Patent GB-1353326-A (GB)
Title: 8-oxo-5-thia-1-azabicyclo-4,2,0-oct-2-ene compounds process for their manufacture and compositions containing them
IPC: C07D499/00
Filed: 1971-02-19
Abstract: 1353326 7 - Amino - ceph - 3 - em - 4 - carboxylic acid compounds CIBA-GEIGY AG 2 June 1971 [19 Feb 1971] 5052/71 Headings C2A C2C and C2P Novel 7 - amino - ceph - 3 - em - 4 - carboxylic acid compounds of the general formula wherein R 1 <SP>a</SP> is a hydrogen atom or an amino protective group R 1 <SP>A</SP>, and R 1 <SP>b</SP> is a hydrogen atom or an acyl group Ac, or R 1 <SP>A</SP> and R 1 <SP>b</SP> together form a bivalent amino protective group, and R 2  is a hydrogen atom or a radical R 2 <SP>A</SP> which, together with the -C(=O)-O- group, forms a protected carboxyl group, and salts of such compounds having salt-forming groups are prepared by oxidation of the carbinol group in a 4# - (2 - hydroxymethyl - 2 - propyl - thio) - 1- (α - phosphoranylidene - esterified carboxymethyl) - 3# - N-R 1 <SP>A</SP>-N-R 1 <SP>b</SP> - amino - azetidin-2-one of the general formula  wherein each of R a , Rb and R c  is an optionally substituted hydrocarbon radical and in which free functional groups present may be protected, to a formyl group with subsequent direct cyclization under the reaction conditions; followed optionally by (a) splitting off the group R 1 <SP>A</SP> and/or R 1 <SP>b</SP> when representing Ac, or the divalent amino protective group formed by R 1 <SP>A</SP> and R 1 <SP>b</SP>; (b) protecting the free amino group; (c) converting the -C(=O)-O-R 2 <SP>A</SP> group to a free carboxyl group or a different -C(=O)-O-R 2 <SP>A</SP> group; (d) converting the free carboxyl group into a -C(=O)-O-R 2 <SP>A</SP> group; (e) liberating protected functional groups in an obtained compound; (f) converting an obtained compound having a salt-forming group into a salt or an obtained salt into the free compound; and (g) separating an obtained isomer mixture into the individual isomers. 4# - (2 - Hydroxymethyl - 2 - propyl - thio) - 1- (α - phosphor - anylidene - esterified carboxymethyl) - 3# - N-R 1 <SP>A</SP>-N-R 1 <SP>b</SP> - amino - azetidin-2-ones of the second general formula above, wherein R a , R b  and R c  are each a phenyl group, R 2 <SP>A</SP> is a t-butyl group, R 1 <SP>b</SP> is a hydrogen atom and R 1 <SP>A</SP> is a t-butyl-oxycarbonyl, benzylcarbonyl or phenoxyacetyl group, are prepared by conversion of a penam-3-carboxylic acid of the general formula when R 0  is a carboxyl group, or a salt thereof into the corresponding azide (R 0  is CON 3 ) by reaction with sodium azide, heating the azide with 2,2,2-trichloroethanol to give a 3-(2,2,2-trichloroethoxycarbonylamino)-penam of the general formula wherein X 0  is a 2,2,2-trichloroethoxy group (when heating is carried out prior to the addition of the 2,2,2-trichloro-ethanol, an isocyanate of the third general formula above wherein R 0  is -NCO may be obtained as an intermediate), treating the product with zinc in the presence of aqueous acetic acid, reducing the resulting 3-hydroxy-penam of the general formula with sodium borohydride, esterifying the resulting azetidinone of the general formula with 2,2,2-trichloroethyl chloroformate, reacting the resulting carbonate of the general formula wherein X is a 2,2,2-trichloroethoxy group, with t-butyl glyoxylate, treatment of the resulting 1 - azetidinyl - α - hydroxyacetic acid t - butyl ester of the general formula with thionyl chloride to give the corresponding 1 - azetidinyl - α - chloroacetic acid t - butyl ester, treating the ester with triphenyl phosphine and treating the resulting phosphoranylidene compound of the general formula with zinc and aqueous acetic acid. 6-(N-t- Butoxycarbonylamino)-penicillanic acid is prepared by reaction of 6-aminopenicillanic acid with fluoroformic acid t-butyl ester. Pharmaceutical compositions having activity against micro-organisms comprise, as active ingredient, a 7-amino-ceph-3-em-4-carboxylic acid compound of the first general formula above or a physiologically tolerable salt of such a compound having a salt-forming group, in association with a suitable carrier.