CN109467582A - One kind being based on avermectin B2Emamectin-benzoate synthetic method and application - Google Patents

One kind being based on avermectin B2Emamectin-benzoate synthetic method and application Download PDF

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CN109467582A
CN109467582A CN201811383572.7A CN201811383572A CN109467582A CN 109467582 A CN109467582 A CN 109467582A CN 201811383572 A CN201811383572 A CN 201811383572A CN 109467582 A CN109467582 A CN 109467582A
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avermectin
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王泊理
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Abstract

The present invention relates to one kind to be based on avermectin B2Emamectin-benzoate (YAB) synthetic method and application, belong to technical field of organic synthesis.Preparation method of the present invention is specifically by avermectin B2Successively carry out hydroxyl protection reaction, hydroxyl oxidation reaction, carbonyl aminating reaction, imine reduction and hydroxyl deprotection reaction, target product YAB is made in salt-forming reaction.Product YAB produced by the present invention and it is now widely used be based on avermectin B1Emamectin-benzoate compare, benzoate pesticide activity of the invention is higher, and toxicity is lower, and cost of material is also low, have the significant market advantage.

Description

One kind being based on avermectin B2Emamectin-benzoate synthetic method And application
Technical field
The invention belongs to technical field of organic synthesis, specifically, being related to a kind of based on avermectin B2Methylamino Ah Tie up the synthetic method and application of rhzomorph benzoate.
Background technique
Avermectin (Avermectins) is developed first by big village's intelligence of Japanese North university etc. and U.S. Merck company One kind have desinsection, mite killing, eelworm-killing activity ten hexa-atomic Macrocyclic lactone compounds, by streptomyces griseus in streptomycete Streptomyces avermitilis fermentation generates.Contain 8 components in natural avermectin, mainly there is 4 kinds i.e. A1a、A2a、 B1aAnd B2a, total content >=80%；The lesser homologue of corresponding 4 ratios is A1b、A2b、B1bAnd B2b, total content≤ 20%.B1And B2Compound (including B1a、B1b、B2a、B2b) structure as shown in following formula one, B1aMolecular formula is C48H72O14, molecule Amount is 873.1；B1bMolecular formula is C47H70O14, molecular weight 859.1；B2aMolecular formula is C48H74O15, molecular weight 891.1；B2b Molecular formula is C47H72O15, molecular weight 877.1, wherein a and b homologue is only the difference (CH of substituent group3And C2H5), such as table Shown in 1, and B1And B2Structure in, the difference on spirocyclic ring scaffold, B1Homologue is unsaturated double bond, and B2Homologue For the structure of alcohol, to a certain extent, B2Spirocyclic ring scaffold, which sloughs a molecular water, can be obtained B1Homologue, this makes it corresponding Possibility is transformed into, but since intramolecular is also containing the hydroxyl at ortho position, there is also the possibility of dehydration, therefore select suitable condition It is crucial that selectivity, which carries out conversion,.
Particular functional group's contrast table in 1 avermectin each group molecular structure of table
avermectin R1 R2 X-Y avermectin R1 R2 X-Y
B1a H C2H5 CH=CH A1a CH3 C2H5 CH=CH
B1b H CH3 CH=CH A1b CH3 CH3 CH=CH
B2a H C2H5 CH2-CH(OH) A2a CH3 C2H5 CH2-CH(OH)
B2b H CH3 CH2-CH(OH) A2b CH3 CH3 CH2-CH(OH)
Presently commercially available avermectin pesticides are with abamectin for main insecticidal constituent (Avermectin B1a+B1b, Middle B1aNot less than 90%, B1bNo more than 5%), with B1aContent demarcate.On this basis, agricultural chemicals research and development personnel are with Avermectin Plain B1For precursor, start to have synthesized emamectin-benzoate (referred to as emamectin benzoate), it is a kind of new and effective half Synthetic antibiotic insecticide, compared with raw medicine avermectin, insecticidal activity first improves 3 orders of magnitude, to lepidopterous insects The activity of larva and other many pests is high, existing stomach poison function again and action of contace poison, low-down dosage (0.084~ There is good effect under 2g/ha), and beneficial insect is not injured during pest control, be conducive to the comprehensive of pest Prevention and treatment is closed, insecticidal spectrum is in addition expanded, reduces the toxicity to people and animals.
Avermectin B2Homologue also has certain insecticidal activity, but with avermectin B1It compares, activity difference It is very big, fail always to be effectively utilized and promote, since its price is relatively relatively inexpensive, if avermectin B can be based on2It is different Structure body effectively modifies its structure, improves its insecticidal activity, reduces toxicity, the advantage based on its price, exploitation and Using with very actual meaning.
Based on the above reasons, special to propose the application.
Summary of the invention
Of the existing technology in order to overcome the problems, such as, the purpose of the present invention is to provide one kind to be based on avermectin B2First The synthetic method and application of amino abamectin benzoate (YAB).
It is provided by the invention to be based on avermectin B in order to realize above-mentioned first purpose of the invention2Methylamino AVM hereinafter The synthetic method of rhzomorph benzoate, the synthetic route of the method is as shown in following formula two:
It is described above based on avermectin B2Emamectin-benzoate synthetic method, the method packet Include following steps:
(1) hydroxyl protection reacts: under room temperature, by avermectin B2Dissolution is in methylene chloride, first under argon gas protection It is added at one time triethylamine and then allyl chlorocarbonate is added dropwise, continue after being passed through 0.5~2h of argon gas after being added dropwise, it is close 48h reacts in closure system, after completion of the reaction, removes solvent, obtains crude product, the crude product methylene chloride and acetone washing, obtain Mesosome I is contained due to the difference of the hydroxyl activity of three kinds of positions, in the intermediate I there are two types of ingredient, is 5- allyl formate base Avermectin B2With 5,23- diformazan allyl propionate base avermectin B2；
(2) hydroxyl oxidation reaction: in methylene chloride by the dissolution of intermediate I made from step (1), it is sub- that dimethyl is added Sulfone is cooled to -60 DEG C, then dehydrating agent is added dropwise, and for 24 hours, after completion of the reaction, yellow is obtained by filtration in isothermal reaction under the conditions of -60 DEG C The yellow solid methylene chloride and acetone washing are obtained intermediate II by solid, the intermediate II contain there are two types of at Point, it is 5- allyl formate base -4 ", C23- carbonyl avermectin B2With 5,23- diformazan allyl propionate base -4 "-carbonyl Avermectin Plain B2；
(3) carbonyl aminating reaction: in methylene chloride by the dissolution of intermediate II made from step (2), seven methyl two are added Silazane reacts 2h at room temperature, after completion of the reaction, uses ethyl alcohol recrystallization after removing solvent, obtains intermediate III, the intermediate III contains there are two types of ingredient, is 5- allyl formate base -4 ", C23- dimethyleneimine base avermectin B2With 5,23- dioctyl phthalate allyl Ester group -4 "-azomethine base avermectin B2；
(4) imine reduction, hydroxyl deprotection reaction: the dissolution of intermediate III that step (3) is obtained in methylene chloride, adds Enter sodium borohydride, react 8h, after completion of the reaction, remove solvent, acetonitrile is then added, and adds sodium borohydride the reaction was continued for 24 hours, Solvent is removed again, is recrystallized in methylene chloride, and intermediate IV is obtained, it is 4 " that the intermediate IV, which contains there are two types of ingredient, C23- dimethylamino avermectin B2With 4 "-emamectin benzoate B2；
(5) intermediate IV made from step (4) is dissolved in ethyl acetate, benzoic acid is added, is stirred at room temperature 30 minutes Afterwards, solvent is removed, product is finally obtained and is based on avermectin B2Emamectin-benzoate (YAB), effectively at Divide shown in following three:
Further, above-mentioned technical proposal, avermectin B described in step (1)2Molar ratio with triethylamine is 1:12.
Further, above-mentioned technical proposal, avermectin B described in step (1)2Molar ratio with allyl chlorocarbonate is 1:2.5.
Further, above-mentioned technical proposal, intermediate I described in step (2) and the molar ratio of dimethyl sulfoxide are 1:20.
Further, above-mentioned technical proposal, intermediate I described in step (2) and the molar ratio of dehydrating agent are 1:10.
Preferably, above-mentioned technical proposal, dehydrating agent described in step (2) are preferably trifluoroacetic anhydride or oxalyl chloride.
Further, above-mentioned technical proposal, intermediate II described in step (3) and the molar ratio of heptamethyldisilazane are 1:5.
Further, the molar ratio of total amount is added in above-mentioned technical proposal, intermediate III described in step (4) and sodium borohydride For 1:30.
Further, the molar ratio of above-mentioned technical proposal, intermediate IV described in step (5) and benzoic acid is 1:1.8.
Second purpose of the present invention is to provide made from method described above based on avermectin B2First ammonia The application of base abamectin benzoate.
It is described above based on avermectin B2Emamectin-benzoate, can be used for killing prodenia litura, Dichocrocis punctiferalis, citrus red mite etc., the effect in poisoning prodenia litura are optimal.
Compared with prior art, of the present invention a kind of based on avermectin B2Emamectin-benzoate Synthetic method and application have the following beneficial effects:
The present invention is with avermectin B2For precursor, synthesis is based on avermectin B2Emamectin-benzoate, hair Its existing activity improves many, and now widely used based on avermectin B1Emamectin-benzoate phase Compare, benzoate pesticide activity of the invention is higher, and toxicity is lower, and cost of material is also low, has the significant market advantage.
Detailed description of the invention
Fig. 1 is high resolution mass spectrum (HRMS) spectrogram for the target product YAB that the embodiment of the present invention 1 is prepared；
Fig. 2 is high performance liquid chromatography (HPLC) spectrogram for the target product YAB that the embodiment of the present invention 1 is prepared；
Fig. 3 is high performance liquid chromatography (HPLC) spectrogram that methylamino avilamycin benzoate (90%) is commercialized.
Specific embodiment
It elaborates with reference to the accompanying drawing to case study on implementation of the invention.The implementation case is in technical solution of the present invention Under the premise of implemented, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to Following case study on implementation.
The information for including according to the application, to those skilled in the art can be easily to essence of the invention Really description carries out various changes, without departing from spirit and scope of the appended claims.It should be understood that the scope of the present invention is not Process, property defined by being confined to or component, because these embodiments and other descriptions are just for the sake of schematic Illustrate certain aspects of the present disclosure.In fact, this field or those skilled in the relevant art obviously can be to embodiment party of the present invention The various changes that formula is made all cover within the scope of the appended claims.
It is not intended to limit the scope of the invention for a better understanding of the present invention, expression dosage used in this application, All numbers of percentage and other numerical value, are understood to be modified with word " about " in all cases.Therefore, Unless stated otherwise, otherwise digital parameters listed in specification and appended book are all approximations, may It can be changed according to the difference for the desirable properties for attempting to obtain.Each digital parameters at least should be considered as according to being reported Effective digital and obtained by the conventional method of rounding up.
Present invention synthesis is based on avermectin B2Emamectin-benzoate process route it is specific as follows:
(1) hydroxyl protection reacts:
With avermectin B2For raw material, through No. 5 positions of allyl chlorocarbonate selective protection and No. 23 position hydroxyls, obtain (the 5- allyl formate base avermectin B of mesosome I2With 5,23- diformazan allyl propionate base avermectin B2)。
(2) hydroxyl oxidation reaction
By obtained intermediate I through dimethylsulfoxide oxidation 4 " and the position C23 hydroxyl, intermediate II (5- formic acid allyl is obtained Ester group -4 ", C23- dicarbapentaborane avermectin B2With 5,23- diformazan allyl propionate base -4 "-carbonyl avermectin B2)。
(3) carbonyl aminating reaction:
By obtained intermediate II using heptamethyldisilazane as aminating agent, (the 5- allyl formate of intermediate III is obtained Base -4 ", C23- dimethyleneimine base avermectin B2With 5,23- diformazan allyl propionate base -4 "-carbonyl avermectin B2)。
(4) imine reduction, hydroxyl deprotection reaction:
By obtained intermediate III through sodium borohydride reduction, (4 ", C23- dimethylamino the avermectin B of intermediate IV is obtained2 With 4 "-emamectin benzoate B2)。
(5) salt-forming reaction:
By obtained intermediate IV and benzoic acid at salt, product YAB is finally obtained, wherein B in the product YAB2aWith B2bMolar ratio be 2:1~3:1.
Embodiment 1
The present embodiment based on avermectin B2Emamectin-benzoate preparation method, the method packet Include following steps:
(1) hydroxyl protection reacts
With avermectin B2Centre is obtained through No. 5 positions of allyl chlorocarbonate selective protection and No. 23 position hydroxyls for raw material (the 5- allyl formate base avermectin B of body I2With 5,23- diformazan allyl propionate base avermectin B2)。
Specific reaction step summary are as follows: by 1mol avermectin B2Dissolution in methylene chloride, under argon gas protection, is added After 12mol triethylamine, 2mol allyl chlorocarbonate is added dropwise, continues after being passed through 1 hour of argon gas after being added dropwise, enclosed system is anti- It answers 48 hours.After completion of the reaction, solvent is removed, crude product, crude product methylene chloride and acetone washing is obtained, obtains intermediate I (5- Allyl formate base avermectin B2With 5,23- diformazan allyl propionate base avermectin B2).Yield 95%.
(2) hydroxyl oxidation reaction
By obtained intermediate I through dimethylsulfoxide oxidation 4 " and the position C23 hydroxyl, intermediate II (5- formic acid allyl is obtained Ester group -4 ", C23- dicarbapentaborane avermectin B2With 5,23- diformazan allyl propionate base -4 "-carbonyl avermectin B2)。
Specific reaction step summary are as follows: the intermediate I dissolution for obtaining 0.8mol step (1) in methylene chloride, adds Enter 16mol dimethyl sulfoxide, under the conditions of -60 DEG C, 24 hours of 8mol trifluoroacetic acid anhydride reactant, after completion of the reaction, mistake are added dropwise Filter obtained yellow solid, with methylene chloride and acetone washing, obtain intermediate II (5- allyl formate base -4 ", bis- carbonyl of C23- Base avermectin B2With 5,23- diformazan allyl propionate base -4 "-carbonyl avermectin B2), yield 82%.
(3) carbonyl aminating reaction
By obtained intermediate II using heptamethyldisilazane as aminating agent, (the 5- allyl formate of intermediate III is obtained Base -4 ", C23- dimethyleneimine base avermectin B2With 5,23- diformazan allyl propionate base -4 "-carbonyl avermectin B2)。
Specific reaction step summary are as follows: the intermediate II dissolution for obtaining 0.5mol step (2) in methylene chloride, adds Enter 2.5mol heptamethyldisilazane, react 2 hours at room temperature, after completion of the reaction, uses ethyl alcohol recrystallization after removing solvent, obtain To intermediate III (5- allyl formate base -4 ", C23- dimethyleneimine base avermectin B2With 5,23- diformazan allyl propionate base- 4 "-carbonyl avermectin B2), yield 68%.
(4) imine reduction, hydroxyl deprotection reaction
By obtained intermediate III through sodium borohydride reduction, (4 ", C23- dimethylamino the avermectin B of intermediate IV is obtained2 With 4 "-emamectin benzoate B2)。
Specific reaction step summary are as follows: the dissolution of intermediate III for obtaining 0.2mol step (3) in methylene chloride, adds Enter 4mol sodium borohydride, react 8 hours, after completion of the reaction, after removing solvent, acetonitrile is added, and add 2mol sodium borohydride After the reaction was continued 24 hours, after removing solvent, recrystallizes in methylene chloride, obtain (4 ", C23- the dimethylamino Ah of intermediate IV Tie up rhzomorph B2With 4 "-emamectin benzoate B2)。
(5) salt-forming reaction
By obtained intermediate IV and benzoic acid at salt, product YAB is finally obtained.
Specific reaction step summary are as follows: the intermediate IV that 0.1mol step (4) obtains is added in ethyl acetate 0.18mol benzoic acid stirs 30 minutes at room temperature, after removing solvent, finally obtains product YAB.
High resolution mass spectrum (HRMS) spectrogram of the target product YAB of the above-mentioned synthesis of the present embodiment is as shown in Figure 1, efficient liquid phase Chromatography (HPLC) spectrogram is as shown in Fig. 2, high resolution mass spectrum shows effective component 4 " in molecular weight and YAB, C23- diformazan ammonia in Fig. 1 Base avermectin B2With 4 "-emamectin benzoate B2Molecular weight error illustrates to synthesize target product YAB within 0.5ppm In containing described in this specification summary of the invention based on avermectin B2Emamectin-benzoate step (5) in retouch The two kinds of effective component B stated2aWith B2b.High performance liquid chromatography shows acquired chemical composition and commercialization emamectin benzoate in Fig. 2 Ingredient is similar, and active constituent content is 90% or more.
By above-mentioned mass spectrum, liquid chromatogram test result, it may be determined that target compound made from the present embodiment be based on Ah Tie up rhzomorph B2Emamectin-benzoate.
Embodiment 2
The present embodiment based on avermectin B2Emamectin-benzoate preparation method, the method packet Include following steps:
(1) hydroxyl protection reacts
With avermectin B2For raw material, through No. 5 positions of allyl chlorocarbonate selective protection and No. 23 position hydroxyls, obtain (the 5- allyl formate base avermectin B of mesosome I2With 5,23- diformazan allyl propionate base avermectin B2)。
Specific reaction step summary are as follows: by 10mmol avermectin B2Dissolution in methylene chloride, under argon gas protection, adds After entering 120mmol triethylamine, 20mmol allyl chlorocarbonate is added dropwise, continues after being passed through 1 hour of argon gas after being added dropwise, it is closed System is reacted 48 hours.After completion of the reaction, solvent is removed, crude product, crude product methylene chloride and acetone washing is obtained, obtains centre (the 5- allyl formate base avermectin B of body I2With 5,23- diformazan allyl propionate base avermectin B2).Yield 96.4%.
(2) hydroxyl oxidation reaction
By obtained intermediate I through dimethylsulfoxide oxidation 4 " and the position C23 hydroxyl, intermediate II (5- formic acid allyl is obtained Ester group -4 ", C23- dicarbapentaborane avermectin B2With 5,23- diformazan allyl propionate base -4 "-carbonyl avermectin B2)。
Specific reaction step summary are as follows: the intermediate I dissolution for obtaining 5mmol step (1) in methylene chloride, is added 100mmol dimethyl sulfoxide is added dropwise 50mmol oxalyl chloride and reacts 24 hours under the conditions of -60 DEG C, after completion of the reaction, filtering Obtained yellow solid, with methylene chloride and acetone washing, obtain intermediate II (5- allyl formate base -4 ", C23- dicarbapentaborane Avermectin B2With 5,23- diformazan allyl propionate base -4 "-carbonyl avermectin B2), yield 82.2%.
(3) carbonyl aminating reaction
By obtained intermediate II using heptamethyldisilazane as aminating agent, (the 5- allyl formate of intermediate III is obtained Base -4 ", C23- dimethyleneimine base avermectin B2With 5,23- diformazan allyl propionate base -4 "-carbonyl avermectin B2)。
Specific reaction step summary are as follows: the intermediate II dissolution for obtaining 3mmol step (2) in methylene chloride, adds Enter 15mmol heptamethyldisilazane, react 2 hours at room temperature, after completion of the reaction, uses ethyl alcohol recrystallization after removing solvent, obtain To intermediate III (5- allyl formate base -4 ", C23- dimethyleneimine base avermectin B2With 5,23- diformazan allyl propionate base- 4 "-carbonyl avermectin B2), yield 69.5%.
(4) imine reduction, hydroxyl deprotection reaction
By obtained intermediate III through sodium borohydride reduction, (4 ", C23- dimethylamino the avermectin B of intermediate IV is obtained2 With 4 "-emamectin benzoate B2)。
Specific reaction step summary are as follows: the dissolution of intermediate III for obtaining 2mmol step (3) in methylene chloride, adds Enter 40mmol sodium borohydride, react 8 hours, after completion of the reaction, after removing solvent, acetonitrile is added, and add 20mmol boron hydrogen Change sodium after the reaction was continued 24 hours, after removing solvent, recrystallizes in methylene chloride, obtain (4 ", C23- the diformazan ammonia of intermediate IV Base avermectin B2With 4 "-emamectin benzoate B2)。
(5) salt-forming reaction
By obtained intermediate IV and benzoic acid at salt, product YAB is finally obtained.
Specific reaction step summary are as follows: the intermediate IV that 1mmol step (4) obtains is added in ethyl acetate 1.8mmol benzoic acid is stirred at room temperature 30 minutes, after removing solvent, finally obtains product YAB.
High resolution mass spectrum (HRMS) spectrogram and high performance liquid chromatography of the target product YAB of the above-mentioned synthesis of the present embodiment (HPLC) test result for the target product that spectrogram is synthesized with embodiment 1 is essentially identical, by above-mentioned mass spectrum, liquid chromatogram test knot Fruit, it may be determined that target compound made from the present embodiment is based on avermectin B2Emamectin-benzoate.
Application Example 1
Target compound made from the present embodiment 1 is applied to the toxicity test to prodenia litura.
Test method is as follows:
1.1 preparation of reagents: weighing 0.1425g emamectin benzoate raw medicine and 0.1294gYAB raw medicine, uses acetone solution respectively, then use 0.1% Tween-80 aqueous solution is diluted to 1000mL, spare as mother liquor；The emamectin benzoate mother liquor prepared is diluted respectively, is configured to Five concentration gradients of 5mg/L, 10mg/L, 15mg/L, 20mg/L and 25mg/L；The YAB mother liquor prepared is diluted respectively, is prepared At five concentration gradients of 3mg/L, 6mg/L, 9mg/L, 12mg/L, 15mg/L.
1.2 chemicals treatments: the bioassay of prodenia litura uses spray-on process: preparation diameter is used for the plastic culture dish of 9cm Gently for 3 consistent, healthy, active instar larvaes of picking Individual Size in culture dish, each culture dish connects larva 30 to No. zero writing brush Head or so.It is sprayed with Potter spray tower, a series of concentration gradients is arranged in medicament, at 0.1% Tween-80 aqueous solution For reason as control, each concentration sets 4 repetitions, past each after spray 12 hours (medical fluid on polypide surface has been done in culture dish) Suitable man-made feeds are added in culture dish, entire bioassay process prodenia litura is in controllable greenhouse culture (temperature 26 ± 1 DEG C, relative humidity 60~80%, illumination L:D=14:10h).
1.3 investigation: after application for 24 hours, 120 test worms are observed in every processing, respectively the insect population number of investigation death and survival.
1.4 calculation methods:
According to survey data, the corrected mortality of each processing is calculated.Corrected mortality such as following formula (1), formula (2) calculate, single Position is percentage (%), and calculated result retains after decimal two:
P1=K/N*100 (1)
In formula:
P1--- the death rate；
K --- dead borer population；
N --- handle total borer population.
P2=(Pt-P0/(1-P0)*100 (2)
In formula:
P2--- corrected mortality；
Pt--- the processing death rate；
P0--- the blank control death rate.
If compareing death rate < 5%, without correction；The death rate is compareed between 5%~20%, should be carried out by formula (2) Correction；Death rate > 20% is compareed, test need to reform.
1.5 statistical analysis: being analyzed with softwares such as statistical analysis system (SAS), data processing systems (DPS), is calculated The LC of each medicament50It is worth (95% confidence limit).
Compare application examples 1
Emamectin benzoate in the prior art is applied to the toxicity test to prodenia litura, test method and Application Example 1 It is essentially identical.
The emamectin benzoate in application examples 1 and the YAB in Application Example 1 is compared to distinguish the toxicity test result of prodenia litura It see the table below shown in 1- table 3.By the toxicity test result (LC of table 150And its confidence limit) as can be seen that two kinds of medicament LC50Value 95% confidence limit is not overlapped, and shows that there are significant differences for virulence of the two to prodenia litura；Work of the YAB to Spodoptera litura larvae Property is significantly higher than the activity of emamectin benzoate, and the activity of YAB is about 1.7 times of emamectin benzoate.
The toxicity test result of 1 emamectin benzoate of table and YAB processing prodenia litura
The corrected mortality of 2 emamectin benzoate of table processing prodenia litura
The corrected mortality of 3 YAB of table processing prodenia litura
In addition, inventor also to several medicaments such as emamectin benzoate to the virulence activity of prodenia litura as shown in the following table 4~8.
Toxicity test (48h) of 4 emamectin benzoate of table to 2 instar larvae of prodenia litura
Toxicity test (48h) of 5 YAB of table to 2 instar larvae of prodenia litura
Toxicity test (48h) of 6 SK of table to 2 instar larvae of prodenia litura
Toxicity test (48h) of 7 ELD of table to 2 instar larvae of prodenia litura
Several medicaments such as 8 emamectin benzoate of table compare the virulence of prodenia litura
Emamectin benzoate, YAB, SK, ELD go out certain difference to the activities present of prodenia litura it can be seen from 4~8 data of table It is different.Wherein YAB has good activity, and the LC50 value of 48h is 3.19 μ g/mL, not significant with emamectin benzoate difference.Also, it tries It has been observed that YAB also shows good quick-acting to prodenia litura in testing, it is preferable to illustrate that the medicament has prodenia litura Potential control efficiency is worth carrying out development and application.SK and ELD is lower to the activity of prodenia litura, after 1000 μ g/mL processing 48h, corrected mortality are no more than 50%, illustrate it to prodenia litura without obvious virulence.

Claims (10)

1. being based on avermectin B2Emamectin-benzoate synthetic method, it is characterised in that: the method includes Following steps:
(1) hydroxyl protection reacts: under room temperature, by avermectin B2Dissolution is in methylene chloride, first primary under argon gas protection Property be added triethylamine, then allyl chlorocarbonate is added dropwise, continue after being passed through 0.5~2h of argon gas after being added dropwise, obturator System reaction 48h removes solvent, obtains crude product, the crude product methylene chloride and acetone washing, obtain intermediate after completion of the reaction I, it is 5- allyl formate base avermectin B containing there are two types of ingredients in the intermediate I2With 5,23- diformazan allyl propionate base Ah Tie up rhzomorph B2；
(2) hydroxyl oxidation reaction: in methylene chloride by the dissolution of intermediate I made from step (1), dimethyl sulfoxide, drop is added Temperature is to -60 DEG C, then dehydrating agent is added dropwise, and for 24 hours, after completion of the reaction, yellow solid is obtained by filtration in isothermal reaction under the conditions of -60 DEG C, By the yellow solid methylene chloride and acetone washing, intermediate II is obtained, it is 5- that the intermediate II, which contains there are two types of ingredient, Allyl formate base -4 ", C23- carbonyl avermectin B2With 5,23- diformazan allyl propionate base -4 "-carbonyl avermectin B2；
(3) carbonyl aminating reaction: in methylene chloride by the dissolution of intermediate II made from step (2), seven methyl, two silicon nitrogen is added Alkane reacts 2h at room temperature, after completion of the reaction, uses ethyl alcohol recrystallization after removing solvent, obtains intermediate III, the intermediate III contains There are two types of ingredients, are 5- allyl formate base -4 ", C23- dimethyleneimine base avermectin B2With 5,23- diformazan allyl propionate base- 4 "-azomethine base avermectin B2；
(4) imine reduction, hydroxyl deprotection reaction: in methylene chloride, boron is added in the dissolution of intermediate III that step (3) is obtained Sodium hydride reacts 8h, after completion of the reaction, removes solvent, acetonitrile is then added, and adds sodium borohydride the reaction was continued for 24 hours, again Solvent is removed, is recrystallized in methylene chloride, intermediate IV is obtained, it is 4 ", C23- bis- that the intermediate IV, which contains there are two types of ingredient, Emamectin benzoate B2With 4 "-emamectin benzoate B2；
(5) intermediate IV made from step (4) is dissolved in ethyl acetate, benzoic acid is added, is stirred at room temperature 30 minutes, removed After solvent, product YAB is finally obtained, is based on avermectin B2Emamectin-benzoate.
2. according to claim 1 be based on avermectin B2Emamectin-benzoate synthetic method, it is special Sign is: avermectin B described in step (1)2Molar ratio with triethylamine is 1:12.
3. according to claim 1 be based on avermectin B2Emamectin-benzoate synthetic method, it is special Sign is: avermectin B described in step (1)2Molar ratio with allyl chlorocarbonate is 1:2.5.
4. according to claim 1 be based on avermectin B2Emamectin-benzoate synthetic method, it is special Sign is: intermediate I described in step (2) and the molar ratio of dimethyl sulfoxide are 1:20.
5. according to claim 1 be based on avermectin B2Emamectin-benzoate synthetic method, it is special Sign is: intermediate I described in step (2) and the molar ratio of dehydrating agent are 1:10.
6. according to claim 5 be based on avermectin B2Emamectin-benzoate synthetic method, it is special Sign is: dehydrating agent described in step (2) is trifluoroacetic anhydride or oxalyl chloride.
7. according to claim 1 be based on avermectin B2Emamectin-benzoate synthetic method, it is special Sign is: intermediate II described in step (3) and the molar ratio of heptamethyldisilazane are 1:5.
8. according to claim 1 be based on avermectin B2Emamectin-benzoate synthetic method, it is special Sign is: the molar ratio of total amount is added as 1:30 in intermediate III described in step (4) and sodium borohydride.
9. according to claim 1 be based on avermectin B2Emamectin-benzoate synthetic method, it is special Sign is: the molar ratio of intermediate IV described in step (5) and benzoic acid is 1:1.8.
10. the method synthesis of any one of claim 1~9 based on avermectin B2Emamectin-benzoate Application in poisoning prodenia litura.
CN201811383572.7A 2018-11-20 2018-11-20 One kind being based on avermectin B2Emamectin-benzoate synthetic method and application Pending CN109467582A (en)

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CN113354695A (en) * 2021-05-26 2021-09-07 河北威远生物化工有限公司 Continuous production process of emamectin benzoate B1/B2
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