Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-06-12
1999-12-28
Owens, Amelia
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D30777
Patent
active
060083824
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel method for the demethylation of podophyllotoxin I in order to access 4'-demethylepipodophyllotoxin of formula II ##STR2##
4'-Demethylepipodophyllotoxin is a key synthetic intermediate in the preparation of novel anticancer substances, of which mention may be made, for example, of etoposide and teniposide.
The preparation of 4'-demethylepipodophyllotoxin II is known and is usually carried out by demethylation of podophyllotoxin I by HBr, according to the original method described by M. Kuhn, Helvetica Chimica Acta, 1969, 52, 944, and then taken up by several groups, such as K. H. Lee, J. Med. Chem., 1986, 29, 1547 and Journal of Natural Products, 1989, 52, 606, O. Buchardt, Acta Chemica Scandinavica, 1993, 47, 1190 or Y. Nishimura, Chemistry Letters, 1987, 799. This method gives moderate yields, according to the amounts involved, and is relatively difficult to carry out, because of the handling of highly aggressive gaseous HBr. Other methods can be envisaged for carrying out this demethylation, by using the usual reagents for such a conversion: mention may be made of BBr.sub.3 or BCl.sub.3 in CH.sub.2 Cl.sub.2 from -20.degree. C. to +20.degree. C. (Tet., 1969, 24, 2289); AlCl.sub.3 in CH.sub.2 Cl.sub.2 at 0.degree. C. or at ordinary temperature (according to J. Chem. Soc., 1944, 330); pyridinium hydrochloride at more or less high temperature; AlBr.sub.3 in the presence of ethanethiol at ordinary temperature.
These various methods result in the degradation or in the non-conversion of podophyllotoxin.
A novel demethylation method has therefore been developed.
The method which is the subject-matter of the present invention consists in treating podophyllotoxin I with the pair of reagents: strong acid-aliphatic, aromatic or functionalized sulfide, in the presence of an organic or inorganic acid or else in the presence of water, with or without water-miscible organic solvent, such as the acetone-water mixture, advantageously, at a temperature of between -20.degree. C. and +40.degree. C.
According to the specific characteristics of the present invention, the strong acid of the pair of reagents is advantageously composed of methanesulfonic acid, whereas the aliphatic, aromatic or functionalized sulfide of the pair of reagents is advantageously chosen from dimethyl sulfides D,L-methionine and methylthioacetic acid.
According to other advantageous characteristics of the method of the invention, the reaction is carried out in the presence of an organic acid of formula RCOOH, where R=H, C.sub.1 -C.sub.4 alkyl or CX.sub.3, with X=Cl or F. It will relate in particular to formic acid or trifluoroacetic acid.
In the case where the reaction is carried out in the presence of an inorganic acid, use can advantageously be made of H.sub.3 PO.sub.4 or a slight stream of HCl or HBr sparging into the reaction mixture.
In accordance with the present invention, the compound II directly resulting from the reaction is isolated and purified by recrystallization from a solvent, such as isopropyl alcohol, acetic acid, water, acetone, dioxane, isopropyl ether, toluene, ethanol and their mixture.
D,L-Methionine can also be replaced by an aliphatic or aromatic sulfide with a low carbon number or with a functionalized sulfide, for example functionalized by an acidic functional group, such as methylthioacetic acid. In this case, the joint presence of an inorganic or organic acid is no longer necessarily indispensable.
It is known in the chemical literature that the methanesulfonic acid, D,L-methionine pair can demethylate the aromatic methoxy of certain compounds, in order to result in the corresponding phenols: see J. C. S., Perkin Trans. I, 1977, 2288; J. C. S. Chem. Comm., 1976, 922; Chem. Lett., 1980, 875; J. Med. Chem., 1984, 27, 28; Heterocycles, 1992, 34, 937; Synth. Comm., 1992, 22 (16), 2313. One of the reaction products is thus the methylsulfonium derivative of methionine, which means that an aliphatic or aryl sulfide can also be used as demethylation reagent, resulting in the corresponding su
REFERENCES:
N Fujii et al, J Chem Soc, Perkin Transaction 1 (1977) pp. 2288-2289.
H Irie et al, Chemistry Letters (1980) pp. 875-878.
J Kunitomo et al, Heterocycles, 34(5) (1992) pp. 937-942.
J Andre et al, Chem Abs 117(23) (1992) No. 234312q.
M Kuhn et al, Helvetica Chimica Acta 52(4) (1969) pp. 944-947.
L Thurston et al, J Med Chem 29 (1986) pp. 1547-1550.
H Hansen et al, Acta Chemica Scandinavica 47 (1993) pp. 1190-1200.
H Saito et al, Chemistry Letters (1987) pp. 799-802.
Guminski Yves
Imbert Thierry
Owens Amelia
Pierre Fabre Medicament
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