Manufacture of semi-synthetic penicillin antibiotics
AssigneeGlaxo Group Limited
InventorsMarco Croci, Gino Cotti
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Abstract
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.
Claims11
In a process for the manufacture of a 6-acylaminopenicillanic acid antibiotic product in which 6-aminopenicillanic acid is reacted in an inert organic solvent with from about 1 to about 2 equivalents of a silylating agent relative to the molar quantity of 6-aminopenicillanic acid to form a silylated compound of formula (III) ##STR2## wherein R.sup.4 is selected from the group consisting of hydrogen, tri(C.sub.1-6)alkylsilyl and tri(C.sub.5-12)arylsilyl and R.sub.5 is selected from the group consisting of tri(C.sub.1-6)alkylsilyl and tri(C.sub.5-12)arylsilyl, and the compound of formula (III) is thereafter contacted with an acid chloride or protected acid chloride corresponding to the desired 6-acylamino group at a temperature of from about +10.degree. to about -30.degree. C., the silyl groups are cleaved with water and the desired antibiotic product is recovered, the improvement wherein silylation is effected using a compound selected from the group consisting of formula (I) and formula (II)
- R.sup.1 R.sup.2 N.COR.sup.3 (I)
- and
- R.sup.1 N.dbd.C(OR.sup.2).R.sup.3 (II)
- wherein R.sup.1 is selected from the group consisting of hydrogen, C.sub.1-6 alkyl and C.sub.7-20 aralkyl in formula (I) or C.sub.1-6 alkyl, C.sub.7-20 aralkyl, tri(C.sub.1-6)alkylsilyl and tri(C.sub.5-12)arylsilyl group in formula (II), R.sup.2 is selected from the group consisting of tri(C.sub.1-6)alkylsilyl and tri(C.sub.5-12)arylsilyl and R.sup.3 is selected from the group consisting of C.sub.1-6 alkyl, C.sub.7-20 aralkyl and an amino group substituted by one or two C.sub.1-6 alkyl groups, and the compound of formula (III) produced is reacted without intermediate isolation and without addition of an additional acid acceptor with the acid chloride or protected acid chloride.
In a process for the manufacture of ampicillin or a salt or hydrate thereof in which 6-aminopenicillanic acid is reacted in an inert organic solvent with from about 1 to about 2 equivalents of a silylating agent relative to the molar quantity of 6-aminopenicillanic acid to form a silylated compound of formula (III) ##STR3## wherein R.sup.4 is selected from the group consisting of hydrogen and trimethylsilyl and R.sup.5 represents a trimethylsilyl group and the compound of formula (III) is thereafter contacted with D- (-)-phenylglycyl chloride hydrochloride at a temperature of from about +10.degree. to about -30.degree. C., the silyl groups are cleaved with water and the cleaved ampicillin product is recovered, the improvement wherein the silylation is effected using a compound selected from the group consisting of N-trimethylsilylacetamideand N,O-bistrimethylsilylacetamide and the compound of formula (III) produced is reacted, without intermediate isolation and without addition of an additional acid acceptor with the D-(-)-phenylglycyl chloride hydrochloride.
Dependencies are inferred from the claim text.