GB1339007A - Antibiotics and processes for their production - Google Patents

Abstract

1339007 6-Disubstituted penicillins MERCK & CO Inc 30 April 1971 [16 June 1970] 29157/70 Heading C2A The invention relates to novel penicillin compounds having the general Formula I and the corresponding 1-sulphoxides, in which R 1 is a hydroxy or mercapto radical, a substituted or unsubstituted methoxy, ethoxy, methyl, ethyl, methylthio or ethylthio radical, a carbamoyloxy, carbamoylthio, C 1-6 alkanoyloxy, C 1-6 alkanoylthio, cyano, carboxy or substituted carboxy (e.g. carbamoyl) radical and Q is an azido, amino or acylamino radical; or R 1 is halogen and Q is azido; and R is an esterifying radical or, when Q is acylamino, is a hydrogen atom, a cation or an esterifying radical. The compounds are prepared by either (i) diazotizing the amino group of a 6-aminopenicillanic acid (6-APA) ester to give a compound of Formula IT wherein R is an esterifying group, the 1-sulphoxides of these compounds (II) being novel and forming part of the invention, and then subjecting the compound (II) to one or more of the reactions described below; or (ii) reacting a 6-APA ester with an aromatic aldehyde having at least one o- or p-electronegative substituent (e.g. NO 2 , CN alkoxycarbonyl, carbamoyl, or methylsulphonyl) to give an imine derivative of the 6-APA ester, reacting this derivative with a compound which introduces the group R 1 (as defined above) and subjecting the product to aminolysis or hydrazinolysis to give a 6-R 1 -6- amino penicillanic acid, the procedure (ii) being illustrated by the following reaction scheme in which R 8 is an esterifying group. In procedure (i) the diazo compound II is formed by a conventional diazotizing procedure. If the 1-sulphoxide is desired, the 6-APA ester may be subjected to a preliminary S-oxidation step e.g. with m-chloroperbenzoic acid. The diazo compound may then be reacted with: (a) a halo-azide (or another azide together with a source of positive halogen such as a bromoacylimide or -amide) to give the corresponding 6-halo-6-azido penicillanic ester which may be subsequently reacted with a nucleophilic reagent capable of replacing the halogen by R 1 ; the latter compound may optionally be subjected to reduction to convert the -N 3 group to -NH 2 , and this amino group may then be acylated; (b) trimethyl- or triethylboron followed by a halo-azide to produce the 6-methyl or -ethyl-6- azido compound; (c) trifluoromethyl iodide, with irradiation and in the presence of a trialkylammonium azide to give the 6-CF 3 -6-azido penicillanic ester. The penicillin compounds (I) have antibacterial activity and may be mixed with a carrier or diluent and made up into pharmaceutical compositions.