Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1987-04-28
1989-07-11
Rizzo, Nicholas S.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514192, 514195, C07D49900, A61K 3143
Patent
active
048472662
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a new and improved method for the preparation of a compound of the formula I ##STR2## in which R stands for halogen, i.e. chlorine, bromine or iodine, and salts thereof. More particularly, it relates to a new and improved method for the preparation of 6.beta.-halopenicillanic acids and salts thereof, which are known .beta.-lactamase inhibitors enhancing the effectiveness of penicillins and cephalosporins against a wide range of .beta.-lactamase producing bacteria.
It has been reported (J. Org. Chem. Vol. 43 pp. 3611-3613, 1978; Proc. Natl. Acad. Sci. USA. Vol. 75, pp. 4145-4149, 1978; U.S. Pat. No. 4,180,506 (1979); Biochem. J. Vol. 177 pp. 365-367, 1979) that mixtures of 6.beta.- and 6.alpha.-bromopenicillanic acid were obtained either by epimerization of the latter or by selective hydrogenation of 6,6-dibromopenicillanic acid. In these references, 6.beta.-bromopenicillanic acid has always been described as the minor component of an inseparable mixture with 6.alpha.-bromopenicillanic acid, the former being present in estimated amounts of from 5 to 15%.
It has further been reported (Tetrahedron Letters No. 48, pp. 4631-4634, 1979; U.S. Pat. No. 4,347,182 (1982); U.S. Pat. No. 4,397,783 (1983)) that selective reduction of esters of 6-arylselenyl-6-chloro- or 6,6-dihalopenicillanic acids with tri-n-butyltin hydride or triphenyltin hydride afforded 6.beta.-halopenicillanic acid esters in about 50% yield, together with substantial amounts of the corresponding esters of penicillanic acid and the 6.alpha.-halo and 6,6-dihalo derivatives. Following separation of the 6.beta.-halo ester from its contaminants and removal of the ester group by hydrolysis, the free 6.beta.-halopenicillanic acid or a salt thereof containing not more than 5% of the corresponding 6.alpha.-epimer was obtained in about 30% yield, based upon the starting 6,6-dihalo ester.
According to British patent application GB No. 2,051,055A and Tetrahedron Letters. Vol. 21 pp. 2991-2994 (1980), similar yields of 6.beta.-halopenicillanic acids or salts thereof were obtained by nucleophilic substitution of 6.alpha.-perfluoroalkylsulphonyloxypenicillanic acid esters with halide ions and subsequent hydrolysis of the resulting 6.beta.-halo substituted esters.
The preparation of pure 6.beta.-halopenicillanic acids and base salts thereof from the corresponding 6.alpha.-halo derivatives by aqueous equilibration of the latter and subsequent separation of the resulting epimeric mixture has been described in British patent GB No. 2,125,035B and J. Antibiotics Vol. 33 pp. 451-452 (1980). The former reference also discloses the selective reduction of 6,6-dihalopenicillanic acids or salts thereof by treatment with alkali metal borohydrides, tetraalkylammonium boranate or sodium cyanoborohydride to give favourably high yields (>50%) of the free 6.beta.-halopenicillanic acids which were separated from the respective reaction mixtures by column chromatography or by fractionate crystallization.
However, it is a disadvantage of the prior art methods leading to the preparation of 6.beta.-halopenicillanic acids that (i) the introduction and removal of the carboxyl-protecting group requires two additional steps in the overall synthesis, and/or (ii) the separation of the 6.beta.-epimer from undesired by-products requires purification by chromatographic methods or by fractionate crystallization.
It has now surprisingly been found that high yields (up to 70% or more) of substantially pure 6.beta.-halopenicillanic acids can be obtained in one step by the present improved method which comprises base-catalyzed epimerization of a suitable salt of a 6.alpha.-halopenicillanic acid suspended in an aqueous-organic solvent mixture with precipitation of the less soluble salt of the corresponding 6.beta.-halopenicillanic acid thus formed. Hereby, the equilibrium of the epimerization reaction, which in solution is strongly in favour of the 6.alpha.-epimer, is shifted in the desired direction to provide precipitation of a substantially pure salt of a com
REFERENCES:
patent: 4296032 (1981-10-01), Dennerly
patent: 4594246 (1986-06-01), von Daehne et al.
Daehne Welf von
Hansen Erik I.
Kran-Nielsen Mogens P.
Leo Pharmaceutical Products Ltd.
Rizzo Nicholas S.
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