Process for the manufacture of gramicidin s

摘要

In a process for the manufacture of gramicidin S a salt of an L-valyl-L-ornithyl-L-leucyl-D-phenylalanyl-L-proline ester in which the d -amino group of the ornithine radical is protected by the introduction of a substituent on the N-atom of the d -amino group, and which contains in the residue of the hydroxy compound from which the ester is derived an electron-attracting substituent, that is to say, a substituent which is meta-directing in aromatic rings or a halogen atom, is treated with a basic agent and the protected d -amino groups are then converted into the free amino groups. Protecting groups mentioned are those which are capable of being split off without opening the ring, e.g. the tosyl, trityl, carbobenzyloxy and trifluoracetyl radicals. Electron-attracting substituents mentioned are cyano, nitro, sulpho or methanesulphonyl groups and examples of hydroxy components specified are cyanomethyl alcohol, p-nitrophenol and p-methane sulphonyl-phenyl. Suitable salts for use in the process are those of hydrohalic acids, e.g. hydrochloric acid or halogenated fatty acids, e.g. trifluoracetic acid. Alkaline agents mentioned include alkali metal hydroxides or carbonates and organic bases such as tertiary amines. Organic solvents may be employed such as dimethyl-formamide, acetonitrile, dioxane or tetrahydrofurane and mixtures thereof. Water may also be present and an acid catalyst, e.g. acetic or sulphuric acid may be employed. In an example L-valyl-Nd - tosyl - L - ornithyl - L - leucyl - D - phenylalanyl-L-proline nitrophenyl ester trifluoroacetate dissolved in dimethyl-formamide and glacial acetic acid are dropped into pyridine, the solvent is evaporated and the mixture dissolved in methanol, isopropanol and water and the solution filtered through columns of basic and acidic ion-exchangers. The residue is crystallized from methanol and water to obtain the dihydrate of di-d -tosyl-gramicidin S which is chromatographed on aluminium oxide, eluted with chloroform and ethyl acetate and recrystallized from methanol and water. The dihydrochloride of gramicidin S is obtained by treating the di-tosyl derivative in liquid ammonia with sodium and subsequently ammonium chloride. L - valyl - Nd - tosyl - L - ornithyl - L - leucyl - D - phenylalanyl - L - proline para - nitrophenyl ester trifluoroacetate is obtained by reacting N - trityl - L - valyl - (Nd - tosyl) - L - ornithyl - L - leucyl - D - phenylalanyl - L - proline with di-(para-nitrophenyl)-sulphite in pyridine, isolating the nitrophenyl ester and reacting it with trifluoracetic acid. Salts of peptide carboxylic acid esters which contain an electron attracting substituent in the alcohol component can be prepared by reacting the N-triphenylmethyl-pentapeptide with a hydrohalic acid ester of the corresponding alcohol in the presence of a tertiary organic base followed by splitting off the triphenyl methyl radical by treatment with a dilute acid or by catalytic hydrogenation of a corresponding ester of the N-carbobenzoyloxy-penta-peptide.