JPS60158191A - Milbemycin derivative, manufacture and vermicidal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides milbemycin (mllbemycln) derivatives represented by formulas (1) and (2) below, a method for producing the same, the use of the compound to obtain other milbemycin derivatives, and , the use of said compounds for controlling pests such as ectoparasites and endoparasites. Furthermore, the present invention provides a pest control agent (or insecticide:
(pesticide) i.

Specifically, the present invention relates to the formula (1) (wherein R4 is a hydrogen atom, a silyl group, or an acyl group, and R2 is a methyl group, an ethyl group, an isozolobyl group, or a B-
butyl group) or a compound represented by formula (2) (in the formula, R1 and R2 have the same meanings as above).

In this specification, compounds in which R2 is an 8-butyl group are also treated as belonging to milbemycin derivatives. Strictly speaking, said compounds are not included in said category according to the usual classification, but are derived from avermectin derivatives.

Avermectin aglycones (containing an α-OH group at position 13) can be converted to milbemycin derivatives as described in US Pat. No. 4,173,571.

Within the scope of the invention, compounds of formula (2) are preferred.

Suitable acyl groups R4 are R, -Co- and R4-802
- group, where R5 is preferably an unsubstituted or halodanated C, -C6 aliphatic group, or is unsubstituted or substituted by a C1-C4 alkyl group or a halodan atom. and R4 is a C,-C4 alkyl group or a phenyl group which is unsubstituted or substituted by a methyl group, a chlorine atom or a nitro group.

Preferred compounds of the formula (S) and formula (2) are such that R4 is a hydrogen atom, R, -Co- group or R4-5o□- group, and R3
is a C1-C4 alkyl group, or is a phenyl group that is unsubstituted or substituted with a methyl group or a chlorine atom, and R4 is a methyl group, an ethyl group, a p-)'J group, , o'-nitrophenyl group or p-chlorophenyl group, and R2 is a methyl group, ethyl group, isozolobyl group or 8-butyl group.

Although not meant to be limiting, typical examples of substituent R3 include methyl group, ethyl group, propyl group, inpropyl group, t-butyl group, phenyl group, p-chlorophenyl group, and p-)IJ group. It is the basis.

Suitable silyl groups are of the formula (wherein R5 is a C,-C4 aliphatic group or a benzyl group, R6 and R7 are
benzyl group or phenyl group).

Another group of preferred compounds of formula (1) and formula (2) is R
1 is a hydrogen atom or the above-mentioned silyl group (herein, R methyl group, ethyl group, propyl group, isozolobyl group or t-
butyl group, C1R6 and R7 are each independently a methyl group, ethyl group, isozolobyl group, t-butyl group, phenyl group or benzyl group), and R2 is a methyl group,
It consists of compounds in which it is an ethyl group, an isozolobyl group or an S-butyl group.

Examples of silyl groups include trimethylsilyl group, tris(
These include the 1-butyl)silyl group, the diphenyl-butylsilyl group, the bis(isopropyl)methylsilyl group, and especially the t-butyl-dimethylsilyl group.

Particularly preferred are compounds of formula (2) above, in which R1 is a hydrogen atom and R2 is a methyl group, ethyl group, isopropyl group, or B-butyl group.

By conventional acylation of the 5-OH group with the corresponding acyl halide (which shall mean acyl chloride or acyl bromide) or acyl anhydride, or by the formula and formula (2)
and X is a silyl residual group] and a 5-OH group. All the above derivatives of formula (1) or formula (2) or the derivatives of formula (3) below, in which R1 has the above meaning other than a hydrogen atom, are provided. X is, for example, bromide, chloride, cyanide,
Consists of azide, acetamide, trifluoroacetate and trifluoromethanesulfonate. This list is not intended to be limiting; other representative silyl residual baselines are known to those of ordinary skill in the art.

5-0-acylation and 5-0-silylation are carried out in an anhydrous medium, preferably in an inert solvent, most preferably in a neutral (
or in an aprotic) solvent. The reaction is conveniently carried out in the temperature range θ°C to 80°C, preferably 10°C to 40°C. Preferably, an organic base is added. Suitable organic bases are, for example, tertiary amines such as triethylamine, triethylenecyamine, triazole, and preferably pyridine, imidazole, or 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU). .

Removal of the silyl group R1 and the acyl group R1 in the 5-position is carried out by selective mild hydrolysis (→R=H), known to those skilled in the art, such as conversion to dilute arylsulfonic acids.

The compounds of formula (1) and formula (2) are represented by formula (3) EL1 [wherein R1 and R2 have the meanings given in formula (1) and formula (2)] 14. 15-Epoxymilbemycin derivative and complex reagent CI (N s ,: l m / (At
(Ethyl) 6].

(In the formula, m and n are each independently 1 or 2 or 1 to
) can be selectively obtained in parallel by reaction in an inert dry solvent phase at a temperature range of -30°C to +10°C, preferably from -20°C to -5°C. can.

Preferred inert solvents are aliphatic and aromatic hydrocarbons such as evabenzene, toluene, xylene and petroleum ethers; ethers such as diethyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and anisole.

Said reaction is advantageously carried out under an inert gas, such as nitrogen or argon.

Epoxide of formula (3) [where R1 is a hydrogen atom and R2 is an inglovir group] and HN3/Et5
14 equivalents of At (molar ratio 1:0.91) and benzene/
When reacted in a toluene mixture at room temperature, the above formula (1
) is obtained in a yield of 6 (1 or more).

Epoxide of the same formula (3) as above and I(N57wt5h
t (in a molar ratio of 1:1.6:13 equivalents) in diethyl ether, in addition to about 10 units of the compound of formula (1), the yield of about 50 units of allyl alcohol of formula (2) (about 80 units) is obtained.
% conversion) is obtained.

The above complex reagent (HN 5 ) / V (ethyl) 3
].

(m and n are mutually independently 1 or 2 or a value between 1 and 20), from the individual components HH5 and At(C2H5)5 in the above temperature range -30°C to +10°C, prepared in an inert solvent and at a temperature below 0°C,
It will be stable for a while. As used herein, the complex reagent may be referred to simply as HN5/Et5At or HN5/Et5At.
It may be written as N5/At(C2H5)s. Any epoxy compound reacts in the presence of the complex to open the oxira/ring and simultaneously open the 1-hydroxy-2
-Azide compound and substituted allyl alcohol (=1
-Hydroxy-Δ2.3 compound). Both reaction products, i.e. those of formula (1) and formula (2), can be separated by physicochemical separation methods such as fractional crystallization or chromatography (
- can be separated by By chromatography is meant column, thick layer or thin layer chromatography on inorganic carrier materials such as silica gel or organic exchange resins.

Hydroazoic acid is prepared by suspending sodium azide in a specific dry solvent or solvent mixture and adding a strong acid such as H2SO.
4 (preferably to ensure completely anhydrous reaction conditions,
By generating HN3 in solution with fuming sulfuric acid) K, CHNs: 1 m/Ckl (
Et ) s ) n complex. AL
(Et)5 is already present in solution or
Immediately add to the solution. The epoxy compound can be already present in the solution or can be added at an appropriate time.

The starting compound of formula (3) used in the present invention can be easily prepared from the following compounds by epoxidation. That is, as known from US Pat. No. 3,950,360, originally rAntibioticsB
-41-AJ, later referred to as "milbemycin A compound", or as known from U.S. Pat. No. 4,346,171;
13-deoxy-avermectin (R2=8-butyl) from what is known as rB-41DJ or "milbemycin p" or from what is known from U.S. Pat. No. 4,173,571 and has the following formula: It is from.

The compound has the following structure.

H Below margin R2 = CH3: Milbemycin A3 R2 = C2) 15: Milbemycin A4R2 = IsoC3H7: Milbemycin DB2 = 5-C4H
5+: 13-deoxy-22,23-dihydro-〇-076-Bla-aglycone.

Said epoxidation is carried out in the solvent phase at a temperature range of -10°C to +20°C, preferably -5°C to +5°C.

Suitable for said epoxidation are peracids such as peracetic acid, trifluoroperacetic acid, perbenzoic acid, chloroperbenzoic acid and the like.

The novel epoxides of formula (3) (R1 and R2 have the meanings given in formulas (1) and (2) above) used as intermediates constitute another object of the present invention. and 14.15-epoxymilbemycin A5 (B, =
H; R2=CH3), 14.15-:r-yf! Ximilbemycin h4'￥ R1: H: R2= C2
H5), and 14.15-epoxymilbemycin D (
1'h=H: R2=isoC3H7) is excluded. Formula (3)
The epoxides are themselves valuable compounds for controlling pests, such as endoparasites and insects.

The compounds of formula (1) and formula (2) are suitable for controlling animal and plant pests, including animal ectoparasites. The pests mentioned last above are of the order Acarinae (Acarinae).
carina), especially Ixodidae
), Dermanyssidae, Psoroptidae, Psoroptidae: /S
Mallophaga, Chiliformes (5ip
honaptera), Anoplura
) [For example, Haematopini
dae ) ): and Diptera
, especially Muscidae, Caliphoridae, and Caliphoridae.
0esterridae), Tabanidae
ae ), Hlppoboscidae
) and Umano Z Technique (Ga5trophilidae
) consisting of harmful organisms.

The compounds of formula (1) and formula (2) are hygienic pests,
In particular, Diptera (Sarcophagids)
ia), Anophilidae
), and Cuic1das ): Orthoptera, Dictyogtera
lctyoptera) (e.g., B.
lattidae)), as well as Hymenoptera (Hyme
noptsra ) [e.g., Formicidae (F'ormlc
idae):] can also be used.

The compounds of formula (1) and formula (2) also have a sustained action against insects and mites that are parasites of plants. When used to control spider mites of the order Acari, the compounds are also effective against eggs, larvae and adults of the family Tetranychidae (Tetranychus species and Panonychua species). The compound is a member of the suborder Homoptera (Ho
moptsra), especially Aphidae (Ap
hididae), planthopper family (Delphacida)
e), C1cadellidae
), Psyllidae, Loaclidae, ff/lz Scalecidae (
Diaspididas), Fusididae (Er1op
hyidae) (e.g. Sabidae on citrus plants =
(rust m1te)) insect; Hemiptera (Hem
1ptsra ), Hymenoptera (Het@roptera
), and insects of the order Thysanoptera; insects of the order Lepidoptera and Coleoptera.
It also has excellent activity against plant pests of the order Diptera, Diptera, and Orthoptera.

The compounds of formula (2) are also suitable for use against organisms in soil.

Therefore, the compounds of formula (1) and formula (2) can be used in all developmental stages of crops such as cereals, cotton, rice, corn, soybeans, potatoes, vegetables, fruits, tobacco, hops, citrus fruits, avocados, etc. Effective against sexual insects and feeding insects.

The compounds of formula (1) and formula (2) are derived from Meloidcine species (M
eloidogyne), 22 species of hetero (Heter
odera), Graty Renchas a! (Pratyl
enchus), Dltyle spp.
nehus), Radolphus sp.
), Rhizoglyphus sp.
It is also effective against plant nematodes such as.

Furthermore, the compounds of formula (1) and formula (2) also act against intestinal parasites. Among intestinal parasites, endoparasitic nematodes cause major diseases in mammals and birds, such as sheep, pigs, goats, cows, horses, donkeys, dogs, cats, guinea pigs, and caged birds. get it. A typical nematode with this tendency is Haemonc
hus), Trichostrongyl nematode
us), Ostertagia,
Nematodirus, Cooperim, Ascari
s), Bunostomum, Oesphagostomum
), Chabertim, Trichuris (T.
richurig), strongyle (Strongylus
), Trichonesma, Dictyocaulus, CapillariM, Het
erakis), large sea bream (Toxocara)
), alkali metal (Ascarldlm), Oxyurlg (Oxyurlg), hookworm (An
cylostoma), Far Eastern hookworm (Unclnar
im ), Toxasearim
and parascarig.

The compounds of formula (1) and formula (2) are used in unaltered form or preferably with auxiliaries (or adjuvants) commonly used in the art of pharmaceutical formulations. Thus, emulsifying concentrates, directly sprayable or dilutable solutions, dilute emulsions, hot water powders, soluble powders, dusts,
Formulated into granules and capsules, for example in polymeric materials. Depending on the nature of the composition, the intended audience and the general situation, the method of application is selected, for example spraying, atomizing, dusting, stearic acid or injection.

Compounds of formula (2) are administered at an application rate of 0.01 to 501 g per body weight for warm-blooded animals and applied to enclosed crop areas, food stores, livestock. 10 to 1 per hectare for storage buildings or other structures
Give in an amount of 000Ii.

Preparations or compositions or formulations containing the active ingredient as described above may be prepared by combining the active ingredient with an extender such as a solvent, a solid carrier, and, if present, a surface-active compound (surfactant). Mix evenly and/or
Prepared by grinding.

Suitably the solvent is an aromatic hydrocarbon, preferably containing 8 carbon atoms.
Fractions containing ~12 xylene mixtures or substituted naphthalenes, phthalate esters such as diptyl phthalate or dioctyl phthalate, aliphatic hydrocarbons such as cyclohexa/or phthalate, alcohols and glycols and their like. Ethers and esters such as ethanol, ethylene glycol monomethyl or monoethyl ether, ketones such as cyclohexanone, strongly protic solvents such as N-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, and also vegetable oils or epoxidized vegetable oils, such as epoxidized Coconut oil or L-soybean oil, or water.

Solid carriers used, for example for dusts and dispersible powders, are the customary natural mineral fillers, such as calcite, talcum, kaolin, montmorillonite or acpalgite. Highly dispersed silicic acid or highly dispersed adsorbent polymers can also be added to improve the physical properties. Suitable granulated adsorptive carriers are those in porous form, for example pumice, crushed brick, sepiolite or bentonite, and suitable non-adsorptive carriers are materials such as calcite or sand. Furthermore, a number of mineral or organic pregranulated materials can be used, such as in particular dolomite or sawdust (or pulverized plant residues).

Depending on the nature of the active ingredient to be formulated, or the nature of the combination with the insecticide or acaricide, suitable surface-active compounds may be non-toxic compounds with good emulsifying, dispersing and wetting properties. Ionic, cationic and (also Fi) anionic surfactants. It is to be understood that "surfactant" herein also includes mixtures of surfactants.

Suitable anionic surfactants can be both water-soluble soaps and water-soluble synthetic surface-active compounds.

Suitable soaps are obtained from alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts of higher fatty acids (C1o-C22), such as oleic acid, stearic acid or, for example, coconut oil or tallow oil. It is a sodium salt or potassium salt of a natural fatty acid compound. Further additional surfactants are fatty acid methyltaurate salts and modified and unmodified phospholipids.

However, more frequently so-called synthetic surfactants are used, in particular aliphatic sulfonates, aliphatic sulfates, sulfonated benzimidazole derivatives or alkylaryl sulfonates.

The aliphatic sulfonates or sulfates mentioned above are usually
in the form of alkali metal salts, alkaline metal salts or unsubstituted or substituted ammonium salts, and containing the alkyl moiety of the acyl group.
Contains -022 alkyl group. For example, the sodium or calcium salts of lignosulfonic acid, dodecyl sulfate or fatty alcohol sulfate mixtures obtained from natural fatty acids. The compounds also include sulfate esters of aliphatic alcohol/ethylene oxide adducts and salts of sulfonic acids. The sulfonated benzimidazole derivatives preferably contain one fatty acid group of 8 to 22 carbon atoms and two sulfonic acid groups. Examples of alkylarylsulfonates include the sodium salt of dotecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid, or naphthalenesulfonic acid/formaldehyde condensation product;
Calcium salt or triethanolamine salt. Corresponding phosphates, such as the salts of the phosphoric acid esters of adducts of p-nonylphenol with 4 to 14 mol of ethylene oxide, are also suitable.

For surfactants commonly used in the formulation industry, see McCutehson's Deter.
gentsand Emu11th tar@Annual
J., MC Publishing, Ridgewood, N. Chassis, USA (1982).

The pesticidal composition usually contains 0.01 to 95 compounds of formula (1) and/or formula (2), preferably o, i to 8
0%, 5-99.99% solid or liquid adjuvants and 0-25% surfactants, preferably 0.1-25%.

Commercially available products are preferably formulated as concentrates and
The final user typically uses concentrations 1 to i o, o o .

Use a ppm diluted formulation.

The compositions may also contain other ingredients such as stabilizers, anti-foaming agents, viscosity modifiers, binders, tackifiers, fertilizers or other active agents to obtain special effects.

The compounds of formula (1) and especially formula (2) are also versatilely reactive compounds for obtaining other milbemycin derivatives.

Preparation examples in the margins below Preparation example 1: Anhydrous station, preparation 1.1 H in benzene, Wolf's r Org, Reaations J
3.307 (1946). The HN and benzene solution thus obtained was heated on an anhydrous Na2804 flame for 30 minutes,
cooled in an exsiecator] and filtered through cotton wool (0.0
℃→5℃). Keep the solution at 4°C in the refrigerator.

The above preparation is carried out analogously to Example 1.1 above, except that the reaction temperature is maintained between -20 DEG C. and -10 DEG C. when adding sulfuric acid. When the addition of H2SO4 is complete, the reaction mixture is warmed to -5°C.

Preparation Example 2: Preparation of 14.15-Epoxymilbemycin D [Formula (3)] While cooling with ice, a solution of 170 μl of chloroperbenzoic acid in methane dichloride 5 was added to milbemycin in methane dichloride 5. Add to the solution of D550~. After stirring at 0°C to 5°C for 1 hour, 170 Da of the above oxidizing agent was added,
Continue stirring for 30 minutes. After the reaction is complete, the solution is poured into water-cooled sodium sulfite solution and extracted with ethyl acetate. - Wash the combined extracts once with water, dry and evaporate in vacuo. The crude product was chromatographed through a silica del column (n-hex 7/ethyl acetate 20:
15 mixture) to give amorphous white 14.15-epoxymilbemycin D450rn9.

Production Example 3: Preparation of 14-azido-15-hydroxymilbemycin D [formula (1)] A magnetic stirrer, a thermometer, and a serum cap.
Into a dry, 50-inch two-necked flask equipped with a cap) is charged 5 ml of anhydrous toluene under argon. While stirring at 0℃, add triethylaluminum (
Et, At) 1.7-(1,39#: 12.2 mmol) is added via syringe. After 5 minutes, slowly add 10.7 d (0,58,51:13° 4 mmol) of benzene solution to the 5.72% river at -20°C while stirring well. Reaction mixture f) temperature from -20°C to -10°C
Keep at °C (this reaction is strong and exothermic). After stirring for an additional 5 minutes, 14.15- in anhydrous toluene 5-
Epoxymilbemycin D0.50. into a solution of F (0.88 mmol) (cooled to -10 °C),
Add the reaction mixture via syringe quickly at -10°C with good stirring (under argon).Stir the reaction mixture for 2 hours at room temperature.

For finishing, add 10 d of methylene chloride and mix '
Stir for 0 minutes in an open Rooflo flask, followed by 2 hours.
Pour 1 t of C2 aqueous solution into 4% HC425(1-) and extract with CH2Ct250-4 times.

The organic phase was washed with NaC2 saturated solution and NIL Z SO
Dry on a. Chromatography through silica 40.9 (eluted with cH2ct2/acetone 25:1) revealed 14-azido-15-hydroxymilbemycin D (
1) 32 sq (61%) are obtained as colorless crystals, melting point Fi 189° C. (recrystallized from methanol).

Production Example 4: Preparation of 15-hydroxy-Δ13°14-Milbemycin D [Formula (2)] According to the method of Production Example 3 above, 6.96%) IN,
Diethyl ether solution 8.4d (0.41, f: 9
．． 53 mmol 17 mol) Y, 2.1 d of triethylaluminum in anhydrous diethyl ether 8.5 at -20°C
(1,751I: 15.3 mmol). The reaction mixture was then heated at -10°C for 14.1
5-Epoxymilbemycin D1.8M (3.15 mmol). The ensuing reaction is strongly exothermic. After 1 hour at room temperature, anhydrous ether 4- is added and the gelatinous reaction mixture is stirred vigorously. 4 hours later,
The reaction mixture is worked up as described in Preparation Example 2. Silica r Lua 09v Tsucho chromatography (CH2CL2/
(eluted with acetone 10:1) didi, 14-azido-15
-Hydroxymilbemycin D (1) 200 Da (10 Ti) and 15=Hydroxy-Δ15°14-Milbemycin D (2) (melting point 151-153°C (recrystallized from methanol)) 820 Da (45%) are obtained. .

H-NMR spectrum k (300M
Hz.

CDCt3. TMS): 1.58 (wide B) (C140H3); 1. Fl
8 (wide 5) (C4CH,): 4.06 (dd)
(J, = 11.1: J2 = 4.6): 5.20
(d) (J=to, 3) (C1, H).

Production example 5: 5-0-t-butyldimethylsilyl-14,
Preparation of 15-epoxymilbemycin D 14.15-epoxy-milbemycin D (R2=isoC3H,) 2.2 in dimethylformamide 4fnt
A solution of 1 g (3,86 mmol), t-butyltzmethylsilyl chloride 757fnt (5,02 mmol) and imidazole 342# (5, (12 mmol)) is stirred at room temperature for 90 minutes. Then, soethyl ether 80
- was added, the mixture was filtered on 20 g of silica dal, and the F solution was concentrated. 5-0-t-butyldimethylsilyl-1
4,15-epoxy-milbemycin D2.65I (1
00chi) is obtained.

'H-NMR (3 (10R'IHz, CDCAs
) :0.12 (s) (cl3)25t-0-, :
0.92 (s3(t-C4H9)Sl-0-: 1
．． 23 (wide s) (C14CH3): 2.56
(d:J=9) (C15H).

In a similar manner, the corresponding 5-0-)
Limethylsilyl-14,15-epoxymilbemycin D (melting point 92-97°C) can be prepared.

Production example 6: 5-0-t-butyldimethylsilyl-15-
Hydroxy-Δ15,14-milbemycin D [formula (2
)] preparation of triethylaluminum 4.97- in anhydrous tetrahydrofuran 7- and group 3 (21-
A solution of f(N,/Et3AL complex reagent, prepared from a solution of tL915-, 2.39 molar solution of
-t-Butyldimethylsilyl-14,15-epoxymilbemycin D5. Under argon, the mixture is heated under reflux for 16 hours. Then 250 of ether, 2-1 of methanol and finally a mixture of N&2SO4.1on2oioy and 10 g of Celite are added at room temperature. The mixture was filtered, concentrated, and the crude product was chromatographed through 160 g of silica dal (eluting with ~30 g of ethyl acetate in hexane) to give a total of 1 of 5-0-t-butyldimethylsilica.
5-hydroxy-Δ13,14-milbemycin D2.
37II (4'l) is obtained.

'H-NMR (300MHz, CDCLs): 1
, 59 (d: J=1) (C14CH5):
4.06(dd:J1=11;Jf4)-(C15H)
;5.15(d;J=8)(C4,H).

Furthermore, 13β-4-azido-5-0-t-butylmethylsilyl-milbemycin D1091# (2%) is obtained.

1H-NMR (300MH2, CDC13): 1.57
(wide s) (C1a CHρ: 3.56 (d:
J=9) (C43H).

IR: 2095z-' (N3).

A solution of 100 to 0,146 mmol of the above product in 1% p-toluenesulfo/acid (in methanol) Zmt is stirred at room temperature for 40 minutes, then diluted with ether 20 and filtered through silica gel.

The crude product is taken up first in ethanol and then in benzene and the respective solvents are evaporated in vacuo.

Yield: 13β-azidomilbemycin D53 (63)' H-NMR (300NU) 1z, CDC45)
:1.57 (wide') (C14CH5):3.54 (d
:I=11) (cl, H).

Mass spectrum mA: 59 units (M”), 569,151
゜Production Example 7: 14,15-epoximylimycin A4
Preparation of [Formula (3)] 2.43 m-chloroperbenzoic acid in 70-methane dichloride
g (14.08 mmol) in methane dichloride
milbemycin A45.71 (10.5 mmol) in 0.0- and 120-9 HCO30.5 molar solution is added dropwise at room temperature. The mixture is stirred vigorously for 1 hour at room temperature and diluted with 300 ml of methane dichloride. organic phase with N
Washing with aHCOs aqueous solution, drying over Na 2 SO 4 and concentration gives epoxide 5.711 as crude product.

Production example 8: 5-0-t-butyldimethylsilyl-14,
Preparation of 15-Epoxy-Milbemycin A4 [Formula (3)] 14. Dissolve 15-Epoxy-Milbemycin A45.7I in dry dimethylformamide 10-.

Next, imidazole 0.6319.16 mmol) and t
-Butyldimethylchlorosilane 1.4. Sl(9,34
mmol) at room temperature. The mixture was stirred at room temperature for 1 hour, and the silica gel 150I! Chromatography through (eluting with hexane/ether 4:1) yields 2.841 silylated epoxy derivatives! (a theoretical amount of 40 qb based on Milbemycin A4) is obtained.

Production example 9: 5-0-t-butyldimethylsilyl-15-
Hydroxy-Δ15,14-milbemycin A4 [formula (
2)] Preparation of complex reagent RN, according to the method described in Production Example 3 above.
/kL(ethyl)3 is prepared as follows: At(C2H5) in anhydrous tetrahydrofuran 4-.

Into 2.8 m (12.2 mmol) of HN, a 10% solution in anhydrous diethyl ether, 5.28 d (20
, 4 mmol) are added slowly under argon at about -20°C. Into this solution, 2.841! of the compound obtained in Production Example 8 was added. A solution of (4.25 mmol) in tetrahydrone 4- is added under argon and the mixture thus obtained is heated under reflux for 4 hours. next,
Ether 500- and NazSO4・10H2010,9
and Celite 10II are added at room temperature. Filter the mixture and concentrate Solution F. The crude product was treated with silica dal xoop
Chromatography through (eluting with hexane/diethyl ether 7:2) gives the title compound 1.72.9 (6 oeIJ theory).

1H-NMR (300MH2, CDCt, ): 1.59
(Hiro 8) (C, 4CH3): 4.05 (Hiro 1
) (C, 5H) Electricity 5.15 (d:J=6)
(C,,H).

Additionally, 13β-azido-5-0-t-butyldimethylsilyl-milbemycin A40.1# is added.

Preparation Example 10: Preparation of 15-Hydroxy-Δ13-4-Milbemycin A4 [Formula (2)] The compound 5da described in the title of Preparation Example 9 above was reacted with 1% p-)luenesulfonic acid 1- in methanol. Hydrolysis and work-up with 5% sodium bicarbonate solution in diethyl ether gives compound 4. as described in the title of this example.
51n9 is obtained.

1H-NMR (300MH!, CDCt3.TMS):
0.98(t) (J=7) (C25CH2-CH,-)
: 1,59 (wide 1) (C, 40H,): 1.87
(wide-) (C4CH,): 4.07 (ddd) (J, =
10.8: J2=3.1.

J, = 1.2) (C15H): 5.15(d)
(J=t o, 4) (C15H).

Production Example 11: 14.15-epoxymilbemycin A,
Preparation of (R2=CH,) According to the method described in Preparation Example 2 above, methane dichloride 5-
Milbemycin A, 220II #y and perbenzoic acid 3201119 in dichlormethane 5- were heated from -2°C to +5°C.
Reaction for 1.5 hours at <RTIgt;C</RTI> and purification through a silica column yields 14.15-epoxymilbemycin As190 da.

Production example 12: 5-0-methylnophenylsilyl-14,
Preparation of 15-Epoxymilbemycin A3 According to the method described in Preparation Example 5 above, 14.15-Epoxymilbemycin ks I QaO# and 120 Da of Cia-4-methylchlorosilane are reacted in the presence of imidazole. The umbrella @217 mentioned in the title of this example
1ny is obtained.

Production example 1-3: 5-0-methyldiphenylsilyl-15
-Hydroxy-ΔIJ! , 14-milbemycin A,
Preparation of (Formula (2)) 5-0-methyldiphenylsilyl-14,15-epoxymilbemycin A52101 in anhydrous diethyl ether according to the method of cleavage described in Preparation Example 6 above.
Using the conjugate reagent HN, /Et, At under argon and purification, the compound 203I described in the title of this example is obtained.

'H-NNfR (300MHz, CDC15):
1.58 (wide) (C14CH!l): 4.0
5 (wide 5) (c15a): 5.15 (d: J=6
) (C13H).

Production example 14: 15-hydroxy-Δ1! Preparation of S, 14-milbemycin A5 and 14-azido-15-hydroxymilbemycin A5 According to the method described in Preparation Example 2 above, reagent HN5/At
(C2H5), freshly prepared and dried - in diethyl ether - 14.15-Epoxymilbemycin A38
In a solution of 301119 (: a, o 5 mmol) -
Add dropwise at 10°C. After finishing treatment, 15-hydroxy-
Δ1s”14-milbemycin A, 3851Ffto1
4-azido-15-hydroxymilbemycin A, 92
■ and are obtained.

Production example 15: 13-deoxy-14,15-epoxy-
Preparation of 13-deoxy-
22,23-dihydroavermectin-Bta-aglycone (Tstrihsdron Lstterg, V
ot.

24, Ya 48, pp. 5333-5336 (1983)) 5
20 Da and m-chloroperbenzoic acid-210IIv in dichloromethane 20- to form the metal compound 51 described in the title of this example.
Production example 16: 5-0-t-butyldimethylsilyl-13
-deoxy;/l-14,15-epoxy-22,23-
Preparation of dihydroavermectin-Bta-aglycone [formula (3)] According to the method described in Production Example 8 above, Preparation Example 15
Compound 220Fn9 and t-butyldimethylsilyl chloride 55Fv described in the title of Tori et al., compound 10 B1n9 described in the title of this example are obtained.

Production example 17: 13-deoxy-15-hydroxy-Δ1
3,14. ．． ．． 22,23-dihydroavermectin-B Moore Glycon [Formula %Formula % Preparation Example 15 according to the method described in Preparation Example 4 above
Compounds 220 to 220 described in the title are reacted with a complex reagent consisting of At (C21(5) 3320 Da and 6.96% volume, solution 110 Da in a total amount of dry diethyl ether of 16-10 kg) to obtain urine. Compound 112 listed in the example title!!1
~ is obtained. Furthermore, 13-deoxy-14-azido-
61 da of 15-hydroxy-22.23-dihydroavermectin-Bta-aglycone [formula (1)] is obtained.

Examples of other intermediate products of formula (3) below 5-0-) dimethylsilyl-14,15-epoxymilpeicin A3 5-0-) lis(t-butyl)silyl-14,15-epoxymilbemycin A3 5-0-diphenyl-1-butylsilyl-14゜15-
Epoxymilbemycin A3 5-0-bis(ingrovir)methylsilyl-14゜1
5-epoxymilbemycin A3 5-0-bis(allyl)(1-butyl)silyl-14゜15-epoxymilbemycin A3 5-0-t-butyldimethylsilyl-14,15-epoxymilbemycin A3 5-01 lis(benzyl) ) Silyl-14,15-epoxymilbemycin A3 5-0-trimethylsilyl-14,15-epoxymilbemycin A4 5-0- ) Lis(t-butyl)silyl-14゜15-
Epoxymilbemycin A4 5-0-diphenyl-t-butylsilyl-14゜15-
Epoxymilbemycin A4 5-0-bis(ingrovir)methylsilyl-14゜1
5-epoxymilbemycin A4 5-0-bis(allyl)(1-butyl)silyl-14,
15-epoxymilbemycin A45-o-t-butyldiethylsilyl-14,15-epoxymilbemycin A4 5-0-methylphenylsilyl-14,15-epoxymilbemycin A4 5-0-)lis(benzyl)silyl-14,15 -Epoxymilbemycin A4 5-0-)lis(ethyl)silyl-14,15-epoxymilbemycin D 5-0-tris(t-butyl)silyl-14,15-epoxymilpemycin D 5-0-diphenyl-1 -Butylsilyl-14゜15-
Epoxymilbemycin D 5-0-bis(ingrovir)methylsilyl-14,1
5-Epoxymilbemycin D 5-〇-Methyldiphenylsilyl-14,15-epoxymilbemycin D 5-0-) Lis(benzyl)silyl-14,15-epoxymilbemycin D Apelmectyl compound (Rz== s -C4H9
)5-0-)Lis(ethyl)silyl-13-deoxy-14,15-epoxy-22,23-dihydro-avermectin-Bta-aglycone5-0-)rifthylsilyl-13-deoxy-14,15-epoxy- 22,
23-dihydro-7 vermectin-BLm-7 glycone 5-0-tris(t-butyl)silyl-13-deoxy-14,15-epoxy-22,23 dihydro-avermectin-Bta-7 glycone 5-0-diphenyl- t-Butylsilyl-13-deoxy-14,15-epoxy-22,23-dihydro-avermectin-Btu-aglycone 5-0-bis(inglovir)methylsilyl-13-deoxy-14,15-epoxy-22,23-dihydro-avermectin Droapermectyl-Bta-aglycone 5-0-bis(allyl)(1-butyl)silyl-13-
7-'oxy-14.15-epoxy22.23-dihydro-avermectin-Bta-aglycone5-0-methyldiphenylsilyl-13-deoxy-1
4,15-epoxy-22,23-dihyl' O-7 vermectin-Btm-7 glycon 5-0-)
benzyl)silyl-13-deoxy-14,15-epoxy-22,23-dihydro-avermectin B1m-
Aglycone 5-0-) Lis(Inglovir)silyl-1
3-deoxy-14,15-epoxy-22゜23-dihydro-avermectin-Bth-aglycone, and 5-0-bis(ingrovir)methyl-13-deoxy-1'4,15-epoxy-22,23-dihydro-avermectin-Bth-aglycone. rLoavermectin-Bta-7/” Recon 5-0-acetyl-14,15-epoxymilbemycin A3 5-0-propionyl-14,15-epoxymilbemycin A3 5-0-pivalyl-14.15-epoxymilpemycin A3 5-0-benzoyl-14,15-epoxymilbemycin A3 5-0-mesyl-14,15-epoxymilbemycin A3 5-0-)yl-14,15-epoxymilbemycin A3 5-0-acetyl-14,15- Epoxymilbemycin A4 5-0-propionyl-14,15-epoxymilbemycin A4 5-0-bivalyl-14.15-epoxymilbemycin A4 5-0-benzoyl-14,15-epoxymilbemycin A4 5-0-p-chloroincy Ru 14.15-epoxymilbemycin A4 5-0-mesyl-14,15-epoxymilbemycin A4 5-0-ethylsulfonyl-14,15-epoxymilbemycin A4 5-0-benzenesulfonyl-14,15-epoxymilbemycin A4 5 -0-tosyl-14,15-epoxymilbemycin A4 5-0-10 lobenzenesulfonyl-14,15-epoxymilbemycin A4 5-0-o-nitrobenzenesulfonyl-14゜15-
Epoxymilbemycin A4 5-0-acetyl-14,15-epoxymilbemycin D 5-0-propionyl-14,15-epoxymilbemycin D 5-0-bivalyl-14,15-epoxymilbemycin D 5-0-benzoyl-14, 15-epoxymilbemycin D 5-0-p-chlorobenzoyl-14,15-epoxymilbemycin D 5-0-mesyl-14,15-epoxymilbemycin D 5-0-ethylsulfonyl-14,15-epoxymilbemycin D 5- 0-benzenesulfonyl-14,15-epoxymilbemycin D 5-0-)yl-14,15-epoxymilbemycin D 5-0-p-chloropenzole sulfonyl-14゜15
-Epoxymilbemycin D 5-0-o-nitrobenzene-14,15-epoxymilbemycin D 5-0-acetyl-13-deoxy-14,15-epoxy-22,23-dihydroaperme5-0-piparyl-13- Deoxy-14,15-epoxy-22,23
-dihydroavermectin-Bta-aglycone 5-0-benzoyl-13-deoxy-14゜15-epoxy-22,23-dihydroavermectin-Bta
-aglycone 5-0-mesyl-13-deoxy-14,15-epoxy-22,23-dihydroavermectin-Bta-aglycone 5-0-) λ-13-deoxy-14,15-epoxy-22.23 -dihydroapermec Examples of other compounds of formula (1) 5-0-)dimethylsilyl-14-azido-15-hydroxymilbemycin A3 5-0-diphenyl-t-butylsilyl-14-azido-15-hydroxymilbemycin 3 5-0-t-butyldimethylsilyl-14-azido-1
5-hydroxymilbemycin 3 5-0-)dimethylsilyl-14-azido-15-hydroxymilbemycin A4 5-0-)lis(t-butyl)silyl-14-azido-
15-Hydroxymilbemycin A45-0-diphenyl-t-butylsilyl-14-7sil'-15-hydroxymilbemycin A4 Below margin 5-o-t-butyldimethylsilyl-14-azido-1
5-hydroxymilbemycin A45, ot-butyldiethylsilyl-14-azido-15-hydroxymilbemycin A45-0-) IJs(ethyl)silyl-14-azido-15-hydroxymilbemycin D 5-0-1-lis (t-butyl)silyl-14-azido-15-hydroxymilbemycin D5-0-methyldiphenylsilyl-14-azido-15-hydroxymilbemycin D5-0-)lis(benzyl)silyl-14-azido-
15-hydroxymilbemycin D5-0-) IJ
(ethyl)silyl-13-deoxy-14-azido-
15-hydroxy-22゜23-dihydro-avermectin-Bta-aglycone 5-0-acetyl-14-azido-15-hydroxymilbemycin A3 5-0-acetyl-14-azido-15-hydroxymilbemycin A4 5-0-acetyl -14-azido-15-hydroxymilpemycin D 5-0-acetyl-13-deoxy-14-azido-1
5-Hydroxy-22,23-dihydro-avermectin-Bta-7 glycone Examples of other compounds of formula (2) 5-0-)rifthylsilyl-15-hydroxy-Δ[
, 14-Milbemycin A3 5-0--/Phenyl-t-butylsilyl-15-hydroxyΔ1B, 14-Milbemycin A35-0-t-
Butyldimethylsilyl-15-hydroxy-Δ15. +
4-Milbemycin A35-0-)rifutylsilyl-
15-hydroxy-Δ15,14-milbemycin A4 5-0- ) lis(t-butyl)silyl-15-hydroxyΔ1j; 14-milbemycin A45-0-diphenyl-1-butylsilyl-15-hydroxy-Δ15°
14-Milbemycin A45-0-t-Butyldimethylsilyl-15-hydroxy-Δ13,14-Milbemycin A45-0-t-Butyldiethylsilyl-15-hydroxy-Δ13°14-Milbemycin A45-0-
) lis(ethyl)silyl-15-human90x-Δ1
3.14-milbemycin D'5-0-)ris(t-
butyl)silyl-15-hydroxy-Δ13,14-milbemycin D5-0-metyldiphenylsilyl-1
5-hydroxy-Δ15,14-milbemycin D5-
0-) Lis(benzyl)silyl-15-hydroxy-Δ
1!5.14-Milbemycin D5-0-)lis(ethyl)silyl-13-deoxy-Δ1A114-15-hydroxy-22゜23-dihydro-avermectin-B
Moore glycon 5-0-acetyl-15-hydroxy-Δ+3.14-
Milbemycin A3 5-0-acetyl-15-hydroxy-Δ1!1.1j
.

Milbemycin A4 5-0-acetyl-15-hydroxy-Δ13・1'-
Milbemycin D 5-0-acetyl-13-deoxy-Δ13・14-1
5-hydroxy-22,23-dihydroavermectin-Bta-abribon.

Examples of formulations of active ingredients (in the following description, reference is based on weight) Wet powder
(a) (b) (c) Compound of formula (1) or formula (2) Section 25 Section 50 Section 75
% Sodium lignosulfonate 5% - Sodium lauryl sulfate 3% - 5% Quinbutylnaphthalene sulfonate - 6% 10% Highly dispersed silicic acid 5% 10% 10 Thikaolin 62% 27% - Active ingredients A wettable powder is obtained by thoroughly mixing with the adjuvants mentioned above and thoroughly grinding the mixture in a suitable mill.

From this it can be diluted with water to obtain a suspension of the desired concentration.

Emulsifying Concentrate Compound of Formula (1) or Formula (2) 10% Cyclohexanone 30% Xylene Mixture 50% By diluting the above concentrate with water, an emulsion of any desired concentration can be obtained. Dust (+a) (b
) ILh glue of formula (1) or formula (2) 5.8 Titalcum 95% - Kaolin - 92 The ready-to-use dust is prepared by mixing the multi-active ingredient with the carrier and milling the mixture in a suitable mill. Obtainable.

The following margin extrusion granules Compound of formula (1) or formula (2) 10% Sodium lignosulfonate 2 Thicaldexymethylcellulose 1 Thikaolin 87% The active ingredient is mixed and ground with the auxiliary agent, and the mixture is subsequently moistened with water. The mixture is extruded and dried in a stream of air.

Instead of a compound of formula (1) or formula (2), one of the biologically active intermediate products of formula (3) can also be prepared in the same manner as described above.

Compounds of formula (1) or formula (2) or compositions containing said compounds may be used in livestock animals such as cattle, sheep, goats and horses.

When used for the control of endoparasitic nematodes in pigs, cats and dogs, the compound or composition is administered to the animal by the pour-on method in single and repeated doses. can do.

Gastric toxicity test compound 3 pPm, 12.5 ppm or 50
ppm in acetone/water at the 5-leaf stage.
Sprayed on cotton plants planted in chi. After drying the spray coating, Spodoptera littoralis
Approximately 30 larvae (L1 stage) of llttorallg) were planted on the plants. Two plants were used for each test compound and test species. The test was carried out at approximately 24°C.
It was conducted at a relative humidity of 60 degrees.

After 24 hours, 48 hours, and 72 hours, evaluations and interim evaluations were made for dead pests, larval production, and damage to rearing.

Even at a concentration of 12.5 ppm, Preparation Examples 1-
Each compound obtained by Membrane Production 17 showed complete insecticidal effect after 24 hours.

B2: Plant-destroying mite: OP-susceptible 16 hours before the start of the test against Tetranicus urticae, bean plants [Phaseolus vulgaris]
) - broad leaves of Tetranicus urticae (Tetr,
infection by infected leaf pieces from a mass culture of P. anychusurtleae). Upon removal of the leaf discs, plants infected with all stages of the mites were treated with 0.0% of the test compound.
Solutions containing 4 ppm or 1.6 ppm were sprayed to the drop point. The temperature inside the greenhouse convoyment was approximately 25°C.

After 78 K, the percentage of migratory (Mobordere) stages (adults and larvae) as well as eggs were determined under a stereomicroscope. Each of the compounds obtained in Preparation Example 1 to Preparation Example 17 was 1.
At a concentration of 6 ppm, it showed complete insecticidal efficacy or 95% activity.

B3: Effect on the (L, ) larvae of the black-and-white fly 1 mg of an aqueous suspension of the test compound was added to 3 tpt of a special larval medium.
/; mixed at about 50℃, 250 ppm or 125p
A homogeneous composition with pm was obtained. In each test tube containing the active ingredient, place a seed of Lueilla 5erlc.
Approximately 30 larvae (Ll) of L. ata) were added. 4 days later,
At a concentration of 100 ppm at which mortality was counted, each of the compounds obtained in Preparation Examples 1 to 17 exhibited an activity of 90% or more.

Claims (1)

[Claims] 1. Formula (1) (wherein R1 is a hydrogen atom, a silyl group, or an acyl group, and R2 is a methyl group, an ethyl group, an isopropyl group, or an 8-
butyl group). 4-azido-15-hydroxy-milbemycin derivative and/or formula (2) (in which R1 and R
2 has the same meaning as above). 2. The compound according to claim 1, wherein R1 is a hydrogen atom and R2 is an isopropyl group. 3. The compound according to claim 1, wherein R1 is a hydrogen atom and R2 is a methyl group, ethyl group, or S-butyl group. 4. The compound according to claim 1, which is represented by the formula (2). 5. Acyl group R1 is R3-C0- group or R4-8o2-
a group in which R3 is an unsubstituted or halogenated C1-C6 aliphatic group, or phenyl, which is unsubstituted or substituted by a C4-C4 alkyl group or a halodane atom; and R is a C-C alkyl 4 1 4 group, or a phenyl group which is unsubstituted or substituted with a methyl group, a chlorine atom or a nitro group, or the formula (1) above or the formula (2) The compound according to claim 1, which is represented by (2). 6, R4 is a hydrogen atom or a formula (wherein R5 is a methyl group, ethyl group, propyl group, isopropyl group, or t-butyl group, and R6 and R7 are each independently a methyl group, an ethyl group, an inpropyl group) base, t
-butyl group, phenyl group or benzyl group), and R2 is a methyl group, ethyl group, isopropyl group or 8-butyl group.
) or the compound according to claim 1, which is represented by formula (2). 7. The silyl group is a trimethylsilyl group, tris(t
7. The compound according to claim 6, which is a -butyl)silyl group, a diphenyl-1-butylsilyl group, or a bis(inzolovyl)methylsilyl group. 8. The compound according to claim 6, wherein the silyl group is a t-butyldimethylsilyl group. 9. The compound according to claim 1, represented by the formula (2), wherein R1 is a hydrogen atom and R2 is an ethyl group. 10. The compound according to claim 1, represented by the formula (2), wherein R and R are hydrogen atoms, and R is an isopropyl group. 11, Formula (3) (wherein, R4 is a hydrogen atom, a silyl group, or an acyl group, and R2 is a methyl group, an ethyl group, an inpropyl group, or an 8-
14.15-Epoxymilbemycin derivative and complex reagent [HN3]m/[:A/, (ethyl)
,]n (wherein m and n are mutually independently 1 or 2 or a value between 1 and 20) in an inert dry solvent phase at a temperature range of -30°C to +10°C. A compound represented by formula (1) (wherein R1 and R2 have the same meanings as above) and formula (2) (wherein R1 and R2 have the same meanings as above) (same meaning as ). ]2. 12. A method according to claim 11, wherein the reaction is carried out at a temperature range of -20<0>C to -5<0>C. 13. The method according to claim 1, wherein the reaction is carried out in an atmosphere containing an inert gas. 4. The method according to claim 11, wherein the final products represented by formulas (1) and (2) are separated by a physicochemical method. ]5. 15. The method of claim 14, wherein said final product is separated by chromatography. 16 Formula (1) as an active ingredient (wherein R1 is a hydrogen atom, a silyl group or an acyl group, and R2 is a methyl group, ethyl group, inpropyl group or S-
is a butyl group) and (or) a compound represented by formula (2) (wherein R1
and R2 have the same meanings as above), together with a suitable carrier for the compound. 17. The composition according to claim 16, comprising a compound represented by formula (1) and/or formula (2), wherein R is a hydrogen atom and R2 is an isopropyl group. 18. The above formula (1,) and (or) where R1 is a hydrogen atom and R2 is a methyl group, ethyl group or S-butyl group
Claim 1 containing the compound represented by formula (2)
Composition according to item 6. 19. The composition according to claim 16, which contains the compound represented by the formula (2). 20, acyl group R1 is R3-C0- group or R, -8o2
- group, in which R3 is an unsubstituted or halodanated C4-06 aliphatic group, or substituted or substituted by a C, -C4 alkyl group or a halodan atom. Iru Feni A4Pi
and R4 is a C4-C4 alkyl group,
Claim 16, which includes a compound represented by the formula (1) or (2), wherein the compound is a phenyl group that is unsubstituted or substituted with a methyl group, a chlorine atom, or a nitro group. Composition. 21, R is a hydrogen atom or a hydrogen atom (wherein R5 is a methyl group, ethyl group, propyl group, isopropyl group, or t-butyl group, and R6 and R7 are each independently a methyl group, an ethyl group, group, inpropyl group, t
-butyl group, phenyl group, or benzyl group), and R2 is a methyl group, ethyl group, isopropyl group, or S-butyl group.
) or a compound represented by formula (2). 22 The silyl group is a trimethylsilyl group, tris(
22. The composition of claim 21, comprising a compound which is a t-butyl)silyl group, a diphenyl-t-butyl, silyl group, or a bis(isopropyl)methylsilyl group. 23. The composition according to claim 21, comprising a compound in which the silyl group is a t-butyldimethylsilyl group. 24. The composition according to claim 16, comprising a compound represented by the formula (2), wherein R1 is a hydrogen atom and R2 is an ethyl group. 25. The composition according to claim 16, comprising a compound represented by the formula (2), wherein R is a hydrogen atom and R2 is an isopropyl group. 26 Formula (3) (wherein, R4 is an acyl group or a silyl group, and R2
is a methyl group, ethyl group, inpropyl group or 8-butyl group, or R4 is a hydrogen atom and R2 is an S-butyl group): x: Poxy rust conductor.