Patent GB-1332722-A (GB)
Title: Carboxylic acids
IPC: C07D501/18
Filed: 1971-01-08
Abstract: 1332722 Cephem-4-carboxylic acids BRITOL-MYERS CO 8 Jan 1971 [12 Jan 1970] 1066/71 Headings C2A and C2C A process for the preparation of 3-azidomethyl - 7 - amino - 3 - cephem - 4 - carboxylic acid comprises the consecutive steps of (A) heating a compound having the Formula II in which each M is hydrogen, a metal cation or an amine cation, and R is (lower) alkyl or an aralkyl group of the formula wherein n is an integer of from 1 to 6 and R<SP>2</SP> and R<SP>3</SP> are alike or different and each is H, Cl, Br F, NO 2 , (lower) alkyl or (lower) alkoxy, with an excess of sodium azide, potassium azide, lithium azide or ammonium azide, at a pH in the range of about 5 to about 9, in a polar solvent, at a temperature in the range of 35‹ to 100‹ C., to produce a compound having the Formula I wherein M and R are as defined above; (B) reacting a compound having the Formula I with a silyl compound of the formula wherein R<SP>5</SP>, R<SP>6</SP> and R<SP>7</SP> are hydrogen, halogen, (lower) alkyl, halo(lower)alkyl or phenyl, at least one of the said R<SP>5</SP>, R<SP>6</SP> and R<SP>7</SP> groups being other than halogen or hydrogen; R<SP>4</SP> is (lower) alkyl, m is an integer of 1 to 2 and X is halogen or wherein R<SP>8</SP> is hydrogen or (lower) alkyl and R<SP>9</SP> is hydrogen, (lower) alkyl or under anhydrous conditions in the presence of an acid deactivating tertiary amine, in an inert solvent, to produce the corresponding silyl ester of compound I; (C) reacting said silyl ester with an excess of a halogenating agent, under anhydrous conditions, in an inert solvent, in the presence of an acid deactivating tertiary amine, at temperatures below 0‹C., to produce in solution the corresponding imino-halide; (D) reacting with said solution of imino-halide an aliphatic alcohol having 1 to 12 carbon atoms or a phenylalkyl alcohol having 1 to 7 alkyl carbon atoms, at a temperature below 0‹ C., to produce in the solution the corresponding imino-ether; and (E) reacting said solution of imino-ether under acidic conditions with water or an aliphatic alcohol, or a mixture of both, to produce 3- azidomethyl - 7 - amino - 3 - cephem - 4 - carboxylic acid. The starting material of Formula II may be prepared from whole fermentation broth containing cephalosporin C. The compound (sodium 7 - [(5 - carboxy - 5 - isobutoxycarbonylamido)valeramido]-cephalosporanate is prepared by adding oxalic acid to the filtered broth, acidifying, extracting with MIBK and discarding the MIBK extract. The residue is treated with acetone, sodium hydroxide and isobutyl chloroformate to yield a product which is extracted with MIBK, the MIBK phase being treated with sodium ethylhexanoate to precipitate N-carbiscbutoxy cephalosporin C sodium salt, the desired product. By using ethyl chloroformate or carbobenzoxy chloride instead of isobutyl chloroformate, the corresponding sodium N-carbethoxy-cephalosporin C and sodium N-carbobenzoxy-cephalosporin C may be obtained. Tert. - butoxycarbonyl - D - phenylglycine is prepared by suspending a mixture of D-( - )-2- phenylglycine and magnesium oxide in aqueous dioxane and t.-butoxycarbonyl azide. The compounds of Formula I are stated to be novel and are claimed per se.