Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1999-06-24
2001-01-23
McKane, Joseph (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
Reexamination Certificate
active
06177589
ABSTRACT:
BRIEF SUMMARY OF THE INVENTION
The present invention concerns the field of organic synthesis. More particularly, it concerns epoxides which are useful as starting products for the preparation of highly prized perfuming ingredients, amongst which the isomers of Hedione® (methyl-3-oxo-2-pentyl-1-cyclopentaneacetate; origin: Firmenich SA, Geneva, Switzerland) which are preferred from an olfactive point of view.
Thus, an object of the present invention is an epoxide of formula
having a cyclanic (1 R) configuration, the group in position 2 being in a trans configuration and the epoxy group being in a cis configuration with respect to that in position 1 of the ring, and in which R represents a lower alkyl group and R
1
represents a saturated or unsaturated, linear or branched hydrocarbon group having from 1 to 8 carbon atoms.
By lower alkyl group it is meant here a linear or branched alkyl group from C
1
to C
4
, and more particularly a methyl or ethyl group.
The structure of the epoxides of formula (I) is novel.
PRIOR ART
International patent application WO 95/33735, published on Dec. 14, 1995, describes epoxides of formula
in which R
3
stands for an alkyl group having from 1 to 8 carbon atoms and R
b
for an alkyl group from C
1
to C
4
. However, one cannot detect therefrom a description or any mention of the precise stereochemistry of compounds (A). Now, trying to reproduce the process described in this document for the preparation of these compounds, we have discovered that it only allows the preparation of a mixture of diastereomers of each epoxide of formula (A), namely in the cases in which R
a
is a pentyl or hexyl group and R
b
a methyl or ethyl group. We have thus found that the process for the preparation of epoxides (A) as described in WO 95/33735 is not diastereoselective and that, moreover, the reaction occurs with very low conversion, of the order of 25%.
We have also discovered that, contrary to what is indicated in WO 95/33735, the transformation of the thus-obtained epoxide, under the described reaction conditions, namely the thermal treatment of the epoxide in presence of a catalytic amount of lithium iodide, leads to the formation of a product which is totally distinct from the desired ketone. So, when applying the process as described in WO 95/33735 to the epoxide of formula (A) wherein R
a
=pentyl and R
b
=CH
3
, we obtained, instead of methyl-3-oxo-2-pentyl-1-cyclopentaneacetate as expected according to the description in the said document, a totally different lactone which was identified by its spectral data as having the structure
i.e. cis-perhydro-6a-pentyl-2-cyclopenta[b]furanone.
It is in fact a lactone which has been known in our laboratories for a long time, possessing a watery-metallic, chemical odor, which is slightly animal. However, not even a trace of the desired cyclic ketone could be detected in this product. The same applied to the cases where R
a
=hexyl and R
b
=methyl or ethyl.
In summary, is apparent from the above that the above-mentioned prior art document does not describe a process which allows either to obtain or to convert the epoxides of formula (1) according to the present invention and that as a result there was no recognition of any particular usefulness of the compounds which are the object of the present invention and have the specific stereochemistry indicated above.
Yet, we have now discovered that compounds (I) are very useful as starting products for the preparation, in a pure state, of optically active perfuming ingredients which are particularly prized by the perfumers.
DETAILED DESCRIPTION OF THE INVENTION
It should also be noticed that, as will be apparent from the comparative examples presented further on, the above-mentioned prior art document does not describe the pure racemates corresponding to epoxides (I), i.e. the epoxides corresponding to the formula
in which the epoxy and carboxy substituents have a relative configuration which is strictly cis and the symbols R et R
1
have the meaning given in formula (I). These compounds, which are equimolar mixtures of an epoxide (I) with its respective enantiomer, are also novel compounds. They turn out to be useful for the preparation of the corresponding ketones having a strictly cis cyclanic configuration and the most interesting example of which, in perfumery, is cis-Hedione® or cis-methyl-3-oxo-2-pentyl-1-cyclopentaneacetate.
According to the invention, the optically active epoxides of formula (I) are preferred compounds and one can cite, as an even more preferred compound, (+)-methyl (1 R,2 S,3 R)-2,3-epoxy-2-pentyl-1-cyclopentaneacetate. The transformation of this compound according to the original process described hereinafter allows the preparation of (+)-cis-Hedione®, or (+)-methyl (1 R)-cis-3-oxo-2-pentyl-1-cyclopentaneacetate, i.e. the isomer which is known to possess at best the typical odor characteristics, in particular the jasmine note, of this well-known cyclic ketone.
Therefore, the invention also concerns the use of epoxides of formula (I) for the preparation of cyclic ketones according to the formula
having a (1 R)-cis cyclanic configuration, according to an original conversion process, comprising the treatment of said epoxide in an inert organic solvent with an acidic agent consisting of an appropriate Lewis acid or an acidic clay.
We have discovered with surprise that these reaction conditions made it possible to obtain the optically active ketones of formula (II) in a selective way and excellent yields, as will be apparent from the examples below. This result is contrary to what could be observed with the prior art process as described in the above-cited document, according to which the epoxide was subjected to a thermal treatment in the presence of a salt of an alkaline or alkaline earth metal of an acid of low molecular weight.
The reaction which characterizes the process of the invention is executed at various temperatures which depend on the reagents used and in particular on the reactivity of the acidic agent. Therefore, and contrary to the process described in WO 95/33735, the process of the invention allows the use of mild temperature conditions, typically below 120° C.
As Lewis acids which are appropriate for the process of the invention, one can cite in particular boron trifluoride, which may be complexated (as etherate, for example), aluminum trichloride and magnesium iodide.
As acidic clays, one can use aluminosilicate based clays from the family of products known under the name of FILTROL® (origin: Harshaw/Filtrol), clays which are commercially available under designations like GK (origin: Georgia Kaolin Co.), montmorillonites known under the name of K catalysts, for example K10, KP10, KSF et KSF/O (origin: S{umlaut over (u)}id-Chemie AG), bentonites, or yet any other acidic clay of current use. According to a preferred embodiment of the invention, one will use, for example, Filtrol® G24.
The proportion in which the acidic agent can be used relative to the starting epoxide varies within a large range of concentrations. We have observed that the ratio between the two reagents could be stoichiometric for example, but equally useful results were obtained with catalytic amounts of acidic agent relative to the epoxide.
As solvents which can be used according to the invention, one can employ a solvent of current use which is inert under the reaction conditions. One can cite in particular cyclic or acyclic hydrocarbons, in particular cyclohexane, xylene and toluene, ethers like diethyl ether or tetrahydrofurane, or even chlorinated solvents, in particular dichloromethane. Particularly useful results were obtained with toluene or dichloromethane.
According to a preferred embodiment of the process of the invention, (+)-methyl (1 R,2 S,3 R)-2,3-epoxy-2-pentyl-1-cyclopentaneacetate is used. This embodiment revealed itself particularly advantageous, since, as is cited above, it allows the preparation of the preferred isomer of Hedione®, namely the (+)-methyl (1 R)-cis-3-oxo-2-penty
Firmenich SA
McKane Joseph
Murray Joseph
Pennie & Edmonds LLP
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