Erythromycin a compounds and process for preparing the same

Details Erythromycin a compounds and process for preparing the same Erythromycin a compounds and process for preparing the same

2001-06-29

2003-03-04

Peselev, Elli (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S007200, C536S018500

Reexamination Certificate

active

06528628

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a new erythromycin A 9-oxime compound which can effectively be used as an intermediate for the preparation of 6-O-alkyl erythromycin A such as 6-O-methyl erythromycin A (hereinafter referred to as “clarithromycin”) or its oxime, a process for preparing the same and a process for preparing 6-O-alkyl erythromycin A or its oxime using the same.
BACKGROUND ART
6-O-alkyl erythromycin A is a semi-synthetic macrolide antibacterial agent showing an excellent antibacterial activity against a number of bacteria which can cause diseases in human or mammals, for example, gram-positive bacteria, a part of gram-negative bacteria, anaerobic bacteria, Mycoplasma, and Chlamidia, etc., and also can be used as a raw material for the synthesis of other antibiotic in this field, and it therefore is a pharmaceutically important material.
6-O-alkyl erythromycin A compound including 6-O-methyl erythromycin A can be prepared by selectively alkylating the 6-position of suitably protected erythromycin A 9-oxime, eliminating the protecting groups and then carrying out deoximation. Since erythromycin A 9-oxime has a number of reactive hydroxy groups including the hydroxy group of oxime and a dimethylamino group at the 3′ position which can also participate in alkylation, it is very important to carry out alkylation of the hydroxy group at the 6 position after protecting these groups with suitable substituents.
Prior art processes for preparing 6-O-alkyl erythromycin A, especially 6-O-methyl erythromycin A from erythromycin A 9-oxime are disclosed in EP patent Nos. 0,158,467, 0,195,960, and 0,272,110 and U.S. Pat. No. 5,719,272 and WO 97/36913.
Separately from the above processes, processes for preparing it from erythromycin A derivatives are disclosed in EP Patent Nos. 0,147,062 and 0,177,696, but these are not practical.
Known processes for preparing 6-O-alkyl erythromycin A compound from erythromycin A 9-oxime can be summarized as follows:
(1) The first method comprises protecting oxime hydroxy group of erythromycin A 9-oxime with an alkyl group, etc. and protecting the hydroxy group at the 2′ position and dimethylamino group at the 3′ position with benzyloxycarbonyl groups, thereafter carrying out alkylation such as methylation of the hydroxy group at the 6 position.
However, this process has some problems in industrial use since benzyloxycarbonyl chloride used as the protecting group is expensive and must be used in an excess amount. Furthermore, it has a drawback that it requires an additional step for regenerating the dimethylamino group at the 3′ position after carrying out alkylation of the hydroxy group at the 6 position.
(2) The second process comprises protection of the oxime hydroxy group and the hydroxy group at the 2′ position of erythromycin A 9-oxime with benzyl groups, together with quarternization of the dimethylamino group at the 3′ position with the same protecting group, and then alkylation of the hydroxy group at the 6 position.
However, this process has a drawback that, after carrying out alkylation of the hydroxy group at the 6 position, the protecting group at the 2′ position is not readily removed in the step of deprotection of the benzyl group by hydrogenation due to catalytic poison phenomenon.
(3) The third process comprises protection of the oxime hydroxy group of erythromycin A 9-oxime with a ketal compound such as cyclohexanone diisopropyl ketal, protection of the hydroxy groups at the 2′ and 4′ positions with silyl groups, and then carrying out alkylation of the hydroxy group at the 6 position. This process has advantages that it does not require protection of the dimethylamino group at the 3′ position, and it is possible to eliminate the protecting groups at one time after carrying out alkylation. However, it has a drawback that ketal compounds which are used in protecting the hydroxy group of oxime should be separately synthesized.
(4) The fourth method comprises carrying out protection of all of the oxime hydroxy group and the hydroxy groups at the 2′ and 4′ positions of erythromycin A 9-oxime with silyl groups, and then carrying out alkylation of the hydroxy group at the 6 position. However, this process has a number of drawbacks that since the silyl group is quite unstable as the protecting group for oxime, the hydroxy group of oxime is also alkylated during the alkylation reaction for the hydroxy group at the 6 position.
DISCLOSURE OF INVENTION
Therefore, the present inventors have extensively conducted a research in order to solve the above mentioned drawbacks involved in the prior art techniques and to prepare 6-O-alkyl erythromycin A in a high yield. As a result, we found that 6-O-alkyl erythromycin A of the general formula (II) and its oxime can conveniently be prepared in a high yield with low cost by a process wherein two molecules of the hydroxy groups of erythromycin A 9-oxime is first protected with one molecule of protecting group using the protecting groups which can react with oxime at two positions to give a erythromycin A 9-oxime compound in symmetric structure; and then up to four hydroxy groups of erythromycin A 9-oxime compound corresponding to the 2′ and 4″ positions of erythromycin A are protected with silyl protecting groups; and the hydroxy group at the 6 position is selectively alkylated; and finally deprotection and deoximation are carried out.
wherein,
R represents hydrogen or a C
1-3
alkyl group; and
X represents O or N—OH.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention provides a process for preparing 6-O-alkyl erythromycin A 9-oxime and 6-O-alkyl erythromycin A represented by the following formula (II) which comprises the steps (a) to (e):
(a) reacting erythromycin A 9-oxime represented by the following formula (III) with a bifunctional linker represented by the following formula (IV) to give an erythromycin A 9-oxime compound represented by the following formula (V);
(b) silylating the erythromycin A 9-oxime compound of formula (V) obtained in the step (a) to give an erythromycin A 9-oxime compound represented by the following formula (VI);
(c) alkylating the compound of formula (VI) obtained in the step (b) to give an erythromycin A 9-oxime compound represented by the following formula (VII);
(d) desilylating the erythromycin A 9-oximie compound of formula (VII) obtained in step (c) to give an erythromycin A 9-oxime compound represented by the following formula (VIII); and
(e) removing the oxime protecting group of the compound of formula (VIII) obtained in the step (d) or consecutively carrying out removal of the oxime protecting group and deoximation reaction:
 wherein,
R represents a C
1-3
alkyl group;
R
1
and R
2
each independently represents a silyl group represented by —SiR
4
R
5
R
6
which R
4
, R
5
, and R
6
each independently represents a C
1-6
alkyl group, a C
1-3
alkyl group substituted with a phenyl group, a phenyl group, a C
5-7
cycloalkyl group, or a C
2-5
alkenyl group; or R
2
represents hydrogen;
R
3
represents hydrogen, a 1-alkenyl group, or an aryl group;
Q represents a cis- or trans-alkenylene group represented by —(CH═CH)
m
—, a &agr;,&ohgr;-dienylene group represented by —[CH═CH—(CH
2
)
m
—CH═CH]—, a phenyl group consisting of ortho-, meta- or para-, etc., an arylene group such as naphthalenyl, anthracenyl or pyridinyl group, etc. or an alkylene group represented by —(CH
2
)
n
— when R
3
represents a 1-alkenyl group or an aryl group, m is an integer of 1 to 3, and n is an integer of 1 to 10, wherein one or more hydrogens in the above alkylene group, alkenylene group, dienylene group or arylene group may be substituted with a suitable alkyl substituent;
X represents O or N—OH; and
Y represents a leaving group such as chloride, bromide, iodide, mesylate, tosylate and triflate.
The present invention also provides an erythromycin A 9-oxime compound represented by the following formula (I) which can be used as an intermediate for th

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