process for the production of a gleichgewichtsmischung 6 alpha - and 6 beta epimerformen ship 'between bases of the esters or salts of 6 aminopenicillansaeure and use of beta epimeren to produce 6 - aminopenicillansaeurederivaten and penicillins

摘要

1312554 Epimerizing penicillins BEECHAM GROUP Ltd 12 Jan 1972 [20 Jan 1971] 2736/71 Heading C2A A penicillin having the general Formula VIII wherein R is an organic or inorganic cation or an esterifying organic radical and RSP1/SP is an alkyl, aryl, aralkyl or heterocyclic group, is epimerized to an equilibrium mixture of the 6-α- and 6-#- epimers thereof, having the respective structures by treating a solution of the penicillin with a base. The compound (VIII) may be initially in the form of its 6-α- or 6-#-epimer or a mixture thereof, and the treatment with base establishes an equilibrium between the two forms, the position of which is governed by the particular base and solvent employed and also the steric properties of the 6-substituent group R. The process is especially directed to conversion of the biologically poorly active 6-α-epimer into the antibacterially active 6-#-form. The latter may be separated from the equilibrium mixture by fractional crystallization or chromatography, e.g. on silica with elution with a chloroformether mixture. The preferred base used in the process is 1,5- diazabicyclo(4,3,0)-non-5-ene, or else sodium ethoxide, potassium carbonate or triethylamine may be used. The solvent for the penicillin may be benzene, chloroform, dimethylsulphoxide, methylene dichloride, acetone, nitromethane, ethanol or methanol. The group R in the formulae above may be an alkali metal cation or an organic cation and may be the same as the cation of the base employed. Alternatively, R may be an easily removed esterifying group, e.g. benzyl, p - methoxybenzyl, methoxymethyl, methyl, phenacyl, trimethylsilyl or tributyltin. The epimerization is usually carried out at room temperature. The starting penicillin may be prepared by reacting 6-aminopenicillanic acid, or a suitable salt or ester thereof, with an aldehyde RSP1/SPCHO. The #-epimer produced may be subsequently de-acylated, e.g. by treatment with an acid such as p-toluenesulphonic acid, to give the corresponding acid-addition salt of 6#-aminopenicillanic acid or its ester, which may then be re-acylated to introduce a different RSP1/SP group as a 6-position substituent.