CN112194634B - Preparation method of N-difluoromethyl imidazole sulfur (selenium) urea derivative - Google Patents
Preparation method of N-difluoromethyl imidazole sulfur (selenium) urea derivative Download PDFInfo
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention discloses a preparation method of an N-difluoromethyl imidazole sulfur (selenium) urea derivative. N-difluoromethyl azole thiourea (selenium) derivatives comprise N-difluoromethyl benzimidazole thiourea, N-difluoromethyl imidazole thiourea, N-difluoromethyl triazole thiourea and related N-difluoromethyl selenourea derivatives. Adding imidazole derivative or triazole derivative, elemental sulfur powder or selenium powder and catalyst into a reaction tube, adding organic solvent into the reaction tube, adding BrCF 2 CO 2 Et, reacting under heating to obtain the N-difluoromethylimidazolium 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
The patent application of the invention is a divisional application with the application number of "CN 201811452050.8", the application date of the original application is "11.30.2018", the application number is "CN 201811452050.8", and the invention name is "an N-difluoromethyl azole sulfur (selenium) urea derivative and a preparation method thereof".
Technical Field
The invention belongs to the technical field of organic chemical reaction, and particularly relates to a preparation method of an N-difluoromethyl imidazole sulfur (selenium) urea 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 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.; 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, R 1 The alkyl may be any alkyl with or without functional group, the carbon number of the alkyl carbon chain is 1-12, and the functional group may be more than one of carbon-carbon double bond, carbon-carbon triple bond, cyano, tetrahydrofuran, dioxolane, ester group, benzyl and pentafluorobenzyl；R 2 Is 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, R 3 Can 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 phenyl, benzyl, ester group, fluorine-containing aromatic hydrocarbon,
One or more of (1);
in the chemical formula III, R 4 Can 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, R 1 The alkyl can be various alkyls containing or not containing various functional groups, the carbon number of the alkyl carbon chain is 1-12, and the functional group can be more than one of carbon-carbon double bond, carbon-carbon triple bond, cyano, tetrahydrofuran, dioxolane, ester group, benzyl and pentafluorobenzyl; r 2 Is 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, R 3 The 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):
compound 1
Compound 2
Compound 3
Compound 4
Compound 5
Compound 6
Compound 7
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 R 1 、R 2 、R 3 And R 4 Compounds I to VII can be obtained by the above reaction route;
the specific steps of the above reaction formula (1-7): weighing azole compound, elemental sulfur powder or selenium powder and catalyst, adding into a reaction tube, adding organic solvent into the reaction tube, and injecting BrCF 2 CO 2 Et, reacting under heating to obtain the compound shown in the formulas I-VII;
in the reaction (1-5), R 1 、R 2 、R 3 、R 4 Are as defined in (1) and R in the compounds I to VII 1 、R 2 、R 3 、R 4 The 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) 1 Is benzyl, R 2 As 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 Cs 2 CO 3 (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, 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 stirrer 8 ) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH) 2 SO 2 Na) (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 Na 2 SO 4 Dry 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 stirrer 8 ) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in anhydrous potassium carbonate (K) 2 CO 3 ) (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 Na 2 SO 4 Drying and rotatingThe solvent was evaporated in vacuo on an 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) 1 Is methyl, R 2 As 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 stirrer 8 ) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH) 2 SO 2 Na) (0.8mmol) as a catalyst in a solution of 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 Na 2 SO 4 Dry 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 II 1 Is 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 stirrer 8 ) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH) 2 SO 2 Na)(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 saline solution and ethyl acetate solvent, and the organic layers were combined and dried over anhydrous Na 2 SO 4 Dry 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 III 1 Is 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 Cs 2 CO 3 (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 stirrer 8 ) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH) 2 SO 2 Na) (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 phases were combinedLayer channel anhydrous Na 2 SO 4 Dry 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) 1 Is 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) 2 SO 2 Na) (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 Na 2 SO 4 Dry 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 I 1 Is 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 directional magnetic forceThe stirrer was charged with N-benzyl-7H-purin-6-amine (5.0mmol), benzyl bromide (6.0mmol) and Cs 2 CO 3 (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 cap 8 ) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH) 2 SO 2 Na) (0.8mmol) as a catalyst in a solution of 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 Na 2 SO 4 Dry 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 stirrer 8 ) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH) 2 SO 2 Na) (0.8mmol) as a catalyst in a solution of N, N-Dimethylacetamide (DMA) (2.0mL) was stirred at 100 ℃ for 24 hours. The reaction is finishedThen, 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 Na 2 SO 4 Dry 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 stirrer 8 ) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH) 2 SO 2 Na) (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 Na 2 SO 4 Dry 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:
in the magnet is provided withOven-dried 15mL sealed tube with tetrafluoroethylene cap with force stirrer was charged with fluconazole (0.4mmol), sulfur powder (S) 8 ) (0.8mmol), ethyl bromodifluoroacetate (1.0mmol) in sodium hydroxymethylsulfinate (HOCH) 2 SO 2 Na) (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 Na 2 SO 4 Dry 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-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 stirrer 2 SO 2 Na) (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 Na 2 SO 4 Dry 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 stirrer 2 CO 3 ) (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 Na 2 SO 4 Dry 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 reacted 1 、R 2 、R 3 、R 4 Substitution 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 N-difluoromethyl imidazole thiourea derivatives 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 BrCF 2 CO 2 Et, reacting under heating to obtain the compound; the azole compound refers to
Y＝C；
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 sulfinate or alkali, and the sulfinate is selected from at least one of sodium hydroxymethyl sulfinate, sodium dithionite, sodium bisulfite, sodium sulfite and sodium thiosulfate; the alkali is at least one selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium phosphate, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium hydroxide, potassium hydroxide and choline;
the reaction route is shown as the following formula:
Y＝C，X＝S；R 4 is a phenyl substituted C1 alkyl group.
2. The method according to claim 1, wherein the organic solvent is at least one selected from the group consisting of N, N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, acetonitrile, and N, N-dimethylacetamide.
3. The method according to claim 1, wherein the sulfinate is selected from at least one of sodium hydroxymethylsulfinate, sodium dithionite, sodium bisulfite and sodium thiosulfate; the alkali is at least one selected from sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
4. The production method according to claim 1, wherein in the reaction formula, the reaction temperature is 40 ℃ to 160 ℃; the reaction time is 12-24 hours.
5. The production method according to claim 4, wherein in the reaction formula, the reaction temperature is 80 ℃ to 120 ℃; the reaction time was 24 hours.
6. The process according to claim 1, wherein the reaction scheme is a reaction scheme in which an azole compound is reacted with sulfur powder and BrCF 2 CO 2 The molar ratio of Et is 1:1-3: 1-3.
7. The process according to claim 1, wherein the reaction scheme is a reaction scheme in which an azole compound is reacted with sulfur powder and BrCF 2 CO 2 The molar ratio of Et was 1:2: 2.5.
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