CN109021034A - A kind of single chiral compound and preparation method thereof inhibiting lepidopterous insects - Google Patents
A kind of single chiral compound and preparation method thereof inhibiting lepidopterous insects Download PDFInfo
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- CN109021034A CN109021034A CN201811192206.3A CN201811192206A CN109021034A CN 109021034 A CN109021034 A CN 109021034A CN 201811192206 A CN201811192206 A CN 201811192206A CN 109021034 A CN109021034 A CN 109021034A
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- 0 C/C(/[C@@](*)(*CC1)[C@](*)(C2)C1=CC=CC[*+2])=*\C(\*)=C\C2(*)C=O Chemical compound C/C(/[C@@](*)(*CC1)[C@](*)(C2)C1=CC=CC[*+2])=*\C(\*)=C\C2(*)C=O 0.000 description 4
- COVKNBOLMSOOOY-VKZKZBKNSA-N C[C@@H](C(CC1)=O)OC1O Chemical compound C[C@@H](C(CC1)=O)OC1O COVKNBOLMSOOOY-VKZKZBKNSA-N 0.000 description 1
- HSTDAGYOXKZEFY-IHDQXYMRSA-N C[C@@H](C([C@H](C1)OC)O[C@@H]2OCCCC2)O[C@H]1O Chemical compound C[C@@H](C([C@H](C1)OC)O[C@@H]2OCCCC2)O[C@H]1O HSTDAGYOXKZEFY-IHDQXYMRSA-N 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N OC(c1ccccc1)=O Chemical compound OC(c1ccccc1)=O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The present invention provides a kind of single chiral compounds and preparation method thereof for inhibiting lepidopterous insects.The compound includes formula (I)-(VI).Wherein, formula (II): (4 " R) -4 "-deoxidation -4 "-methylamino avermectin B2a；Formula (V): (4 " R) -4 "-deoxidation -4 "-methylamino avermectin B2aBenzoate, in formula (V), R‑=Ph-COO‑, compound structure is as follows.The compounds of this invention is with avermectin B2aIt for precursor structure, obtains can inhibit the completely new drug molecule of the lepidopterous insects such as diamondback moth through base group modification, traditional avermectin B can not only be solved1aCompound it is existing drug resistance problems, while also achieving B2aSufficient utilization, provide a series of single chiral biological medicament of green high-efficients for agricultural, commodities market.
Description
Technical field
The present invention relates to field of agrochemicals, in particular to a kind of single chiral for inhibiting lepidopterous insects
Close object and preparation method thereof.
Background technique
Avermectin (Avermectins) is one generated by Avid kyowamycin (Streptomyces avermitilis)
The similar macrolide antibiotics of race's structure.This family antibiotic but has very strong insecticidal activity without antibacterial activity, is so far most
One of effective insecticidal, mite killing worm and antiparasitic drug, are widely used as crops pesticide and poultry enteron aisle pest repellant.
Avermectin includes 4 more component (80%~90%) A1a、A2a、B1aAnd B2aWith 4 less components
(10%~20%) A1b、A2b、B1bAnd B2b.Wherein active is B1aAnd B2a, but since B1a content is high, effect is wider
Spectrum, therefore, to the research of avermectin mainly for B1a, to B2aReport rarely have appearance
Due to B2aThe understanding of insecticidal action is insufficient, results in B2aIt is abandoned in production as by-product always.With Ah
Tie up rhzomorph B1aThe increase of service life, each class pest also inevitably increase biodegradation in its drug resistance and soil
By force.Thus, develop B1aSubstitute products, and realize for B2aMake full use of, then become technology urgently to be resolved at present and ask
Topic.
In view of this, the present invention is specifically proposed.
Summary of the invention
The first object of the present invention is to provide a kind of single chiral compound for inhibiting lepidopterous insects, the chemical combination
Object is with avermectin B2aBased on structure derivative compound, avermectin B can not only be substituted1aTo realize for pest
Effective killing, while also efficiently solving avermectin B2aEffective use problem.
The second object of the present invention is to provide the preparation method of the compound of lepidopterous insects processed described in one kind.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
A kind of single chiral compound inhibiting lepidopterous insects, the compound include such as in following formula (I)-(VI) extremely
Few one kind:
Wherein, compound (IV), (V), in (VI), R-For optional acid group；Preferably, R Cl, ClO, ClO3, Br,
BrO, BrO3, I, IO3, NO3, HCO3, H2PO4, HSO4Or R1Any one of-COO base；Wherein, R1For H, C1-C30's is taken
The substituted or non-substituted aryl of generation or non substituted alkyl or C6-C30.
Meanwhile the present invention also provides the preparation methods of the compound of the inhibition lepidopterous insects, comprising: (a): to
Dissolved with avermectin B2aAtent solvent in, oxidant, pro-oxidant and organic base is added, under the conditions of -35 DEG C~25 DEG C
Reaction time 0.5~for 24 hours, reaction solution separates water phase, is evaporated organic phase, obtain in 5 carbonyls after soda acid or salting liquid processing
Mesosome；5 carbonyl intermediates are dissolved in organic solvent, aminating agent and catalyst is added, are warming up to 30 DEG C~100 DEG C, reaction 1
~for 24 hours, cooling；Under polar solvent conditions, restore to obtain compound (I) with reducing agent；It is anti-with acid and alkali modulating compound (I)
The pH of liquid to 7~8 is answered, acid is then added into salt, obtains compound (IV)；
And/or (b): to dissolved with avermectin B2aAnd in the atent solvent of hydroxyl protection base reagent, organic base is added,
Keeping temperature is -35 DEG C~25 DEG C, reaction 1h~obtain 5 protection intermediates for 24 hours；Then oxidant, pro-oxidant is added, with
And organic base, under the conditions of -35 DEG C~25 DEG C, the reaction time 0.5~for 24 hours, reaction solution is handled with soda acid or salting liquid, separates water
Phase is evaporated organic phase, obtains 4 " position carbonyl intermediates；4 " position carbonyl intermediates are dissolved in organic solvent, be added aminating agent with
And catalyst, it is warming up to 30 DEG C~100 DEG C, reaction 1~for 24 hours, it is cooled to -35 DEG C~25 DEG C；Under polar solvent conditions, with also
Former agent restores to obtain 4 " position methylamino intermediates；Then, under polar solvent, and deprotection catalyst action, it is added second
Reducing agent obtains compound (II)；With acid and alkali solution modulating compound (II) reaction solution to pH7~8, water phase is separated, has been evaporated
Machine phase, products therefrom are dissolved in polar solvent, and acid progress salt-forming reaction is added and obtains compound (V)；
And/or (c): to dissolved with avermectin B2aAnd in the atent solvent of hydroxyl protection base reagent, organic base is added,
Keeping temperature is -35 DEG C~25 DEG C, reaction 1h~obtain 5,4 " positions two protection intermediate for 24 hours；Then, oxidant is added, helps
Oxidant and organic base, under the conditions of -35 DEG C~25 DEG C, the reaction time 0.5~for 24 hours, with soda acid or salting liquid processing reaction
Liquid separates water phase, is evaporated organic phase and obtains 23 carbonyl intermediates；23 carbonyl intermediates are dissolved in organic solvent, are added
Aminating agent and catalyst, are warming up to 30 DEG C~100 DEG C, and reaction 1~for 24 hours, then it is down to -35 DEG C~25 DEG C；In polar solvent
Under the conditions of, it restores to obtain 23 methylamino intermediates with reducing agent；Then, in polar solvent, and deprotection catalyst action
Under, the second reducing agent is added and obtains compound (III)；With acid and alkali solution modulating compound (III) reaction solution pH to 7~8, divide
Water phase out is evaporated organic phase, and products therefrom is dissolved in polar solvent, and acid progress salt-forming reaction is added and obtains compound (VI).
Compared with prior art, the invention has the benefit that
In the present invention, with avermectin B2aFor precursor structure, obtain can inhibit the Lepidopteras elder brother such as diamondback moth through base group modification
The completely new drug molecule of the single chiral of worm can not only solve traditional avermectin B1aCompound it is existing drug resistance ask
Topic, while also can be realized B2aSufficient utilization.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described.
Fig. 1 is 3 compound II Mass Spectrometer Method spectrogram of embodiment；
Fig. 2 is that 3 compound II nuclear-magnetism of embodiment detects spectrogram；
Fig. 3 is 4 compound V Mass Spectrometer Method spectrogram of embodiment；
Fig. 4 is that 4 compound V nuclear-magnetism of embodiment detects spectrogram.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
Novel Abamectin drug molecule provided by the present invention is with avermectin B2aFor precursor structure, pass through group
The obtained six classes derivative compound of modification, to solve existing avermectin B1aClass compound in terms of present in
The problem of.
Specifically, compound structure provided by the present invention is as follows:
Wherein, compound (IV)-(VI) is respectively compound (I)-(III) corresponding salt, can be by compound (I)-
(III) it is obtained with corresponding acid reaction.
Specifically, R base described in compound (IV)-(VI) are as follows: Cl, ClO, ClO3, Br, BrO, BrO3, I, IO3, NO3,
HCO3, H2PO4, HSO4Or R1Any one of-COO base；R1For H, the substituted or non-substituted alkyl or C6- of C1-C30
The substituted or non-substituted aryl of C30, for example, R1Can for substituted or non-substituted methyl, ethyl, propyl, isopropyl, butyl,
Isobutyl group, tert-butyl, amyl, isopentyl, neopentyl, hexyl etc. or R1It can be to replace (such as can be that alkyl replaces)
Or non-substituted phenyl, xenyl, naphthalene etc..
Further, by taking benzoic acid is hydrochloric acid as an example, the present invention prepares single chiral compound (I)-(VI) process such as
Under:
Wherein, (a) compound (I), (IV) can be prepared as follows to obtain:
By raw material avermectin B2a50 times or more moles are dissolved in (using the mole of raw material avermectin B2a as standard volume
" 1 " calculate, similarly hereinafter) atent solvent (one of methylene chloride, dichloroethanes, chloroform, benzene, toluene or dimethylbenzene
Or several) in；
Then, the oxidant of 1~5 times of mole and pro-oxidant (the chloromethyl carbonic acid of 0.4-1 times of mole is added
One of ester, phenyl phosphate diacid chloride, oxalyl chloride and trifluoro-acetic anhydride are a variety of) and 1-3 times of mole organic base ,-
Reaction time 0.5 under the conditions of 35 DEG C~25 DEG C~for 24 hours, reaction solution separates water phase, is evaporated organic after soda acid or salting liquid processing
Phase obtains 5-carbonyl intermediates；
5-carbonyl intermediates are dissolved in organic solvent, at room temperature, the aminating agent of 2~5 times of moles are added
(one of heptamethyldisilazane, Ammoniom-Acetate, acetic acid methylamine and methylamine hydrochloride or a variety of), after being stirred to react 20~40min
The amination catalysis (one of trifluoroacetic acid zinc, zinc chloride and zinc acetate or a variety of) of 0.005~0.05 times of mole is added,
It is warming up to 30 DEG C~100 DEG C, aminating reaction 1~for 24 hours, cooling；
Then, in reaction solution be added 8~20 times of moles polar solvent (one of alkylol of C1-C8 is more
Kind), then, under the conditions of -10~25 DEG C, the reducing agent (NaBH of 1~2 times of mole is added4、NaBH3CN、BH3、B2H6With
NaBH(OAc)3One or more of), react 1~5h, reaction solution is evaporated purifying, and (including column chromatographs and chiral resolution etc. is pure
Change step), obtain compound (I).
Further, by taking benzoic acid is at salt as an example, it is 8 that concentration can also be added into the reaction solution of compound (I)
The acetum of~16 (weight) % be adjusted to reaction solution pH for acidity, add concentration be 10~30 (weight) %NaOH or
NaHCO3The pH to 7~8 of solution adjusting reaction solution；Then stratification takes organic phase, 0.95~1.5 times of mole is added
Benzoic acid obtains compound (IV) at salt.Likewise, being also referred to method as above, HCl, HClO, HClO is added3, HBr,
HBrO, HBrO3, HI, HIO3, HNO3, H2CO3, H3PO4, H2SO4Or R1-COOH(R1For the substituted or non-substituted of H, C1-C30
The substituted or non-substituted aryl of alkyl or C6-C30, for example, R1Can for substituted or non-substituted methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl group, tert-butyl, amyl, isopentyl, neopentyl, hexyl etc. or R1It can be for replace (such as can be with
For alkyl substitution) or non-substituted phenyl, xenyl, naphthalene etc.) (R1- COOH is specifically such as formic acid, acetic acid) other are organic
Or inorganic acids, obtain the compound (IV) of other structures.
(b) compound (II), (V) preparation method can refer to it is as follows:
By raw material avermectin B2aAnd hydroxy protecting agent (allyl chlorocarbonate, monoxone alkene of 1~4 times of mole
One of propyl ester and benzyl chloroformate are a variety of) it is dissolved in atent solvent (methylene chloride, two chloroethenes of 50 times or more moles
One or more of alkane, chloroform, benzene, toluene or dimethylbenzene) in；Then, continuous or be added portionwise 1~4 times mole
The organic base (one of tetramethylethylenediamine, triethylamine, trimethylamine, tri-n-butylamine and pyridine or a variety of) of amount, keep temperature be-
35 DEG C~25 DEG C, reaction 1h~obtain 5 protection intermediates for 24 hours；
Then, 1~5 times of mole is added (with raw material avermectin B2aMole be standard volume " 1 " calculate, similarly hereinafter)
Pro-oxidant (chloromethyl carbonic ester, phenyl phosphate diacid chloride, oxalyl chloride and the trifluoro vinegar of oxidant and 0.4-1 times of mole
One of acid anhydrides is a variety of) and 1-3 times of mole organic base, reaction time 0.5~for 24 hours under the conditions of -35 DEG C~25 DEG C,
Reaction solution separates water phase, is evaporated organic phase, obtain 4 " positions-carbonyl intermediates after soda acid or salting liquid processing；
4 " position carbonyl intermediates are dissolved in organic solvent, aminating agent (seven methyl, the two silicon nitrogen of 2~5 times of moles is added
One of alkane, acetic acid methylamine and methylamine hydrochloride are a variety of), 0.005~0.05 times mole is added after being stirred to react 20~40min
The amination catalysis (one of trifluoroacetic acid zinc, zinc chloride and zinc acetate or a variety of) of amount, is warming up to 30 DEG C~100 DEG C, amine
Change reaction 1~for 24 hours, cooling；
The polar solvent (one of alkylol of C1-C8 or a variety of) of 8~20 times of moles is added in reaction solution；So
Afterwards, under the conditions of -10~25 DEG C, the reducing agent (NaBH of 1~2 times of mole is added4、NaBH3CN、BH3、B2H6And NaBH
(OAc)3One or more of) obtain 4 " position methylamino intermediates；
Then, into reaction solution, (one of alkylol of C1-C8 is more for the polar solvent of 4~10 times of moles of addition
Kind) and 0.0001~0.0081 mole deprotection catalyst (palladium salt, containing one in palladium complex and porous carrier containing palladium
Kind or it is a variety of) and 0.02~0.8 times of mole the second reducing agent (NaBH4、NaBH3CN、BH3、B2H6With NaBH (OAc)3
One of or it is a variety of), and under the conditions of -5~0 DEG C, react 1~5 hour, (including the column chromatography of purifying after reaction solution is evaporated
And the purification steps such as chiral resolution), obtain compound (II).
Further, still by taking benzoic acid is at salt as an example, can also be added into the reaction solution of compound (II) concentration be 8~
The acetum of 16 (weight) % be adjusted to reaction solution pH for acidity, add concentration be 10~30 (weight) %NaOH or
NaHCO3The pH to 7~8 of solution adjusting reaction solution；
Then, water phase is separated, organic phase is evaporated, products therefrom is dissolved in polar solvent (tert-butyl alcohol, isopropanol, isopropyl acetate
Ester, sec-butyl acetate, one of DMSO or DMF or a variety of) in, be added 0.95~1.5 times of mole benzoic acid carry out at
Reactant salt obtains compound (V)；
Likewise, being also referred to method as above, HCl, HClO, HClO is added3, HBr, HBrO, HBrO3, HI, HIO3,
HNO3, H2CO3, H3PO4, H2SO4Or R1-COOH(R1For H, the substituted or non-substituted alkyl of C1-C30 or taking for C6-C30
Generation or unsubstituted aryl, for example, R1Can for substituted or non-substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl group,
Tert-butyl, amyl, isopentyl, neopentyl, hexyl etc. or R1It can be substitution (such as can be that alkyl replaces) or non-substituted
Phenyl, xenyl, naphthalene etc.) (R1- COOH is specifically such as formic acid, acetic acid) other organic or inorganic acids at salt, obtain it
The compound (V) of his structure.
(c) compound (III), (VI) preparation method can refer to it is as follows:
By raw material avermectin B2aAnd hydroxy protecting agent (allyl chlorocarbonate, monoxone alkene of 1~4 times of mole
One of propyl ester and benzyl chloroformate are a variety of) it is dissolved in atent solvent (methylene chloride, two chloroethenes of 50 times or more moles
One or more of alkane, chloroform, benzene, toluene or dimethylbenzene) in；Then, continuous or be added portionwise 1~4 times mole
The organic base (one of tetramethylethylenediamine, triethylamine, trimethylamine, tri-n-butylamine and pyridine or a variety of) of amount, keep temperature be-
35 DEG C~25 DEG C, reaction 1h~obtain 5, the protection intermediate of 4 " position two for 24 hours；
Then, 1~5 times of mole is added (with raw material avermectin B2aMole be standard volume " 1 " calculate, similarly hereinafter)
Pro-oxidant (chloromethyl carbonic ester, phenyl phosphate diacid chloride, oxalyl chloride and the trifluoro vinegar of oxidant and 0.4-1 times of mole
One of acid anhydrides is a variety of) and 1-3 times of mole organic base, reaction time 0.5~for 24 hours under the conditions of -35 DEG C~25 DEG C,
Reaction solution separates water phase, is evaporated organic phase, obtain 23-carbonyl intermediates after soda acid or salting liquid processing；
23 carbonyl intermediates are dissolved in organic solvent, aminating agent (seven methyl, the two silicon nitrogen of 2~5 times of moles is added
One of alkane, acetic acid methylamine and methylamine hydrochloride are a variety of), 0.005~0.05 times mole is added after being stirred to react 20~40min
The amination catalysis (one of trifluoroacetic acid zinc, zinc chloride and zinc acetate or a variety of) of amount, is warming up to 30 DEG C~100 DEG C, amine
Change reaction 1~for 24 hours, cooling；
The polar solvent (one of alkylol of C1-C8 or a variety of) of 8~20 times of moles is added in reaction solution；So
Afterwards, under the conditions of -10~25 DEG C, the reducing agent (NaBH of 1~2 times of mole is added4、NaBH3CN、BH3、B2H6And NaBH
(OAc)3One or more of) obtain 23 methylamino intermediates；
Then, into reaction solution, (one of alkylol of C1-C8 is more for the polar solvent of 4~10 times of moles of addition
Kind) and 0.0001~0.0081 mole deprotection catalyst (palladium salt, containing one in palladium complex and porous carrier containing palladium
Kind or it is a variety of) and 0.02~0.8 times of mole the second reducing agent (NaBH4、NaBH3CN、BH3、B2H6With NaBH (OAc)3
One of or it is a variety of), and under the conditions of -5~0 DEG C, react 1~5 hour, (including the column chromatography of purifying after reaction solution is evaporated
And the purification steps such as chiral resolution), obtain compound (III).
Further, equally by taking benzoic acid is at salt as an example, concentration can also be added into the reaction solution of compound (III) is
The acetum of 8~16 (weight) % be adjusted to reaction solution pH for acidity, add concentration be 10~30 (weight) %NaOH or
NaHCO3The pH to 7~8 of solution adjusting reaction solution；
Then, water phase is separated, organic phase is evaporated, products therefrom is dissolved in polar solvent (tert-butyl alcohol, isopropanol, isopropyl acetate
Ester, sec-butyl acetate, one of DMSO or DMF or a variety of) in, be added 0.95~1.5 times of mole benzoic acid carry out at
Reactant salt obtains compound (VI)；
Likewise, being also referred to method as above, HCl, HClO, HClO is added3, HBr, HBrO, HBrO3, HI, HIO3,
HNO3, H2CO3, H3PO4, H2SO4Or R1-COOH(R1For H, the substituted or non-substituted alkyl of C1-C30 or taking for C6-C30
Generation or unsubstituted aryl, for example, R1Can for substituted or non-substituted methyl, ethyl, propyl, isopropyl, butyl, isobutyl group,
Tert-butyl, amyl, isopentyl, neopentyl, hexyl etc. or R1It can be substitution (such as can be that alkyl replaces) or non-substituted
Phenyl, xenyl, naphthalene etc.) (R1- COOH is specifically such as formic acid, acetic acid) other organic or inorganic acids at salt, obtain it
The compound (VI) of his structure.
Embodiment 1
By raw material avermectin B2aIt is dissolved in 60 times or more mole dichloroethanes；
Then, the trichloromethyl carbonate and 2 times of moles of DMSO and 0.5 times of mole of 2 times of moles is added
Tri-n-butylamine, reaction time 12h under the conditions of -5 DEG C, reaction solution separates water phase after salting liquid is handled, is evaporated organic phase, obtain
To 5-carbonyl intermediates；
5-carbonyl intermediates are dissolved in organic solvent, at room temperature, seven methyl, two silicon of 2 times of moles are added
Azane stirs the amination catalysis trifluoroacetic acid zinc of 0.01 times of mole of addition after 30min, is warming up to 70 DEG C, aminating reaction
12h, cooling；
Then under the conditions of -5 DEG C, 1 times of mole is added in the methanol that 10 times of moles are added in reaction solution
NaBH4, 2h is reacted, reaction solution is evaporated purifying, obtains compound (I),
Structure is as follows:
Its chemical formula are as follows: C49H77NO14；Theoretical molecular weight are as follows: 903.5344, practical Mass Spectrometer Method molecular weight are as follows: 904.1.
Embodiment 2
According to the method for embodiment 1, the reaction solution of compound (I) is obtained, then, is added into the reaction solution of compound (I)
Entering the acetum that concentration is 15% to be adjusted to reaction solution pH is acidity, and adding concentration is 10%NaOH solution, adjusts reaction
The pH to 7~8 of liquid；
Then, the benzoic acid of 1.1 times of moles is added into salt, obtains compound (IV), structure is as follows:
Its chemical formula are as follows: C56H83NO16；Theoretical molecular weight are as follows: 1025.5712, practical Mass Spectrometer Method compound (IV) band lotus
Moieties amount are as follows: 904.2, anti-lotus moieties amount are as follows: 121.2.
Embodiment 3
By avermectin B2aAnd the allyl chlorocarbonate of 2 times of moles is dissolved in the methylene chloride of 60 times of moles；So
Afterwards, the tetramethylethylenediamine of 2 times of moles is added portionwise, keeping temperature is -15 DEG C, and reaction 12h obtains 5 protection intermediates；
Then, the pro-oxidant phenyl phosphate diacid chloride that DMSO and 1 times of mole of 2 times of moles is added and 1 times rub
The triethylamine of your amount, reaction time 12h under the conditions of -5 DEG C, reaction solution separate water phase after soda acid is handled, are evaporated organic phase,
Obtain 4 " positions-carbonyl intermediates；
4 " position carbonyl intermediates are dissolved in organic solvent, the heptamethyldisilazane of 2 times of moles is added, is stirred to react
The zinc chloride of 0.03 times of mole is added after 30min, is warming up to 70 DEG C, aminating reaction 12h, cooling；
The ethyl alcohol of 15 times of moles is added in reaction solution；Then, under the conditions of -5 DEG C, the reduction of 1 times of mole is added
Agent NaBH3CN obtains 4 " position methylamino intermediates；
Then, the polar solvent ethyl alcohol of 5 times of moles and the palladium chloride of 0.005 mole are added into reaction solution, with
And the second reducing agent NaBH (OAc) of 0.5 times of mole3, and under the conditions of 0 DEG C, it reacts 5 hours, reaction solution is evaporated rear pure
Change, obtain compound (II), structure is as follows:
Its chemical formula are as follows: C49H77NO14；Time of-flight mass spectrometer (MALDI-TOF) detects [M+H]+: 904.958 ([M+
Na]+:926.957；[M+K]+: 942.924 in error range).Mass spectrogram is as shown in Figure 1, nuclear magnetic spectrum is as shown in Figure 2.
Nuclear magnetic resonance spectroscopy is analyzed as follows: 1H NMR (400MHz, CDCl3) δ 5.86 (d, J=9.7Hz, 1H), and 5.77-
5.70 (m, 2H), 5.43 (s, 1H), 5.36 (s, 1H), 5.30 (s, 1H), 4.98 (s, 1H), 4.75 (d, J=3.3Hz, 1H),
4.73-4.63 (m, 2H), 4.30 (s, 1H), 3.97 (dd, J=12.7,6.3Hz, 4H), 3.84-3.73 (m, 3H), 3.67 (d, J
=11.6Hz, 1H), 3.57 (d, J=10.9Hz, 2H), 3.52 (d, J=10.1Hz, 1H), 3.42 (s, 3H), 3.39 (s, 3H),
3.29 (s, 1H), 3.24 (t, J=8.9Hz, 1H), 2.69 (s, 1H), 2.59 (s, 3H), 2.52 (s, 1H), 2.31 (t, J=
8.0Hz, 3H), 2.19 (d, J=8.9Hz, 1H), 2.01-1.95 (m, 2H), 1.88 (s, 3H), 1.81-1.74 (m, 2H),
1.70-1.54 (m, 5H), 1.50 (s, 3H), 1.47-1.38 (m, 2H), 1.28 (d, J=6.7Hz, 3H), 1.24 (d, J=
6.2Hz, 3H), 1.16 (d, J=6.9Hz, 3H), 0.96 (t, J=7.2Hz, 3H), 0.92-0.81 (m, 7H).
Embodiment 4
According to the method for embodiment 3, the reaction solution of compound (II) is obtained, is added into the reaction solution of compound (II) dense
It is acidity that the acetum that degree is 15%, which is adjusted to reaction solution pH, and adding concentration is 10%NaOH solution, adjusts reaction solution
PH to 7~8；
Then, water phase is separated, organic phase is evaporated, products therefrom is dissolved in isopropyl acetate, and the benzene of 1.2 times of moles is added
Formic acid carries out salt-forming reaction and obtains compound (V), and structure is as follows:
Its chemical formula are as follows: C56H83NO16；Theoretical molecular weight are as follows: 1025.5712, practical Mass Spectrometer Method compound (IV) band lotus
Moieties amount are as follows: 904.280, anti-lotus moieties amount are as follows: 121.2.Mass spectrogram is as shown in figure 3, nuclear magnetic spectrum such as Fig. 4 institute
Show.
Nuclear magnetic resonance spectroscopy is analyzed as follows: 1H NMR (400MHz, CDCl3) δ 8.13 (d, J=7.7Hz, 2H), 7.62 (t,
J=7.4Hz, 1H), 7.50 (t, J=7.6Hz, 2H), 5.86 (d, J=9.7Hz, 1H), 5.77-5.70 (m, 2H), 5.43 (s,
1H), 5.36 (s, 1H), 5.30 (s, 1H), 4.98 (s, 1H), 4.75 (d, J=3.3Hz, 1H), 4.73-4.63 (m, 2H), 4.30
(s, 1H), 3.97 (dd, J=12.7,6.3Hz, 4H), 3.84-3.73 (m, 3H), 3.67 (d, J=11.6Hz, 1H), 3.57 (d,
J=10.9Hz, 2H), 3.52 (d, J=10.1Hz, 1H), 3.42 (s, 3H), 3.39 (s, 3H), 3.29 (s, 1H), 3.24 (t, J
=8.9Hz, 1H), 2.69 (s, 1H), 2.59 (s, 3H), 2.52 (s, 1H), 2.31 (t, J=8.0Hz, 3H), 2.19 (d, J=
8.9Hz,1H),2.01–1.95(m,2H),1.88(s,3H),1.81–1.74(m,2H),1.70–1.54(m,5H),1.50(s,
3H), 1.47-1.38 (m, 2H), 1.28 (d, J=6.7Hz, 3H), 1.24 (d, J=6.2Hz, 3H), 1.16 (d, J=6.9Hz,
3H), 0.96 (t, J=7.2Hz, 3H), 0.92-0.81 (m, 7H).
Embodiment 5
By raw material avermectin B2aAnd the benzyl chloroformate of 2 times of moles is dissolved in the toluene of 70 times of moles；Then,
The triethylamine of 4 times of moles is added portionwise, keeping temperature is -25 DEG C, and reaction obtains 5, the protection intermediate of 4 " position two for 24 hours；
Then, the oxalyl chloride of DMSO and 1 times of mole of 3 times of moles and the tetramethyl second two of 1 times of mole is added
Amine, reaction solution separated water phase, was evaporated organic phase, obtain after soda acid or salting liquid processing for 24 hours the reaction time under the conditions of -5 DEG C
To 23-carbonyl intermediates；
23 carbonyl intermediates are dissolved in organic solvent, the Ammoniom-Acetate of 4 times of moles are added, after being stirred to react 30min
The amination catalysis zinc acetate of 0.5 times of mole is added, is warming up to 70 DEG C, aminating reaction for 24 hours, cools down；
The ethyl alcohol of 15 times of moles is added in reaction solution；Then, under the conditions of -10~25 DEG C, 1 times of mole is added
B2H6Obtain 23 methylamino intermediates；
Then, into reaction solution, the isopropanol of 8 times of moles and the palladium chloride and 0.5 of 0.005 mole is added
The B of times mole2H6, and under the conditions of 0 DEG C, it reacts 5 hours, purifies, obtain compound (III) after reaction solution is evaporated, tie
Structure is as follows:
Its chemical formula are as follows: C49H77NO14；Theoretical molecular weight are as follows: 903.5344, practical Mass Spectrometer Method molecular weight are as follows:
904.1340。
Embodiment 6
According to the method for embodiment 5, the reaction solution of compound (III) is obtained, is added into the reaction solution of compound (III)
It is acidity that the acetum that concentration is 15%, which is adjusted to reaction solution pH, and adding concentration is 10%NaOH solution, adjusts reaction solution
PH to 7~8；
Then, water phase is separated, organic phase is evaporated, products therefrom is dissolved in isopropyl acetate, and the benzene of 1.2 times of moles is added
Formic acid carries out salt-forming reaction and obtains compound (VI), and structure is as follows:
Its chemical formula are as follows: C56H83NO16；Theoretical molecular weight are as follows: 1025.5712, practical Mass Spectrometer Method compound (VI) band lotus
Moieties amount are as follows: 904.2, anti-lotus moieties amount are as follows: 121.2.
Experimental example 1
With compound V prepared by embodiment 4 for compound to be tested, virulence test is carried out, specific as follows:
1, experimental condition
1.1 for trying target:
Diamondback moth (Plutella xylostella L.) third-instar larvae, size is almost the same, healthy, average worm weight
0.0036 ± 0.0001 gram/head.
1.2 condition of culture:
Insectary condition are as follows: 22~25 DEG C of temperature, relative humidity 70~80%, periodicity of illumination L: D=14: 10, with new
Fresh Turnip Sprouts are raised.
2, experimental design
2.1 reagent
2.1.1 test medicine:
2% compound V missible oil.
5.7% emamectin-benzoate water dispersible granules, Zhejiang Hisun Chemical Co., Ltd's product.
2.1.2 other reagents:
Distilled water etc..
2.2 test process
2.2.1 dosage is arranged:
Reagent agent be directly diluted to respectively with distilled water 1000 times, 2000 times, 4000 times, 8000 times, 16000 times and
32000 times of liquid.Using distilled water as blank control.
2.2.2 test repeats:
It tests each concentration and sets 4 repetitions, every time reprocessing test worm 15.
2.3 processing mode
2.3.1 time and number are handled:
The progress test medicine processing on the 14th of September in 2018.
2.3.2 instrument and administrated method are used:
There are beaker, tweezers, stopwatch, insect box (long 8cm, wide 8cm, high 5cm) etc. using instrument, dip method be respectively adopted,
Dip time is 30 seconds.
3, test method:
Dip method
Will be in the same size, 3 instar larvae pickings of active health are into leaching worm cage, with water suction after impregnating 30 seconds in medical fluid
Paper sucks extra medical fluid, is put into using cabbage leaves to cover box cover in the insect box of foodstuff.
Referring to People's Republic of China's agricultural industry criteria NY/T 1154.6-2006, farm-chemical indoor determination test is quasi-
Then the 6th part: insecticidal activity test, dip method.
4, data survey and statistical analysis
4.1 investigation methods and grade scale:
Pilot survey method is to touch polypide with writing brush by those of skill in the art, motionless, or the person that normally cannot not creep is calculated as
It is dead.
4.2 control times and number:
Pilot survey twice, that is, handle after (72 hours) second day (48 hours), third day inspection test worm death conditions.
4.3 data statistic analysis
Test worm survival condition is investigated, corrected mortality is calculated, statistic analysis result is shown in Table 1.The initial data of test is shown in Table
2。
5 interpretations of result and discussion
5.1 evaluating drug
1 2% compound V missible oil of table is to diamondback moth indoor bioassay result table
By test medicine as above to the result of diamondback moth (dip method) it is found that 2% 1000 times of compound V missible oil of reagent agent
Liquid has preferable virulence to diamondback moth, and 72 hours corrected mortalities are 85.46%.
48 hours after medicine, 72 hours the result shows that: 2% compound V missible oil of reagent agent is lower than phase to the virulence of test worm
The 5.7% emamectin-benzoate water dispersible granules with extension rate are to the virulence of test worm.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of single chiral compound for inhibiting lepidopterous insects, which is characterized in that the compound includes such as following formula (I)-
At least one of (VI):
Wherein, compound (IV), (V), in (VI), R-For optional acid group；
Preferably, R base is Cl, ClO, ClO3, Br, BrO, BrO3, I, IO3, NO3, HCO3, H2PO4, HSO4Or R1In-COO base
It is any；
Wherein R1For H, the substituted or non-substituted alkyl of C1-C30 or the substituted or non-substituted aryl of C6-C30.
2. the preparation method of the single chiral compound described in claim 1 for inhibiting lepidopterous insects, which is characterized in that packet
It includes:
(a): to dissolved with avermectin B2aAtent solvent in, oxidant, pro-oxidant and organic base is added, -35 DEG C~
Reaction time 0.5 under the conditions of 25 DEG C~for 24 hours, reaction solution separates water phase, is evaporated organic phase, obtain after soda acid or salting liquid processing
To 5 carbonyl intermediates；
5 carbonyl intermediates are dissolved in organic solvent, aminating agent and catalyst is added, are warming up to 30 DEG C~100 DEG C, reaction 1
~for 24 hours, cooling；Under polar solvent conditions, restore to obtain compound (I) with reducing agent；
With the pH to 7~8 of acid and alkali modulating compound (I) reaction solution, acid is then added into salt, obtains compound (IV)；
And/or (b): to dissolved with avermectin B2aAnd in the atent solvent of hydroxyl protection base reagent, organic base is added, keeps
Temperature is -35 DEG C~25 DEG C, reaction 1h~obtain 5 protection intermediates for 24 hours；
Then oxidant, pro-oxidant and organic base is added, under the conditions of -35 DEG C~25 DEG C, the reaction time 0.5~for 24 hours,
Reaction solution is handled with soda acid or salting liquid, water phase is separated, is evaporated organic phase, obtain 4 " position carbonyl intermediates；
4 " position carbonyl intermediates are dissolved in organic solvent, aminating agent and catalyst is added, is warming up to 30 DEG C~100 DEG C, instead
Answer 1~for 24 hours, it is cooled to -35 DEG C~25 DEG C；Under polar solvent conditions, restore to obtain 4 " position methylamino intermediates with reducing agent；
Then, under polar solvent, and deprotection catalyst action, the second reducing agent is added and obtains compound (II)；
With acid and alkali solution modulating compound (II) reaction solution to pH7~8, water phase is separated, is evaporated organic phase, products therefrom is dissolved in
In polar solvent, acid progress salt-forming reaction is added and obtains compound (V)；
And/or (c): to dissolved with avermectin B2aAnd in the atent solvent of hydroxyl protection base reagent, organic base is added, keeps
Temperature is -35 DEG C~25 DEG C, reaction 1h~obtain 5,4 " positions two protection intermediate for 24 hours；
Then, oxidant, pro-oxidant and organic base is added, under the conditions of -35 DEG C~25 DEG C, the reaction time 0.5~for 24 hours,
Reaction solution is handled with soda acid or salting liquid, water phase is separated, is evaporated organic phase and obtains 23 carbonyl intermediates；
23 carbonyl intermediates are dissolved in organic solvent, aminating agent and catalyst is added, is warming up to 30 DEG C~100 DEG C, instead
Answer 1~for 24 hours, then it is down to -35 DEG C~25 DEG C；Under polar solvent conditions, restore to obtain among 23 methylaminos with reducing agent
Body；
Then, under polar solvent, and deprotection catalyst action, the second reducing agent is added and obtains compound (III)；
With acid and alkali solution modulating compound (III) reaction solution pH to 7~8, water phase is separated, organic phase is evaporated, products therefrom is molten
In polar solvent, acid progress salt-forming reaction is added and obtains compound (VI).
3. preparation method according to claim 2, which is characterized in that in reaction (a)-(c), the atent solvent is dichloro
One or more of methane, dichloroethanes, chloroform, benzene, toluene or dimethylbenzene；
The mole dosage of atent solvent is raw material avermectin B2a25 times or more of mole；
And/or reaction (a), (b), in (c), organic solvent is the tert-butyl alcohol, isopropanol, isopropyl acetate, sec-butyl acetate,
One or more of DMSO or DMF.
4. preparation method according to claim 2, which is characterized in that in reaction (b), (c), hydroxy protecting agent is chloromethane
One of allyl propionate, allyl chloroacetate and benzyl chloroformate are a variety of；
The dosage of hydroxyl protection base reagent is raw material avermectin B2a1~4 times of mole；
And/or the organic base is one of tetramethylethylenediamine, triethylamine, trimethylamine, tri-n-butylamine and pyridine or a variety of；
The dosage of the organic base is raw material avermectin B2a1~4 times of mole；
The organic base is continuous or is added portionwise.
5. preparation method according to claim 2, which is characterized in that in reaction (a)-(c), the oxidant are as follows: DMSO；
The mole dosage of oxidant is raw material avermectin B2a1~5 times of mole；
And/or the pro-oxidant is in trichloromethyl carbonate, phenyl phosphate diacid chloride, oxalyl chloride and trifluoro-acetic anhydride
It is one or more, the mole dosage of pro-oxidant is raw material avermectin B2a1~3 times of mole；
And/or the organic base are as follows: one of tetramethylethylenediamine, triethylamine, trimethylamine or tri-n-butylamine are a variety of, organic
The mole dosage of alkali is raw material avermectin B2a1~3 times of mole.
6. preparation method according to claim 2, which is characterized in that in reaction (a)-(c), the process of the aminating reaction
Include: that aminating agent is added into reaction solution at room temperature, amination catalysis is added after being stirred to react 20~40min, then exists
Reaction 1~for 24 hours is carried out at 30~100 DEG C；
And/or the aminating agent is selected from one of heptamethyldisilazane, acetic acid methylamine and methylamine hydrochloride or a variety of；
The mole dosage of aminating agent is raw material avermectin B2a2~5 times of mole；
And/or the amination catalysis is selected from one of trifluoroacetic acid zinc, zinc chloride and zinc acetate or a variety of；
The mole dosage of amination catalysis is raw material avermectin B2a0.005~0.05 times of mole.
7. preparation method according to claim 2, which is characterized in that in reaction (a)-(c), the polar solvent is selected from
One of alkylol of C1-C8 is a variety of；
The mole dosage of polar solvent is raw material avermectin B2a8~20 times of mole；
And/or the reducing agent is selected from NaBH4、NaBH3CN、BH3、B2H6And NaBH (OAc)3One of or it is a variety of；
The dosage of reducing agent is raw material avermectin B2a1~2 times of mole.
8. preparation method according to claim 2, which is characterized in that in reaction (a)-(c), the polar solvent is selected from
One of alkylol of C1-C8 is a variety of；
The mole dosage of polar solvent is raw material avermectin B2a4~10 times of mole；
And/or the deprotection catalyst is selected from palladium salt, containing one of palladium complex and porous carrier containing palladium or a variety of；
The mole dosage of deprotection reaction catalyst is raw material avermectin B2a0.0001~0.0081 times of mole；
And/or second reducing agent is selected from NaBH4、NaBH3CN、BH3、B2H6And NaBH (OAc)3One of or it is a variety of；
The dosage of second reducing agent is raw material avermectin B2a0.02~0.8 times of mole.
9. according to the method described in claim 2, it is characterized in that, reacting in (a)-(c), in such a way that acid and alkali adjusts pH value
Include: first to be adjusted with acid reaction solution to acidity, pH value is then adjusted to as 7~8 with alkali；
The acid is the acetic acid or phosphoric acid solution of concentration 8~16%, and the alkali is the NaOH or NaHCO of concentration 10~30%3It is molten
Liquid.
10. sour mole dosage is raw material avermectin according to the method described in claim 2, wherein, reacting in (a)-(c)
B2a0.95~1.5 times of mole.
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|---|---|---|---|---|
| CN103214532A (en) * | 2013-02-28 | 2013-07-24 | 河北威远生物化工股份有限公司 | Avermectin B2a/2b amine derivatives, derivative salts thereof, and preparation method and application of avermectin B2a/2b amine derivative salt |
| CN104497081A (en) * | 2014-05-14 | 2015-04-08 | 孟水强 | Macrolide benzoate compound and application thereof |
| CN105037467A (en) * | 2015-05-29 | 2015-11-11 | 河北威远生化农药有限公司 | 4'-desoxy-4'-alkylated or acylated amino avermectin B2a/2b derivative, and preparation method and application thereof |
| CN106995476A (en) * | 2017-05-16 | 2017-08-01 | 河北美荷药业有限公司 | A kind of preparation method of emamectin benzoate B2 benzoates |
| CN107344954A (en) * | 2017-08-07 | 2017-11-14 | 河北蓝泰化工科技有限公司 | Synergistic type emamectin benzoate B1 or B2 salt and preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103214532A (en) * | 2013-02-28 | 2013-07-24 | 河北威远生物化工股份有限公司 | Avermectin B2a/2b amine derivatives, derivative salts thereof, and preparation method and application of avermectin B2a/2b amine derivative salt |
| CN104497081A (en) * | 2014-05-14 | 2015-04-08 | 孟水强 | Macrolide benzoate compound and application thereof |
| CN105037467A (en) * | 2015-05-29 | 2015-11-11 | 河北威远生化农药有限公司 | 4'-desoxy-4'-alkylated or acylated amino avermectin B2a/2b derivative, and preparation method and application thereof |
| CN106995476A (en) * | 2017-05-16 | 2017-08-01 | 河北美荷药业有限公司 | A kind of preparation method of emamectin benzoate B2 benzoates |
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