Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-02-18
2002-07-23
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S350000, C568S352000, C568S367000, C568S374000, C560S126000
Reexamination Certificate
active
06423874
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods for obtaining compounds useful in perfumery, particularly to methods for obtaining ketones such as that having formula 1a,b (3&agr;-acetyl-2,3,4&agr;,4a&bgr;,5,6,7,8-octahydro-3&bgr;,4&bgr;,5,5-tetramethylnaphthalene) in its racemic or optically active form:
For simplicity, only one enantiomer will be shown for ketone 1 and its precursors in the following text and schemes of this Application, although the invention may relate to either enantiomeric mixtures or optically pure materials.
BACKGROUND OF THE INVENTION
Ketones according to Formula 1 are recognized in the art.
For example, G. Fráter et al. (Tetrahedron, 1998, Vol. 54, pp. 7633-7703, especially pp. 7651-7653) and C. Nussbaumer et al. (Helvetica Chimica Acta, 1999, Vol. 82, pp.1016-1024) discuss ketone 1 as an impurity in a commercial product Iso E Super®, which is obtained by an acid catalyzed cyclization of ketone 2 (Scheme 1) and which contains mainly ketone 3.
Despite its small concentration in Iso E Super®, ketone 1 is apparently responsible for the intense amber-woody odor of the whole product. This is because ketone 1 has an extremely low odor threshold of about 5 pg/L. The formation of ketone 1 during the cyclization of 2 can be explained via partial isomerization of starting material 2 into ketone 4 followed by the cyclization of the latter. However, the small concentration of ketone 1 in the product is believed to be due to a higher rate of the cyclization of 2 into 3 compared to the rate of its isomerization into 4.
Copending U.S. patent application Ser. No. 09/136,488 (M. Erman et al., Millennium Specialty Chemicals, Inc.) shows that the concentration of ketone 1 in the product of cyclization of 2 can be increased when the reaction is carried out in the presence of hydroxyl-containing compounds. While the positive effect on yield by way of this process is significant, the concentration of ketone 1 remains less than about 10%.
Alternatively, a sophisticated multi-step synthesis of ketone 1 from &agr;-ionone according to the Scheme 4 below was disclosed in EP 464357, U.S. Pat. Nos. 5,180,709, and 5,214,160 (F. Etzweller et al., Givaudan-Roure S.A.), and also in: C. Nussbaumer et al. (Helv.Chim. Acta, 1999, Vol. 82, pp.1016-1024). The method comprises a cuprate methylation of &agr;-ionone into ketone 10, haloform oxidation to acid 11, conversion into ester 12, hypochlorite oxidation to allylic chloride 13, ozonolysis and subsequent Zn reduction to ketone 14, addition of acetylene followed by partial hydrogenation of the resulting lactone 15, methylation and silylation of lactone 16 to give enol silyl ether 17, its thermal rearrangement into ketone 18, and finally methylation with MeLi providing ketone 1. Multiplication of yields given in Scheme 4 shows that the total yield of ketone 1 based on &agr;-ionone is below 8% of the theory.
Furthermore, the complexity of this synthesis severely limits its commercial applicability.
Thus, there are basically two known techniques for the preparation of ketone 1:
1) A multi-step synthesis from (&agr;-ionone; and
2) A one-step synthesis from ketone 2, which provides isomeric mixtures containing ketone 1.
Both techniques, however, provide a yield of ketone 1 that is typically less than 10%. Unfortunately, isolation of ketone 1 from mixtures containing less than 10% ketone 1 concentration is a laborious and a low-yield process. Thus, the need still exists for an improved process for making ketone 1.
SUMMARY OF THE INVENTION
The present invention is based, at least in part, on the surprising discovery that contacting a ketone 2 with certain catalytic materials can cause its isomerization into ketone 4, thus providing, in high yield, intermediate mixtures containing ketone 4 and unreacted ketone 2, together with smaller amounts of other ketones, e.g., ketones 19 and 20 with a terminal double bond, and also smaller amounts of other cyclization products, ketones 1, 3, 7, 8, 9. Moreover, it has been discovered that the desirable isomerization of ketone 2 into ketones 4 and 19 can be significantly faster than the cyclization of ketone 2 into ketones 3, 7, and 8, and also faster than the secondary cyclization of 4 into 1 and 9. After a separate step of the cyclization of the intermediate mixture, a significant improvement in the yields of ketone 1 can be obtained.
In one aspect, the present invention relates to a process for obtaining ketone 1 that includes the steps of:
a. isomerization of ketone 2 into a mixture of isomeric ketones including ketone 4;
b. cyclization of the mixture of isomeric ketones into a mixture containing ketone 1, where the amount of ketone 1 is increased as compared to existing techniques. The process can further include an optional purification of ketone 1.
Each of steps a and b preferably employ a catalyst, and the catalyst for step a differs from that of step b.
The present invention will be discussed in greater detail below.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION
One embodiment of the invention process is schematically illustrated below.
Thus, in one preferred embodiment, the invention provides a process for obtaining ketone of formula 1a,b in its racemic or optically active form, comprising:
a. contacting a ketone represented by formula 2a,b in its optically active or racemic form with an isomerization catalyst under conditions and for a time sufficient to obtain an intermediate mixture, which intermediate mixture contains a ketone represented by formula 4a,b in its optically active or racemic form; and
b. subsequently contacting the intermediate mixture, or a fraction thereof, with an acid catalyst.
“Ketone of formula 1a,b in its racemic or optically active form,” refers to ketone of formula 1a, ketone of formula 1b, or a mixture of ketones 1a and 1b in a racemic or optically active ratio. The ketone 2a,b is preferably present in a starting material also containing its structural isomers. To this end, the ketone 2a,b is preferably the main component in the starting material and is preferably present in an amount of about 70% to about 99% by weight of the starting material.
The process of the present invention allows for the production of significant amounts of ketone 4a,b. By “significant” it is meant an amount greater than a trace or impurity level of the component.
The molar conversion of ketone 2a,b to ketone 4a,b in step (a) is preferably greater than about 5%, more preferably 11%, and even more preferably greater than about 20%, specifically about 20% to about 30%. The intermediate mixture further contains unreacted ketone 2, preferably present in an amount greater than 20%, more preferably greater than 30% specifically about 30% to about 60%. The intermediate mixture may further comprise ketones with a terminal double bond, such as those represented by formulas 20a,b and/or 19a,b.
Accordingly, in one particularly preferred embodiment, the ketone 4a,b is one of three major constituents of the intermediate mixture.
The term “mainly” refers to a composition in which the “main” constituent is present in a larger proportion than the other constituent(s).
The term “major” similarly refers to components that are greater in proportion to the overall mixture than any other components. Thus, if a component is one of three major components, the component is the first, second, or third highest concentration component of all components in the composition.
This step employs a catalyst suitable for forming ketone 4a,b, which catalyst is preferably an isomerization catalyst. The isomerization catalysts can include any catalysts recognized in the art that are suitable for catalyzing an isomerization reaction. Examples of suitable materials include various classes and groups of compounds such as salts, oxides, hydroxides, acids, heteropolyacids, complexes, metals, metal hydrides, amides, metal-graphite intercalation compounds, transition metals on carriers, clays, sorbents, zeolites, molecular sieves, etc. It must be understood that this list of catalysts is only exemplary,
Cárdenas Carlos G.
Erman Mark B.
Williams Melissa J.
Millennium Speciality Chemicals, Inc.
Needle & Rosenberg P.C.
Richter Johann
Witherspoon Sikarl A.
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