Patent GB-770913-A (GB)
Title: Esters and thioesters of penicillin and their production
IPC: C07D499/00
Filed: 1954-08-10
Abstract: The invention relates to esters of penicillin with phenols and thiophenols having a basic substituent, and their salts with acids innocuous to human beings, said esters being represented by the formula <FORM:0770913/IV(b)/1> where Z1 is PenCOO- or PenCOS, where PenCO represents penicillin with hydroxyl removed from the carboxyl group; where Z2 is hydrogen or PenCOO- or PenCOS-; where Y is alkylene or alkylene linked to a carbon atom of the phenyl ring through one of the groups -O-, -S-, -NH-, -NR-, -RO-, -RS-, -CO-, -COO-, -CONH-, -CONR-, -COS-, -CSO-, -NHCO-, -NRCO-, -NHCS-, -NRCS-, -CSNH-and -CSNR- where R is 1 to 2 carbon alkyl; and where R1 and R2 are alkyl groups of not more than 4 carbon atoms or together with the nitrogen atom forms a heterocyclic ring.  The esters are prepared by reacting phenols and thiophenols of formula <FORM:0770913/IV(b)/2> where V1 is OH or SH and V2 is H, OH or SH and the rest are as above, with a penicillin derivative of formula PenCO-O-X where PenCO- represents penicillin with hydroxyl removed from the carboxyl group; and X is PenCO-, an acyl group of an aliphatic or aromatic monocarboxylic acid or -COOR3 where R3 is alkyl of not more than 6 C atoms.  The reaction is carried and in the presence of an inert solvent such as methylene chloride, chloroform, ethyl acetate, acetone, ether, dioxane or tetrahydrofuran, as such or in admixture with one another.  A temperature of - 20 DEG  C. to + 40 DEG  C., and preferably 0 DEG  C., is employed and the presence of an organic base such as triethylamine or pyridine is desirable.  Instead of the penicillin anhydride per se, it is preferred to use a mixture of penicillin anhydride with (a) anhydride of aliphatic monocarboxylic acid, (b) anhydride of aromatic monocarboxylic acid, or (c) monoester of carbonic acid.  (c) is prepared by reacting a penicillin salt with a chlorocarbonic acid ester such as ethyl chlorocarbonic acid ester. Other examples are given.  The product may be reacted directly with the phenol or thiophenol of the invention.  The esters may be isolated as such or as a salt with an acid innocuous to human beings, e.g. hydrochloric, hydrobromic, hydriodic, sulphuric, citric, lactic, benzene sulphonic, toluene sulphonic and penicillin acids.  The penicillin is preferably penicillin G, but any other penicillins, e.g. O, K, F, dihydro F, X or mixture thereof may be used.  Examples describe the preparation of (a) benzyl penicillin - 4 - (b  - diethylamino ethyl) phenyl ester citrate; (b) lactate of (a); (c) benzylpenicillin - 4 - (b  - diethylaminopropyl) phenyl ester citrate; (d) benzylpenicillin-4-(o -diethylaminoaceto) phenyl ester hydrobromide; (e) benzyl penicillin - 4 - (o  - diethylaminoacetamino) phenyl ester citrate; (f) benzylpenicillin - 4 - (o  - diethylaminoethyl carboxy amido) phenyl ester citrate; (g) benzyl penicillin-4-(N - methyl - N - diethylaminoethyl) aminophenyl ester dihydrochloride; (h) benzyl penicillin - 4 - (N - diethylaminoethylthiocarbamido) phenyl ester hydrochloride; (i) benzyl penicillin - 4 - (b  - piperidinoethyl) - phenyl ester hydrochloride; (j) benzyl penicillin-4-(b -morpholinoethyl) phenyl ester HCl; (k) benzyl penicillin - 4 - (b  - dimethylaminoethyl) phenyl ester citrate; (l) benzylpenicillin-4-(b -dibutylaminoethyl) phenyl ester sulphate; (m) benzyl penicillin - 4 - (b  - diethylaminoethoxy) phenyl ester citrate; (n) citrate of the benzyl penicillin ester of p-hydroxybenzoic acid diethylaminoethyl ester; (o) benzyl penicillin-2-(diethylaminomethyl) thiophenyl ester; (p) benzyl penicillin - 4 - (diethyl aminoacetamino) - thiophenyl ester HCl; and (q) benzyl penicillin-2-(carbo - b  - diethylaminoethoxy) thiophenyl ester hydrochloride.  Other esters specified are the penicillin esters of p-diethylaminoethoxyphenol; p - hydroxybenzoic acid diethyl aminoethyl ester; p - hydroxybenzoic acid diethylaminoethylamide; N - (p - hydroxyphenyl) - N1 - (diethyl) ethylenediamine; p-(N - b  - diethyl aminoacetyl) aminophenol; and the corresponding thioanisols, thioesters and thioamides.