CN117402125A - Preparation method of noo Bo Suan oxadiazole thioester compound, product and application thereof - Google Patents

Preparation method of noo Bo Suan oxadiazole thioester compound, product and application thereof Download PDF

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CN117402125A
CN117402125A CN202311091009.3A CN202311091009A CN117402125A CN 117402125 A CN117402125 A CN 117402125A CN 202311091009 A CN202311091009 A CN 202311091009A CN 117402125 A CN117402125 A CN 117402125A
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oxadiazole
suan
noose
thioester
acetone
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谷文
郑一鸣
孙雪宝
杨子辉
邱遗贵
金道峻
王石发
崔振楠
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Nanjing Forestry University
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Nanjing Forestry University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P3/00—Fungicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

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  • General Chemical & Material Sciences (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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Abstract

The invention discloses a preparation method and a product of a nopol Bo Suan oxadiazole thioester compound and application thereof, nopol is oxidized to synthesize the nopol Bo Suan, and then the nopol Bo Suan is subjected to acyl chloride to obtain the nopol Bo Xianlv, which is reacted with different substituted oxadiazole thiols in one step to synthesize the nopol Bo Suan oxadiazole thioester compound. The compound has the general formula I:wherein R is benzene ring, thiophene or furan with different substituents respectively; the compound has better prevention effect on sclerotinia sclerotiorum under the in-vitro condition, and can be used for preventing and controlling agricultural plant fungal diseases. The saidThe preparation method of the compound is simple and convenient, and the product has stable properties.

Description

Preparation method of noo Bo Suan oxadiazole thioester compound, product and application thereof
Technical Field
The invention belongs to the field of pesticide synthesis, and particularly relates to a preparation method and a product of a no Bo Suan oxadiazole thioester compound and application thereof.
Background
Crop diseases and insect pests are one of important restriction factors affecting sustainable and healthy development of agricultural products and resources under forests. The pesticide is a special commodity for controlling the biological hazard of crop and forestry crop diseases and insect pests, and plays an important role in protecting the normal growth of crop and forestry crop, improving the production of agriculture, promoting the grain safety, and the like.
The long-term use of a single pesticide variety can also cause plant pathogens, pests, weeds and the like to generate drug resistance, so that the development of a new pesticide variety with a targeting effect is important for the effective treatment of plant diseases.
Up to now, no report on the use of the compound of the formula of the no Bo Suan oxadiazole thioesters as agricultural bactericides is seen.
Disclosure of Invention
This section is intended to outline some aspects of embodiments of the invention and to briefly introduce some preferred embodiments. Some simplifications or omissions may be made in this section as well as in the description summary and in the title of the application, to avoid obscuring the purpose of this section, the description summary and the title of the invention, which should not be used to limit the scope of the invention.
The present invention has been made in view of the above and/or problems occurring in the prior art.
Therefore, the invention aims to overcome the defects in the prior art and provide a preparation method of the noo Bo Suan oxadiazole thioester compound.
In order to solve the technical problems, the invention provides the following technical scheme: a preparation method of a noo Bo Suan oxadiazole thioester compound, which comprises the following steps of,
oxidizing nopol to synthesize nootken Bo Suan;
synthesizing the nootkatol by the reaction of the nootkatol to obtain nootkatol Bo Xianlv;
synthesizing each substituted oxadiazole thiol by reacting each substituted formylhydrazine;
reacting the paranoon Bo Xian chloride with each substituted oxadiazole mercaptan to synthesize a noon Bo Suan oxadiazole thioester compound;
wherein, the structural formula of the noose Bo Suan oxadiazole thioester compound is as follows:
wherein,
as a preferred embodiment of the preparation process according to the invention, there is provided: the synthetic method of the synthetic noose Bo Suan comprises the following steps of,
taking nopol, adding acetone into a single-mouth bottle, slowly dripping Jones reagent into the mixture by using a dropping funnel under ice bath condition, reacting for 1h, detecting by TLC, and rotating and concentrating to remove most of the acetone after the reaction is finished;
adding ethyl acetate for extraction, combining organic layers, washing with saturated saline water, drying with anhydrous sodium sulfate, concentrating in a rotating way to obtain a crude product of the noose Bo Suan, separating and purifying by using 200-300 mesh silica gel column chromatography, and purifying by using petroleum ether/ethyl acetate volume ratio of 40:1-10:1 to obtain oily noose Bo Suan;
wherein, the molar ratio of nopol, acetone and Jones reagent is 1:20.6:2.2.
As a preferred embodiment of the preparation process according to the invention, there is provided: the synthesis method of the oxadiazole thiol with each substituent comprises the following steps of,
dissolving various substituent formylhydrazides in absolute ethanol, adding KOH, and graduallyDripping CS 2 After the addition, reflux reaction is carried out at 85 ℃, TLC detects that the raw materials are completely reacted, 5% hydrochloric acid is added for acidification, distilled water is used for diluting the reaction liquid, the solid is filtered, washed with water and dried, and finally absolute ethyl alcohol is used for recrystallization, thus obtaining the target compound oxadiazole thiol.
As a preferred embodiment of the preparation process according to the invention, there is provided: the synthesis of the Nor Bo Xian chloride comprises the following steps,
adding the Nor Bo Suan and the dichloromethane into a round-bottom flask, stirring in an ice bath, and dropwise adding oxalyl chloride;
the reaction mixture was stirred at room temperature for 2-3 h, after completion, concentrated in vacuo to remove excess oxalyl chloride and solvent to give noose Bo Xianlv, which was used directly in the next step without further purification.
As a preferred embodiment of the preparation process according to the invention, there is provided: the synthesized noose Bo Suan oxadiazole thioester compound comprises,
dissolving oxadiazole thiols as substituents in acetone, adding K 2 CO 3 Dropwise adding noose Bo Xianlv, reacting at room temperature for 3-4 h, rotary concentrating to remove most of acetone, adding ethyl acetate for extraction, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, and rotary concentrating to obtain a crude product;
separating and purifying by 200-300 mesh silica gel column chromatography, and purifying by petroleum ether/ethyl acetate volume ratio of 40:1-10:1 to obtain the no Bo Suan oxadiazole thioester.
As a preferred embodiment of the preparation process according to the invention, there is provided: the substituted hydrazides include benzoyl hydrazine, 4-methylbenzoyl hydrazine, 4-methoxybenzoyl hydrazine, 4-fluorobenzoyl hydrazine, 2-chlorobenzoyl hydrazine, 3-chlorobenzoyl hydrazine, 4-bromobenzoyl hydrazine, 2-thiophenyl hydrazide and 2-furanyl hydrazide.
It is a further object of the present invention to provide a noo Bo Suan oxadiazole thioester compound which overcomes the deficiencies of the prior art.
Another object of the present invention is to overcome the deficiencies in the prior art and to provide the use of the noo Bo Suan oxadiazole thioesters for controlling plant fungi including Rhizoctonia solani, botrytis cinerea and Sclerotinia sclerotiorum in agriculture or forestry.
The invention has the beneficial effects that:
(1) The compound disclosed by the invention is a sulfur ester derivative containing nor Bo Suan oxadiazole, is novel in molecular structure, is novel in chemical structure, is clear in chemical structure characteristics, contains nopic acid and oxadiazole groups in a structural formula, and is connected with oxadiazole through sulfur bonds; the preparation method of the compound is simple and convenient, the raw materials are easy to obtain, and the reaction conditions are mild and easy to control.
(2) The compound disclosed by the invention is a medicament for preventing and treating plant fungi in the field of agriculture or forestry, and the medicament has a good effect on preventing and treating rhizoctonia solani, botrytis cinerea and sclerotinia rot of colza.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings that are needed in the description of the embodiments will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art. Wherein:
FIG. 1 is a schematic illustration of a process for preparing a noose Bo Suan oxadiazole thioester compound according to an embodiment of the present invention.
Detailed Description
In order that the above-recited objects, features and advantages of the present invention will become more apparent, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
Further, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic can be included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
The preparation method of the nopic acid amide compound is schematically shown in figure 1, and comprises the following steps:
(1) Oxidizing nopol to synthesize nootken Bo Suan;
(2) And synthesizing the nor Bo Xian chloride by the reaction of the nopic acid.
(3) And (3) reacting each substituted formylhydrazine to synthesize each substituted oxadiazole thiol.
(4) The reaction of paranoon Bo Xian chloride with each substituted oxadiazole thiol synthesizes the noon Bo Suan oxadiazole thioester.
The method comprises the following specific steps:
(1) Preparation of nopic acid
Taking nopol (6.6 g,39.6 mmol) in a 250mL single-mouth bottle, adding 60mL of acetone for dissolution, slowly dripping 33mL of Jones reagent by using a dropping funnel under ice bath condition, reacting for 1h under ice bath condition, detecting by TLC, after the reaction is finished, rotating and concentrating to remove most of acetone, adding ethyl acetate for extraction (50 mL multiplied by 3), combining organic layers, washing with saturated saline (100 mL multiplied by 2), drying with anhydrous sodium sulfate, rotating and concentrating to obtain a crude product of the nopol Bo Suan, separating and purifying by using 200-300 mesh silica gel column chromatography, and purifying by using petroleum ether/ethyl acetate with a volume ratio of 40:1-10:1 to obtain oil-like nopol Bo Suan 2.1.1 g;
(2) Preparation of Nor Bo Xian chloride
To a round bottom flask was added No Bo Suan (220.6 mg,1.11 mmol) and CH 2 Cl 2 (4 mL) was stirred in an ice bath and oxalyl chloride (281.8 mg,2.22 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2h, after which time the excess oxalyl chloride and solvent were removed by vacuum concentration to give no Bo Xianlv, which was used directly in the next step without further purification.
(3) Preparation of different substituted oxadiazole thiols
Respectively taking benzoyl hydrazine, 4-methyl benzoyl hydrazine, 4-methoxyl benzoyl hydrazine, 4-fluorobenzoyl hydrazine, 2-chlorobenzoyl hydrazine, 3-chlorobenzoyl hydrazine and 4-chlorineBenzoyl hydrazine, 4-bromobenzoyl hydrazine, 2-thiophenecarbazide and 2-furancarbohydrazide (2.38 mmol) were added to a round bottom flask, dissolved in 10mL of absolute ethanol, KOH (2.62 mmol) was added thereto, and CS was added dropwise 2 (4.76 mmol) and reflux-reacting overnight at 85 ℃, concentrating in vacuum to remove the solvent after the reaction is finished, dissolving the solid with water, acidifying the solution to pH 2-3 with 5% hydrochloric acid, filtering the solid, drying, recrystallizing with ethanol to obtain the target compound oxadiazole thiol.
(4) Preparation of different substituted Nor Bo Suan oxadiazole thioesters
A round-bottomed flask was charged with a different substituted oxadiazole thiol (1.11 mmol), dissolved in 6mL of acetone and K was added 2 CO 3 (2.22 mmol) and noon Bo Xianlv (1.11 mmol) were dissolved in 4mL of acetone and added dropwise. After the reaction was completed, acetone was removed by vacuum concentration, 10mL of water was added, extraction was performed with ethyl acetate (3X 10 mL), and the organic phases were combined, washed with water, saturated aqueous sodium bicarbonate solution and saturated sodium chloride in this order, and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo to remove ethyl acetate and the crude product was finally purified by chromatography on a silica gel column (200-300 mesh, petroleum ether/ethyl acetate=40:1-10:1 v/v) to give the noose Bo Suan oxadiazole thioester compound.
Example 1
To obtain the noo Bo Suan oxadiazole thioester derivative (I-1):
5-phenyl-1, 3, 4-oxadiazole-2-thiol (197.8 mg,1.11 mmol) was dissolved in 10ml acetone and K was added 2 CO 3 (306.8 mg,2.22 mmol) was added dropwise to the mixture, and then the mixture was reacted at room temperature for 1h, TLC was conducted to monitor completion of the reaction of the starting materials, most of the acetone was removed by rotary concentration, ethyl acetate was added for extraction, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, rotary concentrated to give crude nor Bo Suan oxadiazole thioester, and finally the crude product was purified by silica gel chromatography (200-300 mesh, petroleum ether/ethyl acetate=40:1-10:1 v/v) to give the objective nor Bo Suan oxadiazole thioester derivative (I-1): white solid; the yield thereof was found to be 80%.
1 H NMR (600 MHz, chloroform) delta 8.03-7.97 (m, 2H), 7.63-7.57 (m, 1H), 7.55-7.50 (m, 2H), 6.81-6.77 (m, 1H), 3.46 (ddt, j=20.9, 9.2,1.7hz, 1H), 2.90 (dddt, j=20.2, 8.5,5.6,2.5hz, 1H), 2.75 (t, j=5.3 hz, 1H), 2.48 (dt, j=10.6, 5.8hz, 1H), 2.17-2.11 (m, 1H), 2.09-2.01 (m, 1H), 2.00-1.91 (m, 1H), 1.45 (d, j=10.2 hz, 1H), 1.33 (s, 3H), 0.81 (s, 3H). 13 C NMR (150 MHz, chloroform) delta 180.2,174.2,160.8,157.8,133.1,129.3,127.2,122.0,110.9,55.1,41.5,40.5,27.5,26.2,24.4,23.9,22.4.
Example 2
To obtain the noo Bo Suan oxadiazole thioester derivative (I-2):
5- (4-methyl) -phenyl-1, 3, 4-oxadiazole-2-thiol (213.3 mg,1.11 mmol) was dissolved in 10ml acetone and K was added 2 CO 3 (306.8 mg,2.22 mmol) and then dropwise adding Nor Bo Xianlv (220.6 mg,1.11 mmol) to react for 1h at room temperature, TLC monitoring the complete reaction of the raw materials, rotary concentrating to remove most of the acetone, adding ethyl acetate for extraction, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, rotary concentrating to obtain crude Nor Bo Suan oxadiazole thioester, finally purifying the crude product on a silica gel chromatographic column (200-300 meshes, petroleum ether/ethyl acetate=40:1-10:1 v/v) to obtain the target Nor Bo Suan oxadiazole thioester derivative (I-2): a pale yellow solid; the yield thereof was found to be 80%.
1 H NMR (600 MHz, chloroform) delta 7.89 (d, j=8.2 hz, 2H), 7.32 (d, j=8.0 hz, 2H), 6.81-6.77 (m, 1H), 3.45 (ddt, j=20.9, 9.2,1.6hz, 1H), 2.89 (dddt, j=20.2, 8.5,5.6,2.6hz, 1H), 2.74 (t, j=5.3 hz, 1H), 2.48 (dt, j=10.6, 5.7hz, 1H), 2.44 (s, 3H), 2.17-2.11 (m, 1H), 2.09-2.00 (m, 1H), 1.99-1.91 (m, 1H), 1.44 (d, j=10.2 hz, 1H), 1.33 (s, 3H), 0.81 (s, 3H). 13 C NMR (150 MHz, chloroform) delta 180.04,174.28,160.80,157.94,143.91,130.04,127.12,119.17,110.95,55.08,41.48,40.47,27.52,26.18,24.36,23.85,22.39,21.92.
Example 3
To obtain the noo Bo Suan oxadiazole thioester derivative (I-3):
5- (4-methoxy) -phenyl-1, 3, 4-oxadiazole-2-thiol (231.1 mg,1.11 mmol) was dissolved in 10ml acetone and K was added 2 CO 3 (306.8 mg,2.22 mmol) and then dropwise adding Nor Bo Xianlv (220.6 mg,1.11 mmol) to react for 1h at room temperature, TLC monitoring the complete reaction of the raw materials, rotary concentrating to remove most of the acetone, adding ethyl acetate for extraction, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, rotary concentrating to obtain crude Nor Bo Suan oxadiazole thioester, finally purifying the crude product on a silica gel chromatographic column (200-300 meshes, petroleum ether/ethyl acetate=40:1-10:1 v/v) to obtain the target Nor Bo Suan oxadiazole thioester derivative (I-3): a pale yellow solid; yield thereof was found to be 79%.
1 H NMR (600 MHz, chloroform) delta 7.96-7.92 (m, 2H), 7.03-6.98 (m, 2H), 6.81-6.78 (m, 1H), 3.89 (s, 3H), 3.45 (ddt, j=20.9, 9.2,1.6hz, 1H), 2.93-2.85 (m, 1H), 2.74 (t, j=5.3 hz, 1H), 2.48 (dt, j=10.7, 5.8hz, 1H), 2.18-2.11 (m, 1H), 2.08-2.01 (m, 1H), 1.99-1.91 (m, 1H), 1.44 (d, j=10.1 hz, 1H), 1.32 (s, 3H), 0.80 (s, 3H). 13 C NMR (150 MHz, chloroform) delta 179.88,174.30,163.41,160.85,157.81,129.07,114.80,114.22,111.02,55.71,55.08,41.48,40.48,27.52,26.19,24.35,23.86,22.39.
Example 4
To obtain the noo Bo Suan oxadiazole thioester derivative (I-4):
5- (4-fluoro) -phenyl-1, 3, 4-oxadiazole-2-thiol (217.6 mg,1.11 mmol) was dissolved in 10ml acetone and K was added 2 CO 3 (306.8 mg,2.22 mmol) and then added dropwise to No Bo Xianlv (220.6 mg,1.11 mmol) for 1h at room temperature, TLC monitored complete reaction of starting material, and rotary concentration removed the bulkSeparating acetone, adding ethyl acetate for extraction, combining organic layers, washing with saturated saline water, drying with anhydrous sodium sulfate, concentrating by rotation to obtain crude nor Bo Suan oxadiazole thioester, and finally purifying the crude product on a silica gel chromatographic column (200-300 meshes, petroleum ether/ethyl acetate=40:1-10:1 v/v) to obtain the target nor Bo Suan oxadiazole thioester derivative (I-4): a pale yellow solid; the yield thereof was found to be 83%.
1 H NMR (600 MHz, chloroform) delta 8.01 (m, 2H), 7.23-7.16 (m, 2H), 6.78-6.74 (m, 1H), 3.49-3.35 (m, 1H), 2.88 (dddd, j=20.2, 10.5,5.7,2.6hz, 1H), 2.73 (t, j=5.3 hz, 1H), 2.47 (dt, j=10.9, 5.8hz, 1H), 2.18-2.10 (m, 1H), 2.08-2.00 (m, 1H), 1.99-1.90 (m, 1H), 1.43 (d, j=10.2 hz, 1H), 1.32 (s, 3H), 0.80 (s, 3H). 13 C NMR (150 MHz, chloroform) δ 180.23,174.01,165.55 (d, j=253.5 Hz), 160.57,156.89,129.56 (d, j=9.1 Hz), 118.32 (d, j=3.3 Hz), 116.79 (d, j=22.4 Hz), 110.83,55.11,41.47,40.46,27.49,26.16,24.36,23.81,22.35.
Example 5
To obtain the noo Bo Suan oxadiazole thioester derivative (I-5):
5- (2-chloro) -phenyl-1, 3, 4-oxadiazole-2-thiol (217.6 mg,1.11 mmol) was dissolved in 10ml acetone and K was added 2 CO 3 (306.8 mg,2.22 mmol) and then dropwise adding Nor Bo Xianlv (220.6 mg,1.11 mmol) to react for 1h at room temperature, TLC monitoring the complete reaction of the raw materials, rotary concentrating to remove most of the acetone, adding ethyl acetate for extraction, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, rotary concentrating to obtain crude Nor Bo Suan oxadiazole thioester, finally purifying the crude product on a silica gel chromatographic column (200-300 meshes, petroleum ether/ethyl acetate=40:1-10:1 v/v) to obtain the target Nor Bo Suan oxadiazole thioester derivative (I-5): white solid; the yield thereof was found to be 69%.
1 H NMR (600 MHz, chloroform) delta 7.93 (dd, j=7.9, 1.5hz, 1H), 7.57 (dd, j=8.1, 1.0hz, 1H), 7.52 (td, j=7.8, 1.6hz, 1H), 7.43 (td, j=7.8, 1.2hz, 1H), 6.78-6.72 (m, 1H), 3.46(ddt,J＝21.0,9.2,1.7Hz,1H),2.89(dddt,J＝20.5,8.5,5.8,2.6Hz,1H),2.72(t,J＝5.3Hz,1H),2.47(dt,J＝10.7,5.8Hz,1H),2.13(m,1H),2.04(m,1H),1.95(m,1H),1.43(d,J＝10.1Hz,1H),1.32(s,3H),0.80(s,3H). 13 C NMR (150 MHz, chloroform) delta 180.44,173.62,160.66,155.68,133.69,133.43,131.73,130.98,127.32,121.12,110.74,55.15,41.46,40.45,27.53,26.16,24.38,23.83,22.37.
Example 6
To obtain the noo Bo Suan oxadiazole thioester derivative (I-6):
5- (3-chloro) -phenyl-1, 3, 4-oxadiazole-2-thiol (217.6 mg,1.11 mmol) was dissolved in 10ml acetone and K was added 2 CO 3 (306.8 mg,2.22 mmol) and then dropwise adding Nor Bo Xianlv (220.6 mg,1.11 mmol) to react for 1h at room temperature, TLC monitoring the complete reaction of the raw materials, rotary concentrating to remove most of the acetone, adding ethyl acetate for extraction, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, rotary concentrating to obtain crude Nor Bo Suan oxadiazole thioester, finally purifying the crude product on a silica gel chromatographic column (200-300 meshes, petroleum ether/ethyl acetate=40:1-10:1 v/v) to obtain the target Nor Bo Suan oxadiazole thioester derivative (I-6): white solid; the yield thereof was found to be 69%.
1 H NMR (600 MHz, chloroform) δ8.00 (t, j=1.7 hz, 1H), 7.88 (d, j=8.0 hz, 1H), 7.56 (ddd, j=8.0, 1.8,0.8hz, 1H), 7.47 (t, j=7.9 hz, 1H), 6.79-6.72 (m, 1H), 3.44 (ddt, j=20.9, 9.2,1.8hz, 1H), 2.89 (ddd, j=20.3, 10.7,5.7,2.7hz, 1H), 2.75 (t, j=5.3 hz, 1H), 2.48 (dt, j=10.8, 5.8hz, 1H), 2.14 (m, 1H), 2.05 (m, 1H), 1.95 (m, 1.44 (d, j=10.hz, 1H), 1.33.3 s,3 s (s, 81). 13 C NMR (150 MHz, chloroform) delta 180.69,173.85,160.52,156.46,135.61,133.07,130.70,127.06,125.19,123.67,110.68,55.12,41.51,40.44,27.50,26.16,24.42,23.82,22.38.
Example 7
To obtain the No Bo Suan amide derivative (I-7):
5- (4-chloro) -phenyl-1, 3, 4-oxadiazole-2-thiol (217.6 mg,1.11 mmol) was dissolved in 10ml acetone and K was added 2 CO 3 (306.8 mg,2.22 mmol) and then dropwise adding Nor Bo Xianlv (220.6 mg,1.11 mmol) to react for 1h at room temperature, TLC monitoring the complete reaction of the raw materials, rotary concentrating to remove most of the acetone, adding ethyl acetate for extraction, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, rotary concentrating to obtain crude Nor Bo Suan oxadiazole thioester, finally purifying the crude product on a silica gel chromatographic column (200-300 meshes, petroleum ether/ethyl acetate=40:1-10:1 v/v) to obtain the target Nor Bo Suan oxadiazole thioester derivative (I-7): white solid; the yield thereof was found to be 73%.
1 H NMR (600 MHz, chloroform) delta 7.99-7.89 (m, 2H), 7.56-7.47 (m, 2H), 6.83-6.73 (m, 1H), 3.44 (ddt, j=20.9, 9.3,1.8hz, 1H), 2.89 (dddd, j=20.2, 10.7,5.6,2.6hz, 1H), 2.74 (t, j=5.3 hz, 1H), 2.53-2.46 (m, 1H), 2.15 (m, 1H), 2.05 (m, 1H), 1.96 (m, 1H), 1.45 (d, j=10.2 hz, 1H), 1.33 (s, 3H), 0.81 (s, 3H). 13 C NMR (150 MHz, chloroform) delta 180.46,174.00,160.57,156.94,139.53,129.80,128.41,120.53,110.82,55.17,41.53,40.51,27.53,26.20,24.43,23.86,22.40.
Example 8
To obtain the noo Bo Suan oxadiazole thioester derivative (I-8):
5- (4-bromo) -phenyl-1, 3, 4-oxadiazole-2-thiol (285.4 mg,1.11 mmol) was dissolved in 10ml acetone and K was added 2 CO 3 (306.8 mg,2.22 mmol) and then dropwise addition of No Bo Xianlv (220.6 mg,1.11 mmol) for 1h at room temperature, TLC monitoring the complete reaction of the starting materials, rotary concentrating to remove most of the acetone, extraction with ethyl acetate, combining the organic layers, washing with saturated brine, drying over anhydrous sodium sulfate, rotary concentrating to give the crude No Bo Suan oxadiazole thioester, finally subjecting the crude product to silica gel column chromatography (200-30Purifying the crude product on a 0 mesh petroleum ether/ethyl acetate=40:1-10:1 v/v) to give the target noose Bo Suan oxadiazole thioester derivative (I-8): white solid; yield thereof was found to be 78%.
1 H NMR (600 MHz, chloroform) delta 7.87 (d, j=8.6 hz, 2H), 7.67 (d, j=8.6 hz, 2H), 6.77 (s, 1H), 3.44 (ddt, j=20.9, 9.2,1.8hz, 1H), 2.89 (dddd, j=20.3, 10.7,5.7,2.7hz, 1H), 2.74 (t, j=5.3 hz, 1H), 2.48 (dt, j=11.0, 6.0hz, 1H), 2.14 (m, 1H), 2.09-1.91 (m, 2H), 1.44 (d, j=10.2 hz, 1H), 1.33 (s, 3H), 0.80 (s, 3H). 13 C NMR (150 MHz, chloroform) delta 180.60,173.96,160.56,157.01,132.75,128.47,128.02,120.92,110.75,55.12,41.51,40.45,27.50,26.18,24.43,23.83,22.39.
Example 9
To obtain the noo Bo Suan oxadiazole thioester derivative (I-9):
2-thiophene-1, 3, 4-oxadiazole-2-thiol (204.5 mg,1.11 mmol) was dissolved in 10mL of acetone and K was added 2 CO 3 (306.8 mg,2.22 mmol) and then dropwise adding Nor Bo Xianlv (220.6 mg,1.11 mmol) to react for 1h at room temperature, TLC monitoring the complete reaction of the raw materials, rotary concentrating to remove most of the acetone, adding ethyl acetate for extraction, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, rotary concentrating to obtain crude Nor Bo Suan oxadiazole thioester, finally purifying the crude product on a silica gel chromatographic column (200-300 meshes, petroleum ether/ethyl acetate=40:1-10:1 v/v) to obtain the target Nor Bo Suan oxadiazole thioester derivative (I-9): a pale yellow solid; the yield thereof was found to be 65%.
1 H NMR (600 MHz, chloroform) delta 7.81-7.78 (m, 1H), 7.65-7.61 (m, 1H), 7.21-7.16 (m, 1H), 6.74 (s, 1H), 3.44 (ddt, j=20.9, 9.2,1.8hz, 1H), 2.88 (dddd, j=20.2, 10.7,5.7,2.7hz, 1H), 2.74 (t, j=5.3 hz, 1H), 2.48 (dt, j=11.1, 5.9hz, 1H), 2.16-2.12 (m, 1H), 2.04 (m, 1H), 1.95 (m, 1H), 1.43 (d, j=10.1 hz, 1H), 1.32 (s, 3H), 0.80 (s, 3H). 13 C NMR (150 MHz, chloroform) delta 180.23,173.58,160.56,154.21,131.87,128.51,123.21,110.84,55.09,41.47,40.49,27.53,26.18,24.37,23.85,22.37.
Example 10
To obtain the noo Bo Suan oxadiazole thioester derivative (I-10):
2-Furan-1, 3, 4-oxadiazole-2-thiol (0.39 g,2 mmol) was dissolved in 10ml acetone and K was added 2 CO 3 (306.8 mg,2.22 mmol) and then dropwise adding Nor Bo Xianlv (220.6 mg,1.11 mmol) to react for 1h at room temperature, TLC monitoring the complete reaction of the raw materials, rotary concentrating to remove most of the acetone, adding ethyl acetate for extraction, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, rotary concentrating to obtain crude Nor Bo Suan oxadiazole thioester, finally purifying the crude product on a silica gel chromatographic column (200-300 meshes, petroleum ether/ethyl acetate=40:1-10:1 v/v) to obtain the target Nor Bo Suan oxadiazole thioester derivative (I-10): a pale yellow solid; the yield thereof was found to be 70%.
1 H NMR (600 MHz, chloroform) delta 7.67 (dd, j=1.7, 0.7hz, 1H), 7.21 (dd, j=3.6, 0.7hz, 1H), 6.72-6.70 (m, 1H), 6.62 (dd, j=3.6, 1.8hz, 1H), 3.43 (ddt, j=20.9, 9.2,1.7hz, 1H), 2.91-2.83 (m, 1H), 2.73 (t, j=5.3 hz, 1H), 2.49-2.42 (m, 1H), 2.16-2.10 (m, 1H), 2.03 (m, 1H), 1.93 (m, 1H), 1.42 (d, j=10.2 hz, 1H), 1.30 (s, 3H), 0.78 (s, 3H). 13 C NMR (150 MHz, chloroform) delta 180.55,173.05,160.56,150.44,147.05,137.47,116.84,112.59,110.59,55.01,41.45,40.41,27.45,26.13,24.36,23.81,22.35.
Example 11
The last step of the synthetic route, namely the synthetic reaction condition for generating the target compound, is discussed, and the influence of different types of catalysts and solvents on the reaction yield is studied. Using the synthesis of compound I-1 as an example, 5-phenyl-1, 3, 4-oxadiazole-2-thiol (197.8 mg,1.11 mmol) was added to a single-necked flask, the corresponding solvent was added for dissolution, the catalyst was added with stirring, and then noon Bo Xianlv (220.6 mg,1.11 mmol) was added dropwise. After the addition, the reaction was performed at room temperature (25 ℃) and examined by TLC.
TABLE 1 investigation of condensation reaction conditions
Four reaction conditions, K, are discussed 2 CO 3 Acetone is used as an experimental condition, the reaction condition is best, and the yield is high; the other reaction conditions are general, and new impurities are generated.
Example 12
Bactericidal activity (ex vivo) experiment:
all the test strains in the experiment are purchased from China center for agricultural microbiological culture collection (ACCC) and China Center for Forestry Culture Collection (CFCC) and are wheat scab germ (ACCC 31060), rice sheath blight germ (ACCC 38870), phytophthora capsici germ (ACCC 36279), botrytis cinerea (ACCC 36027), sclerotium germ (ACCC 30096), pepper anthracnose germ (ACCC 37623) and potato late blight germ (AcCC 37623)MYA-1113 TM )。
The culture medium is potato agarose culture medium (PDA for short). PDA culture medium formula comprises potato (peeled) 200g, glucose 20g, agar 15g, distilled water 1000mL, and preparation method: cleaning potato, peeling, weighing 200g, cutting into small pieces, adding water, boiling for 20-30 min, tearing by a glass rod, filtering with eight layers of gauze, adding 15-20g agar according to experiment requirement, adding 20g glucose, stirring, dissolving completely, cooling slightly, adding water to 1000mL, packaging, sterilizing at 121deg.C for 15 min, and cooling.
The experimental method comprises the following steps: the growth rate method is adopted.
(1) Firstly, 7 plant fungi are cultured on a PDA flat plate at 25 ℃ for about 3-6 days for standby;
(2) Heating PDA culture medium to dissolve, cooling to 45-50deg.C, adding 50mg/L of compound to be tested to obtain culture medium containing 50mg/L of medicinal liquid, and respectively pouring into culture dish for cooling to obtain bixafen as positive control;
(3) Taking circular fungus cakes (with the diameter of 0.50 cm) from the edge of hypha of each strain cultivated for 6d (the growth condition is as consistent as possible) by using a puncher through aseptic operation procedures, picking the circular fungus cakes to the center of a medicine-containing flat plate by using an inoculating needle, and then inverting the culture dish to be cultivated in an incubator (28 ℃);
(4) Observing and measuring the growth condition of hyphae at different times after treatment, measuring the diameter by adopting a crisscross method, processing data, and calculating the inhibition rate; inhibition ratio (%) = (control hypha diameter-treated hypha diameter)/(control hypha diameter-0.5) ×100; each treatment was repeated 3 times.
TABLE 2 test results of inhibitory Activity of Nor Bo Suan oxadiazole thioesters against six agricultural pathogenic fungi
Note that three replicates were set for each treatment in the test, and the data in the table are averages of the three replicates.
Table 3 EC of some of the compounds against Sclerotinia sclerotiorum 50 Value of
The bactericidal activity measurement results of the experimental groups I-1 to I-10 and the comparison medicament bixafen are shown in Table 2. As can be seen from Table 2, at a concentration of 50mg/L, the compounds I-1 to I-10 showed different degrees of bacteriostatic activity against 6 plant fungi. Wherein, the compounds I-5 and I-6 have better antibacterial activity on sclerotinia sclerotiorum, the inhibition rate is 90.5 percent and 90.0 percent, and the positive control bipyramid is approximate. In addition, compounds I-4 and I-7 showed moderate inhibitory activity against Sclerotinia sclerotiorum. And the compounds I-2 and I-9 show moderate inhibition activity on the Rhizoctonia solani, and the inhibition rate is higher than that of the positive control drug bixafen.
In view of the good inhibition effect of the compounds I-5 and I-6 on Sclerotinia sclerotiorum, the EC of the two compounds on Sclerotinia sclerotiorum was tested 50 Values. As can be seen from Table 3, both of these compounds showed a relatively high degree of activityStrong inhibitory activity, EC 50 The values are 1.38 and 1.51mg/L respectively, which is equivalent to the positive control bixafen (1.19 mg/L). Demonstrating the potential of these two compounds for the development of antifungal agents.
It should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention may be modified or substituted without departing from the spirit and scope of the technical solution of the present invention, and it should be covered in the scope of the present invention.

Claims (9)

1. The preparation method of the noo Bo Suan oxadiazole thioester compound is characterized by comprising the following steps: comprising the steps of (a) a step of,
oxidizing nopol to synthesize nootken Bo Suan;
synthesizing the nootkatol by the reaction of the nootkatol to obtain nootkatol Bo Xianlv;
synthesizing each substituted oxadiazole thiol by reacting each substituted formylhydrazine;
reacting the paranoon Bo Xian chloride with each substituted oxadiazole mercaptan to synthesize a noon Bo Suan oxadiazole thioester compound;
wherein, the structural formula of the noose Bo Suan oxadiazole thioester compound is as follows:
wherein R is selected from the following groups:
2. the method of manufacturing according to claim 1, wherein: the synthetic method of the synthetic noose Bo Suan comprises the following steps of,
taking nopol, adding acetone into a single-mouth bottle, slowly dripping Jones reagent into the mixture by using a dropping funnel under ice bath condition, reacting for 1h, detecting by TLC, and rotating and concentrating to remove most of the acetone after the reaction is finished;
adding ethyl acetate for extraction, combining organic layers, washing with saturated saline water, drying with anhydrous sodium sulfate, concentrating in a rotating way to obtain a crude product of the noose Bo Suan, separating and purifying by using 200-300 mesh silica gel column chromatography, and purifying by using petroleum ether/ethyl acetate volume ratio of 40:1-10:1 to obtain oily noose Bo Suan;
wherein, the molar ratio of nopol, acetone and Jones reagent is 1:20.6:2.2.
3. The method of manufacturing as claimed in claim 2, wherein: the synthesis method of the oxadiazole thiol with each substituent comprises the following steps of,
dissolving various substituent formylhydrazides in absolute ethanol, adding KOH, and dropwise adding CS 2 After the addition, reflux reaction is carried out at 85 ℃, TLC detects that the raw materials are completely reacted, 5% hydrochloric acid is added for acidification, distilled water is used for diluting the reaction liquid, the solid is filtered, washed with water and dried, and finally absolute ethyl alcohol is used for recrystallization, thus obtaining the target compound oxadiazole thiol.
4. The method of manufacturing according to claim 1, wherein: the synthesis of the Nor Bo Xian chloride comprises the following steps,
adding the Nor Bo Suan and the dichloromethane into a round-bottom flask, stirring in an ice bath, and dropwise adding oxalyl chloride;
the reaction mixture was stirred at room temperature for 2-3 h, after completion, concentrated in vacuo to remove excess oxalyl chloride and solvent to give noose Bo Xianlv, which was used directly in the next step without further purification.
5. The method of manufacturing according to claim 1, wherein: the synthesized noose Bo Suan oxadiazole thioester compound comprises,
dissolving oxadiazole thiols as substituents in acetone, adding K 2 CO 3 Dropwise adding noose Bo Xianlv, reacting at room temperature for 3-4 h, rotary concentrating to remove most of acetone, adding ethyl acetate for extraction, combining organic layers, washing with saturated saline solution, drying with anhydrous sodium sulfate, and rotary concentrating to obtain a crude product;
separating and purifying by 200-300 mesh silica gel column chromatography, and purifying by petroleum ether/ethyl acetate volume ratio of 40:1-10:1 to obtain the no Bo Suan oxadiazole thioester.
6. The production method according to any one of claims 1 to 5, characterized in that: the substituted hydrazides include benzoyl hydrazine, 4-methylbenzoyl hydrazine, 4-methoxybenzoyl hydrazine, 4-fluorobenzoyl hydrazine, 2-chlorobenzoyl hydrazine, 3-chlorobenzoyl hydrazine, 4-bromobenzoyl hydrazine, 2-thiophenyl hydrazide and 2-furanyl hydrazide.
7. The noose Bo Suan oxadiazole thioester compound produced by the production method as claimed in any one of claims 1 to 6.
8. Use of the noose Bo Suan oxadiazole thioesters of claim 7 for combating plant fungi in agriculture or forestry.
9. The use according to claim 8, wherein: the plant fungi comprise Rhizoctonia solani, botrytis cinerea and Sclerotinia sclerotiorum.
CN202311091009.3A 2023-08-28 2023-08-28 Preparation method of noo Bo Suan oxadiazole thioester compound, product and application thereof Pending CN117402125A (en)

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