Patent GB-1292469-A (GB)
Title: Antibacterial derivatives of coumermycin
IPC: C07H17/075
Filed: 1969-12-16
Abstract: 1292469 Derivatives of coumermycin and intermediates therefor BRISTOL-MYERS CO 16 Dec 1969 [16 Dec 1968] 61268/69 Headings C2A and C2C Novel antibiotics having the Formula I and pharmaceutically acceptable cationic salts thereof, wherein R is H or CH3; R<SP>4</SP> is OH; each of R<SP>5</SP> and R<SP>6</SP> is H, F, Cl, Br, I, CF 3 , CCl 3 , NH 2 , N0 2 , CN, OH, N-(C 1 -C 8 )alkylamino; N,N - di(C 1 -C 8  alkyl) - amino, carboxamido, N - (C 1 -C 8 ) - alkylcarboxamido, N,N - di- (C 1 -C 8  alkyl)-carboxamido, carboxy, carb- (C 1 -C 8 ) alkoxy or acetoxy ; and n is 0 to 8, are prepared by (a) subjecting a tetra-, tri- or ditetrahydrodropyranyl ether of coumermycin A 1  or A 2 , of Formula X wherein R is H or CH 3  and R<SP>2</SP> and R<SP>3</SP> are the same or different and are either H or to acylative cleavage with an acid halide of Formula XI or an acid anhydride of formula or mixed anhydride of formula wherein hal is Cl, Br or I; R<SP>14</SP> is C 1 -C 8  alkanoyloxy; R<SP>5</SP> and R<SP>6</SP> are H, F, Cl, Br, I, CF 3 , CCl 3,  NO 2 , CN, N,N-di(C 1 -C 8  alkyl)amino, N,N-di. (C 1 -C 8  alkyl)carboxamido or carb(C 1 -C 8 )- alkoxy; and n is 0-8, to give an intermediate compound of Formula III and (b) hydrolysing said intermediate by allowing it to stand in a polar solvent in the presence of an acid to produce a compound of Formula I, and if desired (c) when R<SP>5</SP> or R<SP>6</SP> is acetoxy or carb(C 1 -C 8 )alkoxy hydrolysing the compound obtained from (b) to produce the corresponding compound in which R<SP>5</SP> or R<SP>6</SP> is hydroxy or carboxy respectively; or when R<SP>5</SP> or R<SP>6</SP> is nitro reducing the compound obtained from (b) to produce the corresponding compound in which R<SP>5</SP> or R<SP>6</SP> is amino, and (d) if desired when R<SP>5</SP> or R<SP>6</SP> is carboxy aminating the compound to produce the corresponding compound in which R<SP>5</SP> or R<SP>6</SP> is N-substituted or unsubstituted carboxamido ; or when R<SP>5</SP> or R<SP>6</SP> is amino alkylating the compound to produce the corresponding compound in which R<SP>5</SP> or R<SP>6</SP> is N-C 1  to C 8  alkyl amino or N-di(C 1  to C 8  alkyl)amino. 4 - Hydroxy - 3 - phenylacetylbenzoic acid is prepared by reacting ethyl p-hydroxybenzoate with phenylacetyl chloride followed by hydrolysis; the said compound is then reduced to 4- hydroxy - 3 - # -phenylethylbenzoic acid with nascent hydrogen. This compound is acetylated with acetic anhydride in pyridine to 4-acetoxy- 3-#-phenylethylbenzoic acid and converted to the acid chloride with SOCl 2 . 2-Hydroxybiphenyl and acetic acid are heated with boron trifluoride, followed by treatment with ice-water to give 4-hydroxy-3- phenylacetophenone which is reacted with iodine in pyridine and acidified to give 4-hydroxy-3- phenylbenzoic acid. This is converted to 4- acetoxy-3-phenylbenzoic acid with acetic anhydride. Pharmaceutical compositions having antibiotic activity against Gram-positive and Gramnegative bacteria comprise an antibiotic of Formula (I) or a salt thereof together with a pharmaceutically acceptable carrier.