CN104231022A - Preparation and application of macrolide compound - Google Patents
Preparation and application of macrolide compound Download PDFInfo
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Abstract
The invention relates to a macrolide compound as well as a preparation method and application thereof, in particular a modified ivermectin derivative as well as a preparation method and application thereof. General formulas (I) (II) of the compound of the macrolide derivative and salt thereof are as shown in the specification. The compound disclosed by the invention is efficient, safe, stable, wide in spectrum and low in toxicity, and has an excellent agricultural insecticidal and acaricidal activity as well as an activity of killing parasites of domestic animals and medical uronema, wherein n represents 0, 1, 2, 3, 4, 5, 6 or 7; X is either N or O; Y represents Cl<->; Z is either N or O; R1 and R2 are selected from H and C1-C4 alkyl; or ZR1R2 is selected from the following structures as shown in the specification.
Description
Technical field:
The present invention relates to a kind of preparation of macrolides compound, specifically the ivermectin analog derivative and preparation method thereof of modification and the application on Agricultural pests and the parasitic control of livestock and clinical medicine.
Background technology:
So far the typical commercial kind of macrolide as the activator of chloride channel has Avrmectin (abamectin), ivermectin (Ivermectin), emamectin-benzoate (emamectin benzoate) and milbemectin (mi lbemectin) etc.
Avrmectin is ten hexa-atomic macrolide disaccharide glycosides compounds.It is a class wide spectrum class insecticidal/acaricidal agent.Its insecticidal spectrum has more than 80 to plant, and can effectively prevent and treat Diptera, Homoptera, Coleoptera and lepidoptera pest and multiple harmful mite etc.Control spectrum is very extensive, has desinsection, kills mite, nematicide effect, and be often used in agriculture insect and the parasitic control of livestock.Also better prevention effect is had to many animals gastrointestinal nematode parasites, animal lung nematode, warble, lice, mite and tick etc.But, because the former medicine toxicity of Avrmectin is huge poison, its LD
50(male white rat per os) is 10.7mg/kg, and thus it is restricted in the parasitic control of livestock, and Control Insect Pests In Rice Field is also restricted; Be separately, because Avrmectin Applicative time is longer, have bibliographical information both at home and abroad, Populations of Diamondback Moth, Plutella Xylostella has created stronger resistance to Avrmectin.
Ivermectin (Ivermectin or IVM) is a member in macrolide antibiotics insect repellent Avrmectin (Avermectins or AVM) family, by Merck company of the U.S., through selective hydrogenation 22, the 23-two hydroperoxide derivatives obtained reduce to AVERMECTIN B1 component in the twentieth century initial stage eighties.Compared with Avrmectin, ivermectin is stablized and safety more, and acute toxicity is lower than Avrmectin one times, its LD
50(male white rat per os) is 29.5mg/kg, but also belongs to high drugs kind.It is the macrolide antibiotics anthelmintic drug with wide spectrum, efficient, low residue feature of generally acknowledging in the world at present, has developed multiple formulation and has been widely used in livestock industry and clinical medicine.In time decades after ivermectin is found, chemists determine its mechanism of action substantially, and have done large quantity research to its toxicity, pathways metabolism, resistance etc., and these all suffice to show that ivermectin still has good development prospect.
Ivermectin from 1981 as since veterinary drug listing, the feature of, safety efficient by means of it, stable, wide spectrum and be widely used in animal health domain variability and obtain immense success.Ivermectin is also widely used at Human clinical's medical field, is described as " refreshing medicine ", has benefited millions of sufferer since being used for the treatment of human body onchocerciasis first from 1988, and its medical range is also in continuous expansion.In field of animal medicine, for different parasitosis and different treatment targets, ivermectin is developed to several formulations, in Avrmectin family, its type of preparation is the most complete, apply also the most extensive, this is comprising conventional formulation such as paste, tablet, capsule, aerosol, oral liquid, normal injection agent, also comprises this kind of new formulations of release/controlled release such as cutaneous permeable agent, long-acting injection, ivermectin slowly-releasing bolus, Polylactic Acid Microspheres Loading Ivermectin preparation.But this two classes preparation all also exists different shortcomings, such as: conventional formulation often needs repeatedly repeat administration just can reach effective treatment, and it is new formulation complex manufacturing, expensive, and its subsidiary material and device can not be degraded in animal body, detrimentally affect can be produced to the physiological activity of animal.Water-base preparation has easy to use, that Environmental compatibility is good feature, in recent years also has report, such as US2005/0009762A1.But due to the high hydrophobicity of himself, this just determines still needs to add some other cosolvent, tensio-active agents etc. in the process preparing ivermectin water-base preparation, which limits its application in agricultural crops protection.
Traditional Agricultural pharmaceutically dosage form is with missible oil, wettable powder, pulvis and granule are main, along with the manufacture and exploit of pesticides new formulation, following meeting is towards aqua, the future development such as aqueous emulsion and microemulsion, from this development trend, this just has higher requirement to the novel pesticide molecule being about to succeed in developing, not only want efficient, low toxicity, safety and and environmental friendliness, also wish that drug molecule has certain water-soluble simultaneously, directly use if drug molecule has the good water-soluble aqua that just can be made into, so not only can reduce production cost but also can reduce when drug molecule is made into certain preparation needs to add a large amount of solvent, tensio-active agent, the environmental pollution that auxiliary agent and permeate agent etc. bring.From this respect, good water-soluble of drug molecule has very important significance.Meanwhile, having necessarily water-soluble and fat-soluble drug molecule, is also that medicine is effectively necessary through microbial film.
No matter medicine is that epidermal absorption or other approach absorb, and all needs with the form of molecule through barrier membranes.First medicine need dissolve, and if medicine has desirable biopharmaceutical properties, its region from the regional diffusion of high density to lower concentration, strides across cytolemma and enters into the recycle system.All microbial films contain lipid as major ingredient.In biofilm structure, active molecule all has the end structure containing phosphatic high polarity, and, in most of the cases, the hydrocarbon chain of two very hydrophobic.Microbial film has bilayer structure, and hydrophilic chain end structure is towards the aqueous regions of both sides.Very hydrophilic medicine cannot stop wherein as a biomembranous part because of the similar reason mixed by very hydrophobic medicine through biomembranous lipid layer, thus effectively can not enter inner tenuigenin.
Due to himself structures shape, it is the medicine that a kind of hydrophobicity is very strong to ivermectin.The present invention passes through structure activity study, non-active target position to ivermectin B1a is introduced hydrophilic hydramine, diamines or glycol group etc. and is carried out structural modification modification, thus improve their wetting ability, making that it is water-soluble-oil is molten reaches a new better balance, thus improve target organisms to their assimilated efficiency, reduce the loss of in vitro.The novel cpd obtained after transformation all has such constructional feature: in their molecule, a part has lipophilicity (the original molecule main part that hydrophobicity is strong), another part has a wetting ability (one-level that protonated form exists under physiology PH condition, secondary, or tertiary amine group).The molten balance of a water-soluble oil is like this that medicine is effectively through microbial film necessary [Susan Milosovich, et al.J.Pharm.Sci., 82,227 (1993)].Therefore, in their molecules hydrophilic parts can with cytolemma outside phosphoric acid base bonding form the high concentration region of medicine, the concentration difference that itself and cytolemma inside are formed can promote these drug molecules and enter cytolemma; And after these drug molecules enter cytolemma, its hydrophilic parts will promote drugs across cell membranes internal layer and enter tenuigenin, finally arrives action target spot.
Summary of the invention:
The object of this invention is to provide compound and the preparation method and application of a class Novel macrocyclic lactone derivatives and salt thereof.The compounds of this invention has efficiently, safety, the agricultural insecticidal acaricidal activity of excellence of stable, wide spectrum, low toxicity, livestock parasiticide and medically kill Uronema activity.
The invention provides novel ivermectin analog derivative of a class and its preparation method and application, the compound of this macrolide derivatives and salt thereof, as shown in general formula (I), (II):
Wherein:
N=0,1,2,3,4,5,6 or 7; X represents N or O; Y represents Cl
-, Br
-, F
-, I
-, AcO
-, acetylsalicylate, citrate, salicylate, tosic acid root, bisulfate ion, or other negative ions; Z represents N or O.R
1represent the alkyl of 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, the thiazolinyl of a 1-6 carbon atom or aryl; R
2represent the alkyl of 1-6 carbon atom, the alkoxyl group of a 1-6 carbon atom, the thiazolinyl of a 1-6 carbon atom or aryl; Or ZR
1r
2be selected from following structure:
The comparatively preferred compound of the present invention is:
N=1,2,3,4; X represents N or O; Y represents Cl
-, Br
-, F
-, I
-, AcO
-, acetylsalicylate, citrate, salicylate, tosic acid root, bisulfate ion, or other negative ions, Z represents N or O, R
1, R
2be selected from H, C
1-C
4alkyl or ZR
1r
2be selected from following structure:
General formula compound (I, II) of the present invention is prepared by the following method:
Ivermectin B1a and p-nitrophenyl chloroformate ester are dissolved in suitable organic solvent, such as dioxane, benzene, toluene, ethyl acetate, THF, normal hexane, tetracol phenixin, chloroform or methylene dichloride, with organic bases as pyridine, triethylamine, Tetramethyl Ethylene Diamine (TMEDA) is catalyzer, and temperature is react 1-24 hour obtained intermediate 1 under 0 DEG C to room temperature condition.
By upper step gained intermediate 1 and the intermediate 2 shown in above formula, in suitable organic solvent, temperature is react 1-24 hour obtained product (I) under 0 DEG C to boiling point.R
1, R
2, n, X, Y, Z value as claim 1 define.
Organic solvent can be dioxane, benzene, toluene, ethyl acetate, THF, DMF, acetone, normal hexane, tetracol phenixin, chloroform or methylene dichloride etc.Add alkaline matter, as pyridine, triethylamine, DMAP etc. are favourable to reaction.
Be dissolved in suitable organic solvent by product (I), add diluted acid YH, temperature is react 1-24 hour obtained product (II) under 0 DEG C to boiling point.Organic solvent can be dioxane, benzene, toluene, ethyl acetate, THF, acetone, normal hexane, tetracol phenixin, chloroform or methylene dichloride etc.
General formula (I, II) compound of the present invention has efficiently, safety, the agricultural insecticidal acaricidal activity of excellence of stable, wide spectrum, low toxicity, livestock parasiticide and medically kill Uronema activity.
The present invention also comprises with general formula (I), and (II) compound is the insecticide acaricide composition of active ingredient.In this Insecticiding-miticiding component, the weight percentage of active ingredient is 1-99%.Agriculturally acceptable carrier is also comprised in this insecticide acaricide composition.
General formula of the present invention (I), (II) compound and the insecticide acaricide composition as active ingredient thereof can be made several formulations and use.In these compositions, also can add liquid or solid carrier, and add appropriate tensio-active agent and carry out compounding application.
General formula of the present invention (I), (II) compound both can be used alone as insecticidal/acaricidal agent and other known sterilant, weedicide agent, plant-growth regulator or fertilizer also can be coordinated to mix together.
The invention provides compound and the synthetic method of a class Novel macrocyclic lactone derivatives and salt thereof, the compounds of this invention have efficiently, safety, the agricultural insecticidal acaricidal activity of excellence of stable, wide spectrum, low toxicity, livestock parasiticide and medically kill Uronema activity.
Embodiment
The following example and raw test are tested and toxicity test result can be used for illustrating the high-performance of the compounds of this invention further, but do not mean that restriction the present invention.
Synthesis example
The preparation of intermediate 15-O-p-nitrophenyl carbonate ester ivermectin B1a
Add dry ivermectin B1a15.63g (18mmol) at 250ml round-bottomed flask, 150ml tetrahydrofuran (THF) dissolves, under cryosel bath, drip 2.09g (18mmol) Tetramethyl Ethylene Diamine.After stirring 10min, then add 7.21g (36mmol) p-nitrophenyl chloroformate ester, become after brown turbid system until system, remove cryosel bath and change stirring at room temperature into.TLC follows the tracks of reaction and stirs to the unchanged rear stopping of raw material point.Suction filtration removing insolubles, filtrate is revolved steaming and is sloughed tetrahydrofuran (THF) and obtain yellow solid.In gained solid, add 150ml methylene dichloride, obtain brown turbid system, after washing (60ml × 3), then wash once with saturated common salt.After organic phase anhydrous sodium sulfate drying, slough solvent and obtain crude product.Recycle silicon plastic column chromatography carries out purifying, sherwood oil: ethyl acetate=4:1 makees eluent, obtains intermediate 1 white solid 13.86g, yield: 74.04%, fusing point: 148 ~ 149 DEG C.
1H?NMR(CDCl3，400MHz)6(ppm)：8.29(d，2H，J=9.0Hz，β-Hof?p-nitrophenyl)，7.43(d，2H，J=9.0Hz，α-H?of?p-nitrophenyl)，5.88(d，1H，J=10.1Hz，9-H)，5.82～5.64(m，3H，10-H，11-H，3-H)，5.48～5.32(m，3H，1”-H，5-H，19-H)，4.99(d，1H，J=10.1Hz，15-H)，4.78(d，1H，J＝3.1Hz，1’-H)，4.70(dd，2H，J=14.4Hz，8α-H
2)，4.23～4.17(m，2H，6-H，7-OH)，3.95(s，1H，13-H)，3.88～3.73(m，2H，5’-H，5”-H)，3.72～3.58(m，2H，17-H，3’-H)，3.52～3.37(m，8H，3”-H，3’-OMe，3”-OMe，2-H)，3.28～3.13(m，3H，25-H，4’-H，4”-H)，2.58～2.48(m，2H，12-H，4”-OH)，2.39～2.18(m，4H，2”-eH，16-H
2，2’-eH)，1.99(dd，1H，J＝12.0，4.6Hz，20-eH)，1.89(s，3H，4-Me)，1.77(d，1H，J＝9.6Hz，18-eH)，1.70～1.33(m，14H，22-H
2，2’aH，2”-aH，26-H，24-H，14-Me，23-H
2，27-H
2，20-aH)，1.32～1.22(m，6H，5”-Me，5’-Me)，1.17(d，3H，J=6.8Hz，12-Me)，0.94(t，3H，J=7.3Hz，28-H
3)，0.86(d，3H，J=6.5Hz，26-Me)，0.83～0.77(m，4H，18-aH，24-Me).
The preparation of target compound I-Al ~ I-A5
In 50ml single necked round bottom flask, add 1.04g (1mmol) 5-O-p-nitrophenyl carbonate ester ivermectin B1a, dissolve to obtain colourless solution with 10ml DMF.Add the N of 3 ~ 10equiv. wherein with dropper, N-bis-replaces thanomin, then adds a small amount of DMAP (DMAP) catalyzed reaction, and system is yellowing immediately, stirring at room temperature.TLC follows the tracks of reaction and stops stirring after raw material disappears, and is poured by reaction solution in 50ml water, has a large amount of White Flocculus to separate out, extract with methylene dichloride (25ml × 2).Merge gained organic phase, with water (30ml × 3) washing removing DMF and part p-nitrophenol, the more saturated Na of priority 20ml
2cO
3solution and water washing eliminate p-nitrophenol, and now organic phase is colourless solution.Finally wash by saturated NaCl solution, anhydrous Na
2sO
4drying, sloughs solvent and obtains crude product.Product is obtained with after purification by silica gel column chromatography.
The preparation of target compound II-AH
In round-bottomed flask, add the target compound I-A of certain amount of substance, dissolve with CH2Cl2, more slowly drip the ether solution of hydrogen chloride through ether dilution of 1.1equiv. wherein under stirring.Stir 5min again after dropwising, then slough solvent and obtain white solid, then add appropriate anhydrous diethyl ether stirring 1h, suction filtration, a small amount of washed with diethylether of filter cake, obtains product after drying.
The nuclear magnetic data of partial target compound
Target compound I-A1
1h NMR (CDCl
3, 400MHz) and δ (ppm) 5.85 (d, 1H, J=10.3Hz, 9-H), 5.79 ~ 5.66 (m, 2H, 10-H, 11-H), 5.57 (s, 1H, 3-H), 5.42 ~ 5.30 (m, 3H, 1 "-H; 5-H, 19-H), 4.98 (d, 1H, J=10.8Hz; 15-H), 4.78 (d, 1H, J=3.3Hz, 1 '-H); 4.64 (dd, 2H, J=28.4,14.4Hz, 8 α-H
2), 4.33 ~ 4.20 [m, 2H ,-OCO
2-
cH 2 cH
2-N (CH
3)
2], 4.14 ~ 4.08 (m, 2H, 6-H, 7-OH), 3.94 (s, 1H, 13-H), 3.87 ~ 3.73 (m, 2H, 5 '-H, 5 "-H); 3.71 ~ 3.58 (m, 2H, 17-H, 3 '-H), 3.52 ~ 3.40 (m, 7H; 3 "-H, 3 '-OMe, 3 "-OMe), 3.36 (d, 1H; J=2.3Hz, 2-H), 3.27 ~ 3.13 (m, 3H, 25-H; 4 '-H, 4 "-H), 2.69 ~ 2.55 [m, 2H ,-OCO
2-CH
2 cH 2 -N (CH
3)
2], 2.55 ~ 2.44 (m, 2H, 12-H, 4 "-OH), 2.38 ~ 2.18 (m, 10H, 2 "-eH ,-N (CH
3)
2, 16-H
2, 2 '-eH), 1.98 (dd, 1H, J=11.8,4.4Hz, 20-eH), 1.82 (s, 3H, 4-Me), 1.79 ~ 1.73 (m, 1H, 18-eH), 1.69 ~ 1.32 [m, 14H, 22-H
2, 2 '-aH, 2 " and-aH, 26-H, 24-H, 14-Me, 23-H
2, 27-H
2, 20-aH], 1.31 ~ 1.23 (m, 6H, 5 "-Me, 5 '-Me), 1.16 (d, 3H, J=6.9Hz, 12-Me), 0.93 (t, 3H, J=7.3Hz, 28-H
3), 0.86 (d, 3H, J=6.7Hz, 26-Me), 0.82 ~ 0.76 (m, 4H, 18-aH, 24-Me).
Target compound I-A8
1h NMR (CDCl
3, 400MHz) and δ (ppm) 5.84 (d, 1H, J=10.6Hz, 9-H), 5.79 ~ 5.65 (m, 2H, 10-H, 11-H), 5.54 ~ 5.46 (m, 2H, 5-H, 3-H), 5.40 (d, 1H, J=3.5Hz; 1 "-H), 5.37 ~ 5.27 (m, 2H,-OCONH-, 19-H), 4.99 (d, 1H, J=10.5Hz, 15-H), 4.78 (d, 1H, J=3.4Hz, 1 '-H), 4.63 (dd, 2H, J=29.5,15.3Hz, 8 α-H
2), 4.07 (d, 1H, J=5.8Hz, 6-H), 3.98 (s, 1H, 7-OH), 3.94 (s, 1H, 13-H), 3.88 ~ 3.72 (m, 2H, 5 '-H, 5 "-H); 3.72 ~ 3.57 (m, 2H, 17-H, 3 '-H), 3.53 ~ 3.39 (m; 7H, 3 "-H, 3 '-OMe, 3 "-OMe), 3.33 (s; 1H, 2-H), 3.29 ~ 3.07 [m, 5H ,-OCONH-CH
2cH
2-N (i-Pr)
2, 25-H, 4 '-H, 4 " and-H], 2.99 [m, J=2H ,-N (
cHme
2)
2], 2.60 ~ 2.45 [m, 4H ,-OCONH-CH
2 cH 2 -N (i-Pr)
2, 12-H, 4 " and-OH], 2.38 ~ 2.18 (m, 4H, 2 "-eH, 16-H
2, 2 '-eH), 2.01 (dd, 1H, J=11.2,4.4Hz, 20-eH), 1.83 ~ 1.72 (m, 4H, 4-Me, 18-eH), 1.68 ~ 1.31 [m, 14H, 22-H
2, 2 '-aH, 2 " and-aH, 26-H, 24-H, 14-Me, 23-H
2, 27-H
2, 20-aH], 1.30 ~ 1.23 (m, 6H, 5 "-Me, 5 '-Me), 1.17 (d, 3H, J=6.9Hz, 12-Me), 1.01 ~ 0.96 [m, 12H ,-N (CH
me 2 )
2], 0.93 (t, 3H, J=7.3Hz, 28-H
3), 0.86 (d, 3H, J=6.7Hz, 26-Me), 0.82 ~ 0.76 (m, 4H, 18-aH, 24-Me).
Target compound I-B4
1h NMR (CDCl
3, 400MHz) and δ (ppm) 5.85 (d, 1H, J=9.8Hz, 9-H), 5.79 ~ 5.65 (m, 2H, 10-H, 11-H), 5.56 (s, 1H, 3-H), 5.43 ~ 5.30 (m, 3H, 1 "-H; 5-H, 19-H), 4.98 (d, 1H, J=10.5Hz; 15-H), 4.78 (d, 1H, J=3.1Hz, 1 '-H); 4.64 (dd, 2H, J=29.4,14.1Hz, 8 α-H
2), 4.22 (m, 2H ,-OCO
2-
cH 2 cH
2cH
2-NBu
2), 4.11 (d, 1H, J=6.0Hz, 6-H), 4.09 (s, 1H, 7-OH), 3.94 (s, 1H, 13-H), 3.87 ~ 3.72 (m, 2H, 5 '-H, 5 "-H), 3.71 ~ 3.57 (m; 2H, 17-H, 3 '-H), 3.53 ~ 3.40 (m; 7H, 3 "-H, 3 '-OMe, 3 "-OMe); 3.36 (d, 1H, J=2.1Hz; 2-H), 3.28 ~ 3.13 (m, 3H; 25-H, 4 '-H, 4 "-H), 2.57 ~ 2.44 (m, 4H ,-OCO
2-CH
2cH
2 cH 2 -NBu
2, 12-H, 4 " and-OH), 2.42 ~ 2.18 [m, 8H ,-N (
cH 2 cH
2cH
2cH
3)
2, 2 " and-eH, 16-H
2, 2 '-eH], 1.98 (dd, 1H, J=11.8,4.3Hz, 20-eH), 1.87 ~ 1.72 (m, 6H, 4-Me ,-OCO
2-CH
2 cH 2 cH
2-NBu
2, 18-eH), 1.69 ~ 1.22 [m, 28H, 22-H
2, 2 '-aH, 2 " and-aH, 26-H, 24-H, 14-Me, 23-H
2,-N (CH
2 cH 2 cH 2 cH
3)
2, 27-H
2, 20-aH, 5 " and-Me, 5 '-Me], 1.16 (d, 3H, J=6.9Hz, 12-Me), 0.98 ~ 0.75 [m, 16H, 28-H
3,-N (CH
2cH
2cH
2 cH 3 )
2, 26-Me, 18-aH, 24-Me].
Table 1: the compounds of this invention of part as shown in general formula I
Table 2: the compounds of this invention of part as shown in general formula I I
Raw survey example
Part of compounds is to carmine spider mite biological activity determination
Be selected to mite or young mite, adopt pickling process.When the bean seedlings that are for experiment grow to two panels true leaf, selection growing way is relatively more neat, the about 4 ~ 5cm of leaf area
2, plant height connects worm the plant of 10 cm, every strain worm amount is no less than 60, and general control is at about 60 ~ 100.Connect worm and carry out chemicals treatment after 24 hours.To cut from basal part of stem for examination plant, in be with the liquid tested by being immersed by blade together with seedling with worm, soak medicine time controling in 5 seconds.Plant shakes gently, removes unnecessary liquid after taking out from liquid, then moves in water planting cylinder.Plant after process is placed in 25 DEG C of thermostatic chambers.After 96 hours, borer population is anyway checked under paired eyepiece to movable mite process, calculates mortality ratio.Repeat twice again, average.
Selection to mite ovum: with fine, soft fur pen by become female mite be seeded in there is two panels true leaf kidney bean seedling blade on, every strain connect 20 become mites, be placed in 25 DEG C of thermostatic chambers.Mite is removed into after laying eggs 24 hours.Under similarity condition, continue placement can carry out chemicals treatment after 24 hours; If the selection to children mite: first will obtain spawning time consistent ovum, before egg hatching, (the 5th day after laying eggs under 25 DEG C of conditions) has taken off ovum blade, be cut into small pieces be placed on tool two panels true leaf blade above, in greenhouse under sun exposure, the young mite newly hatched afterwards for a day can be transferred on young leaves.Experimental technique is with becoming mite.
Table 3, table 4 are for part test compound of the present invention is to the prevention effect becoming mite, young mite and mite ovum.
Table 3 part the compounds of this invention is to the activity data becoming mite and mite ovum
Table 4 part the compounds of this invention is to the activity data of young mite
Partial target compound is to small cabbage moth biological activity test
Adopt the leaf dipping method that international resistance Action Committee (IRAC) proposes.First will be mixed with the liquid to be measured of desired concn for reagent product, then with straight peen ophthalmology tweezers dipping cabbage leaves, after 3 ~ 5 seconds, get rid of remaining liquid.Each 1, totally 3, each sample.Be successively placed in treatment paper by sample flag sequence.After liquid solvent (water) evaporation completely, blade is put into the straight type pipe that the markd 10cm of tool is long, then access 2 age diamondback moth larvae 30, build the mouth of pipe with gauze.Test process is placed in standard treatment chamber, check result after 96h.Touch polypide with pulling needle, motionless person is dead, calculates mortality ratio.Repeat twice again, average.
Table 5 is for part test compound of the present invention is to the prevention effect of small cabbage moth.
Table 5 part the compounds of this invention is to the activity data of small cabbage moth
Selected part compound, compares with IVM B1a, has carried out the parallel comparison test of preventing and kill off small cabbage moth, the results are shown in Table 6.
Table 6 part the compounds of this invention and IVM B1a are to the insecticidal activity of small cabbage moth
Choose part of compounds I-A1 of the present invention, I-A2 and carry out field Cnaphalocrocis medinali(rice leaf roller) and striped rice borer controlling experiment.
Test method: certain density test compounds carries out foliar spray process Cnaphalocrocis medinali(rice leaf roller) and striped rice borer hatching peak phase, spouting liquid is per hectare 450 liters.Paddy rice plot area is 32 square metres, repeats for 3 times.7 days " Invest, Then Investigate " survival borer populations, calculate mortality ratio.Under result is presented at every mu of 0.6 gram of effective ingredient, after medicine 7 days, their preventive effect was more than 70%.
Toxotest embodiment
Choose the compounds of this invention I-A1 and carry out the test of rat acute Oral toxicity
Method: undertaken by horn method.Select healthy white rat 90, male and female are respectively divided into 9 groups, often organize 5.Take required test sample and add a little tween-80 according to often organizing dosage and be ground and add distilled water to be made into desired concn for subsequent use.Animal fasting is a gastric infusion after 12 hours, and gavage volume is pressed 1ml/100 gram of body weight and calculated, poisoning dosage is 4.64,10.00,21.50,46.40,100.00,215.00,464.00,1000.00,2150.00mg/kg.Continuous Observation 7 days after animal contaminated, observes therebetween and records animal toxicity symptom and death condition, finally obtaining medium lethal dose (LD according to animal dead quantity
50).
Result: the compounds of this invention I-A1 rat acute per os LD
50buck is 501mg/kg, and 95% is crediblely limited to 344 ~ 730mg/kg.According to the criteria for classification of China's toxicity of pesticide, the compounds of this invention I-A1 belongs to low toxicity toxicity.
Claims (10)
1. a compound for macrolide derivatives and salt thereof, is characterized in that as shown in general formula (I, II):
Wherein:
n=1～7；
X represents N or O;
Y represents Cl
-, Br
-, F
-, I
-, AcO
-, acetylsalicylate, citrate, salicylate, tosic acid root, bisulfate ion, or other negative ions;
Z represents N or O;
R
1represent the alkyl of 1 ~ 6 carbon atom, the alkoxyl group of 1 ~ 6 carbon atom, the thiazolinyl of 1 ~ 6 carbon atom or aryl; R
2represent the alkyl of 1 ~ 6 carbon atom, the alkoxyl group of 1 ~ 6 carbon atom, the thiazolinyl of 1 ~ 6 carbon atom or aryl; Or ZR
1r
2be selected from following structure:
2. compound as claimed in claim 1, is characterized in that, in general formula (I, II):
N=1 ~ 4; X represents N or O; Y represents Cl
-, Br
-, F
-, I
-, AcO
-, acetylsalicylate, citrate, salicylate, tosic acid root, bisulfate ion, or other negative ions, Z represents N or O, R
1, R
2be selected from H, C
1-C
4alkyl, or ZR
1r
2be selected from following structure:
3. compound as claimed in claim 1, is characterized in that: in general formula (I, II):
N=1,2; X represents N or O; Y represents Cl
-, Z represents N or O, R
1, R
2be selected from H, C
1-C
4alkyl, or ZR
1r
2be selected from following structure:
4. compound according to claim 1 is used for the insecticidal/acaricidal agent in agricultural.
5. compound according to claim 1 is for the preparation of the parasitic pesticide control of livestock.
6. compound according to claim 1 kills Uronema medicament for the preparation of human body is medical.
7. an insecticide acaricide composition, is characterized in that containing compound according to claim 1 as active ingredient and agriculturally acceptable carrier.
8. insecticide acaricide composition as claimed in claim 7, is characterized in that the weight percentage of active ingredient in composition is 1-99%.
9. the preparation method of compound described in claim 1, is characterized in that comprising following step:
1) ivermectin B1a and p-nitrophenyl chloroformate ester are dissolved in organic solvent, with organic bases pyridine, triethylamine or Tetramethyl Ethylene Diamine for catalyzer, temperature is react 1-24 hour obtained intermediate 1 under 0 DEG C to room temperature condition;
2) by the intermediate 1 that obtains and intermediate 2, in organic solvent, temperature is react 1-24 hour obtained product (I) under 0 DEG C to boiling point;
3) be dissolved in organic solvent by product (I), add diluted acid, temperature is react 1-24 hour obtained product (II) under 0 DEG C to boiling point.
10. method as claimed in claim 9, is characterized in that described organic solvent is dioxane, benzene, toluene, ethyl acetate, THF, normal hexane, tetracol phenixin, chloroform or methylene dichloride.
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| CN109516996A (en) * | 2018-11-26 | 2019-03-26 | 山东农业大学 | A kind of derivative of macrolides, its synthesis and application |
| CN109705181A (en) * | 2019-01-24 | 2019-05-03 | 南开大学 | A kind of preparation method of derivative of macrolides |
| CN109824745A (en) * | 2019-01-24 | 2019-05-31 | 南开大学 | A kind of synthesis and application of ivermectin derivative |
| CN109851648A (en) * | 2019-01-11 | 2019-06-07 | 南开大学 | A kind of synthesis and application of derivative of macrolides |
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| CN109516996A (en) * | 2018-11-26 | 2019-03-26 | 山东农业大学 | A kind of derivative of macrolides, its synthesis and application |
| CN109516996B (en) * | 2018-11-26 | 2021-12-17 | 山东农业大学 | Macrolide derivative, synthesis and application thereof |
| CN109851648A (en) * | 2019-01-11 | 2019-06-07 | 南开大学 | A kind of synthesis and application of derivative of macrolides |
| CN109705181A (en) * | 2019-01-24 | 2019-05-03 | 南开大学 | A kind of preparation method of derivative of macrolides |
| CN109824745A (en) * | 2019-01-24 | 2019-05-31 | 南开大学 | A kind of synthesis and application of ivermectin derivative |
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| CN104231022B (en) | 2018-10-09 |
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