GB1444224A - Cephalosporin compounds' - Google Patents

Abstract

1444224 Cephem compounds GLAXO LABORATORIES Ltd 5 July 1973 [21 July 1972] 34297/72 Heading C2C Cephalospirin compounds having an ethyl or substituted ethyl group at the 3-position, with the exception of compounds having the formula wherein R<SP>11</SP> is carboxylic acyl, R<SP>12</SP> and R<SP>13</SP> are each hydrogen, C 1-8 alkyl, phenyl, substituted phenyl, (C 1-8 alkoxy)carbonyl, mono- or di-aryl (C 1-8 alkoxy)carbonyl, (C 1-8 alkyl)carbonyl, aryl(C 1-8 alkyl), or -C 5-6 cycloalkyl, and R<SP>14</SP> is hydrogen, C 1-8 alkyl, phenyl, substituted phenyl, aryl(C 1-8 alkyl) or C 5-6 cycloalkyl, are prepared by reacting a cephalosporin compound having at the 3-position a group of formula in which X is halogen, and which compound does not possess any free amino or carboxyl groups, with a metal salt of a carbon acid having a pKa in dilute aqueous solution at 25‹ C. of not less than 13. Typical cephalosporin starting materials have the general Formula (IIa) wherein R<SP>a</SP> is a protected (e.g. acylated) amino group, R<SP>b</SP> is a carboxyl blocking group, X is halogen, Z is > S or > S-#O, and the dotted line indicates that the compound has a double bond in the 2,3-position (i.e. ceph-2-em) or in the 3,4-position (i.e. ceph-3-em). Suitable metal carbon acid salts have the Formula (I) wherein M is a metal atom of valence n, (e.g. Li, Na, K, Mg, Cd or Zn) and R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> are the same or different groups selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, alicyclyl, aryl and aryl-(C 1-4 alkyl), or two or three of R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP> together form a di- or tri-valent function and/or form, together with the adjacent carbon atom, a cyclic (carbo- or hetero-cyclic) structure, such as phenyl, dithianyl or dithiolanyl. In the inventive process, the group -CR<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP> replaces the group X in the compound (IIa) to give products of Formula (IVa) wherein (if appropriate, after de-protection of the protected 4-carboxyl group Rb and the protecred 7-amino group R a ), (R a )<SP>1</SP> is amino, acylamino or protonated amino, (R b )1 is hydrogen or a carboxyl blocking group, Z is > S or # S-#O, and R<SP>4</SP>, R<SP>5</SP> and R<SP>6</SP> have the meanings ascribed above to R<SP>1</SP>, R<SP>2</SP> and R<SP>3</SP>. The compounds (IVa) are novel, provided that R<SP>4</SP>, R<SP>5</SP> and R<SP>6</SP> together with the adjacent carbon do not form a pyrrole or indole ring. The reaction is advantageously carried out in the presence of a transition metal (e.g. Cu, Mn, Fe, Co) which forms a complex anion with the carbon acid salt, such metals being added to the reaction mixture as a cuprous, ferrous, manganous or cobaltous salt before the addition of the cephalosporin starting material. Ligandforming trialkylphosphines are preferably also added to stabilize the complex and solubilize the transition metal. The cephalosporin starting material (IIa): diphenylmethyl(1S,6R,7R) - 3 - bromomethyl - 7- formamido - ceph - 3 - em - 4 - carboxylate, 1- oxide, is prepared by reacting diphenylmethyl (6R,7R) - 7 - amino - 3 - methylceph - 3 - em- 4-carboxylate, hydronitrate salt, with formic acid in ethyl formate to give the corresponding 7-formamido compound, oxidizing with peracetic acid to give the 1-oxide of the 7-formamido compound, and reacting the latter with 1,3-dibromo-5,5-dimethylhydantoin under U.V. irradiation.