Process for the manufacture of bis-triazole compounds and interm

Details Process for the manufacture of bis-triazole compounds and interm Process for the manufacture of bis-triazole compounds and interm

1998-02-24

2000-05-16

Morris, Patricia L.

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C07D24908

Patent

active

060639334

DESCRIPTION:

BRIEF SUMMARY
FIELD OF INVENTION

This invention relates to a novel process for the manufacture of bis-triazole derivatives and in particular for the preparation of 2-2,4fluorophenyl)-1,3-bis-(H-1,2,4-triazol-1-yl)-propan-2-ol known as fluconazole, and novel intermediates useful in the manufacture of such bis-triazole compounds, of formulae (IV) and (V): ##STR1##


BACKGROUND OF INVENTION

Among the bis-triazole compounds, fluconazole, ie. 2-(2,4-difluorophenyl)-1,3-bis-(1H-1,2,4triazol-1-yl)-propan-2-ol has antifungal activity.
Fluconazole has been prepared by three methods:
In Canadian Patent 1,181,076 a Friedel-Crafts acylation of 1,3difluorobenzene with chloroacetyl chloride results in the formation of 2,4difluoro-.varies.-chloroacetophenone which is then reacted with 1,2,4-triazole to afford 2.4difluoro-.varies.-(1H-1,2,4-triazol-1-yl)acetophenone. The resulting ketone is subjected to a Corey-Chugaev reaction with trimethyl sulfoxonium iodide to form 2-(2,4difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)-1,2-epoxypropane. Condensation of the resulting epoxide with 1,2,4-triazole affords fluconazole. The overall yield is between 4-8% (Scheme 1).
The preparation can be depicted in the following scheme: ##STR2##
In Canadian Patent 1,181,076, 1-iodo- or 1-bromo-2,4-difluorobenzene is converted to its Grignard or lithiated organometallic complex which is then reacted with 1,3-dichloroacetone to afford 1,3-dichloro-2-(2,4difluorophenyl)-2-propanol. The resulting chlorohydrine is then reacted with two moles of 1,2,4-triazole to afford fluconazole. The last transformation involves the formation of 2-2,4-difluorophenyl)-3-(1H-1,2,4triazol-1-yl)-1,2-epoxypropane as an intermediate as seen in scheme 1.
The process is illustrated in the following scheme: ##STR3##
In Canadian Patent 1,182,822. 1,3-dichloroacetone is reacted with two moles of 1,2,4triazole to afford 1,3di(triazolylacetone). The resulting ketone undergoes a Grignard reaction to lead to fluconazole, as depicted in the following scheme: ##STR4##
In the present application, there is disclosed a process which involves the epoxidation of triazol-containing olefins, followed by reduction of the epoxide obtained to afford fluconazole. The present process offers numerous advantages over the existing art.
First, it allows the obtention of the bis-triazole compounds and specifically fluconazole in considerably higher yields than the existing procedures.
Second, the process is easy to scale up, avoiding the use of a Grignard reaction and a Corey-Chugaev reaction which are extremely air and moisture sensitive and therefore difficult to carry out in large scale.
Third, it does not entail the use of ethers which are extreme fire hazards.
Forth, it results in avoiding the use of highly toxic and corrosive substances such as dichloroacetone and chloroacetyl chloride.
Fifth, the process allows for the formation of a series of unknown epoxide analogues of fluconazole with potential therapeutic value.
Therefore, one object of the present invention is to provide a convenient novel process for the production of bis-triazole derivatives and specifically fluconazole.
It is a further object of the invention to produce new intermediates useful in the manufacture of such bis-triazole compounds. The resulting intermediates are obtained in high yields.


SUMMARY OF THE INVENTION

According to the present invention, a process is provided for preparing bis-triazole derivatives which comprises the steps of converting the E and/or Z olefins (II) and (III) to their corresponding epoxides (IV) and (V) which are then reduced to the bis-triazole compounds of formula (I). The process is depicted as follows: ##STR5##
The present invention also provides for novel intermediates in the form of epoxides (IV) and (V) which may be conveniently reduced to bis-triazole compounds under the influence of a variety of reducing agents. In a preferred embodiment, the process allows for the preparation of fluconazole.
In another preferred embodiment the invention entails the epoxide intermediates.
The starting materials (

REFERENCES:
Murai et al, "Reduction of Epoxides", Comprehensive Organic Synthesis 8:871-893 (1991).
McKillop et al, "Sodium Perborate and Sodium Percarbonate: Cheap, Safe and Versatile Oxidising Agents for Organic Synthesis", Tetrahedron 51(22):6145-6166 (1995).

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