阅读说明：本技术 一种咪唑硫（硒）酮衍生物的制备方法 (Preparation method of imidazole sulfur (selenium) ketone derivative ) 是由 汤日元 邓建超 于 2018-06-22 设计创作，主要内容包括：本发明属于唑类硫(硒)酮衍生物制备技术领域,具体涉及一种咪唑硫(硒)酮衍生物的制备方法。所述制备方法的具体步骤为：称取咪唑类化合物、单质硫或硒中的一种、催化剂亚硫酸盐,在反应容器中加入有机溶剂,注入卤代烷烃,在加热条件下反应获得相应的硫酮或硒酮衍生物即获得所述咪唑硫(硒)酮衍生物。本发明提供了一种工艺简单,条件温和,便宜经济,高效的制备唑类硫(硒)酮衍生物的方法；本发明所述的唑类硫(硒)酮衍生物具有优良杀菌和抑菌活性,对柑橘青霉菌、小麦赤霉菌、香蕉炭疽菌、荔枝炭疽菌具有抑制活性。(The invention belongs to the technical field of preparation of azoles sulfur (selenium) ketone derivatives, and particularly relates to a preparation method of an imidazoles sulfur (selenium) ketone derivative. The preparation method comprises the following specific steps: weighing imidazole compounds, one of elemental sulfur or selenium and catalyst sulfite, adding an organic solvent into a reaction vessel, injecting halogenated alkane, and reacting under heating to obtain corresponding thioketone or selenone derivatives, namely the imidazole sulfur (selenium) ketone derivatives. The invention provides a method for preparing azole sulfur (selenium) ketone derivatives with simple process, mild condition, low price, economy and high efficiency; the azoles sulfur (selenium) ketone derivative has excellent bactericidal and bacteriostatic activity, and has inhibitory activity on penicillium citrinum, gibberella cerealis, banana anthracnose and litchi anthracnose.)

1. The preparation method of the imidazolethione derivative is characterized by comprising the following specific steps: weighing an imidazole compound, elemental sulfur and a catalyst, adding an organic solvent into a reaction vessel, injecting a compound 4, and reacting under a heating condition to obtain a corresponding thioketone derivative, namely a compound shown in a formula II; the catalyst is at least one of sodium hydrosulfite, sodium bisulfite and sodium thiosulfate;

in the reaction formula, X ═ Br or I;

R⁴is C1-C12 alkyl or phenyl, or is a substituent of C1-C12 alkyl containing methyl, fluoroethyl substituted phenyl, ester group or amide;

R⁵in the 4-or 5-position of the imidazole ring are hydrogen, phenyl, p-hydroxyphenyl,

R⁶Is C1-C12 alkyl or a substituent containing ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond or cyano on C1-C12 alkyl.

2. The method for producing an imidazolethione derivative according to claim 1,

in the reaction formula (2), the molar ratio of the compound 3, the sulfur powder and the compound 4 is 1.0 (1.0-3.0) to 1.0-3.0.

3. The method for producing an imidazolethione derivative according to claim 1, wherein the organic solvent is at least one selected from the group consisting of benzene, toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N-dimethylformamide, N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, N-propanol, isopropanol, ethylene glycol monomethyl ether, and 1, 4-dioxane.

4. The method for producing an imidazolethione derivative according to claim 1, wherein in the step of reacting, the reaction temperature is 40 ℃ to 160 ℃; the reaction time is 6-24 hours.

5. The preparation method of the imidazole selenone derivative is characterized by comprising the following specific steps: weighing an imidazole compound, elemental selenium and a catalyst, adding an organic solvent into a reaction container, injecting a compound 4, and reacting under a heating condition to obtain a corresponding selenone derivative, namely the compound shown in the formula V; the catalyst is at least one of sodium hydrosulfite, sodium bisulfite and sodium thiosulfate;

in the reaction formula, X ═ Br or I;

R⁴is C1-C12 alkyl or phenyl, or is a substituent of C1-C12 alkyl containing methyl, fluoroethyl substituted phenyl, ester group or amide;

R⁵in the 4-or 5-position of the imidazole ring are hydrogen, phenyl, p-hydroxyphenyl,

R⁶Is C1-C12 alkyl or a substituent containing ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond or cyano on C1-C12 alkyl.

6. The method for producing imidazolone derivatives according to claim 5,

in the reaction formula (5), the molar ratio of the compound 3, the selenium powder and the compound 4 is 1.0 (1.0-3.0) to 1.0-3.0.

7. The method for preparing imidazolone selenone derivatives according to claim 5, wherein the organic solvent is selected from at least one of benzene, toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N-dimethylformamide, N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, N-propanol, isopropanol, ethylene glycol monomethyl ether, and 1, 4-dioxane.

8. The method for preparing imidazolone selenone derivatives according to claim 5, wherein in the reaction step, the reaction temperature is 40 ℃ to 160 ℃; the reaction time is 6-24 hours.

Technical Field

The invention belongs to the technical field of preparation of azoles sulfur (selenium) ketone derivatives, and particularly relates to a preparation method of an imidazoles sulfur (selenium) ketone derivative.

Background

Azole compounds such as derivatives of benzimidazole, imidazole, triazole and the like have important application in the fields of medicines and materials, and play an important role in the creation of novel efficient medicines. The compounds have the characteristics of high efficiency, low toxicity, excellent bioactivity and various structural changes, have wide application in the aspects of pesticides and medicines, and are always the hot and important points of organic chemistry research (Lanyan, organic chemistry, 2007,28(2): 210; Zhang Ying, pesticide, 2008,47(3), 164-. Azole drug molecules or drug intermediates are directly converted into azole thioketone derivatives, so that a novel candidate drug molecule library can be quickly constructed, and the method has important application value for screening novel drugs. Azolylthione compounds also have excellent biological activity, for example, N-methylimidazolthione is a very good anti-goiter drug (chem. Eur. J.,2010,16(4): 1175-735; J. Med. chem.,2008,51, 7313-7317.). Furthermore, imidazolethiones are excellent organometallic mercury antidotes (chem. eur.j.,2017,23, 5696-9307; Angew. chem. int.ed.,2015,54, 9323-9327.); meanwhile, the fluorescent probe can be used for imaging and detecting hypochlorite anions in living tissues (Angew. chem. int. Ed.,2015,54(16): 4890-. The imidazolethione metal complex also shows excellent catalytic activity and has important application in the field of cross-coupling reaction (Chemical Communications,2010,46(5): 758-.

The application practice of the azolethiones shows that the difference of the substituent functional groups on the nitrogen atom of the azole ring has great influence on the function difference of the azolethiones, and the azolethiones can be respectively applied to medicines, pesticides and biological functional materials. Therefore, introduction of different functional groups on the azole ring has the high possibility of obtaining azolethione functional molecules with different application values. In view of the important functions and application values of azolethiones, it is necessary to develop a simple and efficient technical method for preparing azolethione compounds and create novel azolethione molecules. The existing reaction technology for preparing the azolethiones is generally realized by cyclization reaction of isothiocyanate or thiourea with other substrates, or is obtained by converting imidazole salt and sulfur powder under the action of strong base (Organic Letters,2014,16(21): 5788-. However, isothiocyanate with rich functional groups is difficult to obtain, and the applicability of the substrate is very limited, so that the isothiocyanate is not beneficial to obtaining thioketone compounds with various structures; the use of strong bases also has a varying degree of disruption to the functional groups, resulting in poor functional group compatibility. These deficiencies are very detrimental to the preparation of azolethione functional molecules.

In view of the shortcomings of the existing preparation technology of imidazolethione compounds, a broad-spectrum, economical and efficient reaction technology for preparing azolethione derivatives is needed to be developed; meanwhile, it is very necessary to introduce various functional groups on the azole ring in order to obtain azolylthioketone derivatives with different functional application values.

Disclosure of Invention

In order to overcome the defects and shortcomings in the prior art, the invention mainly aims to provide an azole sulfur (selenium) ketone derivative.

Another object of the present invention is to provide a method for preparing the above azole thio (seleno) one derivative.

Still another object of the present invention is to provide the use of the above-mentioned azolethi (seleno) one derivatives.

The purpose of the invention is realized by the following technical scheme:

the invention provides an azoles sulfur (selenium) ketone derivative, which comprises benzimidazolethione, imidazolethione, triazolethione and related selenium ketone derivatives, and the structural formula of the derivatives is shown as formula I, II, III, IV, V, VI, VII, VIII or IX:

in the chemical formulas I and IV, R¹Can be C1-C12 alkyl or benzyl, or C1-C12 alkyl with one or more carbon atoms being replaced by carbon-carbon double bond, carbon-carbon triple bond, cyano, tetrahydroA furan ring, a dioxolane, an ether, an acetoxy group, an ester group, a benzyl group or a pentafluorobenzyl group, or a group in which one or more hydrogen atoms of the C1-C12 alkyl group are substituted by one or more functional groups selected from a carbon-carbon double bond, a carbon-carbon triple bond, a cyano group, a tetrahydrofuran ring, a dioxolane, an ether, an acetoxy group, an ester group, a benzyl group or a pentafluorobenzyl group; r²Can be any position of a benzene ring, and can be hydrogen, methyl, methoxy, ester group, ether, amino, nitro or halogen (fluorine, chlorine, bromine, iodine); r³Can be C1-C12 alkyl or benzyl, or a group in which one or more carbon atoms of C1-C12 alkyl are substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond, acetoxy or cyano, or a group in which one or more hydrogen atoms of C1-C12 alkyl are substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond, acetoxy or cyano.

In the formulae II and V, R⁴Can be C1-C12 alkyl or benzene ring group, or a group in which one or more carbon atoms on C1-C12 alkyl are substituted by more than one functional group of methyl, fluoro-acetyl substituted phenyl, ester group or amide group, or a group in which one or more hydrogen atoms on C1-C12 alkyl are substituted by more than one functional group of methyl, fluoro-acetyl substituted phenyl, ester group or amide group; r⁵Can be at the 4-or 5-position of the imidazole ring, and can be hydrogen, phenyl, p-hydroxyphenyl,

(dotted line represents a connecting bond) or

(dotted line represents a connecting bond); r⁶Can be C1-C12 alkyl, or C1-C12 alkyl group with one or more carbon atoms substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond or cyano, or C1-C12 alkyl with one or more hydrogen atoms substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond or cyanoMore than one functional group substituted group.

In the formulae III and VI, R⁷Can be C1-C12 alkyl, benzyl or

(the dotted line represents a connecting bond), or a group in which one or more carbon atoms of the alkyl group of C1 to C12 are substituted with one or more functional groups selected from a carbon-carbon double bond, a carbon-carbon triple bond, a cyano group, a tetrahydrofuran ring, a dioxolane, an ether, an acetoxy group, an ester group, a benzyl group, and a pentafluorobenzyl group, or a group in which one or more hydrogen atoms of the alkyl group of C1 to C12 are substituted with one or more functional groups selected from a carbon-carbon double bond, a carbon-carbon triple bond, a cyano group, a tetrahydrofuran ring, a dioxolane, an ether, an acetoxy group, an ester group, a benzyl group, and a pentafluorobenzyl group; r⁸The functional group can be C1-C12 alkyl, or a group in which one or more carbon atoms on the C1-C12 alkyl are substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond or cyano, or a group in which one or more hydrogen atoms on the C1-C12 alkyl are substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond or cyano.

Preferably, the azole thio (seleno) one derivative is a compound shown in the following structural formula:

the present invention also provides a process for preparing the azolethione (selenone) derivatives represented by the above formulae I to IX, which comprises the following reaction route:

in the reaction formulas (1) to (9), X ═ Br or I;

in the reaction formulae (1) and (4), R¹Can be C1-C12 alkyl or benzyl, or a group in which one or more carbon atoms of C1-C12 alkyl are substituted with one or more functional groups selected from carbon-carbon double bond, carbon-carbon triple bond, cyano, tetrahydrofuran ring, dioxolane, ether, acetoxy, ester group, benzyl or pentafluorobenzyl, or a group in which one or more hydrogen atoms of C1-C12 alkyl are substituted with one or more functional groups selected from carbon-carbon double bond, carbon-carbon triple bond, cyano, tetrahydrofuran ring, dioxolane, ether, acetoxy, ester group, benzyl or pentafluorobenzyl; when the ring connected in parallel with the imidazole ring is an aromatic ring, R²Can be any position of a benzene ring, and can be hydrogen, methyl, methoxy, halogen, ester group, nitro, fluorine, chlorine, bromine or iodine; in the reaction formulae (1), (4), (7), (8) and (9), R³Can be C1-C12 alkyl or benzyl, or a group in which one or more carbon atoms of C1-C12 alkyl are substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond, acetoxy or cyano, or a group in which one or more hydrogen atoms of C1-C12 alkyl are substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond, acetoxy or cyano.

In the reaction formulae (2) and (5), R⁴Can be C1-C12 alkyl or benzene ring group, or a group in which one or more carbon atoms on C1-C12 alkyl are substituted by more than one functional group of methyl, fluoro-acetyl substituted phenyl, ester group or amide group, or a group in which one or more hydrogen atoms on C1-C12 alkyl are substituted by more than one functional group of methyl, fluoro-acetyl substituted phenyl, ester group or amide group; r⁵Can be at the 4-or 5-position of the imidazole ring, and can be hydrogen, phenyl, p-hydroxyphenyl,

(dotted line represents a connecting bond) or(dotted line represents a connecting bond); r⁶The functional group can be C1-C12 alkyl, or a group in which one or more carbon atoms on the C1-C12 alkyl are substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond or cyano, or a group in which one or more hydrogen atoms on the C1-C12 alkyl are substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond or cyano.

In the above reaction formulae (3) and (6), R⁷Can be C1-C12 alkyl, benzyl or

(the dotted line represents a connecting bond), or a group in which one or more carbon atoms of the alkyl group of C1 to C12 are substituted with one or more functional groups selected from a carbon-carbon double bond, a carbon-carbon triple bond, a cyano group, a tetrahydrofuran ring, a dioxolane, an ether, an acetoxy group, an ester group, a benzyl group, and a pentafluorobenzyl group, or a group in which one or more hydrogen atoms of the alkyl group of C1 to C12 are substituted with one or more functional groups selected from a carbon-carbon double bond, a carbon-carbon triple bond, a cyano group, a tetrahydrofuran ring, a dioxolane, an ether, an acetoxy group, an ester group, a benzyl group, and a pentafluorobenzyl group; r⁸The functional group can be C1-C12 alkyl, or a group in which one or more carbon atoms on the C1-C12 alkyl are substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond or cyano, or a group in which one or more hydrogen atoms on the C1-C12 alkyl are substituted by more than one functional group of ester group, fluorine, carbon-carbon double bond, carbon-carbon triple bond or cyano.

Preferably, in the reaction formulas (1) and (4), the dosage ratio (mass-mol ratio) of the compound 1, the sulfur powder or the selenium powder and the compound 2 is 1.0 (1.0-3.0) to (1.0-3.0), preferably 1.0:2.0: 2.5. In the reaction formulas (7), (8) and (9), the molar ratio of the starting compound raw material, sulfur powder or selenium powder and halogenated alkane is 1.0 (1.0-3.0) to (1.0-3.0), preferably 1.0:2.0: 2.5.

Preferably, in the reaction formulas (2) and (5), the amount ratio (mass-mol ratio) of the compound 3, the sulfur powder or the selenium powder, and the compound 4 is 1.0 (1.0-3.0) to 1.0 (1.0-3.0), preferably 1.0:2.0: 2.5.

Preferably, in the reaction formulas (3) and (6), the amount ratio (mass-mole ratio) of the compound 5, the sulfur powder or the selenium powder, and the compound 6 is 1.0 (1.0-3.0) to 1.0 (1.0-3.0), preferably 1.0:2.0: 2.5.

The reaction comprises the following specific steps: weighing an azole compound, one of elemental sulfur or selenium and a catalyst sulfite, adding an organic solvent into a reaction vessel, injecting halogenated alkane, and reacting under heating to obtain a corresponding thioketone or selenone derivative, namely the compound shown in the formula I, II, III, IV, V, VI, VII, VIII or IX.

Preferably, in the above method, the reaction solvent is a commonly used organic solvent, and specifically, may be selected from benzene, toluene, xylene, chlorobenzene, dichlorobenzene, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, acetone, butanone, methyl isobutyl ketone, acetonitrile, propionitrile, butyronitrile, N-dimethylformamide, N-dimethylacetamide, N-methyl-formanilide, N-methylpyrrolidone, hexamethylphosphoric triamide, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, N-propanol, isopropanol, ethylene glycol monomethyl ether and at least one of 1, 4-dioxane, preferably at least one of 1, 2-dichloroethane, tetrahydrofuran, toluene, acetonitrile and 1, 4-dioxane, with 1, 2-dichloroethane being the most preferred solvent.

Preferably, the halogenated alkane is brominated alkane or iodoalkane.

Preferably, the catalyst is sulfite, and specifically can be selected from at least one of sodium formaldehyde sulfoxylate, sodium dithionite, sodium bisulfite, sodium sulfite and sodium thiosulfate; at least one of sodium dithionite, sodium bisulfite and sodium thiosulfate is preferable.

Preferably, in the reaction step, the reaction temperature is 40-160 ℃, preferably 80-20 ℃; the reaction time is 6 to 24 hours, preferably 12 to 24 hours, and most preferably 24 hours.

The azoles sulfur (selenium) ketone derivative can be applied to the fields of pesticides, medicines, organic functional materials, transition metal delivery and fluorescent probes.

The azoles sulfur (selenium) ketone derivative has excellent bactericidal and bacteriostatic activity, and has inhibitory activity on penicillium citrinum, gibberella cerealis, banana anthracnose and litchi anthracnose.

Compared with the prior art, the invention has the following advantages and beneficial effects:

(1) the invention provides a method for preparing azole sulfur (selenium) ketone derivatives with simple process, mild condition, low price, economy and high efficiency;

(2) the compound shown in the formula I-IX provided by the invention has important potential application value in pesticides, medicines and organic functional materials.

Detailed Description

The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto. The following examples are preferred embodiments of the present invention, but the present invention is not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.