Organic compounds -- part of the class 532-570 series – Organic compounds – Chalcogen in the nitrogen containing substituent
Patent
1981-08-10
1984-09-18
Coughlan, Jr., Paul M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Chalcogen in the nitrogen containing substituent
C07D50104
Patent
active
044725744
DESCRIPTION:
BRIEF SUMMARY
The (7R,8R)-7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio]-methyl]-3-cephem-4-carboxylic acid is a valuable intermediate product for the manufacture of antibacterially-active cephalosporin derivatives, for example the (7R,8R)-7-[2-(2-amino-4-thiazolyl)-2-(Z-methoxyimino)-acetamido]-3-[[2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)-thio]-methyl]-3-cephem -4-carboxylic acid. These derivatives can be obtained in a known manner from the named intermediate product by acylating the 7-amino group with corresponding carboxylic acids or reactive carboxylic acid derivatives.
It is known, for example from German Offenlegungsschrift 2 804 896, that compounds of the type of intermediate product named at the beginning, namely (7R,8R)-7-amino-3-thiomethyl-3-cephem-4-carboxylic acids with substituted thio group, can be manufactured by reacting the (7R,8R)-7-amino-cephalosporanic acid with a thiol compound in the presence of boron trifluoride or a complex compound thereof in a polar organic solvent. The working-up from the reaction solution is effected in the case of this known method by rendering alkaline with aqueous base up to a pH of about 3.5-4.0, whereby the product precipitates in the form of the free carboxylic acid which is subsequently separated, washed and dried.
If the 2,5-dihydro-6-hydroxy-3-mercapto-2-methyl-5-oxo-as-triazine is employed as the thiol compound in this process, with the usual working-up with aqueous base at pH 3.5-4.0 the desired intermediate product, namely the (7R,8R)-7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio]-methyl]-3-cephem-4-carboxylic acid, is surprisingly obtained not entirely in the form of the free carboxylic acid, but as a mixture with the mono-salt (e.g. as a mixture with the monoammonium salt). This mixture is associated with certain disadvantages, in that it results with a considerable amount of unidentified impurities (>10%). Further, mono-salts of the carboxylic acid are as a rule not suited or only ill-suited for the subsequent 7-acylation, since the 7-acylation should preferably be carried out in anhydrous solution, i.e. in solution in an organic solvent, namely because of the advantages associated therewith having regard to the stability of the reaction participants as well as the yields and purity of the reaction product. The free carboxylic acid required for the 7-acylation is, indeed, not itself soluble in the organic solvent, but it is readily brought into solution by silylation or reaction with a trialkylamine. The mono-salts (insofar as they are not trialkylammonium salts) are, however, neither soluble in organic solvents nor are they brought into solution in the stated manner; they are accordingly, as already stated, unsuitable starting materials for the 7-acylation.
It has now been found that the (7R,8R)-7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio]-methyl]-3-cephem-4-carboxylic acid is obtained entirely as the desired, free carboxylic acid when the pH-value is adjusted to about 1.4-2.0, especially to 1.6-1.8. It is thereby surprising that at this pH-value the 7-amino group is not present as the acid addition salt, in which form it would be blocked for subsequent acylation reactions and thus would not be usable.
By the precipitation of the (7R,8R)-7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl) -thio]-methyl]-3-cephem-4-carboxylic acid as the free carboxylic acid at a pH-value of about 1.4-2.0 there is now obtained after separation, e.g. by filtration, as well as washing with usual solvents and drying, a particularly pure product, namely a product which is as a rule about 98-100% pure (corresponding purity of the mixture of carboxylic acid/sodium salt precipitated at pH 3.5-4.0 is <90%), which in contrast to the ammonium salt can be transformed in non-aqueous, organic phase with silylating agents, e.g. with N,O-bis-(trimethylsilyl)-acetamide, trimethylsilylacetamide, trimethylchlorosilane or dimethyldichlorosilane, or with a trialkylamine, e.g. triet
REFERENCES:
patent: 4178443 (1978-05-01), Montavon et al.
patent: 4317907 (1982-03-01), Saikawa et al.
patent: 4327210 (1982-04-01), Montavon et al.
Coughlan, Jr. Paul M.
Hoffman-La Roche Inc.
Johnston George W.
Leon Bernard S.
Saxe Jon S.
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