CN109369538B - N-difluoromethyl azole thiourea (selenium) derivative and preparation method thereof - Google Patents
N-difluoromethyl azole thiourea (selenium) derivative and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an N-difluoromethyl azole thiourea (selenium) derivative and a preparation method thereof. The N-difluoromethyl azole thiourea (selenium) derivative comprises N-difluoromethyl benzimidazole thiourea, N-difluoromethyl imidazole thiourea, N-difluoromethyl triazole thiourea and related N-difluoromethyl selenourea derivatives. Adding a benzimidazole derivative, an imidazole derivative or a triazole derivative, elemental sulfur powder or selenium powder and a catalyst into a reaction tube, adding an organic solvent into the reaction tube, injecting halogenated hydrocarbon, and reacting under a heating condition to obtain the N-difluoromethyl azole sulfur (selenium) urea derivative. The preparation method is simple and easy to operate, mild in condition, cheap and economical; the provided compound has important potential application value in pesticides, medicines and organic functional materials.
Description
Technical Field
The invention belongs to the technical field of organic chemical reaction, and particularly relates to an N-difluoromethyl azole thiourea (selenium) derivative and a preparation method thereof.
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 compound has the characteristics of high efficiency, low toxicity, excellent bioactivity and various structural changes, has wide application in the aspects of pesticides and medicines, and is always a hotspot and key point of organic chemistry research. (Liyan, organic chemistry, 2007,28(2): 210-217; Zhang Ying, pesticide, 2008,47(3), 164-170). Selective fluorination and fluoroalkylation of organic compounds results in significant changes in the electronic effects and skeletal characteristics of the product. The fluorine-containing compound has wide application in the fields of medicine, pesticide, material chemistry, catalysis and the like. In fluoroalkyl groups, difluoromethyl group behaves like a traditional hydrogen bond donor (N-H, O-H), which shows a stronger lipophilicity. Furthermore, when difluoromethyl is introduced, there is a clear effect on the pharmacokinetic properties of the drug, i.e. membrane permeability, bioavailability, binding affinity, metabolic stability and lipophilicity. (org. Process Res. Dev.2008,12 (2)), 305-. These compounds have a similar structure to herbicides (e.g. Sulfentrazone, Carfentrazone-ethyl and Neuro-peptide Y antagonists) which may have good biological activity for pharmaceutical and agricultural applications. ((a) Dumas, D.J.US Patent 5990315,1999., (b) Poss, K.M.PCT Int.Pat.WO 1990/002120,1990., (c) Sato, N.; Ando, M.; Ishikawa, S.; Nagase, T.; Nagai, K.; Kanatani, A.PCT Int.Pat WO 2004/031175,2004.; and (d) Org.Lett.2014,16, 54.).
In view of the important functions and application values of N-difluoromethylthiourea, it is necessary to develop a simple and efficient method for preparing N-difluoromethylthiourea derivatives. The prior reaction technology for preparing N-difluoromethyl azole thiourea generally realizes the reaction conversion by generating difluoromethyl carbene through a complex reagent of Trimethylsilyl Fluorosulfonyl Difluoroacetate (TFDA) under the catalysis of strong base (Organic Letters,2006,8(24): 5549-5551.). However, the TFDA fluorine-containing reagent is not easy to obtain, and the applicability of the substrate is very limited, so that the preparation of thiourea compounds with various structures is not facilitated; the use of strong base also has destructive effects on functional groups to different degrees, resulting in poor compatibility of the functional groups and being unfavorable for the construction of drug molecule libraries.
In view of the defects of the existing preparation technology of the N-difluoromethyl azole thiourea compound, a broad-spectrum, economical and efficient reaction technology for preparing the N-difluoromethyl azole thiourea derivative is required to be developed.
Disclosure of Invention
In order to overcome the defects and shortcomings in the prior art, the invention mainly aims to provide the N-difluoromethyl azole thiourea (selenium) derivative.
Another object of the present invention is to provide a method for producing the above N-difluoromethyl azole thiourea (selenium) derivative. The method is characterized in that the corresponding N-difluoromethyl azole thiourea derivatives are synthesized by converting heterocycles such as benzimidazole, imidazole, triazole and derivatives thereof.
The purpose of the invention is realized by the following technical scheme:
the invention provides an N-difluoromethyl azole thiourea (selenium) derivative, which comprises N-difluoromethyl benzimidazole thiourea, N-difluoromethyl imidazole thiourea, N-difluoromethyl triazole thiourea and related N-difluoromethyl selenourea derivatives, and the structural general formula of the N-difluoromethyl azole thiourea derivative is shown as chemical formulas I, II, III, IV, V, VI or VII:
in the chemical formula I, R1The functional group can be more than one of carbon-carbon double bond, carbon-carbon triple bond, cyano, tetrahydrofuran, dioxolane, ester group, benzyl and pentafluorobenzyl; r2Is one or more than one substitution on a benzene ring, can be the same or different and is selected from methyl, methoxy, ester group, halogen, nitro and the like at any position of the benzene ring;
in the chemical formula II, R3Can be various alkyl and various aryl groups with or without various functional groups, the carbon number of the alkyl carbon chain is 1-12, and the functional group can be benzene ring, benzyl, ester group, fluorine-containing aromatic hydrocarbon,
One or more of (1);
in the chemical formula III, R4Can be various alkyl groups and various aryl groups with or without various functional groups, the carbon number of the alkyl carbon chain is 1-12, and the functional group can be benzyl and
one or more of (two-bonded N-difluoromethyl), and the like;
in the chemical formula IV, R1Can be various alkyl groups with or without various functional groups, the carbon number of the alkyl carbon chain is 1-12, and the functional group can be carbon-carbon double bond, carbon-carbon triple bond, cyano, tetrahydrofuran, dioxolaneOne or more of a group, an ester group, a benzyl group and a pentafluorobenzyl group; r2Is one or more than one substitution on a benzene ring, can be the same or different and is selected from methyl, methoxy, ester group, halogen and the like at any position of the benzene ring;
in the chemical formula V, R3The functional group can be various alkyls and various aryls with or without various functional groups, the carbon number of the alkyl carbon chain is 1-12, and the functional group can be more than one of benzene ring, benzyl, ester group and fluorine-containing aromatic hydrocarbon;
preferably, the N-difluoromethyl azole sulfur (selenium) urea derivative is a compound represented by the following structural formula:
the invention also provides a method for preparing the compound in the formula I-III, wherein reaction paths are respectively shown as the formula (1), (2) and (3); the reaction path of the preparation method of the compound in the formula IV and V is shown as the formula (4), and the reaction path of the preparation method of the compound in the formula VI is shown as the formula (5); a process for the preparation of a compound of formula VII, the reaction scheme being represented by formula (6):
the azole compounds in the reaction formula (1-7), i.e. the compounds 1-7, can be benzimidazole, substituted benzimidazole derivatives, imidazole, substituted imidazole derivatives, triazole or substituted triazole derivatives, wherein the substituent refers to R1、R2、R3And R4Compounds I to VII can be obtained by the above reaction route;
the specific steps of the above reaction formula (1-7): weighing an azole compound, elemental sulfur powder or selenium powder and a catalyst, adding the azole compound, the elemental sulfur powder or selenium powder and the catalyst into a reaction tube, adding an organic solvent into the reaction tube, injecting halogenated hydrocarbon, and reacting under a heating condition to obtain a compound shown in a formula I-VII;
in the reaction (1-5), R1、R2、R3、R4Are as defined in (1) and R in the compounds I to VII1、R2、R3、R4The same definition is applied.
The method comprises the following steps:
the organic solvent is a commonly used organic solvent, and specifically may be at least one 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 1, 4-dioxane; preferably at least one of N, N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, acetonitrile and N, N-dimethylacetamide;
the catalyst is sulfinate and/or alkali;
the sulfinate can be selected from at least one of sodium hydroxymethyl sulfinate, sodium dithionite, sodium bisulfite, sodium sulfite and sodium thiosulfate, preferably at least one of sodium hydroxymethyl sulfinate, sodium dithionite, sodium bisulfite and sodium thiosulfate; the alkali may be selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydroxide, potassium hydroxide, choline, etc., preferably at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
In the reaction step, the reaction temperature is 40-160 ℃, and preferably 80-120 ℃; the reaction time is 12 to 24 hours, preferably 24 hours.
In the above reaction formulae (1) to (3), (6) and (7), the amount ratio of the compound 1, the compound 2, the compound 3, the compound 6 or the compound 7 to the sulfur powder and the halogenated hydrocarbon (mass-to-mole ratio) is 1:1 to 3, preferably 1:2: 2.5;
in the above reaction formulas (4) and (5), the amount ratio of the compound 4 or the compound 5 to the selenium powder and the halogenated hydrocarbon (mass-mole ratio) is 1:1 to 3, preferably 1:2: 2.5.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the invention provides a technical method for preparing a batch of N-difluoromethyl azole thiourea (selenium) derivatives with simplicity, easy operation, mild condition, low price, economy and high efficiency;
(2) the compounds shown in the formulas I to VII provided by the invention have important potential application values 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 method is a conventional method which is carried out according to the above reaction chemical equation unless otherwise specified.
Example 1:
preparation of benzyl-3- (difluoromethyl) -1, 3-dihydro-2H-benzo [ d ] of formula I]Imidazole-2-thione compounds (R)1Is benzyl, R2As hydrogen):
the synthesis steps of the 1-benzyl benzimidazole are as follows:
in an oven-dried 100 mL round flask, equipped with a magnetic stirrer to which was added benzimidazole (5.0mmol, 0.59g), benzyl bromide (6.0mmol) and Cs2CO3(10.0 mmol). Reaction the mixture was stirred at 80 ℃ under reflux for 8 hours with acetonitrile. After the reaction was complete, the reaction mixture was cooled to room temperature. Acetonitrile was removed under vacuum to give a residueThe mixture was dissolved in dichloromethane and filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the resulting residue was purified by flash column chromatography using petroleum and EtOAc as eluent, isolated in 92% yield (0.957 g).
The method comprises the following steps: 1-Benzylbenzimidazole (0.4mmol), sulfur powder (S) were added to an oven-dried 15mL sealed tube with a tetrafluoroethylene cap equipped with a magnetic stirrer8) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH)2SO2Na) (0.8mmol) as a catalyst in N, N-Dimethylacetamide (DMA) (2.0mL) was stirred at 100 ℃ for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Dry and evaporate the solvent in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC monitoring plates gave the product (I-1) as a yellow solid in m.p. 113.6-113.9 ℃ in 88% yield.
The second method comprises the following steps: 1-Benzylbenzimidazole (0.4mmol), sulfur powder (S) were added to an oven-dried 15mL sealed tube with a tetrafluoroethylene cap equipped with a magnetic stirrer8) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in anhydrous potassium carbonate (K)2CO3) (0.8mmol) as a catalyst in N, N-Dimethylacetamide (DMA) (2.0mL) for 24 hours at 100 ℃. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Dry and evaporate the solvent in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC monitoring plates gave the product (I-1) as a yellow solid in m.p. 113.6-113.9 ℃ in 87% yield.
Example 2:
preparation of 1- (difluoromethyl) -3-methyl-1, 3-dihydro-2H-benzo [ d ] of formula I]Imidazole-2-thione compounds (R)1Is methyl, R2As hydrogen):
1-methylbenzimidazole (0.4mmol), sulfur powder (S) were added to an oven-dried 15mL sealed tube with a tetrafluoroethylene cap equipped with a magnetic stirrer8) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH)2SO2Na) (0.8mmol) as a catalyst in N, N-Dimethylacetamide (DMA) (2.0mL) was stirred at 100 ℃ for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Dry and evaporate the solvent in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC monitoring plates gave the product (I-10) as a white solid in m.p. 111.3-112.5 ℃ in 73% yield.
Example 3:
preparation of 1-benzyl-3- (difluoromethyl) -1, 3-dihydro-2H-imidazole-2-thione Compound (R) represented by formula II1Is benzyl):
1-Benzylimidazole (0.4mmol), sulfur powder (S) were added to an oven-dried 15mL sealed tube with a tetrafluoroethylene cap equipped with a magnetic stirrer8) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH)2SO2Na) (0.8mmol) as a catalyst in N, N-Dimethylacetamide (DMA) (2.0mL) was stirred at 100 ℃ for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Dry and evaporate the solvent in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC monitoring plates gave the product (I-24) as a pale yellow solid in m.p.: 107.5-108.4 ℃ with a yield of 37%。
Example 4:
preparation of 2-benzyl-4- (difluoromethyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione Compound (R) represented by formula III1Is benzyl):
the synthesis steps of the 1-benzyl-1H-1, 2, 4-triazole comprise:
in an oven-dried 100 ml round flask, equipped with a magnetic stirrer to which was added 1,2, 4-triazole (5.0mmol), benzyl bromide (6.0mmol) and Cs2CO3(10.0 mmol). Reaction the mixture was stirred at 80 ℃ under reflux for 8 hours with acetonitrile. After the reaction was complete, the reaction mixture was cooled to room temperature. Acetonitrile was removed under vacuum and the residue was dissolved in dichloromethane and filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the resulting residue was purified by flash column chromatography using petroleum and EtOAc as eluent in 65% isolated yield (0.517 g).
1-benzyl-1H-1, 2, 4-triazole (0.4mmol) and sulfur powder (S) were added to an oven-dried 15mL sealed tube with a tetrafluoroethylene cap equipped with a magnetic stirrer8) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH)2SO2Na) (0.8mmol) as a catalyst in N, N-Dimethylacetamide (DMA) (2.0mL) was stirred at 100 ℃ for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Dry and evaporate the solvent in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC monitoring plates gave the product (I-25) as a yellow solid in m.p. 74.2-74.8 ℃ with a yield of 41%.
Example 5:
preparation of 3- (difluoromethyl) -1-isobutyl-1, 3-dihydro-2H-imidazo [4,5-c ] of formula I]Quinoline-2-thione compounds (R)1Is isopropyl):
1-isobutyl-1H-imidazo [4,5-c ] was added to an oven-dried 15mL sealed tube with a tetrafluoroethylene cap equipped with a magnetic stirrer]Quinoline (0.4mmol), Sulfur powder (S)8) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH)2SO2Na) (0.8mmol) as a catalyst in N, N-Dimethylacetamide (DMA) (2.0mL) was stirred at 100 ℃ for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Dry and evaporate the solvent in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC monitoring plates gave the product (I-29) as a pale yellow solid in m.p.: 177.6-177.9 ℃ yield 33%.
Example 6:
preparation of 7-benzyl-6- (benzylamino) -9- (difluoromethyl) -7, 9-dihydro-8H-purine-8-thione Compound (R) of formula I1Is benzyl):
the synthesis of N, 7-dibenzyl-7H-purine-6-amine comprises the following steps:
in an oven dried 100 ml round flask, equipped with a magnetic stirrer to which was added N-benzyl-7H-purin-6-amine (5.0mmol), benzyl bromide (6.0mmol) and Cs2CO3(10.0 mmol). Reaction the mixture was stirred at 80 ℃ under reflux for 8 hours with acetonitrile. After the reaction was complete, the reaction mixture was cooled to room temperature. Acetonitrile was removed under vacuum and the residue was dissolved in dichloromethane and filtered to remove inorganic salts. The filtrate was concentrated in vacuo and the resulting residue was purified by flash column chromatography using petroleum and EtOAc as eluent in 35% isolated yield (0.552 g).
N, 7-dibenzyl-7H-purin-6-amine (0.4mmol) and sulfur powder (S) were added to an oven-dried 15mL sealed tube equipped with a magnetic stirrer and a tetrafluoroethylene cap8) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH)2SO2Na) (0.8mmol) as a catalyst in N, N-Dimethylacetamide (DMA) (2.0mL) was stirred at 100 ℃ for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Dry and evaporate the solvent in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC monitoring plates gave the product (I-30) as a yellow solid in m.p. 116.8-117.9 ℃ with a yield of 13%.
Example 7:
preparing a 1- (2- ((4-chlorobenzyl) oxy) -2- (2, 4-dichlorophenyl) ethyl) -3- (difluoromethyl) -1, 3-dihydro-2H-imidazole-2-thione compound represented by formula I:
adding econazole (0.4mmol) and sulfur powder (S) into an oven-dried 15mL sealed tube with a tetrafluoroethylene cap and a magnetic stirrer8) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH)2SO2Na) (0.8mmol) as a catalyst in N, N-Dimethylacetamide (DMA) (2.0mL) was stirred at 100 ℃ for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Dry and evaporate the solvent in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC monitoring plates gave the product (I-31) as a yellow solid in m.p. 89.0-89.9 ℃ with a yield of 48%.
Example 8:
preparing a 1- (4- (4- (((2R,4S) -2- (2, 4-dichlorophenyl) -2- ((3- (difluoromethyl) -2-thio-2, 3-dihydro-1H-imidazolepiperazin-1-yl) methyl) -1, 3-dioxolan-4-yl) methoxy) phenyl) piperazin-1-yl) ethan-1-one compound shown in formula I:
ketoconazole (0.4mmol), sulfur powder (S) were added to an oven-dried 15mL sealed tube with a tetrafluoroethylene cap equipped with a magnetic stirrer8) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH)2SO2Na) (0.8mmol) as a catalyst in N, N-Dimethylacetamide (DMA) (2.0mL) was stirred at 100 ℃ for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Dry and evaporate the solvent in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC spot plate gave the product (I-32) as a yellow oil in 43% yield.
Example 9:
preparing a 2,2' - (2- (2, 4-difluorophenyl) -2-hydroxypropane-1, 3-diyl) bis (4- (difluoromethyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-thione) compound shown in formula II:
fluconazole (0.4mmol) and sulfur powder (S) were added to an oven-dried 15mL sealed tube equipped with a magnetic stirrer and a tetrafluoroethylene cap8) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH)2SO2Na) (0.8mmol) as a catalyst in N, N-Dimethylacetamide (DMA) (2.0mL) was stirred at 100 ℃ for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Is dried and is inThe solvent was evaporated in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC spot plate gave the product (I-33) as a yellow oil in 25% yield.
Example 10:
preparing a 1-benzyl-3- (difluoromethyl) -1, 3-dihydro-2H-benzo [ d ] imidazole-2-selenone compound shown as a formula III:
1-Benzylbenzimidazole (0.4mmol), selenium powder (Se) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH) was added to an oven-dried 15mL sealed tube with a tetrafluoroethylene cap equipped with a magnetic stirrer2SO2Na) (0.8mmol) as a catalyst in N, N-Dimethylacetamide (DMA) (2.0mL) was stirred at 100 ℃ for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Dry and evaporate the solvent in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC monitoring plates gave the product (I-34) as a pale yellow solid in m.p. 121.8-122.5 ℃ with a yield of 54%.
Example 11:
preparing a 1- (2- ((4-chlorobenzyl) oxy) -2- (2, 4-dichlorophenyl) ethyl) -3- (difluoromethyl) -1, 3-dihydro-2H-imidazole-2-selenone compound shown as a formula II:
adding econazole (0.4mmol), selenium powder (Se) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in anhydrous potassium carbonate (K) in an oven-dried 15mL sealed tube with a tetrafluoroethylene cap and a magnetic stirrer2CO3) (0.8mmol) as a catalyst in a solution of N, N-Dimethylacetamide (DMA) (2.0mL)The mixture should be stirred at 100 ℃ for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, the mixture was extracted with a saturated brine and ethyl acetate solvent, and the organic layers were combined and washed with anhydrous Na2SO4Dry and evaporate the solvent in vacuo on a rotary evaporator. Flash column chromatography using 300-400 mesh silica gel and purification of the crude mixture by preparative TLC spot plate gave the product (I-36) as a yellow oil in 55% yield.
Following the same procedure as in example 1, only R of the reaction formulae (1) to (7) was reacted1、R2、R3、R4Substitution is carried out as shown in Table 1 to obtain other corresponding products shown as formulas I-VII, which are numbered as I- (1-36). The appearance and yield of the above compounds are shown in Table 1, and the results of infrared, low resolution and nuclear magnetic hydrogen spectroscopy are shown in Table 2. As can be seen from the above, the compounds numbered sequentially as I- (1-36) have the correct structure and are all compounds represented by formulas I-VII.
TABLE 1 physical constants of the compounds of formulae I-III
TABLE 2 Infrared, Low resolution and NMR Hydrogen Spectroscopy data for Compounds of formulae I-III
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, 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.
Claims (7)
1. A preparation method of an N-difluoromethyl azole thiourea derivative is characterized by comprising the following specific steps: weighing azole compound, elemental sulfur powder and catalyst, adding into a reaction vessel, adding organic solvent into the reaction vessel, adding BrCF2CO2Et, reacting under heating to obtain the compound shown in the formula I; the azole compound is a benzimidazole derivative containing a substituent, wherein the substituent is R1、R2(ii) a The organic solvent is at least one 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 1, 4-dioxane; the catalyst is at least one of sodium hydroxymethyl sulfinate, sodium dithionite, sodium bisulfite, sodium sulfite and sodium thiosulfate, or at least one of sodium carbonate and potassium carbonate;
R1is various alkyl groups containing or not containing functional groups, the carbon number of the alkyl carbon chain is 1-12, and the functional groups are more than one of cyano, oxolanyl, dioxygen cyclopentyl, ester groups, benzyl and pentafluorobenzyl; r2Is one or more than one substitution on a benzene ring, and is selected from methyl, methoxy, ester group, halogen and nitro at any position of the benzene ring;
the reaction path is shown as formula (1):
2. a preparation method of N-difluoromethyl azole selenourea derivatives is characterized by comprising the following specific steps: weighing azole compound, elemental selenium powder and catalyst, adding into a reaction vessel, adding organic solvent into the reaction vessel, adding BrCF2CO2Et, reacting under heating condition to obtain the compound shown in the formula IV; the azole compound is a benzimidazole derivative containing a substituent, wherein the substituent is R1、R2(ii) a The organic solvent is at least one 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 1, 4-dioxane; the catalyst is at least one of sodium hydroxymethyl sulfinate, sodium dithionite, sodium bisulfite, sodium sulfite and sodium thiosulfate, or at least one of sodium carbonate and potassium carbonate;
R1is various alkyl groups containing or not containing functional groups, the carbon number of the alkyl carbon chain is 1-12, and the functional groups are more than one of cyano, oxolanyl, dioxygen cyclopentyl, ester groups, benzyl and pentafluorobenzyl; r2Is one or more than one substitution on a benzene ring, and is selected from methyl, methoxy, ester group, halogen and nitro at any position of the benzene ring;
the reaction path is shown as formula (4):
3. the production method according to claim 1 or 2, characterized in that the organic solvent is at least one selected from the group consisting of N, N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, acetonitrile, and N, N-dimethylacetamide.
4. The production method according to claim 1 or 2, wherein in the reaction formulas (1) and (4), the reaction temperature is 40 ℃ to 160 ℃ in both cases; the reaction time is 12-24 hours.
5. The method according to claim 4, wherein in the reaction formulas (1) and (4), the reaction temperature is 80-120 ℃; the reaction time was 24 hours.
6. The production method according to claim 1 or 2, characterized in that in the reaction formula (1), the molar ratio of the compound 1 to the sulfur powder and the halogenated hydrocarbon is 1:1-3: 1-3;
in the reaction formula (4), the molar ratio of the compound 4 to the selenium powder to the halogenated hydrocarbon is 1:1-3: 1-3.
7. The production method according to claim 1 or 2, characterized in that in the reaction formula (1), the molar ratio of the compound 1 to the sulfur powder and the halogenated hydrocarbon is 1:2: 2.5;
in the reaction formula (4), the molar ratio of the compound 4 to the selenium powder to the halogenated hydrocarbon is 1:2: 2.5.
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