Preparation of triazolone compounds

Details Preparation of triazolone compounds Preparation of triazolone compounds

1995-05-11

1998-06-16

Morris, Patricia L.

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

548263, 5482646, C07D40304, C07D24912

Patent

active

057672750

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

This is 371 of application of PCT/EP93/03119 filed Nov. 6, 1993.
This invention relates to a process for the preparation of triazoles.
More particularly, it relates to a process for the preparation of a 1,2,4-triazol-3-one compound substituted in the positions 4 and 5 by an alkyl or aryl group and optionally substituted in the position 2 by an alkyl group.
1,2,4-triazol-3-ones compounds bi-substituted in positions 4 and 5 or tri-substituted in positions 2, 4 and 5 are useful in themselves or as intermediates. Examples of the said compounds useful for human or animal therapy are described by U.S. Pat. No, 3,857,845 and U.S. Pat. No. 4,338,317.
Typical examples are ethoperidone and nefazodone.
The preparation of these compounds, however, implies a number of drawbacks.
U.S. Pat. No. 4,338,317 teaches to preparare the compounds of the formula: ##STR1## where R is ethyl, R' is hydrogen or phenoxyethyl, and R" is 4-(halophenyl)-1-piperazinyl-propyl, by reacting an N-ethoxy-carboxyethiopropionamide of the formula: ##STR2## where R and R' have the meanings set forth above, with a hydrazine compound of the formula:
However, this process presents a drawback in that during the reaction of compound (II) with compound (III) a highly toxic gas, i.e. hydrogen sulfide, is produced.
In addition, although the above-mentioned document states that the 1,2,4-triazol-3-one compounds tri-substituted in positions 2, 4 and 5 can be prepared directly from the compounds (II) wherein R' is not hydrogen, it does not disclose any examples of the preparation thereof.
In a subsequent document, G. D. Madding et al. (J. Het. Chem. 22, 1121-26, 1985) state that the said procedure is suitable only for preparing the intermediate compound bi-substituted in positions 2 and 5, from which the desired tri-substituted compound is then prepared by alkylation. Moreover, even though these Authors don't refer specifically to the production of hydrogen sulfide, they recognize the existence of "factors" which prompt to search for other synthesis pathways.
Then, G. D. Madding et al. (loc. cit.) describe two other routes for preparing bi-substituted intermediates from which the desired tri-substituted compound is prepared by alkylation.
The first route involves the cyclization in an alkaline medium of a semicarbazide of the formula:
In turn the semicarbazide compound (IV) is obtained from an isocyanate compound of the formula:
Hence, this synthesis has the drawback of using isocyanate compounds which are dangerous and toxic, particularly when they have a low molecular weight and are volatile.
On the other hand, through this pathway H. Gehlen et al. (Ann. 675, 180-188, 1964) had already prepared several compounds of formula I, in which the position 4 is substituted by an alkyl or aryl group and position 5 is substituted by an alkyl group.
However, to prepare the compounds which are tri-substituted in positions 2, 4 and 5, H. Gehlen et al. had to employ another method and the only substituent in position 2 was the phenyl group. Therefore, the tri-substituted compounds prepared by these Authors differ from the compounds which are intended to be prepared according to this invention.
The second route described by G. D. Madding et al. involves the cyclization in a basic medium of an N-carbomethoxyamidrazone compound of the formula: ##STR3## where R' is phenoxyethyl.
In turn, compound (VII) is prepared by reacting a compound of the formula: ##STR4## where R' is phenoxyethyl, with methyl carbazate and the compound of formula (VIII) is obtained by treating an amide of the formula:
Therefore, even in this case, a dangerous and toxic gas has to be employed.
Notwithstanding this drawback, the Authors regard this method as the most suitable for large-scale production.
The fact that such a complex process, which does not directly produce the desired tri-substituted compound and involves the use of a dangerous and toxic gas such as phosgene, is considered to be the best one among the methods investigated by the Authors points out the difficulties that the a

REFERENCES:
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patent: 5094683 (1992-03-01), Daum et al.
Davidson, "A Preparation of 3-amino-4,5-diaryl, etc" CA 91: 107946u (1979).
Gehlen et al, "1,2,4-triazolin-5-ones, etc" CA 61: 10674 a,b. (1964).
Senet et al, "Process for the preparation of etc" CA 111: 7413f (1989).
Cohen, "Preparation of some 3-hydroxy, etc" CA 89: 43256 (1978).
VEB Fahlberg-List, "Herbicidal Compositions, etc" C98: 174871 (1983).
Journal of Heterocyclic Chemistry, vol. 22, No. 4, pp. 1121-1125, G.D. Madding, et al. "Synthesis and X-Ray Crystal Structure of a 2,4,5-trisubstituted 1,2,4-triazol-3-one" (1985).

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