Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Cyclic peptides
Patent
1997-10-16
1998-08-04
Henley, Jr., Raymond
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Cyclic peptides
C07K 500
Patent
active
057895376
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR 96/00575 filed Apr. 16, 1996.
The present invention relates to a novel process for the preparation of streptogramins of general formula: ##STR3## in which: either the radical R.sub.1 represents a methyl or ethyl group, the radical R.sub.2 represents a hydrogen atom and X and Y together form an oxo radical, atom and Y represents a hydrogen atom or a hydroxyl radical, radical and X and Y together form an oxo radical, ##STR4## in which the radicals R.sub.1, R.sub.2, X and Y are as defined above.
Streptogramins are a known class of compounds comprising components of combined with components of group A, bring about a synergism of the antimicrobial action.
The product of general formula (I) for which R.sub.1 is ethyl and R.sub.2 is hydrogen is known under the name of pristinamycin IB. The product of general formula (I) for which R.sub.1 is methyl and R.sub.2 is hydrogen is known under the name of vernamycin B.delta.. The product of general formula (II) for which R.sub.1 is ethyl and R.sub.2 is hydrogen is known under the name of pristinamycin IA. The product of general formula (II) for which R.sub.1 is methyl and R.sub.2 is hydrogen is known under the name of pristinamycin IC or vernamycin B.gamma.. The product of general formula (II) for which R.sub.1 is ethyl and R.sub.2 is hydroxyl is known under the name of pristinamycin ID.
General methods of demethylation were already known, for example such as the methods described in Tet. Lett., 18, 1567 (1977); J. Org. Chem., 49, 2795 (1984); J. C. S. Chem. Comm., 905 (1989), Tet. Lett., 33, 6991 (1992); however, these methods could not be adapted to fragile products such as streptogramins, either because the reaction did not take place or because the operating conditions were degrading towards these products. Yet other methods involved toxic reactants which were not totally removable from the final product, this being unacceptable from the pharmaceutical point of view.
It has now been found, and this forms the subject of the present invention, that the streptogramins of general formula (I) could be obtained by demethylation of the corresponding derivative of general formula (II) by treatment with a periodate in acetic medium followed by a treatment in aqueous acidic medium or by a treatment with an agent capable of consuming the formaldehyde in situ.
The periodate used is advantageously tetra-n-butylammonium periodate or an alkaline periodate (sodium periodate). The reaction is carried out in a solvent such as a chlorinated solvent (for example dichloromethane, chloroform, dichloroethane or trichloroethane), an ester (for example ethyl acetate), a nitrile (for example acetonitrile) or in tetrahydrofuran, N-methylpyrrolidone or optionally a mixture of these solvents, in the presence or absence of ethylene glycol. The reaction takes place at a temperature of between 20.degree. and 40.degree. C.
The subsequent treatment is a hydrolysis, in aqueous medium, which releases formaldehyde. It is possible to perform the process by treatment of the product obtained in a homogeneous aqueous medium to which is added a strong acid, or directly in an acidic or non-acidic two-phase medium; in particular, the process may be performed in a dichloromethane/water mixture. In this case, preferably, the pH of the aqueous medium will be weakly acidic; it is understood that the acidity of the medium will be provided, indiscriminately, by addition of a strong or weak acid.
The acids used may be chosen in particular from trifluoroacetic acid, sulphuric acid, hydrochloric acid, methanesulphonic acid, p-toluenesulphonic acid or formic acid. The treatment in acidic medium is carried out at a temperature of between 0.degree. and 40.degree. C.
When the subsequent treatment is carried out, it is also possible further to add an agent capable of consuming the formaldehyde in situ, this agent is advantageously chosen from hydroxylamine, a bisulphite (for example sodium bisulphite) or hydrogen peroxide in aqueous medium. The process is preferably performed in a two-pha
REFERENCES:
patent: 5310900 (1994-05-01), Barriere et al.
patent: 5637565 (1997-06-01), Anger et al.
Derwent Abstract of FR-A-2689518.
Takata et al., "Mild and Selective Oxygen Atom Transfer: .sup.n Bu.sub.4 NIO.sub.4 with Metalloporphyrins," Tetraheron Letters, 24(34):3631-3634 (1983).
Barriere Jean-Claude
Grondard Luc
Lefevre Patrick
Mutti Stephane
Henley, Jr. Raymond
Rhone-Poulenc Rorer S.A.
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