阅读说明：本技术 一种合成咪唑类化合物的方法 (Method for synthesizing imidazole compound ) 是由 周丙伟 陆露露 鲍汉扬 于 2018-08-30 设计创作，主要内容包括：一种合成咪唑类化合物的方法,所述方法为：无水无氧条件下,将式(I)所示化合物、式(II)所示化合物、2-溴烯丙基胺、溶剂混合,接着加入碘化亚铜A,并滴加三乙胺,在室温下搅拌0.5～3h,随后向反应体系中加入碘化亚铜B、碱性物质、配体,升温至80～100℃反应6～12h,之后经后处理,得到式(III)所示咪唑类化合物；本发明安全环保,不产生废气废水；原料易得,底物适应性好,各种取代基都可以实现芳构化；反应条件温和；反应步骤简单,且是一种合成各种含取代基的咪唑类化合物的新路线；<Image he="199" wi="700" file="DDA0001783239870000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(A method for synthesizing an imidazole compound, the method comprising: under the anhydrous and anaerobic conditions, mixing a compound shown as a formula (I), a compound shown as a formula (II), 2-bromoallylamine and a solvent, adding cuprous iodide A, dropwise adding triethylamine, stirring at room temperature for 0.5-3 h, adding cuprous iodide B, an alkaline substance and a ligand into a reaction system, heating to 80-100 ℃, reacting for 6-12 h, and performing post-treatment to obtain an imidazole compound shown as a formula (III); the invention is safe and environment-friendly, and does not produce waste gas and waste water; the raw materials are easy to obtain, the substrate adaptability is good, and various substituent groups can realize aromatization; the reaction condition is mild; the reaction steps are simple, and the method is a new route for synthesizing various imidazole compounds containing substituent groups;)

1. a method for synthesizing imidazole compounds is characterized by comprising the following steps:

under the anhydrous and anaerobic conditions, mixing a compound shown as a formula (I), a compound shown as a formula (II), 2-bromoallylamine and a solvent, adding cuprous iodide A, dropwise adding triethylamine, stirring at room temperature for 0.5-3 h, adding cuprous iodide B, an alkaline substance and a ligand into a reaction system, heating to 80-100 ℃, reacting for 6-12 h, and performing post-treatment to obtain an imidazole compound shown as a formula (III);

the ratio of the amount of the compound shown in the formula (II), the compound shown in the formula (I), 2-bromoallylamine, cuprous iodide A, triethylamine, cuprous iodide B, a basic substance and a ligand is 1: 1-2: 1-2: 0.05-0.3: 0.5-1.5: 0.05-0.3: 1-4: 0.1 to 0.5;

the solvent is one or a mixed solvent of more than two of acetonitrile, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, toluene and 1, 4-dioxane in any proportion;

the alkaline substance is one or a mixture of more than two of potassium carbonate, cesium carbonate and potassium phosphate in any proportion;

the ligand is one or a mixture of more than two of L-proline, N' -dimethyl-1, 2-ethylenediamine, N-methylglycine, N-dimethylglycine, 2-oxocyclohexanecarboxylic acid ethyl ester and 1, 10-phenanthroline in any proportion;

the reaction formula is as follows:

in the formula (I), (II) or (III),

R¹is hydrogen, C1-C4 alkyl or C1-C4 alkoxy;

R²is C6-C12 aryl substituted by C6-C12 aryl, C1-C4 alkyl, C1-C4 alkoxy or C6-C12 aryl, C1-C4 alkyl.

2. The method according to claim 1, wherein the ratio of the amounts of the compound of formula (II), the compound of formula (I), 2-bromoallylamine, copper iodide a, triethylamine, copper iodide B, a basic substance, and a ligand is 1: 1.2: 1: 0.1: 1: 0.1: 2: 0.2.

3. the method according to claim 1, wherein the solvent is used in a volume of 4 to 10mL/mmol based on the amount of the substance of the compound represented by formula (II).

4. The method of claim 1, wherein the solvent is acetonitrile/dimethylsulfoxide in a volume ratio of 2: 1.

5. The method of claim 1, wherein the basic material is potassium carbonate.

6. The method of claim 1, wherein the ligand is N, N' -dimethyl-1, 2-ethylenediamine.

7. The method of claim 1, wherein the post-processing is by: after the reaction is finished, cooling the reaction solution to room temperature, adding a saturated ammonium chloride aqueous solution to quench the reaction, extracting with ethyl acetate, collecting an organic layer, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing column chromatography separation, and taking 200-300-mesh silica gel as a column filler, wherein the volume ratio of petroleum ether to ethyl acetate is 6: 1 as eluent, collecting eluent containing the target compound, evaporating the solvent under reduced pressure, and drying to obtain the product shown in formula (III).

(I) technical field

The invention relates to a method for synthesizing an imidazole compound.

(II) background of the invention

Imidazole is a five-membered heterocyclic compound containing a pyrrole-like nitrogen atom and a pyridine-like nitrogen atom, which are located at the 1, 3-positions, respectively. It is a planar molecule, in the form of an almost regular pentagon. Due to the structural particularity, imidazole derivatives are widely used in the fine chemicals industry. It can be used as intermediate for synthesizing various medicines, catalyst, cross-linking agent and solidifying agent. The molecular structure of the proteinogenic amino acid histidine also contains imidazole groups.

The physiological pH of the imidazole ring is 7.4, and because it can regulate the acid-base equilibrium, it can be present in the histidine of proteins both as the free base and as the conjugate base. It can be used as a buffer reagent and can also form a complex with metal ions, which properties are not possessed by other proteinogenic amino acids. Because imidazole compounds have important positions in organic synthesis and drug synthesis, the synthesis research of the compounds is one of the hot points of organic synthesis, and the classical methods for synthesizing the imidazole compounds mainly comprise the following classes.

The first method forms imidazole derivatives by the cyclocondensation of 1, 2-dicarbonyl compounds, ammonia and aldehydes, imidazole was first prepared by the reaction of glyoxal, ammonia and formaldehyde according to this route, the second method is the Bredereck synthesis, i.e., a synthesis with guanidine and urea or thiourea to give imidazol-2 (3H) -one or thioxothone, respectively, the third is the Marckwald synthesis, i.e., the condensation of α -aminoketone and aminonitrile to form 2-aminoimidazole.

Based on a synthesis route of polysubstituted benzimidazole reported by our group (see adv. Synth. Catal.,2010, 352:347-350.), we designed multicomponent reaction of sulfonyl azide, terminal alkyne and 2-bromoallylamine with participation of cuprous iodide to synthesize the imidazole compound with better yield.

Disclosure of the invention

The invention provides a general, simple and efficient method for synthesizing imidazole compounds.

The technical scheme of the invention is as follows:

a method for synthesizing an imidazole compound, the method comprising:

under the anhydrous and anaerobic conditions, mixing a compound shown as a formula (I), a compound shown as a formula (II), 2-bromoallylamine and a solvent, then adding cuprous iodide A, dropwise adding triethylamine, stirring at room temperature (20-30 ℃) for 0.5-3 h (preferably 1h), then adding cuprous iodide B, an alkaline substance and a ligand into a reaction system, heating to 80-100 ℃ (preferably 80 ℃) to react for 6-12 h (preferably 8h), and then carrying out post-treatment to obtain an imidazole compound shown as a formula (III);

wherein, the terms "cuprous iodide a" and "cuprous iodide B" have no special meaning, and refer to cuprous iodide in the general sense, and the labels "a" and "B" are only used for distinguishing the cuprous iodide used in different operation steps;

the ratio of the amount of the compound shown in the formula (II), the compound shown in the formula (I), 2-bromoallylamine, cuprous iodide A, triethylamine, cuprous iodide B, a basic substance and a ligand is 1: 1-2: 1-2: 0.05-0.3: 0.5-1.5: 0.05-0.3: 1-4: 0.1 to 0.5, preferably 1: 1.2: 1: 0.1: 1: 0.1: 2: 0.2;

the volume usage amount of the solvent is 4-10 mL/mmol, preferably 6mL/mmol, based on the amount of the compound shown in the formula (II);

the solvent is one or a mixed solvent of more than two of acetonitrile, tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, toluene and 1, 4-dioxane in any proportion, and the volume ratio of acetonitrile/dimethyl sulfoxide is preferably 2: 1, a mixed solvent;

the alkaline substance is one or a mixture of more than two of potassium carbonate, cesium carbonate and potassium phosphate in any proportion, preferably potassium carbonate;

the ligand is one or a mixture of more than two of L-proline, N '-dimethyl-1, 2-ethylenediamine, N-methylglycine, N-dimethylglycine, 2-oxocyclohexanecarboxylic acid ethyl ester and 1, 10-phenanthroline in any proportion, and preferably N, N' -dimethyl-1, 2-ethylenediamine;

the post-treatment method comprises the following steps: after the reaction is finished, cooling the reaction solution to room temperature, adding a saturated ammonium chloride aqueous solution to quench the reaction, extracting with ethyl acetate, collecting an organic layer, drying with anhydrous sodium sulfate, concentrating under reduced pressure, performing column chromatography separation, and taking 200-300-mesh silica gel as a column filler, wherein the volume ratio of petroleum ether to ethyl acetate is 6: 1 as eluent, collecting eluent containing a target compound, evaporating the solvent under reduced pressure, and drying to obtain a product shown in a formula (III);

the reaction formula is as follows:

in the formula (I), (II) or (III),

R¹hydrogen, C1-C4 alkyl or C1-C4 alkoxy, preferably hydrogen, methyl or methoxy;

R²is C6-C12 aryl substituted by C6-C12 aryl, C1-C4 alkyl, C1-C4 alkoxy or C6-C12 aryl, C1-C4 alkyl, preferably phenyl, n-butyl, p-methoxyphenyl or phenethyl.

Compared with the prior art, the invention has the beneficial effects that:

(1) the method is safe and environment-friendly, and does not generate waste gas and waste water;

(2) the raw materials are easy to obtain, the substrate adaptability is good, and various substituent groups can realize aromatization;

(3) the reaction condition is mild;

(4) the reaction steps are simple, and the method is a new route for synthesizing various imidazole compounds containing substituent groups.

(IV) detailed description of the preferred embodiments

The present invention will be described in further detail with reference to specific examples, but the scope of the present invention is not limited thereto.