| 摘要 |
1290327 N-Formylating cephalosporin compounds GLAXO LABORATORIES Ltd 24 Oct 1969 [5 Nov 1968] 52438/68 Heading C2A In a process for effecting one or more reactions at the 1, 2, 3 or 4 positions of 7#-amino cephalosporin compounds, the 7#-amino group is protected by N-formylation, the required reaction or reactions at the 1, 2, 3 or 4 positions are carried out and the resulting compound is then N-deformylated to yield the desired 7#- aminocephem-4-carboxylic acid or derivative thereof. N-formylation is suitably performed with formic acid preferably together with a C 1 to C 6 alkanoic acid anhydride; or with a formic ester, e.g. ethyl formate, preferably together with a catalyst such as pyrid-2-one or imidazole: or with an orthoformate such as methyl or ethyl orthoformate; or with a formyl halide such as the fluoride or chloride. N-deformylation is effected by acid-catalysed hydrolysis or alcoholysis, preferably with concentrated HCl in methanol, or better in dioxan or tetrahydrofuran. Specified reactions at the 1, 2, 3 or 4 positions are as follows: (1) oxidation at the 1-position to produce a sulphonyl or sulphoxide compound; (2) isomerization to convert a ceph-3- em ring to a ceph-2-em ring; (3) nucleophilic displacement of the 3-acetoxy group at the 3- position; (4) substitution of the 3-hydroxymethyl group; (5) esterification of the 4-carboxyl group. In the examples the following compounds are prepared via the 7#-formamido derivative: 7#-amino-3-methylthiomethylceph- 3-em-4-carboxylic acid; its sodium and hydrochloride salt, its diphenylmethyl-4-ester and the hydrogentoluene sulphonate and hydrochloride of this ester; 3 - (3 - carbamoylpyridiniummethyl) - and 3 - (4 - carbamoylpyridiniummethyl) - ceph - 3 - em - 4 - carboxylate bishydrochlorides; and 3 - acetoxymethyl - 7#- aminoceph - 2 - em - 4α - carboxylic acid. The last-named compound as its hydrochloride salt is silylated with hexamethyldisilazane and the N-silyl derivative is N-acylated with 2,6-dichlorobenzoyl chloride to give 3-acetoxymethyl- 7# - 2,6 - dichlrobenzamido)ceph - 2 - em - 4α- carboxylic acid, which is isolated as its sodium salt. Novel 7# - formamidoceph - 3 - em - 4 - carboxylic acids possessing the group -CH 2 ZR at the 3-position wherein R is C 1 -C 4 alkyl and Z is and their salts and esters are prepared by N- formylating an appropriate 7#-aminocephalosporin compound as described above. |
