Derivate von Penicillansaeure und Verfahren zu ihrer Herstellung

摘要

1,156,805. Penicillins; isothiazolyl acetic acids. R. & L. MOLECULAR RESEARCH Ltd. 28 June, 1966 [28 June, 1965], No. 29016/66. Headings C2A and C2C. 6 - Isothiazolylacetamido penicillanic acids have the following Formula I: wherein R1 and R2 are H, Cl, Br, I or CH 3 . Salts include the potassium, calcium, aluminium, ammonium and substituted ammonium salts, e.g. procaine and N-ethyl-piperidine salts. The penicillins are prepared by acylating 6-aminopenicillanic acid with an acylating derivative of an acid of Formula II wherein R1 and R2 have the above meanings. Typical penicillins are 6-(isothiazol-5-yl-acetamido) penicillanic acid, 6-(4-chloroisothiazolyl- 3-yl-acetamido) penicillanic acid and 6-(3- methylisothiazol - 5 - yl - acetamido) penicillanic acid. Alternatively, the penicillins are prepared by cultivating Penicillium notatumchrysogenum in a nutrient medium in the presence of a precursor of Formula II or a functional equivalent thereof. Lsothiazol-3-yl acetic acid is prepared by the following steps:- (A) 3-Bromomethylisothiazole is prepared by treating 3-methylisothiazole with N-bromosuccinimide. (B) A mixture of 3-cyanomethylisothiazole and 3-carbonamidomethylisothiazole is prepared by treating 3-bromomethylisothiazole with sodium cyanide and methanol. (C) Methylisothiazol-3-yl acetate is prepared by treating the aforesaid mixture with cone. HCl and methanol. (D) Isothiazol-3-yl acetic acid is prepared by treating methylisothiazol-3-yl acetate with NaOH and methanol. Isothiazol-4-yl acetic acid, isothiazol-5-yl acetic acid, 4-chloroisothiazol-3-yl acetic acid, 4-bromoisothiazol-3-yl acetic acid, 3-methyl isothiazol-4-yl acetic acid and 3-methyl-isothiazol- 5-yl acetic acid are prepared in a similar manner. p-Nitrophenyl isothiazol-3-yl acetate is prepared by treating isothiazol-3-yl-acetic acid with p - nitrophenol and N,N1 - dicyclohexylcarbodiimide. p-Nitrophenyl isothiazol-4-yl acetate, p-nitrophenylisothiazol-5-yl acetate, p-nitrophenyl-4- chloroisothiazol-3-yl acetate, 2,4-dinitrophenyl- 3 - methyl - isothiazol - 4 - yl acetate, p - nitrophenyl - 3 - methyl - isothiazol - 5 - yl - acetate and 2,4 - dinitrophenyl - 4 - bromo - isothiazol - 3 - yl acetate are likewise prepared. Pharmaceutical compositions comprise a 6-isothiazolylacetamido penicillanic acid of Formula I or a salt thereof and a carrier. They may be used for the treatment of mastitis in cattle.