CN112341506B - Acetyl glucose thiadiazole benzamide compound and synthesis method and application thereof - Google Patents

Abstract

式中，R为其所在环上任意位置的取代基。本发明实施例提供的乙酰葡萄糖噻二唑苯甲酰胺类化合物，其合成方法简单，是一种高效、环境友好的杀菌剂，可应用于农业杀菌，尤其对马铃薯晚疫病原菌的活性具有较好的抑制效果，可用于预防和减少马铃薯晚疫病的发生。The invention discloses an acetylglucosyl thiadiazole benzamide compound, a synthesis method and application thereof, and belongs to the technical field of chemical synthesis. The general structural formula of the acetyl glucose thiadiazole benzamide compound is:

In the formula, R is a substituent at any position on the ring. The acetylglucosyl thiadiazole benzamide compound provided in the embodiment of the present invention has a simple synthesis method, is an efficient and environment-friendly fungicide, can be applied to agricultural sterilization, and especially has good activity against the potato late blight pathogen. The inhibitory effect can be used to prevent and reduce the occurrence of potato late blight.

Description

Acetylglucose thiadiazole benzamide compound and its synthesis method and application

technical field

The invention relates to the technical field of chemical synthesis, in particular to an acetylglucosylthiadiazole benzamide compound and a synthesis method and application thereof.

Background technique

Potato late blight is a devastating disease caused by Phytophthora infestans. It has the characteristics of wide occurrence range, fast epidemic speed and serious damage. In general years, the yield can be reduced by 10% to 20%, and in severe years it can reach 50% to 50%. 70% or even no harvest. At present, due to the degradation of disease resistance of varieties and imperfect agricultural management, the control of potato late blight mainly relies on chemical control. The agents used to control potato late blight mainly include protective agents such as copper hydroxide, mancozeb, toadstool tin, isobactil, chlorothalonil, fluopyram, cyazofamid; propamocarb, nail cream, etc. Therapeutic agents such as fenugreek, malamuron, dimethomorph, and biological fungicides such as matrine and eugenol. However, the use of these chemical agents to control potato late blight also brings about problems such as: the long-term use of traditional chemical pesticides makes the pathogen gradually develop resistance, the use of pesticides continues to increase, and the ecological and environmental problems are more serious; While killing pathogenic bacteria, chemical fungicides also poison beneficial microorganisms and natural enemies of insects and pests.

Therefore, the creation of new, efficient and environmentally friendly fungicides is an urgent practical issue to be solved in current agricultural production.

SUMMARY OF THE INVENTION

The purpose of the embodiments of the present invention is to provide a kind of acetylglucosyl thiadiazole benzamide compounds, to solve the problems raised in the above background technology.

To achieve the above purpose, the embodiments of the present invention provide the following technical solutions:

A kind of acetylglucosamine thiadiazole benzamide compound, its general structural formula is formula I:

In the formula, R is a substituent at any position on the ring.

Preferably, in the formula, R is H, 2-CH ₃ , 3-CH ₃ , 4-CH ₃ , 2-OCH ₃ , 3-OCH ₃ , 4-OCH ₃ , 2,3-(CH ₃ ) ₂ , 2,4-(CH ₃ ) ₂ , 2,5-(CH ₃ ) ₂ , 2,6-(CH ₃ ) _{2 ,} 2,3-(OCH ₃ ) ₂ , 2,4-(OCH ₃ ) ₂ , 2,5-(OCH ₃ ) ₂ , 2,6-(OCH ₃ ) ₂ , 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3- At least one of Br, 4-BrPh, 2-NO ₂ , 3-NO ₂ , 4-NO ₂ , 2-CF ₃ , 3-CF ₃ , and 4-CF ₃ .

Another object of the embodiment of the present invention is to provide a kind of synthetic method of the above-mentioned acetylglucosylthiadiazole benzamide compound, it comprises the following steps:

React raw material A with raw material B to obtain intermediate C;

The intermediate C and the raw material D are reacted to obtain the acetylglucosthiadiazole benzamide compound;

Wherein, the structural formulas of raw material A, raw material B, intermediate C and raw material D are respectively formula A, formula B, formula C, formula D:

Preferably, the step of reacting raw material A with raw material B to obtain intermediate C specifically includes:

Mixing raw material B, NaOH, distilled water and acetone to obtain a first mixed solution;

The raw material A is prepared into a solution and added dropwise to the first mixed solution to react, and then purified and separated to obtain the intermediate C.

Preferably, in the step, the raw material A is prepared into an acetone solution of the raw material A.

Preferably, the step of reacting the intermediate C with the raw material D to obtain the acetylglucosylthiadiazole benzamide compound specifically includes:

Intermediate C, dichloromethane and triethylamine are mixed to obtain the second mixed solution;

After the raw material D and thionyl chloride are mixed and reacted completely, the thionyl chloride is removed, and the residue is prepared into a solution of triethylamine and added dropwise to the second mixed solution for reaction, and then purified and separated to obtain the obtained solution. The acetylglucosamine thiadiazole benzamides are described.

Preferably, in the step, the residue is prepared into a dichloromethane solution of acid chloride.

Concrete, the reaction scheme of above-mentioned synthetic method is as follows:

Another object of the embodiments of the present invention is to provide an application of the above-mentioned acetylglucosidazole thiadiazole benzamide compound in inhibiting the potato late blight pathogen.

Compared with the prior art, the beneficial effects of the embodiments of the present invention are:

The acetylglucosylthiadiazole benzamide compound provided in the embodiment of the present invention has a simple synthesis method, is an efficient and environment-friendly fungicide, can be applied to agricultural sterilization, and has a particularly good effect on the activity of the potato late blight pathogen. Good inhibitory effect can be used to prevent and reduce the occurrence of potato late blight.

Detailed ways

The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments.

Example 1

This material example provides a method for synthesizing acetylglucosthiadiazole benzamide compounds. The reaction scheme is as follows, wherein R is a substituent on the ring where R is, specifically 4-CH ₃ :

Specifically, the synthetic method comprises the following steps:

S1, intermediate (2-amino-5-(thio-1,3,4-thiadiazolyl)-2',3',4',6'-tetra-O-acetyl-β-D- Synthesis of glucose): add 400mg (0.01mol) NaOH, 10mL distilled water, 50mL acetone solution, 1.33g (0.01mol) 2-amino-5-mercapto-1,3,4-thiadiazole to a 50mL there-necked flask, stir 30min to obtain the first mixed solution; dissolve 0.98g (2.4mmol) of 2',3',4',6'-tetra-O-acetyl-α-D-bromoglucose with 5mL acetone solution, and add dropwise The reaction was carried out in the first mixed solution, stirred at room temperature, detected by TLC, developing solvent: V (ethyl acetate): V (petroleum ether)=1:2. When the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, 200 mL of dichloromethane was added to the bottle containing the residue, washed twice with water (2×20 mL), and the aqueous phase was extracted twice with dichloromethane (2×20 mL). ), then combine the organic phases. The organic phase was dried over anhydrous magnesium sulfate and filtered, and the solvent was removed by spin-drying under reduced pressure to obtain the crude product, which was separated by silica gel column chromatography to obtain the intermediate (2-amino-5-(thio-1,3,4-thiadiazolyl) -2',3',4',6'-tetra-O-acetyl-β-D-glucose).

S2, in the there-necked flask of 50mL, 2.54mmol (0.345g) of the raw material D whose structural formula is the following formula D is dissolved in 4 mL of thionyl chloride, 60 DEG C of backflow reaction 2 hours, and then the reaction system is fully spin-dried, Add 1.0 mmol of the above intermediate (2-amino-5-(thio-1,3,4-thiadiazolyl)-2',3',4',6'-tetra-O-acetyl-β- D-glucose), 10 mL of dichloromethane and triethylamine (TEA, 1.0 mmol), stirred at room temperature, slowly added dropwise a solution of 1.2 mmol of acid chloride in dichloromethane, stirred and reacted for three hours, followed the reaction by TLC, and after the reaction was complete, Quench with water, separate the organic phase, spin dry, and recrystallize the crude product with isopropanol to obtain acetylglucosthiadiazole benzamide compounds. Wherein, the structural formula of raw material D is:

Example 2

This material embodiment provides a method for synthesizing acetylglucosylthiadiazole benzamide compounds, the reaction scheme is as follows, wherein R is the substituent on the ring where R is, specifically 4-F:

Specifically, the synthetic method comprises the following steps:

S1, intermediate (2-amino-5-(thio-1,3,4-thiadiazolyl)-2',3',4',6'-tetra-O-acetyl-β-D- Synthesis of glucose): add 400mg (0.01mol) NaOH, 10mL distilled water, 50mL acetone solution, 1.33g (0.01mol) 2-amino-5-mercapto-1,3,4-thiadiazole to a 50mL there-necked flask, stir 30min to obtain the first mixed solution; dissolve 0.98g (2.4mmol) of 2',3',4',6'-tetra-O-acetyl-α-D-bromoglucose with 5mL acetone solution, and add dropwise The reaction was carried out in the first mixed solution, stirred at room temperature, detected by TLC, developing solvent: V (ethyl acetate): V (petroleum ether)=1:2. When the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, 200 mL of dichloromethane was added to the bottle containing the residue, washed twice with water (2×20 mL), and the aqueous phase was extracted twice with dichloromethane (2×20 mL). ), then combine the organic phases. The organic phase was dried over anhydrous magnesium sulfate and filtered, and the solvent was removed by spin-drying under reduced pressure to obtain the crude product, which was separated by silica gel column chromatography to obtain the intermediate (2-amino-5-(thio-1,3,4-thiadiazolyl) -2',3',4',6'-tetra-O-acetyl-β-D-glucose).

S2, in the there-necked flask of 50mL, 2.54mmol (0.355g) of the raw material D whose structural formula is the following formula D is dissolved in 4 mL of thionyl chloride, 60 DEG C of reflux reactions are carried out for 2 hours, and then the reaction system is fully spin-dried, Add 1.0 mmol of the above intermediate (2-amino-5-(thio-1,3,4-thiadiazolyl)-2',3',4',6'-tetra-O-acetyl-β- D-glucose), 10 mL of dichloromethane and triethylamine (TEA, 1.0 mmol), stirred at room temperature, slowly added dropwise a solution of 1.2 mmol of acid chloride in dichloromethane, stirred and reacted for three hours, followed the reaction by TLC, and after the reaction was complete, Quench with water, separate the organic phase, spin dry, and recrystallize the crude product with isopropanol to obtain acetylglucosthiadiazole benzamide compounds. Wherein, the structural formula of raw material D is:

Example 3

This material embodiment provides a method for synthesizing acetylglucosylthiadiazole benzamide compounds, and the reaction scheme is as follows, wherein R is a substituent on the ring where R is, specifically 4-Br:

Specifically, the synthetic method comprises the following steps:

S1, intermediate (2-amino-5-(thio-1,3,4-thiadiazolyl)-2',3',4',6'-tetra-O-acetyl-β-D- Synthesis of glucose): add 400mg (0.01mol) NaOH, 10mL distilled water, 50mL acetone solution, 1.33g (0.01mol) 2-amino-5-mercapto-1,3,4-thiadiazole to a 50mL there-necked flask, stir 30min to obtain the first mixed solution; dissolve 0.98g (2.4mmol) of 2',3',4',6'-tetra-O-acetyl-α-D-bromoglucose with 5mL acetone solution, and add dropwise The reaction was carried out in the first mixed solution, stirred at room temperature, detected by TLC, developing solvent: V (ethyl acetate): V (petroleum ether)=1:2. When the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure, 200 mL of dichloromethane was added to the bottle containing the residue, washed twice with water (2×20 mL), and the aqueous phase was extracted twice with dichloromethane (2×20 mL). ), then combine the organic phases. The organic phase was dried over anhydrous magnesium sulfate and filtered, and the solvent was removed by spin-drying under reduced pressure to obtain the crude product, which was separated by silica gel column chromatography to obtain the intermediate (2-amino-5-(thio-1,3,4-thiadiazolyl) -2',3',4',6'-tetra-O-acetyl-β-D-glucose).

S2, in the three-necked flask of 50mL, 2.54mmol (0.508g) of the raw material D whose structural formula is the following formula D is dissolved in 4 mL of thionyl chloride, 60 DEG C of reflux reactions are carried out for 2 hours, and then the reaction system is fully spin-dried, Add 1.0 mmol of the above intermediate (2-amino-5-(thio-1,3,4-thiadiazolyl)-2',3',4',6'-tetra-O-acetyl-β- D-glucose), 10 mL of dichloromethane and triethylamine (TEA, 1.0 mmol), stirred at room temperature, slowly added dropwise a solution of 1.2 mmol of acid chloride in dichloromethane, stirred and reacted for three hours, followed the reaction by TLC, and after the reaction was complete, Quench with water, separate the organic phase, spin dry, and recrystallize the crude product with isopropanol to obtain acetylglucosthiadiazole benzamide compounds. Wherein, the structural formula of raw material D is:

Wherein, can carry out the synthesis of the acetyl bromide glucosyl thiadiazole benzamide compounds containing different R substituents according to the synthetic method that the above-mentioned embodiment 1～3 provides, wherein, part of the acetyl glucos thiadiazole benzamide compounds The spectral data are shown in Table 1.

Table 1

In addition, the in vitro growth rate method in the prior art was used to determine the bacteriostatic activity of the above-mentioned acetylglucosthiadiazole benzamide compounds. Specifically, the potato dextrose agar medium (PDA medium: 200 g of potato, 20 g of agar, 20 g of glucose, and 1000 mL of distilled water) was heated to a molten state (50° C.), and 10 mL of medicinal solution (containing 10 times the final concentration of acetylglucosamine thiadiazole) was added. The drug solution of formamide compounds) was poured into 90 mL of PDA medium, shaken well, evenly poured into a petri dish with a diameter of 9 cm, placed horizontally, and waited to cool and solidify. Use a hole puncher to punch a bacterial plate with a diameter of 4 mm on the edge of the fresh pathogenic bacteria colony that has been cultivated for 4 days, place the bacterial plate upside down on the center of the PDA plate containing the drug, and then place it in a 27°C constant temperature and humidity incubator for upside-down cultivation. When the colony grew to nearly two-thirds of the plate, the observation was started, and the diameter of the colony was measured by the cross method, and the average value was taken. The blank control was unmedicated, but contained the same concentration of solvent and 0.5% Tween 20, and each treatment was replicated three times. The inhibitory rate of the agent on mycelial growth was calculated by the following formula:

I(%)=(C-T)/(C-0.4)×100%;

Among them, I is the inhibition rate, C is the diameter of the blank control (cm), and T is the diameter of the treatment (cm). Samples at 5 concentrations were determined, dose-inhibition curves were drawn, and their _EC50 values were calculated. Each sample was repeated three times, and the results were expressed as mean ± standard deviation.

After calculation, the EC ₅₀ of the acetylglucosylthiadiazole benzamide compound synthesized in the above Example 1 against P. infestans was 6.02 μg/mL.

Taking the above ideal embodiments according to the present invention as inspiration, and through the above description, relevant personnel can make various changes and modifications without departing from the technical idea of the present invention. The technical scope of the present invention is not limited to the contents in the specification, and the technical scope must be determined according to the scope of the claims.

Claims (7)

1. an acetylglucos thiadiazole benzamide compound, is characterized in that, the general structural formula of described acetylglucos thiadiazole benzamide compound is formula I:

In the formula, R is a substituent at any position on the ring, specifically, R is H, 2-CH ₃ , 3-CH ₃ , 4-CH ₃ , 2-OCH ₃ , 3-OCH ₃ , 4-OCH ₃ , 2,3-(CH ₃ ) ₂ , 2,4-(CH ₃ ) ₂ , 2,5-(CH ₃ ) ₂ , 2,6-(CH ₃ ) _2, 2,3-(OCH ₃ ) ₂ , 2,4-(OCH ₃ ) ₂ , 2,5-(OCH ₃ ) ₂ , 2,6-(OCH ₃ ) ₂ , 2-F, 3-F, 4-F, 2-Cl, 3- At least one of Cl, 4-Cl, 2-Br, 3-Br, ₂ -NO2, 3-NO2, ₄ -NO2, ₂ - _CF3 , ₃ - _CF3 , 4-CF3. 2. a synthetic method of acetylglucosyl thiadiazole benzamide compound as claimed in claim 1, is characterized in that, comprises the following steps: React raw material A with raw material B to obtain intermediate C; The intermediate C and the raw material D are reacted to obtain the acetylglucosthiadiazole benzamide compound; Wherein, the structural formulas of raw material A, raw material B, intermediate C and raw material D are respectively formula A, formula B, formula C, formula D:

3. the synthetic method of a kind of acetylglucosyl thiadiazole benzamide compound according to claim 2, is characterized in that, described raw material A and raw material B are reacted, the step that obtains intermediate C, specifically comprises: Mixing raw material B, NaOH, distilled water and acetone to obtain a first mixed solution; The raw material A is prepared into a solution and added dropwise to the first mixed solution to react, and then purified and separated to obtain the intermediate C. 4. the synthetic method of a kind of acetylglucos thiadiazole benzamide compound according to claim 3, is characterized in that, in described step, raw material A is prepared into the acetone solution of raw material A. 5. the synthetic method of a kind of acetylglucosyl thiadiazole benzamide compound according to claim 2, is characterized in that, described intermediate C is reacted with raw material D, obtains described acetyl glucose thiadiazole benzene The steps of the formamide compound specifically include: Intermediate C, dichloromethane and triethylamine are mixed to obtain the second mixed solution; The raw material D and thionyl chloride are mixed and reacted completely, and then the thionyl chloride is removed, and the residue is prepared into a solution, which is added dropwise to the second mixed solution for reaction, and then purified and separated to obtain the acetyl Glucothiadiazole benzamides. 6. the synthetic method of a kind of acetylglucosyl thiadiazole benzamide compound according to claim 5, is characterized in that, in described step, the methylene chloride solution of residue is prepared into acid chloride. 7. the application of the acetylglucosyl thiadiazole benzamide compound as claimed in claim 1 in suppressing the potato late blight pathogen.