CN117777025A - Preparation method of benzimidazole compound - Google Patents

Preparation method of benzimidazole compound Download PDF

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Publication number
CN117777025A
CN117777025A CN202310389789.3A CN202310389789A CN117777025A CN 117777025 A CN117777025 A CN 117777025A CN 202310389789 A CN202310389789 A CN 202310389789A CN 117777025 A CN117777025 A CN 117777025A
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compound
potassium
sodium
mmol
tert
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沈敬山
覃鸿健
朱富强
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Shandong Fuchang Pharmaceutical Co ltd
Topharman Shandong Co Ltd
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Shandong Fuchang Pharmaceutical Co ltd
Topharman Shandong Co Ltd
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Abstract

The invention discloses a preparation method of benzimidazole compound shown in formula (II), which comprises the steps of reacting compound shown in formula (I) or salt thereof in solvent with butyronitrile in the presence of alkaline reagent and or absence of catalyst to prepare the compound shown in formula (II). When the method is used for preparing the key intermediate of the antihypertensive drug telmisartan, some problems existing in the existing method, such as the safety of the nitration reaction, the disposal of the nitration waste liquid, the phosphorus-containing waste liquid caused by using polyphosphoric acid and the like, can be avoided.

Description

Preparation method of benzimidazole compound
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of benzimidazole compounds.
Background
Telmisartan (telmsiartan) is an active ingredient of a medicament for treating hypertension. Benzimidazole (II-2) and bisbenzimidazole (II-1) are key intermediates for the preparation of telmisartan. Patent (EP 502314) reports a method for preparing a mono-benzimidazole intermediate (II-2) from aniline (VIII-3) through reaction steps such as acylation, nitration, reduction, hydrolysis and the like, and obtaining a bis-benzimidazole intermediate (II-1) through cyclization of polyphosphoric acid, wherein the route is as follows:
this method has some problems such as safety of the nitration reaction itself and disposal of the nitration waste liquid, phosphorus-containing waste liquid caused by use of polyphosphoric acid, and the like.
Therefore, the development of a safe, environment-friendly and green sustainable synthesis method of telmisartan key intermediates of mono-benzimidazole (II-2) and bisbenzimidazole (II-1) is still of great significance.
In view of this, the present invention has been made.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provide a preparation method of benzimidazole compounds shown in a formula (II).
In order to achieve the above object of the present invention, the following technical solutions are specifically adopted:
a method for preparing a benzimidazole compound represented by formula (II), the method comprising:
the compound shown in the formula (I) or salt thereof is reacted with butyronitrile in a solvent in the presence of an alkaline reagent and with or without a catalyst to prepare a compound shown in the formula (II);
wherein in the formula (I),
x is chlorine (C1), bromine (Br) or iodine (I); preferably bromine (Br), iodine (I);
r is selected from
R 0 Selected from hydrogen, C1-C5 straight or branched alkyl, preferably hydrogen, methyl, ethyl, propyl, butyl or pentyl, more preferably hydrogen or methyl.
In specific embodiments, the solvent is selected from one or more of dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, xylene, chlorobenzene, acetonitrile, acetone, ethanol, isopropanol, N-butanol, tert-amyl alcohol, ethylene glycol, pyridine, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, water; preferably one or a mixture of more than one of 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, tertiary butanol and tertiary amyl alcohol; more preferably ethylene glycol dimethyl ether, toluene, t-butanol or t-amyl alcohol, and still more preferably toluene, t-butanol or t-amyl alcohol.
In a specific embodiment of the present invention, the alkaline reagent is selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydroxide, magnesium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, sodium hydroxide, magnesium 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-amyl alcohol potassium tert-amyl alcohol, lithium tert-amyl alcohol, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, magnesium tert-amyl alcohol, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, ammonia, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine; preferably sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyl alcohol, potassium tert-amyl alcohol or a combination thereof; more preferably sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyl alcohol or potassium tert-amyl alcohol.
In a specific embodiment, the catalyst is a copper catalyst, and the copper catalyst is selected from one or a mixture of more of metallic copper, cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous cyanide, cuprous acetate, cupric chloride, cupric bromide, cupric oxide, cupric acetate, cupric sulfate and cupric nitrate; preferably one or a mixture of more than one of cuprous oxide, cuprous chloride, cuprous bromide and cuprous iodide; more preferably cuprous oxide, cuprous bromide or cuprous iodide.
In a specific embodiment, the molar ratio of the compound of formula (I) or salt thereof to the butyronitrile feed is from 1:1 to 1:20, more preferably from 1:2 to 1:5.
In a specific embodiment, the molar ratio of the compound of formula (I) or salt thereof to the basic agent is from 1:1 to 1:20, more preferably from 1:2 to 1:4, for example 1:3.
In a specific embodiment, the molar ratio of the compound of formula (I) or salt thereof to catalyst is from 1:0.01 to 1:1, more preferably from 1:0.05 to 1:0.3, for example 1:0.1.
In a specific embodiment, the temperature of the reaction is 50 to 150 ℃, preferably 70 to 120 ℃; the reaction time is 1 to 48 hours, preferably 12 to 24 hours, for example 16 hours.
In a specific embodiment, the salt of the compound of formula (I) is an acid addition salt of the compound of formula (I) with an acid selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid or acetic acid.
Advantageous effects
The invention provides a preparation method of benzimidazole compound. When the method is used for preparing key intermediates of mono-benzimidazole (II-2) and bisphenylbisimidazole (II-1) of telmisartan, the use of nitration reaction and polyphosphoric acid cyclization reaction in the existing synthetic route method is avoided, so that the safety problem associated with the nitration reaction and the environmental protection problem in the disposal of nitration waste liquid and polyphosphoric acid waste liquid are fundamentally avoided at the source.
The invention can also be used for preparing benzimidazole or aryl imidazole compounds in a broader sense. The synthetic method has the advantages of good safety, mild conditions, less pollutants and wastes, and the like, and is suitable for development into a green sustainable production process.
Detailed Description
So that those having ordinary skill in the art can appreciate the features and effects of the present invention, the following general description and definitions apply to the terms and expressions set forth in the specification and claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, in the event of a conflict, the present specification shall control.
As used herein, the terms "comprising," "having," or any other similar language, are intended to cover a non-exclusive inclusion as an open-ended connection (open-ended transitional phrase). For example, a composition or article comprising a plurality of elements is not limited to only those elements listed herein, but may include other elements not explicitly listed but typically inherent to such composition or article. In addition, unless explicitly stated to the contrary, the term "or" refers to an inclusive "or" and not to an exclusive "or". For example, any one of the following conditions satisfies the condition "a or B": a is true (or present) and B is false (or absent), a is false (or absent) and B is true (or present), a and B are both true (or present). Furthermore, the terms "comprising," "having," and the like, herein are to be construed as having a meaning that is specifically disclosed and that is also intended to encompass both "consisting of," and "consisting essentially of," closed or semi-closed terms.
All features or conditions defined herein in terms of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "1-8" should be taken as having specifically disclosed all sub-ranges such as 1-7, 2-8, 2-6, 3-6, 4-8, 3-8, etc., particularly sub-ranges defined by all integer values, and as having specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. The foregoing explanation applies to all matters of the invention throughout its entirety unless indicated otherwise, whether or not the scope is broad.
If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range, whether or not separately disclosed, from any pair of the upper or preferred value for that range and the lower or preferred value for that range is specifically disclosed herein. Furthermore, where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.
In this context, numerical values should be understood to have the accuracy of the numerical significance of the numerical values provided that the objectives of the present invention are achieved. For example, the number 40.0 is understood to cover a range from 39.50 to 40.49.
The invention is further illustrated by the following examples, which are provided for illustrative purposes only and are not to be construed as limiting the scope of the invention as claimed.
Unless otherwise indicated, all materials, reagents, methods and the like used in the examples are those conventionally used in the art. The raw materials and reagents used are commercially available unless otherwise specified.
Compounds I-7 to I-9 were prepared according to the methods described in examples 1 and 2 of CN112707868A or the like.
Example 1
Preparation of Compound II-3:
to t-amyl alcohol (30 mL) was added compound I-1 (2.44 g,10 mmol), cuprous iodide (0.19 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, filtered to remove catalyst and other insoluble materials, the filter cake was washed with dichloromethane (30 mL), the filtrate was added with water (50 mL) to separate the liquid, 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 give compound II-3 (2.24 g, 98% yield).
Characterization data for compound II-3:
1 H NMR(CDCl 3 ，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) + .
example 2
Preparation of Compound II-3:
to t-amyl alcohol (25 mL) was added compound I-1 (2.44 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, filtered to remove catalyst and other insoluble materials, the filter cake was washed with dichloromethane (30 mL), the filtrate was added with water (50 mL) to separate the liquid, 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 give compound II-3 (2.20 g, yield 95%).
Compound II-3 characterization data are consistent with example 1.
Example 3
Preparation of Compound II-3:
to t-amyl alcohol (25 mL) was added compound I-1 (2.44 g,10 mmol), cuprous chloride (0.1 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, the catalyst and other insoluble materials were filtered off, the filter cake was washed with dichloromethane (30 mL), the filtrate was added with water (50 mL) to separate the liquid, 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 give compound II-3 (2.22 g, 96% yield).
Compound II-3 characterization data are consistent with example 1.
Example 4
Preparation of Compound II-3:
to toluene (25 mL) were added compound I-1 (2.44 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) in sequence, nitrogen was replaced, then the mixture was heated and refluxed for 16 hours, cooled to 25 ℃, the catalyst and other insoluble matters were removed by filtration, the filter cake was washed with methylene chloride (30 mL), 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 give compound II-3 (2.16 g, yield 93%).
Compound II-3 characterization data are consistent with example 1.
Example 5
Preparation of Compound II-3:
to ethylene glycol dimethyl ether (25 m 1), compound I-1 (2.44 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol) were added sequentially, butyronitrile (1.66 g,20 mmol) was replaced with nitrogen, then the reaction was performed under reflux at elevated temperature for 16 hours, cooled to 25 ℃ and filtered to remove the catalyst and other insoluble materials, the filter cake was washed with dichloromethane (30 mL), the filtrate was added with water (50 mL) to separate the liquid, 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 give compound II-3 (2.16 g, yield 93%).
Compound II-3 characterization data are consistent with example 1.
Example 6
Preparation of Compound II-3:
to ethylene glycol dimethyl ether (25 m 1), compound I-1 (2.44 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-butoxide (3.36 g,30 mmol) were sequentially added, butyronitrile (1.66 g,20 mmol) was replaced with nitrogen, then the mixture was heated to reflux for 16 hours, cooled to 25 ℃, the catalyst and other insoluble matters were removed by filtration, the filter cake was washed with dichloromethane (30 mL), the filtrate was added with water (50 mL) to separate the liquid, 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 give compound II-3 (2.16 g, yield 93%).
Compound II-3 characterization data are consistent with example 1.
Example 7
Preparation of Compound II-3:
to t-amyl alcohol (25 mL) was added compound I-1 (2.44 g,10 mmol), cuprous oxide (0.14 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, filtered to remove catalyst and other insoluble materials, the filter cake was washed with dichloromethane (30 mL), the filtrate was added with water (50 mL) to separate the liquid, 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 give compound II-3 (2.13 g, 92% yield).
Compound II-3 characterization data are consistent with example 1.
Example 8
Preparation of Compound II-3:
to t-butanol (12 mL) was added compound I-1 (2.44 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-butoxide (3.36 g,30 mmol), butyronitrile (1.66 g,20 mmol) in this order, nitrogen was replaced, then the mixture was heated to reflux for 16 hours, cooled to 25 ℃, the catalyst and other insoluble materials were removed by filtration, the filter cake was washed with methylene chloride (30 mL), 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 give compound II-3 (2.23 g, yield 96%).
Compound II-3 characterization data are consistent with example 1.
Example 9
Preparation of Compound II-3:
to t-butanol (12 mL) was added compound I-1 (2.44 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and sodium t-butoxide (2.88 g,30 mmol), butyronitrile (1.66 g,20 mmol) in this order, nitrogen was replaced, then the mixture was heated to reflux for 16 hours, cooled to 25 ℃, the catalyst and other insoluble materials were removed by filtration, the filter cake was washed with methylene chloride (30 mL), 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 give compound II-3 (2.21 g, yield 95%).
Compound II-3 characterization data are consistent with example 1.
Example 10
Preparation of Compound II-3:
to t-amyl alcohol (25 mL) was added compound I-2 (2.91 g,10 mmol), cuprous iodide (0.19 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, filtered to remove catalyst and other insoluble materials, the filter cake was washed with dichloromethane (30 mL), the filtrate was added with water (50 mL) to separate the liquid, 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 give compound II-3 (2.21 g, yield 95%).
Compound II-3 characterization data are consistent with example 1.
Example 11
Preparation of Compound II-3:
to t-amyl alcohol (25 mL) was added compound I-3 (2.00 g,10 mmol), cuprous iodide (0.19 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, filtered to remove catalyst and other insoluble materials, the filter cake was washed with dichloromethane (30 mL), the filtrate was added with water (50 mL) to separate the liquid, 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 give compound II-3 (1.86 g, 80% yield).
Compound II-3 characterization data are consistent with example 1.
Example 12
Preparation of Compound II-2:
to t-amyl alcohol (25 ml) was added compound I-4 (2.30 g,10 mmol), cuprous iodide (0.19 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, concentrated under reduced pressure, and separated by silica gel column chromatography to give compound II-2 (2.00 g, 92% yield).
Characterization data for 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) + .
example 13
Preparation of Compound II-2:
to t-butanol (11 ml) was added compound I-4 (2.30 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-butoxide (3.36 g,30 mmol), butyronitrile (1.66 g,20 mmol) in this order, nitrogen was replaced, and then the mixture was heated to reflux for 16 hours, cooled to 25℃and concentrated under reduced pressure, followed by silica gel column chromatography to give compound II-2 (2.04 g, yield 94%).
Compound II-2 characterization data are consistent with example 12.
Example 14
Preparation of Compound II-2:
to t-amyl alcohol (25 ml) was added compound I-6 (1.85 g,10 mmol), cuprous iodide (0.19 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, concentrated under reduced pressure, and separated by silica gel column chromatography to give compound II-2 (1.51 g, 69% yield).
Compound II-2 characterization data are consistent with example 12.
Example 15
Preparation of Compound II-2:
to t-amyl alcohol (25 ml) was added compound I-5 (2.77 g,10 mmol), cuprous iodide (0.19 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, concentrated under reduced pressure, and separated by silica gel column chromatography to give compound II-2 (2.10 g, yield 96%).
Compound II-2 characterization data are consistent with example 12.
Example 16
Preparation of Compound II-1:
to t-amyl alcohol (30 mL) was added compound I-7 (3.16 g,10 mmol), cuprous iodide (0.19 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, catalyst and other insoluble matters were removed by filtration, the filter cake was washed with dichloromethane (30 mL), the filtrate was added with water (50 mL) to separate, the organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to give compound II-1 (2.98 g, yield 98%).
Characterization data for compound II-1: 1 H NMR(CDCl 3 ，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) + .
example 17
Preparation of Compound II-1:
to t-amyl alcohol (30 mL) was added compound I-7 (3.16 g,10 mmol), cuprous chloride (0.10 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, catalyst and other insoluble materials were removed by filtration, filter cake was washed with dichloromethane (30 mL), filtrate was added with water (50 mL) to separate the liquid, organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to give compound II-1 (2.89 g, yield 95%).
Compound II-1 characterization data are consistent with example 16.
Example 18
Preparation of Compound II-1:
to t-amyl alcohol (30 mL) were added I-7 (3.16 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃ and filtered to remove catalyst and other insoluble materials, the filter cake was washed with dichloromethane (30 mL), the filtrate was added with water (50 mL) to separate the liquid, the organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to give compound II-1 (2.92 g, yield 96%).
Compound II-1 characterization data are consistent with example 16.
Example 19
Preparation of Compound II-1:
to t-amyl alcohol (30 mL) was added compound I-7 (3.16 g,10 mmol), cuprous oxide (0.14 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, catalyst and other insoluble materials were removed by filtration, filter cake was washed with dichloromethane (30 mL), filtrate was added with water (50 mL) to separate the liquid, organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to give compound II-1 (2.86 g, yield 94%).
Compound II-1 characterization data are consistent with example 16.
Example 20
Preparation of Compound II-1:
to toluene (30 mL) were added compound I-7 (3.16 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) in sequence, nitrogen was replaced, then the mixture was heated and refluxed for 16 hours, cooled to 25 ℃, the catalyst and other insoluble matters were removed by filtration, the filter cake was washed with methylene chloride (30 mL), the filtrate was added with water (50 mL) to separate the liquid, the organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to give compound II-1 (2.88 g, yield 95%).
Compound II-1 characterization data are consistent with example 16.
Example 21
Preparation of Compound II-1:
to ethylene glycol dimethyl ether (30 m 1), compound I-7 (3.16 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-amyl alcohol (3.78 g,30 mmol), butyronitrile (1.66 g,20 mmol) were added sequentially, nitrogen was replaced, then the reaction was performed at reflux for 16 hours with warming, cooling to 25 ℃, water (25 mL) was added to separate the aqueous layer, the aqueous layer was extracted with dichloromethane (50 mL), the organic layers were combined, washed with saturated brine, and the organic phase was concentrated under reduced pressure to give Compound II-1 (2.78 g, yield 91%).
Compound II-1 characterization data are consistent with example 16.
Example 22
Preparation of Compound II-1:
to toluene (30 mL) were successively added compound I-7 (3.16 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-butoxide (3.36 g,30 mmol), butyronitrile (1.66 g,20 mmol), nitrogen was replaced, then the mixture was heated and refluxed for 16 hours, cooled to 25 ℃, the catalyst and other insoluble matters were removed by filtration, the filter cake was washed with methylene chloride (30 mL), 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 give compound II-1 (2.75 g, yield 90%).
Compound II-1 characterization data are consistent with example 16.
Example 23
Preparation of Compound II-1:
to t-amyl alcohol (30 mL) was added compound I-8 (3.63 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-amyl alcohol (3.70 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, catalyst and other insoluble materials were removed by filtration, filter cake was washed with dichloromethane (30 mL), filtrate was added with water (50 mL) to separate the liquid, organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure to give compound II-1 (2.95 g, yield 97%).
Compound II-1 characterization data are consistent with example 16.
Example 24
Preparation of Compound II-1:
to t-amyl alcohol (30 mL) was added compound I-9 (2.71 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-amyl alcohol (3.70 g,30 mmol), butyronitrile (1.66 g,20 mmol) sequentially, nitrogen was replaced, then heated to reflux for 16 hours, cooled to 25 ℃, the catalyst and other insoluble materials were filtered off, the filter cake was washed with dichloromethane (30 mL), the filtrate was added with water (50 mL) to separate the liquid, the organic layer was washed with saturated brine, and the organic phase was concentrated under reduced pressure and separated by silica-based column chromatography to give compound II-1 (2.07 g, yield 68%).
Compound II-1 characterization data are consistent with example 16.
Example 25
Preparation of Compound II-1:
to t-butanol (15 mL) was added compound I-7 (3.16 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and potassium t-butoxide (3.36 g,30 mmol), butyronitrile (1.66 g,20 mmol) in this order, nitrogen was replaced, then heated to reflux for 24 hours, cooled to 25 ℃, the catalyst and other insoluble materials were removed by filtration, the filter cake was washed with dichloromethane (30 mL), 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 give compound II-1 (2.99 g, yield 98%).
Compound II-1 characterization data are consistent with example 16.
Example 26
Preparation of Compound II-1:
to t-butanol (15 mL) was added compound I-7 (3.16 g,10 mmol), cuprous bromide (0.14 g,1 mmol) and sodium t-butoxide (2.88 g,30 mmol), butyronitrile (1.66 g,20 mmol) in this order, nitrogen was replaced, then heated to reflux for 24 hours, cooled to 25 ℃, the catalyst and other insoluble materials were removed by filtration, the filter cake was washed with dichloromethane (30 mL), 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 give compound II-1 (2.93 g, yield 96%).
Compound II-1 characterization data are consistent with example 16.
The above embodiments are only for illustrating the technical solution of the present invention, and are not limited thereto. Although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some or all of the technical features thereof, without departing from the spirit and scope of the present invention as defined in the claims; and such modifications or substitutions are intended to be within the scope of the present invention as defined by the claims.

Claims (10)

1. A method for preparing a benzimidazole compound represented by formula (II), the method comprising:
the compound shown in the formula (I) or salt thereof is reacted with butyronitrile in a solvent in the presence of an alkaline reagent and with or without a catalyst to prepare a compound shown in the formula (II);
wherein in the formula (I),
x is chlorine, bromine or iodine;
r is selected from
R 0 Selected from hydrogen, C1-C5 straight or branched alkyl.
2. The process according to claim 1, wherein in the formula (I),
x is bromine or iodine; and/or the number of the groups of groups,
R 0 selected from hydrogen, methyl, ethyl, propyl, butyl or pentyl, preferably hydrogen or methyl.
3. The preparation method according to claim 1, wherein the solvent is selected from one or more of dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, xylene, chlorobenzene, acetonitrile, acetone, ethanol, isopropanol, N-butanol, tert-amyl alcohol, ethylene glycol, pyridine, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, and water;
preferably, the solvent is selected from one or a mixture of more than one of 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, toluene, tertiary butanol and tertiary amyl alcohol; more preferably, the solvent is ethylene glycol dimethyl ether, toluene, t-butanol or t-amyl alcohol, even more preferably toluene, t-butanol or t-amyl alcohol.
4. The preparation method according to claim 1, wherein the alkaline reagent is selected from one or a mixture of 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-butoxide, lithium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, morpholine, piperidine, 2, 6-tetramethylpiperidine;
preferably, the alkaline reagent is selected from one or a combination of sodium isopropoxide, potassium isopropoxide, sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyl alcohol and potassium tert-amyl alcohol; more preferably sodium tert-butoxide, potassium tert-butoxide, sodium tert-amyl alcohol or potassium tert-amyl alcohol.
5. The method of preparation according to claim 1, wherein the catalyst is a copper catalyst;
preferably, the copper catalyst is selected from one or a mixture of a plurality of metallic copper, cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous cyanide, cuprous acetate, cupric chloride, cupric bromide, cupric oxide, cupric acetate, cupric sulfate and cupric nitrate; preferably one or a mixture of more than one of cuprous oxide, cuprous chloride, cuprous bromide and cuprous iodide; more preferably cuprous oxide, cuprous bromide or cuprous iodide.
6. The process according to claim 1, wherein the molar ratio of the compound of formula (I) or a salt thereof to the butyronitrile is from 1:1 to 1:20, more preferably from 1:2 to 1:5.
7. The process according to claim 1, wherein the molar ratio of the compound of formula (I) or a salt thereof to the alkaline agent is 1:1 to 1:20, more preferably 1:2 to 1:4.
8. The process according to claim 1, wherein the molar ratio of the compound of formula (I) or a salt thereof to the catalyst is from 1:0.01 to 1:1, more preferably from 1:0.05 to 1:0.3.
9. The preparation method according to claim 1, wherein the temperature of the reaction is 50-150 ℃, preferably 70-120 ℃; the reaction time is 1 to 48 hours, preferably 12 to 24 hours.
10. The method according to claim 1, wherein the salt of the compound of formula (I) is an acid addition salt of the compound of formula (I) with an acid selected from one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid or acetic acid.
CN202310389789.3A 2023-04-07 2023-04-07 Preparation method of benzimidazole compound Pending CN117777025A (en)

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