Erythromycin a derivatives and method for preparing same

Details Erythromycin a derivatives and method for preparing same Erythromycin a derivatives and method for preparing same

1992-04-14

2002-01-29

Peselev, Elli (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S018500

Reexamination Certificate

active

06342590

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to erythromycin A derivatives and the method for the preparation of the same.
2. Description of the Prior Art
6-O-Methylerythromycins are useful as anti-bacterial agents or intermediates for synthesis of the antibacterial agents. For example, 6-O-methylerythromycin A is not only stable under the acidic conditions but also has a strong antibacterial activity when compared with erythromycin A. Especially, this compound shows an excellent effect for treatment of infections by oral administration, and therefore it is a useful antibacterial agent.
There are known in the past some methods for methylating the hydroxy group at the 6-position of the erythromycin A derivatives, for example, (1) a method which comprises substituting the hydrogen atom of the hydroxy group at the 2′-position and the methyl group of the dimethylamino group at the 3′-position of the erythromycin A derivatives by benzyloxycarbonyl groups, and then methylating the resulting compound (U.S. Pat. No. 4,331,803), and (2) a method which comprises converting erythromycin A derivatives having the protected hydroxy group at the 2′-position and/or the protected dimethylamino group at the 3′-position into the various kind of the substituted oxime derivative, and then methylating the substituted derivatives (European Patent 158,467).
However, since erythromycin A has many hydroxy groups, there are obtained various kind of erythromycin A derivatives which are methylated at hydroxy groups at any other than the 6-position as the by-products by the method of item (1). Accordingly, this method requires the complicated procedure for purification of the 6-O-methylerythromycin A derivatives, and has drawback of causing low yield of said derivatives. Although it is possible to methylate selectively the 6-hydroxy group by the method of item (2), when the erythromycin A 9-oxime derivative whose 2′-hydroxy group only is protected is methylated, the 3′-dimethylamino group is changed to a methyl quaternary salt under ordinary methylation conditions. Furthermore it is difficult to return the salt to a dimethylamino group, accordingly, it is necessary to protect both of the 2′-hydroxy group and 3′-dimethylamino group for the practical preparation method.
SUMMARY OF THE INVENTION
As a result of the various researches to solve the drawbacks of the above known methods, the present inventors have found the fact that erythromycin A derivative whose 2′-hydroxy group is protected with the substituted silyl groups is not quaternarized at the adjacent 3′-dimethylamino group even under ordinary methylation conditions, and the present invention has been completed.
DETAILED DESCRIPTION OF THE INVENTION
An object of the present invention is to provide 6-O-methylerythromycin A derivatives represented by the general formula
wherein R
1
is a 2-alkenyl group having 3 to 15 carbon atoms, an arylmethyl group, or an arylmethyl group substituted by 1 to 3 of a halogen atom, an alkoxy group having 1 to 4 carbon atoms, a nitro group or an alkoxycarbonyl group having 2 to 6 carbon atoms, R
2
is a substituted silyl group of formula —SiR
4
R
5
R
6
(wherein R
4
, R
5
and R
6
are the same or different, and each is a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, a phenyl substituted alkyl group in which the alkyl moiety has 1 to 3 carbon atoms, a phenyl group, a cycloalkyl group having 5 to 7 carbon atoms or an alkenyl group having 2 to 5 carbon atoms, with the proviso that at least one of R
4
, R
5
and R
6
is other than hydrogen atom) and R
3
is a hydrogen atom or R
2
.
Another object of the present invention is to provide erythromycin A derivatives represented by the general formula
wherein R
1
, R
2
and R
3
are as defined above.
Still another object of the present invention is to provide a method for preparing 6-O-methylerythromycin A derivatives of formula I which comprises reacting, in any desired sequence, erythromycin A 9-oxime with a compound of formula R
1
—X (wherein R
1
is as defined above, and X is a halogen atom) and with a substituted silylating agent having R
2
group to give a compound of formula II, and then reacting the compound of formula II with a methylating agent.
In the present invention, the terms “alkyl”, “alkoxy” and “alkenyl” used alone or as combined with the other group mean those whose carbon chain may be linear or branched. The term “arylmethyl group” means a benzyl group, a benzhydryl group, a trityl group or a naphthylmethyl group. Examples of the substituted arylmethyl group are a p-methoxybenzyl group, a p-chlorobenzyl group, a m-chlorobenzyl group, an o-chlorobenzyl group, a 2,4-dichlorobenzyl group, a p-bromobenzyl group, a m-nitrobenzyl group, a p-nitrobenzyl group and the like. Examples of 2-alkenyl group for R
1
are an allyl group, a methallyl group, a crotyl group, a prenyl group, a 2-pentenyl group, a 2-ethyl-2-butenyl group, a geranyl group, a neryl group and the like. The term “halogen atom” refers to a chlorine, a bromine, an iodine atom and the like. Examples of the substituted silyl group are a trimethylsilyl group, a triethylsilyl group, an isopropyldimethylsilyl group, a tert-butyldimethylsilyl group, a (triphenylmethyl)dimethylsilyl group, a tert-butyldiphenylsilyl group, a diphenylmethylsilyl group, a diphenylvinylsilyl group, a methyldiisopropylsilyl group, a tribenzylsilyl group, a tri(p-xyryl)silyl group, a triphenylsilyl group, a diphenylsilyl group, a dimethyloctadecylsilyl group and the like.
The present invention is illustrated below in more detail. At first, etherification of erythyromycin A 9-oxime with a compound of formula R
1
—X is carried out according to the known method per se, for example, the method described in European Patent No. 158,467 to give a compound of formula
wherein R
1
is as defined above.
The reaction of the compound of formula III with the silylating agent is carried out in a solvent in the presence of a base at 0° C. to the reflux temperature of the solvent, preferably at room temperature with stirring. Examples of the silylating agent used are chlorosilanes such as trimethylchlorosilane, tert-butyldimethychlorosilane and the like; silylamines such as 1,1,1,3,3,3-hexamethyldisilazane, trimethylsilylimidazole, dimethylaminotrimethylsilane and the like; bis(trimethylsilyl)acetamide, trimethylsilyldiphenylurea, bis(trimethylsilyl)urea and the like. The amount of the silylating agent used is 1 to 10 equivalents, preferably 1 to 5 equivalents relative to the compound of formula III.
Examples of the solvent used in the reaction are acetone, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, dioxane, 1,2-dimethoxyethane, dichloromethane, chloroform and the like. Examples of the base are inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like; and organic bases such as trimethylamine, triethylamine, pyridine, 1,8-diaza-bicyclo[5,4,0]unde-7-cene, imidazole and the like.
Although difference of the silylation at the 2-position only between both of the 2′- and 4″-positions of the compound of formula III depends on the reaction conditions, it is preferable to use a chlorosilane for the silylation at the 2-position only, and it is preferable to use both a chlorosilane and a silylamine or 1,1,1,3,3,3-hexamethyldisilazane for the silylation at the 2′- and 4″-positions.
Alternatively, the compound of formula II can be obtained by etherification after silylation of erythromycin A 9-oxime. Namely, erythromycin A 9-oxime is reacted with the silylating agent under the same silylation conditions as described above, and then the resulting compound is reacted with the compound of formula R
1
—X under the same etherification conditions as described above to give the compound of formula II.
The reaction of the compound of formula II with the methylating agent for preparing the compound I can be carried out in a sol

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