Intermediate for azithromycin

Details Intermediate for azithromycin Intermediate for azithromycin

1995-11-13

1997-11-11

Kight, John

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

Organic compounds

Carbohydrates or derivatives

514 29, 536 185, 536125, C07H 1708, C08B 0100

Patent

active

056865872

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to antibiotics, and particularly relates (1) to an intermediate per se, useful for making the known antibiotic azithromycin, (2) to a process for making azithromycin with the intermediate, and (3) to processes for making the intermediate.


BACKGROUND OF THE INVENTION

Erythromycin is an antibiotic formed during the culturing of a strain of Streptomyces erythreus in a suitable medium as taught in U.S. Pat. No. 2,653,899. Erythromycin, which is produced in two forms, A and B, is represented by the following structure (I):


______________________________________ ##STR1## (I) ERYTHROMYCIN Erythromycin R ______________________________________ A OH B H ______________________________________
The structure reveals that the antibiotic is comprised of three main portions: a sugar fragment known as cladinose, a second sugar moiety containing a basic amino substituent known as desosamine and a fourteen membered lactone ring referred to as erythronolide A or B or as the macrolide ring.
Azithromycin is the U.S.A.N. (generic name) for 9a-aza-9a-methyl-9-deoxo-9a-homoerythromycin A, a broad spectrum antibacterial compound derived from erythromycin A. Azithromycin was independently discovered by Bright, U.S. Pat. No. 4,474,768 and Kobrehel et al., U.S. Pat. No. 4,517,359, and was named N-methyl-11-aza-10-deoxo-10-dihydro-erythromycin A in these patents. It has the following structure (II) wherein the numbering system conventionally employed is shown: ##STR2## The above patents also disclose that (II) and certain derivatives thereof possess antibacterial properties.
In particular, the procedure for making azithromycin from erythromycin A involves relatively strong reaction conditions as described, for example, in Djokic et al., J. Chem. Soc. Perkin Trans. I, 1881, (1986), wherein the preparation of 10-dihydro-10-deoxo-11-azaerythromycin A from an imino ether precursor was effected by catalytic hydrogenation in acetic acid under 70 atm of H.sub.2.


SUMMARY OF THE INVENTION

In a first aspect, this invention provides a compound having formula III ##STR3## Compound III, 9-deoxo-11-deoxy-9,11-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A, herein also referred to as a 9,11-imino ether, has utility as an intermediate for making azithromycin, and can be reduced to a direct precursor of azithromycin having formula IV, shown below. The precursor of Formula IV need only be N-methylated (position 9a) to produce azithromycin. Accordingly, in a further aspect, this invention provides a process of making azithromycin, comprising reducing the (9,11-imino ether) compound of formula III to 9a-aza-9-deoxo-9a-homoerythromycin A, a compound having formula IV ##STR4## and thereafter N-methylating the said compound of formula IV.
In a further aspect, this invention provides a process of making an intermediate of formula III, comprising isomerizing a compound of formula V, 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-homoerythromycin A: ##STR5## in a suitable solvent.
In still a further aspect, this invention provides an additional process of making an intermediate of formula III, comprising treating a compound of formula VI ##STR6## with tosyl chloride and pyridine in diethyl ether at a temperature of less than about 10.degree. C. for a time between about 0.5 and about 50 hours.


DETAILED DESCRIPTION

A general reaction scheme for (1) making the intermediate 9,11-imino ether and (2) using the intermediate 9,11-imino ether to make azithromycin is shown in Scheme 1: ##STR7##
In the above scheme the starting material in step A, compound (VI) is the E-isomer of 9-deoxo-9-hydroxyimino erythromycin A and can be made by known procedures such as the straightforward reaction of Erythromycin A with hydroxylamine to produce the erythromycin E-oxime as the major isomer. The oxime is treated with tosyl chloride in the presence of pyridine as a base and in a suitable solvent such as a dialkyl ether (e.g. diethyl ether), thereby initially forming a corresponding O-tosyl oxime which is a su

REFERENCES:
patent: 4328334 (1982-05-01), Kobrehel et al.
patent: 4382085 (1983-05-01), Sciavolino
patent: 4464527 (1984-08-01), Bright
patent: 4474768 (1984-10-01), Bright
patent: 4512982 (1985-04-01), Hauske et al.
patent: 4517359 (1985-05-01), Kobrehel et al.
patent: 4518590 (1985-05-01), Hauske et al.
patent: 4526889 (1985-07-01), Bright
patent: 5189159 (1993-02-01), Wilkening
patent: 5202434 (1993-04-01), Wilkening
Bright et al., J. Antibiotics, vol. XLI, No. 8, 1029-1047 (1988).
Gasc et al., J. Antibiotics, vol. 44, No. 3, No. 313-330 (1991).
Egan et al., J. Org. Chem., vol. 39, No. 17, 2492-2494 (1974).
Djokic et al., J. Chem. Soc. Perkin Trans. I, (1986), 1881-1890.
Jones, J. Org. Chem., vol. 57, 4361-4367 (1992).

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