Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-11-24
1989-03-28
Rizzo, Nicholas S.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
514192, 514195, C07D49900, A61K 31425
Patent
active
048165808
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a new process for the debromination and/or deiodination of 6,6-dihalo- and 6-monohalopenicillanic acids or derivatives thereof by treatment with a dialkyl, trialkyl or diaralkyl phosphite. The compounds prepared according to the present process have useful pharmacological and chemical properties, for example, as .beta.-lactamase inhibitors or as intermediates for the synthesis of .beta.-lactamase inhibitors and other valuable .beta.-lactams.
More particularly, the invention relates to a new and improved process for the preparation of a 6.alpha.-halo compound of the formula I ##STR1## wherein R.sup.1 is chloro, bromo or iodo, R.sup.5 is hydrogen, a carboxylate salt forming cation, a conventional carboxy protecting group or an ester-forming residue readily hydrolyzable under physiological conditions, and n is an integer of 0 to 2, which comprises treatment of a 6,6-dihalo compound of the formula II ##STR2## wherein R.sup.1, R.sup.5 and n are as previously defined and R.sup.2 is bromo or iodo, with substantially one molar equivalent of a dialkyl, trialkyl or diaralkyl phosphite.
The same process can also be applied for the preparation of a deshalogenated compound of the formula III ##STR3## wherein R.sup.5 and n are as previously defined, which comprises treatment of a 6,6-dihalo or 6-monohalo compound of the formula IV ##STR4## wherein R.sup.5 and n are as previously defined and R.sup.3 and R.sup.4 are each bromo or iodo, or one of R.sup.3 and R.sup.4 is bromo or iodo and the other is hydrogen, with at least one or at least two molar equivalents, depending on whether one or both of R.sup.3 and R.sup.4 stand for bromo or iodo, of a dialkyl, trialkyl or diaralkyl phosphite.
Similar dehalogenations have previously been reported, particular attention being paid to the debromination of 6,6-dibromo- and 6-monobromopenicillanic acids or derivatives thereof.
U.S. Pat. No, 4,180,506 describes the catalytic hydrogenation of 6,6-dibromopenicillanic acid in the presence of a palladium-on-carbon catalyst, leading to a mixture of 6.alpha.- and 6.beta.-bromopenicillanic acids.
EP No. 0013617 describes the reduction of various esters of 6,6-dibromopenicillanic acid or derivatives thereof with trialkyl or triaryltin hydrides, giving preferentially the 6.beta.-bromo isomers.
Similarly, U.S. Pat. No. 4,397,783 describes the trialkyl- or triaryltin reduction of various 6,6-dihalopenicillanic acid derivatives to provide preferentially the 6.beta.-halo isomers.
EP No. 0092286 describes the preparation of penicillanic acid 1,1-dioxide and derivatives thereof by debromination of 6.alpha.-bromo and/or 6,6-dibromopenicillanic acid 1,1-dioxides and derivatives thereof using zinc in association with an acid having a pK.sub.a -value of less than 3.5.
EP No. 0129360 and U.S. Pat. No. 4,468,351 describe the debromination of 6-monobromo- and 6,6-dibromopenicillanic acids and various derivatives thereof using a bisulfite salt in a reaction-inert aqueous solvent.
EP Nos. 0138282 and 0139048 describe the debromination of 6,6-dibromo- and 6.alpha.-bromopenicillanic acid 1,1-dioxides using magnesium in association with an acid.
However, it is a common feature of the dehalogenation methods of the prior art that they are difficult to apply on a commercial scale, either due to the use of costly and/or dangerous, often toxic reagents and/or the formation of undesired side products difficult to remove and/or necessitating extra purification steps.
It has now surprisingly been found that the dehalogenation of 6,6-dihalo- and 6-monohalopenicillanic acids or derivatives thereof, including the 1,1-dioxides, can readily be performed by treatment with a dialkyl, trialkyl or diaralkyl phosphite in a suitable aqueous solvent at about 0.degree.-100.degree. C., preferably at about 0.degree.-40.degree. C. Hereby, the desired 6.alpha.-halopenicillanic or penicillanic acid or derivative thereof is obtained in good to excellent yield and in a high state of purity. Furthermore, it has been shown that the process can readily be scal
REFERENCES:
patent: 4714761 (1987-12-01), Carroll et al.
Hirao et al, J. Org. Chem., 46:3745 ff (1981).
Leo Pharmaceutical Products Ltd. A/S
Rizzo Nicholas S.
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