Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-04-22
1995-01-17
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
564209, C07D26308
Patent
active
053826736
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel process for preparing florfenicol, its analogs and oxazoline intermediates thereto.
BACKGROUND OF THE INVENTION
Florfenicol, also known as [R-(R*,S*)]-2,2-dichloro-N-[1-(fluoromethyl)-2-hydroxy-2-[4-(methylsulfony l)phenyl]ethylacetamide, is a broad spectrum antibacterial agent useful in the treatment of gram positive, gram negative and rickettsial infections as disclosed in U.S. Pat. No. 4,361,557. The preparation of various oxazoline intermediates of florfenicol have been taught in U.S. Pat. Nos. 4,876,352; 4,743,700 and Patent Cooperation Treaty (PCT) International application No. PCT/US89/03827 having an international filing date of Sep. 12, 1989. Although a number of the above references teach efficient processes for preparing florfenicol, related analogs or processes for preparing their oxazoline intermediates, it would be desirable to provide a process which is even more efficient and economical by using fewer and/or less expensive starting materials, and which is less labor intensive by using fewer man-hours and simpler apparatus.
SUMMARY
In one embodiment, the present invention is directed toward a process for preparing a compound of formula (IV): ##STR3## wherein Z represents H, halo, nitro or H.sub.3 CSO.sub.x --, wherein x is 0, 1 or 2, comprising ##STR4## wherein Z is as defined hereinbefore, with a reagent capable of causing an equilibrium between oxazoline compound (I) and an oxazoline compound of formula (II): ##STR5## wherein Z is as defined hereinbefore, and the reagent drives the equilibrium toward oxazoline compound (II) by preferential precipitation of oxazoline compound (II); oxazoline compound of formula (III): ##STR6## wherein Z is as defined hereinbefore; and c) hydrolyzing compound (III) to compound (IV). Each arrow points to a carbon atom which is an asymmetric center giving rise to either the R or S stereoisomer configuration.
In a second embodiment, the present invention is directed towards a process for preparing a fluorinated oxazoline compound of formula (III): ##STR7## wherein Z represents H, halo, nitro or H.sub.3 CSO.sub.x --, wherein x is 0, 1 or 2, comprising ##STR8## wherein Z is as defined hereinbefore, with a reagent capable of causing an equilibrium between oxazoline compound (I) and an oxazoline compound of formula (II): ##STR9## wherein Z is as defined hereinbefore, and the reagent drives the equilibrium toward oxazoline compound (II) by preferential precipitation of oxazoline compound (II); and oxazoline compound (III).
In a third embodiment, the present invention is directed toward a process for preparing an oxazoline compound of formula (II): ##STR10## wherein Z represents H, halo, nitro or H.sub.3 CSO.sub.x --, wherein x is 0, 1 or 2, comprising contacting an oxazoline compound of formula (I): ##STR11## wherein Z is as defined hereinbefore, with a reagent capable of causing an equilibrium between oxazoline compound (I) and oxazoline compound (II), and the reagent drives the equilibrium toward oxazoline compound (II) by preferential precipitation of oxazoline compound (II). The process of this embodiment is equivalent to step (a) of the above processes. Preferably, the equilibrium driving reagent is a protic solvent and ammonia or an ammonium salt. Also preferred is that the protic solvent is isopropanol and the ammonium salt is ammonium acetate.
In another embodiment, oxazoline compound of formula (I) is prepared by contacting an aminodiol of formula (V): ##STR12## wherein Z is defined hereinbefore, with dichloroacetonitrile and an alcohol, and optionally in the presence of a catalytic amount of an acid, to give a mixture containing oxazoline compounds (I) and (II).
The present invention has the advantage of being more efficient and economical than other processes for preparing florfenicol, its analogs and oxazoline intermediates thereto, by using fewer or less expensive starting materials. Another advantage is that various embodiments of the present process are less labor intensive because
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Clark Jon E.
Schumacher Doris P.
Wu Guang-Zhong
Daus Donald G.
Majka Joseph T.
Schering Corporation
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