Preparation and application of isoxazoline disulfide derivative

Abstract

The invention relates to preparation and application of a series of isoxazoline disulfide derivatives with novel structures. The series of structural general formula is as shown in formula (I). The invention particularly relates to a synthesis method of an isoxazoline disulfide derivative. The synthesis method has the advantages of mild reaction conditions, high practicability and wide substrate application range; metal catalysis and high-toxicity reagents are not needed, the atom economy is high, and the modern green chemistry concept is met. The compound provided by the invention has relatively good biological activity on agricultural pests / mites / bacteria with common serious harm, such as plutella xylostella, tetranychus cinnabarinus and phytopathogen at low concentration, so that the compound can be used as an insecticide / mite / bacterial agent candidate for research and development of high-efficiency, low-toxicity and environment-friendly novel pesticides.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticides and relates to the preparation of isoxazoline disulfide derivatives and their application in killing diamondback moth, cinnabarinus spider mite and plant pathogenic bacteria. Background Art

[0002] Tetranychus cinnabarinus is a herbivorous arthropod that mainly devours the phloem sap of plant leaves. Extensive infestation of this species can cause yellowing, wilting, and ultimately plant death (J. Agric. Food Chem. 2018, 66, 12898-12910). These mites usually form a filamentous mesh that wraps around the entire plant, hindering normal gas exchange and photosynthetic activity (Trends Plant Sci. 2022, 27, 287-300). In addition, T. cinnabarinius is also a carrier of plant pathogens, transporting these pathogens on its stylus or cuticle, and subsequently infecting healthy plant species (Exp. Appl. Acarol. 2016, 69, 445-451; Funct. Ecol. 2020, 34, 1091-1101). Currently, chemical pesticides are the main strategy for managing herbivorous mites. Nevertheless, the continued use of traditional acaricides, coupled with the strong reproductive capacity and compact life cycle of mites, has led to the increasing resistance of mites to these acaricides (J. Econ. Entomol. 2001, 94, 1577-1583; Insect Biochem. Mol. Biol. 2010, 40, 563-572). Therefore, it is crucial to innovate and develop new and highly effective acaricides.

[0003] Disulfide is an important motif in the fields of natural products, drugs and food chemistry. In agricultural chemistry, disulfides also exhibit insecticidal and antibacterial activities (Top. Curr. Chem. 2018, 376, 14). For example, allicin extracted from garlic is used as a natural fungicide (Pharmacological Research-Modern Chinese Medicine. 2023, 8, 100283). In addition, nereistoxin can be used to manage various foliar pests on crops such as rice, vegetables, sugarcane and fruit trees (J. Agric. Food Chem. 2003, 51, 2646-2652). In view of the various biological activities exhibited by disulfide compounds, the study of acaricides containing disulfide groups may become a new avenue for the development of acaricides. Summary of the invention

[0004] The purpose of the present invention is to provide a novel preparation method of isoxazoline disulfide compounds and the effects of killing diamondback moth, cinnabarinus spider mite and plant pathogenic bacteria at low concentrations.

[0005] To this end, the chemical structure of the isoxazoline disulfide compound provided by the present invention is shown in formula (I):

[0006]

[0007] Wherein, in formula (I): R is independently selected from benzyl, halogen-containing benzyl, alkyl-containing benzyl, C 1-12 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-6 Alkyl, deuterium-substituted alkyl, cycloalkyl, aryl-substituted alkyl;

[0008] Preferably, R is independently selected from benzyl, fluorine-containing, chlorine-containing, bromine-substituted benzyl, alkyl-containing benzyl, C 1-12 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-6 Alkyl, deuterium-substituted alkyl, cycloalkyl containing 3-9 carbon atoms, aryl-substituted alkyl;

[0009] More preferably, R is:

[0010]

[0011] The preparation route of the isoxazoline disulfide derivatives of the present invention is:

[0012]

[0013] The present invention has no particular requirements on the method for preparing intermediates 3 and 4.

[0014] Step 3: Add intermediate IV-4 (1.0 equiv.) and cesium carbonate (1.5 equiv.) to a 250 mL single-necked flask, add DSMO (1.5 equiv.) and methanol under nitrogen and stir at 30 ° C for 16 h. Add saturated brine (50.0 mL) for washing and use EA (3×40.0 mL) for extraction, combine the organic phases, dry over anhydrous Na2SO4, filter, and remove the solvent under reduced pressure. Separate by silica gel column chromatography to obtain intermediate 5 as a colorless oil.

[0015] Step 4: Add intermediate 5 (1.5 equiv.) and cesium carbonate (1.5 equiv.) to a 25 mL reaction tube, add 6 (1.0 equiv.) and methanol under nitrogen, and stir at 30 ° C for 16 h. After the reaction, add saturated brine (50.0 mL) for washing and use EA (3×40.0 mL) for extraction. Combine the organic phases, dry over anhydrous Na2SO4, filter, and remove the solvent under reduced pressure. Separate by silica gel column chromatography to obtain the target compounds 7a-ac.

[0016] The isoxazoline disulfide derivatives of the present invention are used in the prevention and control of agricultural pests and diseases, including common agricultural Plutella xylostella, Tetranychus cinnabarinus and plant bacteria.

[0017] Beneficial effects: Using the compounds provided by the present invention, in terms of the prevention and control of Tetranychus cinnabarinus, all target compounds showed a 100% lethality to the eggs of Tetranychus cinnabarinus at a concentration of 1.0 mg / L, among which compounds 7d, 7o and 7t showed a 100% lethality to the eggs of Tetranychus cinnabarinus at 0.01 mg / L. In addition, the lethality of compounds 5, 7b, 7j, 7l, 7o and 7v to the nymphs of Tetranychus cinnabarinus reached 100% at 10 mg / L, especially the lethality of compounds 5, 7j and 7v reached more than 90% at 0.1 mg / L, and the lethality of compounds 7b, 7g, 7l, 7o and 7q reached more than 50% at 0.1 mg / L.

[0018] In terms of the prevention and control of diamondback moth, the mortality rate of compound 71 to diamondback moth was greater than 70% at 50 mg / L.

[0019] In terms of bacterial control, compounds 5, 7a, 7c, 7d, 7e, 7g, 7i, 7l, 7s, 7t, 7x, 7y, 7z, 7aa and 7ab had an inhibition rate of more than 30% against D.zeae at 100 mg / L. Compounds 7a, 7c, 7d, 7g, 7h, 7i, 7s, 7y, 7z, 7aa and 7ab had an inhibition rate of more than 30% against Xcc. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 .Hydrogen spectrum of compound 7v

[0021] Figure 2 . Carbon spectrum of compound 7v

[0022] Figure 3 . Fluorine spectrum of compound 7v

[0023] Figure 4 . High-resolution mass spectrum of compound 7v DETAILED DESCRIPTION

[0024] Unless otherwise specified, the terms used herein are understood by those of ordinary skill in the art. The terms used herein: "I2" refers to iodine, "EtOH" refers to ethanol, and "Cs2CO3" refers to cesium carbonate. 1-12 " includes branched and straight chain saturated hydrocarbon groups having a specific number of carbon atoms. For example, "C 1-12 Alkyl" (or alkylene) refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 In addition, for example, "C 1-4 "Alkoxy" means an oxygen-containing alkyl group having 1 to 4 carbon atoms. The alkyl group may be unsubstituted or substituted so that one or more of its hydrogen atoms are replaced by other chemical groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl) and the like. "DMSO" is dimethyl sulfoxide. "DSMO" is 4,4'-disulfanediylbis(4-methylpentane-2-one). "EA" is ethyl acetate. "D.zeae" is Dixotria zeae. "Xcc" is Xanthomonas campestris.

[0025] The present invention is further described in detail below with reference to the accompanying drawings and embodiments.

[0026] In view of the good application value of isoxazoline disulfide derivatives, the applicant prepared isoxazoline disulfide derivatives and conducted insecticidal / mite activity studies; the results showed that the isoxazoline disulfide derivatives had significant insecticidal / mite activity and could be used to prepare insecticidal / mite agents, and the compounds also had bactericidal effects. According to the information search conducted by the applicant, no literature reports have been found so far.

[0027] The following are specific embodiments given by the inventor.

[0028] Example

[0029] 1. Synthesis of the intermediate 4,4'-disulfanediylbis(4-methylpentane-2-one) (DSMO)

[0030]

[0031] 4-mercapto-4-methylpentane-2-ketone (7.9g, 60.0mmol) and 95% ethanol (40.0mL) are added in the reaction flask of 150mL.After being cooled to below 0 ℃, iodine ethanol solution (10.0g, iodine in 12.0mL ethanol) is added dropwise, and the reaction solution is kept to be light yellow.After the reaction is completed, saturated NaHCO3 aqueous solution is added to adjust pH>7. EtOH is concentrated under vacuum decompression condition, and EA (40.0mL) is then added, and 10% NaHSO3 and salt water washing organic layer are used. Anhydrous Na2SO4 is subsequently used for drying, filtering and concentrating and oily matter (6.9g, 88%) is obtained by silica gel column chromatography separation and purification.

[0032] 2. Synthesis of Intermediate 5

[0033] 4-((4-(2-(2,6-Difluorophenyl)-4,5-dihydrooxazol-4-yl)benzyl)disulfaneyl)-4-methylpentan-2-one

[0034] (t,J=9.4Hz,1H),4.27(d,J=8.2Hz,1H),3.93(s,2H),2.70(s,2H),2.12(s,3H),1.42(s,6H); 13 C NMR(151MHz,Chloroform-d)δ206.43,161.22(dd,J=256.70,6.06Hz),157.49,141.13,136.65,132.34(t,J=10. 57Hz),129.88,129.63,126.90,111.88(dd,J=4.53,21.14Hz),74.67,69.99,53.46,49.34,45.32,32.04,27.19; 19 F NMR(564MHz,Chloroform-d)δ-108.89.

[0035] 3. Synthesis of target compounds

[0036] 2-(2,6-Difluorophenyl)-4-(4-((methyldisulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0037] 9.1Hz,1H),4.81(t,J=9.3Hz,1H),4.26(t,J=8.1Hz,1H),3.90(s,2H,),2.12(s,3H); 13 CNMR(151MHz,Chloroform-d)δ161.21(dd,J=256.70,6.06Hz),157.54,141.03,137.08,132.37(t,J=10.57Hz),129.71,126.80,111.90(dd,J=4.53,21.14Hz),74.80,70.00,42.68,23.04; 19 F NMR(564MHz,Chloroform-d)δ-108.74.

[0038]

[0039] 2-(2,6-Difluorophenyl)-4-(4-(((methyl-d3)disulfaneyl)methyl)phenyl)-4,5-dihydroox-azole

[0040] colorless oil,yield:71%(53.1mg).Rf=0.3(PE:EA=3:1); 1 H NMR(600MHz,Chloroform-d)δ7.42–7.37(m,1H,Ar-H),7.26(dd,J=27.9,8.0Hz,4H,Ar-H),6.97(t,J=8.2Hz,2H,Ar-H),5.48–5.41(m,1H,-CH-),4.78(dd,J=10.1,8.6Hz,1H,-CH2-),4.24(dd,J=11.9,4.5Hz,1H,-CH2-),3.61(s,2H,-CH2-); 13 C NMR(151MHz,Chloroform-d)δ161.19(dd,J=256.70,6.06Hz),157.48,141.07,136.83,132.36(t,J=10.57Hz),129.81,126.78,111.92(dd,J=4.53,21.14Hz),107.33,107.21,107.09,74.76,70.00,69.97,42.95.

[0041] 2-(2,6-Difluorophenyl)-4-(4-((ethyldisulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0042] 10.0,8.3,1H,-CH-),4.80(dd,J=10.2,8.5,1H,-CH2-),4.29–4.24(m,1H,-CH2-),3.88(s,2H,-CH2-),2.44(q,J=7.3,2H,-CH2-),1.20(t,J=7.3,3H,CH3-); 13 C NMR(151MHz,Chloroform-d)δ161.22(dd,J=256.70,6.06Hz),157.48,140.99,137.11,132.33(t,J=10.57Hz),129.65,126.84,126.74,111.89(dd,J=4.53,21.15Hz),74.76,70.02,43.51,32.53,14.27.

[0043] 19 FNMR(564MHz,Chloroform-d)δ-108.86.

[0044] 2-(2,6-Difluorophenyl)-4-(4-((isopropyldisulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0045] 5.50–5.41(m,1H,-CH-),4.80(t,J=9.3Hz,1H,-CH2-),4.26(t,J=8.1Hz,1H,-CH2-),3.89(s,2H,-CH2-),2.79–2.69(m,1H,-CH-),1.23(d,J=6.5Hz,6H,2CH3-); 13 C NMR(151MHz,Chloroform-d)δ161.19,(dd,J=256.70,6.06Hz),157.51,140.96,137.10,132.38(t,J=10.57Hz),129.66,126.75,111.90(dd,J=4.53,21.15Hz),74.76,69.99,44.27,40.94,22.54; 19F NMR(564MHz,Chloroform-d)δ-108.90.

[0046] 4-(4-((Sec-butyldisulfaneyl)methyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

[0047] (dd,J=28.1,11.5Hz,4H,Ar-H),6.99(d,J=7.1Hz,2H,Ar-H),5.45(s,1H,-CH-),4.80(s,1H,-CH2-),4.26(s,1H,-CH2-),3.88(s,2H,-CH2-),2.51(d,J=5.5Hz,1H,-CH-),1.63(d,J=5.9Hz,1H,-CH-),1.46(d,J=6.0Hz,1H),1.24(d,J=15.4Hz,6H),0.92(d,J=4.5Hz,3H); 13 C NMR(151MHz,Chloroform-d)δ161.20,(dd,J=256.70,6.06Hz),157.53,140.98,137.12,132.34(t,J=10.57Hz),129.67,126.74,111.89(dd,J=4.53,21.15Hz),74.77,69.99,42.80,29.91,20.82,10.93. 19 F NMR(564MHz,Chloroform-d)δ-108.91.

[0048] 2-(2,6-Difluorophenyl)-4-(4-((isobutyldisulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0049] =8.2,2H,Ar-H),5.45(dd,J=10.1,8.2,1H,-CH-),4.80(dd,J=10.3,8.5,1H,-CH2-),4.25(t,J=8.2,1H,-CH2-),3.88(s,2H,-CH2-),2.32(d,J=6.8,2H,-CH2-),1.82(dt,J=13.4,6.7,1H,-CH-),0.91(d,J=6.7,6H,CH3-); 13C NMR(151MHz,Chloroform-d)δ161.22(dd,J=256.70,6.06Hz),157.47,141.01,137.14,132.33(t,J=10.57Hz),129.68,126.73,111.88(dd,J=4.53,21.14Hz),74.77,70.00,48.19,43.32,28.06,21.65; 19 F NMR(564MHz,Chloroform-d)δ-108.90.

[0050] 2-(2,6-Difluorophenyl)-4-(4-((pentyldisulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0051] Ar-H),6.99(t,J=8.2Hz,2H,Ar-H),5.45(dd,J=10.1,8.3Hz,1H,-CH-),4.80(dd,J=10.3,8.5Hz,1H,-CH2-),4.26(t,J=8.3Hz,1H,-CH2-),3.88(s,2H,-CH2-),2.48–2.35(m,2H,-CH2-),1.61–1.50(m,2H,-CH2-),1.32–1.22(m,4H,-CH2CH2-),0.92–0.83(m,3H,CH3-); 13 C NMR(151MHz,Chloroform-d)δ161.22(dd,J=256.70,6.06Hz),157.50,140.98,137.14,132.37(t,J=10.57Hz),129.68,126.75,111.91(dd,J=4.53,21.14Hz),74.76,69.98,43.41,38.71,30.61,28.72,22.21,13.90; 19 F NMR(564MHz,Chloroform-d)δ-108.87.

[0052] 2-(2,6-Difluorophenyl)-4-(4-((dodecyldisulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0053] Ar-H),7.29(t,J=7.4Hz,2H,Ar-H),6.99(t,J=8.2Hz,2H,Ar-H),5.45(dd,J=10.1,8.3Hz,1H,-CH2-),4.80(dd,J=10.2,8.5Hz,1H,-CH2-),4.26(t,J=8.3Hz,1H,-CH2-),3.88(s,2H,-CH2-),2.43(t,J=7.4Hz,2H,-CH2-),1.56(dt,J=14.8,7.3Hz,2H,-CH2-),1.31–1.22(m,18H,-C9H 18 -),0.87(t,J=7.0Hz,3H,CH3-); 13 C NMR(151MHz,Chloroform-d)δ161.22(dd,J=256.70,6.06Hz),157.50,140.98,137.12,132.36(t,J=10.57Hz),129.68,126.75,111.90(dd,J=4.53,21.14Hz),74.77,69.99,43.42,38.78,31.89,29.63,29.60,29.57,29.47,29.32,29.18,29.06,28.46,22.66,14.08; 19 F NMR(564MHz,Chloroform-d)δ-108.86.

[0054]

[0055] 4-(4-((Tert-butyldisulfaneyl)methyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

[0056] colorless oil,yield:74%(58.2mg).Rf=0.3(PE:EA=3:1); 1H NMR(600MHz,Chloroform-d)δ7.43–7.40(m,1H,Ar-H),7.30(q,J=8.2Hz,4H,Ar-H),6.98(t,J=8.2Hz,2H,Ar-H),5.44(dd,J=10.2,8.2Hz,1H,-CH-),4.79(dd,J=10.3,8.5Hz,1H,-CH2-),4.27(t,J=8.3Hz,1H,-CH2-),3.92(s,2H,-CH2-),1.33(s,9H,CH3-); 13 C NMR(151MHz,Chloroform-d)δ161.22(dd,J=256.70,6.06Hz),157.43,140.94,136.91,132.33(t,J=10.57Hz),129.60,126.81,111.87(dd,J=4.53,21.14Hz),74.69,70.03,48.00,45.41,30.01; 19 F NMR(564MHz,Chloroform-d)δ-108.85.

[0057]

[0058] 2-(2,6-Difluorophenyl)-4-(4-(((2-methoxyethyl)disulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0059] colorless oil,yield:68%(53.7mg).Rf=0.2(PE:EA=3:1); 1 H NMR(600MHz,Chloroform-d)δ7.41(dd,J=13.7,7.3Hz,1H,Ar-H),7.31(dd,J=25.2,7.9Hz,4H,Ar-H),6.99(t,J=8.2Hz,2H,Ar-H),5.47–5.42(m,1H,-CH-),4.82–4.78(m,1H),4.26(t,J=8.2Hz,1H),3.90(s,2H,-CH2-),3.51(t,J=6.4Hz,2H,-CH2-),3.32(s,3H,CH3-),2.62(t,J=6.4Hz,2H,-CH2-); 13CNMR(151MHz,Chloroform-d)δ161.20(dd,J=256.70,6.06Hz),157.54,141.08,136.90,132.32(t,J=10.57Hz),129.70,126.82,111.92(dd,J=4.53,21.14Hz),109.99,107.19,74.75,70.68,69.97,58.59,43.45,38.14; 19 F NMR(564MHz,Chloroform-d)δ-108.90.

[0060] 4-(4-(((Cyclopropylmethyl)disulfaneyl)methyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

[0061] –7.31(m,2H),7.28(t,J=10.2Hz,2H),6.99(t,J=8.0Hz,2H),5.48–5.42(m,1H),4.80(t,J=9.1Hz,1H),4.26(t,J=8.1Hz,1H),3.96(d,J=50.2Hz,2H),2.39(t,J=15.9Hz,2H),0.97(s,1H),0.54(d,J=6.9Hz,2H),0.23–0.14(m,2H); 13 C NMR(151MHz,Chloroform-d)δ161.22(dd,J=256.70,6.06Hz),157.49,141.00,137.09,132.32(t,J=10.57Hz),129.70,129.19,126.73,111.89(dd,J=4.53,21.14Hz),74.77,70.00,45.05,43.62,10.85,5.49; 19 F NMR(564MHz,Chloroform-d)δ-108.98.

[0062]

[0063] 4-(4-(((Cyclobutylmethyl)disulfaneyl)methyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

[0064] colorless oil,yield:70%(56.7mg).Rf=0.3(PE:EA=3:1); 1 H NMR(600MHz,Chloroform-d)δ 1 H NMR(600MHz,Chloroform-d)δ7.47–7.39(m,1H),7.30(dt,J=23.9,11.9Hz,4H),6.99(t,J=8.2Hz,2H),5.45(t,J=9.1Hz,1H),4.80(dd,J=10.1,8.5Hz,1H),4.27(dd,J=18.7,10.5Hz,1H),3.87(s,2H),2.62–2.47(m,3H),2.07(d,J=3.7Hz,2H),1.90–1.75(m,2H),1.64(dd,J=16.2,7.6Hz,2H).; 13 C NMR(151MHz,Chloroform-d)δ161.22(dd,J=256.70,6.06Hz),157.51,141.00,137.06,132.35(t,J=10.57Hz),129.69,127.87,126.74,111.89(dd,J=4.53,21.14Hz),74.78,69.98,45.37,43.46,34.82,27.75,18.00; 19 F NMR(564MHz,Chloroform-d)δ-108.88.

[0065] 4-(4-((Cyclopentyldisulfaneyl)methyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

[0066] (s,1H,-CH2-),4.26(s,1H,-CH2-),3.91(s,2H,-CH2-),3.03(s,1H,-CH-),1.87(s,2H,-CH2-),1.74–1.53(m,6H,-CH2CH2CH2-); 13C NMR(151MHz,Chloroform-d)δ161.22(dd,J=256.70,6.06Hz),157.51,140.92,137.14,132.38(t,J=10.57Hz),129.67,126.74,111.90(dd,J=4.53,21.14Hz),74.79,70.00,50.05,43.81,32.98,24.63. 19 F NMR(564MHz,Chloroform-d)δ-108.89.

[0067] 4-(4-((Cyclohexyldisulfaneyl)methyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

[0068] (t,J=9.1Hz,1H),4.80(t,J=9.4Hz,1H),4.27(t,J=7.9Hz,1H),3.88(s,2H),2.44(t,J=10.7Hz,1H),1.94(d,J=12.0Hz,2H),1.73(s,2H),1.60(s,1H),1.25(s,2H),1.19(t,J=9.5Hz,3H); 13 C NMR(151MHz,Chloroform-d)δ161.24(dd,J=256.70,6.04Hz),157.44,140.97,137.13,132.29(t,J=10.57Hz),129.67,126.69,111.87(dd,J=21.14,3.02Hz),74.74,70.01,49.41,44.42,32.79,26.04,25.58; 19 F NMR(564MHz,Chloroform-d)δ-108.89.HRMS(ESI)calcd for[M+Na] + (C 22 H 23 F2NOS2Na):442.1081;found:442.1094.

[0069]

[0070] 4-(4-(((2,2-Difluoroethyl)disulfaneyl)methyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

[0071] colorless oil,yield:61%(48.9mg).Rf=0.4(PE:EA=3:1); 1 H NMR(600MHz,Chloroform-d)δ7.44-7.40(m,1H,Ar-H),7.33(q,J=8.1Hz,4H,Ar-H),7.00(t,J=8.2Hz,2H,Ar-H),5.74(tt,J=56.3,4.4Hz,1H,Ar-H),5.50–5.43(m,1H,-CH-),4.81(dd,J=10.2,8.5Hz,1H,-CH2-),4.26(t,J=8.3Hz,1H,-CH2-),3.93(s,2H,-CH2-),2.75(td,J=15.3,4.4Hz,2H,-CH2-); 13 C NMR(151MHz,Chloroform-d)δ161.22(dd,J=256.70,6.04Hz),157.64,141.45,136.25,132.41(t,J=10.57Hz),129.76,126.96,116.78,115.16,111.91(dd,J=21.14,3.02Hz),74.76(d,J=6.04Hz),69.94,43.28,41.77, 19 FNMR(564MHz,Chloroform-d)δ-108.89,-115.43.

[0072] 2-(2,6-Difluorophenyl)-4-(4-((phenethyldisulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0073] 7.18(t,J=7.4Hz,1H),7.09(d,J=7.4Hz,2H),7.00(t,J=8.3Hz,2H),5.44(t,J=9.1Hz,1H),4.76(t,J=9.4Hz,1H),4.17(t,J=8.3Hz,1H),3.89(s,2H),2.84(t,J=7.8Hz,2H),2.60(t,J=7.8Hz,2H);13 C NMR(151MHz,Chloroform-d)δ161.23(dd,J=256.70,6.04Hz),157.51,141.10,139.99,137.14,132.33(t,J=10.57Hz),129.69,128.50,128.40,126.81,126.30,111.90(dd,J=4.53,21.14Hz),74.75,70.00,43.40,39.60,35.44; 19 F NMR(564MHz,Chloroform-d)δ-108.87.HRMS(ESI)calcd for[M+Na] + (C 24 H 21 F2NOS2Na):464.0925;found:464.0937.

[0074] 4-(4-((Benzyldisulfaneyl)methyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

[0075] 4.26(t,J=8.2Hz,1H),3.65(s,2H),3.57(s,2H); 13 C NMR(151MHz,Chloroform-d)δ162.24(dd,J=256.70,6.04Hz),157.51,141.10,137.20,136.92,135.83,132.40(t,J=10.57Hz),129.72,129.11,128.40,127.81,126.83,111.93(dd,J=4.53,21.14Hz),74.77,70.00,43.35; 19 F NMR(564MHz,Chloroform-d)δ-108.90.

[0076] 2-(2,6-Difluorophenyl)-4-(4-(((4-methylphenethyl)disulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0077]

[0078] Hz,2H,Ar-H),7.13–7.05(m,2H,Ar-H),7.00(t,J=9.5Hz,3H,Ar-H),5.45(t,J=9.1Hz,1H,-CH2-),4.77(t,J=9.3Hz,1H,-CH2-),4.18(t,J=8.0Hz,1H,-CH2-),3.89(s,2H,-CH2-),2.81(t,J=7.7Hz,2H,-CH2-),2.67–2.50(m,2H,-CH2-),2.30(s,3H,CH3-); 13 CNMR(151MHz,Chloroform-d)δ162.24(dd,J=256.70,6.04Hz),157.53,141.08,137.19,136.92,135.83,132.40(t,J=10.57Hz),129.72,129.11,128.40,126.83,111.93(dd,J=4.53,21.14Hz),74.77,70.00,43.40,39.73,34.99,20.99. 19 F NMR(564MHz,Chloroform-d)δ-108.96.

[0079]

[0080] 2-(2,6-Difluorophenyl)-4-(4-(((4-phenylbutan-2-yl)disulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0081] colorless oil,yield:74%(69.4mg).Rf=0.3(PE:EA=3:1); 1H NMR(600MHz,Chloroform-d)δ7.43–7.40(m,J=14.0,7.1Hz,1H,Ar-H),7.32–7.26(m,5H,Ar-H),7.18(d,J=7.7Hz,2H,Ar-H),6.99(td,J=8.4,1.4Hz,2H,Ar-H),5.45(t,J=9.1Hz,1H,-CH2-),4.80(t,J=9.3Hz,1H,-CH2-),4.26(t,J=9.6Hz,1H,-CH2-),3.89(s,2H,-CH2-),2.68(dd,J=12.1,5.9Hz,2H,-CH2-),2.61(dd,J=13.4,6.7Hz,1H,-CH-),1.96(dt,J=15.4,6.9Hz,1H,-CH2-),1.76(dt,J=21.2,7.0Hz,1H,-CH2-),1.29(d,J=6.7Hz,3H,CH3-); 13 C NMR(151MHz,Chloroform-d)δ162.24(dd,J=256.70,6.04Hz),157.49,141.60,141.58,141.01,137.00,132.35(t,J=10.57Hz),129.67,128.37,126.80,126.78,125.88,111.90(dd,J=4.53,21.14Hz),74.75,70.03,45.34,44.27,37.63,33.17,20.67; 19 FNMR(564MHz,Chloroform-d)δ-108.82.

[0082] 2-(2,6-Difluorophenyl)-4-(4-(((2-(thiophen-2-yl)ethyl)disulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0083]

[0084] 7.11(d,J=3.8Hz,1H),7.00(t,J=7.7Hz,2H),6.89(s,1H),6.75(s,1H),5.45(t,J=9.0Hz,1H),4.78(dd,J=18.1,8.7Hz,1H),4.20(t,J=8.1Hz,1H),3.89(s,2H),3.05(t,J=7.4Hz,2H),2.63(d,J=7.0Hz,2H); 13 C NMR(151MHz,Chloroform-d)δ161.24(dd,J=256.70,6.04Hz),157.49,142.45,141.14,137.03,132.32(t,J=10.57Hz)132.23,129.68,126.84,126.76,124.92,123.53,111.97(dd,J=21.14,3.02Hz),74.74,69.99,43.41,39.61,29.51; 19 FNMR(564MHz,Chloroform-d)δ-108.87.

[0085] 2-(2,6-Difluorophenyl)-4-(4-(((naphthalen-1-ylmethyl)disulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0086]

[0087] 7.24(d,J=7.7Hz,2H),7.07(d,J=7.4Hz,2H),6.99(t,J=8.0Hz,2H),5.43(t,J=8.9Hz,1H),4.78(t,J=9.2Hz,1H),4.24(t,J=8.1Hz,1H),4.15(s,2H),3.42(s,2H); 13 CNMR(151MHz,Chloroform-d)δ161.20(dd,J=256.70,6.04Hz),157.50,140.96,136.72,133.94,132.72,132.36,131.26,129.78,128.78,128.51,128.12,126.69,126.20,125.88,125.19,124.04,111.91(dd,J=21.14,3.02Hz),109.99,74.74,69.98,42.88,41.36;19 FNMR(564MHz,Chloroform-d)δ-108.94.

[0088] 2-(2,6-Difluorophenyl)-4-(4-(((3-methoxybenzyl)disulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0089] 2H,Ar-H),6.79(d,J=8.2Hz,1H,Ar-H),5.45(t,J=9.2Hz,1H,-CH-),4.80(t,J=9.4Hz,1H,-CH2-),4.29(t,J=8.3Hz,1H,-CH2-),3.79(s,3H,CH3-),3.60(s,2H,-CH2-),3.56(s,2H,-CH2-); 13 C NMR(151MHz,Chloroform-d)δ161.23(dd,J=256.70,6.04Hz),159.74,157.45,140.50,139.66,137.70,132.36(t,J=10.57Hz),129.42,129.38,126.78,121.37,114.39,112.67,111.90(dd,J=21.14,3.02Hz),107.27(t,J=18.12Hz),74.75,70.04,55.17,35.61,35.33; 19 F NMR(564MHz,Chloroform-d)δ-108.84.

[0090] 2-(2,6-Difluorophenyl)-4-(4-(((2,4,6-trimethylbenzyl)disulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0091]

[0092] -CH-),4.82(t,J=9.4Hz,1H,-CH2-),4.28(t,J=8.3Hz,1H,-CH2-),3.78(s,2H,-CH2-),3.64(s,2H,-CH2-),2.26(s,6H,CH3-),2.24(s,3H,CH3-); 13C NMR(151MHz,Chloroform-d)δ161.25(dd,J=256.70,6.04Hz),157.48,140.54,138.10,136.96,136.40,132.36(t,J=10.57Hz),130.74,129.30,128.92,126.70,111.91(dd,J=22.65,4.53Hz),74.85,70.07,37.18,30.61,20.86,19.37; 19 F NMR(564MHz,Chloroform-d)δ-108.85.

[0093] 4-(4-(((4-Chlorobenzyl)disulfaneyl)methyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxazole

[0094] 1H,-CH-),4.79(t,J=9.4Hz,1H,-CH2-),4.27(t,J=8.3Hz,1H,-CH2-),3.56(s,2H,-CH2-),3.52(s,2H,-CH2-); 13 C NMR(151MHz,Chloroform-d)δ161.21(dd,J=256.70,6.04Hz)157.46,140.64,137.41,136.65,132.66,132.39(t,J=10.57Hz),130.30,129.38,128.55,126.84,111.91(dd,J=21.14,4.53Hz),74.74,70.02,35.30,34.84; 19 F NMR(564MHz,Chloroform-d)δ-108.79.

[0095] 2-(2,6-Difluorophenyl)-4-(4-(((4-(trifluoromethyl)benzyl)disulfaneyl)methyl)phenyl)-4,5-dihydrooxazole

[0096] Hz,2H,Ar-H),5.45(t,J=9.2Hz,1H,-CH-),4.81(t,J=9.3Hz,1H,-CH2-),4.28(t,J=8.2Hz,1H,-CH2-),3.59(d,J=4.6Hz,4H,-CH2-); 13 C NMR(151MHz,Chloroform-d)δ161.22(dd,J=256.70,6.04Hz),157.52,142.35,140.73,137.21,132.37(t,J=10.57Hz),129.37,129.25,126.88,125.35(q,J=4.53Hz),126.18(q,J=27.80Hz),111.90(dd,J=21.14,3.02Hz),74.72,70.01,35.37,35.03,28.58; 19 F NMR(564MHz,Chloroform-d)δ-62.44,-108.89.

[0097]

[0098] 4-(4-(((4-(Tert-butyl)benzyl)disulfaneyl)methyl)phenyl)-2-(2,6-difluorophenyl)-4,5-dihydrooxa zole

[0099] colorless oil,yield:75%(72.6mg).Rf=0.3(PE:EA=3:1); 1 H NMR(600MHz,Chloroform-d)δ7.43(dd,J=14.6,6.4Hz,1H,Ar-H),7.35(d,J=8.0Hz,2H,Ar-H),7.30(d,J=7.9Hz,2H,Ar-H),7.21(dd,J=22.0,7.9Hz,4H,Ar-H),6.99(t,J=8.2Hz,2H,Ar-H),5.45(t,J=9.1Hz,1H,-CH2-),4.80(t,J=9.3Hz,1H,-CH2-),4.26(t,J=8.2Hz,1H,-CH2-),3.64(s,2H,-CH2-),3.59(s,2H,-CH2-),1.31(s,9H,(CH3)3C-); 13C NMR(151MHz,Chloroform-d)δ162.21(dd,J=256.70,6.04Hz),157.52,150.51,141.03,136.84,134.20,132.39(t,J=10.57Hz),129.84,129.11,126.76,125.40,112.00,111.85(dd,J=21.14,3.02Hz),,74.77,69.99,43.02,42.94,34.54,31.35; 19 FNMR(564MHz,Chloroform-d)δ-108.82.

[0100] 4-(4-(((3-(Benzo[d][1,3]dioxol-5-yloxy)propyl)disulfaneyl)methyl)phenyl)-2-(2,6-difluoro phenyl)-4,5-dihydrooxazole

[0101] Hz,2H),6.99(t,J=8.3Hz,2H),6.67(d,J=8.4Hz,1H),6.45(d,J=2.3Hz,1H),6.28(dd,J=8.5,2.3Hz,1H),5.89(s,2H),5.47–5.42(m,1H),4.80–4.77(m,1H),4.25(t,J=8.3Hz,1H),3.92–3.84(m,4H),2.57(t,J=7.0Hz,2H),2.03–1.98(m,2H); 13 C NMR(151MHz,Chloroform-d)δ161.23(dd,J=256.70,6.04Hz),157.49,154.31,148.21,141.65,141.11,136.95,132.31(t,J=10.57Hz),129.69,126.80,111.88(dd,J=21.14,4.53Hz),107.88,105.80,101.04,98.12,74.73,70.01,66.90,43.25,34.86,29.65,28.68; 19 F NMR(564MHz,Chloroform-d)δ-108.88.HRMS(ESI)calcd for[M+Na] + (C 26 H 23F2NO4S2Na):538.0929; found:538.0939. IV. Use of the above compounds in the preparation of agricultural insecticides / fungicides

[0102] Activity Test Example 1: Activity determination of the target compound against Plutella xylostella indoors.

[0103] The leaf dipping method was adopted: the target compound was dissolved in DMSO, and the test insects were 2nd instar larvae of diamondback moth, which were a normal group normally raised indoors. The cabbage leaves were dipped in the prepared solution with tweezers for 10-15 seconds, and naturally dried after being taken out. After the drug solution was dry, it was placed in a culture dish with a diameter of 10 cm and padded with filter paper, and 2nd instar larvae of diamondback moth were inoculated, 20 heads per dish, and then the lid was covered and placed in an incubator with a temperature of 26°C and a relative humidity of 75%. The test results were observed after 48 hours, and three parallels were set for each group of drug solutions.

[0104] After 48 hours, the mortality of Plutella xylostella in the experimental group and the control group was observed and counted. The insect body was lightly touched with a brush, and no obvious reaction was considered dead.

[0105] The 48-hour mortality rate (%) and corrected mortality rate (%) of the test insects were calculated according to the following formula.

[0106]

[0107] Activity Test Example 2: Determination of the ovicidal activity of the target compound against indoor spider mites

[0108] The leaf dipping method was used to determine the egg-inhibiting activity against Tetranychus cinnabarinus eggs.

[0109] Acquisition of Tetranychus cinnabarinus eggs: Use a fine brush to inoculate female adult mites on leaves of bean seedlings with two true leaves. Inoculate 10 female adult mites on each leaf of each plant. Then place in a constant temperature incubator at 26°C and 70% humidity to lay eggs. After 24 hours, remove the female adult mites with a fine brush.

[0110] Activity test method for Tetranychus cinnabarinus eggs: Dissolve the test sample with an appropriate amount of acetone (0.1%). Dilute the acetone solution of each target compound with a 0.1% Tween 80 aqueous solution to obtain the required concentration. Immerse the bean sprout leaves containing Tetranychus cinnabarinus eggs in the prepared concentration solution for 5 seconds while stirring, remove the excess liquid by shaking, and then place the bean sprout leaves in a culture box lined with sponges. Evaluate the egg hatching status 7 days after the test, and repeat three times.

[0111] The adjusted mortality rate was calculated as follows:

[0112] Corrected mortality rate (%) = (TC) × 100 / (100%-C)

[0113] C is the non-hatching rate of CK, and T is the non-hatching rate of treated.

[0114] Activity Test Example 3: Determination of the acaricidal activity of the target compound against indoor Tetranychus cinnabarinus nymphs

[0115] Obtaining juvenile mites of the cinnabar spider mite: Use a fine brush to attach 10 adult female mites to the leaves of true leaf bean seedlings, and then place them in a constant temperature incubator at 26°C and 70% humidity to lay eggs. After 24 hours, remove the adult female mites and continue to culture under the same culture conditions for 5-6 days to obtain juvenile mites.

[0116] Activity test method for juvenile mites of Tetranychus cinnabarinus: Immerse the leaves of true bean seedlings containing juvenile mites in the test solution of the target compound for 5 seconds, then remove the excess liquid and place the leaves in a culture box lined with sponge. Culture them in a constant temperature incubator at 26°C and 70% humidity for 4 days, and then evaluate the number of dead heads.

[0117] The adjusted mortality rate was calculated as follows:

[0118] Corrected mortality rate (%) = (TC) × 100 / (100%-C)

[0119] C is the mortality rate of CK, T is the mortality rate of treated larvae

[0120] Activity Test Example 4: Determination of the acaricidal activity of the target compound against adult mites of Tetranychus cinnabarinus

[0121] The slide immersion method was used: 2 mg of the test compound was weighed, dissolved with 200 μL of acetone, and then the volume was adjusted to 20 mL with 1‰ Tween 80, that is, a 100 μg / mL solution was prepared for standby use. A 1 cm wide double-sided tape was attached to one end of the slide, and healthy and active female adult mites of the same age of cinnabarinus spider mites were selected with a No. 0 brush, and their backs were carefully and neatly attached to the double-sided tape. About 30 mites were attached to each slide, arranged in 2 rows, and the slide with the test mites was placed on an iron plate with a moist sponge, and the iron plate was placed in a light incubator under the conditions of 26±1℃, relative humidity of 60% to 80%, and light L:D=14h:10h. After 4 hours, it was checked with a stereo microscope, and dead and inactive individuals were removed, and the number of live mites on each slide was recorded. The end of the glass slide with the mite stuck to it was shaken and immersed in the test solution for 5 seconds, then taken out. The excess solution was carefully absorbed with a small filter paper strip and returned to the iron plate. It was placed in a light incubator under the same breeding conditions. One glass slide was one treatment, and each treatment was repeated 3 times. 1‰ Tween 80 solution was used as a blank control. After 24 hours of drug treatment, the glass slide was taken out and the results were checked under a stereomicroscope. During the inspection, the mite body was lightly touched with the tip of a brush. Those whose chelicerae did not move were considered dead, and the number of dead individuals was recorded; continuous observation and recording was performed for 72 hours. The mortality rate (%) and corrected mortality rate (%) of the test mite at 48 hours and 72 hours were calculated according to the following formula.

[0122]

[0123] Activity Test Example 5: Determination of in vitro antibacterial activity of target compounds

[0124] The antibacterial activity against D.zeae and Xcc was determined by turbidity method.

[0125] NB medium: Add beef peptone (3.0 g), yeast powder (1.0 g) and glucose (10.0 g) to deionized water (1.0 L) in sequence, stir to dissolve, adjust the pH to 7.0 with NaOH, and then load them into test tubes with silicone stoppers (3.96 mL / tube), respectively, and sterilize at 121°C for 20 min.

[0126] Antibacterial activity test operation process: Use acetone to prepare the test compound to the appropriate concentration (100, 50, 25, 12.5 and 6.25 mg / L). Add 0.04 mL of the prepared liquid to a test tube containing 3.96 mL of culture medium. Then shake well and use a pipette to take 0.2 mL for initial OD 600 Then add 4 μL of bacteria (OD 600 =0.6-0.9) solvent. The bacterial culture was incubated in a shaker (180 rpm, 28°C) until the blank control absorbance (OD 600 =0.6-0.9)(180rpm, 28°C). Acetone was used as a blank control. All test groups were measured three times in parallel.

[0127] Inhibition rate calculation formula:

[0128] Inhibition rate % = [[(control absorbance OD 600 -Control initial OD 600 )-(Processing absorbance OD 600 - Processing initial OD 600 )] / (control absorbance OD 600 -Control initial OD 600 )]x 100%

[0129] in conclusion

[0130] Activity tests showed that in terms of the prevention and control of Tetranychus cinnabarinus, all target compounds showed 100% mortality against Tetranychus cinnabarinus eggs at a concentration of 1.0 mg / L, among which compounds 7d, 7o and 7t showed 100% mortality against Tetranychus cinnabarinus eggs at 0.01 mg / L. In addition, compounds 5, 7b, 7j, 7l, 7o and 7v showed 100% mortality against Tetranychus cinnabarinus nymphs at 10 mg / L, especially compounds 5, 7j and 7v showed a mortality of more than 90% at 0.1 mg / L, and compounds 7b, 7g, 7l, 7o and 7q showed a mortality of more than 50% at 0.1 mg / L.

[0131] In terms of the prevention and control of diamondback moth, the mortality rate of compound 71 to diamondback moth was greater than 70% at 50 mg / L.

[0132] In terms of bacterial control, compounds 5, 7a, 7c, 7d, 7e, 7g, 7i, 7l, 7s, 7t, 7x, 7y, 7z, 7aa and 7ab had an inhibition rate of more than 30% against D.zeae at 100 mg / L. Compounds 7a, 7c, 7d, 7g, 7h, 7i, 7s, 7y, 7z, 7aa and 7ab had an inhibition rate of more than 30% against Xcc.

[0133] In view of this, the difluoroolefin ether and oxime ether derivatives disclosed in the present invention have significant insecticidal / mite activity and are expected to be used in the preparation of new and highly effective insecticidal / mite agents in the future.

[0134] 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. An isoxazoline disulfide derivative, characterized in that: The general structural formula of this series of derivatives is shown in formula (I): In formula (I), R is independently selected from benzyl, halogen-containing benzyl, alkyl-containing benzyl, C 1-12 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-6 Alkyl, deuterium-substituted alkyl, cycloalkyl, aryl-substituted alkyl.

2. The difluoroolefin ether and oxime ether derivatives according to claim 1, characterized in that: R is independently selected from benzyl, halogen-containing benzyl, alkyl-containing benzyl, C 1-12 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-6 Alkyl, deuterium-substituted alkyl, cycloalkyl, aryl-substituted alkyl; Preferably, R is independently selected from benzyl, fluorine-containing, chlorine-containing, bromine-substituted benzyl, alkyl-containing benzyl, C 1-12 Alkyl, C 1-4 Alkoxy, halogen-substituted C 1-6 Alkyl, deuterium-substituted alkyl, cycloalkyl containing 3-9 carbon atoms, alkyl substituted with aryl.

3. The isoxazoline disulfide derivative according to claim 2, characterized in that Selected from the following specific compounds:

4. The method for preparing the isoxazoline disulfide derivatives according to claim 3, characterized in that: The preparation method is characterized in that it comprises the following steps: Step (3), using intermediate 4 As raw material, it reacts with disulfide transfer reagent (DSMO) to obtain unilaterally substituted isoxazoline disulfide intermediate 5 Step (4), unilaterally substituted isoxazoline disulfide intermediate 5 The compound represented by formula (I) is prepared by reacting with halogenated alkane.

5. The method for preparing isoxazoline disulfide derivatives according to claim 4, characterized in that: The reaction solvent in step (3) is selected from one or more of N,N-dimethylformamide, N,N-diethylformamide, 1,4-dioxane, tetrahydrofuran, toluene, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, acetonitrile, acetone, and water, and the reaction temperature is 25 to 80° C. The base is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, DBU, diisopropylethylamine, sodium hydrogen hydride, sodium tert-butoxide, and sodium methoxide.

6. The method for preparing isoxazoline disulfide derivatives according to claim 4, characterized in that: The reaction solvent in step (4) is characterized by: The reaction solvent is selected from one or more of N,N-dimethylformamide, N,N-diethylformamide, 1,4-dioxane, tetrahydrofuran, toluene, ethyl acetate, dimethyl sulfoxide, methanol, ethanol, acetonitrile, acetone, and water, and the reaction temperature is 25-80° C. The base is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, DBU, diisopropylethylamine, sodium hydrogen, sodium tert-butoxide, and sodium methoxide.

7. Use of the isoxazoline disulfide derivatives prepared by the method for preparing isoxazoline disulfide derivatives as claimed in claim 4 in preparing acaricides.

8. Use of the isoxazoline disulfide derivatives prepared by the method for preparing the isoxazoline disulfide derivatives as claimed in claim 4 in preparing sterilization.

9. Use of the isoxazoline disulfide derivatives prepared by the method for preparing isoxazoline disulfide derivatives as claimed in claim 4 in preparing insecticides.

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