Derivative containing chiral thioether and sulfone units and preparation method and application thereof

Abstract

The invention discloses a derivative containing chiral thioether and sulfone units as well as a preparation method and application of the derivative. The derivative containing the chiral thioether and the sulfone unit is applied to preparation of medicaments for preventing and treating rice bacterial leaf blight, rice bacterial leaf streak, citrus canker, tobacco bacterial wilt, muskmelon bacterial leaf blight, tomato bacterial wilt, watermelon fruit rot, Chinese cabbage soft rot, peach tree shot hole disease and cabbage black rot fungus. The invention further discloses application of the derivative containing the chiral thioether and sulfone unit to preparation of medicaments for preventing and treating rice bacterial leaf blight, rice bacterial leaf streak, citrus canker, tobacco bacterial wilt, muskmelon bacterial leaf blight, tomato bacterial wilt, watermelon fruit rot and cabbage black rot. The derivative containing chiral thioether and sulfone units has the characteristics of broad bactericidal spectrum and high activity, has excellent prevention and treatment effects on bacterial diseases, and is simple and feasible in preparation steps and low in production cost.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticides, and in particular to a derivative containing chiral thioether and sulfone units, and a preparation method and application thereof. Background Art

[0002] Bacterial diseases of crops are common diseases in my country's agricultural production. Their degree of harm has surpassed viruses and become the second largest pathogen after fungi. Every year, the area affected by bacterial diseases exceeds 120 million mu, and in severe cases, it can lead to crop failure. At present, commercial antibacterial agents in production are mainly copper preparations and chlorpyrifos, thiophanate-methyl and agricultural streptomycin. Large-scale use of them may cause crop damage, copper poisoning, damage and pollution of the ecosystem, and negative impacts on human health. Therefore, finding and developing new green pesticides that are efficient and low-risk for the prevention and control of plant bacterial diseases has become an important scientific and technological issue that urgently needs to be tackled.

[0003] Sulfide and sulfone derivatives have a wide range of biological activities, such as antibacterial, antifungal, antiviral, insecticidal, nematicidal and herbicidal, and have great application prospects and research value. The synthesis and activity research of sulfide and sulfone derivatives have attracted widespread attention from drug researchers, and a number of pesticides have been developed, such as ethoxylated, thioether phosphine, oxycarboxin, bacteriostatic and tolylfluanid.

[0004] In 2012, Muralikrishna et al. (Muralikrishna, A.; Venkatesh, BC; Padmavathi, V.; Padmaja, A.; Kondaiah, P.; Siva Krishna, N. Synthesis, antimicrobial and cytotoxic activities of sulfone linked bis heterocycles [J]. Eur. J. Med. Chem. 2012, 54, 605-614.) synthesized a class of sulfone linked bis heterocycles, namely pyrrole acyl / pyrazolyl arylaminosulfonylmethyl 1,3,4-oxadiazole, 1,3,4-thiadiazole and 1,2,4-triazole, and tested their antibacterial activity and cytotoxicity. Among them, compounds 5c, 8c and 14c showed antibacterial activity comparable to chloramphenicol against Pseudomonas aeruginosa, and compound 5c showed antifungal activity comparable to ketoconazole against Penicillium.

[0005] In 2013, Konduru et al. (Konduru, NK; Dey, S.; Sajid, M.; Owais, M.; Ahmed, N. Synthesis and antibacterial and antifungal evaluation of some chalconebased sulfones and bisulfones [J]. Eur. J. Med. Chem. 2013, 59, 23-30.) designed and synthesized sulfone derivatives containing chalcone, and tested the antibacterial activity of the compounds against strains of Bacillus subtilis and Staphylococcus aureus (Gram-positive bacteria), Pseudomonas aeruginosa and Salmonella typhimurium (Gram-negative bacteria). Among them, compound 1c had slightly better antibacterial activity against Bacillus subtilis, and compared with the control agents ampicillin and kanamycin, compounds 5c, 6c and 7c showed excellent antibacterial activity against Salmonella typhimurium.

[0006] In 2014, our team's doctoral student Li Pei et al. (Li, P.; Shi, L.; Yang, X.; Yang, L.; Chen, X. W.; Wu, F.; Shi, Q. C.; Xu, W. M.; He, M.; Hu, D. Y.; Song, B. A. Design, synthesis, and antibacterial activity against rice bacterial leaf blight and leaf streak of 2,5-substituted-1,3,4-oxadiazole / thiadiazole sulfone derivative [J]. Bioorg. Med. Chem. Lett. 2014, 24, 1677-1680.) designed and synthesized the compound 2-methylsulfonyl-5-(4-fluorobenzyl)-1,3,4-oxadiazole, and tested the antibacterial activity of the compound against Xanthomonas oryzae and Xanthomonas oryzae using the bacterial liquid turbidity method. The results showed that the antibacterial activity of compound 4 against the two pathogens was EC 50 The values ​​were 1.07μg / mL and 7.14μg / mL, respectively, which were lower than the control agents chlorothalonil and thiophanate-methyl. It was found that the introduction of the bridge bond can significantly improve the antibacterial activity of this type of compound.

[0007] In 2017, Zheng Yutao and his team (Zheng, YT; Zhang, TT; Wang, PY; Wu, ZB; Zhou, L.; Ye, YQ; Zhou, X.; He, M.; Yang, S. Synthesis and bioactivities of novel 2-(thioether / sulfone)-5-pyrazolyl-1,3,4-oxadiazole derivatives [J]. Chinese Chem. Lett. 2017, 28, 253-256.) introduced a pyrazole group at the 5-position of 1,3,4-oxadiazole to synthesize a series of new 2-(thioether / sulfone)-5-pyrazolyl-1,3,4-oxadiazole derivatives. They also tested the antibacterial activity of these compounds against Xanthomonas oryzae and found that compound 8 showed the best antibacterial effect against Xanthomonas oryzae, with an antibacterial activity of EC 50 The value was 16.6 μg / mL, which was better than the control agents chlorpyrifos (92.6 μg / mL) and thiophanate-methyl (121.8 μg / mL).

[0008] In 2019, doctoral student Wang Shaobo and others in our team (Wang, SB; Gan, XH; Wang, YJ; Li, SY; Yi, CF; He, FC; Yang, YY; Hu, DY; Song, BA Novel 1,3,4-oxadiazole derivatives containing a cinnamic acid moiety as potential bactericide for rice bacterial diseases [J]. Int. J. Mol. Sci. 2019, 20, 1020.) used substituted cinnamic acid as the starting material to synthesize a series of 1,3,4-oxadiazole sulfone derivatives containing a styrene structure, and used the bacterial liquid turbidity method to test the antibacterial activity of the series of compounds against rice bacterial leaf blight and rice bacterial leaf streak pathogen. The results showed that compound 10 showed the best antibacterial activity against the two pathogens, and the antibacterial activity EC against rice bacterial leaf blight and rice bacterial leaf streak pathogen was 2.34%. 50 The values ​​were 0.44 and 0.20 μg / mL, respectively, which were significantly better than the control agents chlorothalonil and thiophanate-methyl; in addition, the therapeutic and protective efficacy of compound 10 against rice white leaf blight and rice leaf streak pathogen in living pots at a concentration of 200 μg / mL were 56.05%, 66.02% and 55.92%, 58.22%, respectively, which were significantly better than the control agents chlorothalonil and thiophanate-methyl.

[0009] In 2020, our team's master's student Xiang Jie and others (Xiang, J.; Liu, DY; Chen, JX; Hu, DY; Song, BA Design and synthesis of novel 1,3,4-oxadiazole sulfone compounds containing 3,4-dichloroisothiazolylamide moiety and evaluation of rice bacterial activity [J]. Pestic. Biochem. Phys. 2020, 170, 104695.) designed and synthesized a series of 1,3,4-oxadiazole sulfone derivatives containing 1,3,4-dichloroisothiazolylamide structure. The results of bioassays showed that this class of compounds exhibited excellent in vitro antibacterial activity against rice white leaf blight and rice leaf streak pathogen, among which compound 14 had an antibacterial activity EC of 1.34 against the two pathogens. 50 The values ​​were 0.79 and 2.21 μg / mL, respectively, which were significantly better than the commercial control agents chlorothalonil and thiophanate-methyl. The results of the antibacterial activity of living potted plants showed that the therapeutic and protective efficacy of compound 14 against rice bacterial blight at a concentration of 200 μg / mL was 41.06% and 43.99%, respectively, which was better than the control agents chlorothalonil and thiophanate-methyl.

[0010] 2023, Khabibrakhmanova et al. Possessing Terpene Moiety:Synthesis andBiologicalActivity[J].Molecules.2023,28,2543.) designed and synthesized 30 novel chiral 2(5H)-furanonesulfone compounds, and tested the antibacterial activity of these compounds against a variety of Gram-positive and Gram-negative bacteria. It was found that compound 26 had a significant inhibitory effect on Staphylococcus aureus (S.aureus) and Bacillus subtilis (B.subtilis), with a MIC value of 8 μg / mL. When used in combination with antibiotics (gentamicin and amikacin), compound 26 showed a significant synergistic effect and significantly reduced the MIC value of the antibiotics.

[0011] In 2023, Chen Jixiang (Chen Jixiang, Chen Yifang, Luo Xin, Zhang Yong, Liu Xing, Zou Yue, Wang Sheng, Cai Qingfeng, Song Hongyi, patent publication number CN116508771A) disclosed the application of 1,3,4-oxadiazole sulfone compounds in the fight against citrus Huanglongbing. The results showed that compounds A, B, C, D, E, F and G had good therapeutic activity against citrus Huanglongbing at 200 mg / L, which were better than the control agent streptomycin. Compounds A, B, C, E and G still had certain therapeutic activity against citrus Huanglongbing at 100 mg / L.

[0012] In 2024, our team's doctoral student Zhang A.W. and others (Zhang A.W.; He, HF; Sheng, ZJ; Wu, ZX; Song, RJ; Song, B.A. Synthesis, bioactivities, and antibacterial mechanism of 5-(thioether)-N-phenyl / benzyl-1,3,4-oxadiazole-2-carboxamide / amine derivatives [J]. J. Agric. Food. Chem. 2024, 72, 1444-1453.) synthesized a series of novel 1,3,4-oxadiazole sulfide compounds containing carboxamide / amine groups, and found that compounds A10 and A18 had excellent activity against rice white leaf blight and rice bacterial leaf streak pathogen, and their EC 50 The values ​​were 5.32 (7.58) and 4.63 mg / L (7.65 mg / L) respectively.

[0013] In 2024, Zhang Weihua et al. (Zhang Weihua, Dai Peng, Jiao Jian, patent publication number CN117551092A) disclosed chromone compounds containing 5-sulfone-1,3,4-thiadiazole, their preparation methods and fungicidal applications, and tested the antibacterial activity of compounds 1-86 against rice bacterial blight pathogen and citrus canker at a concentration of 50 μg / mL. The results showed that most of the compounds had significant antibacterial activity against rice bacterial blight pathogen and citrus canker pathogen, and their antibacterial activity was better than that of chlorothalonil.

[0014] In recent years, the inventor team (Song Runjiang, Liu Ting, Song Baoan, Li Jianzhuan, Hu Deyu, Zhang Wenbo, Wu Sikai, Wang Jian, Application of florfenicol in preventing and controlling plant bacterial diseases, patent publication number CN117158425A) discovered during the synthesis and activity screening of antibacterial drugs that a class of florfenicol compounds containing chiral sulfones have excellent antibacterial activity against plant bacterial diseases such as rice bacterial leaf blight, rice bacterial leaf streak pathogen, and citrus canker pathogen.

[0015] In summary, sulfone and chiral sulfone compounds have excellent antibacterial activity and are an excellent class of active skeletons. In order to further improve the antibacterial activity, based on the previous research foundation of chiral sulfone, chiral sulfone compounds were further derived, and a series of chiral bissulfone and chiral thioether compounds were designed and synthesized. The chiral bissulfone and chiral thioether compounds were tested and found to have excellent antibacterial activity against plant bacterial diseases such as rice white leaf, rice leaf streak fungus, citrus canker fungus, tobacco wilt, melon horn, tomato wilt, watermelon fruit rot, cabbage soft rot, peach tree perforation and cabbage black rot fungus. Therefore, the synthesis of chiral bissulfone and chiral thioether compounds is expected to develop novel anti-plant bacterial disease control agents. Summary of the invention

[0016] The object of the present invention is to overcome the above disadvantages and provide a derivative containing chiral sulfide and sulfone units which has excellent biological activity against plant bacterial diseases and low production cost.

[0017] Another object of the present invention is to provide a method for preparing the derivative containing chiral sulfide and sulfone units.

[0018] Another object of the present invention is to provide the use of the derivatives containing chiral thioether and sulfone units in the preparation of agents for preventing and controlling rice bacterial leaf blight, rice bacterial leaf streak, citrus canker, tobacco bacterial wilt, melon fine corner disease, tomato bacterial wilt, watermelon fruit rot, cabbage soft rot, peach punch hole disease and cabbage black rot.

[0019] The derivatives containing chiral sulfide and sulfone units of the present invention have the following general formulas (A) and (B):

[0020]

[0021] Where: R 1 R is independently selected from one or more of optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl; 2 Independently selected from one or more of optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted alkyl, and optionally substituted or unsubstituted aryl; n is 1-4.

[0022] Preferably, R1 is independently selected from C1-C 12 Alkyl, C1-C 12 Alkenyl, C1-C 12 Alkynyl, substituted or unsubstituted C6-C 15 aryl, substituted or unsubstituted C5-C6 heteroaryl; R2 is independently selected from C1-C 12 Alkoxy, C1-C12 Alkyl, substituted or unsubstituted C6-C 15 aryl, substituted or unsubstituted C5-C6 heteroaryl, or one or more thereof.

[0023] More preferably, the derivatives containing chiral thioether and sulfone units are as follows:

[0024] Compound F1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)-2-(methylthio)propyl acetate;

[0025] Compound F2: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(prop-2-yn-1-ylthio)acetate;

[0026] Compound F3: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-((4-(trifluoromethyl)benzyl)thio)acetate;

[0027] Compound F4: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(ethylthio)acetate;

[0028] Compound F5: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(propylthio)acetate;

[0029] Compound F6: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(butylthio)acetate;

[0030] Compound F7: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(cyclopropyl)acetate;

[0031] Compound F8: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(4-(methylsulfonyl)phenyl)acetate;

[0032] Compound F9: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(allylthio)acetate;

[0033] Compound F10: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(pentylthio)acetate;

[0034] Compound F11: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-((2-methylprop-1-en-1-yl)thio)acetate;

[0035] Compound F12: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-3-(prop-2-yn-1-ylthio)propanoate;

[0036] Compound F13: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(but-3-yn-1-ylthio)acetate;

[0037] Compound F14: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(hexylthio)acetate;

[0038] Compound F1-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(methylsulfonyl)acetate;

[0039] Compound F2-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(prop-2-yn-1-ylsulfonyl)acetate;

[0040] Compound F3-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(allylsulfonyl)acetate;

[0041] Compound F4-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-3-(prop-2-yn-1-ylsulfonyl)propanoate.

[0042] The preparation method of the derivative containing chiral sulfide and sulfone units of the present invention has the following synthetic route:

[0043]

[0044] The chiral sulfide and sulfone unit-containing derivatives of the present invention are used in the preparation of agents for preventing and treating rice bacterial leaf blight, rice bacterial leaf streak, citrus canker, tobacco bacterial wilt, melon fine corner disease, tomato bacterial wilt, watermelon fruit rot, cabbage soft rot, peach punch and cabbage black rot.

[0045] Beneficial effects:

[0046] The derivatives of the invention have the characteristics of broad-spectrum bactericidal effect and high activity, have excellent prevention and treatment effect on bacterial diseases, and have simple and easy preparation steps and low production cost. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The protective activity of the example compounds against Xanthoceras oryzae, wherein CK is a blank control; SZX is a zinc thiazole control;

[0048] Figure 2 The synthetic process route of compounds F1-F14 is shown in FIG.

[0049] Figure 3 This is a synthetic process route for the compounds of Examples 15 to 18. DETAILED DESCRIPTION

[0050] Example 1: A method for preparing (1R, 2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)-2-(methylthio)propyl acetate (compound number F1), comprising the following steps:

[0051] (1) Preparation of 2-(methylthio)acetic acid (Intermediate 1):

[0052] Dissolve thioglycolic acid (5 mmol) and sodium hydroxide (5 mmol) in 30 mL of anhydrous ethanol, slowly add iodomethane (5 mmol) dropwise under ice bath conditions, move to room temperature for reaction for 12 h after the addition is complete, remove the solvent under reduced pressure, add water to dissolve the residue, adjust the pH to 3-4 with dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 0.52 g of colorless liquid, with a yield of 86.6%.

[0053] (2) Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)-2-(methylthio)propyl acetate (target compound F1):

[0054] 2-(Ethylthio)acetic acid (2.0 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (2.0 mmol), 4-dimethylaminopyridine (DMAP) (1.0 mmol) and 2,2-dichloro-N-[(1R,2S)-3-fluoro-1-hydroxy-1-(4-methylsulfonylphenyl)-2-propyl]acetamide (2.0 mmol) were dissolved in anhydrous DMF. The reaction system was monitored by TLC until the conversion of the raw materials was complete. The reaction was stopped, and water was added for washing. The mixture was extracted with ethyl acetate, and the organic layer was collected and dried over anhydrous magnesium sulfate. The reaction mixture was concentrated under reduced pressure to obtain a crude product as a light yellow solid, which was then purified by column chromatography to obtain 0.72 g of a white solid with a yield of 75.3% and a melting point of 101-102°C.

[0055] Example 2: Synthesis of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(prop-2-yn-1-ylthio)acetate (compound number F2), comprising the following steps:

[0056] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0057] Example 3: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-((4-(trifluoromethyl)benzyl)thio)acetate (compound number F3), comprising the following steps:

[0058] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0059] Example 4: Preparation of (1R, 2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(ethylthio)acetate (compound number F4), comprising the following steps:

[0060] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0061] Example 5: Preparation of (1R, 2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(propylthio)acetate (compound number F5), comprising the following steps:

[0062] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0063] Example 6: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(butylthio)acetate (compound number F6), comprising the following steps:

[0064] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0065] Example 7: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(cyclopropyl)acetate (compound number F7), comprising the following steps:

[0066] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0067] Example 8: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(4-(methylsulfonyl)phenyl)acetate (compound number F8), comprising the following steps:

[0068] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0069] Example 9: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(allylthio)acetate (compound number F9), comprising the following steps:

[0070] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0071] Example 10: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(pentylthio)acetate (compound number F10), comprising the following steps:

[0072] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0073] Example 11: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-((2-methylprop-1-en-1-yl)thio)acetate (compound number F11), comprising the following steps:

[0074] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0075] Example 12: Preparation of (1R, 2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-3-(prop-2-yn-1-ylthio)propanoate (compound number F12), comprising the following steps:

[0076] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1, except that thioglycolic acid is replaced by an equimolar amount of mercaptopropionic acid.

[0077] Example 13: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(but-3-yn-1-ylthio)acetate (compound number F13), comprising the following steps:

[0078] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0079] Example 14: Preparation of (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(hexylthio)acetate (compound number F14), comprising the following steps:

[0080] Steps (1) to (2) are synthesized using the same method and conditions as steps (1) to (2) in Example 1.

[0081] Example 15: Preparation of (1R, 2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(methylsulfonyl)acetate (compound number F1-1), comprising the following steps:

[0082] (1) Preparation of 2-(methylthio)acetic acid (Intermediate 1):

[0083] The same method and conditions as step (1) of Example 1 were used for synthesis.

[0084] (2) Preparation of 2-(methylsulfonyl)acetic acid

[0085] Under room temperature, 2-(methylthio)acetic acid (4 mmol) was dissolved in 10 mL of glacial acetic acid, and hydrogen peroxide (8.0 mmol) was slowly added dropwise. After the addition was completed, the reaction system was monitored by TLC until the conversion of the raw materials was complete, the reaction was stopped, water was added for washing, and the mixture was extracted with ethyl acetate. The organic layer was collected and dried over anhydrous magnesium sulfate; the reaction mixture was concentrated under reduced pressure, and then purified by column chromatography to obtain 21 g of a white solid with a yield of 42.65% and a melting point of 131-133°C.

[0086] Example 16: Preparation of (1R, 2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(prop-2-yn-1-ylsulfonyl)acetate (target compound is F2-1):

[0087] Step (3) is synthesized using the same method and conditions as step (2) in Example 1.

[0088] Example 17: Preparation of (1R, 2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(allylsulfonyl)acetate (compound number F3-1), comprising the following steps:

[0089] Steps (1) to (3) are synthesized using the same method and conditions as steps (1) to (3) in Example 15.

[0090] Example 18: Preparation of (1R, 2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-3-(prop-2-yn-1-ylsulfonyl)propanoate (compound number F4-1), comprising the following steps:

[0091] Steps (1) to (3) are synthesized using the same method and conditions as steps (1) to (3) in Example 15.

[0092] The physicochemical properties of the chiral sulfide and sulfone derivatives prepared in the above examples are shown in Table 1. Their structural formulas, H NMR spectra ( 1 H NMR), carbon spectrum ( 13 C NMR) and high resolution mass spectrometry (HRMS) data are shown in Table 2.

[0093] Table 1 Physicochemical properties of target compounds in the examples

[0094]

[0095] Table 2. Structural formula and spectral data of target compounds F1-F14 / F1-1-F1-4 in the examples

[0096]

[0097]

[0098]

[0099]

[0100] Test Example 1: The indoor activity test of the target compound in inhibiting rice bacterial blight fungus is shown in Table 3.

[0101] The test compound was prepared into a corresponding concentration of drug-containing NB liquid culture medium, and then 40 μL of the above-prepared medium containing rice bacterial blight pathogen (Xoo) was added, and cultured in a constant temperature shaker at 28°C and 180 rpm for 24-48 h. The OD value (OD 595 ). The OD values ​​of the NB liquid culture medium of the corresponding concentration of the drug and the control drug were measured, and the OD values ​​caused by the drug itself were corrected. The calculation formula for the corrected OD value and inhibition rate is as follows:

[0102] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium;

[0103] Inhibition rate (%) = (corrected OD value of control culture medium - corrected OD value of toxic culture medium) / corrected OD value of control culture medium × 100;

[0104] Table 3. Antibacterial activity of Examples F1-F14 / F1-1-F1-4 against Xanthomonas oryzae

[0105]

[0106]

[0107] As shown in Table 1, the in vitro activity of chiral thioether and sulfone derivatives against Xanthomonas oryzae was tested by turbidity. Most of the compounds had excellent antibacterial activity, such as F1, F2, F4, F6, F14, F1-1 and F2-2, which were better than the control agent zinc thiazole (EC 50 =28.37 μg / mL).

[0108] Test Example 2: From Table 3, it can be seen that the antibacterial activity of compounds F2 and F2-1 against rice bacterial blight is more significant, so the antibacterial activity of compounds F2 and F2-1 against other bacterial diseases was tested. The test results are shown in Table 3.

[0109] The test compound was prepared into a corresponding concentration of drug-containing NB liquid culture medium, and then 40 μL of the above-prepared medium containing rice bacterial blight pathogen (Xoo) was added, and cultured in a constant temperature shaker at 28°C and 180 rpm for 24-48 h. The OD value (OD 595 ). The OD values ​​of the NB liquid culture medium of the corresponding concentration of the drug and the control drug were measured, and the OD values ​​caused by the drug itself were corrected. The calculation formula for the corrected OD value and inhibition rate is as follows:

[0110] Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium;

[0111] Inhibition rate (%) = (corrected OD value of control culture medium - corrected OD value of toxic culture medium) / corrected OD value of control culture medium × 100;

[0112] The antibacterial activity of the target product against these 11 types of bacteria was tested by turbidity method. As shown in Tables 4 and 5, the target compound had excellent antibacterial activity against rice white leaf blight, rice bacterial streak, citrus canker, tobacco bacterial wilt, peach tree perforation and cabbage black rot at 10 μg / mL, and the inhibition rate was above 80%, which was better than the control drugs thiophanate-copper and thiazole zinc. Based on the test results of the antibacterial activity of the target compound, the in vitro EC values ​​of the target compound against rice white leaf blight, rice bacterial streak, citrus canker, tobacco bacterial wilt, melon horn, tomato bacterial wilt, watermelon fruit rot, cabbage soft rot, kiwi canker, peach tree perforation and cabbage black rot were further tested. 50 As shown in Tables 6 and 7, the EC values ​​of target compound F2-1 against these eleven types of bacteria 50 The values ​​were 0.19, 0.41, 0.24, 1.86, 9.86, 4.32, 9.01, 0.88, 0.73, 1.35 and 1.24 μg / mL, respectively.

[0113] Table 4. Antibacterial activity of target compounds

[0114]

[0115]

[0116] Table 5. Antibacterial activity of target compounds

[0117]

[0118] Table 6. In vitro EC values ​​of target compounds 50 value

[0119]

[0120] Table 7. In vitro EC values ​​of target compounds 50 value

[0121]

[0122] Test Example 3: Live pot test of rice bacterial blight with highly active compounds

[0123] Protective effect of living pot experiment on rice bacterial blight

[0124] The target compound was tested for its in vivo activity against the pathogen of rice bacterial leaf blight. The control agents were thiophanate-copper and thiothiazol-zinc. The agents were prepared into a drug-containing solution with a concentration of 200 μg / mL using 0.1% Tween 20 solution, respectively, and sprayed on the surface of rice leaves until droplets fell. After 24 hours, the tip of the rice leaf was cut off with scissors dipped in rice bacterial leaf blight solution at a distance of 1 to 2 cm from the tip of the leaf, and the wound was soaked in the bacterial solution for about 10 seconds. At the same time, a clear water control without the agent and a bacterial solution control were set up. Thirty rice seedlings were treated for each treatment. The disease was checked 14 days after the application of the drug, the length of the lesions on the rice leaves was recorded, and the disease index and control effect were calculated. The results are shown in Table 8.

[0125] Prevention effect (%) = (lesion length of control group - lesion length of treatment group) / lesion length of control group × 100

[0126] Table 8. Protective activity of compounds against rice bacterial blight at a concentration of 100 μg / mL

[0127]

[0128] As shown in Table 8, at a concentration of 100 μg / mL, the in vivo protective activities of the target compounds F1-F12 and F1-1-F4-1 against Xanthomonas oryzae were 57.5%, 66.3%, 65.1%, 70.0%, 54.8%, 51.3%, 65.1%, 53.6%, 59.0%, 60.2%, 66.9%, 71.5%, 73.7%, 63.7%, 73.1%, and 66.1%, respectively. They were significantly better than the control agent zinc thiazole (38.4%) in in vivo protective activities against Xanthomonas oryzae. The effects are as follows: Figure 1 shown.

[0129] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the technical solution of the present invention still falls within the scope of the technical solution of the present invention.

Claims

1. A derivative containing chiral sulfide and sulfone units, characterized in that: Its general structural formula is as follows: Where: R 1 is one or more of optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted epoxyalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl; R 2 Independently selected from one or more of an optionally substituted or unsubstituted alkoxy group, an optionally substituted or unsubstituted alkyl group, and an optionally substituted or unsubstituted aryl group.

2. The derivative containing chiral sulfide and sulfone units according to claim 1, characterized in that: R 1 Independently selected from C1-C 12 Alkyl, C1-C 12 Alkenyl, substituted or unsubstituted C6-C 15 aryl, substituted or unsubstituted C5-C6 heteroaryl; R2 is independently selected from C1-C 12 Alkoxy, C1-C 12 Alkyl, substituted or unsubstituted C6-C 15 aryl, substituted or unsubstituted C5-C6 heteroaryl or more.

3. The derivative containing chiral sulfide and sulfone units according to claim 1 or 2, characterized in that: The derivatives containing chiral thioether and sulfone units include any of the following specific compounds: Compound F1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)-2-(methylthio)propyl acetate; Compound F2: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(prop-2-yn-1-ylthio)acetate; Compound F3: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-((4-(trifluoromethyl)benzyl)thio)acetate; Compound F4: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(ethylthio)acetate; Compound F5: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(propylthio)acetate; Compound F6: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(butylthio)acetate; Compound F7: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(cyclopropyl)acetate; Compound F8: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(4-(methylsulfonyl)phenyl)acetate; Compound F9: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(allylthio)acetate; Compound F10: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(pentylthio)acetate; Compound F11: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-((2-methylprop-1-en-1-yl)thio)acetate; Compound F12: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-3-(prop-2-yn-1-ylthio)propanoate; Compound F13: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(but-3-yn-1-ylthio)acetate; Compound F14: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(hexylthio)acetate; Compound F1-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(methylsulfonyl)acetate; Compound F2-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(prop-2-yn-1-ylsulfonyl)acetate; Compound F3-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-2-(allylsulfonyl)acetate; Compound F4-1: (1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-(4-(methylsulfonyl)phenyl)propyl-3-(prop-2-yn-1-ylsulfonyl)propanoate.

4. The method for preparing the derivative containing chiral sulfide and sulfone units according to any one of claims 1 to 3, characterized in that: The synthetic route of the derivative containing chiral sulfide and sulfone units is any one of the following:

5. Use of the derivative containing chiral sulfide and sulfone units as claimed in any one of claims 1 to 3 in the preparation of an agent for preventing and controlling rice bacterial leaf blight, rice bacterial leaf streak, citrus canker, tobacco bacterial wilt, melon fine corner disease, tomato bacterial wilt, watermelon fruit rot, cabbage soft rot, peach punch and cabbage black rot.

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