CN109485683A - Fluorine-containing serial avermectin derivatives of one kind and preparation method thereof - Google Patents
Fluorine-containing serial avermectin derivatives of one kind and preparation method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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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
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- 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
Abstract
The present invention relates to a kind of pharmaceutically acceptable fluorine-containing serial avermectin derivatives and their preparation methods.The present invention passes through to the C in avermectin precursor structure4 ＂Hydroxyl position introduces trifluoromethyl amine groups through chemical modification and obtains fluorine-containing serial avermectin derivatives, such avermectin derivatives has high bioactivity.Shown in its general structure such as formula (II):Wherein, R1=CH3Or-CH2CH3R is hydrogen atom, the alkyl of C1~6, the alkyl halide alkyl of C1~6, the naphthenic base of C3~8, the halogenated cycloalkyl of C3~8, the alkane carbonyl of C1~6, the halogenated alkane carbonyl of C1~6, the alkane sulfonic acid base of C1~6, the alkene of C3~6, the alkenyl halide of C3~6, the alkynes base of C3~6, phenyl, phenyl substituent or heterocycle.
Description
Technical field
The present invention relates to a kind of pharmaceutically acceptable fluorine-containing serial avermectin derivatives and their preparation method,
Belong to technical field of organic synthesis.
Background technique
Reinforcement with countries in the world to environment for human survival and natural ecology protective awareness, the mankind are for agricultural product quality
With the care of own health, the Pesticide Residue that high-toxic pesticide causes becomes the hot spot of social concerns, and country orders to prohibit comprehensively
The only production and sales and use of high-toxic pesticide.In face of this market structure, pesticide producing enterprise is all endeavouring research and development super quality and competitive price
Green non-pollution pesticide.In numerous research, it is chemically modified using natural products or microbial fermentation product as parent
And the new pesticide obtained, become one of effective way of pesticide developing, this kind of new pesticide is usually known as biogenic pesticide.
Biogenic pesticide is once listing, just because many merits such as its hypotoxicity, low-residual, degradable, environmentally friendly are by market
Pro-gaze obtains significant progress space.
Last century the seventies, biofermentation product avermectin is because of its unique insecticidal mechanism and low toxicity causes agriculture
The concern in medicine market, and put goods on the market and be widely used as a kind of novel agrochemical formulations.Avermectin is by grey strepto-
Bacterium Streptomyces avermitilis fermentation generates, using the γ-aminobutyric acid (GABA) of insect and glutamic acid as work
Use target spot.The 16th National Congress of Communist Party of China cyclic lactone mixture that the structure of its molecule is made of the close homologue of 8 structures, including A1a, A2a,
B1a (>80%), B2a and A1b, A2b, B1b (<20%), B2b this eight kinds of components, this 8 kinds of components all have pest extremely strong
The insecticidal activity highest of killing effect, especially AVERMECTIN B1, and toxicity is minimum, is to play desinsection in Avermectins pesticide
The main constituents of effect.It forms in the big ring of lactone of avermectin molecular structure and is given birth to containing a disaccharides (oleandrose)
At glycosides (C13), the also Spiroketals alcohol system (C containing 2 hexatomic rings17~C28) and hexahydro benzo furan nucleus system (C2~C8), at it
In molecular structure, lactonic ring is actually to be tightly wrapped, and conformation is almost without changeability.Studies have shown that Avermectin
The structure of modification of element cannot destroy the conformation of lactonic ring, and the destruction of lactonic ring conformation will lead to being greatly reduced for insecticidal activity, but
Change to other structures, such as the transformation to Spiroketals, hexahydro benzo furan nucleus, because it is outside lactonic ring, to lactonic ring
Conformation influences less, so this analog derivative is able to maintain its bioactivity substantially.
With going deep into for research and development, using avermectin as parent, mutagenesis, bioconversion and chemistry are carried out to its structure
The a series of transformations such as modification, on the basis of guaranteeing that its insecticidal activity group is complete, to C4 ＂、C4、C25On side chain and C13
The groups such as the disaccharides connected carry out structural modification, obtain a series of derivatives, wherein activity has better than the compound of parent:
Ivermectin, doractin, salad rhzomorph, Ai Bailinuo rhzomorph, emaricin etc., and commercialization has been carried out.?
In Avermectins medicine through being commercialized, emaricin because it is wide with insecticidal spectrum, efficiently, low toxicity, low-residual, can with it is a variety of
The advantages that pesticide is used in combination has begun and replaces other similar products, extensive in the control of insect of agricultural and animal husbandry
Use, have become the main product of existing market insecticide.
Emaricin scientific name emamectin benzoate, full name: emamectin-benzoate is developed and is listed by Novartis Co., Ltd
A kind of environmental type biological source insecticide.Shown in its molecular structural formula such as formula (I):
Wherein, R1=CH3Or CH2CH3
The structural modification of emamectin benzoate is using fermented product AVERMECTIN B1 as parent, in C4 ＂Position introduces after methylamino and benzene first
The mixture of B1a and B1b that acid is obtained at salt are most representational one kind in numerous avermectin chemical derivatives.Make
For the derivative of biological tunning avermectin, compared with parent, bioactivity improves the 1-3 order of magnitude and expands
Insecticidal spectrum, the mechanism of action is essentially the same with avermectin, and main desinsection mode is stomach toxicity mode, while also having certain touching concurrently
The effect of killing.In addition, emamectin benzoate penetration is strong, insecticidal spectrum is wide, and can use with most mixed pesticides, be widely used in vegetables, fruit tree,
The prevention and treatment of various pests on the crops such as cotton is that current world's dosage is maximum, one of the insecticide that use scope is most wide.
The preparation process of emamectin benzoate experienced the improved course of gradual perfection.Raymond J.Cvetovich was in 1994
The synthetic technology of emamectin benzoate is reported, i.e., using AVERMECTIN B1 as raw material, by its C4”Hydroxyl on position is through chemical improvement at methylamine
Base is made.In the structure of AVERMECTIN B1,3 hydroxyls are co-existed in, C is located at4 ＂、C5And C7On position, wherein C7- OH is located at
In glucosides ring, steric hindrance is larger, and reactivity is minimum；C5- OH is located at allylic, and reactivity is most strong, while the hydroxyl is also
It is the essential group of insecticidal activity, therefore, when carrying out structural modification to avermectin, in order to ensure C5The integrality of-OH,
It needs to continue selective protection to this hydroxyl in activity modifying.Therefore, the synthetic route of emamectin benzoate classics substantially includes to C5-OH
Carry out selective protection, C4 ＂- OH oxidation reaction, C4 ＂Ketone group aminating reaction, C4 ＂Imido grpup reduction reaction, C5- OH deprotection is anti-
It answers, C4 ＂The six-step processes such as methylamino salt-forming reaction.Some synthesis documents and materials about emamectin benzoate that recent domestic is delivered,
Its synthetic route does not change substantially.In the route synthesis process, by C4 ＂The Swern oxidation that the hydroxyl of position is oxidized to carbonyl is anti-
It answers, uses DMSO as oxidant in oxidation process, the sulfur byproduct species such as dimethyl sulphide can be generated in oxidation process, cause to produce
Foul waste gas is generated in the process, to environmental effects.Meanwhile sulfur byproduct species will lead to catalyst used in subsequent reactions
Activity reduces and poisoning, needs to increase catalyst amount, production cost is caused to rise；In addition, largely being used in aminating process
Acids solvent has a large amount of solid wastes and generates, not easy to handle, pollutes the environment.
In order to solve to pollute the environment in the above production process, the reaction time is long, at high cost, solid waste amount is big asks
Topic, researcher have carried out various methods and have improved, and propose the preparation method suitable for large-scale production.
As proposed in Chinese patent CN105017358A, by avermectin C5After the hydroxyl protection of position, with sulphonic acid ester to C4 ＂
The hydroxyl of position is esterified, and then carries out amination and reduction reaction again, and finally and benzoic acid at salt obtains emamectin benzoate.This synthesis
Although method avoids in Swern oxidation preparation method using DMSO reagent, solve the problems, such as the smell in production, but prepare
Sulphonic acid ester activity is lower, carry out amination when reaction speed it is slow, the reaction time be up to 50 hours, generate by-product it is more, so as to cause
Finished product purity is low, and product quality is not able to satisfy market demands.
The Yu Yanchao seminar of Harbin University of Science and Technology, is optimized synthesis technology on the basis of traditional route.
In 3 hydroxyls in AVERMECTIN B1 structure, C7Hydroxyl on position is not easy to participate in reaction since steric hindrance is larger, so,
They think, can be by C5Position and C4 ＂Hydroxyl Simultaneous Oxidation on position is carbonyl, then using suitable selective amination reagent
And strict control reaction condition, the generation of imidization selectivity can be made in the higher C of activity4 ＂On the carbonyl of position, to obtain
Imine intermediate, can be with reducing agent by C in imine intermediate5Carbonyl and C on position4 ＂The synchronous reduction of imido grpup on position, system
Emamectin benzoate, finally and benzoic acid at salt obtains emamectin benzoate.This optimization shortens synthetic route, eliminates to C5
The protection step of the hydroxyl of position, but the selectivity for the amination reagent selected is poor, so that C5Position and C4 ＂Carbonyl while quilt on position
Amination causes that product yield is low, purity difference so as to cause the generation of a large amount of by-products, and the application prospect of industrialized production is smaller.
In addition, there is researcher to think, C4 ＂Position and C5Hydroxyl on the position activity after derivatization is protected can change, and pass through
After the protection of one step derivatization, C4 ＂The activity of hydroxyl can be higher than C on position5Hydroxyl activity on position, it is subsequent so as to directly carry out
The reaction such as oxidation, amination.This is the relatively new synthesis thinking of item, but deeper to this progress without relevant patent and document
The report of one step.
For there are various problems in current emamectin benzoate and the like synthesis process: environment odor contamination is serious, production
Higher cost, solid waste generate more, and product yield and content are lower, and by-product is more, purity is low, and the reaction time is long and product
It is easy to produce the technical problem of drug resistance, needs a kind of production cost is low, product yield is high, with high purity, reaction time is short one
The environmentally protective synthetic method of the novel emamectin benzoate of kind.
Recently as a large amount of reuses of emamectin benzoate, not scientific unreasonable medication, in addition what pest was formed for a long time
The survival of the fittest, administration time is long, and host plant itself can also stimulate pest to develop drug resistance, and leads to the drug resistance of pest gradually
Enhancing.Recent study and field resistance monitoring discovery, have part pest to produce resistance to emamectin benzoate, and have into one
Walk the trend of development.Due to the generation of drug resistance, emamectin benzoate has become current via the specific drug of prevention and treatment Lepidoptera class pest
Efficient medicine.
Pest resistance to insecticide is the key points and difficulties for preventing and treating agricultural pests.The research and development of novel pesticide are for preventing and administering agriculture
It the drug resistance of industry pest and controls its harm and has very important effect.In addition, effective multi-targeted receptor is to kill in insecticide
The exploitation of worm agent provides valuable source.Currently, more than 180 kinds of neuromuscular toxicity insecticides being commercialized, act only on
Less than the molecular target of 10 nervous systems.Therefore, modern innovation mechanism is while finding new molecular target, sufficiently
The different insecticide of chemical structure and abundant insecticide variety are developed using existing molecular target and promote resistance management
Effective way.
Hetero atom and heterocycle are introduced into a trend in avermectin and to its structure of modification.Contain what is carried out
It is found in the research experiment of fluorine pesticide, the compound with fluorine or fluoroalkyl substituents not only shows important pharmacology and pesticide
The property of aspect, and be also the important as precursors of some biologically effective preparations of synthesis.The introducing of fluorine atom can cause compound to exist
The significant changes of physics, chemistry and physiological activity etc., this is mainly caused by the special physicochemical properties of fluorine atom
's.Fluorine atom due to its high electronegativity and small size, be introduced into organic molecule can result in organic compound lipophilicity,
The increase of permeability of the membrane, antimetabolic stability and chemical stability increases their bioavilability and target point protein
Binding affinity, to improve chemical combination microbic activity, organism is to its relatively raw resistance of difficult labour.Just because of fluorine atom has
Above-mentioned characteristic, fluorochemical are of great significance in terms of biology, and the development and application of fluorochemical is by people
More and more extensive concern.Even to this day, people take in terms of developing and utilizing the fluorinated organic compound with physiological activity
Very big achievement was obtained, there is many active fluorinated organic compound of special physiological to be applied to marketed drug.
Currently, at least containing a fluorine atom in about 50% drug and agricultural compound, in these fluorine-containing chemical combination
In object, trifluoromethyl compound accounts for very big ratio.It has been confirmed that many perfluoroalkyls replace especially trifluoromethyl to replace
Fluorochemical there is significant lipophilicity, in vivo to the enhancing of the penetration power of film, tissue etc., greatly improving
Close the absorption and transmission speed of object in vivo.Very important point is exactly to need trifluoromethyl base in organic synthesis
Group is introduced into required compound molecule.Trifluoromethyl is introduced into compound molecule can greatly change its molecule soda acid
The physicochemical properties such as degree, polarity improve the lipophilicity of compound, to improve to the permeability of organism film and tissue and same
Electron attractivity when biological precursor reactant enhances the physiological activity of compound.Trifluoromethyl is introduced into molecule as setting as a result,
One of new medicine and the conventional means of novel pesticide are counted, not only plays an important role on clinical medicine, is also widely applied to
Harm of the pesticide field to control agricultural pests.
As the progress and its mechanism of action of fluorine chemistry synthetic technology are understood in depth, discovery Drugs Containing Fluorine is more fluorine-containing than not
Drug toxicity wants low, drug effect higher, and metabolic capability is reinforced, and especially the pesticide containing trifluoromethyl has special performance and use
On the way, have become the hot spot developed both at home and abroad now.By avermectin C4 ＂The hydroxyl of position is transformed into through chemical modification containing trifluoro
The compound of methyl group, since the introducing of fluorine atom reduces the resistance of this insecticides, increased activity, and have concurrently and kill
Worm composes wide feature.Accelerate the research of fluorinated avermectin derivatives, the avermectin derivatives for developing a series of new kill
Worm agent can not only increase a kind of insecticide of high-efficiency low-toxicity, further increase the drug level of world pesticide, also give current agriculture
The problems such as faced environmental pollution of industry production and pest resistance to insecticide, provides new resolving ideas and approach.Therefore, reinforcement pair
The concern and research of fluorine-containing avermectin analog derivative are particularly important, this can improve insecticide medication feelings in agricultural production
Condition is of great immediate significance to the promotion world about the exploitation of such pesticide with studying and reducing drug cost.However,
Academic research related to this and business news report are had not yet to see both at home and abroad.
Summary of the invention
In order to solve in the prior art, the problem of emamectin benzoate and the like synthesis process: environment odor contamination
Seriously, production cost is higher, and solid waste generation is more, and product yield and content are lower, and by-product is more, purity is low, and the reaction time is long,
And product is easy to produce drug resistance, the present invention provides a kind of fluorine-containing serial avermectin derivatives, the fluorine-containing serial Avermectin
Plain derivative lipophilicity and physiological activity are high, and are not easy to develop drug resistance.
The present invention also provides a kind of preparation method of fluorine-containing serial avermectin derivatives, this method has high income, pair
It reacts less, the distinguishing feature of suitable industrialized production.
The present invention is achieved through the following technical solutions:
Fluorine-containing serial avermectin derivatives of the invention, by the C in avermectin precursor structure4 ＂Hydroxyl position is through changing
Modification introducing trifluoromethyl amine groups are learned to obtain, shown in general structure such as formula (II):
Wherein,
R1=CH3Or-CH2CH3
R be hydrogen atom, the alkyl of C1~6, the alkyl halide alkyl of C1~6, the naphthenic base of C3~8, C3~8 halogenated ring
Alkyl, the alkane carbonyl of C1~6, the halogenated alkane carbonyl of C1~6, the alkane sulfonic acid base of C1~6, the alkene of C3~6, C3~6
Alkenyl halide, C3~6 alkynes base, phenyl, phenyl substituent or heterocycle.
Preferred according to the present invention, fluorine-containing series avermectin derivatives, trifluoromethyl amine groups described in formula (II) are
Fatty amine containing trifluoromethyl, the aromatic amine containing trifluoromethyl or the heterocyclic amine containing trifluoromethyl.
It is further preferred that the fatty amine containing trifluoromethyl be selected from trifluoroethylamine, trifluoro isopropylamine, trifluoro propylamine or
Trifluoro butylamine etc.；
Aromatic amine containing trifluoromethyl is selected from 5-trifluoromethylaniline, trifluoromethyl benzylamine or trifluoromethyl second two
Amine；
Heterocyclic amine containing trifluoromethyl is selected from trifluoromethyl cyclohexylamine, trifluoromethyl cyclopropylamine, trifluoromethyl benzyloxy
Amine or 5- (trifluoromethyl) thiazole -2- amine.
Preferred according to the present invention, fluorine-containing series avermectin derivatives are free form or hydrate described in formula (II)
Form or solvate forms.
Preferred according to the present invention, the analog of fluorine-containing series avermectin derivatives is that fluorine-containing serial avermectin is derivative
The amine salt compound that object and acid reagent are obtained at salt.
The acid reagent is organic acid or inorganic acid.
The preparation method of the fluorine-containing serial avermectin derivatives of one kind of the invention, comprises the following steps that
(1) using allyl chloroacetate to the C in avermectin structure5Hydroxyl on position is protected, and C is obtained5Position hydroxyl
The avermectin of protection；
(2) using halogenating agent to C5The avermectin C of position hydroxyl protection4 ＂Hydroxyl on position carries out halogenating reaction and obtains halogen
For object；
(3) halides of step (2) and dimethylamine or fluorine-containing aminated compounds are subjected to aminating reaction, obtain aminate；
(4) aminate obtains fluorine-containing serial avermectin derivatives through deprotection reaction；
(5) fluorine-containing serial avermectin derivatives and acid reagent obtain fluorine-containing serial avermectin derivatives at salt
Analog.
Preferred according to the present invention, in step (1), the specific method is as follows for hydroxyl protection: will with meltage methylene chloride
Avermectin dissolution, is down to -30~-20 DEG C, and tetramethylethylenediamine and catalyst four-(triphenylphosphine) target are added into solution,
Then allyl chloroacetate is added dropwise, feed liquid temperature maintains -20~-10 DEG C during dropwise addition, drips within the used time 90~120 minutes
Finish, then react 60 minutes for -20~-10 DEG C of heat preservation, sample detection avermectin residual after residual is qualified, adds into reaction solution
Enter 10% phosphoric acid solution and terminates reaction.Avermectin: tetramethylethylenediamine: four-(triphenylphosphine) targets: allyl chloroacetate rubs
You are ratio=1:1.20:0.05:1.30.
It is preferred according to the present invention, in step (2), the halogenating reaction are as follows: by C5The avermectin of position hydroxyl protection
Dissolution in organic solvent, at a temperature of -100~100 DEG C, is added halogenating agent, insulation reaction 0.1~100 hour, has reacted
Quan Hou, washing, extraction, drying obtain halogenated material liquid, and vacuum distillation obtains halides.
It is further preferred that halide reagent is the reagent containing chlorine atom, bromine atom or iodine atom in step (2).
It is further preferred that the reagent containing chlorine atom is hydrogen chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride or chlorine
Change sulfoxide.
It is further preferred that the reagent containing bromine atom is hydrobromic acid, phosphorus tribromide, tribromo oxygen phosphorus or NBS.
It is further preferred that the reagent containing iodine atom is hydroiodic acid or Iodotrimethylsilane.
It is preferred according to the present invention, in step (2), the halide reagent be phosphorus oxychloride, thionyl chloride, hydrobromic acid,
It is one of in phosphorus tribromide, tribromo oxygen phosphorus or NBS.
It is preferred according to the present invention, in step (2), C5The avermectin of position hydroxyl protection and the molar ratio of halogenating agent are
1:0.5~1:100；Preferred molar ratio is 1:1~1:50.
Preferred according to the present invention, in step (2), reaction temperature is -50~50 DEG C.
Preferred according to the present invention, in step (2), the reaction time is 0.1~50 hour.
It is preferred according to the present invention, in step (2), C5The position avermectin of hydroxyl protection and the quality volume of organic solvent
Than 1:0.5~100, unit: g/L, it is preferred that C5The position avermectin of hydroxyl protection and the mass volume ratio 1:1 of organic solvent
~50, unit: g/L.
It is preferred according to the present invention, in step (3), the aminating reaction are as follows: halides are added in organic solvent,
Under basic catalyst catalysis, at a temperature of -100~100 DEG C, with dimethylamine or the aminated compounds containing trifluoromethyl is replaced
Reaction, after fully reacting, is extracted, distills to obtain aminate.
It is further preferred that the catalyst is organic base and/or inorganic base in step (3).
It is further preferred that in step (3), the catalyst be sodium hydroxide, sodium iodide, sodium bicarbonate, potassium hydroxide,
Potassium carbonate, triethylamine, tri-n-butylamine, N, accelerine or N more than N- diethylaniline either or both of them are mixed.
It is further preferred that the catalyst is sodium bicarbonate and/or triethylamine in step (3).
It is preferred according to the present invention, in step (3), the aminated compounds containing trifluoromethyl be alkanes, arene or
Heterocyclic.
Preferred according to the present invention, in step (3), the aminated compounds containing trifluoromethyl is selected from following one of which: three
Fluorine methylamine, trifluoroethylamine hydrochloride, trifluoro butylamine, 1- trifluoromethyl cyclopropyl amine hydrochlorate, 5-trifluoromethylaniline, trifluoromethyl benzyl
Amine, trifluoromethyl ethylenediamine, trifluoromethyl cyclohexylamine, 5- (trifluoromethyl) thiazole -2- amine, 4- trifluoromethyl-biphenyl -4-
Amine, 2- (trifluoromethyl) -1- cyclopentamine or 5- (trifluoromethyl) -1H- pyrazoles -3- amine, 6- (trifluoromethyl) pyridine -2- methylamine salt
Hydrochlorate.
It is further preferred that the aminated compounds containing trifluoromethyl is trifluoroethylamine, trifluoromethyl benzylamine in step (3)
Or trifluoromethyl cyclohexylamine.
It is preferred according to the present invention, in step (3), mole of halides and dimethylamine or the amine compound containing trifluoromethyl
Than being 1:0.001~100, preferred molar ratio is 1:0.5~50.
Preferred according to the present invention, in step (3), the molar ratio of halides and basic catalyst is 1:0.001~100,
Preferred molar ratio is 1:0.5~50.
Preferred according to the present invention, in step (3), the mass volume ratio of halides and organic solvent is 1:0.5~100,
Unit: g/L, it is preferred that the mass volume ratio of halides and organic solvent is 1:1~50, unit: g/L.
Organic solvent used in step (2) of the present invention, step (3) is conventional organic solvent, and existing organic solvent is equal
It can.
Preferred according to the present invention, in step (3), reaction temperature is -50~50 DEG C.
Preferred according to the present invention, in step (3), the reaction time is 0.1~100 hour, preferably 0.1~50 hour.
Preferred according to the present invention, in step (4), the deprotection reaction is popular response, specifically: by aminate
Through sodium borohydride reduction, C is sloughed5Position hydroxy-protective group.
Preferred according to the present invention, in step (5), the acid reagent is inorganic acid, organic acid or acidic amino acid
Middle one of which.
Preferred according to the present invention, in step (5), the acid reagent is selected from following one of which: hydrochloric acid, hydrogen bromine
Acid, sulfuric acid, hydroiodic acid, citric acid, sorbic acid, benzoic acid, glutamic acid or aspartic acid.
Preferred according to the present invention, in step (5), the molar ratio of aminate and acid reagent is 1:0.01~50；It is preferred that
Molar ratio is 1:0.1~10.
Preferred according to the present invention, in step (5), salt-forming reaction temperature is -100~100 DEG C, it is preferred that salt-forming reaction
Temperature is -50~50 DEG C.
Preferred according to the present invention, in step (5), obtained amine salt compound can be the form or solvation of hydrate
Object form.
Preparation method of the invention is simple and practical, is suitable for industrialized production, and obtained fluorine-containing serial avermectin is derivative
Object is with good stability, can be used as a kind of biogenic pesticide and applies in agricultural and Animal husbandry production.
Shown in the structure of avermectin such as formula (III),
Wherein, R1=CH3Or CH2CH3。
Shown in synthetic route of the invention such as formula (IV):
Wherein, X is Cl or Br or I
Technical characterstic and advantage of the invention:
The insecticide that the present invention makes full use of existing molecular target exploitation chemical structure different, by avermectin C4“On position
Hydroxyl be chemically modified, introduce trifluoromethyl amido group, a series of trifluoromethyl amine for obtaining avermectin is derivative
Then emamectin benzoate analog can be obtained at salt with benzoic acid or other acid reagents in object.The introducing of trifluoromethyl amido group,
The physicochemical properties for not only changing avermectin derivative compound improve the bioactivity of compound, can also be from conjunction
At compound in screening be found to have the candidate compound of high activity, while by research chemical combination microbic activity and structure it
Between structure-activity relationship, make guidance for the derivative optimization of further structure, also the design studies for other subsequent compounds provide
Valuable reference.It enriches constantly such compound structure and type, it will be to the environmental pollution that current agricultural production is faced
And the problems such as pest resistance to insecticide, provides new resolving ideas and approach.
Therefore, there is provided the large-scale preparation methods of such compound for one of innovative point of the invention.In preparation process
In, abandon traditional C4 ＂The synthetic method of amination is not only kept away using more economical halogenated amination method after the hydroxyl initial oxidation of position
Exempt to lead to the problem of a large amount of solid wastes using environment odor contamination and aminating reaction caused by oxidant DMSO, also improve each
Reaction yield is walked, solves the problems, such as that the production cost of emamectin benzoate and the like is higher and content is lower.
According to the present invention, the physicochemical property of prepared several series avermectin derivatives fluorine-containing as shown in formula (II) and
See Table 1 for details for yield.
Wherein, R1=CH3Or CH2CH3
The physicochemical properties and yield of the emamectin benzoate analog as shown in formula (II) of table 1
Detailed description of the invention
Fig. 1 is II -1 4 ＂ of compound-trifluoroethylamine base avermectin derivatives infrared spectrogram of embodiment 1.
Fig. 2 is that II -1 4 ＂ of compound-trifluoroethylamine base avermectin HPLC of embodiment 1 schemes.
Fig. 3 is proliferation inhibition rate of 2 formula of embodiment, II -1 4 ＂-trifluoroethylamine base abamectin benzoate to Sf9 cell
Histogram；
Using cytologic technology, pass through the integration test to cell viability and cell inhibitory effect situation, discoverable type II -1
Emamectin benzoate analog has significant toxic effect to Noctuidae Sf9 cell.
Fig. 4 is 2 formula of embodiment, II -1 4 ＂ of compound-trifluoroethylamine base avermectin benzoate13C mass spectrogram.
Fig. 5 is 2 formula of embodiment, II -1 4 ＂ of compound-trifluoroethylamine base avermectin benzoate NMR spectrum
Figure.
Fig. 6 is the HPLC map of chloro thing in embodiment.
Specific embodiment
To further illustrate the present invention, it is exemplified below specific embodiment, but institute's protection scope of the present invention is not limited only to this.
Embodiment 1
A kind of preparation method of fluorine-containing serial avermectin derivatives, comprises the following steps that
(1) protection reaction
In dry reaction flask put into 300ml methylene chloride, under nitrogen protection be added 88g avermectin,
5mlTMEDA, stirring start to be cooled to -20~-15 DEG C after ten minutes.When temperature is down to -15 DEG C, 0.1g tetra--(triphen is added
Base phosphine) target, dichloromethane solution (18ml chloro-carbonic acid isopropyl enester and the 90ml dichloro of 2/5 chloro-carbonic acid isopropyl enester is then added dropwise
Methane), it is kept between feed liquid temperature -20~-10 DEG C during being added dropwise.It is reacted 30 minutes after adding, continues to be added dropwise remaining 3/5
The dichloromethane solution of chloro-carbonic acid isopropyl enester, while 20ml tetramethylethylenediamine is added dropwise, time for adding is unlimited, can be according to temperature
Rate of addition is controlled, two kinds of feed liquids drip simultaneously.
It is added dropwise, reaction 30~sample after sixty minutes, after HPLC detects fully reacting, it is pure that 200ml is added into feed liquid
Change water, 10% phosphoric acid is then added dropwise, adjust material liquid pH neutrality, layering, water phase uses 100ml methylene chloride to extract again, merges gained
Anhydrous sodium sulfate 30g is added in organic phase, and stirring is filtered after sixty minutes, and a small amount of methylene chloride washing obtains C5The protection of position hydroxyl
Avermectin feed liquid.
(2) synthesis of chloro thing:
It by feed liquid obtained by upper step, is stirred at room temperature, 16ml thionyl chloride is added dropwise, was added dropwise within the used time 60~90 minutes,
Then insulated and stirred is reacted 3 hours, and feed liquid after fully reacting, is poured slowly into 500ml saturated sodium bicarbonate by sampling HPLC detection
In solution, feed liquid Ph > 7, layering are detected, water phase uses 200ml methylene chloride to extract again, merges gained organic phase, is then added
The washing of 150ml saturated sodium chloride solution obtains chloride feed liquid, and vacuum distillation obtains chloride about to doing at 35~40 DEG C
85g, yield 95%.Product purity 93%.HPLC map is shown in Fig. 6.
(3) it by the resulting chloride 80g of upper step, is added in 300ml acetonitrile and dissolves, add 1ml purified water, be then added
2,2,2- trifluoroethylamine hydrochloride of 12g is added portionwise in 40g sodium bicarbonate and 1g sodium iodide, keeps the temperature 50 DEG C, is stirred to react 6~10
Hour, sample detection after fully reacting, is down to room temperature, filters, and removes solid.
(4) 50ml methanol is added into feed liquid, after mixing evenly, 15g sodium borohydride is added portionwise, added within the used time 120 minutes
It is complete, it is stirred to react after adding 2~3 hours, sample detection, after fully reacting, is cooled to 0~5 DEG C, dense salt is added dropwise into feed liquid
Acid adjusts material liquid pH 2~3 or so, there is white solid generation, filters, is washed with 50ml acetonitrile, merging filtrate.
(5) II -1 4 ＂ of compound of formula-trifluoroethylamine base avermectin preparation
300 purified waters are added into feed liquid, pH to 7.5~8.0 are adjusted with saturated sodium bicarbonate solution, then into feed liquid
Isopropyl acetate 100ml × 3 is added to extract, merges gained organic phase, addition anhydrous magnesium sulfate is 3 hours dry, filtering, gained material
Liquid vacuum distillation removal solvent, vacuum drying obtain II -1 compound solid about 80g of off-white color formula, yield 81%, HPLC detection
Purity is 94%.
Fig. 1 is the infrared spectroscopy of II -1 compound.From attached drawing it can be seen that in 1328cm-1Place occurs composing entirely strongest
Peak, this is trifluoromethyl C-F stretching vibration absworption peak.
Fig. 2 is the HPLC map of II -1 compound, and the purity of II -1 compound reaches 94%.
The synthesis of 2 formula of embodiment, II -1 compounds benzoic acid salt
Resulting II -1 compound of 20g formula of embodiment 1 is dissolved in 100ml isopropenyl acetate, 5g benzoic acid is added,
Be warming up to 60 DEG C it is entirely molten to solid, be then cooled to room temperature, 300ml acetone be added, off-white powder is precipitated, stirs 60 after adding
Minute, filtering, acetone washing is drained, and is dried in vacuo, is obtained II -1 compounds benzoic acid salt solid about 20g, yield 90%.
II -1 compounds benzoic acid salt13C-NMR map such as Fig. 4, NMR spectrum figure as shown in figure 5,
13C-NMR(300MHzCDCl3)δ:13.2,15.9,17.3,18.4,18.7,20.3,29.6,35.0,38.1,
45.9,48.8,57.4,67.8,
68.3,71.3,72.3,74.4,77.1,81.3,82.0,85.5,86.5,103.3,106.4,447.7,111.9,
121.4,124.8,127.9,129.4,135.5,136.4,138.1,139.7,173.3ppm。
Pass through13II -1 compound and benzene first in resulting II -1 compounds benzoic acid salt compound of formula of C-NMR analytical proof
The molar ratio of acid is II -1 compound of formula: benzoic acid=1:1.
The synthesis of 3 formula of embodiment, II -1 compound sorbate
Resulting II -1 compound of 10g formula of embodiment 1 is dissolved in 120ml isopropenyl acetate, 2g benzoic acid is added,
Be warming up to 60 DEG C it is entirely molten to solid, be then cooled to room temperature, 150ml acetone be added, off-white powder is precipitated, stirs 60 after adding
Minute, filtering, acetone washing is drained, and is dried in vacuo, is obtained II -1 compounds benzoic acid salt solid about 10g of formula, yield
90.9%.
The synthesis of 4 emamectin benzoate of embodiment
Step (1), step (2) press the progress of embodiment 1, and step (3), step (4) carry out by the following method,
The resulting chloride 80g of step (2) is added in 300ml acetonitrile and is dissolved, add 1ml purified water by step (3),
Then 30g sodium bicarbonate and 1g sodium iodide is added, the acetonitrile solution of 20g methylamine is added, keeps the temperature 50 DEG C, it is small to be stirred to react 5~10
When, sample detection after fully reacting, is down to room temperature.Filtering removes solid.
Step (4) is added 80ml methanol into feed liquid and 16g sodium borohydride is added portionwise after mixing evenly, and the used time 120 divides
Clock adds, and is stirred to react after adding 2~3 hours, sample detection, after fully reacting, is cooled to 0~5 DEG C, is added dropwise into feed liquid dense
Hydrochloric acid adjusts material liquid pH 2~3 or so, there is white solid generation, filters, is washed with 50ml acetonitrile, merging filtrate.
300 purified waters are added into feed liquid, water phase adjusts pH to 7.5~8.0 with saturated sodium bicarbonate solution, and acetic acid is added
Isopropyl ester 100ml × 3 shift to an earlier date, and merge organic phase, and anhydrous magnesium sulfate drying 3 hours, filtering is added.
15g benzoic acid is added into feed liquid for step (5), is warming up to 50 DEG C and is completely dissolved to solid.Then feed liquid is slow
It is down to room temperature, there is white solid precipitation in temperature-fall period, is stirred at room temperature 60 minutes, n-hexane is then added dropwise into feed liquid
Feed liquid is down to 0~5 DEG C after adding by 300ml, is stirred growing the grain 60 minutes, and filtering is drained, and vacuum drying obtains off-white color first dimension
Salt solid about 85g, yield 85%, it is 93.8% that HPLC, which detects purity,.
Embodiment 5
A kind of preparation method of fluorine-containing serial avermectin derivatives, comprises the following steps that
(1) protection reaction
In dry reaction flask put into 500ml methylene chloride, under nitrogen protection be added 90g avermectin,
5mlTMEDA, stirring start to be cooled to -20~-15 DEG C after ten minutes.When temperature is down to -15 DEG C, 20ml is added dropwise into feed liquid
Tetramethylethylenediamine.Then dichloromethane solution (20ml chloro-carbonic acid isopropyl enester and the 100ml bis- of chloro-carbonic acid isopropyl enester is added dropwise
Chloromethanes), it is kept between feed liquid temperature -20~-10 DEG C during being added dropwise.It is reacted 60 minutes after adding, HPLC detection has been reacted
220ml purified water is added into feed liquid by Quan Hou, and 10% phosphoric acid is then added dropwise, and adjusts material liquid pH neutrality, layering, and water phase is used again
200ml methylene chloride extracts, and merges gained organic phase, is washed with 100ml saturated sodium chloride solution, is layered, obtains C5Position hydroxyl
Protection avermectin feed liquid.
(2) synthesis of bromo-derivative:
By C5The avermectin feed liquid of the protection of position hydroxyl, is stirred at room temperature, dropwise addition 30ml phosphorus tribromide, and the used time 60~
It is added dropwise within 90 minutes, then insulated and stirred is reacted 2~3 hours, sampling HPLC detection, after fully reacting, feed liquid is down to 0~
It 5 DEG C, is then poured slowly into the cold saturated sodium bicarbonate solution of 500ml, detects feed liquid Ph > 7, layering, water phase uses 200ml bis- again
Chloromethanes extracts, and the washing of 150ml saturated sodium chloride solution is then added, obtains the feed liquid containing bromo-derivative.It is depressurized at 35~40 DEG C
Distillation obtains bromo-derivative about 86g, yield 94% to doing.
(3) II -1 4 ＂ of compound of formula-trifluoroethylamine base avermectin synthesis
Gained bromo-derivative 80g is added in 300ml acetonitrile, 2,2,2- trifluoroethyl amine hydrochlorate of 15g is then added, protects
Then temperature is added dropwise 30ml triethylamine, was added dropwise within the used time 60 minutes to 45~50 DEG C.Then 45~50 DEG C are kept the temperature to react 6 hours,
Sample detection is to bromo-derivative fully reacting.
30ml ethyl alcohol is added into feed liquid, 20g sodium borohydride is added portionwise after mixing evenly, added within the used time 120 minutes,
It is stirred to react after adding 2~3 hours, sample detection, after fully reacting, is cooled to 0~5 DEG C, concentrated hydrochloric acid is added dropwise into feed liquid, adjusted
There are white solid generation in material-saving liquid pH2~3 or so, filter, with 60ml ethanol washing, merging filtrate.
200 purified waters are added into feed liquid, pH to 7.0~8.0 are adjusted with saturated sodium bicarbonate solution, then into feed liquid
Isopropyl acetate 120ml × 3 is added to extract, merges gained organic phase, addition anhydrous magnesium sulfate is 3 hours dry, filtering, gained material
Liquid vacuum distillation removal solvent, vacuum drying obtain II -1 compound solid about 78g of off-white color formula, yield 80%, HPLC detection
Purity is 92%.
Embodiment 6
A kind of preparation method of fluorine-containing serial avermectin derivatives, preparation method step (1) with embodiment 1, difference
Be in:
The synthesis of step (2) iodo object:
By C5The avermectin feed liquid 30g of the protection of position hydroxyl, is stirred at room temperature, and under nitrogen protection, tri- second of 10ml is added
Amine and 20mlN, N- diethylaniline, stir evenly, and 25ml Iodotrimethylsilane is added dropwise, was added dropwise within the used time 10~20 minutes,
Then insulated and stirred is reacted 3 hours, and the feed liquid of the object containing iodo is arrived in sampling HPLC detection after fully reacting.
2,2,2- trifluoroethyl amine of 10g is added in gained iodo object solution by step (3), is reacted 3 hours at room temperature, sampling
Whether HPLC detection reaction is complete, after fully reacting,
6N hydrochloric acid solution 200ml is added into feed liquid for step (4), is then allowed to stand layering, and gained water phase is cooled to 0~5 DEG C,
200ml acetone is added into feed liquid, 45 minutes used times dropwise addition triethylamine adjusts material liquid pH 4.5~5.0, solid, stirring is precipitated
Growing the grain 30 minutes, continues that 500ml acetone is added dropwise into feed liquid, be added dropwise, filter, acetone washing obtains off-white color formula II -2
It is 91.8% that compound solid about 79g, yield about 80%, HPLC, which detect purity,.
Embodiment 7
The synthesis of embodiment 5 or the fluorine-containing serial avermectin derivatives benzoate of embodiment 6
Embodiment 5 or resulting II -1 compound of 20g formula of embodiment 6 are dissolved in 12ml isopropenyl acetate, are added
6g benzoic acid, being warming up to 60~70 DEG C keeps solid entirely molten, is then cooled to room temperature, in 150ml acetone is added in 60 minutes, is precipitated
Off-white powder stirs 60 minutes after adding, and filtering, acetone washing is drained, and is dried in vacuo, obtains -2 compounds benzoic acid of Formulas I
Salt solid about 20g, yield 90%.
Claims (10)
1. fluorine-containing series avermectin derivatives, pass through the C in avermectin precursor structure4 ＂Hydroxyl position is introduced through chemical modification
Trifluoromethyl amine groups obtain, shown in general structure such as formula (II):
Wherein,
R1=CH3Or CH2CH3
R be hydrogen atom, the alkyl of C1~6, the alkyl halide alkyl of C1~6, the naphthenic base of C3~8, C3~8 halogenated cycloalkanes
Base, the alkane carbonyl of C1~6, the halogenated alkane carbonyls of C1~6, the alkane sulfonic acid base of C1~6, the alkene of C3~6, C3~6
Alkenyl halide, the alkynes base of C3~6, phenyl, phenyl substituent or heterocycle.
2. fluorine-containing serial avermectin derivatives according to claim 1, which is characterized in that contain fluorine system described in formula (II)
Column avermectin derivatives, trifluoromethyl amine groups be the fatty amine containing trifluoromethyl, the aromatic amine containing trifluoromethyl or
Heterocyclic amine containing trifluoromethyl；
Preferably, the fatty amine containing trifluoromethyl is selected from trifluoroethylamine, trifluoro isopropylamine, trifluoro propylamine or trifluoro butylamine；
Aromatic amine containing trifluoromethyl is selected from 5-trifluoromethylaniline, trifluoromethyl benzylamine or trifluoromethyl ethylenediamine；
Heterocyclic amine containing trifluoromethyl be selected from trifluoromethyl cyclohexylamine, trifluoromethyl cyclopropylamine, trifluoromethyl benzyloxy amine or
5- (trifluoromethyl) thiazole -2- amine.
3. fluorine-containing serial avermectin derivatives according to claim 1, which is characterized in that fluorine-containing series avermectin is spread out
The analog of biology is the amine salt compound that fluorine-containing serial avermectin derivatives and acid reagent are obtained at salt, the acidity
Reagent is organic acid or inorganic acid.
4. a kind of preparation method of fluorine-containing serial avermectin derivatives, comprises the following steps that
(1) using allyl chloroacetate to the C in avermectin structure5Hydroxyl on position is protected, and C is obtained5Position hydroxyl protection
Avermectin；
(2) using halogenating agent to C5The avermectin C of position hydroxyl protection4 ＂Hydroxyl progress halogenating reaction on position obtains halogenated
Object；
(3) halides of step (2) and dimethylamine or fluorine-containing aminated compounds are subjected to aminating reaction, obtain aminate；
(4) aminate obtains fluorine-containing serial avermectin derivatives through deprotection reaction；
(5) fluorine-containing serial avermectin derivatives and acid reagent obtain the similar of fluorine-containing serial avermectin derivatives at salt
Object.
5. the preparation method according to claim 4, which is characterized in that in step (1), the specific method of hydroxyl protection is such as
Under: avermectin is dissolved with meltage methylene chloride, is down to -30~-20 DEG C, tetramethylethylenediamine is added into solution and urges
Agent four-(triphenylphosphine) target, is then added dropwise allyl chloroacetate, and feed liquid temperature maintains -20~-10 DEG C during dropwise addition,
It was added dropwise within used time 90~120 minutes, then keeps the temperature -20~-10 DEG C and react 60 minutes, sample detection avermectin residual is residual
After staying qualification, 10% phosphoric acid solution is added into reaction solution and terminates reaction, avermectin: tetramethylethylenediamine: four-(triphenyls
Phosphine) target: mass ratio=1:1.20:0.05:1.30 of allyl chloroacetate.
6. the preparation method according to claim 4, which is characterized in that in step (2), the halogenating reaction are as follows: by C5Position
In organic solvent, at a temperature of -100~100 DEG C, halogenating agent, insulation reaction is added in the avermectin dissolution of hydroxyl protection
0.1~100 hour, after fully reacting, washing, extraction, drying obtained halogenated material liquid, and vacuum distillation obtains halides；
Preferably, in step (2), halide reagent is the reagent containing chlorine atom, bromine atom or iodine atom；
It is further preferred that the reagent containing chlorine atom is hydrogen chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride or protochloride
Sulfone；
It is further preferred that the reagent containing bromine atom is hydrobromic acid, phosphorus tribromide, tribromo oxygen phosphorus or NBS；
It is further preferred that the reagent containing iodine atom is hydroiodic acid or Iodotrimethylsilane.
7. the preparation method according to claim 4, which is characterized in that in step (2), C5The avermectin of position hydroxyl protection
Molar ratio with halogenating agent is 1:0.5~1:100；Preferred molar ratio is 1:1~1:50；
In step (2), reaction temperature is -50~50 DEG C, and the reaction time is 0.1~50 hour, C5The avermectin of position hydroxyl protection
With mass volume ratio 1:0.5~100 of organic solvent, unit: g/L, it is preferred that C5Position hydroxyl protection avermectin with it is organic
Mass volume ratio 1:1~50 of solvent, unit: g/L.
8. the preparation method according to claim 4, which is characterized in that in step (3), the aminating reaction are as follows: by halogen
It is added in organic solvent for object, under basic catalyst catalysis, at a temperature of -100~100 DEG C, with dimethylamine or containing fluoroform
The aminated compounds of base carries out substitution reaction, after fully reacting, is extracted, distills to obtain aminate；
The catalyst is organic base and/or inorganic base；
Aminated compounds containing trifluoromethyl is alkanes, arene or heterocyclic；
Aminated compounds containing trifluoromethyl be selected from following one of which: trifluoro methylamine, trifluoroethylamine hydrochloride, trifluoro butylamine,
1- trifluoromethyl cyclopropyl amine hydrochlorate, 5-trifluoromethylaniline, trifluoromethyl benzylamine, trifluoromethyl ethylenediamine, trifluoromethyl
Cyclohexylamine, 5- (trifluoromethyl) thiazole -2- amine, 4- trifluoromethyl-biphenyl -4- amine, 2- (trifluoromethyl) -1- cyclopentamine or 5- (three
Methyl fluoride) -1H- pyrazoles -3- amine, 6- (trifluoromethyl) pyridine -2- methylamine hydrochloride.
9. the preparation method according to claim 4, which is characterized in that in step (3), halides are with dimethylamine or containing trifluoro
The molar ratio of the amine compound of methyl is 1:0.001~100, and preferred molar ratio is 1:0.5~50, halides and basic catalyst
Molar ratio be 1:0.001~100, preferred molar ratio is 1:0.5~50, and the mass volume ratio of halides and organic solvent is 1:
0.5~100, unit: g/L, it is preferred that the mass volume ratio of halides and organic solvent is 1:1~50, unit: g/L；Reaction
Temperature is -50~50 DEG C；Reaction time is 0.1~100 hour, preferably 0.1~50 hour.
10. the preparation method according to claim 4, which is characterized in that in step (4), the deprotection reaction is normal
Rule reaction, specifically: by aminate through sodium borohydride reduction, slough C5Position hydroxy-protective group；
In step (5), the acid reagent is one of in inorganic acid, organic acid or acidic amino acid；
In step (5), the acid reagent be selected from following one of which: hydrochloric acid, hydrobromic acid, sulfuric acid, hydroiodic acid, citric acid,
Sorbic acid, benzoic acid, glutamic acid or aspartic acid；
In step (5), the molar ratio of aminate and acid reagent is 1:0.01~50；Preferred molar ratio is 1:0.1~10；
In step (5), salt-forming reaction temperature is -100~100 DEG C, it is preferred that salt-forming reaction temperature is -50~50 DEG C.
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