while being maintained at 60°C to complete the reaction. 300.0g distilled water is added and the internal temperature is cooled to 10-15°C by using an ice bath, after which the resulting mixture is stirred for 12 hours and crystallized. The crystals are filtered and the filtrate is washed with pure water. The obtained solid was vacuum dried at 40° C. to give 109.2 g of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide (yield: 90%).

[0244] 1H-NMR(400MHz,DMSO-d6):10.7(s,1H),7.6(d,1H),7.1(s,2H),7.0(s,1H),3.0(s,6H)

[0245] Example 1-3. Preparation of 4-trifluoroacetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide

[0246] 1010.8g purified water, 685.6g dimethyl sulfoxide and 141.1g potassium carbonate are added to the reactor in sequence. The resulting solution is stirred for 90 minutes while the internal temperature is raised to 45°C. 3.7g copper bromide (I), 7.2g trans-N, N-dimethylcyclohexane-1,2-diamine and 336.9g purified water are added and stirred while maintaining the internal temperature at 45°C. Then, a solution obtained by dissolving 163.0g 4-trifluoroacetylamino-3-bromo-N, N-dimethyl-5-nitrobenzamide in 37.6g dimethyl sulfoxide is added to the reactor. The reaction solution is stirred for 60 minutes while being maintained at 45°C to complete the reaction. 337.0g distilled water is added and the internal temperature is cooled to 10-15°C by using an ice bath, after which the resulting mixture is stirred for 12 hours and crystallized. The resulting crystals are filtered and the filtrate is washed with pure water. The obtained solid was vacuum dried at 40° C. to give 117.2 g of 4-trifluoroacetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide (yield: 86%).

[0247] 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)

[0248] Example 1-4. Preparation of 4-acetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide

[0249] 1034.8g purified water, 701.9g dimethyl sulfoxide and 144.4g potassium carbonate are added to the reactor in sequence. The resulting solution is stirred for 30 minutes while the internal temperature is raised to 37°C. 3.8g copper bromide (I), 5.9g trans-1,2-diaminocyclohexane and 344.9g purified water are added and stirred while maintaining the internal temperature at 37°C. Then, a solution obtained by dissolving 172.5g 4-acetylamino-3-bromo-N,N-dimethyl-5-nitrobenzamide in 38.5g dimethyl sulfoxide is added to the reactor. The reaction solution is stirred for 60 minutes while being maintained at 37°C to complete the reaction. 345.0g distilled water is added and the internal temperature is cooled to 10-15°C by using an ice bath, after which the resulting mixture is stirred for 12 hours and crystallized. The resulting crystals are filtered and the filtrate is washed with pure water. The obtained solid was vacuum dried at 40° C. to give 125.6 g of 4-acetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide (yield: 90%).

[0250] 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)

[0251] Example 1-5. Preparation of 4-amido-3-hydroxy-N,N-dimethyl-5-nitrobenzamide

[0252] 899.8g purified water, 610.3g dimethyl sulfoxide and 125.6g potassium carbonate are added to the reactor in sequence. The resulting solution is stirred for 30 minutes while the internal temperature is raised to 60°C. 15.5g copper bromide (I), 5.1g trans-1,2-diaminocyclohexane and 299.9g purified water are added and stirred while maintaining the internal temperature at 60°C. Then, a solution obtained by dissolving 155.2g 4-amino-3-bromo-N,N-dimethyl-5-nitrobenzamide in 33.5g dimethyl sulfoxide is added to the reactor. The reaction solution is stirred for 10 minutes while being maintained at 60°C to complete the reaction. 300.0g distilled water is added and the internal temperature is cooled to 10-15°C by using an ice bath, after which the resulting mixture is stirred for 12 hours and crystallized. The crystals are filtered and the filtrate is washed with pure water. The obtained solid was vacuum dried at 40° C. to give 104.3 g of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide (yield: 86%).

[0253] 1H-NMR(400MHz,DMSO-d6):10.7(s,1H),7.6(d,1H),7.1(s,2H),7.0(s,1H),3.0(s,6H)

[0254] Example 1-6. Preparation of 4-trifluoroacetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide

[0255] 1010.8g purified water, 685.6g dimethyl sulfoxide and 141.1g potassium carbonate are added to the reactor in sequence. The resulting solution is stirred for 90 minutes while the internal temperature is raised to 45°C. 3.7g copper bromide (I), 5.8g trans-1,2-diaminocyclohexane and 336.9g purified water are added and stirred while maintaining the internal temperature at 45°C. Then, a solution obtained by dissolving 163.0g 4-trifluoroacetylamino-3-bromo-N,N-dimethyl-5-nitrobenzamide in 37.6g dimethyl sulfoxide is added to the reactor. The reaction solution is stirred for 60 minutes while being maintained at 45°C to complete the reaction. 337.0g distilled water is added and the internal temperature is cooled to 10-15°C by using an ice bath, after which the resulting mixture is stirred for 12 hours and crystallized. The resulting crystals are filtered and the filtrate is washed with pure water. The obtained solid was vacuum dried at 40° C. to give 117.2 g of 4-trifluoroacetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide (yield: 86%).

[0256] 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)

[0257] Example 1-7. Preparation of 4-acetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide

[0258] 1034.8g purified water, 701.9g dimethyl sulfoxide and 144.4g potassium carbonate are added to the reactor in sequence. The resulting solution is stirred for 30 minutes while the internal temperature is raised to 37°C. 3.8g copper bromide (I), 4.6g 1,2-dimethylethylenediamine and 344.9g purified water are added and stirred while maintaining the internal temperature at 37°C. Then, a solution obtained by dissolving 172.5g 4-acetylamino-3-bromo-N, N-dimethyl-5-nitrobenzamide in 38.5g dimethyl sulfoxide is added to the reactor. The reaction solution is stirred for 60 minutes while being maintained at 37°C to complete the reaction. 345.0g distilled water is added and the internal temperature is cooled to 10-15°C by using an ice bath, after which the resulting mixture is stirred for 12 hours and crystallized. The resulting crystals are filtered and the filtrate is washed with pure water. The obtained solid was vacuum dried at 40° C. to give 132.6 g of 4-acetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide (yield: 95%).

[0259] 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)

[0260] Example 1-8. Preparation of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide

[0261] 899.8g purified water, 610.3g dimethyl sulfoxide and 125.6g potassium carbonate are added to the reactor in sequence. The resulting solution is stirred for 30 minutes while the internal temperature is raised to 60°C. 15.5g copper bromide (I), 4.0g 1,2-dimethylethylenediamine and 299.9g purified water are added and stirred while maintaining the internal temperature at 60°C. Then, a solution obtained by dissolving 155.2g 4-amino-3-bromo-N, N-dimethyl-5-nitrobenzamide in 33.5g dimethyl sulfoxide is added to the reactor. The reaction solution is stirred for 10 minutes while being maintained at 60°C to complete the reaction. 300.0g distilled water is added and the internal temperature is cooled to 10-15°C by using an ice bath, after which the resulting mixture is stirred for 12 hours and crystallized. The crystals are filtered and the filtrate is washed with pure water. The obtained solid was vacuum dried at 40° C. to give 117.7 g of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide (yield: 97%).

[0262] 1H-NMR(400MHz,DMSO-d6):10.7(s,1H),7.6(d,1H),7.1(s,2H),7.0(s,1H),3.0(s,6H)

[0263] Example 1-9. Preparation of 4-trifluoroacetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide

[0264] 1010.8g purified water, 685.6g dimethyl sulfoxide and 141.1g potassium carbonate are added to the reactor in sequence. The resulting solution is stirred for 90 minutes while the internal temperature is raised to 45°C. 3.7g copper bromide (I), 4.5g 1,2-dimethylethylenediamine and 336.9g purified water are added and stirred while maintaining the internal temperature at 45°C. Then, a solution obtained by dissolving 163.0g 4-trifluoroacetylamino-3-bromo-N, N-dimethyl-5-nitrobenzamide in 37.6g dimethyl sulfoxide is added to the reactor. The reaction solution is stirred for 60 minutes while being maintained at 45°C to complete the reaction. 337.0g distilled water is added and the internal temperature is cooled to 10-15°C by using an ice bath, after which the resulting mixture is stirred for 12 hours and crystallized. The resulting crystals are filtered and the filtrate is washed with pure water. The obtained solid was vacuum dried at 40° C. to give 122.7 g of 4-trifluoroacetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide (yield: 90%).

[0265] 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)

[0266] Example 2. Step 2)

[0267] Example 2-1. Preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide

[0268] 994.8 g of methanol and 104.3 g of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide were added to the reactor in sequence. The resulting solution was stirred at 20-30° C. to dissolve all solids therein, after which 2.6 g of 10% palladium carbonate was added and the internal temperature was raised to 40° C. After the interior of the reactor was replaced with hydrogen, the resulting mixture was stirred for 30 minutes at a hydrogen pressure of 0.2 MPa. After slowly cooling the internal temperature of the reactor to 20-30° C., 225.4 g of triethyl orthoacetate was added and stirred for 12 hours to complete the reaction. The reaction solution was vacuum concentrated 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 and filter them out, and the filtrate was washed with purified water. The obtained solid was dried under vacuum at 40° C. to give 96.5 g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (yield: 95%).

[0269] 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)

[0270] Example 2-2. Preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide

[0271] 548.2 g of methanol, 138.4 g of 4-trifluoroacetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide and 45.8 g of triethylamine were added to the reactor in sequence. The resulting solution was stirred at 20-30° C. to dissolve all solids therein, after which 3.1 g of 10% palladium carbonate was added and the internal temperature was raised to 40° C. After the interior of the reactor was replaced with hydrogen, the resulting mixture was stirred for 30 minutes at a hydrogen pressure of 0.2 MPa. After slowly cooling the internal temperature of the reactor to 20-30° C., 185.9 g of triethyl orthoacetate was added and stirred for 12 hours to complete the reaction. The reaction solution was vacuum concentrated at 40° C. to remove methanol, and then 1840.5 g of purified water was added. The resulting mixture was stirred at 20-30° C. for 12 hours to ripen the crystals and filter them out, and then the filtrate was washed with purified water. The obtained solid was dried under vacuum at 40° C. to give 73.7 g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (yield: 88%).

[0272] 1H-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)

[0273] Example 2-3. Preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide

[0274] 1458.6 g of dimethyl sulfoxide, 1046.2 g of ethanol, 132.6 g of 4-acetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide and 432.0 g of sodium dithionite were added to the reactor in sequence. The resulting solution was stirred for 24 hours while the internal temperature was raised to 90° C. to complete the reaction. The reaction solution was concentrated under vacuum at 40° C. to remove ethanol, and then 1989.0 g of purified water was added. The resulting mixture was stirred at 20-30° C. for 12 hours to ripen the crystals and filter them out, and then the filtrate was washed with purified water. The obtained solid was dried under vacuum at 40° C. to produce 87.0 g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (yield: 80%).

[0275] 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)

[0276] Example 2-4. Preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide

[0277] 1387.7 g of acetic acid and 132.2 g of 4-amino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide were added to the reactor in sequence. 65.6 g of powdered reduced iron was added while stirring at 20-30° C., and the resulting mixture was stirred for 12 hours while the internal temperature was raised to 70° C. After the internal temperature of the reactor was slowly cooled to 20-30° C., the reaction solution was passed through diatomaceous earth filter paper to remove residual solids. Thereafter, 285.6 g of triethyl orthoacetate was added and stirred for 12 hours to complete the reaction. 1982.5 g of purified water was added to the reaction solution, the solution pH was adjusted to 7-8, and the resulting solution was stirred at 20-30° C. for 12 hours to mature the crystals and filter them out. Then, the filtrate was washed with purified water. The obtained solid was dried under vacuum at 40° C. to give 96.5 g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (yield: 75%).

[0278] 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)

[0279] Example 2-5. Preparation of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide

[0280] 548.2 g of methanol, 138.4 g of 4-trifluoroacetylamino-3-hydroxy-N,N-dimethyl-5-nitrobenzamide and 45.8 g of triethylamine were added to the reactor in sequence. The resulting solution was stirred at 20-30° C. for one hour and concentrated under vacuum at 40° C. to remove methanol. 1453.6 g of acetic acid was added to the resulting concentrate, followed by 48.1 g of powdered reduced iron and stirring the resulting mixture for 12 hours while raising the internal temperature to 70° C. After the internal temperature of the reactor was slowly cooled to 20-30° C., the reaction solution was passed through diatomaceous earth filter paper to remove residual solids. Thereafter, 129.5 g of triethyl orthoacetate was added and stirred for 12 hours to complete the reaction. 2076.0 g of purified water was added to the reaction solution, the solution pH was adjusted to 7-8, and the resulting solution was stirred at 20-30° C. for 12 hours to mature the crystals and filter them out. Then, the filtrate was washed with purified water. The obtained solid was dried under vacuum at 40° C. to give 73.7 g of 4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide (yield: 78%).

[0281] 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)

[0282] Example 3. Step 3)

[0283] Example 3-1. Preparation of 6-(dimethylcarbamoyl)-2-methyl-1-toluenesulfonyl-1H-benzo[d]imidazole-4-acetate

[0284] A mixed solution of 887.1 g of dichloromethane and 65.0 g of pyridine was prepared in a reactor. After the solution was cooled 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 then stirred at 3-5 ° C for two hours. After observing that the solid in the reaction solution was completely dissolved and reprecipitated, the temperature of the reaction solution was raised to 20-30 ° C, and 42.0 g of potassium carbonate and 58.0 g of p-toluenesulfonyl chloride were added in sequence, and stirred for another 30 minutes. The internal temperature was slowly cooled to 3-5 ° C by using an ice bath, and 333.5 g of purified water was added to complete the reaction. The solution was stirred for one hour while the temperature was raised to 20-30 ° C. The organic layer was separated and vacuum concentrated at 40 ° C to remove the reaction solvent, after which 157.3 g of acetonitrile and 200.1 g of purified water were added and stirred to crystallize. The obtained crystals were filtered, and the filtrate was washed with a mixed solution of acetonitrile and purified water. The obtained solid was vacuum dried at 40°C to give 116.3 g of 6-(dimethylcarbamoyl)-2-methyl-1-tosyl-1H-benzo[d]imidazole-4-acetate (yield: 92%).

[0285] 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)

[0286] Example 3-2. Preparation of 6-(dimethylcarbamoyl)-2-methyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazole-4-acetate

[0287] A mixed solution of 691.6 g of dichloromethane and 37.5 g of pyridine was prepared in a reactor. 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 while the solution was slowly stirred to 20-30 ° C, and then stirred at 20-30 ° C for one hour. After observing that the solid in the reaction solution was completely dissolved and reprecipitated, 32.8 g of potassium carbonate and 40.0 g of trifluoromethanesulfonyl chloride were added in sequence and stirred for another three hours. The internal temperature was slowly cooled to 3-5 ° C by using an ice bath, and 260.0 g of purified water was added to complete the reaction. The solution was stirred for one hour while the temperature was raised to 20-30 ° C. The organic layer was separated and vacuum concentrated at 40 ° C to remove the reaction solvent, after which 312.0 g of purified water was added and stirred to crystallize. The resulting crystals were filtered, and the filtrate was washed with methanol. The obtained solid was dried under vacuum at 40°C to give 76.5 g of 6-(dimethylcarbamoyl)-2-methyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazol-4-yl acetate (yield: 82%).

[0288] 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)

[0289] Example 3-3. Preparation of 6-(dimethylcarbamoyl)-2-methyl-1-(methylsulfonyl)-1H-benzo[d]imidazole-4-acetate

[0290] A mixed solution of 980.2 g of dichloromethane and 26.6 g of pyridine was prepared in a reactor. After the solution was heated to 35-40 ° C, 73.7 g of 4-hydroxy-N, N, 2-trimethyl-1H-benzo [d] imidazole-6-carboxamide and 26.4 g of acetyl chloride were added in sequence while slowly stirring, and then stirred at 40 ° C for 30 minutes. After observing that the solid in the reaction solution was completely dissolved and reprecipitated, the temperature of the solution was raised to 20-30 ° C, and 46.5 g of potassium carbonate and 38.5 g of methanesulfonyl chloride were added in sequence, and stirred for another three hours. The internal temperature was slowly cooled to 3-5 ° C by using an ice bath, and 368.5 g of purified water was added to complete the reaction. The solution was stirred for one hour while the temperature was raised to 20-30 ° C. The organic layer was separated and vacuum concentrated at 40 ° C to remove the reaction solvent, and then 291.9 g of methanol was added and stirred to crystallize. The resulting crystals were filtered, and the filtrate was washed with methanol. The obtained solid was dried under vacuum at 40°C to give 91.3 g of 6-(dimethylcarbamoyl)-2-methyl-1-(methylsulfonyl)-1H-benzo[d]imidazol-4-yl acetate (yield: 80%).

[0291] 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)

[0292] Example 4. Step 4)

[0293] Example 4-1. Preparation of 4-hydroxy-N,N,2-trimethyl-1-toluenesulfonyl-1H-benzo[d]imidazole-6-carboxamide

[0294] A mixed solution of 213.8 g of methanol and 270.0 g of purified water was prepared in a reactor. 90.0 g of acetic acid 6-(dimethylcarbamoyl)-2-methyl-1-toluenesulfonyl-1H-benzo[d]imidazole-4-ester was added while slowly stirring the solution at 20-30° C. The internal temperature was slowly cooled to 3-5° C. by using an ice bath, and the pH of the reaction solution was adjusted to 10.0-10.2 by using 30-35% ammonia water. The reaction solution was stirred at 3-5° C. for another 16 hours while maintaining its pH value. The resulting crystals were filtered and washed with a mixed solution of methanol and purified water. The obtained solid was vacuum dried at 40° C. to produce 76.8 g of 4-hydroxy-N,N,2-trimethyl-1-toluenesulfonyl-1H-benzo[d]imidazole-6-carboxamide (yield: 95%).

[0295] 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)

[0296] Example 4-2. Preparation of 4-hydroxy-N,N,2-trimethyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazole-6-carboxamide

[0297] A mixed solution of 130.8 g of methanol and 165.1 g of purified water was prepared in a reactor. 55.0 g of 6-(dimethylcarbamoyl)-2-methyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazole-4-ester was added while slowly stirring the solution at 20-30° C. The internal temperature was slowly cooled to 3-5° C. by using an ice bath, and the pH of the reaction solution was adjusted to 8.0-8.2 by using 30-35% ammonia water. After adding 330.2 g of purified water, the reaction mixture was stirred at 3-5 for another 16 hours while maintaining its pH. The resulting crystals were filtered and washed with a mixed solution of methanol and purified water. The obtained solid was vacuum dried at 40° C. to produce 46.2 g of 4-hydroxy-N,N,2-trimethyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazole-6-carboxamide (yield: 94%).

[0298] 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)

[0299] Example 4-3. Preparation of 4-hydroxy-N,N,2-trimethyl-1-(methylsulfonyl)-1H-benzo[d]imidazole-6-carboxamide

[0300] A mixed solution of 171.1 g of methanol and 216.0 g of purified water was prepared in a reactor. 72.0 g of acetic acid 6-(dimethylcarbamoyl)-2-methyl-1-(methylsulfonylsulfonyl)-1H-benzo[d]imidazole-4-ester was added while slowly stirring the solution at 20-30°C. The internal temperature was slowly cooled to 3-5°C by using an ice bath, and the pH of the reaction solution was adjusted to 10.0-10.5 by using 30-35% ammonia water. After adding 216.0 g of purified water, the reaction mixture was stirred at 3-5 for another 16 hours while maintaining its pH. The resulting crystals were filtered and washed with a mixed solution of methanol and purified water. The obtained solid was vacuum dried at 40°C to produce 59.3 g of 4-hydroxy-N,N,2-trimethyl-1-(methylsulfonyl)-1H-benzo[d]imidazole-6-carboxamide (yield: 94%).

[0301] 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)

[0302] Example 5. Step 3) + Step 4) (in situ)

[0303] Example 5-1. Preparation of 4-hydroxy-N,N,2-trimethyl-1-toluenesulfonyl-1H-benzo[d]imidazole-6-carboxamide

[0304] A mixed solution of 663.7 g of dichloromethane and 48.7 g of pyridine was prepared in a reactor. After the solution was cooled 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 then stirred at 3-5 ° C for two hours. After observing that the solid in the reaction solution was completely dissolved and reprecipitated, the temperature of the reaction solution was raised to 20-30 ° C, and 31.5 g of potassium carbonate and 87.0 g of p-toluenesulfonyl chloride were added in sequence, and stirred for another 30 minutes. The internal temperature was slowly cooled to 3-5 ° C by using an ice bath, and 50.0 g of purified water and 7.4 g of tetra-n-butylammonium bromide were added thereto. While the reaction solution was vigorously stirred, 157.6 g of potassium carbonate was added and the reaction was continued for 16 hours. The reaction was completed by adding 250.0 g of purified water and adjusting the pH of the reaction solution to 5-7. The solution was stirred for one hour while the temperature was raised to 20-30°C. The organic layer was separated and concentrated in vacuo 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 for crystallization. The resulting crystals were filtered, and the filtrate was washed with a mixed solution of methanol and purified water. The obtained solid was dried in vacuo at 40°C to produce 76.7 g of 4-hydroxy-N,N,2-trimethyl-1-tosyl-1H-benzo[d]imidazole-6-carboxamide (yield: 90%).

[0305] 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)

[0306] Example 5-2. Preparation of 4-hydroxy-N,N,2-trimethyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazole-6-carboxamide

[0307] A mixed solution of 663.6 g of dichloromethane and 36.1 g of pyridine was prepared in a reactor. 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 the solution was slowly stirred to 20-30 ° C, and then stirred at 20-30 ° C for one hour. After observing that the solid in the reaction solution was completely dissolved and reprecipitated, 31.5 g of potassium carbonate and 76.9 g of trifluoromethanesulfonyl chloride were added in sequence and stirred for another three hours. The internal temperature was slowly cooled to 3-5 ° C by using an ice bath, and 50.0 g of purified water and 7.4 g of tetra-n-butylammonium bromide were added thereto. While the reaction solution was vigorously stirred, 44.0 g of 30-35% ammonia water was added and the reaction was continued for 16 hours. The reaction was completed by adding 250.0 g of purified water and adjusting the pH of the reaction solution to 5-7. The solution was stirred for one hour while the temperature was raised 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 for crystallization. The resulting crystals were filtered, and the filtrate was washed with a mixed solution of methanol and purified water. The obtained solid was dried under vacuum at 40°C to produce 64.1 g of 4-hydroxy-N,N,2-trimethyl-1-((trifluoromethyl)sulfonyl)-1H-benzo[d]imidazole-6-carboxamide (yield: 80%).

[0308] 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)

[0309] Example 5-3. Preparation of 4-hydroxy-N,N,2-trimethyl-1-(methylsulfonyl)-1H-benzo[d]imidazole-6-carboxamide

[0310] A mixed solution of 663.5 g of dichloromethane and 18.0 g of pyridine was prepared in a reactor. After the solution was heated to 35-40 ° 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 then stirred at 40 ° C for 30 minutes. After observing that the solid in the reaction solution was completely dissolved and reprecipitated, the temperature of the solution was raised to 20-30 ° C, and 31.5 g of potassium carbonate and 52.2 g of methanesulfonyl chloride were added in sequence, and stirred for another three hours. The internal temperature was slowly cooled to 3-5 ° C by using an ice bath, and 50.0 g of purified water and 7.4 g of tetra-n-butylammonium bromide were added thereto. While the reaction solution was vigorously stirred, 88.0 g of 30-35% ammonia water was added and the reaction was continued for 16 hours. The reaction was completed by adding 250.0 g of purified water and adjusting the pH of the reaction solution to 5-7. The solution was stirred for one hour while the temperature was raised to 20-30°C. The organic layer was separated and concentrated in vacuo 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 for crystallization. The resulting crystals were filtered, and the filtrate was washed with a mixed solution of methanol and purified water. The obtained solid was dried in vacuo at 40°C to produce 53.6 g of 4-hydroxy-N,N,2-trimethyl-1-(methylsulfonyl)-1H-benzo[d]imidazole-6-carboxamide (yield: 80%).

[0311] 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)

[0312] Although the specific parts of the present invention have been described in detail above, it is obvious to those skilled in the art that such detailed description is only for illustrative purposes and does not constitute a limitation on the scope of the present invention. Therefore, it should be understood that the essential scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a benzimidazole derivative, the method comprising: 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) preparing a compound represented by the following Formula 5 by reacting a compound represented by the following Formula 2; and 3) preparing a compound represented by the following Formula 1 by reacting a compound represented by the following Formula 5, acetyl chloride and a compound represented by the following Formula 6 in the presence of a base, [Formula 1] [Formula 2] [Formula 3] [Formula 4] [Formula 5] [Formula 6] in, R1 is C 1-4 Alkyl or phenyl, wherein the C 1-4 At least one of the H groups of the alkyl and phenyl groups may be replaced by halogen or C 1-4 Alkyl substitution, R2 is H, C 1-4 an alkyl group or an acetyl group, wherein at least one H of the acetyl group may be substituted with a halogen, R3 and R4 are each independently selected from H, C 1-4 Alkyl and C 3-7 or together form a 3- to 7-membered alicyclic ring, wherein the C 1-4 Alkyl, C 3-7 The cycloalkyl group and at least one H of the formed 3- to 7-membered alicyclic ring may be substituted with halogen, and R5 is H, C 1-4 Alkyl or acetyl.

2. The method according to claim 1, wherein: R1 is methyl, trifluoromethyl or tolyl, R2 is H, acetyl or trifluoroacetyl, R3 and R4 are methyl, or together form a 6-membered aliphatic ring, and R5 is H or methyl.

3. The method according to claim 1, further comprising: 4) By adjusting the pH of the compound represented by the above formula 1, a compound represented by the following formula 1-1 is prepared: [Formula 1-1] in, R1 is the same as in the above formula I according to claim 1.

4. The method according to claim 1, wherein R1 is methyl, trifluoromethyl or tolyl.

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

6. The method according to claim 1, wherein 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 the stereoisomer thereof in the above 1) is 10:2:4 to 10:0.5:0.

5.

7. The method according to claim 1, wherein the above 1) is carried out in at least one solvent selected from the group consisting of: water, acetonitrile, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide and 1,4-dioxane.

8. The method according to claim 1, wherein the above 1) is performed by adjusting the temperature between 37°C and 60°C and stirring for 10 to 60 minutes.

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

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

11. The method according to claim 10, wherein the reducing agent is at least one selected from the group consisting of H2 / 10% palladium carbon, reduced iron and sodium dithionate.

12. The method according to 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) above 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 a molar ratio of the compound represented by the above Formula 5 to the compound represented by the above Formula 6 in the above 3) is 1:1 to 1:2.

5.

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

4.

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

5.

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

19. The method according to claim 18, wherein the above 3) comprises: a) adding a compound represented by the above formula 5 and acetyl chloride to a solvent; as well as b) Adding the compound represented by the above Formula 6 in the presence of a base. 20 . The method according to claim 19 , wherein the compound represented by the above Formula 5 in the above a) is added in an amount of 5% (w / v) to 33% (w / v) relative to the solvent.

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

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

23. The method according to claim 3, wherein the pH is adjusted between 8 and 12 in 4) above.

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

25. The method according to claim 3, wherein the above 3) and 4) are performed in situ.

26. A compound represented by the following formula 1: [Formula 1] in, R1 is C 1-4 Alkyl or phenyl, wherein the C 1-4 At least one of the H groups of the alkyl and phenyl groups may be replaced by halogen or C 1-4 Alkyl substitution.

27. The compound according to claim 26, wherein R1 is methyl, trifluoromethyl or tolyl.

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

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