Glaxo Group Limited

Marco Croci

Gino Cotti

Gennaro Maruzzelli

Improvements in or relating to the manufacture of semi-synthetic penicillin antibiotics are described. More particularly an improved process for the preparation of a 6.beta.-acylamino penicillanic acid antibiotic product is described in which 6.beta.-aminopenicillanic acid (6-APA) is reacted in an inert solvent with a silylating agent to form a silylated compound of formula (I) ##STR1## wherein R.sup.1 represents a hydrogen atom or a tri(C.sub.1-6 alkyl)silyl group, and R.sup.2 represents a tri(C.sub.1-6 alkyl)silyl group and the compound of formula (I) is thereafter contacted with an acyl chloride or protected acyl chloride corresponding to the desired 6.beta.-acylamino group, the silyl groups are cleaved and the desired antibiotic product is recovered, silylation being effected using a tri(C.sub.1-6 alkyl) silylurea or tri(C.sub.1-6 alkyl) halosilane and the compound of formula (I) produced being reacted without intermediate isolation with the acyl chloride or protected acyl chloride, wherein acylation is effected in the presence of a hydrogen halide acceptor mixture comprising in excess of 0.15 and preferably up to 3.00 moles of urea per mole of 6-APA; in excess of 0.15, and preferably up to 1.30 moles of bis-tri-(C.sub.1-6 alkyl)silylurea per mole of 6-APA; and in excess of 0.25, and preferably up to 3.30 moles of tri-(C.sub.1-6 alkyl)-ammonium halide per mole of 6-APA. The process is especially useful for the preparation of ampicillin and amoxycillin in high yield and high purity.

Manufacture of semi-synthetic penicillin antibiotics

A process for preparing semi-synthetic penicillin antibiotics, especially ampicillin, is disclosed which comprises acylating a silylated 6-aminopenicillanic acid in the presence of primary or secondary carboxamide bases as hydrogen halide acceptors. The products may be obtained in good yield and high purity and the amount of toxic contaminants in the products is significantly reduced, thus substantially eliminating unpleasant side-effects.

A process for preparing semi-synthetic penicillin antibiotics, especially ampicillin, is disclosed which comprises silylating 6-aminopenicillanic acid using a silylating agent which generates a primary or secondary carboxamide base, and then acylating the silylated 6-aminopenicillanic acid in situ using the primary or secondary carboxamide base as hydrogen halide acceptor. No further base needs to be added, and the products may be obtained in good yield and high purity with the amount of toxic contaminants in the products significantly reduced. Unpleasant side-effects may thus be substantially eliminated.

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Milan, Italy

Marco Croci