Patent GB-654093-A (GB)
Title: Improvements in or relating to the preparation of penicillin salts
IPC: C07D499/24
Filed: 1948-02-20
Abstract: Penicillin salts of the general formula <FORM:0654093/IV (b)/1> wherein A represents an alcohol residue of at least 16 carbon atoms (especially a sterol residue), Y represents an aliphatic residue of 1-11 carbon atoms (especially CH2), R and R1 each represent hydrogen or an alkyl group of 1-4 carbon atoms (especially ethyl in both cases), and Z represents a penicillin residue, are manufactured by reacting the corresponding high molecular weight alcohol ester of an amino-carboxylic acid with a penicillin, or by reacting a salt of the amino-carboxylic ester with a salt (e.g. the sodium salt) of the penicillin.  The products may be used for therapeutic administration, e.g. in aqueous, saline, vegetable oil or vegetable oil-wax suspensions, or in tablets.  In examples, cholesteryl diethylaminoacetic is reacted in ethereal solution with penicillin G, F, X and K. Additional starting materials specified are, on the one hand, those in which A is the residue of stigmasterol, sitosterol, phytosterol, ergosterol, calciferol, lumisterol or cetyl, ceryl, myricyl or octadecyl alcohol, Y is the hydrocarbon chain of propionic, butyric, valeric, caproic, oenanthylic, caprylic, pelargonic, capric, undecylic, lauric or isobutyric acid, and NRR1 is amino or dimethyl-, dipropyl-, dibutyl-, methylethyl-, di-isopropyl-, ethylisopropyl-, methyl- or ethyl-amino, and on the other hand, gigantic acid, flavicidin and the special penicillins obtained by the use of precursor substances according to Specification 646,819.  A list of additional products is also given.  Amino-carboxylic esters of the general formula <FORM:0654093/IV (b)/2> are obtainable by esterifying an alcohol containing at least 16 carbon atoms in the molecule with an acid AOCOYW (where W represents a halogen atom or a nitro, cyano, formyl or carboxyl group), and thereafter replacing the halogen atom by NRR1 by reaction with ammonia or a primary or secondary amine, reducing the nitro group to an amino group or the cyano group to an aminomethyl group, or converting the formyl or carboxyl group to an aminomethyl group by reaction with an amine followed by reduction.  The esterification may be effected by reacting the alcohol with a halide of the acid or reacting a halide (e.g. bromide or iodide), of the alcohol with a metal salt of the acid, or (when W is halogen), by reacting the alcohol with the acid itself in the presence of an acidic catalyst or with the anhydride of the acid.  The aminocarboxylic esters may also be prepared directly by reaction of the alcohol with a salt of a halide of the aminoacid HOOCYNRR1 or by ester interchange with an ester of the said amino-acid.  In an example, cholesterol is refluxed with choracetyl chloride in toluene and the product is refluxed with diethylamine in benzene.  The chloracetyl chloride may be replaced by bromoacetyl chloride or bromide, chloracetyl bromide, iodacetyl chloride, bromide or iodide, a - or b -halopropionyl or -halo-isobutyryl halides, or haloacyl halides corresponding to the other values for Y specified above, and the cholesterol by the other alcohols specified above. The Specification as open to inspection under Sect. 91 comprises also the manufacture of aminoester salts of other acid antibiotics, e.g. penicillic acid, citrinic acid and aspergillic acid.  This subject-matter does not appear in the Specification as accepted.ALSO:Therapeutic preparations contain penicillin salts of the general formula <FORM:0654093/VI/1> (wherein A represents an alcohol residue of at least 16 carbon atoms, especially a sterol residue, Y represents an aliphatic residue of 1-11 carbon atoms, especially CH2, R and R1 each represent hydrogen or an alkyl group of 1-4 carbon atoms, especially ethyl in both cases, and Z represents a penicillin residue), which may be suspended in water, a saline solution, a vegetable oil (e.g. peanut oil) or an oil-wax (e.g. beeswax), base, or may be incorporated in an inert tablet base and formed into tablets, which may be enteric coated if desired.