Patent GB-1268536-A (GB)
Title: Penicillanic acid derivatives
Inventor: HENNINGER P W
IPC: C07D499/04
Filed: 1969-06-18
Abstract: 1,268,536. 6-lsocyanatopenicillanic acid esters. KONINKLIJKE NEDERLANDSCHE GISTEN SPIRITUS-FABRIEK N.V. 18 June, 1969 [19 June, 1968], No. 30958/69. Heading C2A. Novel 6-isocyanatopenicillanic acid esters of Formula (I) wherein E is a group easily removable and replaceable by hydrogen to give a free carboxy group, are prepared by reacting phosgene with a penicillanic acid ester of formula wherein W is a hydrogen atom or a group such that the group W-NH- is easily convertible to an isocyanate group by reaction with phosgene without the rest of the molecule being affected and E is as above, in a dry inert organic solvent. E may be a silyl group of formula where R is C 1 -C 6  alkyl, aryl or aralkyl; or a phenacyl group optionally ring substituted by halogen preferably in the para-position. W is preferably a silyl group as defined above for E and most preferably both E and W are identical and are such silyl groups. The reaction is performed in an anhydrous organic solvent (e.g. toluene and/or methylene chloride) preferably at or below -20 C. in the presence of an acidbinding agent such as a tertiary amine of which the hydrochloride precipitates rather than dissolves in the reaction medium, e.g. triethylamine. The inventive compounds are intermediates for conversion to antibiotically active 6-N- acylated penicillanic acids by virtue of the reactivity of the 6-isocyanato group. They may be reacted with (1) carboxylic acids of formula X-COOH wherein X is a group in which R 1  is optionally substituted hydrocarbon, or a phenoxy group, R 2  is H, halogen, cyano, or -NH-COOY or-OY where Y is C 1 -C 6  alkyl, aryl or aralkyl, and R 3  is H, aryl or C 1 -C 6  alkyl, whereby they are converted to penicillanic esters having a group X-CO-NH in the 6- position. By reaction with (2) organo-metal compounds of formula A-Me<SP>I</SP>, A-Me<SP>II</SP>Hal, or A-Me<SP>II</SP>-A where Me is a metal atom of valency I or II, Hal is halogen and A is a group of formula wherein R 1  and R 3  are as above in (1), and R 2 <SP>1</SP> is H, halogen, cyano, or -NH-COOY 1  or -COOY 1  -or -OY 1  in which Y 1  is C 1 -C 6  alkyl, aryl or a group readily removable and replaceable by H, or alternatively A is a naphthyl group substituted by one or more C 1 -C 6  alkoxy groups, the isocyanate penicillin esters are converted to penicillin esters having a group A-CO-NH in the 6-position. The isocyanato group may be converted to a group of formula or by reaction (3) with a corresponding amine or amide wherein R 4  is C 1 -C 6  alkyl, up to C 8  isocyclic, optionally substituted aryl, penicillanyl, or a group : (in which R 6  is H or aryl, n and m are 0 or 1 to 4, and R 7  is H, C 1 -C 6  alkyl, or a group readily removable and replaceable by hydrogen) and R 5  is C 1  to C 6  alkyl, or alternatively in the formula R 4  and R 5  and the N atom may together form a heterocycle. The ester may be reacted (4) with a hydroxylic compound Y 2 OH where Y 2  is an optionally substituted hydrocarbon group, to convert the isocyanato group to a urethane group. Typical hydroxy compounds are benzyl alcohol, phenol, ethanol, p-methoxy-phenol and p-bromo-phenol. Finally if desired, the group E may be converted to hydrogen to give the required antibiotically active penicillanic acid. Pharmaceutical compositions comprise a penicillanic acid prepared by any of processes (1) to (4) above or a non-toxic salt or ester thereof together with a pharmaceutically acceptable carrier.