Process for the synthesis of trisubstituted oxazoles

Details Process for the synthesis of trisubstituted oxazoles Process for the synthesis of trisubstituted oxazoles

2000-10-26

2001-12-25

Higel, Floyd D. (Department: 1626)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S235000

Reexamination Certificate

active

06333414

ABSTRACT:

The present invention relates to a novel process for the synthesis of oxazoles, in particular trisubstituted oxazoles. Oxazoles are known to be useful for the treatment of inflammation and inflammation-related disorders.
Oxazoles are well known in the literature, which describes several possible routes for the synthesis thereof.
Oxazles can be prepared by reaction of a diazide with a cyano derivative, in the presence of tungsten as a catalyst. See, for example, Tetrahedron Letters, 1974, 16, 1531, the disclosure of which is specifically incorporated by reference. This process can be illustrated by the following scheme:
Trisubstituted oxazoles can also be prepared by using a primary amine as cyclization reactant. See, for example, J.A.C.S., 1943, 65, 2159, the disclosure of which is specifically incorporated by reference. This process can be illustrated by the following scheme:
However, the synthesis of trisubstituted oxazoles according to either of these processes can be limited by the starting compound, and some starting materials can be either unavailable commercially or very difficult to synthesize. Consequently, depending on the nature of the substituents, some trisubstituted oxazoles cannot be prepared by either of these processes.
Trisubstituted oxazoles have also been prepared by the thermolysis and photolysis of an acylisoxazolone derivative. See, for example, J. Chem. Soc. Perkin, 1997, 2665, the disclosure of which is specifically incorporated by reference. This process can be illustrated by the following scheme:
However, this process can require highly specialized equipment, for example to realize the photolysis of the starting materials. Therefore, the process may not easily be carried out industrially.
It is also known, by U.S. Pat. No. 5,719,163, the disclosure at which is specifically incorporated by reference, to synthesize certain trisubstituted oxazoles by using ammonium acetate in acetic acid at reflux, according to the following scheme:
However, this process can exhibit the disadvantage of being carried out in the presence of acetic acid and thus in an acid medium.
An aim of the present invention is to provide a novel process for preparation of trisubstituted oxazoles which can be carried out from starting materials which are relatively easy to synthesize or already commercially available, and/or which does not require highly specialized equipment and/or which can be carried out under reaction conditions, particularly with respect to pH, which are industrially more favorable.
A subject-matter of the present invention is thus a process for the preparing a trisubstituted oxazole of formula (II):
by reaction of thiourea with a diketone ester of formula (I):
in which the R
1
, R
2
and R
3
radicals, which may be identical or different, have the meanings given below.
It has been found that the process according to the invention can be carried out at a basic pH value, and even at a pH value close to neutral. Furthermore, the starting materials can be relatively easy to synthesize and this process can be carried out industrially and relatively inexpensively. Moreover, the reaction typically only comprises a single stage, which therefore can also facilitate its implementation on an industrial scale. Finally, it is possible, by virtue of this process, to prepare a large variety of trisubstituted oxazoles.
The present invention thus relates to a novel process for the preparation of an oxazole, including a trisubstituted oxazole, by reaction of thiourea with the diketone ester according to the following reaction scheme:
In the above reaction scheme, the R
1
, R
2
and R
3
radicals, which are identical or different, are chosen from:
saturated and unsaturated, linear and branched C
1
-C
12
hydrocarbon groups optionally substituted by at least one substituent chosen from —OR, —SR, —NRR′, —COOR, —CN, —SO
n
CH
3
, —CF
3
, and halogens, wherein the halogens are, for example, chosen from chlorine and fluorine, n has a value chosen from 0, 1, and 2, and wherein R and R′, which are identical or different, are each chosen from hydrogen atoms and saturated and unsaturated, linear, branched, and cyclic C
1
-C
12
hydrocarbons, such as, for example, alkyl, aryl, aralkyl, and alkylaryl groups;
aryl groups optionally substituted by at least one substituent chosen from saturated and unsaturated, linear and branched C
1
-C
12
hydrocarbon groups, —OR, —NRR′, —COOR, —CN, —SO
n
CH
3
, —SR, —CF
3
and halogens, such as chlorine and fluorine, and wherein R, R′ and n have the same meanings as above; and
saturated and unsaturated C
5-10
heterocyclic groups comprising at least one heteroatom chosen from N, S, and O, which are optionally substituted by at least one substituent chosen from linear and branched C
1
-C
12
hydrocarbon groups, —OR, —NRR′, —COOR, —CN, —SO
n
CH
3
, —SR, —CF
3
and halogens, such as chlorine and fluorine, and R, R′ and n have the same meanings as above.
The R
1
, R
2
and R
3
groups, which may be identical or different, also may each be chosen from:
saturated, linear and branched C
1
-C
6
hydrocarbon groups, such as methyl, ethyl, propyl, n-butyl, isobutyl, and tert-butyl groups;
saturated, linear and branched C
2
-C
6
hydrocarbon groups, substituted by at least one —OR group where R is chosen from phenyl and alkylaryl groups, such as —(CH
2
)
n
-phenyl groups, where n has a value ranging from 1 to 4, such as from 1 and 2;
phenyl groups;
phenyl groups substituted by at least one group chosen from saturated C
1
-C
4
hydrocarbon groups, such as methyl, ethyl, propyl, n-butyl, isobutyl, and tert-butyl groups;
phenyl groups substituted by at least one group chosen from —NRR′ groups, wherein R and R′, which can be identical or different, are each chosen from saturated C
1
-C
4
hydrocarbon groups, such as methyl, ethyl, propyl, n-butyl, isobutyl, and tert-butyl groups;
phenyl groups substituted by at least one halogen, such as fluorine; and
unsaturated C
5-6
heterocyclic groups comprising a ring having at least one nitrogen atom in the ring.
The reaction can be carried out in a dipolar aprotic solvent, such as dipolar aprotic solvents having a boiling point of greater than 130° C., such as greater than 140° C. and further such as greater than 160° C. The reaction can be carried out, for example, in DMF (dimethylformamide).
The reaction can be carried out at a temperature of at least 130° C., such as greater than 140° C. and further such as greater than 160° C. The reaction can be carried out at the reflux temperature of the solvent.
The reaction can also be carried out in the absence of a solvent, for example, under vacuum, at a temperature close to or greater than the melting point of at least one of the two reactants.
In one exemplary, but non-limiting, embodiment the process of the present invention can be carried out as follows:
the diketone ester (I) and thiourea are dissolved in the solvent, any useful amounts and ratios of reactants may be used, such as approximately 2 equivalents of thiourea per 1 equivalent of diketone ester; and
the mixture is heated at a temperature of at least 130° C. for the time needed to bring the reaction to completion, which can be of the order of 5 to 10 hours.
The desired product, i.e., the oxazole of formula (II), can subsequently be isolated by an isolation method, such as an isolation method chosen from at least one of precipitation, filtration, and extraction.
Finally, the desired product can be subjected to at least one step chosen from washing, drying, recrystallizing, and purifying according to the usual methods, as needed or desired.
The desired product is generally obtained with a good yield.


REFERENCES:
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patent: 5380738 (1995-01-01), Norman et al.
patent: 5403852 (1995-04-01), Barreau et al.
patent: 5719163 (1998-02-01), Norman et al.
patent: 6090834 (2000-07-01), Talley et al.
patent: 1 206 403 (1970-09-01), None
A.E. Siegrist, “Über eine neue Synthese zur Darstellung heterocyclisch substituierter Stilbenverbindungen,

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