14- and 15-hydroxy milbemycin derivatives for controlling plant and animal parasites

The present invention relates to milbemycin derivatives of the formula I, 
to the preparation thereof by singulett oxygen oxidation, and to the use 
of said derivatives in pest control by themselves or in suitable 
formulations. 
Compounds of formula I 
##STR4## 
are obtained in two basic structures side by side. In compounds of formula 
Ia 
A is the structure 
##STR5## 
and in compounds of formula Ib 
A is the structure 
##STR6## 
and in both structures X is either 
##STR7## 
and 
R.sub.1 is hydrogen or a silyl or acyl group, and 
R.sub.2 is methyl, ethyl, isopropyl or sec-butyl. 
Compounds of the formulae Ia and Ib can be separated by physicochemical 
methods. 
Throughout this specification, compounds wherein R.sub.2 is sec-butyl shall 
also be considered as belonging to the milbemycin derivatives, although 
strictly they do not come into this category according to conventional 
classification, but are derived from avermectin derivatives as disclosed 
in U.S. Pat. No. 4,173,571. 
Compounds of formula Ia are preferred within the scope of the present 
invention and, among these, those compounds wherein X is either --CHOH-- 
or --CO--. Acyl and silyl groups R.sub.1 will in principle be understood 
as meaning protective groups, the presence of which, however, does not 
diminish the biological value of the compounds in which R.sub.1 is 
hydrogen. 
Suitable acyl groups R.sub.1 are R.sub.3 --CO-- and R.sub.4 --SO.sub.2 -- 
radicals, in which R.sub.3 is preferably an unsubstituted or a halogenated 
C.sub.1 -C.sub.6 aliphatic radical, or is a phenyl radical which is 
unsubstituted or substituted by C.sub.1 -C.sub.4 alkyl or halogen, and 
R.sub.4 is a C.sub.1 -C.sub.4 alkyl radical or a phenyl radical which is 
unsubstituted or substituted by methyl, chlorine or nitro. 
Preferred compounds of the formula I are those wherein R.sub.1 is hydrogen, 
a R.sub.3 --CO-- or R.sub.4 --SO.sub.2 -- radical, in which R.sub.3 is a 
C.sub.1 -C.sub.4 alkyl radical or a phenyl radical which is unsubstituted 
or substituted by methyl or chlorine, and R.sub.4 is methyl, ethyl, 
phenyl, p-tolyl, o-nitrophenyl or p-chlorophenyl, and R.sub.2 is methyl, 
ethyl, isopropyl or sec-butyl. 
Without any restriction being implied, typical examples of substituents 
R.sub.3 are methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl, 
p-chlorophenyl, and p-tolyl. 
Suitable silyl groups are those of the formula 
##STR8## 
wherein R.sub.5 is a C.sub.1 -C.sub.4 aliphatic radical or benzyl, and 
R.sub.6 and R.sub.7 are each independently of the other a C.sub.1 -C.sub.4 
aliphatic radical, benzyl or phenyl. 
An important group of compounds comprises milbemycin derivatives of the 
formula I, wherein A is as defined for formula I, X is --CHOH-- or --CO-- 
and R.sub.2 is isoC.sub.3 H.sub.7. 
Another group of preferred compounds of the formula Ia comprises those 
compounds wherein R.sub.1 is the silyl group specified above in which 
R.sub.5 is methyl, ethyl, propyl, isopropyl or tert-butyl, and R.sub.6 and 
R.sub.7 are each independently of the other methyl, ethyl, isopropyl, 
tert-butyl, phenyl or benzyl, and R.sub.2 is methyl, ethyl, isopropyl or 
sec-butyl. 
Examples of silyl groups are trimethylsilyl, methyldiphenylsilyl, 
tri-(tert-butyl)silyl, diphenyl-tert-butylsilyl, bis(isopropyl)methylsilyl 
and, in particular, tert-butyl-dimethylsilyl. 
The 13-position is unsubstituted in naturally occurring milbemycins 
(R.sub.1 =H; R.sub.2 =CH.sub.3, C.sub.2 H.sub.5 or isoC.sub.3 H.sub.7). 
Avermectins, however, carry in the 13-position a .beta.-hydrogen atom and 
an .alpha.-L-oleandrosyl-.alpha.-L-oleandrose radical which is linked 
through oxygen in the .alpha.-configuration to the macrolide molecule. 
Moreover, avermectins differ structurally from the milbemycins in that 
they contain a 23-OH group or a .DELTA..sup.22,23 double bond and usually 
a substituent R.sub.2 =sec-C.sub.4 H.sub.9. Hydrolysis of the sugar 
residue of avermectins readily affords the corresponding avermectin 
aglycones, which carry an allylic 13.alpha.-hydroxy group. This OH group 
can be converted with o-nitrobenzenesulfonyl chloride into a 
13.beta.-chloro derivative, the chloro substituent of which can be removed 
reductively with tri-(n-butyl)tin hydride. In this manner it is possible 
to convert avermectin derivatives into the milbemycin series (q.v. 
Tetrahedrone Letters, Vol. 24, No. 48, pp. 5333-5336, 1983). 
In the process of this invention, compounds of formula I are obtained by 
singulett oxygen oxidation from appropriately substituted milbemycin 
derivatives [X=--CH(OR.sub.1)--] or 5-keto-milbemycin derivatives 
[X=--CO--] of the formula II 
##STR9## 
wherein X and R.sub.2 are as defined for formula I, and subsequent 
selective reduction on the 15-peroxide and 14-peroxide obtained as 
intermediate 
##STR10## 
with sodium borohydride, lithium aluminium hydride or triphenylphosphine. 
The reaction is carried out in visible light in the presence of a 
sensitiser, under normal pressure and in the temperature range from 
-90.degree. C. to +45.degree. C., preferably from 0.degree. to +20.degree. 
C., in an inert solvent. It is preferred to carry out the reaction in an 
irradiating apparatus. 
The reaction course can be illustrated as follows: 
(1) oxygen+light+sensitiser 
(2) reduction 
compounds of formula II.fwdarw.compounds I 
(q.v. H. H. Wassermann et al, "Singulett Oxygen", Academic Press, New York 
1979; or B. Ranby etz al., "Singulett Oxygen Reactions with Organic 
Compounds and Polymers", Wiley, New York 1978). 
Examples of suitable solvents are ethers and ethereal compounds such as 
diethyl ether, diisopropyl ether, dioxan and tetrahydrofuran; aromatic 
hydrocarbons such as benzene, toluene and xylenes; ketones such as 
acetone, methyl ethyl ketone and cyclohexanone; nitriles such as 
acetonitrile; esters such as ethyl acetate and butyl acetate; and 
dimethylformamide, dimethylsulfoxide and halogenated hydrocarbons; or 
mixtures of these solvents with water. 
Suitable sensitisers are dyes such as methylene blue, Bengal, pink, 
chlorophyll, erythrosin, eosine, zinc tetraphenyl porphine, 
hematoporphyrin, riboflavine, fluorescein or acridine orange. Selective 
reduction is carried out in the temperature range from 0.degree. to 
20.degree. C., without further purification, after conclusion of the 
oxidation. 
As light source it is convenient to use a lamp having a strength of 60 to 
500 watt, preferably of 100 to 350 watt. If it is desired to protect the 
5-hydroxy group, then suitable protective groups are the silyl and acyl 
groups mentioned for R or e.g. a benzyl ether, methoxyethoxymethyl ether, 
or dihydrofuran or dihydropyran radicals. These protective groups can be 
introduced into compounds of formula II and later removed again in 
conventional manner. Conventional acylation of the 5-OH group with the 
corresponding acyl halides or acyl anhydrides or by reaction of the 5-OH 
group with the appropriately substituted silane derivative of the formula 
##STR11## 
affords all those previously mentioned derivatives of the formula I or II 
in which R.sub.1 has a meaning different from hydrogen, and R.sub.5, 
R.sub.6 and R.sub.7 are as defined for formula I, with the term acyl 
halide signifying acyl chloride or acyl bromide and X being a silyl 
leaving group. Silyl leaving groups X comprise for example bromide, 
chloride, cyanide, azide, acetamide, trifluoroacetate, and 
trifluoromethanesulfonate. The above recitation constitutes no limitation, 
and other typical silyl leaving groups are known to the skilled person. 
5-O-Acylations and 5-O-silylations are carried out in anhydrous medium, 
preferably in inert solvents and, most preferably, in aprotic solvents. 
The reaction conveniently takes place in the temperature range from 
0.degree. to 80.degree. C., preferably from 10.degree. to 40.degree. C. It 
is preferred to add an organic base. Examples of suitable bases are 
tertiary amines such as triethylamine, triethylenediamine, triazole and, 
preferably, pyridine, imidazole or 1,8-diazabicyclo[5.4.0]-undec-7-ene 
(DBU). 
The removal of these silyl and acyl radicals R.sub.1 in the 5-position is 
effected by selective mild hydrolysis (.fwdarw.R=H) with e.g. an 
arylsulfonic acid in alcoholic solution, or by another method commonly 
known to the skilled person. 
The compounds of formula II, wherein R.sub.1 is hydrogen, are either known 
from U.S. Pat. No. 3,950,360 and were originally designated as 
"Antibiotics B-41-A", later called "milbemycin A compounds", or they are 
known from U.S. Pat. No. 4,346,171 and designated as "B-41D" or 
"milbemycin D"; or they are known from U.S. Pat. No. 4,173,571 and 
designated as 13-deoxy-22,23-dihydro-avermectin (R.sub.2 =sec-butyl). They 
have the structure 
##STR12## 
R.sub.2 =CH.sub.3 ; milbemycin A.sub.3 R.sub.2 =C.sub.2 H.sub.5 ; 
milbemycin A.sub.4 
R.sub.2 =isoC.sub.3 H.sub.7 ; milbemycin D 
R.sub.2 =sec-C.sub.4 H.sub.9 ; 13-deoxy-22,23-dihydro-C-076-Bla-aglycon, or 
13-deoxy-22,23-dihydro-avermectin-Bla-aglycon. 
The present invention further relates to pesticidal compositions for 
controlling ecto- and endoparasites as well as harmful insects, which 
compositions contain as at least one active ingredient a compound of the 
formula I, together with conventional carriers and/or dispersing agents. 
The compounds of formula I are most suitable for controlling pests of 
animals and plants, including ectoparasites of animals. These last 
mentioned pests comprise those of the order Acarina, in particular pests 
of the families Ixodidae, Dermanyssidae, Sarcoptidae, Psoroptidae; of the 
orders Mallophaga, Siphonoptera, Anoplura (e.g. family of the 
Haematopinidae); and of the order Diptera, in particular pests of the 
families Muscidae, Calliphoridae, Oesterridae, Tabanidae, Hippoboscidae, 
and Gastrophilidae. The compounds of formula I can also be used against 
hygiene pests, especially of the order Diptera (families Sarcophigidae, 
Anophilidae and Culicidae); of the order Orthoptera, of the order 
Dictyoptera (e.g. family of the Blattidae), and of the order Hymenoptera 
(e.g. family of the Formicidae). 
The compounds of formula I also have a lasting action against mites and 
insects which are parasites of plants. When used to control spider mites 
of the order Acarina, they are effective against eggs, nymphs and adults 
of Tetranychidae (Tetranychus spp. and Panonychus spp. They also have 
excellent activity against sucking insects of the order Homoptera, in 
particular against pests of the families Aphididae, Delphacidae, 
Cicadellidae, Psyllidae, Loccidae, Diaspididae and Eriophyidae (e.g. the 
rust mite or citrus fruit); of the orders Hemiptera, Heteroptera and 
Thysanoptera; and against plantdestructive insects of the orders 
Lepidoptera, Coleoptera, Diptera and Orthoptera. 
The compounds of formula I are also suitable for use against pests in the 
soil. 
The compounds of formula I are therefore effective against all development 
stages of sucking and eating insects in crops such as cereals, cotton, 
rice, maize, soybeans, potatoes, vegetables, fruit, tabacco, hops, citrus 
fruit, avocados and others. 
The compounds of formula I are also affective against plant nematodes of 
the species Meloidogyne, Heteroders, Pratylenchus, Ditylenchus, Radolphus, 
Rhizoglyphus and others. 
Furthermore, the compounds of formula I act against helminths, among which 
the endoparasitic nematodes can be the cause of severe diseases in mammals 
and fowl, for example in sheep, pigs, goats, cattle, horses, donkeys, 
dogs, cats, guinea pigs, cage-birds. Typical nematodes having this 
indication are: Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, 
Cooperia, Ascaris, Bunostomum, Oesphagostomum, Chabertia, Trichuris, 
Strongylus, Trichonema, Dictyocaulus, Cappillaria, Heterakis, Toxocara, 
Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. The 
particular advantage of the compounds of formula I is their activity 
against those parasites which are resistant to benzimidazole-based 
endoparasiticides. 
The compounds of formula I are used in unmodified form or, preferably, 
together with the adjuvants conventionally employed in the art of 
formulation, and are therefore formulated in known manner to emulsifiable 
concentrates, directly sprayable or dilutable solutions, dilute emulsions, 
wettable powders, soluble powders, dusts, granulates, and also 
encapsulations in e.g. polymer substances, As with the nature of the 
compositions, the methods of application such as spraying, atomising, 
dusting, scattering or pouring, are chosen in accordance with the intended 
objectives and the prevailing circumstances. 
The compounds of formula I are administered to warm-blooded animals at 
rates of application of 0.01 to 50 mg/kg of body weight, and are applied 
to enclosed crop areas, to pens, livestock buildings or other buildings in 
amounts of 10 g to 1000 g per hectare. 
The formulations, i.e. the compositions or preparations containing the 
compound (active ingredient) of the formula I are prepared in known 
manner, e.g. by homogeneously mixing and/or grinding the active 
ingredients with extenders, e.g. solvents, solid carriers and, in some 
cases, surface-active compounds (surfactants). 
Suitable solvents are: aromatic hydrocarbons, preferably the fractions 
containing 8 to 12 carbon atoms, e.g. xylene mixtures or substituted 
naphthalenes, phthalates such as dibutyl phthalate or dioctyl phthalate, 
aliphatic hydrocarbons such as cyclohexane or paraffins, alcohols and 
glycols and their ethers and esters, such as ethanol, ethylene glycol 
monomethyl or monoethyl ether, ketones such as cyclohexanone, strongly 
polar solvents such as N-methyl-2-pyrrolidone, dimethyl sulfoxide or 
dimethyl formamide, as well as vegetable oils or epoxidised vegetable oils 
such as epoxidised coconut oil or soybean oil; or water. 
The solid carriers used e.g. for dusts and dispersible powders are normally 
natural mineral fillers such as calcite, talcum, kaolin, montmorillonite 
or attapulgite. In order to improve the physical properties it is also 
possible to add highly dispersed silicic acid or highly dispersed 
absorbent polymers. Suitable granulated adsorptive carriers are porous 
types, for example pumice, broken brick, sepiolite or bentonite; and 
suitable nonsorbent carriers are materials such as calcite or sand. In 
addition, a great number of pregranulated materials of inorganic or 
organic nature can be used, e.g. especially dolomite or pulverised plant 
residues. 
Depending on the nature of the compound of the formula I to be formulated, 
or of combinations thereof with other insecticides or acaricides, suitable 
surface-active compounds are nonionic, cationic and/or anionic surfactants 
having good emulsifying, dispersing and wetting properties. The term 
"surfactants" will also be understood as comprising mixtures of 
surfactants. 
Suitable anionic surfactants can be both water-soluble soaps and 
water-soluble synthetic surface-active compounds. 
Suitable soaps are the alkali metal salts, alkaline earth metal salts or 
unsubstituted or substituted ammonium salts of higher fatty acids 
(C.sub.10 -C.sub.22), e.g. the sodium or potassium salts of oleic or 
stearic acid, or of natural fatty acid mixtures which can be obtained, 
e.g. from coconut oil or tallow oil. Further suitable surfactants are also 
the fatty acid methyltaurin salts as well as modified and unmodified 
phospholipids. 
More frequently, however, so-called synthetic surfactants are used, 
especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole 
derivatives or alkylarylsulfonates. 
The fatty sulfonates or sulfates are usually in the form of alkali metal 
salts, alkaline earth metal salts or unsubstituted or substituted ammonium 
salts and contains a C.sub.8 -C.sub.22 alkyl radical which also includes 
the alkyl moiety of acyl radicals, e.g. the sodium or calcium salt of 
lignosulfonic acid, of dodecylsulfate, or of a mixture of fatty alcohol 
sulfates obtained from natural fatty acids. These compounds also comprise 
the salts of sulfuric acid esters and sulfonic acids of fatty 
alcohol/ethylene oxide adducts. The sulfonated benzimidazole derivatives 
preferably contain 2 sulfonic acid groups and one fatty acid radical 
containing 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the 
sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, 
dibutylnaphthalenesulfonic acid, or of a naphthalenesulfonic 
acid/formaldehyde condensation product. Also suitable are corresponding 
phosphates, e.g. salts of the phosphoric acid ester of an adduct or 
p-nonylphenol with 4 to 14 moles of ethylene oxide. 
The surfactants customarily employed in the art of formulation are 
described e.g. in "McCutcheon's Detergents and Emulsifiers Annual", MC 
Publishing Corp. Ridgewood, N.J., 1982. 
The pesticidal compositions usually contain 0.01 to 95%, preferably 0.1 to 
80%, of a compound of the formula I, 5 to 99.99% of a solid or liquid 
adjuvant, and 0 to 25%, preferably 0.1 to 25%, of a surfactant. 
Whereas commercial products are preferably formulated as concentrates, the 
end user will normally employ dilute formulations having a concentration 
of 1-10,000 ppm. 
The composition may also contain further ingredients, such as stabilisers, 
antifoams, viscosity regulators, binders, tackifiers as well as 
fertilisers or other active ingredients in order to obtain special 
effects. 
The compounds of formula I are also versatile reactive compounds for 
obtaining further milbemycin derivatives.

EXAMPLE 1 
Preparation of .DELTA..sup.14,29 -15-hydroxymilbemycin D (formula Ia) and 
14-hydroxy-.DELTA..sup.15,16 -milbemycin D (formula Ib) from milbemycin D 
In a glass irradiation apparatus, a solution of 5.56 g of milbemycin D and 
0.03 g of methylene blue in 400 ml of acetonitrile is irradiated, under a 
stream of oxygen, with visible light for 10 hours at a temperature of 
20.degree. C. (200 watt projector lamp). The reaction mixture is then 
reduced with 3.9 g of triphenylphosphine at 20.degree. C. The reaction 
mixture is concentrated and the residue is chromatographed through a 
column of silica gel eluted with a 3:1 mixture of methylene chloride/ethyl 
acetate, affording 4.10 g of .DELTA..sup.14,29 -5-hydroxy-milbemycin D 
with a melting point of 228.degree.-229.degree. C.; mass spectrum m/e: 572 
(M.sup.+), 554. Also obtained is 0.34 g of 14-hydroxy-.DELTA..sup.15,16 
-milbemycin D with a melting point of 252.degree.-254.degree. C.; mass 
spectrum m/e: 572 (M.sup.+), 554. 
EXAMPLE 2 
Preparation of 5-keto-.DELTA..sup.14,29 -15-hydroxy-milbemycin D (formula 
Ia) and 5-keto-14-hydroxy-.DELTA..sup.15,16 -milbemycin D (formula Ib) 
from 5-keto-milbemycin D. 
(a) Preparation of 5-keto-milbemycin D. A mixture of 1 g of milbemycin D, 2 
g of activated manganese dioxide and 50 ml of anhydrous methylene chloride 
is stirred for 4 hous at 20.degree.-25.degree. C. The reaction mixture is 
filtered and the filtrate is purified over a short column (about 30 cm) of 
silicagel, affording 1 g of yellowish amorphous 5-keto-milbemycin with a 
melting point of 140.degree.-150.degree. C. 
(b) The singulett oxidation of the 5-keto-milbemycin prepared in (a) and 
the further working up are effected by the method described in Example 1. 
After chromatography over silicagel there is obtained 0.6 g of 
5-keto-.DELTA..sup.14,29 -15-hydroxy-milbemycin D with a melting point of 
160.degree.-165.degree. C.; mass spectrum m/e: 570 (M.sup.+), 552. 
Also obtained are 30 mg of 5-keto-14-hydroxy-.DELTA..sup.15,16 -milbemycin 
D with a melting point of 170.degree.-174.degree.-C. 
EXAMPLE 3 
Preparation of 5-keto-.DELTA..sup.14,29 -15-hydroxy-milbemycin D (formula 
Ia) and 5-keto-14-hydroxy-.DELTA..sup.15,16 -milbemycin D (formula Ib) for 
milbemycin D 
The oxidation with manganese dioxide as follow-up reaction of 
.DELTA..sup.14,29 -15-hydroxymilbemycin D and 14-hydroxy-.DELTA..sup.15,16 
-milbemycin D obtained by the singulett oxygen oxidation of Example 1 
affords, in quantitative yield, 5-keto-.DELTA..sup.14,29 
-15-hydroxy-milbemycin D and 5-keto-14-hydroxy-.DELTA..sup.15,16 
-milbemycin D respectively 
EXAMPLE 4 
Preparation of 5-acetyl-.DELTA..sup.14,29 -15-hydroxy-milbemycin D and 
5-acetyl-14-hydroxy-.DELTA..sup.15,16 -milbemycin D from milbemycin D 
(a) Preparation of 5-acetyl-milbemycin D. 
To 560 g (1.0 Mm) of milbemycin D in 20 ml of pyridine are added 160 mg 
(1.6 mM) of acetic anhydride and the mixture is stirred at room 
temperature overnight. The pyridine is evaporated off and the residue is 
taken up in 20 ml of ethyl acetate. The organic phase is shaken once with 
10 ml of a 1N solution of hydrochloric acid and then with 10 ml of a 
saturated solution of NaHCO.sub.3 and finally with 10 ml of a concentrated 
solution of NaCL. The organic phase is separated and dried over Na.sub.2 
SO.sub.4, filtered and concentrated by evaporation, affording 580 mg of 
5-acetyl-milbemycin D as an amorphous, slightly yellow powder with a 
melting point of 115.degree.-120.degree. C. 
The acyl derivatives, milbemycin A.sub.3, milbemycin A.sub.4 and the 
13-desoxy-avermectin derivative (R.sub.2 =sec-butyl) can also be prepared 
in analogous manner. 
(b) 560 mg of 5-acetyl-milbemycin D and 20 g of methylene blue in 40 ml of 
acetonitrile are treated with oxygen for 8 hours at 18.degree.-22C. in an 
irradiation apparatus (200 watt projector lamp). The reaction mixture is 
then reduced with 40 mg of triphenylphosphine at room temperature. The 
reaction mixture is concentrated and the residue is chromatographed 
through a column of silica gel eluted with a 3:1 mixture of methylene 
chloride/ethyl acetate, affording 390 mg of 5-acetyl-.DELTA..sup.14,29 
-15-hydroxy-milbemycin D with a melting point of 153.degree.-156.degree. 
C.; mass spectrum m/e: 614 (M.sup.+), 596. Also obtained are 45 mg of 
5-acetyl-14-hydroxy-.DELTA..sup.15,16 -milbemycin D with a melting point 
of 151.degree.-154.degree. C. 
EXAMPLE 5 
Preparation of .DELTA..sup.14,29 -15-hydroxy-milbemycin A.sub.4 and 
14-hydroxy-.DELTA..sup.15,16 -milbemycin A.sub.4 from milbemycin A.sub.4 
540 mg (1 mM) of milbemycin A.sub.4 in 100 ml of acetonitrile are oxidised 
with singulett oxygen in accordance with Example 1 and subsequently 
reduced with triphenylphosphine. Purification by flash chromatography 
through silica gel eluted with a 1:1 mixture of cyclohexane/ethyl acetate 
yields 310 mg of .DELTA..sup.14,29 -15-hydroxymilbemycin A.sub.4 with a 
melting point of 222.degree.-225.degree. C.; mass spectrum m/e: 558 
(M.sup.+), 540. Also obtained are 40 mg of 14-hydroxy-.sup.15,16 
-milbemycin A.sub.4 with a melting point of 147.degree.-152.degree. C.; 
mass spectrum m/e: 558 (M.sup.+), 540. 
EXAMPLE 6 
Preparation of 5-dimethyl-tert-butylsilyl-.DELTA..sup.14,29 
-15-hydroxy-milbemycin A.sub.3 and 
5-dimethyl-tert-butylsilyl-14-hydroxy-.DELTA..sup.14,15 -milbemycin 
A.sub.3 from milbemycin A.sub.3 
(a) Preparation of 5-dimethyl-tert-butylsilyl-milbemycin A.sub.3. 
A reaction vessel is charged at room temperature with 480 mg (7 mM) of 
imidazole and 460 mg (3 mM) of dimethyl tert-butylchlorosilane in 20 ml of 
methylene chloride. With stirring, a solution of 655 mg (1.2 mM) of 
milbemycin A.sub.3 in 10 ml of methylene chloride is slowly added dropwise 
and the reaction mixture is heated overnight under reflux (40.degree. C.). 
The reaction mixture is concentratd and the residue is purified over 
silica gel and dried, affording 730 mg of amorphous 
5-dimethyl-tert-butylsilyl-milbemycin A.sub.3 with a melting point of 
55.degree.-60.degree. C. 
Milbemycin A.sub.4, milbemycin D and the 13-desoxy-avemectin derivative 
(R.sub.2 =sec-butyl) can be silylated in the same manner. Methyldiphenyl 
chlorosilane or bis(isopropyl)methyl chlorosilane can also be used with 
advantage in this reaction. 
(b) In accordance with the procedure described in Example 4b), 550 mg of 
5-dimethyl-tert-butylsilyl-.DELTA..sup.14,29 -15-hydroxy-milbemycin 
A.sub.3 (m.p. 238.degree.-240.degree. C.; mass spectrum m/e: 658 
(M.sup.+), 640) can be obtained from 720 mg of 
5-dimethyl-tert-butylsilyl-mibemycin A.sub.3 by singulett oxygen oxidation 
with Bengal pink as sensitiser, and subsequent reaction of the peroxides 
with triphenylphosphine. 
Also obtained are 42 mg of amorphous 
5-dimethyl-tert-butylsilyl-14-hydroxy-.DELTA..sup.15,16 -milbemycin 
A.sub.3 with a melting point of 45.degree.-50.degree. C. 
EXAMPLE 7 
Preparation of .DELTA..sup.14,29 -15-hydroxy-milbemycin A.sub.3 and 
14-hydroxy-.DELTA..sup.15,16 -milbemycin A.sub.3 
120 mg of 5-dimethyl-tert-butylsilyl-.DELTA..sup.14,29 
-15-hydroxy-milbemycin A.sub.3 and 2 ml of a 1% solution of 
p-toluenesulfonic acid in methanol are stirred for 9 hours at room 
temperature and then treated with a 5% aqueous solution of NaHCO.sub.3. 
After extraction with three 2 ml portions of diethyl ether, the organic 
phase is concentrated by evaporation and the crude product is 
chromatographed over 20 g of silica gel eluted with a 1:12 mixture of 
acetone/methylene chloride, affording 67 mg of .DELTA..sup.14,29 
-15-hydroxy-milbemycin A.sub.3 with a melting point of 
219.degree.-222.degree. C. 
In corresponding manner, 38 mg of 14-hydroxy.DELTA..sup.15,16 -milbemycin 
A.sub.3 (m.p. 128-.degree.132.degree.-C.) are obtained from 60 mg of 
5-dimethyl-tert-butylsilyl-14-hydroxy-.DELTA..sup.15,16 -milbemycin 
A.sub.3. 
Compounds of formula I can be prepared in accordance with the foregoing 
Examples. In the following Table: Ia=.DELTA..sup.14,29 -15-ol derivative, 
Ib=14-hydroxy-.DELTA..sup.15,16 derivative. 
If no particulars are given in the R.sub.1 column, the compound in question 
is a 5-keto-milbemycin (X=CO). .sup.1 HNMR data were determined in 
CDCL.sub.3 at 250 MHz, using Si(CH.sub.3).sub.4 as reference. 
______________________________________ 
Com- 
pound A R.sub.1 R.sub.2 
Physical data 
______________________________________ 
1.1 Ia --OH isoC.sub.3 H.sub.7 
m.p. 228-229.degree. C. 
1.2 Ib --OH " m.p. 252-254.degree. C. 
1.3 Ia --OSi(CH.sub.3).sub.2 t-C.sub.4 H.sub.9 
" m.p. 235-238.degree. C. 
1.4 Ib " " m.p. 145-150.degree. C. 
1.5 Ia --OSiCH.sub.3 (C.sub.6 H.sub.5).sub.2 
" 
1.6 Ib " " 
1.7 Ia --O--COCH.sub.3 
" m.p. 153-156.degree. C. 
1.8 Ib --O--COCH.sub.3 
" m.p. 151-154.degree. C. 
1.9 Ia --O--COC.sub.2 H.sub.5 
" m.p. 157-160.degree. C. 
1.10 Ib --O--COC.sub.2 H.sub.5 
" m.p. 155-159.degree. C. 
1.11 Ia -- " m.p. 160-165.degree. C. 
1.12 Ib -- " m.p. 170-174.degree. C. 
1.13 Ia --OSi(CH.sub.3).sub.3 
" 
1.14 Ib --OSi(CH.sub.3).sub.3 
" 
2.1 Ia --OH C.sub.2 H.sub.5 
m.p. 222-225.degree. C. 
2.2 Ib --OH " m.p. 147-152.degree. C. 
2.3 Ia --OSi(CH.sub.3).sub.2 t-C.sub.4 H.sub.9 
" amorphous 
2.4 Ib " " m.p. 58-62.degree. C. 
2.5 Ia --O--SO.sub.2 CH.sub.3 
" 
2.6 Ib --O--SO.sub.2 CH.sub.3 
" 
2.7 Ia --O--COCH.sub.3 
" m.p. 158-161.degree. C. 
2.8 Ib --O--COCH.sub.3 
" m.p. 156-160.degree. C. 
2.9 Ia --O--COC(CH.sub.3).sub.3 
" 
2.10 Ib --O--COC(CH.sub.3).sub.3 
" 
2.11 Ia -- " NMR:4.91(s); 
5,24(s) (C.sub.13 = CH.sub.2) 
2.12 Ib -- " amorphous 
3.1 Ia --OH CH.sub.3 
m.p. 220-223.degree. C. 
3.2 Ib --OH CH.sub.3 
amorphous 
3.3 Ia --OSi(CH.sub.3).sub.2 t-C.sub.4 H.sub.9 
CH.sub.3 
m.p. 238-240.degree. C. 
3.4 Ib " CH.sub.3 
m.p. 45-50.degree. C. 
3.5 Ia --O--COCH.sub.3 
CH.sub.3 
3.6 Ib --O--COCH.sub.3 
CH.sub.3 
3.7 Ia --O--COC.sub.6 H.sub.5 
CH.sub.3 
3.8 Ib --O--COC.sub.6 H.sub.5 
CH.sub.3 
3.9 Ia --O--SO.sub.2 C.sub.6 H.sub.5 
CH.sub.3 
amorphous 
3.10 Ib --O--SO.sub.2 C.sub.6 H.sub.5 
CH.sub.3 
3.11 Ia -- CH.sub.3 
m.p. 145-148.degree. C. 
3.12 Ib -- CH.sub.3 
m.p. 152-156.degree. C. 
4.1 Ia --OH sec-C.sub.4 H.sub.9 
NMR:4.92(s); 
5.25(s)(C.sub.13 = CH.sub.2) 
4.2 Ib --OH sec-C.sub.4 H.sub.9 
4.3 Ia -- sec-C.sub.4 H.sub.9 
NMR:4.91(s); 
5.25(s)(C.sub.13 = CH.sub.2) 
4.4 Ib -- sec-C.sub.4 H.sub.9 
______________________________________ 
FORMULATION EXAMPLES FOR ACTIVE INGREDIENTS OF THE FORMULA I 
(throughout, percentages are by weight) 
______________________________________ 
Wettable powders (a) (b) (c) 
______________________________________ 
compound of formula I 
25% 50% 75% 
sodium lignosulfonate 
5% 5% -- 
sodium laurylsulfate 3% 5% -- 
sodium diisobutylnaphthalenesulfonate 
-- 6% 10% 
octylphenol polyethylene glycol ether 
-- 2% -- 
(7-8 moles of ethylene oxide) 
highly dispersed silicic acid 
5% 10% 10% 
kaolin 62% 27% -- 
______________________________________ 
The active ingredient is thoroughly mixed with the adjuvants and the 
mixture is thoroughly ground in a suitable mill, affording wettable 
powders which can be diluted with water to give suspensions of the desired 
concentration. 
______________________________________ 
Emulsifiable concentrate 
______________________________________ 
compound of formula I 10% 
octylphenol polyethylene glycol ether 
3% 
(4-5 moles of ethylene oxide) 
calcium dodecylbenzenesulfonate 
3% 
castor oil polygycol ether 
4% 
(36 moles of ethylene oxide) 
cyclohexanone 30% 
xylene mixture 50% 
______________________________________ 
Emulsions of any required concentration can be obtained from this 
concentrate by dilution with water. 
______________________________________ 
Dusts (a) (b) 
______________________________________ 
compound of formula I 
5% 8% 
talcum 95% -- 
kaolin -- 92% 
______________________________________ 
Ready for use dusts are obtained by mixing the active ingredient with the 
carriers, and grinding the mixture in a suitable mill. 
______________________________________ 
Extruder granulate 
______________________________________ 
compound of formula I 
10% 
sodium lignosulfonate 
2% 
carboxymethylcellulose 
1% 
kaolin 87% 
______________________________________ 
The active ingredient is mixed and ground with the adjuvants, and the 
mixture is subsequently moistened with water. The mixture is extruded and 
then dried in a stream of air. 
______________________________________ 
Coated granulate 
______________________________________ 
compound of formula I 
3% 
polyethylene glycol 200 
3% 
kaolin 94% 
______________________________________ 
The finely ground active ingredient is uniformly applied, in a mixer, to 
the kaolin moistened with polyethylene glycol. Non-dusty coated granulates 
are obtained in this manner. 
______________________________________ 
Suspension concentrate 
______________________________________ 
compound of formula I 40% 
ethylene glycol 10% 
nonylphenol polyethylene glycol ether 
6% 
(15 moles of ethylene oxide) 
sodium lignosulfonate 10% 
carboxymethylcellulose 1% 
37% aqueous formaldehyde solution 
0.2% 
silicone oil in the form of a 75% 
0.8% 
aqueous emulsion 
water 32% 
______________________________________ 
The finely ground active ingredient is intimately mixed with the adjuvants, 
giving a suspension concentrate from which suspensions of any desired 
concentration can be obtained by dilution with water. 
If the compounds of formula I, or compositions containing them, are used 
for controlling endoparasitic nematodes in domestic animals ands 
productive livestock, for example cattle, sheep, goats, horses, pigs, cats 
and dogs, they can be administered to the animals in both single and 
repeated doses. Depending on the species of animal, the individual doses 
are preferably administered in amounts ranging from 0.1 to 10 mg/kg of 
body weight. A better action is often achieved by protracted 
administration, or lower total doses will also suffice. The compounds, or 
compositions containing them, can also be added to feeds and drinks. The 
ready-prepared feeds contain the active ingredients preferably in a 
concentration of 0.005 to 0.1 percent by weight. The compositions can be 
administered to the animals perorally in the form of solutions, emulsions, 
suspensions, powders, tablets, boluses or capsules. 
If the physical and toxicological properties of solutions or emulsions 
permit it, the compounds of formula I, or compositions containing them, 
can also be injected into animals, for example subcutaneously or by 
intraruminal injection, or applied to the bodies of the animals by the 
pour-or method. Administration by means of salt licks or molasses blocks 
is also possible. 
BIOLOGICAL EXAMPLES 
B1: Insecticidal stomach poison action against Spodoptera littoralis 
Cotton plants are sprayed with a solution which contains 3, 12.5 or 50 ppm 
of the test compound. After the spray coating has dried, the plants are 
populated with larvae (L.sub.1 stage) of Spodoptera littoralis. Two plants 
are used for each test compound and test species. The test is carried out 
at about 24.degree.-C. and 60% relative humidity. Evaluations and 
intermediate evaluations are made about 24, 48 and 72 hours. At 
concentrations of 12.5 ppm, compounds 1.1, 1.2, 1.7, 1.11, 1.12, 1.13, 
2.1, 2.2, 2.5, 2.7, 2.11, 2.12, 3.1, 3.2, 3.11, 4.1 and 4.3 effect 
complete kill after 24 hours. 
B2: Action against plant destructive acarids: OP-sensitive Tetranychus 
urticae 
16 hours before the start of the test, the primary leaves of bean plants 
(Phaseolus vulgaris) are infected with an infested piece of leaf from a 
mass culture of Tetranychus urticae. Upon removal of the piece of leaf, 
the artificially infected plants are sprayed to drip point with a solution 
containing 0.4 ppm or 1.6 ppm of the test compound. The temperature in the 
greenhouse compartment is about 25.degree. C. A count of living and dead 
imagines and larvae is made under a stereoscopic microscope after 1 day 
and after 8 days. Compounds 1.1, 1.2, 1.3, 1.4, 1.7, 1.8, 1.9, 1.11, 1.12, 
2.1, 2.2, 2.3, 2.7, 2.11, 2.12, 3.1, 3.2, 3.3, 3.4, 3.11, 3.12, 4.1 and 
4.3 effect complete kill at a concentration of 1.6 ppm after 24 hours. 
B3: Action against L.sub.1 larvae of Lucilia sericata 
1 ml of an aqueous suspension of test compound is mixed with 3 ml of a 
special larval culture medium at about 50.degree. C. such that a 
homogeneous composition containing 250 ppm or 125 ppm is obtained. About 
30 Lucilia sericata larvae (L.sub.1) are put into each test tube 
containing active ingredient. A mortality count is made after 4 days. 
Compounds 1.1, 1.2, 1.11, 1.12, 2.1, 2.2, 2.3, 2.7, 2.11, 3.1, 3.2, 4.1 
and 4.3 effect 100% kill at a concentration of 250 ppm. 
B4: Acaricidal action against Boophilus microplus (Biarra strain) 
Adhesive tape is applied vertically across a PVC plate so that 10 fully 
replete female Boophilus microplus ticks (Biarra strain) can be affixed 
thereto with their backs, side by side, in a row. Each tick is injected 
from an injection needle with 1 .mu.l of a liquid which contains a 1:1 
mixture of polyethylene glycol and acetone, in which mixture a specific 
amount of test compound of 1, 0.1 or 0.01 .mu.g per tick is dissolved. 
Control ticks are injected with liquid containing no test compound. After 
this treatment, the ticks are detached from the support and kept in an 
insectarium at about 28.degree. C. and 80% relative humidity until 
oviposition has taken place and the larvae have hatched from the eggs of 
the control ticks. The activity of the test compound is determined with 
the IR.sub.90, i.e. the effective dose is determined at which 9 out of 10 
female ticks (90%) even after 30 days lay eggs from which larvae are 
unable to hatch. Compounds 1.1, 1.2, 1.3, 1.7, 1.9, 1.10, 1.11, 1.12, 2.1, 
2.2, 2.3, 2.7, 2.11, 2.12, 3.1, 3.2, 3.3, 3.4, 3.9, 4.1, 4.2 and 4.3 
effected an IR.sub.90 of 0.1 .mu.g. 
B5: Trial with sheep infected with nematodes (Haemonchus concortus and 
Trichostrongylus colubriformis) 
The test compound is administered in the form of a suspension with a 
stomach probe or by intraruminal injection to sheep which have been 
artifically infected with Haemonchus concortus and Trichostrongylus. One 
to three animals are used for each dose. Each sheep is treated only once 
with a single dose, namely with 1 mg or 2 mg/kg of body weight. Evaluation 
is made by comparing the number of worm eggs excreted in the faeces of the 
sheep before and after treatment. Untreated sheep infected simultaneously 
and in the same manner are used as controls. In comparison with untreated 
and infected control groups, nematode infestation is reduced by 90 to 100% 
in sheep which have been treated with one of compounds 1.1-1.4, 1.7-1.12, 
2.1-2.4, 2.7, 2.8, 2.11, 2.12, 3.1-3.4, 3.11, 3.12, 4.1 and 4.3 at 2 mg/kg 
.