Patent GB-1283222-A (GB)
Title: A process for the preparation of 7-aminocephalosporanic acid and derivatives thereof
Inventor: JOHNSON D
IPC: C07F7/18
Filed: 1969-07-01
Abstract: 1283222 Cephalosporin C derivatives; preparing 7-ACA BRISTOL-MYERS CO 1 July 1969 [1 July 1968] 33138/69 Heading C2A Derivatives of cephalosporin C having the Formula I wherein R is C 1  to C 10  alkyl or a group of formula in which n is an integer of 1 to 6 and R<SP>2</SP> and R<SP>3</SP> are the same or different and are each H, Cl, Br, F, NO 2 , C 1  to C 10  alkyl or C 1  to C 10  alkoxy, are prepared by treating an acid incubated cephalosporin C-contaming fermentation broth with a haloformate of formula wherein R is as defined above and X is Cl, Br or I, in a ratio of at least 2 moles of haloformate per mole of cephalosporin C, at a pH above 7 and a temperature no greater than 60 C., and recovering the said derivative from the reaction mixture. The fermentation broth is preferably filtered before or after the acid-incubation step. The latter, which is to destroy any cephalosporin N present in the broth before the acylation with haloformate, is effected by acidification to about pH 2 with a mineral acid, e.g. HCl, H 2 SO 4  or H 3 PO 4 , followed by incubating for 2 to 20 hours. The pH is then brought to about pH 8 with a base, e.g. NaOH or KOH the broth is diluted with about 25% by volume of acetone and 2 to 10 moles of acylating agent per mole of cephalosporin C is added. The reaction temperature is suitably 0 to 25 C. The mixture is then brought to pH 1 to 3 and the derivative is recovered by extracting with a water-immiscible solvent, preferably methyl isobutyl ketone. The derivative may be isolated by concentrating the extract and adding sodium 2-ethyl-hexanoate to precipitate the derivative sodium salt. The derivatives (I) or preferably an alkali metal or amine-salt thereof, are subsequently converted to 7-aminocephalosporanic acid (7- ACA) by the following sequence of steps: (A) Treatment with at least two equivalents of a silyl compound of formula wherein R<SP>5</SP>, R<SP>6</SP> and R<SP>7</SP> are the same or different and each is H, halogen, C 1  to C 10  alkyl, halo C 1  to C 10  alkyl or phenyl, at least one of R<SP>5</SP>, R<SP>6</SP> and R<SP>7</SP> being other than halogen or hydrogen ; R<SP>4</SP> is C 1  to C 10  alkyl, m is 1 or 2 and X is halogen or a group of formula in which R<SP>8</SP> is H or C 1  to C 10  alkyl and R<SP>9</SP> is H, C 1  to C 10  alkyl or a group of formula under anhydrous conditions in the presence of an acid-deactivating tert. amine in an inert solvent, to 'give the silyl di-ester of the compound (I). (B) Treating the silyl di-ester with at least 2 molar proportions of a halogenating agent under anhydrous conditions in the presence of an an acid deactivating tert. amine in an inert solvent at below 0 C., to give -the iminohalide of the compound (I). (C) Treating the imino-halide with a C 1  to C 12  aliphatic alcohol or a phenylalkyl alcohol having 1 to 7 alkyl carbons at below 0 C., to give. the. imino-ether of the compound (I). (D) Treating the imino-ether with water and/or an alcohol under acidic contions to give 7-ACA.