Production of cefotaxime and new sodium salts

Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...

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C07D50156

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active

058310860

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BRIEF SUMMARY
This invention relates to a process for the production of a cephalosporin, i.e. of--cefotaxime of formula ##STR1##
Cefotaxime is a broad spectrum third generation cephalosporin and one of the most important parenterally applied antibiotics. It is generally administered in the form of its sodium salt.
According to processes known in the production of cefotaxime a corresponding side chain in which the amine group may be in protected or unprotected form may be introduced into 7-ACA of formula ##STR2##
Cefotaxime in the form of the free acid may be converted into the corresponding sodium salt in a further step, using a source of sodium ions.
A highly effective method for introduction of the side chain into 7-ACA is the reaction thereof with a reactive thioester of formula ##STR3##
i.e. MAEM.
According to the reaction route described it is not necessary to protect the amine group of the 2-aminothiazolyl function, and the acylation reaction results in high yields without notable secondary reactions. This active ester technology was first described in EP-0 037 380.
According to examples 1 and 2 of EP-0 037 380, the production of cefotaxime in the form of the free acid is carried out by dichloromethane acetate/butanol mixture washing with diethylether.
This process is economically feasible, however, dichloromethane is for ecological reasons difficult to use on industrial scale, especially in the production of medicaments and diethyl ether should be avoided for technological safety reasons. Work up of the reaction mixture according to EP-0 037 380 is complicated.
Cefotaxim in the form of the free acid has a high tendency to bind solvents and to form solvates as described for example in U.S. Pat. No. 5,336,776 or in U.S. Pat. No. 4,224,371.
The production of a sodium salt of cefotaxime from a cefotaxime solvate carries along the solvent which corresponds to the solvate into the sodium salt formation step. This results in undesired contamination of the sodium salt with solvents used in the acylation step and in recovery problems of solvents used in the salt formation step.
A simplified, ecologically friendly and economical process for the production of cefotaxim has now surprisingly been found, which overcomes the disadvantages of prior art processes and which provides cefotaxim and the sodium salt thereof in excellent purity, stability and in high yields.
In one aspect the present invention provides a process for the production of a compound of formula ##STR4## by reacting a compound of formula ##STR5## with a compound of formula ##STR6## in acetone.
The process of the invention may be carried out as follows:
A compound of formula II is acylated with a compound of formula III using acetone as a solvent. Water may be present. Preferably a mixture of acetone/water is used. The concentration of the reactants in the acylation reaction mixture has generally no influence on the reaction per se. It was, however, surprisingly found that the yields may be dependent on the concentration of the reactants in water and acetone used, although cefotaxime is known to be almost insoluble in water and/or acetone. The yields may decrease with the dilution of the reaction mixture. Thus, the reaction may be carried out in high concentration. Optimal yields may be obtained if per gram of 7-ACA about 3 to 6 ml, for example 3 to 5, e.g. 3.1 to 4.5 ml of acetone and about 0.1 to 0.3, for example 0.1 to 0.25, e.g. 0.13 to 0.18 ml of water are used.
The water:acetone ratio may be such, that a solution is obtained in the presence of a base, for example about 8:1 to about 45:1, e.g. 10:1 to about 35:1. Acylation may be carried as usual.
In one embodiment of the invention 7-ACA of formula II may be suspended in a mixture of acetone and water in the presence of MAEM of formula III and in the presence of a base. Suitable bases include tert.(C.sub.1 -C.sub.8)alkyl amines, for example triethylamine, N-ethyl-dimethylamine, a picoline, a N-substituted morpholine; or an inorganic base such as sodium hydroxide, sodium bicarbonate or sodium carbonate or

REFERENCES:
patent: 4093803 (1978-06-01), Cook et al.
patent: 4138555 (1979-02-01), Cook et al.
patent: 4196205 (1980-04-01), Heymes et al.
patent: 4224371 (1980-09-01), Amiard et al.
patent: 4680390 (1987-07-01), Ochiai et al.
patent: 4758556 (1988-07-01), Durckheimer et al.
patent: 4973684 (1990-11-01), Ochiai et al.
patent: 5079369 (1992-01-01), Takaya et al.
patent: 5574154 (1996-11-01), Abu-Nasrieh
Journal of Pharmaceutical Sciences (4 pages) vol. 73, No. 4, Apr. 1984.
Journal of Parenteral Science & Technology (5 pages) vol. 43, No. 2, Mar.-Apr. 1989.

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