CN113563395A - Abamectin B2 derivative and preparation method and application thereof - Google Patents
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Abstract
The invention provides an avermectin B2 derivative, a preparation method and application thereof, and the structure of the avermectin B2 derivative is shown as a formula (I). The invention carries out structural optimization on the abamectin B2 with lower utilization rate in the abamectin production process, designs and synthesizes a series of abamectin B2 derivatives with brand-new structures, has stable chemical properties, higher insecticidal activity and more excellent insecticidal persistence, can effectively prevent and treat various in vivo and in vitro parasites such as parasites, louse, mites, flies and the like of livestock, has special effect on cow nematode disease in particular, is a novel and efficient abamectin biological pesticide, and has the advantages of novel and efficient abamectin biological pesticide, and capability of preventing and treating the livestock in vivo and in vitro parasites such as parasites, louse, mites, flies and the likeHas high pesticide research value and wide application prospect in agriculture and livestock industry.
Description
Technical Field
The invention relates to the technical field of agricultural chemicals and preparation, in particular to an avermectin B2 derivative and a preparation method and application thereof.
Background
In the production process of animal husbandry, serious insect pests are frequently encountered, the pests deprive the nutrition of animal bodies in a parasitizing mode and the like, and meanwhile, the pests can generate mechanical damages such as organ blockage, damage, tissue compression and the like to livestock; or toxicity to livestock through secretions or excretions, resulting in malnutrition, wasting, weakness and even death of livestock. The most common method currently used to effectively control livestock pests is the use of insecticides or insect repellents.
Acetaminoavermectin was the first broad-spectrum antiparasitic drug developed by Merck in 1997 to be applicable to cows and beef cattle without the need for a drug holiday. On the basis of the structure of abamectin B1, acetyl is modified at the 4' position to obtain acetyl abamectin. The acemectin is a high-efficiency, broad-spectrum and low-residue animal repellent, is the only broad-spectrum repellent approved by the Food and Drug Administration (FDA) and the European Union and applied to lactating cows without abandoning milk, and the preparation of the acemectin is approved to be put on the market in the countries of the United states, the European Union, New Zealand and the like.
In the process of avermectin fermentation, avermectin B1(B1a + B1B) and avermectin B2(B2a + B2B) are the most main products, and the activity of avermectin B1 is far higher than that of avermectin B2, so that the commercial avermectin original drug in the current market is avermectin B1(B1a is more than or equal to 96%, and B1B is less than or equal to 4%). After the abamectin B1 is extracted from the fermentation liquor, more than 20 percent of abamectin B2 contained in the fermentation liquor can be greatly left or discarded, thereby causing huge resource waste and environmental pollution. Therefore, the exploration and application of the abamectin B2 component is becoming increasingly important.
Disclosure of Invention
Aiming at the problems, the invention provides an avermectin B2 derivative and a preparation method and application thereof.
In order to solve the technical problems, the technical scheme provided by the invention is as follows:
an avermectin B2 derivative has a structure shown in formula (I):
wherein R is1Is methyl or ethyl; r2Is hydroxy or a hydroxyamine subunit; r3Is H, C1-C3 alkyl or halogenated C1-C3 alkyl; r4Is C1-C4 alkyl or halogenated C1-C4 alkyl.
The invention carries out structural optimization on the abamectin B2 with lower utilization rate in the abamectin production process, designs and synthesizes a series of abamectin derivatives with brand-new structures, has stable chemical properties, higher insecticidal activity and more excellent insecticidal persistence, can effectively prevent and treat various in-vivo and in-vitro parasites such as parasites, louses, mites, flies and the like of livestock, particularly has special effect on the nematode disease of dairy cows, is a novel and efficient abamectin biological pesticide, has very high pesticide research value and has wide application prospect in agriculture and livestock industry.
The invention also provides a preparation method of the avermectin B2 derivative, when R3 is C1-C3 alkyl or halogenated C1-C3 alkyl, the preparation method comprises the following steps:
step a, preparing a compound shown as a formula (II) by using abamectin B2 as a raw material;
step b, in an inert solvent, a compound shown as a formula (II) and R3Carrying out substitution reaction on X under the action of organic base to obtain a compound shown as a formula (III); whereinX is halogen, R5 is a hydroxy protecting group;
step c, in an inert solvent, reacting the compound shown in the formula (III) with
Carrying out substitution reaction under the action of organic base to obtain a compound shown in a formula (IV);
and d, carrying out dehydroxylation protection reaction on the compound shown in the formula (IV) to obtain the compound shown in the formula (I).
Preferably, when R3 is C1-C3 alkyl or halogenated C1-C3 alkyl, the preparation method of the avermectin B2 derivative comprises the following steps:
step a, preparing a compound shown as a formula (II) by using abamectin B2 as a raw material;
b, dissolving the compound shown in the formula (II) in an inert solvent, controlling the reaction temperature to be-15-0 ℃, and adding organic base and R3X, carrying out substitution reaction under the condition of heat preservation, and slowly dripping into the mixture after the residual amount of the compound shown as the formula (II) is less than 1 percent through high performance liquid chromatography detection
Carrying out substitution reaction, detecting by high performance liquid chromatography until the reaction is complete, adding a hydroxyl deprotection reagent and a catalyst, removing a 5-bit protecting group, washing with water, drying, and concentrating to obtain a crude compound of the formula (I).
When R3 is H, the preparation method of the avermectin B2 derivative comprises the following steps:
step a, preparing a compound shown as a formula (II) by using abamectin B2 as a raw material;
step b, in an inert solvent, the compound shown as the formula (II) is reacted with
Carrying out substitution reaction under the action of organic base to obtain a compound shown in a formula (IV); x is halogen, R5 is a hydroxy protecting group;
c, carrying out dehydroxylation protection reaction on the compound shown in the formula (IV) to obtain a compound shown in a formula (I);
preferably, when R3 is H, the preparation method of the avermectin B2 derivative comprises the following steps:
step a, preparing a compound shown as a formula (II) by using abamectin B2 as a raw material;
b, dissolving the compound shown as the formula (II) in an inert solvent, controlling the reaction temperature to be-15-0 ℃, adding organic base, uniformly mixing, and dropwise adding under the protection of inert atmosphere
Carrying out substitution reaction, detecting by high performance liquid chromatography until the reaction is complete, adding a hydroxyl deprotection reagent and a catalyst, removing a 5-bit protecting group, washing with water, drying, and concentrating to obtain a crude compound of the formula (I).
The structures of the abamectin B2a and abamectin B2B are shown as a formula (1) and a formula (2). The invention takes avermectin B2a/B2B as raw materials, synthesizes a plurality of avermectin B2 derivatives with novel structure, provides a series of novel medicaments for preventing and treating the cow nematode diseases, has simple preparation method, higher product yield and purity, the yield can reach more than 90 percent, the purity can reach more than 80 percent, the prepared medicament has high activity, the required application dosage is less, the duration is long, the medicament usage amount can be reduced, the medicament cost can be reduced, the efficient utilization of the avermectin byproduct B2 can be realized, the pollution to the environment can be reduced, the invention has higher economic benefit and environmental benefit, and has higher popularization and application value.
Preferably, the inert solvent is at least one of dichloromethane, dichloroethane, toluene, sec-butyl acetate or ethyl acetate.
Preferably, the amount of the inert solvent added is 3 to 10 times of the amount of the compound represented by the formula (II).
Preferably, the organic base is at least one of triethylamine, pyridine, tetramethylethylenediamine, lithium diisopropylamide or potassium tert-butoxide.
Preferably, the molar ratio of the organic base to the compound represented by the formula (II) is 1.0-2.5: 1.
Preferably, the catalyst for the dehydroxylation protection reaction is Pd (PPH)3)2Cl2、PdCl2Or Pd (OAc)2At least one of them.
More preferably, the amount of the dehydroxylation protection catalyst added is 0.01 to 0.1% of the mole number of the compound represented by the formula (II).
Preferably, the deprotection reagent for the dehydroxylation protection reaction is at least one of methanol, ethanol, sodium borohydride, sodium triacetoxyborohydride, ammonium fluoride or tetrabutylammonium fluoride.
More preferably, the amount of the dehydroxylation protecting agent added is 0.5 to 10 times the mole number of the compound represented by the formula (II).
Optionally, R5 is allyloxycarbonyl, trimethylsilyl or tert-butyldimethylsilyl.
Preferably, the preparation method of the avermectin B2 derivative further comprises the following purification steps: and (3) dissolving the obtained crude compound shown in the formula (I) in a mixed solution of n-butyl ether, isopropyl ether and cyclohexane, and cooling and crystallizing to obtain the compound product shown in the formula (I).
More preferably, the volume ratio of the n-butyl ether to the isopropyl ether to the cyclohexane is 1:1:2 to 1:3: 6.
Further preferably, the temperature of the cooling crystallization is 0-5 ℃.
Further preferably, the mass ratio of the mixed solution to the crude compound shown in the formula (I) is 3: 1-10: 1.
Preferably, when R2 is hydroxyl, step a specifically includes the following steps: under the condition of organic base, abamectin B2 is used as a raw material, and 5-position hydroxyl protection, 4 '-position hydroxyl oxidation and 4' -position amination reduction are sequentially carried out to obtain the compound shown in the formula (II).
Further preferably, when R2 is hydroxyl, step a specifically includes the following steps:
s101, dissolving an abamectin B2 raw material in an inert solvent, adding an organic base, uniformly mixing, cooling, adding a hydroxyl protecting reagent to perform 5-bit hydroxyl protecting reaction, after the reaction is completed, adding an oxidant into a reaction solution to perform Swern oxidation reaction, adding water after the reaction is finished, splitting phases, drying an organic phase by anhydrous magnesium sulfate, and concentrating to obtain a solid;
s102, dissolving the solid obtained in the step S101 in an inert solvent, adding an aminating agent and a catalyst, heating to carry out amination reaction, cooling after the reaction is completed, adding alcohol and a reducing agent to carry out reduction reaction, quenching the reaction after the reaction is completed, carrying out phase separation, concentrating an organic phase, and drying to obtain the compound shown in the formula (II).
More preferably, in the step S101, the mass ratio of the inert solvent to the raw material of abamectin B2 is 5-10: 1.
More preferably, in step S101, the hydroxyl protecting reagent is allyl chloroformate, trimethylsilane or tert-butyldimethylsilane; the organic base is tetramethylethylenediamine or triethylamine; the oxidant is dimethyl sulfoxide and phenyl phosphate diacid chloride.
More preferably, in step S101, the adding amount of the hydroxyl protecting reagent is 15 to 17 wt% of the raw material abamectin B2, the adding amount of the phenyl phosphate diacid chloride is 19 to 21 wt% of the raw material abamectin B2, and the adding amount of the dimethyl sulfoxide is 25 to 27 wt% of the raw material abamectin.
More preferably, in the step S101, in the 5-position hydroxyl protection reaction, the amount of the organic base added is 16 to 18 wt% of the abamectin raw material.
More preferably, in step S101, the temperature is reduced to-15 ℃ to-10 ℃, a hydroxyl protecting reagent is added to carry out 5-position hydroxyl protecting reaction, and the temperature in the hydroxyl protecting reaction process is controlled not to exceed-10 ℃.
More preferably, in step S101, the Swern oxidation reaction is carried out at a temperature of-15 ℃ to-10 ℃.
More preferably, in step S102, the amination agent is hexamethyldisilazane, the catalyst is zinc acetate, and the reducing agent is sodium borohydride or sodium triacetoxyborohydride.
More preferably, in the step S102, the adding amount of the amination agent is 30 to 35 wt% of the raw material of the avermectin B2, and the adding amount of the catalyst is 5 to 5.5 wt% of the raw material of the avermectin B2.
More preferably, in the step S102, in the reduction reaction, the adding amount of the reducing agent is 6 to 6.5 wt% of the raw material of the avermectin B2.
More preferably, in step S102, the mass-to-volume ratio of the added amount of the alcohol to the raw material of abamectin B2 is 1: 1-1.5, wherein the unit of mass is g, and the unit of volume is ml.
Optionally, the alcohol is absolute ethyl alcohol or absolute methyl alcohol.
More preferably, in step S101 and step S102, the inert solvent is at least one of dichloromethane, toluene, sec-butyl acetate or isopropyl acetate.
More preferably, in step S102, the temperature of the amination reaction is 60 ℃ to 65 ℃ and the reaction time is 6h to 7 h.
More preferably, in step S102, the temperature of the reduction reaction is-5 ℃ to 0 ℃ and the reaction time is 0.5h to 1 h.
The preferred reaction conditions are favorable for improving the yield and purity of the compound represented by the formula (II).
Preferably, when R2 is a hydroxyimino group, step a specifically includes the following steps: under the condition of organic base, abamectin B2 is used as a raw material to carry out hydroxyl oxidation at 5-position and 4 '-position, O-allyloxyamine is added to convert the 5-position into allyloxy hydroxylamine subunit, and then the 4' -position is aminated and reduced to obtain the compound shown in the formula (II).
More preferably, when R2 is a hydroxyimino group, step a specifically includes the following steps:
r101, dissolving an abamectin B2 raw material in an inert solvent, adding an organic base, uniformly mixing, cooling, adding an oxidant, carrying out Swern oxidation reaction at 5-position and 4-position, adding O-allyloxyamine into a reaction solution after the reaction is finished, carrying out heat preservation for reaction, adding water after the reaction is finished, carrying out phase separation, and drying an organic phase by anhydrous magnesium sulfate to obtain a solid;
r102, dissolving the solid obtained in the step S101 in an inert solvent, adding an aminating agent and a catalyst, heating for amination reaction, cooling after the reaction is completed, adding alcohol and a reducing agent for reduction reaction, quenching the reaction after the reaction is completed, carrying out phase separation, concentrating an organic phase, and drying to obtain the compound shown in the formula (II).
More preferably, in the step R101, the adding amount of the O-allyloxyamine is 13-14 wt% of the raw material of the abamectin B2.
More preferably, the adding amount of the phenyl phosphate diacid chloride is 39-41 wt% of the raw material abamectin B2, and the adding amount of the dimethyl sulfoxide is 51-53 wt% of the raw material abamectin B2.
More preferably, in the step R101, the adding amount of the organic base is 25-27 wt% of the raw material of the abamectin B2.
More preferably, in step R101, the Swern oxidation reaction is carried out at a temperature of-25 ℃ to-20 ℃.
When R2 is a hydroxyimino group, the remaining reaction conditions in step a are the same as when R2 is a hydroxyl group.
The invention also provides application of the avermectin B2 derivative in preventing and treating livestock diseases and insect pests.
The avermectin B2 derivative of formula (I) can be used as veterinary drug, and can be used for controlling pests in various useful livestock with good effect, wherein the useful livestock comprises but is not limited to conventional breeding livestock, protective animals, wild animals, cloned animals and the like.
Preferably, the avermectin B2 derivative of formula (I) is particularly suitable for beef cattle, dairy cows, goats, sheep, pigs, horses, donkeys and rabbits.
The pests can be intestinal and gastric system roundworm, Ostertagia, Cupressus caenorhabditis, esophageal oral nematode, Trichostrongylus Serpentis, Dermatophagoides bovis Seu Bubali, sarcoptic mite, lice, etc.
The invention also provides application of the avermectin B2 derivative in treating or preventing the dairy cattle nematode disease.
The invention also provides a pharmaceutical composition for treating or preventing the nematode disease of the dairy cattle, which comprises the avermectin B2 derivative shown in the formula (I).
When the active pharmaceutical ingredient is used for controlling livestock pests, various application methods or techniques can be used, such as wiping or spraying on the surface of livestock bodies by adding water in a conventional manner, or directly spreading the active pharmaceutical ingredient in feed. The spreading time can be varied or adjusted in a wide range in the domestic animal growth period and the whole breeding period, and depends on the disease state of the domestic animal, the specific method of application, the specific type of domestic animal, the age of domestic animal, the type of pest control, the local climate environment and other factors.
The invention is generally used in an amount of 0.1 to 20mg of active ingredient per kilogram, more preferably 0.5 to 10mg of active ingredient per kilogram.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The content of the abamectin B2a in the raw material of the abamectin B2a/2B used in the following examples is more than 98%.
NMR spectra were measured using Bruker ARX-500 and mass spectra were measured using Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
Example 1
This example provides a process for the preparation of a compound of formula (ii):
when R2 is hydroxyl, the method comprises the following steps:
adding 10g of raw material abamectin B2a/2B into 50g of dichloromethane, stirring and dissolving, adding 1.7g of tetramethylethylenediamine, cooling to-15 to-10 ℃, slowly dropwise adding 1.6g of allyl chloroformate, preserving heat and reacting for 30min after dropwise adding, then adding 2.6g of dimethyl sulfoxide, slowly dropwise adding 2.0g of phenyl phosphate diacyl chloride, preserving heat and reacting for 1h, adding 50mL of water, stirring at room temperature for 30min, then carrying out phase separation, drying an organic phase by anhydrous magnesium sulfate, and concentrating to be dry to obtain 10.3g of light yellow solid;
adding the solid obtained in the previous step into 50mL of isopropyl acetate, stirring for dissolving, adding 0.5g of zinc acetate and 3.0g of hexamethyldisilazane, heating for reflux reaction for 6 hours, then cooling to 0 ℃, adding 10mL of methanol, slowly adding 0.6g of sodium borohydride, keeping the temperature, stirring for reaction for 30min, then adding 50mL of water into the reaction solution, adjusting the pH to 4-5 by using a 5 wt% hydrochloric acid solution, adjusting the pH to 7-8 by using a 10 wt% sodium hydroxide solution, carrying out phase separation, and concentrating the organic phase to dryness to obtain 9.8g of a compound (4' -amino-5-allyloxycarbonyl abamectin B2a/B2B) shown in the formula (II), wherein the HPLC content is 96%.
When R2 is hydroxylamine subunit, the method comprises the following steps:
adding 10g of raw material abamectin B2a/2B into 50g of dichloromethane, stirring for dissolving, adding 2.6g of tetramethylethylenediamine and 5.2g of dimethyl sulfoxide, cooling to-25 to-20 ℃, slowly dropwise adding 4.0g of phenyl phosphate diacyl chloride, keeping the temperature for reaction for 30min after dropwise adding, then adding 1.35g of O-allyloxy amine, stirring for reaction for 1h, adding 50mL of water, stirring for 30min at room temperature, then carrying out phase separation, drying an organic phase by anhydrous magnesium sulfate, and concentrating to be dry to obtain 10.0g of a light yellow solid;
adding the solid obtained in the previous step into 50mL of isopropyl acetate, stirring for dissolving, adding 0.5g of zinc acetate and 3.0g of hexamethyldisilazane, heating for reflux reaction for 6h, then cooling to 0 ℃, adding 10mL of methanol, slowly adding 0.6g of sodium borohydride, keeping the temperature, stirring for reaction for 30min, then adding 50mL of water into the reaction solution, adjusting the pH to 4-5 by using a 5 wt% hydrochloric acid solution, adjusting the pH to 7-8 by using a 10 wt% sodium hydroxide solution, carrying out phase separation, and concentrating the organic phase to dryness to obtain 9.0g of a compound (5-allyloxyimino-4' -aminoavermectin B2a/B2B) shown in the formula (II), wherein the HPLC content is 95%.
Other reaction conditions, hydroxyl group protecting agents, solvents and the like defined in the description of the present invention can be adopted to achieve technical effects basically equivalent to those described above.
Example 2
A preparation method of an avermectin B2 derivative comprises the following steps:
step one, preparation of 4' -acetamido-5-allyloxycarbonyl abamectin B2 a/B2B:
adding 39.2g (40.8mmol) of 4 ' -amino-5-allyloxycarbonyl abamectin B2a/B2B (the content of 4 ' -amino-5-allyloxycarbonyl abamectin B2a is more than 95%) into 120g of dichloromethane, cooling the reaction liquid to 0 ℃, adding 5.2g (44.7mmol) of tetramethylethylenediamine, slowly adding 3.5g of acetyl chloride (44.7mmol) under the protection of nitrogen, and reacting for 2 hours at 0 ℃ after dropwise addition is finished to obtain the reaction liquid containing 4 ' -acetamido-5-allyloxycarbonyl abamectin B2 a/B2B;
and (3) concentrating and drying a small amount of the reaction solution, and then carrying out structure confirmation:
MS[M+H+](m/z):1003.55。
1H NMR(500MHz,CDCl3)δ6.77(s,1H),5.96(ddt,J＝16.6,10.4,6.2Hz,1H),5.78–5.70(m,2H),5.42(p,J＝7.0Hz,1H),5.32–5.19(m,4H),5.20–5.12(m,2H),5.03–4.95(m,3H),4.92–4.80(m,3H),4.3(p,J＝6.9Hz,1H),4.13(p,J＝6.8Hz,1H),4.06–3.93(m,2H),3.83(t,J＝7.0Hz,1H),3.72(qd,J＝7.0,4.9Hz,1H),3.61(dq,J＝17.2,7.0Hz,2H),3.44(s,3H),3.32(s,3H),3.23(t,J＝6.9Hz,1H),3.07(t,J＝7.0Hz,1H),2.89(s,1H),2.52(pd,J＝6.7,4.4Hz,1H),2.45–2.35(m,1H),2.23–2.03(m,4H),1.90(s,3H),1.85–1.48(m,16H),1.25(d,J＝6.8Hz,3H),1.18–1.06(m,7H),0.95–0.86(m,9H)。
13C NMR(500MHz,CDCl3)δ138.88ppm,132.37,126.14,122.25,119.78,119.01,116.77,99.43,93.81,84.20,80.79,79.44,79.37,77.04,73.37,71.00,70.69,69.99,69.95,68.21,67.75,67.30,67.02,57.82,57.02,54.68,45.93,41.28,41.22,38.94,36.57,35.89,35.80,35.15,34.60,33.80,27.30,23.09,19.56,19.16,19.08,18.38,13.75,13.42,12.45,11.65。
step two, preparation of 4' -acetamido abamectin B2 a/B2B:
adding 0.65g of methanol (20.3mmol) into the reaction liquid containing the 4' -acetamido-5-allyloxycarbonyl abamectin B2a/B2B in the step one, then cooling to-5 ℃, and adding 0.05g (0.04mmol) of Pd (PPh)3)4Then, 0.76g (20.2mmol) of sodium borohydride is added in batches, the addition is completed within about 2 hours, after the reaction is completed, 5 wt% of phosphoric acid solution is used for adjusting the pH value to 6-7, then 5 wt% of sodium hydroxide solution is used for adjusting the pH value to 7, phase separation is carried out, an organic phase is dried by anhydrous sodium sulfate, 5g of activated carbon is added, stirring is carried out for 20min, filtering is carried out, mother liquor is concentrated, and thus 41.2g of brown yellow solid is obtained, the HPLC content is 83%, and the yield is 92%;
carrying out structure verification on the brown yellow solid:
MS[M+H+](m/z):933.15。
1H NMR(500MHz,CDCl3)δ6.77(s,1H),5.81–5.70(m,2H),5.43(t,J＝6.9Hz,1H),5.01–4.89(m,2H),4.83(t,J＝7.2Hz,2H),4.30(dt,J＝20.1,6.9Hz,2H),4.20–3.90(m,5H),3.86–3.73(m,2H),3.73–3.57(m,4H),3.44(s,3H),3.38(s,3H),3.31(t,J＝7.0Hz,1H),3.06(dd,J＝11.4,7.0Hz,1H),2.89(s,1H),2.60–2.50(m,2H),2.54–2.41(m,2H),2.17–2.00(m,2H),1.96(ddd,J＝13.2,10.4,7.1Hz,2H),1.90(s,3H),1.76–1.55(m,7H),1.54–1.40(m,7H),1.43–1.29(m,2H),1.32–1.21(m,4H),1.16(dd,J＝14.8,6.8Hz,6H),0.96–0.86(m,9H)。
13C NMR(500MHz,CDCl3)δ138.88,127.16,127.10,122.25,122.00,101.29,93.81,84.20,80.79,80.01,79.37,77.37,71.65,71.00,70.08,69.95,69.20,68.58,67.70,67.18,67.02,57.82,57.02,52.38,44.15,41.28,38.95,38.20,35.80,35.15,34.65,34.60,27.30,23.09,19.48,19.16,18.38,16.86,13.75,13.42,12.45,11.65。
and step three, dissolving the brown yellow solid obtained in the step two by using a mixed solution of 34.2g of n-butyl ether and 34.2g of isopropyl ether, slowly dropwise adding 68.4g of cyclohexane, slowly cooling to 0 ℃ after dropwise adding, keeping the temperature for 30min, filtering, and drying a filter cake to obtain 29.2g of off-white solid, wherein the HPLC content is 99.1%, the crystallization yield is 85%, and the structure is shown as follows.
Example 3
A preparation method of an avermectin B2 derivative (5-hydroxylamine subunit-4' -acetamido avermectin B2a/B2B) comprises the following steps:
step one, adding 49.3g (0.05mol) of 5-allyloxyimino-4 '-amino abamectin B2a/B2B (5-allyloxyimino-4' -amino abamectin B2a content is not less than 95%) into 446g of dichloromethane, cooling the reaction liquid to-5 ℃, adding 5.8g (0.05mol) of tetramethyl ethylenediamine, slowly adding 12.6g of trifluoroacetic anhydride (0.06mol), carrying out heat preservation stirring reaction for 30min after dropwise addition, and finishing the reaction after the residual amount of 5-allyloxyimino-4 '-amino abamectin B2a/B2B is less than 1% through high performance liquid phase detection to obtain the reaction liquid containing 5-allyloxyhydroxylamine subunit-4' -acetamido abamectin B2 a/B2B;
step two, the step oneCooling the reaction solution containing 5-allyloxyhydroxylamine subunit-4' -acetamido abamectin B2a/B2B to 0 deg.C, adding 13g methanol (0.4mol), adding 0.035g Pd (PPH)3)2Cl2(0.05mmol), then adding 1.9g (0.05mol) of sodium borohydride in batches, reacting for 0.5h, adjusting the pH to 2 by using a 7.6 wt% phosphoric acid solution, then adjusting the pH to 7 by using a 10 wt% sodium hydroxide solution, carrying out phase separation, drying an organic phase by using anhydrous sodium sulfate, adding 5g of activated carbon, stirring for 20min, filtering, and concentrating a mother liquor to obtain 49.9g of brown yellow solid with the HPLC content of 88% and the yield of 93%;
carrying out structure verification on the brown yellow solid:
MS[MH+](m/z):946.14。
1H NMR(500MHz,CDCl3)δ6.87(s,1H),5.88–5.76(m,2H),5.53(t,J＝6.9Hz,1H),5.11–4.99(m,2H),4.93(t,J＝7.2Hz,2H),4.60(dt,J＝20.1,7.0Hz,2H),4.30–4.00(m,5H),390–3.83(m,2H),3.79–3.47(m,4H),3.40(s,3H),3.35(s,3H),3.30(t,J＝7.0Hz,1H),3.20(dd,J＝11.4,7.0Hz,1H),2.30(s,1H),2.77–2.50(m,2H),2.44–2.21(m,2H),2.20–2.00(m,2H),1.90(ddd,J＝13.2,10.4,7.1Hz,2H),1.89(s,3H),1.66–1.55(m,7H),1.51–1.45(m,7H),1.41–1.30(m,2H),1.29–1.20(m,4H),1.10(dd,J＝14.8,6.8Hz,6H),0.90–0.80(m,9H)。
13C NMR(500MHz,CDCl3)δ138.88,127.16,127.10,122.25,122.00,101.29,93.81,84.20,80.79,80.01,79.37,77.37,71.65,71.00,70.08,69.95,69.20,68.58,67.70,67.18,67.02,57.82,57.02,52.38,44.15,41.28,38.95,38.20,35.80,35.15,34.65,34.60,27.30,23.09,19.48,19.16,18.38,16.86,13.75,13.42,12.45,11.65。
and step three, dissolving the brown yellow solid obtained in the step two by using a mixed solution of 50g of n-butyl ether and 150g of isopropyl ether, slowly dropwise adding 300g of cyclohexane, slowly cooling to-5 ℃ after dropwise adding, keeping the temperature for 30min, filtering, and drying a filter cake to obtain 36.2g of off-white solid, wherein the HPLC content is 99.5%, the crystallization yield is 82%, and the structure is shown as follows.
Example 4
A preparation method of an avermectin B2 derivative comprises the following steps:
step one, adding 49.3g (0.05mol) of 5-allyloxyimino-4 '-amino abamectin B2a/B2B (5-allyloxyimino-4' -amino abamectin B2a content is not less than 95%) into 446g of toluene, cooling the reaction liquid to-15 ℃, adding 5.9g (0.06mol) of dichloroethane and 0.05g of sodium bromide, stirring uniformly, slowly adding 5.6g (0.05mol) of potassium tert-butoxide in batches, stirring for 30min after the addition is finished, adding 5.8g of tetramethyl ethylenediamine (0.05mol), then slowly dropping 10.5g (0.05mol) of trifluoroacetic anhydride, sampling, detecting that the reaction of the raw materials is finished by high performance liquid chromatography, and obtaining the reaction liquid;
step two, adding 0.65g of methanol (20.3mmol) into the reaction solution obtained in the step one, cooling the solution to-5 ℃, and adding 0.0088g of PdCl2(0.05mmol), then adding 0.76g (20.2mmol) of sodium borohydride in batches, completing the addition for about 2 hours, adjusting the pH to 6 by using a 5 wt% phosphoric acid solution after the reaction is finished, then adjusting the pH to 7 by using a 5 wt% sodium hydroxide solution, carrying out phase separation, drying an organic phase by using anhydrous sodium sulfate, adding 2g of activated carbon, stirring for 20 minutes, filtering, concentrating a mother liquor to obtain 58.2g of a brown yellow solid, wherein the HPLC content is 82%, and the yield is 90%;
carrying out structure verification on the brown yellow solid:
1H NMR(500MHz,CDCl3)δ5.81–5.70(m,2H),5.22(t,J＝7.2Hz,1H),5.16(tt,J＝6.8,1.0Hz,1H),5.00(dt,J＝8.0,1.0Hz,1H),4.95–4.87(m,2H),4.61(dt,J＝13.7,6.9Hz,2H),4.33–4.08(m,2H),4.00–3.90(m,2H),3.80–3.71(m,4H),3.70–3.60(m,3H),3.50(t,J＝7.0Hz,1H),3.46(s,3H),3.30(s,3H),3.20(t,J＝7.0Hz,1H),3.15–3.00(m,2H),2.90(s,1H),2.60–2.30(m,2H),2.25–2.05(m,2H),2.00(dd,J＝13.2,7.0Hz,1H),1.90–1.70(m,6H),1.60(s,3H),1.59–1.52(m,4H),1.50–1.46(m,4H),1.38(dt,J＝14.0,7.0Hz,1H),1.30–1.29(m,6H),1.20–1.10(m,4H),1.00(d,J＝6.7Hz,3H),0.92–0.83(m,9H)。
13C NMR(500MHz,CDCl3)δ150.30,140.0,139.00,130.40,125.15,124.10,123.35,122.50,106.00,100.78,95.88,86.80,84.80,81.80,80.98,80.48,77.64,75.85,73.00,71.38,70.0,69.50,68.50,68.00,67.78,67.52,59.46,58.02,57.52,46.65,45.28,40.05,39.80,36.40,35.85,35.55,35.0,34.90,26.30,20.08,18.18。
and step three, dissolving the brown yellow solid obtained in the step two by using a mixed solution of 58.2g of n-butyl ether and 174.6g of isopropyl ether, slowly dropwise adding 349.2g of cyclohexane, slowly cooling to-5 ℃ after dropwise adding, keeping the temperature for 30min, filtering, and drying a filter cake to obtain 41.1g of white solid, wherein the HPLC content is 98.5%, the crystallization yield is 85%, and the structure is shown as follows.
Examples 5 to 9
The synthesis of compounds 5-9 was carried out according to the methods described above, and the specific process parameters were routinely adjusted as described in examples 1-4.
Compounds 5-9 have the following structural formula:
the HPLC conditions for the intermediate and final products were:
a chromatographic column: c18, 4.6mm × 150mm × 5 μm;
mobile phase: acetonitrile: water (0.1% TFA) 84: 16;
flow rate: 1.4 mL/min;
detection wavelength: 245 nm;
sample introduction amount: 20 μ L.
Study of insect-resistant Activity
The avermectin B2 derivative prepared in the embodiments 2-9 of the invention is prepared into a pouring agent with the concentration of 1 wt% according to a conventional method for carrying out an insect expelling curative effect test, and the positive control product is acetamido avermectin.
(1) Nematode disease curative effect test (fecal nematode egg detection)
Materials:
drug group: 1 wt% of the avermectin derivative pour-on formulation prepared in examples 2 to 9;
positive control group: 1 wt% of an acetyl abamectin sprinkling agent;
blank group: physiological saline.
Test protocol:
100 Chinese Holstein cows with the ages of 1-5 years (which are confirmed to be all natural infection nematode diseases) are selected, the experimental cows are not treated by any antibiotics 60 days before the beginning of the experiment, the feeding living conditions are consistent, the experimental cows are divided into 10 groups, and 10 cows are each group. Wherein, 1 group to 8 groups are respectively administered with 1 wt% of the avermectin derivative pour-on preparation prepared in the examples 2 to 9, the 9 th group (positive control group) is administered with 1 wt% of the acetamido avermectin pour-on preparation, the 10 th group (blank group) is administered with normal saline, and the dosage of each group except the 10 th group is 0.5mg of active ingredient/kg.
The test method comprises the following steps:
before dosing, wiping the back of a test cow by using dry cotton cloth, sucking the test medicament by using a plastic injector, pouring the test medicament on the cleaned part of the cow, collecting the excrement of each cow respectively at 1d before dosing and 7d, 14d, 28d and 42d after dosing, and counting the number of ova of the cow by using a precipitation method.
And (3) detecting worm eggs:
taking 10g of detected cow dung, preparing soup with 3-5 times of water, filtering with an 80-mesh copper sieve, washing with a proper amount of water while filtering, precipitating the filtrate for 30min, discarding the supernatant, adding water for precipitation, repeating the steps for three times, discarding part of the supernatant, quantifying the rest filtrate to 5mL, fully shaking up the precipitate, quickly taking a small amount of sample, transferring the sample into two counting chambers of a counter, counting parasite eggs in the two counting chambers under a microscope, and counting, wherein the test results are shown in Table 1.
Per gram of fecal Egg (EPG) ═ 5mL egg count in two small squares of counter)/(10 g 0.2)
Insect-repellent ratio (P1) ((N-K)/N) × 100%
In the formula:
EPG is the number of eggs per gram of excrement; p1The insect repellent rate is expressed in percent (%); k number of eggs after administration, unit is head; number of eggs before N administration in head.
TABLE 1
Residue test in milk
Materials:
drug group: 1 wt% of the avermectin derivative pour-on formulation prepared in examples 2 to 9;
positive control group: 1 wt% of an acetyl abamectin sprinkling agent;
blank group: physiological saline.
Test protocol:
100 Chinese Holstein cows with the ages of 1-5 years (which are confirmed to be all natural infection nematode diseases) are selected, the experimental cows are not treated by any antibiotics 60 days before the beginning of the experiment, the feeding living conditions are consistent, the experimental cows are divided into 10 groups, and 10 cows are each group. Wherein, 1 group to 8 groups are respectively administered with 1 wt% of the avermectin derivative pour-on preparation prepared in the examples 2 to 9, the 9 th group (positive control group) is administered with 1 wt% of the acetamido avermectin pour-on preparation, the 10 th group (blank group) is administered with normal saline, and the dosage of each group except the 10 th group is 0.5mg of active ingredient/kg.
The test method comprises the following steps:
collecting milk sample before administration, and detecting to determine that there is no drug residue in the milk. After pouring the medicine, the milk samples are uniformly collected from four teats of the cow, 15mL of milk is collected from each nipple, and the milk samples are stored in a centrifuge tube, wherein the total volume of the milk samples is about 60 mL. Milk samples before administration were used as blank group, and the milk collection time after administration of the drug was 2h, 8h, 12h, 24h, 48h, 96h, 192h, and 364h, respectively.
And (3) sample determination:
adding 10.0mL of sample into a 50mL centrifuge tube, adding 300 μ L (250ng/mL) of doramectin internal standard solution, uniformly mixing, adding 10.5mL of acetonitrile, uniformly mixing, standing for 20min, centrifuging at 4500rpm for 20min, removing supernatant, passing through a DS C18 column, collecting eluent, concentrating to dryness, adding 1mL of methanol for dissolving, taking 20 μ L of sample, and detecting by HPLC, wherein the result is shown in Table 2.
TABLE 2 detection of drug residues in Dairy cows (residue unit ng/mL)
As can be seen from the above data, the maximum residual limit of 20ng/mL specified by FAO/WHO was not exceeded in the groups other than examples 3 and 6, and the remaining examples had a residual elimination curve close to or better than that of the positive drug. Example 7 had a residual below the detection limit after 96 hours, and example 2 and example 9 had a residual below the detection limit after 192 hours. Meanwhile, the rest of the components except for the embodiment 3 and the embodiment 6 can ensure that no milk abandoning period is left after the medicine is applied.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. An avermectin B2 derivative is characterized in that the structure is shown as formula (I):
wherein R is1Is methyl or ethyl; r2Is hydroxy or a hydroxyamine subunit; r3Is H, C1-C3 alkyl or halogenated C1-C3 alkyl; r4Is C1-C4 alkyl or halogenated C1-C4 alkyl.
2. The process for preparing avermectin B2 derivatives as claimed in claim 1, which comprises the following steps when R3 is C1-C3 alkyl or halogenated C1-C3 alkyl:
step a, preparing a compound shown as a formula (II) by using abamectin B2 as a raw material;
step b, in an inert solvent, a compound shown as a formula (II) and R3Carrying out substitution reaction on X under the action of organic base to obtain a compound shown as a formula (III); wherein X is halogen and R5 is a hydroxy protecting group;
step c, in an inert solvent, reacting the compound shown in the formula (III) with
Carrying out substitution reaction under the action of organic base to obtain a compound shown in a formula (IV); wherein X is halogen;
and d, carrying out dehydroxylation protection reaction on the compound shown in the formula (IV) to obtain the compound shown in the formula (I).
3. The process for preparing avermectin B2 derivatives as claimed in claim 1, wherein when R3 is H, the process comprises the following steps:
step a, preparing a compound shown as a formula (II) by using abamectin B2 as a raw material;
step b, in an inert solvent, the compound shown as the formula (II) is reacted with
Carrying out substitution reaction under the action of organic base to obtain a compound shown in a formula (IV); wherein X is halogen and R5 is a hydroxy protecting group;
c, carrying out dehydroxylation protection reaction on the compound shown in the formula (IV) to obtain a compound shown in a formula (I);
4. the process for preparing avermectin B2 derivative of claim 2 or 3, wherein the inert solvent is at least one of dichloromethane, dichloroethane, toluene, sec-butyl acetate or ethyl acetate; and/or
The organic base is at least one of triethylamine, pyridine, tetramethyl ethylene diamine, lithium diisopropylamide or potassium tert-butoxide; and/or
The catalyst for the dehydroxylation protection reaction is Pd (PPH)3)2Cl2、PdCl2Or Pd (OAc)2At least one of (1); and/or
And the deprotection reagent for the dehydroxylation protection reaction is at least one of methanol, ethanol, sodium borohydride, sodium triacetoxyborohydride, ammonium fluoride or tetrabutylammonium fluoride.
5. A process for the preparation of avermectin B2 derivatives as claimed in claim 2 or 3, further comprising the step of purification: and (3) dissolving the obtained crude compound shown in the formula (I) in a mixed solution of n-butyl ether, isopropyl ether and cyclohexane, and cooling and crystallizing to obtain the compound product shown in the formula (I).
6. A method for preparing avermectin B2 derivatives as claimed in claim 2 or 3, wherein when R2 is hydroxy, step a comprises the following steps: under the condition of organic base, abamectin B2 is used as a raw material, and 5-position hydroxyl protection, 4 '-position hydroxyl oxidation and 4' -position amination reduction are sequentially carried out to obtain the compound shown in the formula (II).
7. The method for preparing avermectin B2 derivatives as claimed in claim 2 or 3, wherein when R2 is hydroxyimino, the step a comprises the following steps: under the condition of organic base, abamectin B2 is used as a raw material to carry out hydroxyl oxidation at 5-position and 4 '-position, O-allyloxyamine is added to convert the 5-position into allyloxy hydroxylamine subunit, and then the 4' -position is aminated and reduced to obtain the compound shown in the formula (II).
8. The use of avermectin B2 derivatives as claimed in claim 1 for the control of livestock pests.
9. The use according to claim 8, wherein the avermectin B2 derivative is used for the control of cow nematode disease.
10. A pharmaceutical composition for controlling nematode diseases in dairy cows, which comprises the avermectin B2 derivative of claim 1.
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