CN107266511B - The compound and the preparation method and application thereof of a kind of novel 5- oxime ester B2a structure - Google Patents
The compound and the preparation method and application thereof of a kind of novel 5- oxime ester B2a structure Download PDFInfo
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Abstract
The present invention provides compound of a kind of novel 5- oxime ester B2a structure and preparation method thereof and the application as desinsection, mite killing, nematicide.The structural formula of the compound is as shown in formula I, Formula II or formula III.The present invention has carried out structure optimization to the by-product B2a in avermectin production process, and design has synthesized a series of completely new 5- oxime ester B2a series compound of structures, and has carried out extensive insecticidal activity assay to such compound, finds the good compound of drug effect.Reaction route is simple, and product has good insecticidal activity.The bioactivity rate of most compounds is more than comparison medicament avermectin, and bioactivity significantly improves, therefore compound of the present invention is worth with very high pesticide research.
Description
Technical field
The present invention relates to compound of a kind of novel 5- oxime ester B2a structure and preparation method thereof with as desinsection, mite killing,
The application of nematicide.
Background technique
Avermectin is hexa-atomic by streptomyces griseus (Streptomyces avermitilis) fermentation obtain one group ten
Macrolides compound, 8 homologues similar in structure form (A1a, A1b, A2a, A2b, B1a, B1b, B2a, B2b).
Avermectin has good desinsection, mite killing and Antiparasitic Activity, and to mammalian safe, the mechanism of action is excitation nerve
Non- tip release γ-aminobutyric acid (GA-BA) and regulation glutamic acid gate chloride channel, the chloride channel for promoting GABA to gate
Open with glutamic acid gate chloride channel, a large amount of chloride ions, which pour in, causes neural membrane potentials hyperpolarization, and neu is caused to be in
Holddown keeps insect paralysis dead.
China is avermectin big producer, and in fermentation process, B1 (B1a+B1b) and B2 (B2a+B2b) are two most main
The product wanted.Due to preventing and treating target to the overwhelming majority, the activity of B1 is significantly larger than the activity of B2, is commercialized in the market for a long time
The former medicine of AVM refers in particular to B1 (B1a >=96%, B1b≤4%) structure.And avermectin production in account for total amount one third with
On B2 (B2a >=95%, B2b≤5%) because its application value it is not high, the long-term auxiliary material as B1 is at home with the shape of " ointment "
Formula is introduced to the market, and the pollution to environment and the serious waste of resource are caused.As the Ministry of Agriculture, China is to the disabling of ointment, B2 is found
Application value in agricultural disease, reducing the wasting of resources becomes the important topic that China's pesticide industry faces.China main Ah
One of rhzomorph fermentation enterprise is tieed up, Shijiazhuang Xingbai Biological Engineering Co., Ltd. finds B2a to the activity of corn food root (first) worm
It is 3 times of B1a, to open application (number of patent application 201210547804.4) of the B2 in prevention and treatment subterranean pest-insect.
Derivative optimization based on Structures of Natural Products is one of the important channel of New pesticides discovery, on the basis of AVERMECTIN B1
It is then its successful illustration that the emamectin benzoate that sugar-ring modification obtains, which improves 1000 times to beet armyworm insecticidal activity ratio B1,.And the knot of B2
Structure derives at home and abroad still blank, and due to the limited efficacy of B2, content specific gravity is high in tunning, and it is excellent to carry out structure to it
Change, there is high researching value.
Summary of the invention
An object of the present invention is to provide series compound CAU-AVM and its preparation side of a kind of 5- oxime ester B2a structure
Method.
The structural formula of compound CAU-AVM provided by the present invention is as shown in formula I, Formula II or formula III:
In above-mentioned formula I and Formula II, R1, R2It can be independently selected from phenyl, phenethyl, 2- fluorophenyl, 2- chlorphenyl, 2- bromobenzene
Base, 2- trifluoromethyl, 3- aminomethyl phenyl, 4- methoxyphenyl, 4- chlorphenyl, 4- nitrobenzophenone, 2,4- dichlorophenyl, 3-
The chloro- phenyl of trifluoromethyl -4-, 3- pyridyl group, 2- chloro-3-pyridyl base, 1- (4- chlorphenyl) -2- methyI-oropvD, 3- (the chloro- 2- of 2-
Trifluoromethyl vinyl) in -2,2- dimethylcyclopropane base and 3- (2,2- dimethyl ethenyl) -2,2- dimethylcyclopropane base
One kind；
In above-mentioned formula III, R3It can be selected from phenyl, phenethyl, 2- fluorophenyl, 2- chlorphenyl, 2- bromophenyl, 3- methylbenzene
Base, 4- chlorphenyl, 4- nitrobenzophenone, 2,4- dichlorophenyl, the chloro- phenyl of 3- trifluoromethyl -4-, 3- pyridyl group and the chloro- 3- pyrrole of 2-
One of piperidinyl.
The pharmaceutically acceptable salt of above compound CAU-AVM also belongs to protection scope of the present invention.
Above-mentioned I compound represented CAU-AVM of formula is prepared by the method comprising the following steps:
1) B2a (compound shown in formula IV) and AllocCl are first subjected to esterification, after completion of the reaction, purifying, then
In above-mentioned Formula V, Alloc indicates allyloxycarbonyl, and TBDMS indicates t-butyldimethylsilyi；
2) make compound shown in Formula V that the reaction of removing allyloxycarbonyl protecting group occur, obtain compound shown in Formula IV；
3) making compound elder generation shown in Formula IV and PhosphorodichloridicAcid Acid Phenyl Ester, DMSO, tetramethylethylenediamine reacts to obtain 23,
4 "-two-O-TBDMS-5-O avermectin B2a, reacts again with hydrogen fluoride pyridine solution after post-processing, obtains Formula VII
Shown compound；
4) it reacts compound shown in Formula VII with hydroxylamine hydrochloride, obtains compound shown in Formula VIII；
5) make compound and R shown in Formula VIII1Condensation reaction occurs for COOH carboxylic acid, obtains compound shown in Formulas I,
R1In COOH, R1It can be selected from phenyl, phenethyl, 2- fluorophenyl, 2- chlorphenyl, 2- bromophenyl, 2- trifluoromethylbenzene
Base, 3- aminomethyl phenyl, 4- methoxyphenyl, 4- chlorphenyl, 4- nitrobenzophenone, 2,4- dichlorophenyl, 3- trifluoromethyl -4- are chloro-
Phenyl, 3- pyridyl group, 2- chloro-3-pyridyl base, 1- (4- chlorphenyl) -2- methyI-oropvD, 3- (the chloro- 2- trifluoromethyl ethylene of 2-
Base) one of -2,2- dimethylcyclopropane base and 3- (2,2- dimethyl ethenyl) -2,2- dimethylcyclopropane base.
In above method step 1), the molar ratio of B2a and AllocCl, TBDMSCl successively can be 1:1-1.5, and 4-6 is specific
It can be 1:1.2:5；
The temperature of the esterification is -20--30 DEG C, concretely -25 DEG C；
The esterification carries out in a nitrogen atmosphere；
The time of the esterification is 0.5-1h, concretely 0.6h.
The temperature reacted with TBDMSCl can be 0--10 DEG C, and concretely -5 DEG C, the time can be 40-60h, concretely
48h。
In above method step 2), mixing of the reaction for removing allyloxycarbonyl protecting group in MeOH/THF=1:1
It is carried out in solvent.
The reaction of the removing allyloxycarbonyl protecting group is under the effect of tetrakis triphenylphosphine palladium, sodium borohydride and ammonium acetate
It carries out.
The molar ratio of compound shown in Formula V and tetrakis triphenylphosphine palladium, sodium borohydride and ammonium acetate successively may be used are as follows: 1:
0.02-0.08:0.4-0.6:18-25, concretely 1:0.04:0.52:20.
The temperature of the reaction of the removing allyloxycarbonyl protecting group can be -5-5 DEG C, and concretely 0 DEG C, the time can be
0.1-0.3h, concretely 0.2h.
In above method step 3), compound shown in the Formula IV and PhosphorodichloridicAcid Acid Phenyl Ester, DMSO, tetramethylethylenediamine
Molar ratio successively may be used are as follows: 1:1-2:3-6:4-7, concretely 1:1.5:4:4.9.
The reaction carries out in organic solvent, the organic solvent concretely methylene chloride.
The reaction carries out under ice bath.
In above method step 4), the molar ratio of compound and hydroxylamine hydrochloride shown in Formula VII can be 1:4-7, concretely
1:5.
The reaction carries out in the mixed solution of methanol and 1,4- dioxane.
The temperature of the reaction can be 20-30 DEG C, and the time can be 5-8h, concretely 6h.
In above method step 5), the condensation reaction carries out in the presence of DCC, DAMP.
The molar ratio of compound shown in Formula VIII and carboxylic acid, DCC, DAMP successively can be 1:1-2:1-2:0.01-0.10.
The reaction temperature of the condensation reaction can be 20-30 DEG C, and the time can be 36-60h, concretely 48h.
The condensation reaction carries out in organic solvent, the organic solvent concretely methylene chloride.
Above-mentioned Formula II compound represented CAU-AVM is prepared by the method comprising the following steps:
1) compound shown in Formula VII is dissolved in 3% (sulfuric acid: methanol volume ratio=97:3) methanolic solution, is reacted,
Obtain compound shown in Formula IX；
2) it reacts compound shown in Formula IX with hydroxylamine hydrochloride, obtains compound shown in Formula X；
3) make compound and R shown in Formula X2Condensation reaction occurs for COOH carboxylic acid, obtains compound shown in Formula II；
R2In COOH, R2It can be selected from phenyl, phenethyl, 2- fluorophenyl, 2- chlorphenyl, 2- bromophenyl, 2- trifluoromethylbenzene
Base, 3- aminomethyl phenyl, 4- methoxyphenyl, 4- chlorphenyl, 4- nitrobenzophenone, 2,4- dichlorophenyl, 3- trifluoromethyl -4- are chloro-
Phenyl, 3- pyridyl group, 2- chloro-3-pyridyl base, 1- (4- chlorphenyl) -2- methyI-oropvD, 3- (the chloro- 2- trifluoromethyl ethylene of 2-
Base) one of -2,2- dimethylcyclopropane base and 3- (2,2- dimethyl ethenyl) -2,2- dimethylcyclopropane base.
In above method step 1), the temperature of the reaction can be -10-0 DEG C, concretely -5 DEG C.
The time of the reaction can be 20-42h, concretely for 24 hours.
In above method step 2), the reaction carries out in methanol and Isosorbide-5-Nitrae-dioxane mixed solution.
The molar ratio of compound and hydroxylamine hydrochloride shown in Formula IX can be 1:4-6, concretely 1:5.
The temperature of the reaction can be 20-30 DEG C, and the time can be 5-7h, concretely 6h.
In above method step 3), the condensation reaction carries out in the presence of DCC, DAMP.
The molar ratio of compound shown in Formula X and carboxylic acid, DCC, DAMP successively can be 1:1-1.8:1-1.8:0.01-0.1.
The reaction temperature of the condensation reaction can be 20-30 DEG C, and the time can be 20-30h, concretely for 24 hours.
The condensation reaction carries out in organic solvent, the organic solvent concretely methylene chloride.
Above-mentioned formula III compound represented CAU-AVM is prepared by the method comprising the following steps:
1) compound shown in Formula VII is dissolved in 5% (sulfuric acid: methanol volume ratio=95:5) methanolic solution, is reacted,
Obtain compound shown in Formula IX；
2) it reacts compound shown in Formula XI with hydroxylamine hydrochloride, obtains compound shown in Formula XII；
3) make compound and R shown in Formula XII3Condensation reaction occurs for COOH carboxylic acid, obtains compound shown in formula III；
R3In COOH, R3It can be selected from phenyl, phenethyl, 2- fluorophenyl, 2- chlorphenyl, 2- bromophenyl, 3- aminomethyl phenyl, 4-
In chlorphenyl, 4- nitrobenzophenone, 2,4- dichlorophenyl, the chloro- phenyl of 3- trifluoromethyl -4-, 3- pyridyl group and 2- chloro-3-pyridyl base
One kind.
In above method step 1), the temperature of the reaction can be -10-0 DEG C, concretely -5 DEG C.
The time of the reaction can be 10-15h, concretely 12h.
In above method step 2), the reaction carries out in methanol and Isosorbide-5-Nitrae-dioxane mixed solution.
The molar ratio of compound and hydroxylamine hydrochloride shown in Formula IX can be 1:4-6, concretely 1:5.
The temperature of the reaction can be 20-30 DEG C, and the time can be 5-8h, concretely 5h.
In above method step 3), the condensation reaction carries out in the presence of DCC, DAMP.
The molar ratio of compound shown in Formula XII and carboxylic acid, DCC, DAMP successively can be 1:1-1.5:1-1.5:0.01-0.1.
The reaction temperature of the condensation reaction can be 20-30 DEG C, and the time can be 15-25h, concretely 18h.
The condensation reaction carries out in organic solvent, the organic solvent concretely methylene chloride.
It is a further object of the present invention to provide the purposes of above-mentioned 5- oxime ester B2a structural series compound CAU-AVM.
The purposes of the 5- oxime ester B2a structural series compound CAU-AVM is 5- oxime ester B2a structural series compound CAU-
Application of the AVM in prevention and treatment agricultural and animal husbandry pest and disease damage.
The pest and disease damage concretely red spider, beet armyworm, caenorhabditis elegan, Bursaphelenchus xylophilus, Meloidogyne incognita and dish
Pest and disease damage caused by bean aphid.
Preferably, active constituent or auxiliary agent of the 5- oxime ester B2a structural series compound CAU-AVM as pesticide.
The present invention also provides a kind of pesticide or veterinary drugs, and it includes in above-mentioned 5- oxime ester B2a structural series compound CAU-AVM
It is one or more.
The present invention has carried out structure optimization to the by-product B2a in avermectin production process, and design has synthesized a series of
The completely new 5- oxime ester B2a series compound of structure, and extensive insecticidal activity assay has been carried out to such compound, find drug effect
Good compound.
Raw material needed for prepare compound CAU-AVM of the present invention is the by-product B2a in avermectin production process, reacts road
Line is simple, and product has good insecticidal activity.The bioactivity rate of most compounds is more than comparison medicament avermectin, raw
Object activity significantly improves, therefore compound of the present invention is worth with very high pesticide research.
Detailed description of the invention
Fig. 1 is the synthetic route chart of compound CAU-AVM-01 in the embodiment of the present invention 1.
Fig. 2 is the synthetic route chart of compound CAU-AVM-18 in the embodiment of the present invention 2.
Fig. 3 is the synthetic route chart of compound CAU-AVM-35 in the embodiment of the present invention 3.
Fig. 4 is the hydrogen nuclear magnetic resonance spectrogram of formula CAU-AVM-01 compound represented prepared by the embodiment of the present invention 1.
Fig. 5 is the carbon-13 nmr spectra figure of formula CAU-AVM-01 compound represented prepared by the embodiment of the present invention 1.
Fig. 6 is the hydrogen nuclear magnetic resonance spectrogram of formula CAU-AVM-18 compound represented prepared by the embodiment of the present invention 2
Fig. 7 is the carbon-13 nmr spectra figure of formula CAU-AVM-18 compound represented prepared by the embodiment of the present invention 2.
Fig. 8 is the hydrogen nuclear magnetic resonance spectrogram of formula CAU-AVM-35 compound represented prepared by the embodiment of the present invention 3.
Fig. 9 is the carbon-13 nmr spectra figure of formula CAU-AVM-35 compound represented prepared by the embodiment of the present invention 3.
Specific embodiment
The present invention will be described below by way of specific embodiments, but the present invention is not limited thereto.
Experimental method used in following embodiments is conventional method unless otherwise specified；Institute in following embodiments
Reagent, material etc., are commercially available unless otherwise specified.
Embodiment 1, the preparation of compound CAU-AVM-01 (R=phenyl in formula I) and Structural Identification
Synthetic route chart according to figure 1 synthesizes compound CAU-AVM-01.
(1) B2a (6g, 6.7mmol) is added in the round-bottomed flask of 250ml, anhydrous methylene chloride 45ml dissolution is rear to be added
Triethylamine (1.0g, 10mmol), at -25 DEG C and under the conditions of nitrogen protection, be slowly added dropwise allyl chlorocarbonate (0.97g,
8mmol), the reaction was continued after dripping off 40min, TLC monitor fully reacting, 1ml methanol are added to be quenched, and methylene chloride extraction is successively used
1N hydrochloric acid, saturated sodium chloride solution, water washing organic phase, steaming vibrating dichloromethane after anhydrous sodium sulfate is dry, column chromatographic purifying obtain
To faint yellow solid 5-O-Alloc avermectin B2a 6.1g, yield 93%.By 5-O-Alloc avermectin B2a
(6.0g, 6.2mmol) is dissolved in 40ml DMF, is added triethylamine (4.4g, 43mmol), reaction flask is placed in -5 DEG C of low temperature cryostats
It in slot, after 5min, is added TBDMSCl (5.6g, 37mmol), adds catalytic amount DMAP, after reacting 48h, TLC detection has been reacted
Entirely, it is diluted, is washed with ethyl acetate, aqueous layer with ethyl acetate extracts twice, merges organic phase, successively uses saturated salt solution, water
It washes, anhydrous sodium sulfate dries, filters, and concentration rear pillar chromatographs to obtain 23,4 "-two-O-TBDMS-5-O-Alloc of faint yellow solid
Avermectin B2a 6.8g, yield 91%.
(2) taking 23,4, "-two-O-TBDMS-5-O-Alloc avermectin B2a (6.0g, 5.0mmol), are dissolved in 30ml
In MeOH:THF=1:1 mixed liquor, it is added ammonium acetate (7.7g, 100mmol), reaction flask is placed in ice salt bath, after 10min,
Be added sodium borohydride (0.045g, 1.3mmol), after sequentially add tetra-triphenylphosphine palladium (0.23g, 0.20mmol), boron hydrogen immediately
Change sodium (0.045g, 1.3mmol), after 10min, TLC detects fully reacting, concentration, methylene chloride dilution, washing, and water layer is with two
Chloromethanes extracts twice, merges organic phase, successively uses saturated salt solution, washing, and anhydrous sodium sulfate dries, filters, and rear pillar is concentrated
Chromatograph to obtain faint yellow solid 23,4 "-two-O-TBDMS avermectin B2a 5.3g, yield 95%.
(3) taking 23,4, "-two-O-TBDMS avermectin B2a (5g, 4.5mmol), are dissolved in 30ml DCM, are added
30ml bis- is added dropwise under the conditions of ice bath and nitrogen protection in tetramethylethylenediamine (2.6g, 22mmol), DMSO (1.4g, 18mmol)
Chlorination phenyl phosphate (1.4g, 6.8mmol) dichloromethane solution, TLC detects fully reacting, methylene chloride dilution, water after 1 hour
It washes, water layer is extracted with dichloromethane twice, merges organic phase, successively uses dilute hydrochloric acid, saturated salt solution, washing, anhydrous sodium sulfate
Drying, filtering, 23,4 are obtained after concentration, "-two-O-TBDMS-5-O avermectin B2a, are dissolved in 30ml THF without further purification
It in 15ml pyridine, is placed in ice bath, 5ml70% hydrogen fluoride pyridine solution, rear room temperature reaction about 4 days, TLC detection reaction is added dropwise
Completely, it is concentrated, methylene chloride dilution, washing, water layer is extracted with dichloromethane twice, merges organic phase, successively uses dilute hydrochloric acid, satisfies
And saline solution, washing, anhydrous sodium sulfate dry, filter, concentration rear pillar chromatographs to obtain faint yellow solid 5-O avermectin B2a
2.3g, yield 66%.
(4) 5-O avermectin B2a (2.0g, 2.3mmol) is taken to be dissolved in 10ml MeOH and 10ml Isosorbide-5-Nitrae-dioxane
In solution；Hydroxylamine hydrochloride (0.94g, 13mmol) is dissolved in 8ml water, after be added dropwise into reaction system, TLC detection reaction
Completely, it is concentrated, methylene chloride dilution, washing, water layer is extracted with dichloromethane twice, merges organic phase, successively uses dilute hydrochloric acid, satisfies
And saline solution, washing, anhydrous sodium sulfate dry, filter, concentration rear pillar chromatography recrystallizes to obtain white solid 5-NOH
Avermectin B2a 1.9g, yield 91%.
(5) it takes benzoic acid (0.2g, 1.7mmol) to be dissolved in 20ml DCM, sequentially adds DCC (0.34g, 1.7mmol), 5-
NOH avermectin B2a (1.0g, 1.1mmol), for 24 hours, TLC detects fully reacting, methylene chloride dilution, water for room temperature reaction
It washes, water layer is extracted with dichloromethane twice, merges organic phase, successively uses dilute hydrochloric acid, saturated salt solution, washing, anhydrous sodium sulfate
It dries, filters, concentration rear pillar chromatography recrystallizes to obtain white solid 5- cupron ester avermectin B2a 0.8g, yield
73%
Structural identification data:
1HNMR(CDCl3, 300MHz) and δ: 8.02~8.19 (m, 2H, Ar-H), 7.56~7.69 (m, 1H, Ar-H), 7.41
~7.54 (m, 2H, Ar-H), 6.08~6.17 (m, 1H, H3), 5.92~6.06 (m, 1H, H9), 5.70~5.89 (m, 2H,
H10, H11), 5.22~5.51 (m, 2H, H15, H19), 5.01 (t, J=7.2Hz, 1H, H1 "), 4.71~4.91 (m, 4H,
H1 ', H8ax2, H6), 3.99 (s, 1H, 7-OH), 3.72~3.93 (m, 4H, H23, H13, H5 ", H5 '), 3.41~3.71 (m,
11H,H2,H25,H17,H3″,H3′,3″-OCH3,3′-OCH3), 3.28 (t, J=9.0Hz, 1H, H4 '), 3.19 (t, 1H, J=
9.1Hz, H4 "), 2.50~2.65 (m, 1H, H12), 1.92~2.46 (m, 10H, H24, H18, H16x2, H2 ', H2 ", Me4a,
), H20 1.43~1.85 (m, 11H, Me14a, H20, H26, H27x2, H22x2, H2 ', H2 "), 1.25~1.39 (m, 6H,
Me6 ', Me6 "), 1.21 (d, J=6.9Hz, 3H, Me12a), 0.77~1.07 (m, 10H, H28, Me24a, Me26a, H18) (see
Fig. 4)
13C NMR(75MHz,CD3DH)δ:172.37,163.06,157.35,138.75,137.57,135.60,
133.35,131.84,129.77,129.71,128.68,128.47,124.64,121.89,117.52,99.57,98.42,
94.79,81.60,80.33,79.22,79.04,78.11,77.20,75.96,74.35,70.77,69.75,68.97,
68.26,68.08,67.95,67.21,56.37,56.29,46.36,41.83,41.08,40.69,39.86,36.31,
35.62,35.04,34.39,34.16,34.00,27.19,26.89,24.87,20.03,18.29,17.59,17.51,
15.08,13.67,12.33,11.72. (see Fig. 5)
HRMS(ESI)calcd for C55H78NO16(M+H)+1008.5321,found 1008.5315.
Embodiment 2, the preparation of compound CAU-AVM-18 (R=phenyl in Formula II) and Structural Identification
Synthetic route chart according to Fig.2, synthesizes compound CAU-AVM-18.
(1) 5-O avermectin B2a (4g, 3.6mmol) is taken to be dissolved in 3% methanolic solution, -5 DEG C are reacted for 24 hours,
The neutrality of triethylamine neutralization, concentration, methylene chloride extraction, anhydrous sodium sulfate dry, filter, and concentration rear pillar chromatographs to obtain pale yellow colored solid
Body 5-O avermectin B2a monosaccharide 2.3g, yield 85%.
(2) take 5-O avermectin B2a monosaccharide (1.7g, 2.3mmol) be dissolved in 10ml MeOH and
In 10ml 1,4- dioxane solution；Hydroxylamine hydrochloride (0.94g, 13mmol) is dissolved in 8ml water, after be added dropwise into reaction
In system, TLC detects fully reacting, concentration, and methylene chloride dilution is washed, and water layer is extracted with dichloromethane twice, merges organic
Phase successively uses dilute hydrochloric acid, and saturated salt solution is washed, and anhydrous sodium sulfate dries, filters, and concentration rear pillar chromatography recrystallizes white
Solid 5-NOH avermectin B2a monosaccharide 1.6g, yield 90%.
(3) it takes benzoic acid (0.2g, 1.7mmol) to be dissolved in 20ml DCM, sequentially adds DCC (0.34g, 1.7mmol), 5-
NOH avermectin B2a monosaccharide (0.8g, 1.1mmol), for 24 hours, TLC detects fully reacting for room temperature reaction,
Methylene chloride dilution, washing, water layer is extracted with dichloromethane twice, merges organic phase, successively uses dilute hydrochloric acid, saturated salt solution,
Washing, anhydrous sodium sulfate dry, filter, and concentration rear pillar chromatography recrystallizes to obtain white solid 5- cupron ester avermectin
B2a monosaccharide 0.78g, yield 82%
Structural identification data:
1HNMR(CDCl3, 300MHz) and δ: 8.03~8.15 (m, 2H, Ar-H), 7.54-7.66 (m, 1H, Ar-H), 7.41~
7.52 (m, 2H, Ar-H), 6.05~6.10 (m, 1H, H3), 5.93~6.03 (m, 1H, H9), 5.72~5.85 (m, 2H, H10,
), H11 5.3 2~5.49 (m, 1H, H19), 4.98 (t, J=6.7Hz, 1H, H15), 4.68~4.89 (m, 4H, H1 ', H8ax2,
), H6 3.98 (s, 1H, 7-OH), 3.71~3.92 (m, 4H, 23-OH, H23, H13, H5 '), 3.43~3.63 (m, 7H, H17,
H25,H2,H3′,3′-OCH3), 3.17 (t, 1H, J=9.2Hz, H4 '), 2.51~2.58 (m, 2H, H12, H24), 2.2 2~
2.40 (m, 3H, H16x2, H2 '), 2.15 (s, 3H, Me4a), 1.93~2.07 (m, 2H, H18, H20), 1.43~1.78 (m,
10H, Me14a, H20, H2 ', H26, H27x2, H22x2), 1.28 (d, J=6.2Hz, 3H, Me6 '), 1.17 (d, J=6.9Hz,
3H, Me12a), 0.83~1.02 (m, 10H, H28, Me 24a, Me26a, H18) (see Fig. 6)
13C NMR(75MHz,CD3DH)δ:172.20,163.02,157.34,138.68,137.50,135.51,
133.32,131.70,129.88,129.66,128.63,128.44,124.60,121.92,117.48,99.54,94.91,
81.47,79.02,78.18,75.89,74.35,70.69,69.73,68.90,68.24,68.08,67.87,56.43,
46.32,41.01,40.67,39.82,36.25,35.56,35.00,33.95,33.85,27.14,20.00,17.59,
17.48,15.04,13.64,12.29,11.69. (see Fig. 7)
HRMS(ESI)calcd for C48H66NO13(M+H)+864.4534,found 864.4528.
Embodiment 3, the preparation of compound CAU-AVM-35 (R=phenyl in formula III) and Structural Identification
Synthetic route chart according to Fig.3, synthesizes compound CAU-AVM-35.
(1) 5-O avermectin B2a (4g, 3.6mmol) is taken to be dissolved in 5% methanolic solution, -5 DEG C are reacted for 24 hours,
The neutrality of triethylamine neutralization, concentration, methylene chloride extraction, anhydrous sodium sulfate dry, filter, and concentration rear pillar chromatographs to obtain pale yellow colored solid
Body 5-O avermectin B2a aglycone 2.0g, yield 93%.
(2) 5-O avermectin B2a aglycone (1.4g, 2.3mmol) is taken to be dissolved in 10ml MeOH and 10ml 1,
In 4- dioxane solution；Hydroxylamine hydrochloride (0.94g, 13mmol) is dissolved in 8ml water, after be added dropwise into reaction system,
TLC detects fully reacting, concentration, and methylene chloride dilution is washed, and water layer is extracted with dichloromethane twice, merges organic phase, successively
With dilute hydrochloric acid, saturated salt solution is washed, and anhydrous sodium sulfate dries, filters, and concentration rear pillar chromatography recrystallizes to obtain white solid 5-
NOH avermectin B2a aglycone 1.2g, yield 86%.
(3) it takes benzoic acid (0.2g, 1.7mmol) to be dissolved in 20ml DCM, sequentially adds DCC (0.34g, 1.7mmol), 5-
NOH avermectin B2a aglycone (0.7g, 1.1mmol), for 24 hours, TLC detects fully reacting, dichloromethane for room temperature reaction
Alkane dilution, washing, water layer are extracted with dichloromethane twice, merge organic phase, successively use dilute hydrochloric acid, saturated salt solution, washing, nothing
Aqueous sodium persulfate dries, filters, and concentration rear pillar chromatography recrystallizes to obtain white solid 5- cupron ester avermectin B2a
Aglycone 0.7g, yield 91%
Structural identification data:
1HNMR(CDCl3,300MHz)δ:8.02-8.14(m,2H,Ar-H),7.53-7.65(m,1H,Ar-H),7.40-
7.53(m,2H,Ar-H),6.03-6.10(m,1H,H3),5.87-5.96(m,1H,H9),5.69-5.85(m,2H,H10,
H11),5.27-5.38(m,1H,H19,H15),4.68-4.88(m,3H,H8ax2,H6),4.01(s,1H,7-OH),3.92(s,
1H,23-OH),3.65-3.83(m,2H,H23,H13),3.39-3.61(m,2H,H17,H25),3.37-3.45(m,1H,H2),
2.45-2.59(m,1H,H12),1.86-2.40(m,8H,H16x2,H24,Me4a,H18,H20),1.36-1.75(m,9H,
Me14a, H20, H26, H27x2, H22x2), 1.17 (d, J=7.0Hz, 3H, Me12a), 0.80-1.04 (m, 10H, H28,
Me24a, Me26a, H18) (see Fig. 8)
13C NMR(75MHz,CD3DH)δ:172.15,163.11,157.42,139.14,138.11,137.55,
133.36,131.69,129.97,129.72,128.70,128.48,124.53,121.99,116.47,99.53,78.95,
77.36,74.39,71.33,69.86,69.02,68.35,67.90,46.34,41.10,40.81,40.18,36.15,
35.64,35.10,34.12,27.41,19.03,17.52,14.52,13.73,12.44,11 .41. (see Fig. 9)
HRMS(ESI)calcd for C41H54NO10(M+H)+720.3742,found 720.3738.
Other general formulas are that the series compound of CAU-AVM is prepared according to corresponding method.Their compound is compiled
Number, the corresponding substituent group of R, physicochemical data are shown in Table 1, and the nuclear magnetic resonance spectroscopy of Structural Identification, mass spectrometric data are shown in Table 2.
The biological activity determination of embodiment 2, the compound that general formula is CAU-AVM
Red spider: 4 age red spider larvas impregnate 5s in medical fluid, and borer population is recorded after drying and is put into the training added with moisturizing filter paper
It supports in ware, is put into after capping in (25 ± 1) DEG C illumination box.Each chemicals treatment 30 or more.Inspection result after 48 hours.
Beet armyworm: impregnating 10s for rape leave in medical fluid, is put into the culture dish added with moisturizing filter paper, connects after drying
Enter 4 instar larvae of beet armyworm, is put into after capping in (25 ± 1) DEG C illumination box.Each chemicals treatment 10 or more.Exist respectively
2,3 days inspection results.Polypide is touched, the individual that cannot normally creep is considered as death.Calculate its corrected mortality (%).With comparison medicine
Agent compares, and judges medicament virulence size
Caenorhabditis elegan: M9 buffer, avermectin dilution and caenorhabditis elegan (about 50) are added in 24 orifice plates, is placed in room
20 DEG C of cultures of temperature.The blank control of not adding medicine is set, and every processing is repeated 3 times.Microscopy under microscope, observes nematode after for 24 hours
Activity condition, and count the number of dead and live insects of caenorhabditis elegan.
Bursaphelenchus xylophilus, Meloidogyne incognita: concave slide is placed in the good drier of leakproofness and (adds 5mL in drier
Sterile water), take 50 μ L, 2 000/mL nematode suspension to be added in two hole concave slide depressions respectively.Avermectin processing is recessed
Avermectin dilution (ware bottom is placed in drier) is added in slide, closes the lid rapidly after application and is sealed with sealed membrane,
It is placed in 25 DEG C of room temperature cultures.The blank control that fumigation medicament is not added is set, and every processing is repeated 3 times.It is stifling to take out recessed glass afterwards for 24 hours
Piece, 3min is placed in exposure in air, and microscopy under stereomicroscope observes the activity condition of nematode, and count root-knot nematode it is dead,
Borer population living.
Kidney bean aphid: selection band aphid blade will impregnate 5s with aphid blade in medical fluid, borer population is recorded after drying and is put into added with guarantor
In the culture dish of wet filter paper, it is put into after capping in (25 ± 1) DEG C illumination box.Each chemicals treatment 30 or more.24-48 is small
When after inspection result.
1 general formula of table is the number of the series compound of CAU-AVM, substituent group, physicochemical data
2 CAU-AVM series compound nuclear magnetic resonance spectroscopy of table, mass spectrometric data (Pos: the positive ion mode of mass spectroscopy；
Neg: the negative ion mode of mass spectroscopy)
The insecticidal activity of 3 CAU-AVM series compound of table
From table 3 it can be seen that most compounds CAU-AVM to red spider, beet armyworm, caenorhabditis elegan, Bursaphelenchus xylophilus,
Meloidogyne incognita and Kidney bean aphid have stronger insecticidal activity, show insecticidal activity more better than Avermectin B1a, B2a,
The insecticidal activity of part of compounds reaches 90% or more, such as intermediate X II and CAU-AVM-06, shows chemical combination involved by the application
Object has good bioactivity.
Claims (1)
1. the method for compound shown in preparation formula I,
In formula I, R1Selected from phenyl, phenethyl, 2- fluorophenyl, 2- chlorphenyl, 2- bromophenyl, 2- trifluoromethyl, 3- methylbenzene
Base, 4- methoxyphenyl, 4- chlorphenyl, 4- nitrobenzophenone, 2,4- dichlorophenyl, the chloro- phenyl of 3- trifluoromethyl -4-, 3- pyridine
Base, 2- chloro-3-pyridyl base, 1- (4- chlorphenyl) -2- methyI-oropvD, 3- (the chloro- 2- trifluoromethyl vinyl of 2-) -2,2- diformazan
One of basic ring propyl and 3- (2,2- dimethyl ethenyl) -2,2- dimethylcyclopropane base；
Include the following steps:
1) B2a shown in formula IV and AllocCl is first subjected to esterification, after completion of the reaction, purifying, then reacted with TBDMSCl, it obtains
To compound shown in Formula V；
In above-mentioned Formula V, Alloc indicates allyloxycarbonyl, and TBDMS indicates t-butyldimethylsilyi；
2) make compound shown in Formula V that the reaction of removing allyloxycarbonyl protecting group occur, obtain compound shown in Formula IV；
3) make compound elder generation shown in Formula IV and PhosphorodichloridicAcid Acid Phenyl Ester, DMSO, tetramethylethylenediamine reacts to obtain 23,4 "-
Two-O-TBDMS-5-O avermectin B2a, react with hydrogen fluoride pyridine solution again after post-processing, obtain Formula VII institute
Show compound；
4) it reacts compound shown in Formula VII with hydroxylamine hydrochloride, obtains compound shown in Formula VIII；
5) make compound and R shown in Formula VIII1Condensation reaction occurs for COOH carboxylic acid, obtains compound shown in Formulas I,
R1In COOH, R1Selected from phenyl, phenethyl, 2- fluorophenyl, 2- chlorphenyl, 2- bromophenyl, 2- trifluoromethyl, 3- first
Base phenyl, 4- methoxyphenyl, 4- chlorphenyl, 4- nitrobenzophenone, 2,4- dichlorophenyl, the chloro- phenyl of 3- trifluoromethyl -4-, 3-
Pyridyl group, 2- chloro-3-pyridyl base, 1- (4- chlorphenyl) -2- methyI-oropvD, 3- (the chloro- 2- trifluoromethyl vinyl of 2-) -2,2-
One of dimethylcyclopropane base and 3- (2,2- dimethyl ethenyl) -2,2- dimethylcyclopropane base.
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