JPH06345769A - Milbemycin macrolide 13-ester derivative - Google Patents

Abstract

PURPOSE:To obtain the subject derivative having a specific structure and exhibiting high activity and broad spectrum against persistent mites, plant vermin and animal parasites. CONSTITUTION:The derivative of formula I [R<1> is ethyl, methyl, isopropyl, etc.; R<2> and R<3> are H or methyl; R<4> is methyl or ethyl; X-Y is CH2CH2, CH2 CH(OH), etc.; A is 6-membered aromatic heterocyclic group containing 2-3 N atoms]. The compound of formula I can be produced e.g. by reacting a compound of formula II with a carboxylic acid in the presence of an acid and reacting the obtained compound of formula III with a reducing agent, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a milbemycin macrolide 13-ester derivative having ester bonds at the 13- and 26-positions showing insecticidal, acaricidal and anthelmintic activities.

[0002]

BACKGROUND OF THE INVENTION Milbemycins, avermectins and LL-F28249 are macrolide compounds having a series of 16-membered rings, for example, JP-A-50-2.
9742, 56-32481, 54-6119.
No. 8, No. 61-10589, etc.,
It is a known compound represented by the following formula (II).

[0003]

[Chemical 2]

[In the formula, X ¹ -Y ¹ has the same meaning as X-Y, and R ⁶ is a hydrogen atom or L-oleandrosyl-L.
An oleandrosyloxy group, R ⁷ represents a methyl, ethyl, isopropyl or sec-butyl group. ] ──────────────────────────────────── X ¹ −Y ¹ R ⁶ R ⁷ Macrolide name ────────────────────────────────── CH ₂ CH ₂ H CH ₃ Milbemycin A ₃ CH ₂ CH ₂ H C ₂ H ₅ milbemycin A ₄ CH ₂ CH ₂ H i-C ₃ H ₇ milbemycin D CH = CH L-oleandro s-C ₄ H ₉ avermectin B _1a syl-L-oleandrosyloxy CH = CH L-oleandro i- C ₃ H ₇ Avermectin B _1b Syl-L-oleandrosyloxy CH ₂ CH (OH) H CH ₃ LL-F28249β CH ₂ CH (OH) Hi-C ₃ H ₇ LL-F28249α ─────────── ─────────────────────────── Mill above Clarithromycin compounds, avermectins and LL
-F28249 is known to have insecticidal, acaricidal and anthelmintic activities, and in particular, semisynthetic milbemycins having various substituents introduced at the 13-position are excellent insecticidal,
It has been reported to have acaricidal and anthelmintic activity.

As milbemycins having an ester bond at the 13-position, JP-A-61-180787 describes 13-ester milbemycins with alkanoic acid. Further, in JP-A No. 1-1040708, 1 in which an alkyl group is substituted at the α-position of alkanoic acid
3-ester milbemycins have been described.

On the other hand, the following formula (II
The milbemycins represented by I) are also described, for example, in JP-A-1-193270, both of which are insecticidal,
It is known to have acaricidal and anthelmintic activity.

[0007]

[Chemical 3]

[In the formula, R ⁸ represents a methyl or ethyl group,
R ⁹ is the formula: CH = C (CH ₃₎ a group represented by R ^10, R ¹⁰ represents a methyl group or an ethyl group. ] ────────────────────────────────── R ⁸ R ⁹ Milbemycin ─────────── ──────────────────────── CH ₃ CH = C (CH ₃ ) CH ₃ α ₁₁ CH ₃ CH = C (CH ₃ ) C ₂ H ₅ α ₁₃ C ₂ H ₅ CH = C (CH ₃ ) CH ₃ α ₁₄ ────────────────────────────────── ─ However, it still has ester bonds at the 13th and 26th positions 1
There is no disclosed example of a 3,26-diester milbemycin derivative, and particularly, there is no report of a 13-ester milbemycin derivative with an alkanoic acid in which the heterocyclic group is substituted at the α-position of the present invention.

[0009]

[Problems to be solved by the invention] Mites difficult to control,
The aim is to develop new milbemycin derivatives with high activity and broad spectrum against plant pests and animal parasites.

[0010]

[Constitution of the invention]

[0011]

DISCLOSURE OF THE INVENTION In order to obtain milbemycin macrolides showing stronger biological activity, the present inventors have 13,26 having ester bonds at the 13 and 26 positions.
As a result of intensive studies focused on a diester milbemycin derivative, a new 26,26-diester milbemycin derivative having a strong biological activity as shown below was found, and the present invention was completed.

That is, the present invention has the general formula (I)

[0013]

[Chemical 4]

[Wherein R ¹ is a methyl, ethyl, isopropyl, sec-butyl group or the formula: --CH (CH ₃ ) ═CH
A group represented by -R ^5, R ⁵ represents a methyl group, an ethyl group or an isopropyl group, R ² and R ³ each independently represent a hydrogen atom or a methyl group, R ⁴ is a methyl or ethyl group, -X-Y- is, -CH ₂ CH
_{2 -, - CH 2 CH (} OH) -, - CH = CH- or -
A CH ₂ CO- group is shown, and A is a 6-membered aromatic heterocyclic group containing 2 to 3 nitrogen atoms. ] It is related with the milbemycin macrolide 13-ester derivative represented by these. The details will be described below.

In the above, a 6-membered aromatic heterocyclic group containing 2 to 3 nitrogen atoms in the definition of A is, for example, 3
-Pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 2- (1,3,5-) triazinyl, 3- (1,2,4-) triazinyl , 5- (1,
2,4-) triazinyl, 6- (1,2,4-) triazinyl group, preferably a 6-membered aromatic heterocyclic group containing two nitrogen atoms, and more preferably pyrimidinyl. It may be a group, optimally a 2-pyrimidinyl group.

The compound of the present invention represented by the above general formula (I) may have α or β coordination with respect to the 13-position configuration of the milbemycin skeleton. Therefore, the present invention includes each isomer and mixtures thereof.

Next, suitable compounds will be listed.

1) R ¹ is an ethyl, sec-butyl group or a formula:
-CH (CH ₃₎ = R ⁵ in CH-R ⁵ is a group represented by isopropyl compound, 2) a compound wherein R ² is a hydrogen atom, 3) compounds wherein R ³ is methyl group, 4) Compounds in which R ⁴ is a methyl or ethyl group, 5) —X—Y— is —CH ₂ CH ₂ —, —CH ₂ CHO.
H -, - CH ₂ CO- or -CH ₂ = CH ₂ - compound is a group, 6) A is obtained like the compound is 2-pyrimidinyl or 3-pyridazinyl group, and more preferably, 7) R ¹ is , Ethyl, a compound which is a sec-butyl group, 8) a compound in which R ⁴ is a methyl group, 9) a compound in which A is a 2-pyrimidinyl group 10) —X—Y— is —CH ₂ CH ₂ — or -CH ₂ =
A compound that is a CH ₂ — group, particularly preferably 11) a compound in which R ¹ is an ethyl group, 12) —X—Y— is a compound that is a —CH ₂ CH ₂ — group, I can mention.

Next, specific examples of the compound of the present invention are shown in Table 1. In the table, R ¹ , R ⁴ and A are the same as those shown in the general formula (I), respectively, and R ² Is a hydrogen atom, R ³
Represents a methyl group.

Further, K in the compound number means that in the general formula (I), —X—Y— is —CH ₂ CH ₂ —, and L means —CH ₂ CH (OH). ) -, the term M is, -CH = CH-, the term N is, -CH ₂ C
Indicates O-.

[0021]

[Chemical 5]

[0022]

[Table 1] ──────────────────────────────────── Compound number R ¹ R ⁴ A ─── _{───────────────────────────────── K-1 CH 3 CH 3} 2- pyrimidinyl _K-2 CH ₃ C 2 H ₅ 2-pyrimidinyl _{K-3 C 2 H 5 CH} 3 2- pyrimidinyl _{K-4 C 2 H 5 C} 2 H 5 2- pyrimidinyl _{K-5 C 2 H 5 CH} 3 4- pyrimidinyl K-6 C ₂ H ₅ CH ₃ 3- pyridazinyl _{K-7 i-C 3 H} 7 CH 3 2- pyrimidinyl _{K-8 s-C 4 H} 9 CH 3 2- pyrimidinyl _{K-9 C (CH 3)} = CH (CH 3) CH 3 2 - pyrimidinyl _{K-10 C (CH 3)} = CH (iC 3 H 7) CH 3 2- pyrimidinyl _{L-11 C 2 H 5 CH} 3 2- pyrimidinyl _{L-12 iC 3 H 7 CH} 3 2- pyrimidinyl L -13 s- ₄ H ₉ CH ₃ 2- pyrimidinyl _{L-14 C (CH 3)} = CH (CH 3) CH 3 2- pyrimidinyl _{L-15 C (CH 3)} = CH (iC 3 H 7) CH 3 2- pyrimidinyl M- 16 CH ₃ CH ₃ 2-pyrimidinyl M-17 CH ₃ C ₂ H ₅ 2-pyrimidinyl M-18 C ₂ H ₅ CH ₃ 2-pyrimidinyl M-19 C ₂ H ₅ C ₂ H ₅ 2-pyrimidinyl M-20 C ₂ H ₅ CH ₃ 4-pyrimidinyl M-21 C ₂ H ₅ CH ₃ 3-pyridazinyl M-22 i-C ₃ H ₇ CH ₃ 2-pyrimidinyl M-23 s-C ₄ H ₉ CH ₃ 2-pyrimidinyl M- 24 C (CH ₃ ) = CH (CH ₃ ) CH ₃ 2-pyrimidinyl M-25 C (CH ₃ ) = CH (iC ₃ H ₇ ) CH ₃ 2-pyrimidinyl N-26 C ₂ H ₅ CH ₃ 2-pyrimidinyl _{N-27 i-C 3 H} 7 CH 3 2- pyrimidinyl _{N-28 s-C 4 H} 9 CH 3 2- pyrimidinyl N-2 _{C (CH 3) = CH (} CH 3) CH 3 2- pyrimidinyl _{N-30 C (CH 3)} = CH (iC 3 H 7) CH 3 2- pyrimidinyl ───────────── ─────────────────────── Of the above compounds, the compound numbers K-3 and K- are preferred.
4, K-6, K-8, K-10, L-11, L-13,
L-15, M-18, M-19, M-21, M-23,
The compounds of M-25, N-26, N-28 and N-30 can be mentioned, and more preferably, compound numbers K-3, K-4 and K-.
8, M-18, and M-23 can be mentioned, and the compounds of compound numbers K-3 and M-18 are particularly preferable.

The compound represented by formula (I) of the present invention can be produced by the method shown in the following process chart.

[0024]

[Chemical 6]

In the formula, XY, R ¹ , R ² , R ³ , R ⁴ and A have the same meanings as described above.

Step A is a step of producing a compound represented by the general formula (V), which is carried out in the presence of an acid acting as a catalyst on the compound represented by the general formula (IV).
It is carried out by reacting a carboxylic acid represented by

A—S—CH (C ₆ H ₅ ) —COOH (VI) (In the formula, A is the same as described above) The acid used may be either an inorganic acid or an organic acid, for example, hydrochloric acid. , Sulfuric acid, trifluoroacetic acid, trichloroacetic acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-trienesulfonic acid, p-nitrobenzenesulfonic acid, benzenesulfonic acid, and preferably sulfuric acid, trifluoromethanesulfone. Acid, methanesulfonic acid, p-
It is nitrobenzene sulfonic acid.

The amount of acid used is, in principle, a catalytic amount, usually one equivalent or less is sufficient, but can vary considerably depending on the reactivity of the carboxylic acid used, and is usually , From the catalytic amount to 5 equivalents.

When an inorganic compound powder is added to the reaction system, the reaction may be promoted and good results may be given in some cases. Examples of such an inorganic compound include copper trifluoromethanesulfonate, cuprous iodide, zinc iodide, cobalt iodide, metal salts such as nickel iodide, celite, silica gel, alumina, and the like. Are copper salts such as copper trifluoromethanesulfonate and cuprous iodide, most preferably copper trifluoromethanesulfonate and cuprous iodide.

The solvent used in the reaction is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably it is an aromatic hydrocarbon such as benzene, toluene or xylene. Kinds; methylene chloride, 1,
Halogenated hydrocarbons such as 2-dichloroethane and chloroform; Esters such as ethyl acetate and propyl acetate; Ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; Dimethylformamide, dimethylacetamide, hexamethylphosphorotriene Examples thereof include amides such as amides; sulfoxides such as dimethyl sulfoxide, acetonitrile and the like.

The reaction temperature is -10 ° C to 100 ° C, preferably 0 ° C to 50 ° C.

The reaction time is usually 5 minutes to 6 hours, preferably 10 minutes to 2 hours, varying mainly depending on the reaction temperature, the kind of the raw material compound or the solvent used.

Step B is a step of producing a compound represented by the general formula (I), which comprises reacting the compound represented by the general formula (V) with a reducing agent to convert the carbonyl group at the 5-position into a hydroxyl group. It is achieved by reducing to.

As a reagent used for the reduction, a compound (V) which can reduce a carbonyl group and is represented by the general formula (V)
Any other functional group may be used without particular limitation. As such a reducing agent, a reducing agent using a hydrogen anion such as sodium borohydride or diborane can be used, but sodium borohydride is preferable.

The reaction solvent can be used without particular limitation as long as it does not participate in the reaction. When sodium borohydride is used as the reducing agent, for example, a lower alcohol such as methanol, ethanol or propanol is used. Are particularly preferred. The reaction is usually 0 ° C. to 50
The reaction time is 5 minutes to 2 hours. After completion of the reaction in each step, the desired compounds of formulas (V) and (I) are isolated from the reaction mixture by a well-known method and, if necessary, purified by a known means such as column chromatography. It

The compound represented by the general formula (IV) is derived from natural milbemycins and their related compounds. Such starting milbemycins and their related compounds are fermentation products, and a large number of fractions are produced at various ratios, and each fraction is used in the reaction after isolation or as a mixture. Attached. Therefore, the compound of formula (IV) can be either a single compound or a mixture thereof. Therefore, the compound represented by the general formula (I) can also be produced as a single compound or a mixture.

The compound represented by the general formula (IV), which is a starting material for producing the compound represented by the general formula (I) of the present invention, can be produced by the method described in JP-A-60-158191. It can be manufactured according to the above, and more specific steps are shown below.

[0038]

[Chemical 7]

[0039]

[Chemical 8]

(Wherein R ¹ , R ² , R ³ , R ⁴ and X-
Y has the same meaning as described above, and TBDMS
Represents a t-butyldimethyl group, and TMS represents a trimethylsilyl group. The compound represented by the general formula (VII), which is a starting material for producing the compound represented by the general formula (IV), is a known compound described in JP-A-64-31776.

[0041]

INDUSTRIAL APPLICABILITY 1 of the present invention represented by the above general formula (I)
The 3-ester milbemycin analog compounds are useful as acaricides, insecticides, and anthelmintics, and exhibit excellent control effects against various diseases caused by mites, plant pests or animal parasites.

That is, the compound (I) of the present invention is an adult and an egg such as worm ticks (Tetranychus), apple spider mites, citrus spider mites (Panonychus) and rust mites that parasitize fruit trees, vegetables and flowers, and ticks (Ixodidac) that parasitize animals. Arachnidae (Dermanysside)
It has excellent acaricidal activity against e) etc.

Furthermore, sheep flies (Oestrus) and fruit flies (Lu
cilia), Bullflies (Hypoderma), and bots (Gautrophil)
us) etc. and chisel, ectoparasites of animals and birds such as bryophytes;
Sanitary pests such as cockroaches and house flies; other aphids,
It is active against various agricultural and horticultural insects such as Lepidoptera larvae. In addition, root-knot nematodes (Meloidogyne) and mite (Ph
(izoglyphus) and so on.

To use the compound (I) of the present invention as a miticide, the active compound is diluted with a carrier and, if necessary, other auxiliary agents are added thereto to give a powder, coarse powder, granules or fine granules. , A wettable powder, an emulsion, an oil, and the like can be prepared and used.

Further, the compound (I) of the present invention has excellent parasiticidal activity as an anthelmintic agent for animals and humans. Diseases commonly described as parasitic diseases are helminths (Helmin
infection of the animal host by a protozoa known as th). Parasitic diseases are endemic to cattle, poultry and pets such as pigs, sheep, goats, cattle, horses, dogs, cats and chickens and cause serious economic damage. The parasite group described as nematodes in helminths is infested by various animals and often causes serious infections. The most common genus of nematodes that infect the aforementioned animals are Haemonchus, Trichostrongylus, and Ostertergia.
tertagia), Nematodirus genus, Cooperia genus, Ascaris genus, Bunostomum genus, Oesophagostomum genus, Chaberturi genus
s), the genus Strongylus, the genus Triconema, and the genus Dictyocaulu.
s), Capillaria, Heterakis (H
eterakis), Toxocara genus, Ascaridia genus, Oxyuris genus, Ancylostoma genus, Uncina genus
ria), the genus Toxascaris, and the genus Parascaris.

Some of the genera Nematodales, Cooperia and Esophagogosthum attack the intestinal tract, while those of the genus Hemonx and Ostertergia parasitize the stomach and parasites of the genus Dichthiocaurus Found in the lungs.

Parasites of the family Filariidae and Setariidae are also found in other tissues and organs of the body such as heart and blood vessels, subcutaneous and lymphatic tissues.

Furthermore, it has a broad spectrum of activity against many endoparasites in various animals, such as the dog genus Dirofilaia, the genus Nematospiroides of the genus Kessian, the sifiacia. Genus (Syphacia) and Aspicularis (Aspiculu
ris) also shows activity.

The compound (I) of the present invention is also useful against parasites that infect humans, and the most common parasites in the human digestive tract are Ancylostoma and Necator. , Ascaris, Strongyloides, Trichinella (Tr
ichinella), Capillaria, Trichuris and Enteropius
s).

Other medically important parasites found in blood or other tissues and organs outside the gastrointestinal tract are the genus Wuchereria, genus Brusia (Bruchia) of the family Filaria.
ugia), Onchocerca and Loa filamentous worms (Loa), and Dracunculidae dracunculus (Dracunculus), in addition to parasites of the intestinal parasite They are the genus Strongiroides and the genus Trichinella.

When the compound (I) of the present invention is used as an anthelmintic in animals and humans, it can be orally administered as a liquid beverage. Beverages are usually solutions, suspensions or dispersions in suitable non-toxic solvents or water with suspending agents such as bentonite and wetting agents or other excipients.
Beverages also generally contain an antifoaming agent. Beverage formulations generally contain from about 0.01 to 0.5% by weight of active compound, preferably 0.01 to 0.1% by weight.

When the compound (I) of the present invention is administered by animal feed, it is dispersed homogeneously in the feed, used as a top dressing or used in the form of pellets. Usually, in order to achieve the desired antiparasitic effect, the active compound is added in an amount of 0.0001 to 0.0001 in the final feed.
It contains 0.02%.

Further, the compound (I) of the present invention dissolved or dispersed in a liquid carrier excipient may be parenterally administered to animals by injection in the forestomach, intramuscularly, intratracheally or subcutaneously. it can. For parenteral administration, the active compounds are preferably mixed with suitable vegetable oils such as peanut oil, cottonseed oil.
Such formulations generally contain from 0.05 to 50% by weight of active compound.
contains.

The compounds (I) of this invention may also be topically administered by admixture with a suitable carrier such as dimethylsulfoxide or a hydrocarbon solvent. This formulation is applied directly to the external surface of the animal by spraying or direct pouring.

The optimum amount of active compound used for the best results depends on the kind of animal to be treated and on the type and degree of parasite infection, but is generally about 0.01 to 100 mg, preferably 1 to 100 mg per kg of animal body weight. Is 0.5 to 50.0 mg
Orally administered. Such doses may be given at once or in divided doses over a relatively short period such as 1-5 days.

Next, the present invention will be specifically described with reference to Examples and Reference Examples.

Example 1 (Step A) 5-keto-13- [α- (2-pyrimidinylthio) phene
Nylacetoxy] -milbemycin α ₁₄ (V: XY = CH ₂ CH ₂ , R ² = H, R ³ = R ⁴ =
CH ₃ , A = 2-pyrimidinyl) 15-hydroxy-
5-Ketomylbemainishi α ₁₄ (100 mg) and α- (2-
To a solution of pyrimidinylthio) phenylacetic acid (190 mg) in dichloromethane at room temperature under an argon stream, copper (I) iodide (60 mg) and trifluoromethanesulfonic acid (7 mg) were added.
0 μl) was sequentially added, and the mixture was further stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate.
The extract was washed with 4% aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel caracam chromatography to give 33 mg (24%) of the desired product.

Mass spectrum (m / z): 882 (M ⁺ ) Nuclear magnetic resonance spectrum (270 MHz) δ (CDCl ₃ ): 8.40 to 8.
55 (m, 2H), 7.41 ~ 7.56 (m, 2H), 7.33 (br.s, 3H), 6.94
~ 7.00 (m, 1H), 6.30 (m, 1H), 5.73 ~ 5.89 (m, 1H), 5.70
(s, 1H), 4.91 to 5.01 (m, 1H). Example 2 (Step B) 13- [α- (2-pyrimidinylthio) phenylacetate
[Xy] -milbemycin α ₁₄ (Compound No. K-3) (I: XY = CH ₂ CH ₂ , R ² = H, R ³ = R ⁴ =
CH ₃ , A = pyrimidinyl) 5-keto-13 [α- (2
To a methanol solution of -pyrimidinylthio) phenylacetoxy] -milbemycin α ₁₄ (90 mg) was added sodium borohydride (10 mg) under ice cooling, and the mixture was stirred at room temperature for 30 minutes.

After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give 27 mg (30%).
I got the object.

Mass spectrum (m / z): 884 (M ⁺ ), 577,
538, 520, 430, 412, 279, 246,229 Nuclear magnetic resonance spectrum (270MHz) δ (CDCl ₃ ): 8.48 (d, J
= 4.6Hz) and 8.44 (d, J = 4.6Hz) (2H), 7.48 ~ 7.53 (m, 2H),
7.28 ~ 7.40 (m, 3H), 6.98 (t, 1H, J = 4.9Hz), 5.67 ~ 5.83
(m, 4H), 5.51 (s, 1H), 5.25 ~ 5.41 (m, 3H), 4.96 (d, J = 10.
4Hz) and 4.97 (d, J = 10.4Hz) (1H), 4.55 ~ 4.85 (m, 4H), 4.43
-4.51 (m, 1H). Reference Example 1 (Step C and Step D) 5-O- (t-butyldimethylsilyl) -26-hydroxymilbemycin A ₄ (607 mg) in N, N-dimethylformamide solution was added to imidazole. (317 mg) and t
-Butyldimethylsilyl chloride (348 mg) was added,
Stir at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was dried and then concentrated. The residue was purified by silica gel column chromatography to give 683 mg (9
7%) of 5-O- (t-butyldimethylsilyl) -26
- was obtained (t- butyldimethylsilyloxy) milbemycin A _4. Subsequently, this was dissolved in dichloromethane, imidazole (104 mg) and trimethylsilyl chloride (0.15 ml) were added, and the mixture was stirred at 55 ° C. for 7 hours. The reaction solution is poured into water, extracted with ethyl acetate, the extract is dried,
Concentrated. The residue was purified by silica gel column chromatography to obtain 5-O-a (t-butyldimethylsilyl) -26- (t-butyldimethylsilyloxy) -7-O-trimethylsilyl milbemycin A ₄ of 660 mg (88%) It was Mass spectrum (m / z): 858 (M ⁺ ), 486, 445, 355, 3
13, 264, 223, 195, 167 Reference Example 2 (Step E and Step F) 5-O- (t-butyldimethylsilyl) -26- (t-
To a dichloromethane solution of butyldimethylsilyloxy) -7-O-trimethylsilylmilbemycin A ₄ (440 mg) was added m-chloroperbenzoic acid (198 mg), and the mixture was stirred under ice cooling for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give 5-O- (t-butyldimethylsilyl) -26-
(T-Butyldimethylsilyloxy) -14,15-epoxy-7-O-trimethylsilylmilbemycin A ₄
450 mg of crude product was obtained. This crude product was dissolved in toluene, 2,6-lutidine (0.20 ml) was added, and -25
After cooling to ℃, trimethylsilyl trifluoromethanesulfonate (0.15 ml) was added dropwise. After stirring at 0 ° C for 4 hours, water was added and the mixture was extracted with ethyl acetate. Extract 1N
Wash with hydrochloric acid and 10% sodium bicarbonate water, dry, concentrate, and purify the residue by silica gel column chromatography.
mg (55%) of 5-O- (t-butyldimethylsilyl)
-26- (t-butyldimethylsilyloxy) -15-
Hydroxy-7-O-trimethylsilyl milbemycin A ₄ was obtained.

NMR (200 MHz) δ (CDCl ₃ ) ppm: 5.61-5.89
(m, 3H), 5.21 (dd, 1H, J = 10.2,13.0Hz), 5.04 (d, 1H, J =
9.9Hz), 4.50 to 4.75 (m, 4H), 3.86
(D, 1H, J = 5.9 Hz). Reference Example 3 (Step G) 5-O- (t-butyldimethylsilyl) -26- (t-
Butyldimethylsilyloxy) -15-hydroxy-7
-O-trimethylsilyl milbemycin A ₄ (266
p-toluenesulfonic acid (3
7 mg) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, and the extract was dried. After concentration,
The residue was purified by silica gel column chromatography, 15,26- dihydroxy milbemycin A ₄ 14
Obtained 3 mg (82%).

Mass spectrum (m / z): 574 (M ⁺ ), 556,
430, 412, 394, 372, 330, 307, 195, 167 Nuclear magnetic resonance spectrum (270MHz) δ (CDCl ₃ ): 5.66 ~ 5.
88 (m, 3H), 5.26 (dd, 1H, J = 10.2,14.1Hz), 5.15 (d, 1H, J
= 9.3Hz), 4.90 (m, 1H), 4.72 and 4.67 (ABq, 2H, J = 15.
5Hz), 4.58 (d, 1H, J = 6.5Hz). Reference Example 4 (Process H and Process I) 15,26-Dihydroxymilbemycin A ₄ (190
Pyridine (53 μl) and senecioic acid chloride (55 μl) were added to a dichloromethane solution of (mg) and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The extract solution was dried and concentrated to give 15-hydroxymilbemycin α.
180 mg of ₁₄ crude products were obtained. This crude product was dissolved in dichloromethane, manganese dioxide (2 g) was added, and 3
Stir vigorously for 0 minutes. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give 90 mg (41%) of 15-hydroxy-5-.
Ketomilbemycin α ₁₄ was obtained.

Mass spectrum (m / z): 654 (M ⁺ ), 554,
536, 430, 394, 327, 307, 195, 167 Nuclear magnetic resonance spectrum (270MHz) δ (CDCl ₃ ): 6.78 (m, 1
H), 5.74 to 5.88 (m, 2H), 5.72 (t, 1H, J = 2.2Hz), 5.29 (m, 1
H), 5.17 (d, 1H, J = 9.2Hz), 4.95 (m, 1H), 4.68 ~ 4.90 (m, 4
H). Example 3 Insecticidal test against diamondback moth Emulsion containing 1% of the compound No. K-3 was diluted with water so that the concentration of the active ingredient was 10 ppm.
Cabbage leaves were immersed in the chemical solution for 10 seconds, air-dried, and then put in a polyethylene cup having a diameter of 8 cm. Konaga 3 in it
Ten instar larvae were placed and the lid was covered. Then, the sample was placed in a constant temperature chamber at 25 ° C., and the mortality rate (including anguish) was investigated 3 days later.
The test was conducted in two consecutive cycles. As a result, the mortality rate was 100%. Example 4 Insecticidal test against Spodoptera litura Emulsion containing 1% of compound No. K-3 was diluted with water so that the concentration of active ingredient was 10 ppm. Immerse 5 g of artificial feed (Insector L) in the drug solution for 20 seconds,
After air-drying, it was placed in a polyethylene cup having a diameter of 8 cm. Ten third-instar larvae of Spodoptera litura were placed in it and the lid was closed.
Then, the sample was placed in a constant temperature chamber at 25 ° C., and the mortality rate (including anguish) was investigated 3 days later. The test was conducted in two consecutive cycles. As a result, the mortality rate was 100%.

Example 5 Insecticidal test against Scutellaria baicalensis Emulsion containing 1% of the compound No. K-3 was diluted with water so that the concentration of the active ingredient was 10 ppm. Immerse 5 g of artificial feed (Insector L) in the drug solution for 20 seconds,
After air drying, it was placed in a polyethylene cup having a diameter of 8 cm. Ten fourth-instar larvae of Chacococca japonicus were put in it and the lid was covered. Then, the sample was placed in a constant temperature chamber at 25 ° C., and the mortality rate (including anguish) was investigated 3 days later. The test was conducted in two consecutive cycles.
As a result, the mortality rate was 100%.

Claims (1)

[Claims] 1. A general formula: [In the formula, R ¹ is methyl, ethyl, isopropyl, sec-
Butyl group or the formula: -CH (CH ₃₎ = indicates CH-R ^5, a group represented by, R ⁵ represents a methyl group, an ethyl group or an isopropyl group, R ² and R ³ are each independently ,
Represents a hydrogen atom or a methyl group, R ⁴ represents a methyl or ethyl group, —X—Y— represents —CH ₂ CH ₂ —, —CH
_{2 CH (OH) -, -} CH = CH- or -CH ₂ CO-
Represents a group, and A represents a 6-membered aromatic heterocyclic group containing 2 to 3 nitrogen atoms. ] The milbemycin macrolide 13-ester derivative represented by these.