Process for preparing triazole antimycotic compounds

Details Process for preparing triazole antimycotic compounds Process for preparing triazole antimycotic compounds

2000-06-02

2001-02-27

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06194584

ABSTRACT:

The present invention refers to a process for the preparation of azole compounds endowed with antimycotic activity.
The compounds of formula I
wherein R
1
is chlorine, fluorine or trifluoromethyl,
R
2
is hydrogen, chlorine, fluorine or trifluoromethyl;
R
3
is C
1-4
alkyl; and
R
4
is a C
1-5
polyfluoroalkyl group containing at least two fluorine atoms and optionally other halogen atoms selected from chlorine and bromine;
and their salts with pharmaceutically acceptable acids, are known as antimycotic and antifungal agents.
The patent application WO 97/31903 (in the Applicant's name) shows a class of compounds which those of formula I above fall within, as broad spectrum antimycotics against human and animal pathogenic fungi. Such compounds are obtained from the intermediate of formula VII
wherein R
1
, R
2
and R
3
are as defined above, which reacted with the suitable polyfluoroalkyl derivative provides the desired compound of formula I.
It has been now found a new method for preparing the compounds of formula VII constituting an alternative to the synthetic routes described in the above cited prior art.
Therefore the present invention refers to a method for preparing compounds of formula VII as illustrated hereinbelow.
The synthesis of the compounds I according to the invention starts from the olefin of formula II
wherein R
1
and R
2
are as defined above, and R is hydrogen or a protecting group for the hydroxy moiety. This compound is described and claimed per se in the co-pending patent application filed in the same date of the present one by the Applicant. It is epoxidized, for example according to what described in the patent EP-0 046 033 (in the name of Standford University) which uses titanium alcoholate in the presence of a suitable derivative of tartaric acid and of an organic hydroperoxide, for example tert.butyl- or cumyl-hydroperoxide, or according to what taught in Synthesis, 1986, page 89. It is thus obtained the oxirane of formula III
wherein R, R
1
and R
2
are as defined above, which, treated with (C
1-4
)alkyl-magnesium halide in the presence of copper(I) iodide, prepared according to what described in
Organocopper Reagents: a practical approach,
page 39. ed. R. I. K Tavlor, provides the triol of formula IV
wherein R, R
1
, R
2
and R
3
are as defined above.
The triol of formula IV is treated with a sulfonic acid chloride, such as, for example methansulfonyl-cliloride or tosyl chloride, or with a halogenating agent such as, for example, phosphorous tribrornide, thionyl chloride or phosphorous pentachloride and, sequentially, with a strong base, for example NaOH, to give the compound of formula V
wherein R
1
, R
2
and R
3
are as defined above, and Lg is halogen or a OSO
2
R
IV
group wherein R
IV
is a (C
1-4
)alkyl or an optionally methyl-substituted phenyl group, which subdued to a reaction for substituting the leaving group Lg according to known methods gives the compound of formula VI
wherein R
1
, R
2
and R
3
are as defined above. This is treated with 1,2,4-triazole in basic medium to give the desired compound of formula VII.
Hereinbelow fulfilment examples of the present invention are provided.


REFERENCES:
patent: 0 315 946 (1989-05-01), None
patent: 0 363 582 (1990-04-01), None
patent: 0 667 346 (1995-08-01), None
patent: WO 96 31490 (1996-10-01), None
patent: WO 97 31903 (1997-09-01), None
Erdik, E., “Copper(I) Catalyzed Reactions of Organolithiums and Grignard Reagents”, Tetrahedron, vol. 40, 1984, pp. 641-657.
R.J.K. Taylor, “Organocopper Reagents”, 1994, Oxford University Press, Oxford.
March, J., “Advanced Organic Chemistry”, 1985, J. Wiley & Sons., Chichester.
Tanaka, T. et al., “Triazole Antifungals. V. Synthesis and Antifungal Activity of Some Amides Related to 3-Acylamino-2-aryl-1-triazolyl-2-butanol” Chem. Pharm. Bull., vol. 40, No. 3, 1992, pp. 661-665.
Xianming, H. et al., “Phase-Transfer Synthesis of Optically Pure Oxetanes Obtained from 1,2,2-Trisubstituted 1,3-Propandiols”, Synthesis, May 1995, pp. 533-538.

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