CN108840894B - 4' -hydrazone group substituted avermectin B2a/B2B derivative and salt thereof - Google Patents
4' -hydrazone group substituted avermectin B2a/B2B derivative and salt thereof Download PDFInfo
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Abstract
The invention discloses 4' -hydrazone group substituted abamectin B2a/B2bThe compound has a chemical structural general formula shown as a formula I, can effectively improve the stability and insecticidal activity of the compound, can solve the problem that pests have resistance to the existing pesticides, has special effect on mites, aphids and lepidoptera pests, and particularly can effectively prevent and treat the mites which have resistance;
Description
Technical Field
The invention relates to a compound, in particular to avermectin B2a/B2bThe derivative and its salt are agricultural insecticides.
Background
A group of macrolide congeners with similar structures is separated and extracted from streptomyces fermentation hyphae in 1975 by the company Dacun Zhi and Merck of Japan and is named as avermectin (AVM for short). The abamectin fermentation liquor contains abamectin A1aAbamectin A1bAbamectin A2aAbamectin A2bAbamectin B1aAbamectin B1bAbamectin B2aAbamectin B2bEtc., wherein abamectin B1As the main component, abamectin B2The content is next to that of other components.
Abamectin B1The series of the insecticide and the acaricide are widely applied to the protection of animal and plant pests due to the excellent insecticidal and acaricidal properties of the insecticide and the acaricide. For example emamectin B1Benzoate, ivermectin, epothilones and the like, but the drug resistance of the insect body is obviously enhanced along with the prolonging of the medication time.
Abamectin B2a/B2bAs a new product of abamectin, the abamectin compound is an excellent pesticide, and the insecticidal spectrum is different from that of abamectin B1The pesticide has special effect on soil and underground nematodes and pests on the surface of animals, but the problem of enhanced drug resistance of the pests is gradually shown. Due to former avermectin B2a/B2bIs not separated out in large quantities, in general for abamectin B2a/B2bDerivatives are less studied. At present, to abamectin B2a/B2bThe exploration mainly focuses on the abamectin B2a/B2bChanging ester bond to amido bond at position 1 to synthesize avermectin B2a/B2bSpiroketal-cleaved derivatives and the like, such as patent documents CN105820202A, CN105037467A and CN103214532A, have not been found in avermectin B2a/B2bThe research report of introducing hydrazone group into the 4' position.
Disclosure of Invention
The technical problem to be solved by the invention is to provide 4' -hydrazone group substituted abamectin B2a/B2bDerivatives and salts thereof, effective in improving stability and insecticidal activity of compoundsThe pesticide can solve the problem that pests have resistance to the existing pesticides, and has special effects on mites, aphids and lepidoptera pests.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
4' -hydrazone group substituted abamectin B2a/B2bThe derivative has a chemical structural general formula shown in a formula I,
wherein R is1Is methyl or ethyl;
R2and R3Selected from hydrogen, alkoxy substituted phosphoryl,
any one of (1) to (2), wherein n is 0 to 10;
R5is hydrogen, halogen, phenyl, furyl, thiazolyl, thienyl, pyridyl, imidazolyl, pyrrolyl, pyranyl, pyrimidinyl, benzothiazolyl, indolyl, triazolyl, substituted by 1-2R21Phenyl substituted by a group, 1-2R21Furyl substituted by 1-2R21Thiazolyl substituted by a group, 1-2R21Thienyl substituted by 1-2R21Pyridyl substituted by a group, 1-2R21Imidazolyl substituted with a group, 1 to 2R21A pyrrolyl group substituted with a group, 1-2R21Pyranyl substituted by 1-2R21Pyrimidinyl substituted by 1-2R21A benzothiazolyl group substituted with 1 to 2R21Indole substituted by a group, 1-2R21Any one of a group-substituted triazolyl group;
R6is C1-C10Alkyl, halo C1-C10Alkyl, acyl substituted C1-C10Alkyl, phenyl, furyl, thiazolyl, thienyl, pyridyl, imidazolyl, pyrrolyl, pyranyl, pyrimidinyl, benzothiazolyl, indole, triazolyl, substituted with 1-2R21Phenyl substituted by a group, 1-2R21Furyl substituted by 1-2R21Thiazolyl substituted by a group, 1-2R21Thienyl substituted by 1-2R21Pyridyl substituted by a group, 1-2R21Imidazolyl substituted with a group, 1 to 2R21A pyrrolyl group substituted with a group, 1-2R21Pyranyl substituted by 1-2R21Pyrimidinyl substituted by 1-2R21A benzothiazolyl group substituted with 1 to 2R21Indolyl substituted by 1-2R21Any one of a group-substituted triazolyl group;
R21any one selected from the group consisting of halogen, alkyl-substituted amino, haloalkyl, sulfonyl, alkanoyl, nitro, cyano, alkoxy, and carboxyl;
R2and R3Not hydrogen at the same time;
R4is any one of hydroxyl, acetyl and hydroxyamino subunit.
The technical scheme of the invention is further improved as follows:
when R is4In the case of hydroxyl, the preparation process of the compound with the structure shown in the formula I is as follows:
dissolving a hydrazine compound in alcohol, adding organic base, reacting for 20-40 minutes at 0-50 ℃, and adding 5-allyloxycarbonyl abamectin B dissolved in an inert solvent2a/B2bOr dimethyl tert-butyl silicon base-4' -carbonyl abamectin B2a/B2bAdjusting the temperature to-10 ℃, reacting for 1.5-2.5 hours, adding a deprotection catalyst and sodium borohydride, reacting for 20-40 minutes, washing with water after the reaction is finished, separating and drying the organic phase, and removing the inert solvent under reduced pressure to obtain a compound with a structure shown in a formula III;
when R is4In the case of acetyl, the structure of formula IThe preparation process of the compound comprises the following steps:
mixing avermectin B2a/B2bDissolving in an inert solvent, adding organic base at the temperature of-20-0 ℃, adding acetyl chloride or acetic anhydride solution dissolved in the inert solvent, reacting for 0.5-1.5 hours, adding the organic base, dimethyl sulfoxide and an oxidant, reacting for 0.5-5 hours, then washing with water, separating the organic phase, drying, adding a hydrazine compound dissolved in alcohol and triethylamine solution dissolved in the inert solvent, reacting for 0.5-1.5 hours at the temperature of 0-50 ℃, then washing with water, separating and drying the organic phase, and removing the inert solvent under reduced pressure to obtain a compound with a structure shown in a formula IV;
when R is4In the case of hydroxyamino subunit, the preparation process of the compound with the structure shown in formula I is as follows:
mixing avermectin B2a/B2bDissolving in an inert solvent, adding an organic base and an oxidant, reacting for 0.5-5 hours at-20-0 ℃, then adjusting the temperature to 20-100 ℃, adding allyloxyhydroxylamine, reacting for 0.5-5 hours, adjusting the temperature to-20-0 ℃, adding the organic base and the oxidant, reacting for 0.5-5 hours, washing with water, separating the organic phase, drying and filtering, then adding a hydrazine compound dissolved in alcohol and the organic base, reacting for 1.5-2.5 hours, then adding a catalyst and sodium borohydride at-10 ℃, reacting for 20-40 minutes, washing with water, separating the organic phase, drying, and removing the inert solvent under reduced pressure to obtain the compound with the structure shown in the formula V.
The technical scheme of the invention is further improved as follows: the inert solvent is any one of dichloromethane, dichloroethane, chloroform, sec-butyl acetate, dimethyl sulfoxide or dimethylformamide, and the using amount of the inert solvent is avermectin B2a/B2b3-10 times of the mass of the derivatives;
the organic base is any one of triethylamine, tributylamine or tetramethyl ethylenediamine, and the using amount of the organic base is avermectin B2a/B2b1-2 times of the molar weight of the derivative;
the oxidant is any one of oxalyl chloride, trifluoroacetic anhydride, solid phosgene or phenyl phosphate diacid chloride, and the dosage of the oxidant is abamectin B2a/B2b0.5-2 times of the molar weight of the derivative;
the deprotection catalyst is a dechlorination allyl formate protection catalyst or a desiliconization protection catalyst;
the hydrazine compound has a chemical structure shown in a formula VII;
the technical scheme of the invention is further improved as follows: the allyl chloroformate dechlorination protection catalyst is any one of palladium acetate, palladium chloride or palladium tetratriphenylphosphine, and the using amount of the catalyst is abamectin B2a/B2b0.01-0.1% of the molar weight of the derivative;
the de-organosilicon protective catalyst is tetrabutylammonium fluoride or ammonium fluoride, and the using amount is avermectin B2a/B2bThe molar weight of the derivative is 1-5 times.
The technical scheme of the invention is further improved as follows: 4' -hydrazone group substituted avermectin B2a/B2bThe salt of the derivative has a chemical structural general formula shown in a formula II,
wherein HX represents an organic acid or an inorganic acid.
The technical scheme of the invention is further improved as follows: 4' -hydrazone group substituted avermectin B2a/B2bThe salt of the derivative is abamectin B substituted by 4' -hydrazone group2a/B2bThe derivative is prepared by reacting with organic acid or inorganic acid;
the organic acid is C1-C20Alkyl sulfonic acid, C1-C20Phenylsulfonic acid, C1-C20P-tolylsulfonic acid, C1-C20Alkyl phosphonic acid, C1-C20Phenylphosphonic acid, C1-C20P-tolylphosphonic acid, C1-C20Alkyl carboxylic acidAcid, aryl substituted C1-C20Alkyl carboxylic acids, benzoic acids, halogen-substituted benzoic acids, C1-C10Alkyl substituted benzoic acids;
the inorganic acid is any one of phosphoric acid, nitric acid, sulfuric acid or hydrochloric acid.
The technical scheme of the invention is further improved as follows: the 4' -hydrazone group substituted abamectin B2a/B2bDerivative and 4' -hydrazone group substituted abamectin B2a/B2bThe salts of the derivatives are used for controlling mites, aphids and lepidoptera pests.
Due to the adoption of the technical scheme, the invention has the technical progress that:
the 4' -hydrazone group substituted abamectin B provided by the invention2a/B2bThe derivative and the salt thereof can effectively improve the stability and insecticidal activity of the compound, can solve the problem that pests have resistance to the existing pesticide, have special effect on mites, aphids and lepidoptera pests, and particularly can effectively prevent and control the mites which have resistance.
4' -hydrazone group substituted abamectin B with structure shown in formula I2a/B2bIn the derivatives R2、R3The compound is preferably phenyl substituted by 1-2 halogens, and experiments prove that the compound has better control effect on pests than alkyl substituted hydrazone compounds, particularly has special effect on mite pests, has particularly outstanding insecticidal activity on resistant mite pests, and has high mortality rate and quick response.
The 4' -hydrazone group of the invention substitutes avermectin B2a/B2bThe derivative not only can effectively act on the imagoes of target pests, but also has higher lethality rate to the eggs and the larvae of the pests, so the derivative can be applied in the early stage or the later stage of the occurrence of diseases, can play a role in preventing the occurrence of the pests, can effectively avoid the large-scale diffusion of the pests, and prevents the eggs left and buried in the soil from continuously propagating to damage crops in the next season particularly when nearby plots with the pests or the pests which occur periodically and repeatedly occur.
4' -hydrazone group substituted avermectin B2a/B2bDerivatives and their use as anti-inflammatory agentsThe salt has obviously enhanced control effect on aphids, mites and lepidoptera pests, has better stability, greatly enhances the persistence on target organisms, obviously prolongs the retention time of pesticide effect, can reduce the pesticide application frequency, is favorable for radically controlling the pests and avoids repeated attack of the pests.
The 4' -hydrazone group of the invention substitutes avermectin B2a/B2bDerivatives compared to Avermectin B2a/B2bAnd abamectin B commonly used at present2a/B2bDerivatives, and avermectin B1a/B1bAnd the derivatives thereof not only obviously improve the control effect on target organisms, but also have lower concentration when being applied in fields, can save the control cost, have low toxicity to people and livestock, reduce chemical pollution to soil and crops, are safer and more environment-friendly, and are more beneficial to reducing or delaying the generation of drug resistance of insect bodies.
Detailed Description
The present invention will be described in further detail with reference to the following examples:
the compound naming in the invention refers to the organic compound naming principle published by 2017 scientific press and approved by the Committee for naming of the Chinese chemical organic compounds.
4' -hydrazone group substituted abamectin B2a/B2bThe derivative has a chemical structural general formula shown in a formula I,
wherein R is1Is methyl or ethyl; when R is1When it is ethyl, the parent avermectin is B2a(ii) a When R is1When it is methyl, the parent avermectin is B2b。
R2And R3Selected from hydrogen, alkoxy substituted phosphoryl;
R2and R3Selected from hydrogen, alkoxy substituted phosphoryl,
any one of (1) to (2), wherein n is 0 to 10;
R5is hydrogen, halogen, phenyl, furyl, thiazolyl, thienyl, pyridyl, imidazolyl, pyrrolyl, pyranyl, pyrimidinyl, benzothiazolyl, indolyl, triazolyl, substituted by 1-2R21Phenyl substituted by a group, 1-2R21Furyl substituted by 1-2R21Thiazolyl substituted by a group, 1-2R21Thienyl substituted by 1-2R21Pyridyl substituted by a group, 1-2R21Imidazolyl substituted with a group, 1 to 2R21A pyrrolyl group substituted with a group, 1-2R21Pyranyl substituted by 1-2R21Pyrimidinyl substituted by 1-2R21A benzothiazolyl group substituted with 1 to 2R21Indole substituted by a group, 1-2R21Any one of a group-substituted triazolyl group;
R6is C1-C10Alkyl, halo C1-C10Alkyl, acyl substituted C1-C10Alkyl, phenyl, furyl, thiazolyl, thienyl, pyridyl, imidazolyl, pyrrolyl, pyranyl, pyrimidinyl, benzothiazolyl, indole, triazolyl, substituted with 1-2R21Phenyl substituted by a group, 1-2R21Furyl substituted by 1-2R21Thiazolyl substituted by a group, 1-2R21Thienyl substituted by 1-2R21Pyridyl substituted by a group, 1-2R21Imidazolyl substituted with a group, 1 to 2R21A pyrrolyl group substituted with a group, 1-2R21Pyranyl substituted by 1-2R21Pyrimidinyl substituted by 1-2R21A benzothiazolyl group substituted with 1 to 2R21Indolyl substituted by 1-2R21Any one of a group-substituted triazolyl group;
R21any one selected from the group consisting of halogen, alkyl-substituted amino, haloalkyl, sulfonyl, alkanoyl, nitro, cyano, alkoxy, and carboxyl;
R2and R3Can be the same or different and is not hydrogen at the same time;
R4is any one of hydroxyl, acetyl and hydroxyamino subunit.
4' -hydrazone group substituted avermectin B2a/B2bThe hydrazone group in the derivative is a mixture of cis-trans isomers.
4' -hydrazone group substituted avermectin B2a/B2bThe preparation method of the derivative comprises the following steps:
1) when R is4In the case of hydroxyl, the compound of formula I (as shown in formula III below) is prepared by the following steps:
dissolving a hydrazine compound in alcohol, adding organic base, reacting for 20-40 minutes at 0-50 ℃, and adding 5-allyloxycarbonyl abamectin B dissolved in an inert solvent2a/B2b(shown as formula VI) or dimethyl tert-butyl silicon base-4' -carbonyl avermectin B2a/B2bAdjusting the temperature to-10 ℃ and reacting for 1.5-2.5 hours to obtain 5-allyloxycarbonyl-4' -hydrazone substituted B2a/B2bThe derivative (shown as formula VIII) or dimethyl tert-butyl silyl-4' -hydrazone substituted B2a/B2bAdding a deprotection catalyst and sodium borohydride into the derivative to react for 20-40 minutes to remove a protecting group, washing the derivative with water after the reaction is finished, separating and drying the organic phase, and removing the inert solvent under reduced pressure to obtain a compound with a structure shown in a formula III;
the reaction flow is as follows:
2) when R is4In the case of acetyl, the compound of formula I (as shown in formula IV below) is prepared by the following steps:
mixing avermectin B2a/B2bDissolving in an inert solvent, adding organic base at the temperature of-20-0 ℃, adding acetyl chloride or acetic anhydride solution dissolved in the inert solvent, reacting for 0.5-1.5 hours, adding organic base, dimethyl sulfoxide and an oxidant, and reacting for 0.5-5 hours to obtain 4' -carbonyl-5-acetyl B2a/B2b(shown as formula IX), then washing with water, separating an organic phase, drying, adding a hydrazine compound dissolved in alcohol and a triethylamine solution dissolved in an inert solvent, reacting for 0.5-1.5 hours at 0-50 ℃, then washing with water, separating and drying the organic phase, and removing the inert solvent under reduced pressure to obtain a compound with a structure shown as formula IV;
the reaction flow is as follows:
3) when R is4In the case of hydroxyamino groups, compounds of formula I (as shown in formula V below) are prepared by:
mixing avermectin B2a/B2bDissolving in inert solvent, adding organic solventAlkali and an oxidant are reacted for 0.5 to 5 hours at the temperature of minus 20 to 0 ℃ to obtain 5-carbonyl abamectin B2a/B2b(shown as a formula X), then adjusting the temperature to 20-100 ℃, adding allyloxyhydroxylamine (shown as a formula XIV) to react for 0.5-5 hours to obtain a compound shown as a formula XI, adjusting the temperature to-20-0 ℃, adding organic alkali, dimethyl sulfoxide and an oxidant to react for 0.5-5 hours to obtain a compound shown as a formula XII, after washing treatment, separating organic phase, drying and filtering, then adding a hydrazine compound and an organic alkali dissolved in alcohol to react for 1.5-2.5 hours to obtain a compound shown as a formula XIII, then adding a catalyst, methanol and sodium borohydride at-10 ℃, reacting for 20-40 minutes to remove a protective group, then washing treatment, separating an organic phase, drying, and removing an inert solvent under reduced pressure to obtain a compound shown as a formula V;
the reaction flow is as follows:
the inert solvent is any one of dichloromethane, dichloroethane, chloroform, sec-butyl acetate, dimethyl sulfoxide or dimethylformamide, and the using amount of the inert solvent is abamectin B2a/B2bThe molar weight of the derivative is 3-10 times that of the derivative;
the organic base is any one of triethylamine, tributylamine or tetramethyl ethylenediamine, and the using amount of the organic base is avermectin B2a/B2b1-2 times of the molar weight of the derivative;
the oxidant is any one of oxalyl chloride, trifluoroacetic anhydride, solid phosgene or phenyl phosphate diacid chloride, and the dosage of the oxidant is abamectin B2a/B2b0.5-2 times of the molar weight of the derivative;
the deprotection catalyst is a dechlorination allyl formate protection catalyst or a desiliconization protection catalyst;
the hydrazine compound has a chemical structure shown in a formula VII;
the allyl chloroformate dechlorination protection catalyst is any one of palladium acetate, palladium chloride or palladium tetratriphenylphosphine, and the using amount of the catalyst is abamectin B2a/B2b0.01-0.1% of the molar weight of the derivative;
the de-organosilicon protective catalyst is tetrabutylammonium fluoride or ammonium fluoride, and the using amount is avermectin B2a/B2bThe molar weight of the derivative is 1-5 times.
4' -hydrazone group substituted avermectin B2a/B2bThe salt of the derivative has a chemical structural general formula shown in a formula II,
wherein HX represents an organic acid or an inorganic acid.
4' -hydrazone group substituted avermectin B2a/B2bThe salt of the derivative is abamectin B substituted by 4' -hydrazone group2a/B2bThe derivative is prepared by reacting with organic acid or inorganic acid; in particular to 4' -hydrazone group substituted abamectin B obtained after the reaction is finished2a/B2bAfter the derivative is washed by water, separating a water phase from an organic phase, adding corresponding organic acid or inorganic acid into the organic phase, stirring for 15-45 minutes, and evaporating the inert solvent to obtain the 4' -hydrazone group substituted abamectin B2a/B2bSalts corresponding to the derivatives;
the organic acid is C1-C20Alkyl sulfonic acid, C1-C20Phenylsulfonic acid, C1-C20P-tolylsulfonic acid, C1-C20Alkyl phosphonic acid, C1-C20Phenylphosphonic acid, C1-C20P-tolylphosphonic acid, C1-C20Alkyl carboxylic acids, aryl-substituted C1-C20Alkyl carboxylic acids, benzoic acids, halogen-substituted benzoic acids, C1-C10Alkyl substituted benzoic acids; the inorganic acid is any one of phosphoric acid, nitric acid, sulfuric acid or hydrochloric acid.
Example 1
When 4' -hydrazone group substituted avermectin B2a/B2bThe derivative is 5-hydroxy-4 '-deoxy-4' -N- (2-pyridyl) hydrazone abamectin B2a/B2bThe preparation method comprises the following steps:
a. 10g of 5-allyloxycarbonyl-4' -carbonyl abamectin B2a/B2bThe oxide was dissolved in 50g of dichloromethane and used.
b. Adding 2.0g of 2-hydrazine-pyridine hydrochloride into 10g of methanol for dissolving, adding 1.6g of tetramethylethylenediamine for reacting for 0.5h at 25 ℃, and then adding 5-allyloxycarbonyl-4' -carbonyl abamectin B2a/B2bThe temperature of the dichloromethane solution of the oxide is adjusted to 5 ℃, and the reaction is stirred for 2 hours.
c. Adding 0.005g of palladium tetratriphenylphosphine, adding 0.4g of sodium borohydride in batches, reacting for 0.5h, washing with water, and separating out organic substancesRemoving dichloromethane under reduced pressure, and passing through column to obtain 95% 5-hydroxy-4 '-deoxy-4' -N- (2-pyridyl) hydrazone abamectin B2a/B2b。
lH NMR(CDCl3)δppm:8.05(d,J＝8.0,1H),7.55(dd,J＝8.0,4.3,1H), 6.65(m,2H),6.00(m,1H),5.95(m,1H),5.90(m,1H),5.66(dd,J＝0.8,2.6,lH), 5.52(d,J＝3.0,1H),5.40(m,lH),4.80(d,J＝3.2,1H),4.76(brd,J＝13.0,2H), 4.71(brd,J＝13.0,2H),4.20(s,lH),4.13(brq,J＝6.7,lH),3.90(d,J＝6.2,lH), 3.84(brs,lH),3.75(m,1H),3.70(m,1H),3.65(dq,J＝11.1,6.2,2H),3.60(ddd,J ＝11.5,5.0,3.8,lH),3.57(s,3H),3.54(m,lH),3.53(dd,J＝9.9,1.3,lH),3.50(s, 3H),3.48(8,3H),3.38(m,lH),3.36(q,J＝2.0,lH),3.13(dd,J＝9.1,8.7,lH),2.71 (brd,J＝3.8,lH),2.52(m,lH),2.30(s,3H),2.31-2.25(m,2H),2.10-1.91(m,2H), 1.77(m,lH),1.75(d,J＝4.1,2H),1.70-1.50(m,6H),1.47(brs,2H),1.44(d,J＝6.7, 3H),1.28(d,J＝6.2,3H),1.19(d,J＝7.0,3H),1.15(d,J＝7.6,3H),1.00-0.92(m, 9H),0.90(m,1H)。
LC-MS [ M + H ] liquid mass analysis]+980.54, [ 5-hydroxy-4 '-deoxy-4' -N- (2-pyridyl) hydrazone based avermectin B2aOf [ M + H]+Calculated values: 980.54]。
The product also contains a small amount of 5-hydroxy-4 '-deoxy-4' -N- (2-pyridyl) hydrazone abamectin B2bLiquid chromatography mass spectrometry LC-MS [ M + H ]]+966.52, [ M + H of the molecule]+Calculated values: 966.52]。
Example 2
When 4' -hydrazone group substituted avermectin B2a/B2bThe salt of the derivative is 5-hydroxy-4 '-deoxy-4' -N-N- (2-chloro-5-methylthiazolyl) hydrazone abamectin B2a/B2bWhen the hydrochloride is prepared, the preparation method comprises the following steps:
a. 10g of 5-allyloxycarbonyl-4' -carbonyl abamectin B2a/B2bDissolved in 60g of dichloroethane for further use.
b. Dissolving 4.0g 2-chloro-5-methyl-thiazolehydrazide hydrochloride in 12g ethanol, adding 2.0g triethylamine, reacting at 50 deg.C for 20 min, and adding dissolved 5-allyloxycarbonyl-4' -carbonylAbamectin B2a/B2bThe temperature of the dichloroethane solution is adjusted to 10 ℃, and the dichloroethane solution is stirred and reacts for 2.5 hours.
c. Cooling to 0-5 ℃, adding 0.005g of palladium tetratriphenylphosphine, adding 0.6g of sodium borohydride in batches, reacting for 40 minutes, washing with water, separating out an organic phase, dropwise adding 3.0g of 10% hydrochloric acid, stirring for 0.5 hour, removing dichloroethane under reduced pressure, adding petroleum ether, stirring for 20 minutes to obtain 9.0g of 90% 5-hydroxy-4 '-deoxy-4' -N- (2-chloro-5-methyl-thiazolyl) hydrazone based abamectin B2a/B2bA hydrochloride salt.
LC-MS [ M + H ] liquid mass analysis]+1034.47, [ 5-hydroxy-4 "-deoxy-4" -N- (2-chloro-5-methyl-thiazolyl) hydrazonyl abamectin B2aOf [ M + H]+Calculated values: 1034.47]。
The product also contains a small amount of 5-hydroxy-4 '-deoxy-4' -N- (2-chloro-5-methyl-thiazolyl) hydrazone abamectin B2bLiquid chromatography mass spectrometry LC-MS [ M + H ]]+1020.46, [ M + H of the molecule]+Calculated values: 1020.46]。
Example 3
When 4' -hydrazone group substituted avermectin B2a/B2bThe derivative is 5-hydroxy-4 '-deoxy-4' -N- (5-bromo-2-pyridyl) hydrazone abamectin B2a/B2bThe preparation method comprises the following steps:
a. 5g of 5-dimethyl tert-butyl silicon base-4' -carbonyl abamectin B2a/B2bDissolved in 30g of chloroform for use.
b. Adding 3.5g of 5-bromo-2-hydrazine-pyridine hydrochloride into 8.5g of propanol for dissolving, adding 1.5g of tributylamine for reacting for 40 minutes at 0 ℃, and then adding the dissolved 5-dimethyl tert-butyl silicon-4' -carbonyl abamectin B2a/B2bThe temperature of the chloroform solution is adjusted to-10 ℃, and the reaction is stirred for 1.5 h.
c. Adding 1.5g of tetrabutylammonium fluoride in batches, reacting for 20 minutes, washing with water, separating an organic phase, removing chloroform under reduced pressure, adding N-hexane, and stirring for 30 minutes to obtain 8.5g of 92 percent 5-hydroxy-4 '-deoxy-4' -N- (5-bromo-2-pyridyl) hydrazone abamectin B2a/B2b。
LC-MS [ M + H ] liquid mass analysis]+1058.45, [ 5-hydroxy-4 '-deoxy-4' -N- (5-bromo-2-pyridyl) hydrazone based avermectin B2aOf [ M + H]+Calculated values: 1058.45]。
The product also contains a small amount of 5-hydroxy-4 '-deoxy-4' -N- (5-bromo-2-pyridyl) hydrazone abamectin B2bLiquid chromatography mass spectrometry LC-MS [ M + H ]]+1044.44, [ M + H of the molecule]+Calculated values: 1044.44]。
Example 4
When 4' -hydrazone group substituted avermectin B2a/B2bThe derivative is 5-hydroxy-4 '-deoxy-4' -N- (2-furoyl) hydrazone-based abamectin B2a/B2bThe preparation method comprises the following steps:
a. 10g of 5-dimethyl tert-butyl silicon base-4' -carbonyl abamectin B2a/B2bDissolved in 55g of sec-butyl acetate for further use.
b. Adding 2.5g of furoyl hydrazine hydrochloride into 10g of methanol for dissolving, adding 1.8g of tetramethyl ethylenediamine for reacting for 25 minutes at the temperature of 30 ℃, and then adding the dissolved 5-dimethyl tert-butyl silicon-4' -carbonyl avermectin B2a/B2Adjusting the temperature of the sec-butyl acetate solution to 0 ℃, and stirring for reaction for 2 hours.
c. Adding 0.4g of ammonium fluoride, adding 0.5g of acetic acid, reacting for 35 minutes, washing with water, separating out an organic phase, removing sec-butyl acetate under reduced pressure, adding petroleum ether, and stirring for 20 minutes to obtain 8.4g of 92 percent 5-hydroxy-4 '-deoxy-4' -N- (2-furoyl) hydrazone-based abamectin B2a/B2b。
LC-MS [ M + H ] liquid mass analysis]+997.52, [ 5-hydroxy-4 '-deoxy-4' -N- (2-furoyl) hydrazone based avermectin B2aOf [ M + H]+Calculated values: 997.52]。
The product also contains a small amount of 5-hydroxy-4 '-deoxy-4' -N- (2-furoyl) hydrazone abamectin B2bLiquid chromatography mass spectrometry LC-MS [ M + H ]]+983.50, [ M + H of the molecule]+Calculated values: 983.50]。
Example 5
When the 4' -hydrazone group is takenAbamectin B of generations2a/B2bThe salt of the derivative is 5-hydroxy-4 '-deoxy-4' -N- (3-chlorphenyl) hydrazone abamectin B2a/B2bIn the case of benzoate, the preparation method is as follows:
a. 10g of 5-allyloxycarbonyl-4' -carbonyl abamectin B2a/B2bDissolved in 50g of dimethyl sulfoxide for use.
b. Adding 1.5g of 2-chloro-5-methyl-thiazolehydrazide hydrochloride into 9g of methanol for dissolving, adding 1.4g of tributylamine for reacting for 25 minutes at 28 ℃, and then adding the dissolved 5-allyloxycarbonyl-4' -carbonyl abamectin B2a/B2The temperature of the dimethyl sulfoxide solution is adjusted to 4 ℃, and the dimethyl sulfoxide solution is stirred and reacts for 2.5 hours.
c. Adding 0.008g of palladium acetate, then adding 0.5g of sodium borohydride in batches, reacting for 25 minutes, washing with water, separating out an organic phase, dropwise adding 1.1g of benzoic acid, stirring for 25 minutes, and removing dimethyl sulfoxide under reduced pressure to obtain 8.8g of 91% 5-hydroxy-4 '-deoxy-4' -N- (3-chlorophenyl) hydrazone abamectin B2a/B2bA benzoate salt.
LC-MS [ M + H ] liquid mass analysis]+1013.51, [ 5-hydroxy-4 '-deoxy-4' -N- (3-chlorophenyl) hydrazone based avermectin B2aOf [ M + H]+Calculated values: 1034.47]。
The product also contains a small amount of 5-hydroxy-4 '-deoxy-4' -N- (3-chlorphenyl) hydrazone abamectin B2bLiquid chromatography mass spectrometry LC-MS [ M + H ]]+999.49, [ M + H of the molecule]+Calculated values: 999.49]。
Example 6
When 4' -hydrazone group substituted avermectin B2a/B2bThe salt of the derivative is 5-hydroxy-4 '-deoxy-4' -N- (4-fluorophenyl) hydrazone abamectin B2a/B2bIn the case of benzoate, the preparation method is as follows:
a. 10g of 5-allyloxycarbonyl-4' -carbonyl abamectin B2a/B2bDissolved in 50g of dimethylformamide for use.
b. 2.0g of 4-fluorophenylhydrazine hydrochloride was dissolved in 4g of methanol, 1.0g of tetramethylethylenediamine was added thereto to react at 15 ℃ for 35 minutes,then adding the dissolved 5-allyloxycarbonyl-4' -carbonyl abamectin B2a/B2The temperature of the dimethylformamide solution is adjusted to 2 ℃, and the reaction is stirred for 2 hours.
c. Adding 0.007g of palladium chloride, then adding 0.6g of sodium borohydride in batches, reacting for 30 minutes, washing with water, separating out an organic phase, dropwise adding 1.25g of benzoic acid, stirring for 15 minutes, removing dimethylformamide under reduced pressure, adding petroleum ether, stirring for 25 minutes, and filtering to obtain 9.0g of 92% 5-hydroxy-4 '-deoxy-4' -N- (4-fluorophenyl) hydrazone-based abamectin B2a/B2bA benzoate salt.
LC-MS [ M + H ] liquid mass analysis]+997.54, [ 5-hydroxy-4 '-deoxy-4' -N- (4-fluorophenyl) hydrazone based avermectin B2aOf [ M + H]+Calculated values: 997.54]。
The product also contains a small amount of 5-hydroxy-4 '-deoxy-4' -N- (4-fluorophenyl) hydrazone abamectin B2bLiquid chromatography mass spectrometry LC-MS [ M + H ]]+983.52, [ M + H of the molecule]+Calculated values: 983.52.
example 7
When 4' -hydrazone group substituted avermectin B2a/B2bThe salt of the derivative is 5-acetyl-4 '-deoxy-4' -N- (2-pyridyl) hydrazone abamectin B2a/B2bThe preparation method of oleate is as follows:
a. mixing 9g of abamectin B2a/B2bDissolved in 45g of dichloromethane, 0.9g of acetyl chloride in 5g of dichloromethane, 3.0g of 2-hydrazine-pyridine hydrochloride in 10g of methanol and 2.2g of triethylamine in 10g of dichloromethane are used.
b. At-10 deg.C, adding abamectin B2a/B2bAdding 1.2g of tetramethylethylenediamine into a dichloromethane solution, dropwise adding a dichloromethane solution of acetyl chloride, reacting for 1 hour, adding 1.5g of tetramethylethylenediamine and 1.5g of dimethyl sulfoxide, dropwise adding 1.5g of phenyl phosphate diacid chloride, reacting for 3 hours, washing with water, layering, drying an organic phase for 1 hour by using anhydrous magnesium sulfate, and filtering.
c. Adding a solution of 2-hydrazine-pyridine hydrochloride in methanol and triethylamine in dichloromethane at 20 deg.CReacting for 1 hour, washing with water, separating organic phase, adding 2.0g oleic acid, removing dichloromethane under reduced pressure to obtain 8.0g 90% 5-acetyl-4 '-deoxy-4' -N- (2-pyridyl) hydrazone abamectin B2aOleate of/B2B.
LC-MS [ M + H ] liquid mass analysis]+1022.55, [ 5-acetyl-4 '-deoxy-4' -N- (2-pyridyl) hydrazone based avermectin B2aOf [ M + H]+Calculated values: 1022.55]。
The product also contains a small amount of 5-acetyl-4 '-deoxy-4' -N- (2-pyridyl) hydrazone abamectin B2bLiquid chromatography mass spectrometry LC-MS [ M + H ]]+1008.54, [ M + H of the molecule]+Calculated values: 1008.54.
example 8
When 4' -hydrazone group substituted avermectin B2a/B2bThe derivative is 5-hydroxyaminolidene-4 '-deoxy-4' -N- (3-chloro-phenyl) hydrazone-based abamectin B2a/B2bThe preparation method comprises the following steps:
a. 9.0g of 5-allyloxycarbonyl-4' -carbonyl abamectin B2a/B2bDissolving in 50g of dichloromethane, adding 1.5g of triethylamine and 1.5g of dimethyl sulfoxide at the temperature of-20-0 ℃, dropwise adding 1.5g of solid phosgene, and reacting for 3 hours;
b. adjusting the temperature to 25 ℃, adding 3g of 30% allyloxyhydroxylamine dichloromethane solution, and reacting for 0.5-5 hours;
c. adjusting the temperature to-10 ℃, adding 1.5g of triethylamine and 1.5g of dimethyl sulfoxide, dropwise adding 1.5g of phenyl phosphate diacyl chloride, reacting for 2 hours, washing with water, drying an organic phase with anhydrous sodium sulfate, and filtering;
d. dissolving 2.5g of 3-chlorophenylhydrazine hydrochloride in 10g of methanol, adding 1.6g of tetramethylethylenediamine for reaction for 0.5h, then adding the mixture into the organic phase obtained in the step c for reaction for 2h under stirring, cooling to 4 ℃, adding 0.005g of palladium tetratriphenylphosphine, adding 0.5g of sodium borohydride in batches for reaction for 0.5h, washing, separating the organic phase, drying with anhydrous sodium sulfate, removing dichloromethane under reduced pressure, and separating by a column to obtain a target product 5-hydroxyaminoidene-4 '-deoxy-4' -N- (3-chlorophenyl) hydrazone base abamectin with the content of 95%Bacterin B2a/B2b。
lH NMR(CDCl3)δppm:7.24(d,J＝8.0,1H),7.20(d,J＝8.0,1H),7.14(d,J ＝8.0,1H),7.00(brs,1H),5.93(m,1H),5.90(m,1H),5.81(m,1H),5.51(dd,J＝0.8, 2.6,lH),5.47(d,J＝3.0,1H),5.38(m,lH),4.80(d,J＝3.2,1H),4.77(brd,J＝13.0, 2H),4.65(brd,J＝13.0,2H),4.10(s,lH),3.88(d,J＝6.2,lH),3.84(brs,lH), 3.78(m,1H),3.67(m,1H),3.60(dq,J＝11.1,6.2,2H),3.59(ddd,J＝11.5,5.0,3.8, lH),3.54(s,3H),3.52(m,lH),3.51(dd,J＝9.9,1.3,lH),3.50(s,3H),3.48(8,3H), 3.38(m,lH),3.36(q,J＝2.0,lH),3.13(dd,J＝9.1,8.7,lH),2.52(m,lH),2.30(s, 3H),2.31-2.25(m,2H),2.05-1.90(m,2H),2.0(s,1H),1.78(m,lH),1.72(d,J＝4.1, 2H),1.65-1.46(m,6H),1.42(brs,2H),1.38(d,J＝6.7,3H),1.29(d,J＝6.2,3H), 1.20(d,J＝7.0,3H),1.15(d,J＝7.6,3H),0.96-0.91(m,9H),0.90(m,1H)。
LC-MS [ M + H ] liquid mass analysis]+1026.50, [ 5-hydroxyaminoidene-4 '-deoxy-4' -N- (3-chlorophenyl) hydrazone-based avermectin B2aOf [ M + H]+Calculated values: 1026.50]。
The product also contains a small amount of 5-hydroxyamino subunit-4 '-deoxy-4' -N- (3-chlorophenyl) hydrazone abamectin B2bLiquid chromatography mass spectrometry LC-MS [ M + H ]]+1012.49, [ M + H of the molecule]+Calculated values: 1012.49.
test of drug efficacy
In a field pesticide effect test aiming at lepidoptera pests such as rice stem borers, collybia albuminosa and the like, 4' -hydrazone group substituted abamectin B is applied when the application concentration is 20ppm2a/B2bThe death rate of pests of the derivative is about 92 percent, and emamectin benzoate B is applied1a/B1bMethylamino abamectin B2a/B2bThe average mortality rate at time was about 86%; 4' -hydrazone group substituted avermectin B2a/B2bThe derivative has stronger control effect.
In a field pesticide effect test aiming at target aphids, mite pests and nematodes, 4' -hydrazone group substituted abamectin B is applied when the application concentration is 10ppm2a/B2bThe derivative has a pest mortality rate of about 90%, and is applied to the firstAminoavermectin B1a/B1bMethylamino abamectin B2a/B2bAbamectin B2a/B2bThe average death rate of the pests is about 83 percent, and in a low-concentration pesticide effect test, the 4' -hydrazone group substituted abamectin B2a/B2bThe derivative has more outstanding control effect.
Claims (7)
1. 4' -hydrazone group substituted abamectin B2a/B2bA derivative characterized by: has a chemical structural general formula shown as a formula I,
wherein R is1Is methyl or ethyl;
R2and R3Selected from hydrogen or R5-CnH2n-any one of (a), (b), (c), (d), (e) and (d);
R5is phenyl, pyridyl, substituted by 1-2R21Phenyl substituted by a group, 1-2R21Any one of a group-substituted pyridyl group;
R21selected from halogens;
R2and R3Not hydrogen at the same time;
R4is any one of acetyl and hydroxyamino subunit.
2. The 4' -hydrazone group substituted abamectin B of claim 12a/B2bA derivative characterized by: 4' -hydrazone group substituted avermectin B2a/B2bThe hydrazone group in the derivative is a mixture of cis-trans isomers.
3. The 4' -hydrazone group substituted abamectin B of claim 12a/B2bA derivative characterized by:
when R is4When acetyl, the compound of formula IThe preparation process comprises the following steps:
mixing avermectin B2a/B2bDissolving in an inert solvent, adding organic base at the temperature of-20-0 ℃, adding acetyl chloride or acetic anhydride solution dissolved in the inert solvent, reacting for 0.5-1.5 hours, adding the organic base, dimethyl sulfoxide and an oxidant, reacting for 0.5-5 hours, then washing with water, separating the organic phase, drying, adding a hydrazine compound dissolved in alcohol and triethylamine solution dissolved in the inert solvent, reacting for 0.5-1.5 hours at the temperature of 0-50 ℃, then washing with water, separating and drying the organic phase, and removing the inert solvent under reduced pressure to obtain a compound with a structure shown in a formula IV;
when R is4In the case of hydroxyamino subunit, the preparation process of the compound with the structure shown in formula I is as follows:
mixing avermectin B2a/B2bDissolving in an inert solvent, adding an organic base and an oxidant, reacting for 0.5-5 hours at-20-0 ℃, then adjusting the temperature to 20-100 ℃, adding allyloxyhydroxylamine, reacting for 0.5-5 hours, adjusting the temperature to-20-0 ℃, adding the organic base and the oxidant, reacting for 0.5-5 hours, washing with water, separating the organic phase, drying and filtering, then adding a hydrazine compound dissolved in alcohol and the organic base, reacting for 1.5-2.5 hours, then adding a catalyst and sodium borohydride at-10 ℃, reacting for 20-40 minutes, washing with water, separating the organic phase, drying, and removing the inert solvent under reduced pressure to obtain a compound with a structure shown in a formula V;
4. the 4' -hydrazone group substituted abamectin B of claim 32a/B2bA derivative characterized by: the inert solvent is dichloromethane, dichloroethane, chloroform,Any one of sec-butyl acetate, dimethyl sulfoxide or dimethyl formamide, and the using amount of the inert solvent is avermectin B2a/B2b3-10 times of the mass of the derivatives;
the organic base is any one of triethylamine, tributylamine or tetramethyl ethylenediamine, and the using amount of the organic base is avermectin B2a/B2b1-2 times of the molar weight of the derivative;
the oxidant is any one of oxalyl chloride, trifluoroacetic anhydride, solid phosgene or phenyl phosphate diacid chloride, and the dosage of the oxidant is abamectin B2a/B2b0.5-2 times of the molar weight of the derivative;
the hydrazine compound has a chemical structure shown in a formula VII;
5. the 4' -hydrazone group substituted abamectin B of claim 12a/B2bA derivative characterized by: 4' -hydrazone group substituted avermectin B2a/B2bThe salt of the derivative has a chemical structural general formula shown in a formula II,
wherein HX represents C1-C20An alkyl carboxylic acid.
6. The 4' -hydrazone group substituted abamectin B of claim 52a/B2bA derivative characterized by: 4' -hydrazone group substituted avermectin B2a/B2bThe salt of the derivative is abamectin B substituted by 4' -hydrazone group2a/B2bThe derivative is prepared by reacting with organic acid C1-C20An alkyl carboxylic acid.
7. The 4' -hydrazone group substituted abamectin B of claim 52a/B2bA derivative characterized by: the 4' -hydrazone group substituted abamectin B2a/B2bDerivative and 4' -hydrazone group substituted abamectin B2a/B2bThe salts of the derivatives are used for controlling mites, aphids and lepidoptera pests.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0343708A2 (en) * | 1988-05-23 | 1989-11-29 | Merck & Co. Inc. | Avermectin derivatives |
| WO2004066725A2 (en) * | 2003-01-31 | 2004-08-12 | Syngenta Participations Ag | Avermectin- and avermectin monosaccharide derivatives substituted in the 4”- or 4’-position having pesticidal properties |
| CN107513088A (en) * | 2016-06-17 | 2017-12-26 | 浙江海正药业股份有限公司 | The purposes of its dimension streptozotocin derivative and its anti parasitic |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0343708A2 (en) * | 1988-05-23 | 1989-11-29 | Merck & Co. Inc. | Avermectin derivatives |
| WO2004066725A2 (en) * | 2003-01-31 | 2004-08-12 | Syngenta Participations Ag | Avermectin- and avermectin monosaccharide derivatives substituted in the 4”- or 4’-position having pesticidal properties |
| CN107513088A (en) * | 2016-06-17 | 2017-12-26 | 浙江海正药业股份有限公司 | The purposes of its dimension streptozotocin derivative and its anti parasitic |
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| Title |
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| "4-(1-硫杂-2-亚氨基-3,4-二氮杂-1,4-亚丁基)-4-脱氧阿维菌素B1a 的合成";颜世强;《有机化学》;20091231;第29卷(第12期);第2005-2016页 * |
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