Production of avermectin compounds

Details Production of avermectin compounds Production of avermectin compounds

2000-04-06

2001-07-03

Peselev, Elli (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06255463

ABSTRACT:

TECHNICAL FIELD
This invention relates to a novel and improved process for preparing an avermectin compound of the formula (I) from an avermectin B2 compound of the formula (II), a fermentation derived avermectin product. This avermectin compound of the formula (I) is known to be of value as antiparasitic agents. This process results in a significant improvement in the overall yield.
BACKGROUND ART
In accordance with the prior art, there has already been described certain compounds which are known to be of value as antiparasitic agents. Included among these are such avermectin compounds which are described and claimed by Bishop Bernard Frank et al., in International Publication Number WO 94/15944, and by Fisher, Michael H. et. al., in European Publication Number EP 0 379 341 A2. However, according to the above conventional methods, the yield of the final reaction product was not always satisfactory. It is an object of this invention to convert the avermectin compound of formula (II) to avermectin compound of the formula (I) in high yield.
BRIEF DESCRIPTION OF THE INVENTION
The present invention provides a process for preparing a compound of the formula
wherein R
1
is H or a hydroxyimino-protecting group; R
2
is H, C
1-4
alkyl or C
1-4
alkoxy; R
3
is C
1-8
alkyl (preferably C
1-4
alkyl), C
2-8
alkenyl (preferably C
2-5
alkenyl) or C
3-8
cycloalkyl (preferably cyclohexyl); and R
4
is H, halo, C
1-4
alkyl or C
1-4
alkoxy, which process comprises the steps of:
(a) reacting a compound of formula (II):
 with an oxidizing agent to form a 5-oxo compound;
(b) allowing the 5-oxo compound to react with a compound of formula R
1
—O—NH
2
wherein R
1
is H or a hydroxyimino-protecting group, to form a 5-imino compound;
(c) reacting the 5-imino compound with a thionocarbonizing agent to form a 4″, 23-bisthionocarbonyl ester;
(d) reacting the 4″, 23-bisthionocarbonyl ester with a deoxygenation agent to form a 4″,23-dideoxy compound; and
(e) reacting the 4″, 23-dideoxy compound with an acid to form a compound of the formula (I).
This process further comprises, when R
1
is H, adding halotriphenylsilane, tert-butyldimethylsilane, halotrimethylsilane, halo(halomethyl)silane, haloallyldimethylsilane, halotriethylsilane, halotriisopropylsilane, halo(3-cyanopropyl)dimethylsilane, halodimethylloctylsilane, halotribenzylsilane, halotrihexylsilane or the like (preferably halotriphenylsilane), and triethylamine, tri-n-propylamine, diisopropylethylamine, imidazole, pyridine or 4-dimethylaminopyridine after the step (b) to protect the hydroxyimino group. Also, the reaction in step (e) (optionally followed by deprotection process) may be carried out in the presence of a palladium catalyst when R
1
is an allyl group. As previously indicated, the final products produced by this process of the present invention are useful compounds as antiparasitic agents.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term “C
1-8
alkyl” means straight or branched chain saturated radicals of 1 to 8 carbon atoms, including, but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl, pentyl, hexyl, and the like.
As used herein, the term “C
2-8
alkenyl” means straight or branched chain unsaturated radicals of 2 to 8 carbon atoms, including, but not limited to 1-ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 2-methyl-1-propenyl and the like.
As used herein, the term “C
3-8
cycloalkyl” means carbocyclic radicals, of 3 to 8 carbon atoms, including, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
As used herein, the term “halo” means fluoro, chloro, bromo or iodo.
As used herein, the term “allyl group” means alkyl or substituted alkyl group having a carbon-carbon double bond at the 2,3-position, including, but not limited to allyl, methylallyl, crotyl, chloroallyl, cinnamyl, and the like.
The process of the invention is described in detail herein below.
In the reaction in step (a), a compound of formula (II):
is reacted with an oxidizing agent to form a corresponding 5-oxo compound. More specifically, in this reaction, a hydroxyl group at the 5-position of the compound (II) is converted to an oxo group by oxidation. The compound of the formula (II) is an avermectin B2 compound which is a fermentation derived avermectin product. The compound of formula (II) can be isolated via fermentation of an avermectin producing strain of
Streptomyces avermitilis
such as ATCC 31267, 31271 or 31272, as described in U.S. Pat. No. 5,089,480. Other methods for obtaining the compound of formula (II) includes isolation from the fermentation broth of
Streptomyces avermitilis
ATCC 53568, as described in Dutton et al., Journal of Antibiotics, 44, 357-65 (1991).
Suitable oxidizing agents include, for example, manganese dioxide, nickel peroxide or pyridinium dichromate. Preferred is manganese dioxide in view of the selective oxidation of the &agr;-position of a double bond. The oxidizing agent used in step (a) may be used in an amount of from 1 to 200 equivalents, preferably from 10 to 70 equivalents, against the compound of the formula (II) to be treated. The reaction in step (a) may be carried out at a temperature of 0 to 80° C. for 10 minutes to 10 hours. This reaction may be carried out in an inert solvent selected from, but no limited to chloroform, dichloromethane, benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, acetone, acetonitrile, tert-butyl methyl ester and a mixture thereof. Preferred is dichloromethane.
In the reaction in step (b), the 5-oxo compound obtained is reacted with a compound of formula R
1
—O—NH
2
wherein R
1
is H or a hydroxyimino-protecting group to form a 5-imino compound. Suitable hydroxyimino-protecting groups include, for example, triphenylsilyl, tert-butyldimethylsilyl, tetrahydropyranyl, methylthiomethyl, allyl, methylallyl, crotyl, chloroallyl, cinnamyl or allyoxycarbonyl (preferably triphenylsilyl or allyl [CH
2
═CHCH
2
—]). The iminizing agent used in step (b) (R
1
—O—NH
2
) may be used in an amount of from 0.5 to 50 equivalents, preferably from 1 to 10 equivalents, against the 5-oxo compound to be treated. The reaction in step (b) is carried out at a temperature of −10 to 80° C. for 5 minutes to 20 hours. This reaction may be carried out in an inert solvents selected from, but no limited to chloroform, dichloromethane, benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, methanol, tert-butyl methyl ether, acetonitrile, isopropanol, water and a mixture thereof. Preferred is a mixture of methanol, dioxane and water.
In the reaction in step (c), the 5-imino compound is reacted with a thionocarbonizing agent to form a 4″, 23-bisthionocarbonyl ester. Suitable thionocarbonizing agents include, for example, R
5
O—C(S)-halo or R
5
S—C(S)-halo (preferably the halo is chloro) wherein R
5
is C
1-4
alkyl, phenyl or naphthyl, the phenyl or naphthyl being optionally substituted with one or two substituents selected from C
1-4
alkyl, C
1-4
alkoxy, halo-substituted C
1-4
alkyl, halo-substituted C
1-4
alkoxy, nitro, hydroxy, amino and halo. Preferred is phenyl chlorothionoformate. The thionocarbonizing agent used in step (c) may be used in an amount of from 1 to 20 equivalents, preferably from 2 to 5 equivalents, against the 5-imino compound to be treated. The reaction is carried out at a temperature of 0 to 130° C. for 5 minutes to 10 hours in an inert solvents selected from, but not limited to chloroform, dichloromethane, benzene, toluene, xylene, tetrahydrofuran, dioxane, dimethylformamide, acetonitrile, ethyl acetate and a mixture thereof. Preferred is toluene.
In the reaction in step (d), the 4″, 23-bisthionocarbonyl ester is reacted with a radical deoxygenation agent to form a 4″, 23-dideoxy compound. Suitable deoxygenation agents include, for example, tributyltin hydride, tris(trimethylsilyl)silane, triethylsilane, tripropylsilane, phenylsilane, diphenylsilane, triphenylsilane, dialkylphos

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