A method for preparing a benzimidazole compound

Abstract

This invention discloses a method for preparing a benzimidazole compound represented by formula (II). The method comprises reacting the compound represented by formula (I) or its salt in a solvent with butyronitrile in the presence or absence of an alkaline reagent to prepare the compound represented by formula (II). When this method is used to prepare a key intermediate of the antihypertensive drug telmisartan, it can avoid some problems existing in the prior art, such as the safety of the nitration reaction itself, the disposal of nitration waste liquid, and the phosphorus-containing waste liquid caused by the use of polyphosphoric acid.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing benzimidazole compounds. Background Technology

[0002] Telmisartan is the active ingredient in a medication for treating hypertension. Benzimidazole (II-2) and bisbenzimidazole (II-1) are key intermediates in the preparation of telmisartan. Patent (EP502314) reports a method for first preparing a monobenzimidazole intermediate (II-2) from aniline (VIII-3) through acylation, nitration, reduction, and hydrolysis, followed by polyphosphate cyclization to obtain the bisbenzimidazole intermediate (II-1). The route is as follows:

[0003]

[0004] This method has some problems, such as the safety of the nitration reaction itself, the disposal of nitration waste liquid, and the phosphorus-containing waste liquid caused by the use of polyphosphoric acid.

[0005] Therefore, developing synthetic methods for the key intermediates of telmisartan, benzimidazole (II-2) and bisbenzimidazole (II-1), which are safe, environmentally friendly, green and sustainable, remains of great significance.

[0006] In view of this, the present invention is hereby proposed. Summary of the Invention

[0007] The purpose of this invention is to overcome the problems in the prior art described above and to provide a method for preparing benzimidazole compounds represented by formula (II).

[0008] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted:

[0009] A method for preparing a benzimidazole compound of formula (II), the method comprising:

[0010]

[0011] The compound shown in formula (I) or its salt is reacted with butyronitrile in a solvent in the presence or absence of a basic reagent and a catalyst to prepare the compound shown in formula (II);

[0012] In equation (I),

[0013] X is chlorine (Cl), bromine (Br), or iodine (I); preferably bromine (Br) or iodine (I);

[0014] R is selected from

[0015] R0 is selected from hydrogen, C1-C5 straight-chain or branched alkyl groups, preferably hydrogen, methyl, ethyl, propyl, butyl or pentyl, and more preferably hydrogen or methyl.

[0016] In specific embodiments, the solvent is selected from one or a mixture of several of the following: dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, xylene, chlorobenzene, acetonitrile, acetone, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, pyridine, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and water; preferably, it is a mixture of one or more of 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, tert-butanol, and tert-amyl alcohol; more preferably, it is ethylene glycol dimethyl ether, toluene, tert-butanol, or tert-amyl alcohol; and even more preferably, it is toluene, tert-butanol, or tert-amyl alcohol.

[0017] In specific embodiments, the alkaline reagent is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide, potassium tert-pentoxide, lithium tert-pentoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, magnesium tert-pentoxide, sodium amino, and lithium diisopropylamino. The following are one or a mixture of several of the following: lithium hexamethyldisilamide, sodium hexamethyldisilamide, potassium hexamethyldisilamide, ammonia, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, and 2,2,6,6-tetramethylpiperidine; preferably one or a combination of sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyloxide, and potassium tert-amyloxide; more preferably one or a mixture of sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyloxide, and potassium tert-amyloxide.

[0018] In a specific embodiment, the catalyst is a copper catalyst, which is selected from one or a mixture of several of the following: metallic copper, cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous cyanide, cuprous acetate, copper chloride, copper bromide, copper oxide, copper acetate, copper sulfate, and copper nitrate; preferably, it is selected from one or a mixture of several of the following: cuprous oxide, cuprous chloride, cuprous bromide, and cuprous iodide; more preferably, it is selected from cuprous oxide, cuprous bromide, or cuprous iodide.

[0019] In a specific embodiment, the molar ratio of the compound shown in formula (I) or its salt to nitrile is 1:1 to 1:20, more preferably 1:2 to 1:5.

[0020] In a specific embodiment, the molar ratio of the compound shown in formula (I) or its salt to the alkaline reagent is 1:1 to 1:20, more preferably 1:2 to 1:4, for example 1:3.

[0021] In a specific embodiment, the molar ratio of the compound or its salt shown in formula (I) to the catalyst is 1:0.01 to 1:1, more preferably 1:0.05 to 1:0.3, for example 1:0.1.

[0022] In a specific embodiment, the reaction temperature is 50–150°C, preferably 70–120°C; the reaction time is 1–48 hours, preferably 12–24 hours, for example 16 hours.

[0023] In a specific embodiment, the salt of the compound shown in formula (I) is an acid addition salt formed by the compound shown in formula (I) and an acid, wherein the acid is selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid or acetic acid.

[0024] Beneficial effects

[0025] This invention provides a method for preparing benzimidazole compounds. When the method described in this invention is used to prepare the key intermediates of telmisartan, namely benzimidazole (II-2) and bisbenzimidazole (II-1), it avoids the use of nitration and polyphosphoric acid cyclization reactions in existing synthetic routes. This fundamentally avoids the safety issues associated with nitration and the environmental problems related to the disposal of nitration and polyphosphoric acid wastewater.

[0026] This invention can also be used to prepare benzimidazole or arylzimidazole compounds in a broader sense. The synthetic method embodied in this invention has the advantages of good safety, mild conditions, and low pollutant and waste production, making it suitable for development into a green and sustainable production process. Detailed Implementation

[0027] To enable those skilled in the art to understand the features and effects of this invention, the terms and expressions used in the specification and claims are explained and defined in general below. Unless otherwise specified, all technical and scientific terms used herein have the ordinary meaning understood by those skilled in the art regarding this invention, and in case of conflict, the definitions in this specification shall prevail.

[0028] In this document, the terms “comprising,” “having,” or any other similar terms are open-ended transitional phrases intended to encompass non-exclusive inclusions. For example, a composition or article containing a plural element is not limited to the elements listed herein, but may also include other elements not explicitly listed but typically inherent to the composition or article. Furthermore, unless explicitly stated otherwise, the term “or” is inclusive, not exclusive. For example, the condition “A or B” is satisfied in any of the following cases: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); A and B are both true (or exist). Moreover, in this document, the terms “comprising” and “having” should be interpreted as specifically disclosed and simultaneously encompassing closed or semi-closed transitional phrases such as “consisting of” and “substantially composed of.”

[0029] In this document, all features or conditions defined in the form of numerical ranges or percentage ranges are for the sake of brevity and convenience only. Accordingly, descriptions of numerical ranges or percentage ranges should be considered as covering and specifically disclosing all possible sub-ranges and individual values ​​within those ranges, particularly integer values. For example, a range description of "1 to 8" should be considered as specifically disclosing all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be considered as specifically disclosing individual values ​​within those ranges such as 1, 2, 3, 4, 5, 6, 7, 8, etc. Unless otherwise specified, the foregoing interpretation applies to all content throughout this invention, regardless of its scope.

[0030] If a quantity or other numerical value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that this document has specifically disclosed all ranges consisting of any upper or preferred value of that range and the lower or preferred value of that range, regardless of whether such ranges are separately disclosed. Furthermore, when a range of numerical values ​​is mentioned herein, unless otherwise stated, the range shall include its endpoints and all integers and fractions within the range.

[0031] In this document, numerical values ​​are to be understood as having a precision with significant digits, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.

[0032] The present invention will be further described below with reference to the embodiments. It should be noted that the following embodiments are provided for illustrative purposes only and do not constitute a limitation on the scope of protection of the present invention.

[0033] Unless otherwise specified, the raw materials, reagents, and methods used in the examples are all conventional in the art. Unless otherwise specified, all raw materials and reagents used are commercially available.

[0034] Compounds I-7 to I-9 were prepared according to the methods described in Examples 1 and 2 of CN112707868A or similar methods.

[0035] Example 1

[0036] Preparation of compound II-3:

[0037]

[0038] Compound I-1 (2.44 g, 10 mmol), cuprous iodide (0.19 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (30 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-3 (2.24 g, 98% yield).

[0039] Characterization data of compound II-3:

[0040] 1 H NMR (CDCl3, 400MHz) δ: 1.0 (t, J=8.0, 3H), 1.9 (m, 2H), 2.4 (s, 3H), 2.9 (t, J=8.0, 2H), 3.9 (s, 3H), 7.8 (s, 1H), 8.1 (s, 1H). ESI-MS (m / z): 233.12 (M+H) + .

[0041] Example 2

[0042] Preparation of compound II-3:

[0043]

[0044] Compound I-1 (2.44 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (25 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-3 (2.20 g, 95% yield).

[0045] The characterization data for compound II-3 are consistent with those in Example 1.

[0046] Example 3

[0047] Preparation of compound II-3:

[0048]

[0049] Compound I-1 (2.44 g, 10 mmol), cuprous chloride (0.1 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (25 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-3 (2.22 g, 96% yield).

[0050] The characterization data for compound II-3 are consistent with those in Example 1.

[0051] Example 4

[0052] Preparation of compound II-3:

[0053]

[0054] Compound I-1 (2.44 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-amyloxide (3.78 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to toluene (25 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-3 (2.16 g, 93% yield).

[0055] The characterization data for compound II-3 are consistent with those in Example 1.

[0056] Example 5

[0057] Preparation of compound II-3:

[0058]

[0059] Compound I-1 (2.44 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-amyloxide (3.78 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to ethylene glycol dimethyl ether (25 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-3 (2.16 g, 93% yield).

[0060] The characterization data for compound II-3 are consistent with those in Example 1.

[0061] Example 6

[0062] Preparation of compound II-3:

[0063]

[0064] Compound I-1 (2.44 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-butoxide (3.36 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to ethylene glycol dimethyl ether (25 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-3 (2.16 g, 93% yield).

[0065] The characterization data for compound II-3 are consistent with those in Example 1.

[0066] Example 7

[0067] Preparation of compound II-3:

[0068]

[0069] Compound I-1 (2.44 g, 10 mmol), cuprous oxide (0.14 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (25 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-3 (2.13 g, 92% yield).

[0070] The characterization data for compound II-3 are consistent with those in Example 1.

[0071] Example 8

[0072] Preparation of compound II-3:

[0073]

[0074] Compound I-1 (2.44 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-butoxide (3.36 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to tert-butanol (12 mL). Nitrogen gas was then introduced, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-3 (2.23 g, 96% yield).

[0075] The characterization data for compound II-3 are consistent with those in Example 1.

[0076] Example 9

[0077] Preparation of compound II-3:

[0078]

[0079] Compound I-1 (2.44 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), sodium tert-butoxide (2.88 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to tert-butanol (12 mL). Nitrogen gas was then introduced, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-3 (2.21 g, 95% yield).

[0080] The characterization data for compound II-3 are consistent with those in Example 1.

[0081] Example 10

[0082] Preparation of compound II-3:

[0083]

[0084] Compound I-2 (2.91 g, 10 mmol), cuprous iodide (0.19 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (25 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-3 (2.21 g, 95% yield).

[0085] The characterization data for compound II-3 are consistent with those in Example 1.

[0086] Example 11

[0087] Preparation of compound II-3:

[0088]

[0089] Compound I-3 (2.00 g, 10 mmol), cuprous iodide (0.19 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (25 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-3 (1.86 g, 80% yield).

[0090] The characterization data for compound II-3 are consistent with those in Example 1.

[0091] Example 12

[0092] Preparation of compound II-2:

[0093]

[0094] Compound I-4 (2.30 g, 10 mmol), cuprous iodide (0.19 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (25 ml). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-2 (2.00 g, 92% yield).

[0095] Characterization data of compound II-2: 1 H NMR (CDCl3, 400MHz) δ: 0.99 (t, J=7.4, 3H), 1.86 (q, J=7.3, 2H), 2.05 (s, 3H), 2.80 ( t, J=7.4, 2H), 3.89 (s, 3H), 7.2-7.7 (m, 6H), 7.8 (s, 1H). ESI-MS (m / z): 219.11 (M+H) + .

[0096] Example 13

[0097] Preparation of compound II-2:

[0098]

[0099] Compound I-4 (2.30 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-butoxide (3.36 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-butanol (11 ml), nitrogen was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-2 (2.04 g, 94% yield).

[0100] The characterization data for compound II-2 are consistent with those in Example 12.

[0101] Example 14

[0102] Preparation of compound II-2:

[0103]

[0104] Compound I-6 (1.85 g, 10 mmol), cuprous iodide (0.19 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (25 ml). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-2 (1.51 g, yield 69%).

[0105] The characterization data for compound II-2 are consistent with those in Example 12.

[0106] Example 15

[0107] Preparation of compound II-2:

[0108]

[0109] Compound I-5 (2.77 g, 10 mmol), cuprous iodide (0.19 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (25 ml). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the mixture was concentrated under reduced pressure and separated by silica gel column chromatography to obtain compound II-2 (2.10 g, 96% yield).

[0110] The characterization data for compound II-2 are consistent with those in Example 12.

[0111] Example 16

[0112] Preparation of compound II-1:

[0113]

[0114] Compound I-7 (3.16 g, 10 mmol), cuprous iodide (0.19 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (30 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain compound II-1 (2.98 g, 98% yield).

[0115] Characterization data of compound II-1: 1 H NMR (CDCl3, 400MHz) δ: 0.79 (t, J=8Hz, 3H), 1.68 (m, 2H), 2.47 (s, 3H), 2.70 (t, J=8Hz, 2H), 3.85 (s , 3H), 7.26(s, 1H), 7.30-7.42(m, 3H), 7.68(s, 1H), 7.74-7.77(m, 1H).ESI-MS(m / z): 305.18(M+H) + .

[0116] Example 17

[0117] Preparation of compound II-1:

[0118]

[0119] Compound I-7 (3.16 g, 10 mmol), cuprous chloride (0.10 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (30 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain compound II-1 (2.89 g, 95% yield).

[0120] The characterization data for compound II-1 are consistent with those in Example 16.

[0121] Example 18

[0122] Preparation of compound II-1:

[0123]

[0124] I-7 (3.16 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (30 mL), nitrogen was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain compound II-1 (2.92 g, 96% yield).

[0125] The characterization data for compound II-1 are consistent with those in Example 16.

[0126] Example 19

[0127] Preparation of compound II-1:

[0128]

[0129] Compound I-7 (3.16 g, 10 mmol), cuprous oxide (0.14 g, 1 mmol), potassium tert-amyl alcohol (3.78 g, 30 mmol), and butyronitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (30 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain compound II-1 (2.86 g, 94% yield).

[0130] The characterization data for compound II-1 are consistent with those in Example 16.

[0131] Example 20

[0132] Preparation of compound II-1:

[0133]

[0134] Compound I-7 (3.16 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-amyloxide (3.78 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to toluene (30 mL). Nitrogen gas was then introduced, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain compound II-1 (2.88 g, 95% yield).

[0135] The characterization data for compound II-1 are consistent with those in Example 16.

[0136] Example 21

[0137] Preparation of compound II-1:

[0138]

[0139] Compound I-7 (3.16 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-amyloxide (3.78 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to ethylene glycol dimethyl ether (30 mL). Nitrogen gas was then introduced, and the mixture was refluxed for 16 hours. After cooling to 25 °C, water (25 mL) was added, and the mixture was separated. The aqueous layer was extracted with dichloromethane (50 mL), and the organic layers were combined. The organic layers were washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain compound II-1 (2.78 g, 91% yield).

[0140] The characterization data for compound II-1 are consistent with those in Example 16.

[0141] Example 22

[0142] Preparation of compound II-1:

[0143]

[0144] Compound I-7 (3.16 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-butoxide (3.36 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to toluene (30 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain compound II-1 (2.75 g, 90% yield).

[0145] The characterization data for compound II-1 are consistent with those in Example 16.

[0146] Example 23

[0147] Preparation of compound II-1:

[0148]

[0149] Compound I-8 (3.63 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-amyl alcohol (3.70 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (30 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain compound II-1 (2.95 g, 97% yield).

[0150] The characterization data for compound II-1 are consistent with those in Example 16.

[0151] Example 24

[0152] Preparation of compound II-1:

[0153]

[0154] Compound I-9 (2.71 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-amyl alcohol (3.70 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to tert-amyl alcohol (30 mL). Nitrogen gas was purged, and the mixture was refluxed for 16 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica column chromatography to obtain compound II-1 (2.07 g, yield 68%).

[0155] The characterization data for compound II-1 are consistent with those in Example 16.

[0156] Example 25

[0157] Preparation of compound II-1:

[0158]

[0159] Compound I-7 (3.16 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), potassium tert-butoxide (3.36 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to tert-butanol (15 mL), nitrogen was purged, and the mixture was refluxed for 24 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain compound II-1 (2.99 g, 98% yield).

[0160] The characterization data for compound II-1 are consistent with those in Example 16.

[0161] Example 26

[0162] Preparation of compound II-1:

[0163]

[0164] Compound I-7 (3.16 g, 10 mmol), cuprous bromide (0.14 g, 1 mmol), sodium tert-butoxide (2.88 g, 30 mmol), and nitrile (1.66 g, 20 mmol) were added sequentially to tert-butanol (15 mL). Nitrogen gas was then introduced, and the mixture was refluxed for 24 hours. After cooling to 25 °C, the catalyst and other insoluble substances were removed by filtration. The filter cake was washed with dichloromethane (30 mL), and the filtrate was separated by adding water (50 mL). The organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to obtain compound II-1 (2.93 g, 96% yield).

[0165] The characterization data for compound II-1 are consistent with those in Example 16.

[0166] The above embodiments are merely illustrative of the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein, without departing from the spirit and substance defined by the claims of the present invention; and such modifications or substitutions are still within the scope defined by the claims of the present invention.

Claims

1. A method for preparing a benzimidazole compound of formula (II), the method comprising: The compound shown in formula (I) or its salt is reacted with butyronitrile in a solvent in the presence of an alkaline reagent and a catalyst to prepare the compound shown in formula (II). The alkaline reagent is one or a mixture of sodium tert-butoxide, potassium tert-butoxide, sodium tert-pentoxide or potassium tert-pentoxide, and the catalyst is one or a mixture of cuprous oxide, cuprous chloride, cuprous bromide or cuprous iodide. In equation (I), X represents chlorine, bromine, or iodine; R is selected from , or ; R0 is selected from hydrogen, C1-C5 straight-chain or branched alkyl groups.

2. The preparation method according to claim 1, characterized in that, In formula (I), X represents bromine or iodine.

3. The preparation method according to claim 1, characterized in that, In formula (I), R0 is selected from hydrogen, methyl, ethyl, propyl, butyl or pentyl.

4. The preparation method according to claim 3, characterized in that, R0 is hydrogen or methyl.

5. The preparation method according to claim 1, characterized in that, The solvent is selected from one or a mixture of several of the following: dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, xylene, chlorobenzene, acetonitrile, acetone, ethanol, isopropanol, n-butanol, tert-butanol, tert-amyl alcohol, ethylene glycol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide.

6. The preparation method according to claim 5, characterized in that, The solvent is selected from one or a mixture of several of 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, tert-butanol, and tert-amyl alcohol.

7. The preparation method according to claim 6, characterized in that, The solvent is ethylene glycol dimethyl ether, toluene, tert-butanol, or tert-amyl alcohol.

8. The preparation method according to claim 7, characterized in that, The solvent is toluene, tert-butanol, or tert-amyl alcohol.

9. The preparation method according to claim 1, characterized in that, The molar ratio of the compound shown in formula (I) or its salt to nitrile is 1:1 to 1:

20.

10. The preparation method according to claim 9, characterized in that, The molar ratio of the compound shown in formula (I) or its salt to nitrile is 1:2 to 1:

5.

11. The preparation method according to claim 1, characterized in that, The molar ratio of the compound or its salt shown in formula (I) to the alkaline reagent is 1:1 to 1:

20.

12. The preparation method according to claim 11, characterized in that, The molar ratio of the compound or its salt shown in formula (I) to the alkaline reagent is 1:2 to 1:

4.

13. The preparation method according to claim 1, characterized in that, The molar ratio of the compound or its salt shown in formula (I) to the catalyst is 1:0.01 to 1:

1.

14. The preparation method according to claim 13, characterized in that, The molar ratio of the compound or its salt shown in formula (I) to the catalyst is 1:0.05 to 1:0.

3.

15. The preparation method according to claim 1, characterized in that, The reaction temperature is 50–150°C; the reaction time is 1–48 hours.

16. The preparation method according to claim 15, characterized in that, The reaction temperature is 70–120°C; the reaction time is 12–24 hours.

17. The preparation method according to claim 1, characterized in that, The salt of the compound shown in formula (I) is an acid addition salt formed by the compound shown in formula (I) and an acid selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid or acetic acid.

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