There are disclosed avermectin derivatives with a hydroxy and hydrocarbon substituents at the 5, 10, 13, 23, 4' and 4" positions which are prepared by the reaction of the 5, 10, 13, 23, 4' or 4" ketone compound with an organo-metallic Grignard reagent. The compounds are potent antiparasitic and anthelmintic agents in human and animal therapy and are potent pesticidical agents against agricultural pests. Compositions containing such compounds as the active agent are also disclosed.

BACKGROUND OF THE INVENTION 
The term avermectin (previously referred to as C-076) is used to describe a 
series of compounds isolated from the fermentation broth of an avermectin 
producing strain of Streptomyces avermitilis and derivatives thereof. The 
morphological characteristics of the culture are completely described in 
U.S. Pat. No. 4,310,519. The avermectin compounds are a series of 
macrolides, each of which is substituted thereon at the 13-position with a 
4-(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose group. The avermectin 
compounds and the instant derivatives thereof have a very high degree of 
anthelmintic and anti-parasitic activity. 
The avermectin series of compounds isolated from the fermentation broth 
have the following structure: 
##STR1## 
wherein R is the 4'-(.alpha.-1-oleandrosyl)-60 -1-oleandrose group of the 
structure: 
##STR2## 
and wherein the broken line at the 22,23-position indicates a single or a 
double bond; R.sub.1 is hydrogen or hydroxy and is present only when said 
broken line indicates a single bond; 
R.sub.2 is iso-propyl or sec butyl; and 
R.sub.3 is methoxy or hydroxy. 
There are eight different avermectin natural product compounds and they are 
given the designations A1a, A1b, A2a, A2b, B1a, B1b, B2a and B2b based 
upon the structure of the individual compounds. 
In the foregoing structural formula, the individual avermectin compounds 
are as set forth below. (The R group is 
4'(.alpha.-L-oleandrosyl)-.alpha.-L-oleandrose): 
______________________________________ 
R.sub.1 R.sub.2 R.sub.3 
______________________________________ 
A1a (22,23-Double Bond) 
sec-butyl --OCH.sub.3 
A1b (22,23-Double Bond) 
iso-propyl 
--OCH.sub.3 
A2a --OH sec-butyl --OCH.sub.3 
A2B --OH iso-propy --OCH.sub.3 
B1a (22,23-Double Bond) 
sec-butyl --OH 
B1b (22,23-Double Bond) 
iso-propyl 
--OH 
B2 --OH sec-butyl --OH 
B2b --OH iso-propyl 
--OH 
______________________________________ 
The avermectin compounds are generally isolated as mixtures of a and b 
components. Such compounds differ only in the nature of the R.sub.2 
substituent and the minor structural differences have been found to have 
very little effect on the isolation procedures, chemical reactivity and 
biological activity of such compounds. 
SUMMARY OF THE INVENTION 
The instant invention is concerned with certan derivatives of avermect in 
compounds wherein certain hydroxy groups at the 5, 10, 13, 23, 4' and 4" 
positions are selectively oxidized to a ketone function and the ketone is 
treated with a Grignard reagent to result in novel compounds which are 
disubstituted at such positions with a hydroxy group and an alkyl, 
cycloalkyl, substituted alkyl or unsaturated alkyl group. Thus, it is an 
object of this invention to describe such compounds. It is a further 
object of this invention to describe the processes used to prepare such 
compounds. A still further object is to describe the uses of such 
compounds as animal antiparasitic or agricultural pesticidal agents. A 
still further object is to describe compositions containing such compounds 
as the active ingredient. Further objects will be apparent from the 
following description. 
DESCRIPTION OF THE INVENTION 
The compounds of this invention are best described in the following 
structural formula: 
##STR3## 
wherein A and B are independently single or double bonds; 
wherein R.sub.1 is hydroxy, and R.sub.2 is loweralkyl, cycloloweralkyl, 
loweralkenyl or substituted loweralkyl; 
or when R.sub.1 is hydrogen, R.sub.2 is hydroxy or methoxy; 
when A is a double bond R.sub.4 is not present and R.sub.3 is hydrogen or 
loweralkyl; 
when A is a single bond R.sub.3 is hydroxy and R.sub.4 is loweralkyl, 
cycloloweralkyl, loweralkenyl or substituted loweralkyl; 
when R.sub.5 is hydroxy, R.sub.6 is loweralkyl, cycloloweralkyl, 
loweralkenyl or substituted loweralkyl; 
or when R.sub.5 is hydrogen R.sub.6 is hydrogen, halogen, hydroxy, 
##STR4## 
when R.sub.7 is hydroxy and R.sub.8 is loweralkyl, cycloloweralkyl, 
loweralkenyl, cycloloweralkyl, or substituted loweralkyl; 
or when R.sub.7 is hydrogen, R.sub.8 is hydroxy, amino, loweralkylamino, 
diloweralkylamino, loweralkanoylamino, or loweralkanoyl(loweralkyl) amino; 
when B is a single bond, R.sub.9 is hydroxy and R.sub.10 is loweralkyl, 
cycloloweralkyl, loweralkenyl, or substituted loweralkyl; 
or R.sub.9 is hydrogen and R.sub.10 is hydrogen or hydroxy; 
when B is a double bond R.sub.10 is not present and R.sub.9 is hydrogen; 
and 
R.sub.11 is methyl, ethyl, isopropyl, sec. butyl, or 
C(CH.sub.3).dbd.CHCH.sub.3, --C(CH.sub.3).dbd.CHCH.sub.2 CH.sub.3 or 
--C(CH.sub.3).dbd.CHCH(CH.sub.3).sub.2 ; 
provided that when R.sub.1, R.sub.5, R.sub.7 and R.sub.9 are all hydrogen 
and A is a double bond, R.sub.4 is not present and R.sub.3 is loweralkyl 
or provided that at the disubstituted positions 5, 10, 13, 23, 4' and 4" 
the combination is present whereby at least one of R.sub.1, R.sub.3, 
R.sub.5, R.sub.7, and R.sub.9 is hydroxy and the corresponding R.sub.2, 
R.sub.4, R.sub.6, R.sub.8, and R.sub.10 is loweralkyl, cycloloweralkyl, 
loweralkenyl or substituted loweralkyl. 
In the instant invention, the term "loweralkyl": is intended to include 
those alkyl groups of from 1 to 6 carbon atoms of either a straight or 
branched chain. Exemplary of such alkyl groups are methyl, ethyl, propyl, 
isopropyl, butyl, sec. butyl, pentyl, hexyl and the like. 
The term "cycloloweralkyl" is intended to include those cyclic alkyl groups 
of from 3 to 6 carbon atoms exemplified by cyclopropyl, cycloalkyl, 
cyclopentyl, and cyclohexyl. 
The term "loweralkenyl" is intended to include those alkenyl groups of from 
2 to 6 carbon atoms with one or two unsaturations and is either a straight 
or branched configuration. Exemplary of such alkenyl groups are ethenyl, 
propenyl, butenyl, butadienyl, pentenyl, isopentenyl, hexenyl and the 
like. 
The term "substituted loweralkyl" is intended to include one or more 
substituents, preferably from 1 to 3 substituents on a loweralkyl group 
which may be selected from hydroxy, loweralkoxy or halogen. 
One aspect of the preferred embodiment of the instant invention is realized 
in the above formula when: 
A is a double bond; 
B is a single or a double bond; 
R.sub.1 is a hydrogen; 
R.sub.2 is hydroxy or methoxy; 
R.sub.3 is hydrogen and R.sub.4 is not present; 
R.sub.5 is hydrogen; 
R.sub.6 is hydrogen, hydroxy, 
##STR5## 
R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are as defined in claim 1; and 
R.sub.11 is methyl, ethyl, isopropyl or sec butyl. 
Further preferred embodiments of the instant invention are realized when: 
A is a double bond; 
B is a single or a double bond; 
R.sub.1 and R.sub.2 are as defined above; 
R.sub.3 is hydrogen and R.sub.4 is absent; 
R.sub.5 is hydrogen 
R.sub.6 is 
##STR6## 
R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are as defined in claim 1; and 
R.sub.11 is isopropyl or sec. butyl. 
Examples of preferred compounds of the invention are: 
23-methyl avermectin B2a/B2b 
23-methyl avermectin B2a/B2b monosaccharide 
23-ethyl avermectin B2a/B2b 
23-vinyl avermectin B2a/B2b 
4"-methyl avermectin B1a/B1b 
22,23 -dihydro-4'-methyl avermectin B1a/B1b monosaccharide 
22,23-dihydro-5 methyl avermectin B1a/B1b 
22,23-dihydro-13-methyl avermectin B1a/B1b aglycone 
22,23-dihydro-13 vinyl avermectin B1a/B1b aglycone 
22,23-dihydro-13-allyl avermectin B1a/B1b aglycone 
23-methyl-4"-deoxy-4"-epi-methylamino avermectin B2a/B2b 
4"-epi(N-acetyl-N-methylamino)4"-deoxy-23-methyl avermectin B2a/B2b. 
22,23-dihydro-4"-methyl avermectin B1a/B1b 
4"-butyl-avermectin B1a/B1b 
4"-ethenyl-avermectin B1a/B1b 
22,23-dihydro-4"-ethenyl avermectin B1a/B1b 
4"-methyl avermectin B2a/B2b 
13-deoxy-23-ethenyl-avermectin B2a/B2b aglycone 
13-deoxy-23-methyl-avermectin B2a/B2b aglycone 
The compounds of the instant invention are prepared from an organo metallic 
Grignard reagent, usually a magnesium compound of the formula RMgX where R 
is the loweralkyl, cycloloweralkkyl, loweralkenyl or substituted 
loweralkyl of the above structural formula and X is a halogen, preferably 
bromine or chlorine. The Grignard reagent is reacted with the avermectin 
compound with a ketone group at the 5, 10, 13, 23, 4' or 4" positions. 
The disubstituted carbon atoms at the 5, 10, 13, 23, 4' or 4"-positions are 
assymetric and in most cases a mixture of two epimers is formed. These 
diastereoisomers can be separated by chromatoqraphic procedures or they 
can be used as a mixture of a pair of diasteromers. 
The Grignard reaction follows the generalized reaction scheme of: 
##STR7## 
See Grignard, Compt. Record 130, 1322 (1900) and Wakefield Organometal. 
Chem. Rev. 1, 131 (1966). 
Thus, in the above structural formula I where the starting material is, for 
example, a 5-keto avermectin the reaction would proceed as outlined in the 
following partial structural formula: 
##STR8## 
The following structural formula 11 is a compilation of all the Grignard 
reactions which may be carried out at the 5, 10, 13, 23, 4' and 4" 
positions, although it will be appreciated that generally all of the 
reactions at the possible positions are not carried out at the same time, 
although reactions at multiple sites are certainly possible and included 
within the ambit of this invention. 
##STR9## 
where the braces indicate that the disaccharide or saccharide is attached 
to the rest of the avermectin molecule at the 13-position. 
The reaction is carried out under standard Grignard reaction conditions. 
The reaction is enerally carried out in an organic solvent such as an 
ether, preferably diethyl ether or tetrahydrofuran. The reaction solvents, 
reagents and glassware should be scrupulously dried since the Grignard 
reagent very readily reacts with water. For the same reasons, the reaction 
is carried out under a blanket of a dry, inert gas such as nitrogen. The 
reaction is carried out at from 0.degree. C. to the reflux temperature of 
the reaction mixture although the reaction is preferably carried out at 
about room temperature. The reaction is complete in from about 10 minutes 
to 18 hours, preferably between about 1/2 and 3 hours, whereupon the 
intermediate magnesium complex is treated with water or an aqueous salt 
solution, such as aqueous ammonium chloride, to prepare the final product 
which is isolated using techniques known to those skilled in the art. 
Those compounds wherein A is a double bond, R.sub.4 is not present and 
R.sub.3 is loweralkyl are prepared from the 10-hydroxy 10-loweralkyl 
compounds (and A is a single bond) by preparing a sulfonate ester of the 
10-hydroxy group under basic conditions whereby the sulfonate ester will 
be eliminated along with the adjacent hydrogen to recreate the 
10,11-double bond while leaving the 10-loweralkyl group intact. Preferred 
reagents for the preparation of the sulfonate ester are methane sulfonyl 
chloride, p-toluene sulfonyl chloride, trifluoromethyl sulfonyl chloride, 
trifluoromethyl sulfonyl anhydride and the like. The reaction is generally 
very rapid with the formation and elimination of the sulfonate ester 
occuring very quickly after its formation. Generally the reaction is 
carried out in an inert solvent such as tetrahydrofuran and the reaction 
is complete in from 1/2 to 5 hours when carried out at about room 
temperature. The preferred bases which promote the elimination of the 
sulfonate ester are tertiary organic amines such as triethylamine or 
pyridine. 
PREATION OF STARTING MATERIALS 
The ultimate starting materials for the compounds of this invention are the 
avermectin fermentation products defined above. Thus it is apparent that 
additional reactions are required to prepare the instant compounds. 
Specifically, reactions are carried out at the 5, 13, 22, and 23-positions 
and at the 10, 11 double bond. It is generally preferred to prepare 
whatever substituents are required at these positions before the oxidation 
of the hydroxy groups to the ketone groups and subsequent Grignard 
reaction on the thus produced ketone. Such a procedure generally avoids 
undesirable ide reactions. This technique is not required, however, and if 
desired other sequences may be used. In addition, during the oxidation and 
Grignard reaction described above, it is often necessary to protect the 
hydroxy groups at the 5-and 23-positions to avoid oxidation or 
substitution at such positions. With these positions protected the 
reactions may be carried out at the 4"- and 4' positions without affecting 
the remainder of the molecule. Subsequent to any of the above described 
reactions the protecting group may be removed and the unprotected product 
isolated. The protecting group employed is ideally one which may be 
readily synthesized, will not be affected by the reactions at the 4"- and 
4'positions and may be readily removed without affecting any other 
functions of the molecule. One preferred type of protecting group for the 
avermectin type of molecule is the tri-substituted silyl group, preferably 
the trialkyl silyl group. One especially preferred example, is the t-butyl 
dimethylsilyl group. The reaction preparing the protected compound is 
carried out by reacting the hydroxy compound with the appropriately 
substituted silylhalide, preferably the silylchloride in an aprotic polar 
solvent such as dimethylformamide. Imidazole is added as a catalyst. The 
reaction is complete in from 1 to 24 hours and at from 0.degree. to 
25.degree. C. For the 5-position hydroxy group the reaction is complete in 
from 1/2 to 3 hours at from 0.degree. C. to room temperature. This 
reaction is selective to the 5 position under the conditions above 
described and very little, if any, silylation is observed at other hydroxy 
substituted positions. If it is desired to protect the 23-hydroxy group a 
4", 5,23-tri(phenoxyacetyl) derivative can be prepared. Basic hydrolysis 
will leave the highly hindered 23-O-substituent but hydrolize the 5- and 
4"-O-phenoxy acetyl groups. The 5-position is then protected as described 
above, selectively with a t-butyldimethylsilyl group. 
The silyl group is most conveniently removed just prior to the Grignard 
reaction but may be removed as the final step after the other contemplated 
reactions are carried out. The silyl group or groups are removed by 
stirring the silyl compound in methanol catalized by an acid preferably a 
sulfonic acid hydrate such as methanolic 1.0% p-toluene sulfonic acid 
monohydrate. The reaction is complete in about 1 to 12 hours at from 
0.degree. to 50.degree. C. Alternatively the silyl group or groups may be 
removed by treatment of the silyl compound with anhydrous 
pyridine-hydrogen fluoride in tetrahydrofuran. The reaction is complete in 
from 3 to 24 hours at from 0.degree. to 25.degree. C. 
Another of the starting materials used in the foregoing reaction scheme are 
those in which the 22,23 double bond of the "1" type compounds has been 
reduced to a single bond. As is readily apparent from an analysis of the 
structure of avermectin starting materials there are 5 unsaturations in 
the 1-series of compounds. Thus in the 1-series of compounds it is 
necessary to reduce the 22,23 double bond while not affecting the 
remaining four unsaturations or any other functional group present on the 
molecule in order to selectively prepare the 22,23 dihydro avermectins. It 
is necessary to select a specific catalyst for the hydrogenation, one that 
will selectively hydrogenate the least hindered from among a series of 
unsaturations. The preferred catalyst for such a selective hydrogenation 
procedure is one having the formula: 
EQU [(R.sub.12).sub.3 P).sub.3 RhY)] 
wherein 
R.sub.12 is loweralkyl, phenyl or loweralkyl substituted phenyl and Y is 
halogen. The reduction procedure is completely described in U.S. Pat. No. 
4,199,569. 
The other starting materials which are used in the above reaction scheme 
involve the preparation of the mono-saccharide compound. That is those 
compounds wherein one of the .alpha.-1-oleandrosyl groups have been 
removed. The removal of the terminal .alpha.-1-oleandrose leaves a hydroxy 
group at the 4'-position which is equally amenable to the reactions 
described in the foregoing reaction scheme. The processes which may be 
used to prepare the monosaccharide derivatives of the avermectin compounds 
are described in U.S. Pat. No. 4,206,205. The reaction consists generally 
of treating the starting material disaccharide with acid in an aqueous 
organic solvent mixture. Water concentrations of from 0.1 to 20% by volume 
and acid concentrations of from about 0.01 to 0.1% will predominantly 
produce the monosaccharide product. 
A further procedure for the preparation of the monosaccharide utilizes a 1% 
mineral acid solution in isopropanol at for 20.degree.-40.degree. C. 
preferably at room temperature for from 6 to 24 hours. Mineral acids such 
as sulfuric, hydrohalic, phosphoric and the like may be employed. 
Some of the compounds of the instant invention differ from other avermectin 
compounds in that the 10,11 double bond is reduced. The effect of reducing 
the 10,11 double bond is that the conjugated diene system is broken. The 
elimination of the conjugated double bonds has a considerable effect on 
the ultraviolet absorption characteristics of the molecule and has 
resulted in a surprising and very significant increase in the stability of 
the molecule when it is exposed to ultraviolet light, as well as ordinary 
sunlight which has a significant component of ultraviolet light. This 
increased stability in the presence of ultraviolet light makes these 
compounds particularly suited to agricultural applications and also to 
topical animal applications where photoinstability would be detrimental to 
the optimum performance of each compound. 
The 10,11 double bond of the avermectin starting materials is either 
reduced catalytically or is chemically modified. The catalytic reduction 
is carried out using platinum group metals as catalysts such as platinum, 
palladium, rhodium, and the like. Generally, the metal catalyst is 
dispersed on nd supported on a substrate such as powdered carbon. The 
reaction is carried out under a blanket of hydrogen gas either at 
atmospheric pressure or pressurized up to 10 atmospheres (gauge) of 
hydrogen pressure in pressurable equipment ordinarily used for such 
reactions. The reaction is carried out in a solvent which is stable to the 
hydrogenation conditions and which will not adversely affect the catalyst. 
Lower alkanols, such as methanol, ethanol, isopropanol and the like, ethyl 
acetate, cyclohexane, and the like are suitable. The reaction is generally 
carried out at room temperature although temperature as high as 50.degree. 
C. are suitable and under such conditions the reaction is complete in from 
1 to 24 hours. If the hydrogenation apparatus is so equipped, the progress 
of the reaction may be followed by observing the amount, either in volume 
or in pressure drop, of hydrogen that is consumed. The products are 
isolated using techniques known to those skilled in the art. 
The catalytic hydrogenation process generally yields a mixture of products 
since the avermectin starting materials have three or four double bonds 
which may be hydrogenated. This would include the 3,4 and 22,23 double 
bonds. The 14,15 double bond is sterically hindered and generally requires 
more vigorous reaction conditions than are described above in order to 
effect hydrogenation. The various hydrogenation products are isolated from 
the mixture of reaction products using standard techniques such as 
fractional crystallization and chromatography. The double bonds which are 
desired to be retained in the final product may be protected to render 
them inert during the hydrogenation procedure. When the hydrogenation is 
complete, the double bond may be regenerated by removing the protecting 
groups. 
The 10,11 double bond may also be reacted chemically and in the process 
various substituents at the 10 position (R.sub.3 and R.sub.4) are 
introduced according to the following reaction scheme where only the furan 
ring and carbon atoms 6 to 12 are shown in the partial structural 
formulas. 
##STR10## 
wherein R', and R" are as defined above and Hal is a halogen. 
Partial structure (1) is reacted with a reagent capable of preparing a 
halohydrin group (a 10-hydroxy, 11-halo function). Various reagents and 
reaction conditions are capable of preparing a halohydrin such as 
N-haloacetamide, N halosuccimide, addition of hydrochloric acid to an 
epoxide, and the like. Bromine is the preferred halogen. When reagents 
such as N haloacetamide and N halo succinimide are used, the reaction is 
carried out in an inert solvent, such as acetone, ether, tetrahydrofuran, 
and the like. The reaction is generally carried out at from -20.degree. to 
50.degree. C. and is complete in from 30 minutes to 24 hours and is 
generally carried out in the dark. 
The halohydrin compound (2) may be treated with a reducing agent, such as a 
trialkyltin hydride to displace the halogen with a hydrogen. Partial 
structures (2) and (3), with the 11 position substituent being a halogen 
or hydrogen constitutes the definition of R" as shown in partial structure 
(3). Further reactions are possible at the 10-position to convert the 
hydroxy group to other groups (partial structure (4)) using techniques 
known to those skilled in the art. 
The novel compounds of this invention have significant parasiticidal 
activity as anthelmintics, ectoparasiticides, insecticides and acaricides, 
in human and animal health and in agriculture. 
The disease or group of diseases described generally as helminthiasis is 
due to infection of an animal host with parasitic worms known as 
helminths. Helminthiasis is a prevalent and serious economic problem in 
domesticated animals such as swine, sheep, horses, cattle, goats, dogs, 
cats and poultry. Among the helminths, the group of worms described as 
nematodes causes widespread and often times serious infection in various 
species of animals. The most common genera of nematodes infecting the 
animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, 
Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia, 
Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, 
Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and 
Parascaris. Certain of these, such as Nematodirus, Cooperia and 
Oesphagostomum attack primarily the intestinal tract while others, such as 
Haemonchus and Ostertagia, are more prevalent in the stomach while still 
others such as Dictyocaulus are found in the lungs. Still other parasites 
may be located in other tissues and organs of the body such as the heart 
and blood vessels, subcutaneous and lymphatic tissue and the like. The 
parasitic infections known as helminthiases lead to anemia, malnutrition, 
weakness, weight loss, severe damage to the walls of the intestinal tract 
and other tissues and organs and, if left untreated, may result in death 
of the infected host. The substituted avermectin compounds of this 
invention have unexpectedly high activity against these parasites, and in 
addition are also active against Dirofilaria in dogs, Namatospiroides, 
Syphacia, Aspiculuris in rodents, arthropod ectoparasites of animals and 
birds such as ticks, mites, lice, fleas, blowfly, in sheep Lucilia sp., 
biting insects and such migrating diperous larvae as Hypoderma sp. cattle, 
Gastrophilus in horses, and Cuterebra sp. in rodents. 
The instant compounds are also useful against parasites which infect 
humans. The most common genera of parasties of the gastro-intestinal tract 
of man are Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, 
Capillaria, Trichuris, and Enterobius. Other medically important genera of 
parasites which are found in the blood or other tissues and organs outside 
the gastrointestinal tract are the filiarial worms such as Wuchereria, 
Brugia, Onchocerca and Loa, Dracunculus and extra intestinal stages of the 
intestinal worms Strongyloides and Trichinella. The compounds are also of 
value against arthropods parasitizing man, biting insects and other 
dipterous pests causing annoyance to man. 
The compounds are also active against household pests such as the 
cockroach, Blatella sp., clothes moth, Tineola sp., carpet beetle, 
Attagenus sp., and the housefly Musca domestica. 
The compounds are also useful against insect pests of stored grains such as 
Tribolium sp., Tenebrio sp. and of agricultural plants such as spider 
mites, (Tetranychus sp.), aphids, (Acyrthiosiphon sp.); against migratory 
orthopterans such as locusts and immature stages of insects living on 
plant tissue. The compounds are useful as a nematocide for the control of 
soil nematodes and plant parasites such as Meloidoqyne spp. which may be 
of importance in agriculture The compounds are active against other plant 
pests such as the southern army worm and Mexican bean beetle larvae. 
These compounds may be administered orally in a unit dosage form such as a 
capsule, bolus or tablet, or as a liquid drench where used as an 
anthelmintic in mammals. The drench is normally a solution, suspension or 
dispersion of the active ingredient usually in water together with a 
suspending agent such as bentonite and a wetting agent or like excipient. 
Generally, the drenches also contain an antifoaming agent. Drench 
formulations generally contains from about 0.001 to 0.5% by weight of the 
active compound. Preferred drench formulations may contain from 0.01 to 
0.1% by weight. The capsules and boluses comprise the active ingredient 
admixed with a carrier vehicle such as starch, talc, magnesium stearate, 
or di-calcium phosphate. 
Where it is desired to administer the avermectin derivatives in a dry, 
solid unit dosage form, capsules, boluses or tablets containing the 
desired amount of active compound usually are employed. These dosage forms 
are prepared by intimately and uniformly mixing the active ingredient with 
suitable finely divided diluents, fillers, disintegrating agents and/or 
binders such as starch, lactose, talc, magnesium stearate, vegetable gums 
and the like. Such unit dosage formulations may be varied widely with 
respect to their total weight and content of the antiparasitic agent 
depending upon factors such as the type of host animal to be treated, the 
severity and type of infection and the weight of the host. 
When the active compound is to be administered via an animal feedstuff, it 
is intimately dispersed in the feed or used as a top dressing or in the 
form of pellets which may then be added to the finished feed or optionally 
fed separately. Alternatively, the antiparasitic compounds of our 
invention may be administered to animals parenterally, for example, by 
intraruminal, intramuscular, intratracheal, or subcutaneous injection in 
which event the active ingredient is dissolved or dispersed in a liquid 
carrier vehicle. For parenteral administration, the active material is 
suitably admixed with an acceptable vehicle, preferably of the vegetable 
oil variety such as peanut oil, cotton seed oil and the like Other 
parenteral vehicles such as organic preparation using solketal, glycerol 
formal, and aqueous parenteral formulations are also used. The active 
avermectin compound or compounds are dissolved or suspended in the 
parenteral formulation for administration; such formulations generally 
contain from 0.005 to 5% by weight of the active compound. 
Although the antiparasitic agents of this invention find their primary use 
in the treatment and/or prevention of helminthiasis, they are also useful 
in the prevention and treatment of diseases caused by other parasites, for 
example, arthropod parasites such as ticks, lice, fleas, mites and other 
biting insects in domesticated animals and poultry. They are also 
effective in treatment of parasitic diseases that occur in other animals 
including humans. The optimum amount to be employed for best results will, 
of course, depend upon the particular compound employed, the species of 
animal to be treated and the type and severity of parasitic infection or 
infestation. Generally good results are obtained with our novel compounds 
by the oral administration of from about 0.001 to 10 mg per kg of animal 
body weight, such total dose being given at one time or in divided doses 
over a relatively short period of time such as 1-5 days. With the 
preferred compounds of the invention, excellent control of such parasites 
is obtained in animals by administering from about 0.025 to 0.5 mg per kg 
of body weight in a single dose. Repeat treatments are given as required 
to combat re-infections and are dependent upon the species of parasite and 
the husbandry techniques being employed. The techniques for administering 
these materials to animals are known to those skilled in the veterinary 
field. 
When the compounds described herein are administered as a component of the 
feed of the animals, or dissolved or suspended in the drinking water, 
compositions are provided in which the active compound or compounds are 
intimately dispersed in an inert carrier or diluent. By inert carrier is 
meant one that will not react with the antiparasitic agent and one that 
may be administered safely to animals. Preferably, a carrier for feed 
administration is one that is, or may be, an ingredient of the animal 
ration. 
Suitable compositions include feed premixes or supplements in which the 
active ingredient is present in relatively large amounts and which are 
suitable for direct feeding to the animal or for addition to the feed 
either directly or after an intermediate dilution or blending step. 
Typical carriers or dilutents suitable for such compositions include, for 
example, distillers' dried grains, corn meal, citrus meal, fermentation 
residues, ground oyster shells, wheat shorts, molasses solubles, corn cob 
meal, edible bean mill feed, soya grits, crushed limestone and the like. 
The active avermectin compounds are intimately dispersed throughout the 
carrier by methods such as grinding, stirring, milling or tumbling. 
Compositions containing from about 0.005 to 2.0% by weight of the active 
compound are particularly suitable as feed premixes Feed supplements, 
which are fed directly to the animal, contain from about 0.0002 to 0.3% by 
weight of the active compounds. 
Such supplements are added to the animal feed in an amount to give the 
finished feed the concentration of active compound desired for the 
treatment and control of parastic diseases. Although the desired 
concentration of active compound will vary depending upon the factors 
previously mentioned as well as upon the particular avermectin derivative 
employed, the compounds of this invention are usually fed at 
concentrations of between 0.00001 to 0.002% in the feed in order to 
achieve the desired antiparasitic result. 
The avermectin compounds of this invention are also useful in combatting 
agricultural pests that inflict damage upon crops while they are growing 
or while in storage. The compounds are applied using known techniques as 
sprays, dusts, emulsions and the like, to the growing or stored crops to 
effect protection from such agricultural pests. 
In using the compounds of this invention, the individual substituted 
avermectin components may be prepared and used in that form. 
Alternatively, mixtures of two or more of the individual avermectin 
components may be used, as well as mixtures of the parent avermectin 
compounds, other avermectin compounds or other active compounds not 
related to avermectin, with the compounds of this invention. 
The products of this invention may be used in any of a variety of 
pharmaceutical preparations. They may be employed in capsule, powder form, 
in liquid solution, or in suspension. They may be administered by a 
variety of means; those of principal interest include: orally, topically 
or parenterally by injection (intravenously or intramuscularly). 
Such tablets and capsules, designed for oral administration, may be in unit 
dosage form, and may contain conventional excipients, such as binding 
agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or 
polyvinylpyrrolidone; fillers, for example, lactose, sugar, cornstarch, 
calcium phosphate, sorbitol, or glycerine; lubricants, for example, 
magnesium stearate, talc, polyethylene qlycol, silica; disintegrants, for 
example, potato starch, acceptable wetting agents such s sodium lauryl 
sulphate. The tablets may be coated according to methods well known in the 
art. Oral liquid preparations may be in the form of aqueous or oily 
suspensions, or solutions, or they may be presented as a dry product for 
reconstitution with water or other suitable vehicle before use. Such 
liquid preparations may contain conventional additives such as suspending 
agents, for example, sorbitol, methyl cellulose, glucose/sugar syrup, 
gelatin, hydroxyethylcellulose, or carboxymethyl cellulose. Suppositories 
will contain conventional suppository bases, such as cocoa butter or other 
glycerides. 
Compositions for injection, the preferred route of delivery, may be 
prepared in unit dosage form in ampules, or in multidose containers. The 
compositions may take such forms as suspensions, solutions, or emulsions 
in oily or aqueous vehicles, and may contain formulatory agents. 
Alternatively, the active ingredient may be in powder form for 
reconstitution, at the time of delivery, with a suitable vehicle, such as 
sterile water. 
The compositions may also be prepared in suitable forms for absorption 
through the mucous membranes of the nose and throat or bronchial tissues 
and may conveniently take the form of liquid sprays or inhalants, 
lozenges, or throat paints. For medication of the eyes or ears, the 
preparation may be presented in liquid or semi solid form. Topical 
applications may be formulated in hydrophobic or hydrophilic bases as 
ointments, creams, lotions, paints, or powders. 
The dosage to be administered depends to a large extent upon the condition 
and size of the subject being treated as well as the route and frequency 
of administration--the parenteral route by injection being preferred for 
generalized infections. Such matters, however, are left to the routine 
discretion of the therapist according to principles of treatment well 
known in the antibiotic art. In general, a daily dosage consists of from 
about 0.1 to about 5 mg of active ingredient per kg. of body weight of the 
subject in one or more treatments per day. A preferred daily dosage for 
adult humans lies in the range of from about 0.1 to 20 mg. of active 
ingredients per kg. of body weight. Another factor influencing the precise 
dosage regimen, apart from the nature of the infection and peculiar 
identity of the individual being treated, is the molecular weight of the 
chosen species of this invention. 
The compositions for human delivery per unit dosage, whether liquid or 
solid, may contain from 0.1% to 99% of active material, the preferred 
range being from about 10-60%. The composition will generally contain from 
about 5 mg. to about 50 mg. of the active ingredient; however, in general, 
it is preferable to employ a dosage amount in the range of from about 5 mg 
to 100 mg. In parenteral administration, the unit dosage is usually the 
pure compound I in sterile water solution or in the form of a soluble 
powder intended for solution. 
In the isolation of the avermectin compounds, which serve as starting 
materials for the instant process, from the fermentation broth, the 
various avermectin compounds will be found to have been prepared in 
unequal amounts. In particular an "a" series compound will be prepared in 
a higher proportion than the corresponding "b" series compound. The 
difference between the "a" series and "b" series is constant throughout 
the avermectin compounds and consists of a sec butyl group and an iso 
propyl group respectively at the 25 position. This difference, of course, 
does not interfere with any of the instant reactions. In particular it may 
not be necessary to separate the "b" components from the related "a" 
component. Separation of these closely related compounds is generally not 
practiced since the "b" compound is present only in a very small percent 
by weight, and the structural difference has negligible effect on the 
reaction processes and biological activities. 
In particular it has been found that the starting materials for the 
compounds of this invention are very often prepared in a ratio of about 
80% avermectin B1a or A1a and 20% avermectin B1b or A1b. Thus the 
preferred composition of this invention is one which contains more than 
about 80% of the "a" component and less than about 20% of the "b" 
component. 
The following examples are provided in order that this invention might be 
more fully understood; they are not to be construed as limitative of the 
invention. 
The substituted avermectin derivatives prepared in the following examples 
are generally isolated as amorphous solids and not as crystalline solids. 
They are thus characterized analytically using techniques such as mass 
spectrometry, nuclear magnetic resonance, and the like. Being amorphous, 
the compounds are not characterized by sharp melting points, however, the 
chromatographic and analytical methods employed indicate that the 
compounds are pure. 
In the following examples, the various starting materials therefor are 
avermectin compounds or derivatives of avermectin compounds. The 
avermectin compounds and the preparation and isolation thereof from 
fermentation broths are described in U.S. Pat. No. 4,310,519 issued Jan. 
12, 1982. The 4"- and 4'-keto starting materials are described in U.S. 
4,427,663. The selective 22,23-dihydro derivatives of avermectin compounds 
are described in U.S. Pat. No. 4,199,569 issued Apr. 22, 1980. The 
monosaccharide derivatives of avermectin compounds are described in U.S. 
Pat. No. 4,206,205 issued Jan. 3, 1980.

EXAMPLE 1 
23 Methylavermectin B2a and/or B2b. 
A solution of 250 mg of 23-oxoavermectin B2a/B2b in 12 ml of anhydrous 
tetrahydrofuran was stirred under nitrogen at room temperature while 0.5 
ml of a 2.85 molar methylmagnesium bromide solution in ether was added 
dropwise from a syringe. After 1 hour the reaction mixture was poured onto 
60 ml of a 10 % aqueous ammonium chloride solution, and the product was 
extracted with ethyl acetate. The extract was washed with water, dried 
over MgSO.sub.4, and concentrated in vacuo to 210 mg of yellow glass. This 
was purified by preparative layer silica gel chromatography with methylene 
chloride containing 3 to 5 % of methanol to give 155 mg white foam. It was 
further purified by preparative high performance liquid chromatography on 
a reverse phase column (Whatman M20 Partisil 10/50 ODS -3) with a 
methanol-H.sub.2 O 85:15 solvent mixture to give 81 mg of 23 
methylavermectin B2a and/or B2b, which was characterized by its mass 
spectrum (m/e.sup.+ : 904=M.sup.+, 337, 319) and .sup.1 H-NMR spectrum. 
EXAMPLE 2 
23-Methylavermectin B2a and/or B2b monosaccharide. 
When 35 mg of 23 oxoavermectin B2a and/or B2b monosaccharide was reacted 
according to the procedure fully described in example 1, 15 mg of 
23-methylavermectin B2a and/or B2b monosaccharide was obtained as a white 
foam, which was characterized by its mass spectrum (m/e.sup.+ : 742 
=M.sup.+ -18, 337, 319) and .sup.1 H-NMR spectrum. 
EXAMPLE 3 
23-Ethylavermectin B2a and/or B2b. 
A solution of 90 mg of 23-oxoavermectin B2a/B2b in 7 ml of anhydrous ether 
was stirred under nitrogen in an ice bath while 0.3 ml of a 2.0 molar 
ethylmagnesium bromide in tetrahydrofuran solution was added dropwise from 
a syringe. After 30 minutes the reaction mixture was stirred at room 
temperature, and after 90 min. an additional 0.4 ml of ethyl magnesium 
bromide solution was added. After a total reaction time of 2 hours the 
mixture was poured onto 50 ml of a 10 % aqueous ammonium chloride 
solution, and the product was extracted with ether. The extract was washed 
with water, dried over magnesium sulfate and concentrated in vacuo to 80 
mg of light colored glass. This was purified by preparative high 
performance liquid chromatography on a reverse phase column (Whatman M9 
Partisil 10/50 ODS -3) with a MeOH-H.sub.2 O 85:15 solvent mixture to give 
14 mg of 23-ethylavermectin B2a and/or B2b, which was characterized by its 
mass spectrum (m/e.sup.+ : 612=M.sup.+ -306, 351, 333) and .sup.1 H-NMR 
spectrum. 
EXAMPLE 4 
23-Vinylavermectin B2a and/or B2b. 
A solution of 90 mg of 23-oxoavermectin B2a/B2b in 7.5 ml of anhydrous 
ether was stirred under nitrogen in an ice bath while 0.3 ml of a 1.7 
molar vinylmagnesium bromide in tetrahydrofuran solution was added 
dropwise from a syringe. After 30 minutes the reaction mixture was stirred 
at room temperature, and an additional 0.3 ml of vinylmagnesium bromide 
solution was added. After a total reaction time of 90 minutes the mixture 
was poured onto 50 ml of a 10% aqueous ammonium chloride solution, and the 
product was extracted with ethyl acetate. The extract was washed with 
water, dried over magnesium sulfate, and concentrated in vacuo to 90 mg of 
light foam. This was purified by preparative high performance liquid 
chromatography on reverse phase column (Whatman M9 Partisil 10/50 ODS-3) 
with a methanol -H.sub.2 O 85:15 solvent mixture to give 15 mg of 
23-vinylavermectin B2a and/or B2b, which was characterized by its mass 
spectrum (m/e.sup.+ : 898=M.sup.+ 18, 610=M.sup.+- 306, 349, 331) and 
.sup.1 H -NMR spectrum. 
EXAMPLE 5 
4"-Methylavermectin B1a and/or B1b. 
A solution of 110 mg of 4"-oxoavermectin B1a/B1b in 7.0 ml of anhydrous 
ether was stirred under nitrogen in an ice bath while 0.25 ml of a 2.85 
molar methylmagnesium bromide in ether solution was added dropwise from a 
syringe. After 20 minutes the reaction mixture was poured onto 30 ml of a 
10% aqueous ammonium chloride solution, and the product was extracted with 
ethyl acetate. The extract was washed with water, dried over magnesium 
sulfate, and concentrated in vacuo to 90 mg of yellow glass. Purification 
via preparative layer silica gel chromatography with methylene chloride 
containing 4% of MeOH gave 75 mg of a glass, which showed three peaks by 
high performance liquid chromatography. Separation via preparative HPLC on 
a reverse phase column (Whatman M20 Partisil 10/50 ODS -3) with a 
methanol-H.sub.2 O 85:15 solvent mixture gave 12 and 13 mg respectively of 
the two 4"-epimers of 4"-methyl-avermectin B1a and/or B1b, which were 
characterized by their mass spectra (m/e.sup.+ : 868=M.sup.+ -18, 159 
=145+14) and .sup.1 H NMR spectrum. 
EXAMPLE 6 
22,23-Dihydro 4'-methylavermectin B1a and/or B1b monosaccharide. 
When 22,23-dihydro 4'-oxoavermectin B1a and/or B1b monosaccharide was 
reacted and isolated according to the procedure described in example 5 the 
two 4'-epimers of 22,23 dihydro-4"-methylavermectin B1a and/or B1b were 
obtained, which were characterized by their mass and .sup.1 H-NMR spectra. 
EXAMPLE 7 
2,23-Dihydro -5-methylavermectin B1a and/or B1b. 
A solution of 90 mg of 22,23-dihydro-5-oxoavermectin B1a/B1b in 5.0 ml of 
anhydrous ether was stirred under nitrogen in an ice bath while 0.2 ml of 
a 2.8 molar methylmagnesium chloride in tetrahydrofuran solution was added 
dropwise from a syringe. After 25 minutes the reaction mixture was poured 
onto cold aqueous ammonium chloride solution, and the product was 
extracted with ethyl acetate. The extract was washed with water, dried 
over magnesium sulfate, and concentrated in vacuo to 100 mg of yellow 
foam. Purification via preparative silica gel layer chromatography with 
methylene chloride containing 4% of methanol and extraction of the 
appropriate band gave 20 mg of one of the two C -5 epimeric 22,23-dihydro 
-5-methylavermectin B1a and/or B1b as a white glass. A second band of 
slightly slower moving material than the first epimer was further purified 
by repeated silica gel preparative layer chromatography with methylene 
chloride containing 3% methanol to give 21 mg of the other C -5 epimeric 
product. Both compounds were characterized by mass and .sup.1 -HNMR 
spectrometry. 
EXAMPLE 8a 
5-O-tert-Buthyldimethylsilyl- 22,23-dihydro-13-methyl-avermectin avermectin 
B1a and/or B1b aglycone. 
A solution of 500 mg of 5-tert butyldimethylsilyl-22,23-dihydro-avermectin 
B1a and/or B1b aglycone in 30 ml of ether was stirred under nitrogen in an 
ice bath. Then 1.0 ml of a methyl magnesium chloride solution (2.8 molar 
in tetrahydrofuran) was added. After 10 minutes of stirring the reaction 
mixture was poured into an aqueous ammonium chloride solution, and the 
product was extracted with ether. The ether extract was washed with water, 
saturated aqueous sodium chloride, dried over magnesium sulfate and 
concentrated in vacuo to 510 mg of crude 5-O-tert-butyldimethylsilyl 
22,23-dihydro-13-methyl avermectin B1a and/or B1b aglycone as a yellow 
foam, which was characterized by its mass spectrum (m/e : 696=M.sup.+ - 
H.sub.2 O, 321 =307 peak+CH2) and .sup.1 H-NMR spectra (new methyl peak at 
1.3 PPM). 
EXAMPLE 8b 
22,23 Dihydro-13 methyl avermectin B1a and/or B1b aglycone. 
A solution of 490 mg of crude 5-O-tert butyl-dimethylsilyl-22,23 
dihydro-13-methyl-avermectin B1a and/or B1b aglycone and 500 mg of 
p-toluenesulfonic acid in 50 ml of methanol was held at room temperature 
for 35 minutes and then poured into 130 ml of dilute aqueous sodium 
bicarbonate solution. The product was extracted with ether and ethyl 
acetate. The extract was washed with water, saturated aqueous sodium 
chloride, dried over magnesium sulfate and concentrated in vacuo to 420 mg 
of yellow foam. Purification by preparative silica gel thin layer 
chromatography with a methylene chloride nitrogen-ethyl acetate 85:15 
solvent mixture afforded 350 mg of pure 22,23-dihydro-13-methyl-avermectin 
B1a and/or B1b aglycone, which was characterized by its mass spectrum (m/e 
: 600=M.sup.+, 321=base peak=307 fragment+CH.sub.2) and .sup.1 H-NMR (new 
methyl at 1.29 PPM) spectra. It was crystallized from CH.sub.2 Cl.sub.2 : 
mp 149.degree.-152.degree., [.alpha.]D= +87.2.degree. (acetone). 
EXAMPLE 9a 
5-O-tert-Butyldimethylsilyl-22,23-dihydro-13-vinyl avermectin B1a and/or 
B1b aglycone. 
A solution of 70 mg of 5-O-tert butyldi-methylsilyl 
22,23-dihydro-avermectin B1a and/or B1b aglycone in 5 ml of ether was 
reacted with 0.22 ml of an 1.7 molar solution of vinyl magnesium bromide 
in tetrahydrofuran and worked up according to the procedure of example 8a 
to give 80 mg of crude 
5-O-tert-butyldimethylsilyl-22,23-dihydro-13-vinylavermectin B1a and/or 
B1b aglycone, which was characterized by its mass spectrum (m/e : 
708=M.sup.+ -H.sub.2 O, 651=M.sup.+ -H.sub.2 O-C.sub.4 H.sub.9, 484=458 
fragment+C=CH.sub.2) and .sup.1 H-NMR spectra. 
EXAMPLE 9b 22,23-Dihydro-13-vinylavermectin B1a and/or B1b aglycone. 
80 Mg of crude 5-O-tert butyldimethylsilyl-22,23-dihydro-13-vinylavermectin 
B1a and/or B1b aglycone was deprotected according to the procedure fully 
described in example 8b using 80 mg of p-toluenesulfonic acid and 8 ml of 
methanol and purified by preparative silica gel thin layer chromatography 
with a methylene chloride nitrogen-ethyl acetate-methanol 82:15:3 solvent 
mixture to give 40 mg of 22,23-dihydro 13 vinylavermectin B1a and/or B1b 
aglycone, which was characterized by its mass spectrum (m/e : 594.357 
=M.sup.+ -H.sub.2 O, 333=307 fragment +C=CH.sub.2) and .sup.1 H-NMR 
spectra. It was crystallized from CH.sub.2 Cl.sub.2, mp 
154.degree.-156.degree.. 
EXAMPLE 10a 
5-O-tert Butyldimethylsilyl-22,23-dihydro -13-allylavermectin B1a and/or 
B1b aglycone. 
A solution of 70 mg of 5-O-tert-butyldimethylsilyl-22,23-dihydro avermectin 
B1a and/or B1b aglycone in 5 ml of ether was reacted with 0.1 ml of an 2.6 
molar solution of allyl magnesium chloride in tetrahydrofuran and worked 
up according to the procedure of EXAMPLE 8a to give 70 mg of light foam. 
Purification by preparative silica gel thin layer chromatography with 
methylene chloride nitrogen as solvent afforded 45 mg of pure 
5-O-tert-butyldimethyl silyl -22,23-dihydro -13 allylavermectin B1a and/or 
B1b aglycone, which was characterized by its mass spectrum (m/e: 
740=M.sup.+, 722=M.sup.+ -H.sub.2 O, 347=307 fragment+CHCH=CH.sub.2) and 
.sup.1 H-NMR spectra (showing additional vinylic protons). 
EXAMPLE 10b 
22,23-Dihydro -13 -allylavermectin B1and/or B1b aglycone. 
45 Mg of crude 5-O-tert-butyldimethylsilyl 22,23 dihydro 13 allylavermectin 
B1a and/or B1b aglycone was deprotected according to the procedure fully 
described in example 8b using 45 mg of p-toluenesulfonic acid and 5 ml of 
methanol, and was purified by preparative silica gel thin layer 
chromatography with a methylene chloride nitrogen-ethyl acetate 90:10 
solvent mixture to give 20 mg of 22,23-dihydro -13-allylavermectin B1a 
and/or B1b aglycone, which was characterized by its mass spectrum (m/e : 
626 =M.sup.+ H.sub.2 O, 347=307 fragment +CHCH=CH.sub.2) and .sup.1 H-NMR 
spectra. 
EXAMPLE 11 
5-O-t-Butyldimethylsilyl-23-methylavermectin B2a and/or B2b. 
A solution of 500 mg of 23methylavermectin B2a and/or B2b, 240 mg of 
imidazole and 240 mg of tert-butyldimethylsilyl chloride in 4 ml of 
anhydrous dimethyl formamide is stirred at room temperature for 50 
minutes. Then the reaction mixture is poured into 150 ml of ice cold water 
and the aqueous phase is extracted four times with 20 ml of ether. The 
organic phase is washed twice with water, aqueous sodium chloride 
solution, dried with magnesium sulfate and concentrated in vacuo to a 
white foam. The crude product is purified by silica gel column 
chromatography with a methylene chloride nitrogen ethyl acetate 90:10 to 
70:30 solvent system to give 5-O-butyldimethylsilyl-23-methylavermectin 
B2a and/or B2b as an amorphous foam, which is characterized by its .sup.1 
H-NMR- and mass spectra. 
EXAMPLE 12 
5-O-t-Butyldimethylsilyl -23 methyl-4"-oxoavermectin B2a and/or B2b. 
To a solution containing 0.091 ml of oxalyl chloride in 2.3 ml of dry 
methylene chloride nitrogen stirred at -60.degree. C. is added 0.015 ml of 
dry dimethylsulfoxide dissolved in 1.2 ml of dry methylene chloride 
nitrogen during 15 min. Then a solution of 465 mg of 
5-O-t-butyldimethylsilyl-23-methylavermectin B2a and/or B2b dissolved in 
2.3 ml of dry methylene chloride nitrogen is added over a period of 15 
minutes while maintaining the temperature at -60.degree. C. The reaction 
mixture is stirred at this temperature for 30 minutes when 0.065 ml of dry 
triethylamine is added. The mixture is stirred for 5 additional minutes at 
-60.degree. C., and then the cooling bath is removed and the reaction 
mixture is allowed to come to ambient temperature. After addition of water 
the reaction product is extracted with CH.sub.2 Cl.sub.2, the extract is 
washed with water, dried and concentrated in vacuo to a yellow foam. This 
is identified by its mass and NMR spectra as 5-O-t-butyldimethylsilyl 
23-methyl-4"-oxoavermectin B2a and/or B2b, which is used for further 
chemical reactions without purification. 
EXAMPLE 13 
5-O-t-Butyldimethylsilyl-23-methyl 4"-deoxy-4"-epimethylaminoavermectin 
B2a and/or B2b. 
A solution of 0.026 ml of glacial acetic acid in 3.0 ml of methanol is 
treated with methylamine gas at 0.degree. C. until the pH of the solution 
reaches 9.0. To this a solution containing 445 mg of 
5-O-t-butyldimethylsilyl-23-methyl-4"-oxoavermectin B2a and/or B2b in 2.0 
ml of methanol is added, and the reaction mixture is stirred at room 
temperature for 1 hour, when a solution of 350 mg of sodium 
cyanoborohydride in 0.075 ml of methanol is added slowly over 10 min. 
After 50 min the reaction mixture is poured into 150 ml of cold aqueous 
sodium carbonate solution and the product is extracted with ether. The 
extract is washed with water, dried, and concentrated in vacuo to a yellow 
foam. Thin layer chromatography (silica gel, methylene chloride 
nitrogen-ethyl acetate 85:15) of the crude product at this point will show 
several spots. Further purification by silica gel column chromatography 
using methylene chloride nitrogen ethyl acetate solvent mixtures gives as 
major reaction product 
5-O-t-butyldimethylsilyl-23-methyl-4"-deoxy-4"-epi-methylamino avermectin 
B2a and/or B2b, accompanied by small amounts of 
5-O-t-butyldimethylsilyl-23-methyl-4"-deoxy-4"-methylaminoavermectin B2a 
and/or B2b, and, 5-O-t-butyldimethylsilyl-23-methyl-4"-epi-avermectin B2a 
and/or B2b as light foams, which are characterized by their mass and 
.sup.1 H-NMR spectra. 
EXAMPLE 14 
23-Methyl-4"-deoxy-4"-epi-methylaminoavermectin B2a and/or B2b. 
A solution of 140 mg of 5-O-t-butyldimethylsilyl-23-methyl-4"-deoxy-4"-epi- 
methylaminoavermectin B2a and/or B2b in 2.0 ml of methanol and a solution 
of 70 mg of p-toluenesulfonic acid monohydrate in 5.0 ml of methanol is 
mixed and stirred at room temperature for 45 minutes, and then poured into 
dilute aqueous sodium bicarbonate solution. The product is extracted with 
ethyl acetate, washed with water and dried over magnesium sulfate, 
concentrated in vacuo, and purified by preparative silica gel column 
chromatography with a methylene chloride nitrogen-methanol 95:5 solvent 
mixture to give 23-methyl -4"-deoxy-4"-epi-methylaminoavermectin B2a 
and/or B2b, which is identified by NMR and mass spectra. 
EXAMPLE 15 
4"-epi-(N-Acetyl-N-methylamino)-4"-deoxy-5-O-t-butyl 
dimethylsilyl-23-methylavermectin B2a and/or B2b 
A solution of 100 mg of 
5-O-t-butyldimethyl-silyl-23-methyl-4"-deoxy-4"-epi-methylaminoavermectin 
B2a and/or B2b, 100 .mu.l of ethyl diisopropylamine in 1.5 ml of methylene 
chloride nitrogen is treated with 8 .mu.l of acetyl chloride and stirred 
at room temperature for several hours. Then it is poured onto ice, 
extracted with methylene chloride nitrogen, washed with aqueous sodium 
bicarbonate, dried and concentrated in vacuo to a light solid. 
Purification by preparative silica gel layer chromatography with methylene 
chloride nitrogen +1% of methanol gives as a white solid, which is 
characterized by its mass and .sup.1 H-NMR spectra. 
EXAMPLE 16 
4"-epi-(N-Acetyl-N-methylamino)-4"-deoxy-23-methylavermectin B2a and/or B2b 
A solution of 70 mg of 
4"-epi(N-acetyl-N-methylamino)-4"-deoxy-5-O-t-butyldimethylsilyl 
-23-methylavermectin B2a and/or B2b in 1.0 ml of methanol and a solution 
of 35 mg of p-toluenesulfonic acid monohydrate in 2.5 ml of methanol is 
mixed and stirred at room temperature for 45 minutes, and then poured into 
dilute aqueous sodium carbonate solution. The product is extracted with 
ethyl acetate, washed with water and dried over magnesium sulfate, 
concentrated in vacuo, and purified by preparative silica gel column 
chromatography with a methylene chloride nitrogen-methanol 95:5 solvent 
mixture to give 4"-epi-(N-acetyl 
N-methylamino)-4"deoxy-23-methylavermectin B2a and/or B2b, which is 
identified by its NMR and mass spectra. 
EXAMPLE 17a 
5-O-t-Butyldimethylsilyl-10,11-dihydro-10-hydroxy-11-bromoavermectin B1a/lb 
To a solution of 500 mg of 5-O-t-butyldimethylsilyl avermectin B1a/lb in 10 
mL of acetone and 1 mL of water was added 110 mg of N-bromoacetamide in 
one portion. The mixture was stirred at 20.degree. C. in the dark for 1 
hour. The mixture was then poured into a separatory funnel containing 100 
mL of water and subsequent extraction with ether afforded the crude 
product. Preparative layer chromatography using three 0.1 mm thick silica 
gel plates eluted in 60% ethyl acetate in hexane provided 180 mg of 
product (Rf=0.4) which was characterized by its NMR and mass spectra. 
NMR(200 mHz): 0.14 (s), 0.94 (s), 1.18 (d, J=7 Hz), 1.24 (D, J=6 Hz), 1.25 
(d, J=6 Hz), 1.51 (m), 1.59 (s), 1.82 (s), 3.18 (t, J=9 Hz), 3.24 (t, J=9 
Hz), 3.41 (s), 3.45 (s), 3.45 (m), 3.80 (m), 3.82 (d, J=5 Hz), 4.04 (m), 
4.30 (br m), 4.45 (br s), 4.54 (s), 4.72 (d, J=2 Hz) 4.72 (ABq, J=16 Hz), 
5.24 (br d, J=8 Hz), 5.33 (s), 5.40 (d, J=2 Hz, 5.40 (m), 5.58 (dd, J=3, 
10 Hz), 5.80 (dd, J=2, 10 Hz), 5.86 (br s). 
EXAMPLE 17b 
5-O-tert-Butyldimethylsilyl-10,11-dihydro-10-hydroxy avermectin B1a/lb 
A solution of 168 mg of 5-O-tert 
butyldimethylsilyl-10,11-dihydro-10-hydroxy-1-bromoavemectin B1a/lb in 6 
mL of toluene and 0.4 mL of tri-n-butyltinhydride was heated in a 
100.degree. C. oil bath under nitrogen for 2 hours. The mixture was then 
cooled to 20.degree. C. and flash chromatographed through a column of 50 g 
of silica gel eluting with dichloromethane, then 1:1 hexane:ethyl acetate. 
Final HPLC purification (Whatman Partisil M20 10/50 ODS-3 column, 90:10 
methanol:water) afforded 60 mg of pure 
5-O-tert-butyldimethyl-silyl-10,11)dihydro-10-hydroxy avermectin B1a/lb 
characterized by its NMR and mass spectra. 200 MHz NMR: 0.15 (s), 0.95 
(s), 1.11 (d, J=7 Hz), 1.14 (d, J=6 Hz), 1.26 (d, J=6 Hz), 1.30 (d, J=6 
Hz), 1.55 (s), 1.55 (m), 1.81 (s), 2.0 (m), 2.19 (s), 2.2-2.5 (m), 2.54 
(d, J=2 Hz), 3.19 (t, J=9 Hz), 3.26 (t, J=9 Hz), 3.36 (s), 3.44 (s), 3.48 
(s), 3.50 (m), 3.66 (d, J=6 Hz), 3.80 (m), 4.03 (br s, m), 4.40 (br s), 
4.50 (br s), 4.76 (d, J=2 Hz), 4.80 (ABq, J =15 Hz), 5.00 (br s), 5.28 
(s), 5.30 (s), 5.38 (s), 5.43 (d, J=3 Hz), 5.44 (m), 5.60 (dd, J=3,10 Hz), 
5.80 (dd, J=2,10 Hz). 
EXAMPLE 17c 
5-O-tert-butyldimethylsilyl-10-oxo-11-hydro-avermectin B1a/lb 
A solution of 800 mg of 
5-O-t-butyldimethyl-silyl-10,11-dihydro-10-hydroxyavermectin B1a/lb in 12 
mL of dichloromethane was stirred with 1 g of celite and 1.3 g of 
pyridinum chlorochromate at 20.degree. C. for 5 hours. The dark slurry was 
then filtered through a pad of silica gel using 1:1 hexane:ethyl acetate 
as eluant. Evaporation of the solvent afforded 678 mg of 
5-O-tert-butyldimethylsilyl-10oxo-11-hydroavermectin B1a/lb characterized 
by its NMR and mass spectra. 
200 MHz NMR: 0.14 (s), 0.92 (s), 1.16 (d, J=7 Hz), 1.26 (d, J=6 Hz), 1.28 
(d, J=6 Hz), 1.53 (s), 1.55 (m), 1.80 (s), 2.30 (m), 2.60 (s), 3.16 (t, 
J=9 Hz), 3.24 (t, J=9 Hz), 3.32 (d, J=2 Hz), 3.42 (s), 3.44 (s), 3.45 (m), 
3.68 (m), 3.84 (d, J=6 Hz), 3.86 (s), 4.44 (br s), 4.74 (d, J=3 Hz), 4.89 
(d, J=3 Hz), 4.96 (s), 5.00 (m), 5.26 (d, J=2 Hz), 5.40 (d, J=3 Hz), 5.50 
(m), 5.56 (dd, J=3, 10 Hz), 5.78 (dd, J=2, 10 Hz), 6.12 (s). 
EXAMPLE 17d 
5-O-tertbutyldimethylsilyl-4",7-di-O-trimethylsilyl-10-oxo-11-hydroavermec 
t 
in B1a/lb 
To 1.1 g of 5-O-tertbutyldimethylsilyl-10-oxo-11-hydroavermectin B1a/1b in 
5 mL of dimethylformamide at 22.degree. C. was added 2 mL of 
bis-trimethylsilyltrifluoroacetamide (BSTFA). The mixture was stirred at 
22.degree. C. for 16 hours before the solvent was removed in vacuo. The 
residual solid was filtered through a column of silica gel with 20% ethyl 
acetate in hexane. The filtrate was evaporated in vacuo to afford 1.2 g of 
5-O-tertbutyldimethylsilyl-4",7-di 
-O-trimethylsilyl-10-oxo-11-hydroavermectin B1a/lb characterized by the 
pressure of a trimethylsilyl signal at 0.13 ppm of the NMR and its mass 
spectra. 
EXAMPLE 17e 
5-O-tertbutyldimethylsilyl-4",7-di-O-trimethylsilyl-10-hydroxy-10-methyl-10 
,11-dihydro avermectin B1a/1b 
To a solution of 379 mg of 
5-O-tertbutyl-dimethylsilyl-4",7-di-O-trimethylsilyl-10-oxo-11-hydroaverme 
ctin B1a/1 in 10 mL of distilled THF at -78.degree. C. was added 1.5 mL of 
a 3.2 M methyl magnesium bromide solution in ether. The mixture was 
stirred at 0.degree. C. for 2.5 hours before 3 mL of a saturated ammonium 
chloride solution was added to stop the reaction. Thin layer silica gel 
chromatographic analysis indicated a new uv-inactive product with an 
R.sub.f of 0.25 in 20% ethyl-acetate hexane. The reaction mixture was 
combined with 50 mL of pH7 buffer and extracted with ether. The ethereal 
extracts were combined, dried over MgSO.sub.4, and evaporated in vacuo to 
yield a solid. Purification of this solid by preparative layer 
chromatography (PLC) afforded 217 mg of 
5-O-tertbutyldimethylsilyl-4",7-di-O-trimethylsilyl-10,11-dihydro-10-hydro 
xy-10-methylavermectin B1a/1b. Its NMR spectrum showed the presence of the 
new methyl group as a singlet at 1.32 ppm and the upfield shift of the C9 
proton from 6.12 to 5.55 ppm. 
EXAMPLE 17f 
10-Methyl-10-hydroxy-10,11-dihydroavermectin B1a/lb 
To a solution of 58 mg of 
4",7-di-O-trimethylsilyl-O-tertbutyldimethylsilyl-10-methyl-10-hydroxy 
10,11-dihydroavermectin B1a/b in 1 mL of THF in a stoppered polypropylene 
vial was added 6 mL of HF pyridine solution (prepared by diluting 10 mL of 
commercially available HF pyridine complex with 20 mL of dry pyridine and 
70 mL of THF). The reaction was stirred at 22.degree. C. for 18 hours and 
then diluted with ice water. The hydrofluoric acid was neutralized with 
aqueous sodium bicarbonate and the organic product was extracted with 
ether. The ethereal extracts were combined, dried over MgSO.sub.4, and 
evaporated in vacuo to yield a glossy solid. PLC on two 0.5 mm silica gel 
plates eluted in ethyl acetate provided 36 mg of 
10-methyl-10-hydroxy-10,11-dihydrovermectin B1a/1b characterized by its 
NMR and mass spectra. 
EXAMPLE 17g 
5-O-tertbutyldimethylsilyl-4",7-di-O-trimethylsilyl-10-methylavermectin 
B1a/1 b 
To a solution of 127 mg of 5-O-tertbutyldimethyl 
silyl-4",7-di-O-trimethylsilyl-10-hydroxy-10-methyl-10,11-dihydroavermecti 
n B1a/lb in 4 mL of THF and 0.5 mL of distilled triethylamine was added 0. 
170 mL of methanesulfonyl chloride. After 1 hour the cloudy mixture was 
loaded onto two 1000 micron thick silica gel plates and the plates were 
eluted in 20% ethyl acetate in hexane. Extraction of the appropriate band 
provided 42 mg of 
5-O-tertbutyldimethylsilyl-4",7-di-O-trimethylsilyl-10-methylavermectin 
B1a/1b characterized by its NMR and mass spectra. 
NMR (300 MHz): new vinylic methyl group at 1.78 ppm next to the C.sub.4 
methyl at 1.74 ppm, C.sub.11 H at 5.75 ppm. 
EXAMPLE 17h 
10-Methylavermectin B1a/lb 
To a solution of 33 mg of 
5-O-tert-butyldimethylsilyl-4",7-di-O-trimethylsilyl-10-methyl avermectin 
B1a/B1b in 2 mL of THF was added 2 mL of hydrogen fluoride-pyrimidine 
solution (same as in Example 17f). After 16 hours at 22.degree. C. the 
solution was poured into a separatory funnel containing ice water and the 
hydrofluoric acid was neutralized with sodium bicarbonate. The organic 
product was extracted from the aqueous phase with ether. The ethereal 
extracts were combined and dried over MgSO.sub.4 and evaporation of the 
solvent in vacuo provided a solid. PLC on two 0.5 mm silica gel plates in 
75% ethylacetate hexane afforded 21 mg of pure 10-methylavermectin B1a/lb 
characterized by its NMR and mass spectra. 
EXAMPLE 18a 
4"-Vinyl-5-O-tert-butyldimethylsilylavermectin B1a/lb 
To 0.9 mL of a 1.6 M vinyl Grignard solution in tetrahydrofuran was added 9 
mL of distilled tetrahydrofuran. The solution was cooled to 0.degree. C. 
before a solution of 100 mg of 4"-oxo-5-O-tert-butyldimethylsilyl 
avermectin B1a/B1b in 0.5 mL of THF was added dropwise. After 15 min, 
analysis by thin layer chromatography indicated all starting material to 
be reacted. The reaction was quenched after 30 min by the addition of 5 mL 
of ammonium chloride solution and the product was extracted with ether. 
The ether extracts were combined, dried over MgSO.sub.4 and evaporated in 
vacuo to afford a glossy solid. Preparative layer chromatography on two 
0.05 mm silica gel plates eluted in 2:1 hexane:ethyl acetate afforded 40 
mg of 4"-vinyl -5-O-tert-butyldimethylsilyl avermectin B1a/lb 
characterized by its NMR and mass spectra. 
200 MHz NMR: .delta.0.15 (s), 0.96 (s), 1.14 (d, J=6 Hz), 1.20 (d, J=7 Hz), 
1.27 (d, J=6 Hz), 1.53 (s), 1.82 (s), 1.78-2.40 (m), 2.56 (m), 3.25 (t, 
J=9 Hz), 3.43 (s), 3.48 (s), 3.60 (m), 3.90 (m), 4.17 (s), 4.44 (br d), 
4.68 (ABq, J=15 Hz), 4.81 (d, J=3 Hz), 5.04 (m), 5.32 (dd, J=3, 10 Hz), 
5.45 (m), 5.52 (d, J=2 Hz), 5.60 (dd, J=3, 10 Hz), 5.80 (m). 
EXAMPLE 18b 
4"-Vinylavermectin B1a/lb 
To a solution of 35 mg of 4"vinyl 5-O-tert-butyldimethylsilylavermectin 
B1a/1b in 2 mL of freshly distilled THF at 22.degree. C. in a 
polypropylene vial under nitrogen was added 2 mL of a solution of hydrogen 
fluoride pyridine in THF (prepared by diluting 10 mL of commercially 
available HF-pyridine complex with 20 mL of dry pyridine and 70 mL of 
THF). The mixture was stirred at 22.degree. C. for 16 hours. The reaction 
was then diluted with ice water, the HF was neutralized with aqueous 
sodium bicarbonate and the organic product was extracted with ether. The 
ethereal extracts were combined and dried over MgSO.sub.4, evaporated in 
vacuo to yield a glossy solid. Preparative layer chromatography on a 0.05 
mm thick silica gel plate eluted in 50% ethyl acetate-hexane afforded 31 
mg of 4"-vinylavermectin B1a/1b characterized by its NMR and mass spectra. 
EXAMPLE 19a 
4"-butyl-5-O-tertbutyldimethylsilylavermectin B1a/lb 
To 210 mg of CuBr.SMe.sub.2 in a dry flask under nitrogen was added 8 mL of 
distilled ether. The slurry was cooled to 0.degree. C. and 0.80 mL of a 
2.5 M n-butyllithium solution in hexane was added dropwise. A dark red 
solution was obtained. A solution of 100 mg of 
4"-oxo-5-O-tert-butyldimethyl silylavermectin B1a/lb in 0.5 mL of THF was 
then added dropwise to the chilled (0.degree. C.) lithium cuprate 
solution. After 30 min the reaction was stopped by the addition of 5 mL of 
saturated aqueous ammonium chloride solution. The mixture was extracted 
with ether and evaporation of the dried (MgSO.sub.4) ethereal extracts 
provided a glossy solid. Preparative thin layer chromatography on silica 
gel provided 60 mg of 4"-butyl-5-O-tertbutyldimethylsilyl avermectin B1/1b 
characterized by its NMR and mass spectra. 
200 MHz NMR: 0.15 (s), 0.97 (s), 1.20 (d, J=7 Hz), 1.26 (d, J=6 Hz), 
0.80-1.80 (m), 1.54 (s), 1.83 (s), 1.80-2.40 (m), 2.56 (m), 3.30 (t, J=9l 
Hz), 3.44 (s), 3.48 (s), 3.60 (m), 3.87 (d, J=6 Hz), 3.96 (m), 4.17 (s), 
4.48 (br s), 4.68 (ABq J=15 Hz), 4.81 (d, J=4 Hz), 5.06 (m), 5.38 (s), 
5.40 (m), 5.46 (d, J=3 Hz), 5.60 (dd, J=3, 10 Hz), 5.80 (m). 
EXAMPLE 19b 
4"-n-Butylavermectin B1a/1b 
To a solution of 55 mg of 4"-n-butyl-5-O-tert-butylavermectin B1a/lb in 2 
mL of THF was added 2 mL of hydrogen fluoride-pyridine in THF solution 
(prepared as described in Example 18b). The mixture was stirred in a 
polypropylene vessel for 16 hours under anhydrous nitrogen. The reaction 
was then worked up by the addition of ice water, aqueous sodium 
bicarbonate solution, and extraction with ether. Evaporation of the ether 
solvent and preparative layer chromatography of the residual solid on a 
0.1 mm silica gel plate eluted in 50% ethyl acetate-hexane provided 45 mg 
of 4"-n-butylavermectin B1a/lb characterized by its NMR and mass spectra. 
EXAMPLE 20a 
5-O-t-Butyldimethylsilyl-13-deoxyavermectin B2a and/or B2b Aglycone 
A solution of 324 mg (0.55 mmole) of 13-deoxyavermectin B2a and/or B2b 
aglycone, 240 mg of imidazole and 240 mg of tert-butyldimethylsilyl 
chloride in 4 ml of anhydrous DMF is stirred at room temperature for 50 
minutes. Then the reaction mixture is poured into 150 ml of ice cold water 
and the aqueous phase is extracted four times with 20 ml of ether. The 
organic phase is washed twice with water, aqueous NaCl solution, dried 
with MgSO.sub.4 and concentrated in vacuo to a white foam. The crude 
product is purified by silica gel column chromatography with a CH.sub.2 
Cl.sub.2 -EtOAc-90:10 to 70:30 solvent system to give 
5-O-t-butyldimethylsilyl -13-deoxyavermectin B2a and/or B2b aglycone as an 
amorphous foam, which is characterized by its .sup.1 H-NMR and mass 
spectra. 
EXAMPLE 20b 
5-O-t-Butyldimethylsilyl-13-deoxy-23-oxoavermectin B2a and/or B2b Aglycone 
To a solution containing 0.091 ml of oxalyl chloride in 2.3 ml of dry 
CH.sub.2 Cl.sub.2 stirred at -60.degree. C. is added 0.015 ml of dry 
dimethylsulfoxide dissolved in 1.2 ml of dry CH.sub.2 Cl.sub.2 during 15 
min. Then a solution of 320 mg (0.46 mmole) of 
5-O-t-butyldimethylsilyl-13-deoxyavermectin B2a and/or B2b aglycone 
dissolved in 2.3 ml of dry CH.sub.2 Cl.sub.2 is added over a period of 15 
minutes while maintaining the temperature at 60.degree. C. The reaction 
mixture is stirred at this temperature for 30 minutes when 0.065 ml of dry 
triethylamine is added. The mixture is stirred for 5 additional minutes at 
-60.degree. C., and then the cooling bath is removed and the reaction 
mixture is allowed to come to ambient temperature. After addition of water 
the reaction product is extracted with CH.sub.2 Cl.sub.2, the extract is 
washed with water, dried and concentrated in vacuo to a yellow foam. This 
is identified by its mass and NMR spectra as 
5-O-t-butyldimethylsilyl-13-deoxy 23-oxoavermectin B2a and/or B2b 
aglycone, which is used for further chemical reactions without 
purification. 
EXAMPLE 20c 5-O-t-Butyldimethylsilyl-13-deoxy-23-methylavermectin B2a 
and/or B2b Aglycone 
A solution of 195 mg (0.28 mmole) of 
5-O-t-butyldimethylsilyl-13deoxy-23-oxoavermectin B2a and/or B2b aglycone 
in 12 ml of anhydrous tetrahydrofuran is stirred under N.sub.2 at room 
temperature while 0.5 ml of 2.85 molar methylmagnesium bromide solution in 
ether is added dropwise from a syringe. After 1 hour the reaction mixture 
is poured onto 60 ml of a 10% aqueous ammonium chloride solution, and the 
product is extracted with EtOAc. The extract is washed with water, dried 
over MgSO.sub.4, and concentrated in vacuo to a yellow glass. This is 
purified by preparative silica gel layer chromatography with CH.sub.2 
Cl.sub.2 containing 3 to 5% of MeOH to give a white foam, which is 
characterized as 5-O-t-butyldimethylsilyl-13deoxy-23-methylavermectin B2a 
and/or B2b aglycone by its mass spectrum and .sup.1 H-NMR spectrum. 
EXAMPLE 20d 
13-Deoxy-23-methylavermectin B2a and/or B2b Aglycone 
A solution of 250 mg (0.34 mmole) of crude 5-O-t-butyldimethylsilyl 
13-deoxy -23-methylavermectin B2a and/or B2b aglycone and 250 mg of 
p-toluene sulfonic acid in 25 ml of MeOH is held at room temperature for 
35 minutes and then poured into 65 ml of dilute aqueous NaHCO.sub.3 
solution. The product is extracted with ether and EtOAc. The extract is 
washed with water, saturated aqueous NaCl, dried over MgSO.sub.4, and 
concentrated in vacuo to a yellow foam. Purification by preparative silica 
gel thin layer chromatography with a CH.sub.2 Cl.sub.2 -EtOAc 85:15 
solvent mixture affords the pure 13-deoxy-23-methylavermectin B2a and/or 
B2b aglycone, which is characterized by its mass and .sup.1 H-NMR spectra. 
PREATION OF STARTING MATERIALS 
PREATION 1 
23-Oxo-avermectin B2a/B2b 
23 -Oxo-avermectin B2a/B2b was prepared as described by V. P. Gallo et al. 
in Pestic. Sci. 1983, 4, 153-157, and in U.S. Pat. No. 4,289,760: 23 Keto 
derivatives of C-076 compounds, ex. 2,4,5). 
PREATION 2 
23-Oxo-avermectin B2a/B2b Monosaccharide 
A solution of 190 mg of 23-oxo-avermectin B2a/B2b in 6.0 ml of i propanol 
containing 0.06 ml of concentrated sulfuric acid was left for 18 hours at 
room temperature. Then dilute aqueous NaHCO.sub.3 solution was added, and 
the product was extracted with EtOAc, washed with water, and dried and 
concentrated to 170 ml of light glass. Purification by preparative silca 
gel layer chromatography with 1:1 CH.sub.2 Cl.sub.2 EtOAc solvent mixture 
gave 75 mg of 23-oxo avermectin B2a/B2b monosaccharide, which was 
characterized by its mass, .sup.1 H--, NMR and UV spectra. 
PREATION 3a 
5-O-t-butyl-dimethylsilyl-22,23-dihydro avermectin B1a/B1b 
3 g of 22,23-dihydro avermectin B1a/B1b in 0 ml of dry dimethylformamide 
was combined with 1.4 g of imidazole and stirred at room temperature until 
all the materials had dissolved. Then 1.56 g of t-butyl-dimethylsilyl 
chloride was added and the reaction mixture stirred at room temperature 
for 70 minutes. The reaction mixture was diluted with 150 ml of ether, 
water was added and the layers were separated. The aqueous layer was 
extracted twice more with ether and the combined ether layers washed four 
times with water and once with saturated sodium chloride solution. The 
ether layer was dried over magnesium sulfate and concentrated to dryness 
in vacuo affording 4.2 g of a white foam. The foam is chromatographed on 
135 g. of 70-230 mesh silica gel and eluted with 5% tetrahydrofuran in 
methylene chloride. 1.15 G of 4"-5-di-O-t-butyl-dimethylsilyl 22,23 
dihydro avermectin B1a/B1b and 2.6 g of 5-O-t-butyl 
dimethylsilyl-22,23-dihydro avermectin B1a/B1b were recovered as pure 
amorphous foams. 
PREATION 3b 
5-O-t-butyl-dimethylsilyl 4"-keto-22,23-dihydro avermectin B1a/B1b 
In a dried flask purged with dry nitrogen was placed 97 .mu.l of oxalyl 
chloride and 1.5 ml of methylene chloride. The reaction mixture was cooled 
to -60.degree. C., 1 ml of the methylene chloride solution containing 160 
.mu.l of dimethylsulfoxide was added over a period of 3 minutes and the 
reaction mixture stirred at -60.degree. C. for two minutes. 3 Ml of 
methylene chloride containing 500 mg of 5-O-t-butyl-dimethylsilyl 
22,23-dihydro avermectin B1a/B1b was added dropwise over a period of 5 
minutes and the reaction mixture stirred at room temperature for 30 
minutes. At the end of this period, 0.71 ml of triethylamine was added 
dropwise and the reaction mixture was stirred at -60.degree. C. for 5 
minutes. The cold bath was removed and the reaction mixture was allowed to 
come to room temperature over a period of 45 minutes. 50 Ml of water was 
added and the reaction mixture was extracted 3 times with 40 ml of ether. 
The ether extracts were combined and washed 4 times with 20 ml of water, 
dried over magnesium sulfate and concentrated to dryness in vacuo 
affording 520 mg of a yellow glass. The yellow glass was dissolved in 
methylene chloride and placed on three 2,000.mu. silica gel preparative 
layer chromatography plates. The plates were developed with 10% ethyl 
acetate in methylenechloride and afforded 470 ml of yellow foam which was 
characterized by its 300 MHz nuclear magnetic resonance spectrum as 
5-O-t-butyl dimethyl-silyl-4"-keto-22,23-dihydro avermectin B1a/B1b. 
PREATION 3c 
4"-Keto-5-O-t-butyldimethylsilylavermectin B1a/B1b 
If avermectin B1a/B1b is reacted according to the procedures of Preparation 
3a and 3b, 4"-keto-5-O-t-butyldimethylsilylavermectin-B1a/B1b is obtained. 
PREATION 3d 
4"-Keto-avermectin B1a/B1b 
If the product of Preparation 3c is reacted according to the procedures of 
Example 17f, 4"-keto- avermectin B1a/B1b is obtained. 
PREATION 4a 
4"-Keto-5-O-t-butyldimethylsilyl-22,23-dihydroavermectin B1a/B1b 
monosaccharide 
If 22,23-dihydroavermectin B1a/B1b-monosaccharide is reacted according to 
the procedures of Preparations 3a and 3b, 4'-keto-5-- 
O-t-butyldimethylsilyl-22,23-dihydroavermectin B1a/B1 b monosaccharide is 
obtained. 
PREATION 4b 
4"-Keto-22,23-dihydroavermectin B1a/B1b monosaccharide 
If the product of preparation 4a is reacted according to the procedures of 
Example 17f 4'-keto-22,23-dihydroavermectin B1a/B1b monosaccharide is 
obtained. 
PREATION 5 
22,23-dihydro-5-oxo-avermectin B1a/B1b 
22,23-dihydro 5oxo avermectin B1a/B1b was prepared as described by J. D. 
Stong Anal. Chem. 1987, 59, 266-270 and J. C. Chabala et al. J Agric. Food 
Chem. 1981, 29, 881-884. 
PREATION 6 
5-O-tert-Butyldimethylsilyl-22,23-dihydro avermectin B1a and/or B1b 
aglycone 
5-O-tert-Butyldimethylsilyl-22,23-dihydro avermectin B1a and/or B1b 
aglycone was prepared as described by H. Mrozik et al. Tetrahedron Lett. 
1983, 24, 5333-5336. 
PREATION 7 
5-O-tert-Butyldimethylsilylavermectin B2a/B2b aglycone 
A solution of 400 mg of avermectin B2a/B2b aglycone (described by G. 
Albers-Schonberg et al. J. Am. Chem. Soc. 1981, 103, 4216-4221) in 8.0 ml 
of DMF was treated with 544 mg of imidazole and 600 mg of 
tert-butyldimethylsilyl-chloride and stirred at room temperature for 50 
minutes. Then water was added and the product was extracted with ether. 
The ether extracts were washed repeatedly with water, dried and 
concentrated in vacuo to 800 mg of a light foam. Purification by 
preparative silica gel layer (2 mm thickness) chromatography with 95:5 
CH.sub.2 Cl.sub.2 -THF solvent mixture gave 138 mg of 
5,23-O-tert-butylimethylsilylavermectin B2a and/or B2b aglycone and 330 mg 
of the desired 5-O-tert-butyldimethylsilylavermectin B2a and/or B2b 
aglycone, which were characterized by their mass and .sup.1 H-NMR spectra. 
PREATION 8 5-O-tert-Butyldimethylsilyl-13-beta-chloro-13-deoxyavermectin 
B2a and/or B2b aglycone 
A solution of 150 mg of 5-O-tert-butyldimethylsilylavermectin B2a and/or 
B2b aglycone (obtained in Preparation 7), 40 mg of 
4-dimethylaminopyridine, 0.3 ml (=222 mg) of N,N-diisopropylethylamine in 
5.0 ml of anhydrous CH.sub.2 Cl.sub.2 stirred at room temperature was 
treated with a solution of 286 mg of 2-nitrobenzenesulfonyl chloride in 
0.5 ml of anhydrous CH.sub.2 Cl.sub.2. After 3 hours water was added and 
the product was extracted with CH.sub.2 Cl.sub.2. The extract was washed 
with water, dried and concentrated in vacuo to 300 mg of an orange colored 
solid. Purification by preparative silica gel layer chromatography using 
CH.sub.2 Cl.sub.2 containing 4% of THF and 0.1% of ethanol as solvent gave 
88 mg of 5"-O-tert-butyldimethylsilyl-13-beta chloro-13-deoxyavermectin 
B2a and/or B2b aglycone as a yellow glass, which was characterized by its 
mass and 300 MHz .sup.1 H-NMR spectra. 
PREATION 9 
5-O-tert-Butyldimethylsilyl 13-deoxyavermectin B2a and/or B2b aglycone 
A solution of 67 mg of 5-O-tert-butyldimethylsilyl-13-beta 
chloro-13-deoxyavermectin B2a and/or B2b aglycone and 20 mg of 
2,2'-azobis(2-methylpropionitrile) in 1.5 ml of tributyltin hydride was 
stirred for 3.3 hours at 85.degree. C. It was cooled to room temperature, 
diluted with CH.sub.2 Cl.sub.2 and poured through a column containing 50 g 
of silica gel. Several column volumes of CH.sub.2 Cl.sub.2 were used to 
wash off the tin compounds. Then EtOAc was used to elute the product. 
Evaporation of the solution to dryness in vacuo gave 100 mg of crude 
5-O-tert-butyldimethylsilyl-13-deoxyavermectin B2a and/or B2b aglycone, 
which was characterized by its mass spectrum. Further purification is 
achieved using preparative silica gel layer chromatography.