CN105732747A - Abamectin oil deep processing method - Google Patents

Abstract

The invention discloses an abamectin oil deep processing method and belongs to organic chemical synthesis of the chemical synthesis field.The abamectin oil deep processing method includes subjecting abamectin oil to abamectin oil pretreatment, protection reaction, oxidizing reaction, amination reduction reaction, deprotection reaction and salt forming reaction so as to obtain a mixture of abamectin B2a amino derivative salts and abamectin B1a amino derivative salts.The abamectin oil deep processing method changing a utilizing way of existing abamectin oil has the advantages that refining and crystallizing technological steps are decreased in synthesis processing, further preparation processing is facilitated greatly, higher safety and more environment friendliness are achieved, and unnecessary farmland pollution and subsequent preparation processing cost are reduced effectively.

Description

A kind of deep processing processing method of abamectin ointment

Technical field

The invention belongs to the organic chemical synthesis in the field of chemical synthesis, specifically a kind of Ah The deep processing processing method of the leftover bits and pieces abamectin ointment of dimension rhzomorph.

Background technology

Avilamycin is to be produced by Sterptomyces avermitills, belongs to Lycoperdon polymorphum Vitt strepto- Bacterium.Last century, the eighties, public with Merck by Japan's university scientific Jia great village, North intelligence etc. Department's joint development, fermented extraction process produces.Merck company therefrom extracts one group to be had The mixture of the homologue composition that eight structures are similar, and by its named avilamycin.

Avilamycin is a hexa-atomic macrolide antibiotics of class ten, in its structure, sixteen-ring Lactone and disaccharide oleandrose form glucosides, and with hexa-atomic Spiroketals system and hexahydro benzo furan It is connected for muttering.Avilamycin is the mixture of natural fermented component, total A₁a、A₂a、B₁a、 B₂a、A₁b、A₂b、B₁b、B₂Eight kinds of component compositions of b；A₁a、A₂a、B₁a、B₂A tetra-kinds is main Composition total content >=80%, corresponding four kinds of composition A₁b、A₂b、B₁b、B₂B content is less, always Content≤20%.

Avilamycin is a kind of never poison, and its mechanism is to act on insect neuron synapse or god Through the GABA receptor of muscle synapse, the information of interference insect nerves within the body tip is transmitted, the most sharp The non-tip of going crazy releases neurotransmission inhibitor Y--aminobutyric acid (GABA), promotes GABA door The chloride channel of control extends open, has activation, a large amount of chloride ion to chloride channel Pour in and cause neural membrane potentials hyperpolarization, cause neurolemma to be in inhibitory state, thus block god Through contacting of the non-tip and muscle, make insect paralysis, refusing to eat, death.Because its mechanism of action is unique, So with conventional medicament no interactions resistance.Insecticide and snail class are had and tag and stomach poison function, But can not ovicidal, have broad-spectrum high efficacy, resist resistance, lasting period length, low toxicity, low-residual, Degradable, on natural enemy little, the safety high of impact.

Avilamycin is present in the mycelium of fermentation liquid, discards filtrate through filtering, and filter cake is used Through desaccharide after ethanol extraction, concentrate, crystallize available avilamycin fine work (containing AbamectinB₁ 95%), the mother solution after crystallization through be evaporated under reduced pressure be concentrated into solvent-free after add toluene or dimethylbenzene it The organic solvent of class obtains abamectin ointment after being formulated into appointment viscosity, wherein avilamycin B₁The content of a typically (i.e. contains AbamectinB between 3～9%₁3%～9%).

The world today is along with people's call to pollution-free food, biological pesticide and semi-synthetic biological agriculture Medicine demonstrates its importance day by day；Artificial semi-synthetic biological pesticide is increasingly by the weight of people Depending on.Avilamycin carries out deep processing, and artificial semi-synthetic Avermectins pesticide has obtained people Common recognition.But in published patent or non-patent literature, no matter to avilamycin B₁a Deep processing still to avilamycin B₂The deep processing of a none be not with avilamycin series fine powder Process the most abroad through row research and development, the deep processing to abamectin ointment for parent Or the domestic blank field of still genus；The present invention intends by the main component in abamectin ointment B₂A and B₁A performs the derivatization synthesis and becomes salt that abamectin ointment is carried out deep processing process.

Summary of the invention:

The present invention changes the utilization ways of existing abamectin ointment, it is provided that a kind of new Ah The deep processing processing method of dimension rhzomorph ointment, makes synthesis processing decrease refining crystallization technique step Suddenly, make further preparation processing simpler, convenient；More safe and environment-friendly；More add and subtract Few unnecessary farmland pollution and the processing cost of follow-up preparation.

A kind of deep processing processing method of the abamectin ointment of the present invention, through the following steps that Carry out:

One, the pretreatment of abamectin ointment

(1) avilamycin commodity ointment is mixed homogeneously in the ratio of quality 20～22: 1 with water After be evaporated under reduced pressure, remove contained solvent, obtain the paste of abamectin ointment；

(2) in gained paste, in mass ratio 1: 1 addition petroleum ether and stirring dissolves paste, Static layering, removes contained oils and fats in ointment；

(3) mass percent that quality is above-mentioned petroleum ether quality 20% it is added thereto to again Concentration is the solution of trichloroacetic acid of 10%, stirs, static layering, removes in ointment contained Protein；

(4) again surplus solution is evaporated under reduced pressure, removes contained solvent, obtain paste；

Two, protection reaction

Dichloromethane is added molten by avilamycin paste and dichloromethane mass volume ratio 1: 2 Solving paste, after paste is completely dissolved, cooling system temperature, to-20 DEG C～-15 DEG C, is dripped Add the bright ester of chloro-carbonic acid alkene and tetramethylethylenediamine solution carry out protection and reacts, response time 2h, Notice that system temperature must not be higher than-15 DEG C, by B in ointment₂A and B₁The C of a₅Position hydroxyl is carried out Protection；

Three, oxidation reaction

After protection reaction completes, dissolve abamectin ointment B with isopropyl acetate₂A and B₁A's C₅Position hydroxyl protection thing, in mass ratio 1: 10: 3: 3 add abamectin ointment B₂A and B₁A's C₅Position hydroxyl protection thing, dimethyl sulfoxide, four Shen base ethylenediamines, phenyl phosphate carry out oxidation instead Should, keep system temperature-20 DEG C～-15 DEG C, response time 2h, after having reacted, obtain Ah The B of dimension rhzomorph ointment₂A and B₁A 4 " position keto compounds；

Four, amination reduction reaction

(1) after oxidation reaction completes, by the B of abamectin ointment₂A and B₁A 4 " position ketone group Oxide is dissolved in isopropyl acetate, and in mass ratio 2: 5: 1 add the B of abamectin ointment₂a And B₁" position ketone group oxide, heptamethyldisilazane, that trifluoroacetic acid zinc carries out amination to a 4 is anti- Should, heat up and keep system temperature 40 DEG C～60 DEG C, response time 2h, obtaining after having reacted C to amination₅The B of position hydroxyl protection₂A and B₁A 4 " position imido grpup derivant；

(2) after aminating reaction completes, reduction system temperature to-10 DEG C～-15 DEG C, add nothing Water-ethanol and borane reducing agent sodium hydride, response time 1h, obtain avilamycin after having reacted The B of ointment₂A and B₁a C₅The methylamino derivant of position protection；

Five, deprotection reaction

By the B of abamectin ointment₂A and B₁a C₅The methylamino derivant of position protection is dissolved in anhydrous In ethanol, keep reacting liquid temperature-5 DEG C, after response time 1h, reacting liquid temperature is heated up To 30 DEG C, keeping 1h, use ethanol extraction reactant after having reacted, precipitation obtains Avermectin The B of vegetable oil cream₂A and B₁The methylamino derivant of a.

Six, salt-forming reaction

(1) B of abamectin ointment is pressed₂A and B₁The methylamino derivant of a and benzoic acid matter Amount is reacted than 2: 1 ratios, and response time 1h obtains avilamycin B after having reacted₂a Amido derivative salt and avilamycin B₁The mixture of a amido derivative salt；

(2) after question response is fully completed, it is evaporated under reduced pressure obtaining solution, treats that solvent steams After Faing, add and obtain paste quality 40% toluene and 0.3%BHT, i.e. obtain Avermectin Element avilamycin B₂The amido derivative salt of a and avilamycin B₁The mixing of a amido derivative salt Thing.

Beneficial effect

The present invention changes the utilization ways of existing abamectin ointment, it is provided that a kind of new Ah The deep processing processing method of dimension rhzomorph ointment, makes synthesis processing decrease refining crystallization technique step Suddenly, make further preparation processing simpler, convenient；More safe and environment-friendly；More add and subtract Few unnecessary farmland pollution and the processing cost of follow-up preparation.

Detailed description of the invention

It is described in detail below by way of specific embodiment, but scope not office It is limited to following illustrated embodiment.

Embodiment 1: the deep processing processing method of a kind of abamectin ointment of present embodiment is Carried out by following steps:

One, the pretreatment of abamectin ointment

(1) in 500ml flask, avilamycin commodity ointment 120g (B1a content is added 8.6%), it is evaporated under reduced pressure after the 6g that adds water mixing, removes contained solvent, obtain the Ah of paste Dimension rhzomorph ointment 70g；

(2) the abamectin ointment 70g of gained paste, is added thereto to petroleum ether 70g and stirs Mix the abamectin ointment dissolving paste, static layering, remove contained oils and fats in ointment；

(3) trichlorine that mass percent concentration is 10% that quality is 14g it is added thereto to again Acetic acid solution, stirs, static layering, removes protein contained in ointment；

(4) again surplus solution is evaporated under reduced pressure, removes contained solvent, obtain paste；

Two, protection reaction

Molten by the avilamycin paste 68g after precipitation adds dichloromethane 130g stirring again Xie Hou, cools to-20 DEG C, drips allyl chlorocarbonate 3g, tetramethylethylenediamine 2.5g, instead After answering 2h, terminating reaction, precipitation obtains abamectin ointment B₂A and B₁The C of a₅Position hydroxyl Protection intermediate；

Three, oxidation reaction

Abamectin ointment B₂A and B₁The C of a₅It is different that position hydroxyl protection intermediate 60g is dissolved in acetic acid In propyl ester solution, add dimethyl sulfoxide 4g, tetramethyl different diamidogen 5g, cool to-20 DEG C, drip Add phenyl phosphate 4g, with the pH to 2.0～3.0 of acid solution regulation solution, response time 2h, terminates reaction, collects dichloromethane phase, regulates pH to 7.0 with alkaline solution, then Dichloromethane is removed in decompression, obtains Simultaneous Oxidation product Intermediate；

Four, amination reduction reaction

(1) Simultaneous Oxidation product 57g and the isopropyl acetate 200g obtained stirring is mixed, Add trifluoroacetic acid zinc 1g and heptamethyldisilazane 4g mix homogeneously, be then warmed up to 50 DEG C, react 3h, obtain aminate；

(2) after aminating reaction terminates, reaction system is cooled to-10 DEG C, to the amine obtained Change and product adds dehydrated alcohol 100g, add borane reducing agent sodium hydride 2g, must mix molten Liquid, reacts 1h, the pH to 3.0 of regulation mixed solution, terminates reaction, then use alkaline solution Regulation mixed solution pH to 7.0, obtains isopropyl acetate and extracts reactant liquor, and reduce pressure precipitation, Obtain C₅The abamectin ointment B of position hydroxyl protection₂A and B₁The methylamino product of a；

Five, deprotection reaction

To the C obtained₅The abamectin ointment B of position hydroxyl protection₂A and B₁The methylamino product of a Middle addition dehydrated alcohol, cools to-5 DEG C, adds triphenylphosphine 0.001g, sodium borohydride 0.01g, reacts 1h, adds hydrochloric acid and adjusts PH to 3, be then warmed up to 30 DEG C, reacts 1h, After reaction terminates, after decompression precipitation, i.e. obtain abamectin ointment B₂A and B₁A methylamino derivant Salt 46g.

Six, salt-forming reaction

At the 46g abamectin ointment B obtained₂A and B₁A methylamino derivative salt adds matter Amount 18g toluene and 0.13gBHT, i.e. obtain avilamycin avilamycin B₂The amido derivative of a Salt and avilamycin B₁The mixture of a amido derivative salt.

Embodiment 2: the deep processing processing method of a kind of abamectin ointment of present embodiment is Carried out by following steps:

One, the pretreatment of abamectin ointment

(1) in 5L reactor, avilamycin commodity ointment 1200g (B1a content is added 8.6%), the 60g that adds water is evaporated under reduced pressure after being uniformly mixed, and removes contained solvent, Abamectin ointment to paste；

(2) the abamectin ointment 700g of gained paste, is added thereto to petroleum ether 700g The abamectin ointment of stirring and dissolving paste, static layering, remove contained oils and fats in ointment；

(3) trichlorine that mass percent concentration is 10% that quality is 140g it is added thereto to again Acetic acid solution, stirs, static layering, removes protein contained in ointment；

(4) again surplus solution is evaporated under reduced pressure, removes contained solvent, obtain paste；

Two, protection reaction

Molten by the avilamycin paste 680g after precipitation adds dichloromethane 130g stirring again Xie Hou, cools to-20 DEG C, drips allyl chlorocarbonate 30g, tetramethylethylenediamine 25g, instead After answering 2h, terminating reaction, precipitation obtains abamectin ointment B₂A and B₁The C of a₅Position hydroxyl Protection intermediate；

Three, oxidation reaction

Abamectin ointment B₂A and B₁The C of a₅Position hydroxyl protection intermediate 600g is dissolved in acetic acid In isopropyl ester solution, add dimethyl sulfoxide 40g, tetramethyl different diamidogen 50g, cool to-20 DEG C, drip phenyl phosphate 40g, regulate the pH to 2.0～3.0 of solution with acid solution, instead 2h between Ying Shi, terminates reaction, collects dichloromethane phase, regulates pH to 7.0 with alkaline solution, Then dichloromethane is removed in decompression, obtains Simultaneous Oxidation product Intermediate；

Four, amination reduction reaction

(1) Simultaneous Oxidation product 570g and the isopropyl acetate 2000g obtained stirring is mixed, Add trifluoroacetic acid zinc 10g and heptamethyldisilazane 40g mix homogeneously, then heat up To 50 DEG C, react 3h, obtain aminate；

(2) after aminating reaction terminates, reaction system is cooled to-10 DEG C, to the amine obtained Change and product adds dehydrated alcohol 1000g, add borane reducing agent sodium hydride 20g, obtain mixing Solution, reacts 1h, the pH to 3.0 of regulation mixed solution, terminates reaction, more molten by alkalescence Liquid regulation mixed solution pH to 7.0, obtains isopropyl acetate and extracts reactant liquor, and reduce pressure precipitation, Obtain C₅The abamectin ointment B of position hydroxyl protection₂A and B₁The methylamino product of a；

Five, deprotection reaction

To the C obtained₅The abamectin ointment B of position hydroxyl protection₂A and B₁The methylamino product of a Middle addition dehydrated alcohol, cools to-5 DEG C, adds triphenylphosphine 0.01g, sodium borohydride 0.1g, Reaction 1h, adds hydrochloric acid and adjusts PH to 3, be then warmed up to 30 DEG C, react 1h, and reaction terminates After, i.e. obtain abamectin ointment B after decompression precipitation₂A and B_1aMethylamino derivative salt 460g；

Six, salt-forming reaction

At the 460g abamectin ointment B obtained₂A and B₁A methylamino derivative salt adds matter Amount 180g toluene and 1.3gBHT, i.e. obtain avilamycin avilamycin B₂The amido derivative of a Salt and avilamycin B₁The mixture of a amido derivative salt.

Claims (1)

1. the deep processing processing method of an abamectin ointment, it is characterised in that: include with Lower step:

One, the pretreatment of abamectin ointment:

(1) ratio of avilamycin commodity ointment with water in mass ratio 20～22: 1 is mixed all It is evaporated under reduced pressure after even, removes contained solvent, obtain paste abamectin ointment；

(2) in mass ratio 1: 1 addition petroleum ether and stirring in gained paste abamectin ointment Dissolve paste abamectin ointment, static layering, remove contained oil in paste abamectin ointment Fat；

(3) adding quality again in the product of step (2) is the stone described in step (2) The solution of trichloroacetic acid that mass percent concentration is 10% of oil ether quality 20%, stirs, Static layering, removes protein contained in ointment；

(4) again surplus solution is evaporated under reduced pressure, removes contained solvent, obtain paste；

Two, protection reaction: by avilamycin paste and dichloromethane mass volume ratio 1: 2 Add dichloromethane and dissolve paste, after paste is completely dissolved, cooling system temperature to-20 DEG C～-15 DEG C, dropping the bright ester of chloro-carbonic acid alkene and tetramethylethylenediamine solution carry out protection reaction, Response time 2h, notices that system temperature must not be higher than-15 DEG C, by B in ointment₂A and B₁A's C₅Position hydroxyl is protected；

Three, oxidation reaction: after protection reaction, dissolve abamectin ointment with isopropyl acetate B₂A and B₁The C of a₅Position hydroxyl protection thing, in mass ratio 1: 10: 3: 3 add Avermectin vegetable oil Cream B₂A and B₁The C of a₅Position hydroxyl protection thing, dimethyl sulfoxide, tetramethylethylenediamine, phosphoric acid Phenyl ester carries out oxidation reaction, keeps system temperature-20 DEG C～-15 DEG C, response time 2h, instead The B of abamectin ointment should be obtained after completing₂A and B₁A 4 " position keto compounds；

Four, amination reduction reaction:

(1) after oxidation reaction completes, by the B of abamectin ointment₂A and B₁A 4 " position ketone group Oxide is dissolved in isopropyl acetate, and in mass ratio 2: 5: 1 add the B of abamectin ointment₂a And B₁" position ketone group oxide, heptamethyldisilazane, that trifluoroacetic acid zinc carries out amination to a 4 is anti- Should, heat up and keep system temperature 40 DEG C～60 DEG C, response time 2h, obtaining after having reacted C to amination₅The B of position hydroxyl protection₂A and B₁A 4 " position imido grpup derivant；

(2) after aminating reaction completes, reduction system temperature to-1 DEG C～-15 DEG C, add anhydrous Ethanol and borane reducing agent sodium hydride, response time 1h, obtain Avermectin vegetable oil after having reacted The B of cream₂A and B₁a C₅The methylamino derivant of position protection；

Five, deprotection reaction: by the B of abamectin ointment₂A and B₁a C₅The methylamine of position protection Radical derivative is dissolved in dehydrated alcohol, keeps reacting liquid temperature-5 DEG C, after response time 1h, Reacting liquid temperature is warmed up to 30 DEG C, keeps 1h, after having reacted, use ethanol extraction reactant, Precipitation obtains the B of abamectin ointment₂A and B₁The methylamino derivant of a.

Six, salt-forming reaction:

(1) B of abamectin ointment is pressed₂A and B₁The methylamino derivant of a and benzoic acid matter Amount is reacted than 2: 1 ratios, and response time 1h obtains avilamycin B after having reacted₂a Amido derivative salt and avilamycin B₁The mixture of a amido derivative salt；

(2) after question response is fully completed, it is evaporated under reduced pressure obtaining solution, treats that solvent steams After Faing, add and obtain paste quality 40% toluene and 0.3%BHT, i.e. obtain Avermectin Element avilamycin B₂The amido derivative salt of a and avilamycin B₁The mixing of a amido derivative salt Thing.