This invention relates to a process for preparing 7-(1H-tetrazol-1-yl)acetamido-3-(2-methyl-1,3,4-thiadiazol-5-yl)thiomethyl -3-cephem-4-carboxylic acid (cefazolin).
Cefazolin is disclosed and claimed in U.S. Pat. No. 3,516,997. One of the generalized methods described in this United States patent for preparing cefazolin as well as other compounds of the therein defined genus involves reacting the corresponding 7-amino cephalosporin with an appropriate acid or reactive derivative thereof to achieve acylation of the amino function in the 7-position of the cephalosporin. The acylation reaction, the United States patent suggests, is carried out in the presence of an inert solvent, which is exemplified by acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, pyridine, and the like, or a mixture of such solvents or an aqueous solution of such solvents or water or any other suitable diluent. When the cephalosporin reactant is in the form of its zwitterion, it is suggested that the reaction be effected in the presence of a base.
The acylating agent can be in its free acid form in which case the presence of a condensing agent such as N,N'-diethylcarbodiimide is employed. Alternatively, the acylating agent can be derivatized by conversion to its corresponding acid chloride, and the acid chloride can be used directly as the acylating agent. Any of the above represent generally recognized techniques for accomplishing acylation of a 7-amino cephalosporin compound.
U.S. Pat. No. 3,502,665 is directed specifically to a method for accomplishing acylation of 7-aminocephalosporanic acid (7-ACA) or derivatives of 7-ACA in which the acetoxy function in the 3-position has been displaced by other well-recognized nucleophiles. By the definition of the process of this patent, a 7-acylamidocephalosporanic acid is prepared by acylation of 7-aminocephalosporanic acid or an acid addition salt thereof by treatment with an acyl halide under substantially anhydrous conditions and in an inert Lewis base liquid which, under the conditions of the reaction, has a dielectric constant above 15 and which contains a hydrogen halide acceptor, which acceptor may itself be the Lewis base.
Included among those compounds considered as Lewis bases and mentioned for use in accordance with the process of U.S. Pat. No. 3,502,665 are certain N,N-dialkylamides. Those specifically mentioned are N,N-dimethylformamide, N,N-diethylformamide, N,N-dipropylformamide, N,N-dibutylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethyl valeramide, N,N-dimethylpropionamide, N-formylpiperidine, and N-formylmorpholine. It is stated that from this group it is preferred to use N,N-dimethylacetamide or N,N-dimethylformamide.
This invention is moderately related to the subject matter of the aforementioned patents and is directed to the discovery, in the preparation of cefazolin by acylation of the 7-aminocephalosporin nucleus of cefazolin, that it is highly preferred to carry out the reaction using tetrazoleacetyl chloride in the presence of N,N-dimethylacetamide as solvent. This discovery includes the finding that N,N-dimethylacetamide is highly preferred as solvent over the artrecognized, closely-related, and expected equivalent N,N-dimethylformamide.