IE37510L - 7-azido-cephalosporin compounds - Google Patents

Abstract

1424373 dl - 7 - Azido - cephalosporin compounds; phosphonate intermediates MERCK & CO Inc 10 April 1973 [14 April 1972 30 June 1972 (2) 10 Oct 1972 5 March 1973] 17050/73 Headings C2C and C2P Novel dl-7-azido-cephalosporin compounds of the Formula (V) in which R is alkyl or aryl, R 1 is a blocking group, R<SP>1</SP> is H, halogen, carbamoyloxy, which may be N-substituted or N,N-disubstituted, alkoxyalkoxy, alkoxy, aryloxy, aralkyloxy, heterocyclic-thio or acyloxy, and B is H, the azido being in α-position or B is -CH 3 or -OCH 3 , the azido then being in #-position, may be obtained by the processes shown in the flowsheet (A) wherein (I) is reacted with a thioformylating agent (e.g. a thionoformate ester) to form (II), which is reacted with a substituted acetone R<SP>1</SP>CH 2 COCH 2 X, where X is halogen or a sulphonate ester, to form (III), the latter is converted to thiazine (IV), or alternatively (IV) is formed directly by reaction of II and the substituted acetone, and finally (IV) is reacted with an azido acetyl reagent where X<SP>1</SP> is halogen, p-toluenesulphonyloxy, -OSO 2 CF 3 or -OSO 2 CH 3 , in the presence of a base. Alternatively, the desired 7-azido compound (V) is obtained by reacting a mixture of III and IV or IV or III per se with the azidoacetyl compound. An intermediate, 1,3,5-tribenzyl-sym-hexahydrotriazine (XXIII) is obtained by reacting benzylamine with formaldehyde, and the α- aminophosphonoacetate ester (I) is obtained as in the following flowsheet (B) XXIII is reacted with a disubstituted phosphite to yield XXIV, isolated as an acid salt, the latter is reduced in the presence of Pd/C forming the salt of XXV. The salt is connected to the amine XXVI by reaction with NH 3 . The amine on reaction with benzaldehyde forms a Schiff base XXVII, which on reaction with a strong base, e.g. an organolithium compound and then a haloformate ester forms imine XXVIII. Treatment of this imine with 2,4- dinitrophenyl hydrazine in the presence of p-toluenesulphonic acid monohdyrate or with p-toluenesulphonic acid hydrate in ether followed by neutralization of the amine acid salt yields the compound I. Other intermediate preparations described are: reaction of methyl 2-chloro-2-methoxyacetate and NaN 3 to give methyl 2-azido-2- methoxyacetate, hydrolysed to 2-azido-2- methoxyacetic acid and reaction with thionyl chloride to 2-azido-2-methoxyacetyl chloride; the latter is reacted with silver trifluoromethyl sulphonate yielding azidoacetyl trifluoromethyl sulphonate; azido acetic acid, mercuric acetate and propyne form isopropenyl azido acetate, which reacts with methane sulphonic acid forming azidoacetyl methanesulphonate; methyl glycolate is phosgenated and reacted with di-pmethoxybenzylamine forming methyl (N,N-dip - methoxybenzyl) - carbamoyloxyacetate which is converted in turn to the corresponding acid and acid chloride, then to 1-diazo-3-(N,N- di - p - methoxybenzyl)carbamoyloxy-2-propanone. [GB1424373A]