Patent GB-1412886-A (GB)
Title: Penicillin and cephalosporin compounds
IPC: C07D499/68
Filed: 1973-01-23
Abstract: 1412886 Cephalosporins and penicillins ELI LILLY & CO 23 Jan 1973 [31 Jan 1972 27 Oct 1972] 3400/73 Heading C2C Compounds of the general formula wherein R is hydrogen, C 1 -C 6  alkyl, 4-amino-4- carboxybutyl, phenyl, substituted phenyl, or a group of the formula wherein n is 0, P is phenyl, C 1 -C 4  lower alkylphenyl, halophenyl, hydroxyphenyl, C 1 -C 4  lower alkoxyphenyl, 2-thienyl, 3-thienyl, 2- furyl, 3-furyl, or l-tetrazyl; and where n is 1, P is phenyl, C 1 -C 4  lower alkylphenyl, halophenyl, hydroxyphenyl, C 1 -C 4  lower alkoxyphenyl; Z is an oxygen or a sulphur atom; a is hydrogen or C 1 -C 3  lower alkyl; b is hydrogen, C 1 -C 3  lower alkyl, hydroxy, protected hydroxy, amino, or protected amino; and R 1  is hydrogen, an alkali metal cation or a readily removable ester forming group; R 2  is C 1 -C 4  lower alkyl, allyl, propargyl, C 3 -C 6  cycloalkyl, or benzyl; and Y is a 3-carbon fragment of the formula (A) or a substituted 3-carbon fragment of the formula wherein R 3  is hydrogen, C 2 -C 4  alkanoyloxy, C 1 -C 4  alkoxy, C 1 -C 4  alkylthio, pyridine, wherein R 4 , R 5  and R 6  are hydrogen, C 1 -C 4  lower alkyl, phenyl, C 1 -C 4  lower alkylphenyl, C 1 -C 4  lower alkoxyphenyl, halophenyl or hydroxyphenyl; or R 3  is a carbamoyloxy group of the formula (B) wherein R 7  and R 8  are the same or different and are hydrogen or C 1 -C 4  lower alkyl; subject to the limitation that when R 3  is C 2  alkanoyloxy or a carbamoyloxy group wherein R 7  and R 8  are both hydrogen or when Y is the 3-carbon fragment (A) then R 2  is C 2 -C 4  alkyl, allyl, propargyl, C 3 -C 6  cycloalkyl or benzyl; and R 2  and R when taken together is the group wherein R 10  is phenyl, C 1 -C 4  lower alkylphenyl, halophenyl, hydroxyphenyl or C 1 -C 4  lower alkoxyphenyl and then Y is a 3-carbon fragment of the formula (A) or a substituted 3-carbon fragment of the formula wherein R 11  is hydrogen, C 2 -C 4  alkanoyloxy, C 1 -C 4  alkoxy, C 1 -C 4  alkylthio; or a carbamoyloxy group of the formula (B) wherein R 7  and R 8  are as defined above, are prepared by a process which comprises (a) reacting in an inert, anhydrous solvent at a temperature between - 90 and -15 C. a #-lactam ester of the Formula II wherein R 9  is acetoxymethyl or a readily removable ester-forming group, with between 2 and 6 equivalents per 1 equivalent of #-lactam ester of an alkali metal salt of the formula wherein R 2  is as defined above, in the presence of an excess of the corresponding alcohol of the formula HOR 2 ; (b) adding between 1 and 5 equivalents of a halogenating agent; (c) acidifying said mixture; and (d) recovering the substituted #-lactam ester from the reaction mixture; (e) and when R 3  is to be pyridine preparing the compound by steps (a) to (d) wherein R 3  is acetoxy and heating the acetoxy compound of Formula I with pyridine in an inert solvent. When a compound of Formula II is used wherein represents the acyl moiety derived from mandelic acid or a substituted mandelic acid having an unprotected hydroxyl group, an intramolecular alkoxylation takes place to provide the novel spiro #-lactams of formula