Glutaryl 7-ACA derivatives and processes for obtaining them

Details Glutaryl 7-ACA derivatives and processes for obtaining them Glutaryl 7-ACA derivatives and processes for obtaining them

1996-03-13

1998-05-12

Shah, Mukund J.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

540230, C07D50160

Patent

active

057506825

DESCRIPTION:

BRIEF SUMMARY
This is a .sctn.371 application of PCT/EP95/02802, filed Jul. 17, 1995.
The present invention relates to new cephalosporin intermediates, particularly to new 7-.beta.-glutarylamido cephalosporins and to processes for obtaining them, useful for the preparation of therapeutically, important cephalosporinic antibiotics.
It is well known that the major part of semisynthetic cephalosporins is obtained from 7-aminocephalosporanic acid (7-ACA) by acylation reactions of the amino group in 7 and by nucleophilic substitution of the acetoxy group in 3'. 7-ACA is still industrially produced by chemical hydrolysis of cephalosporin C through a complicated process which involves reagents and solvents very toxic and polluting and extreme working conditions.
Enzymatic or chemical-enzymatic processes by glutaryl 7-ACA have been lately developed to overcome these shortcomings. Said processes provide two steps, in the first step cephalosporin C is transformed enzymatically in an aqueous medium in glutaryl 7-ACA, by oxidative deamination with EP-A-0496993 (Antibioticos)!, or chemically, by oxidative transamination (Antibioticos)!.
7-ACA cannot be used per se for the syntheses of the latest cephalosporins, for instance the 3-alkenyl-ones (Cefprozil, Cefdinir), and the quaternary 3'-ammoniummethyl ones (Cefepime), but it has to be first undergone to protection reactions of the amino group (for instance by acylation or transforming it in a Schiff's base) and of the carboxy group (for instance by esterification). Besides, using 7-ACA is expensive for preparing specific cephalosporins such as the 3-cephem-3-halo substituted (for instance Cefaclor) or the unsubstituted ones (norcephalosporins, for instance Ceftizoxime and Ceftibuten), and the industrial processes known hitherto for the production thereof use, as starting materials, compounds containing the penicillinic core, for instance penicillin G or V, and come to obtaining the desired final products by a complicated sequence of chemical reactions which may provide, subsequently, protecting of carboxyl, sulfoxidation, the opening of the penicillanic ring, the rearrangement to cephalosporanic ring, etcetera. See, at this purpose, U.S. Pat. No. 4,052,387, U.S. Pat. No. 4,075,203, U.S. Pat. No. 4,081,440, U.S. Pat. No. 4,153,72, U.S. Pat. No. 4,031,084 and U.S. Pat. No. 4,346,218.
It is apparent that the glutaryl 7-ACA is not only cheaper than 7-ACA but it shows a variety of advantages, from a chemical-synthetic point of view, in respect with 7-ACA and cephalosporin C itself, the latter being sometimes used to produce cephalosporinic antibiotics. Yet, isolating glutaryl 7-ACA , given its high water solubility, is technically hard and expensive.
Other 7-ACA derivatives such as the known halomethyl derivatives, for instance the 3-chloroismethyl or 3-bromomethyl derivatives, are obtained from 7-ACA by a complicated sequence of protection reactions of the amino and carboxy groups, or by esters-sulfoxides of penicillin G by sophisticated technologies (opening of the penicillinic ring, electrochemical chlorinating, rearrangement to cephalosporinic ring).
Also the 3-exomethylene-derivatives of 7-ACA have a key structure for obtaining important cephalosporinic antibiotics. A few methods are known for transforming cephem derivatives into 3-exomethylene cepham derivatives.
These methods require the use of harmful and toxic compounds of Cr (II) (J. Chem. Soc. Chem. Comm. 800, 1972) or the utilize of electrochemical reductions, expensive and technologically complicated (Torii et al, Bull. Chem. Soc. Jpn. 59, 3975, 1986) starting from 3-acetoxymethyl or 3-halomethyl cephem, respectively.
There are other procedures which utilize Zn, as a reducing agent, yet starting from more expensive 3-thio-functionalized derivatives.
The present invention relates to compounds having the following general formula (I) ##STR1## wherein R is: a hydrogen atom; substituted by at least a phenyl group or at least a hydrogen atom; -C.sub.4 alkyl or alkoxy group or a nitro group; substituted C.sub.1 -C.sub.4 alkyl grou

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