Process for the conversion of 6-aminopenicillanic acid (6-APA) in 7-aminodesacetoxycephalosporanic acid (7-ADCA)

#This invention relates to a process for the conversion of 6-aminopenicillanic acid (6-APA) to 7-aminodesacetoxycephalosporanic acid (7-ADCA).

#The conversion of 6-APA to 7-ADCA takes place through the acylation of 6-APA and oxidation of the sulphur atom to produce alpha-chlorobenzyl penicillin-(s)-sulphoxide through the application of normal techniques, whereas the cycloexpansion of the thiazoline nucleus to thiazine and unblocking to form 7-ADCA is effected in a single process as shown in Reaction Scheme I. ##STR1##

#The process is equally applicable both if 6-APA or epi-6-APA are used, namely, with the epimers beta-6-APA and alpha-6-APA to obtain the corresponding epimers of 7-ADCA, with a C-6 epimer of alpha-chlorobenzyl penicillin-(s)-sulphoxide being used as starting material.

#A solution of 0.1 mole of alpha-chlorobenzylpenicillin-(s)-sulphoxide sodium salt (40.57g) was adjusted to pH 2 and extracted with methylene chloride, dried with anhydrous sodium sulphate and evaporated at reduced pressure. The residue was dissolved in 250 ml of acetonitrile.

#To the above solution, there were added 0.28 mole of 3-trimethylsilyl-2-oxazolidinone (TMSO, 38.2 ml) and 0.02 mole of triethylamine p-toluenesulphonate (8.468 g). After stirring for 15 minutes, the mixture was heated under reflux for 120 minutes. Thereafter 0.1 mole of dimethylaniline p-toluene sulphonate (29.3 g) and 0.12 mole of thiourea (9.13 g) were added and heating was maintained for a further 60 minutes. Thereafter the mixture was concentrated at reduced pressure and water (100 ml) was added to the residue. The pH was adjusted to 8.5 in the presence of methylene chloride, the phenyl-pseudothio-hydantoin was filtered out and the water phase was decanted off. After further adjustment To pH 4.2, the mixture was filtered again to give 7-ADCA (14.9 g) with 70% yield. Identified by its IR spectrum, m.p. 232- 42 (d) and [.alpha.] .sub.D.sup.2 = 105.0.degree. (C = 1%, 0.5 N HCL).

#The pH of an aqueous solution of 0.1 mole (38.87 g) of alpha-chlorobenzyl desacetoxycephalosporin sodium salt was adjusted to 1.5 and the solution was extracted with chloroform (100 ml). 0.12 mole (18.4 ml) of TMSO and 0.01 mole (1.4 ml) of triethylamine were added to the dry solution, wth stirring for 15 minutes at room temperature. Thereafter dimethylacetamide (150 ml) and thiourea (9.13 g) were added, the mixture was heated under reflux for 60 minutes, followed by cooling, addition of 100 ml water and hydrochloric acid to an acid pH. The solution was filtered, the organic phase was drawn off and the aqueous liquors were extracted with more chloroform. The water phase was treated as in Example I. The precipitate was filtered, washed with water, acetone an dried to give 7-ADCA (16 g), with a yield of 75%, m.p. 230- 42(d) and [.alpha.] .sub.D.sup.20 = + 104.8.degree. (0.5N HCL).