Diol compounds as intermediates for preparing antimycotic...

Details Diol compounds as intermediates for preparing antimycotic... Diol compounds as intermediates for preparing antimycotic...

2000-06-05

2001-04-03

Dentz, Bernard (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C556S486000, C568S660000, C568S662000

Reexamination Certificate

active

06211387

ABSTRACT:

The present invention relates to diol compounds as intermediates useful in the preparation of antimycotic azole compounds.
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 polyfluoroalkyl C
1-5
group containing at least two fluorine atoms and optionally other halogen atoms selected from chlorine and bromine;
and the pharmaceutically acceptable salts thereof, are known as antimycotic and antifungal agents.
The patent application WO 97/31903 (in the Applicant's name) shows a class of compounds where the above compounds of formula I fall, as wide spectrum antimycotics against human and animal pathogenic fungi.
Two preparation processes being a synthetic alternative with respect to the synthetic routes taught by the above said prior art are described in two patent applications filed at the same date of the present one by the Applicant. These two processes use a new intermediate which constitutes the object of the present invention.
Therefore the present invention relates to a compound of formula II
wherein
R
1
is chlorine, fluorine or trifluoromethyl;
R
2
is hydrogen, chlorine, fluorine or trifluoromethyl; and
R is hydrogen or a protective group for the hydroxy moiety.
The synthesis of the compounds of formula II according to the present invention starts from the iodo- or bromo-benzene derivative of formula III
wherein R
1
and R
2
are as defined above, and X is bromine or iodine, which is first turned into the corresponding Grignard reactant according to known methods and then into the corresponding phenyl-zinc halide or phenyl-boron acid by treatment with zinc halide, preferably chloride, or with trialkyl borate followed by hydrolysis, which is treated with iodo- or bromo-fumarate, prepared as described in
J. Am. Chem. Soc.
1972, 94 (12), 4363-4, in the presence of a suitable transition metal(0)-based catalyst. Preferred examples of catalyst are palladium or nickel, optionally supported by ligands such as, for example, triphenylphosphine.
The transition metal(0)-based catalysts may be in case prepared in situ starting from the corresponding salts such as, for example, nickel chloride, cobalt chloride, nickel acetylacetonate, ferric chloride, palladium chloride, lithium tetrachlorocuprate, palladium acetate and palladium acetylacetonate.
Only for practical reasons palladium tetrakis(triphenylphosphine), nickel tetrakis(triphenylphosphine) or palladium on charcoal in the presence of triphenylphosphine are preferred, optionally prepared in situ as described, for example, in Org. Synth., 66, 67-74, 1988.
In this way a diester of formula IV
wherein R
1
and R
2
are as defined above, and R
I
and R
II
are independently a (C
1-4
)alkyl group, is obtained, which is reduced according to common techniques, for example with diisobutyl-aluminium hydride (DIBAH) to give the compound II wherein R═H.
Another synthetic route for yielding product II starts from the derivative of formula III which, turned into the corresponding Grignard compound and, then, reacted with a diester of oxalic acid, gives the compound of formula V
wherein R
1
and R
2
are as defined above, and R
III
is a (C
1-4
)alkyl group, which is reacted in the presence of a base such as, for example, sodium ethylate or methylate, optionally prepared in situ, or sodium hydride, according to the procedures of the so-called Wittig reaction, for example with trialkyl phosphonoacetate.
It is thereby obtained the compound of formula IV which is turned into the compound of formula II wherein R═H as already explained above.
It is intended that the product of formula II wherein R is a protective group of the hydroxy moiety may also be obtained by reacting a compound of formula II wherein R is hydrogen with a protective group of the alcoholic function (see, for example, T. W. Greene and P. G. M. Wuts, Protective groups in organic synthesis, John Wiley & Sons, New York).
Preferred protective groups according to the present invention are those stable in the presence of bases and nucleophilic reactants, in particular silyl ethers, benzyl ether, 2-methoxy-ethoxy-methyl ether, methoxy-methyl ether and tetrahydropyranyl ether.
A further method for yielding the product II entails the reaction of the magnesium derivative of the compound of formula III with the diol of formula VI
wherein X′ is a halogen atom and R is as defined above or is a MgX′ group.
Hereinbelow fulfilment examples of the present invention are provided.


REFERENCES:
patent: 0 315 946 (1989-05-01), None
Ishino, Y. et al., “A New Synthesis Of Trans-2-Substituted-2-Butene-1,4-Diols From 2-Butyne-1,4-Diol Via Nucleophilic Addition Of Grignard Reagents”, Chemistry Letters, No. 5, 1984, pp. 765-768.
Cohen, T. et al., “Copper-Induced Coupling Of Coupling Of Vinyl Halides”, Journal of American Chemical Society, vol. 94, No. 12, 1972, pp. 4363-4364.
Anthony N. De Silva et al., “Grignard Addition Reactions to 1,4-Difunctionalized But-2-ynes”,Australian Journal of Chemistry, vol. 46, 1996, pp. 1657-1671.

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