Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-04-04
2002-02-26
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S001000, C560S109000
Reexamination Certificate
active
06350897
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a process for preparing 2,3,5-trimethylhydroquinone diesters (TMHQ-DA) by the oxidative aromatization of 2,6,6-trimethylcyclohexane-1,4-dione (dihydro-ketoisophorone=DH-KIP), by reaction with a sulfonating agent in the presence of an acylating agent, and in the presence of an acid catalyst which may be present in the reaction medium either in dissolved form or else as a heterogeneous solid catalyst. The trimethyl-hydroquinone diesters obtained may be converted directly to vitamin E acetate by reaction with phytol derivatives, in particular isophytol (IP), or may instead be first hydrolyzed in the presence of suitable catalysts to give trimethylhydroquinone (TMHQ), which can then be converted into vitamin E by condensation with isophytol derivatives followed by acylation to give vitamin E acetate.
2,3,5-trimethylhydroquinone and 2,3,5-trimethylhydroquinone diesters are very important intermediates in the synthesis of vitamin E and other chromane compounds which are pharmaceutically active substances and which are used, inter alia, as antioxidants. Vitamin E-acetate, in turn, is used in the form of special formulations as an animal feedstuffs additive in addition to applications in the human sector.
2. Description of the Related Art
To produce 2,3,5-trimethylhydroquinone diesters, 4-oxoisophorone (KIP) is normally used as the initial reactant, which can be rearranged in the presence of strong acid catalysts and an acylating agent such as carboxylic anhydrides or acyl halides. The rearrangement of ketoisophorone (KIP) is described in U.S. Pat. No. 4,247,720, which describes rearrangement in the gas phase under hydrogenating conditions. With maximum conversions of 30%, a selectivity to give a TMHQ yield of only 50% is achieved.
Bull. Korean Chem. Soc. 1991, 12, pages 253 et seq., discloses the rearrangement of KIP in a 5% strength solution in acetanhydride, with the addition of 5 equivalents of concentrated sulfuric acid. The TMHQ-DA yields achieved are only 30%.
DE-OS 2 149 159 discloses the rearrangement of KIP in the presence of acetanhydride, in a rearrangement reaction catalyzed by proton or Lewis acids, to give trimethylhydroquinone diacetate, which is then saponified to give TMHQ. In order to achieve complete conversion, large excesses of acid have to be used. The resulting isolation yields (maximum 66%, with respect to the ketoisophorone used) are unsatisfactory because costly recrystallization procedures are required due to the presence of secondary products.
DE-OS 196 27 977 discloses the rearrangement of KIP in the presence of stoichiometric amounts of acetanhydride and catalytic amounts of various acids (trifluoromethanesulfonic acid, chlorosulfonic acid, and oleum, in various concentrations).
Other processes which describe basically the same procedure, that is, the reaction of ketoisophorone with acetanhydride or acetic acid in the presence of a proton acid to give trimethylhydroquinone diacetate, are described in EP 0 850 912 and EP 0 916 642 A1 and JP OS 11-49712. (Suyama et al., 23.2.99; rearrangement of KIP in the gas phase in the presence of a heterogeneous acidic solid catalyst).
A common feature of all these processes is that the trimethylhydroquinone ester, and the trimethylhydroquinone obtainable therefrom by hydrolysis, are prepared starting from a non-aromatic starting compound, that is 2,6,6-trimethylcyclohex-2-ene-1,4-dione. In this reaction, the initial reactant (KIP) already has the same oxidation state as the product, TMHQ-DA, which means that the reaction can be explained by a simple Wagner-Meerwein rearrangement. The diagram given below reproduces the reaction normally used to prepare TMHQ-DA:
The KIP enolester can be detected when following the course of the reaction using gas chromatography, from which it is assumed that the enolester is the intermediate product of the reaction.
However, the ketoisophorone used for the synthesis is relatively expensive as a starting material. It is obtained using known processes by the oxygen oxidation of &bgr;-isophorone. The mixture obtained is then worked up by distillation.
To prepare TMHQ-DA, 2,2,6-trimethylcyclohexane-1,4-dione (DH-KIP=dihydro-KIP) is especially interesting, this being obtainable by oxidation, starting from &bgr;-isophorone, via &bgr;-isophorone epoxide and 4-hydroxyisophorone. The preparation of the aliphatic 1,4-diketone (DH-KIP) or its precursor 4-hydroxyisophorone (HIP) is described, for example, in the following references:
Journal Mol. Cat. 172, 427-435, (1997) discloses the epoxidation of &bgr;-isophorone with tert-butyl-hydroperoxide as oxidizing agent, in the presence of a heterogeneous catalyst (SiO
2
-TiO
2
solid catalyst), giving &bgr;-isophorone epoxide (&bgr;-IPO) and 4-hydroxy-isophorone (HIP).
Tetrahedron Lett., Suppl. 8, Part I, 1-7, discloses the oxidation of &bgr;-isophorone to &bgr;-IP epoxide by oxidation with meta-chlorobenzoic acid, followed by isomerization in basic medium, to give HIP, which is rearranged to give DH-KIP (yield: 78%), in the presence of an apolar solvent and in the presence of catalytic amounts of p-toluenesulfonic acid.
Helv. Chim. Acta 39, 2041 (1956) discloses the oxidation of &bgr;-IP with peracetic acid as oxidizing agent, followed by treatment of the reaction product with NaOH, and the formation of HIP in 57% yield.
DP 38 06 835 discloses the oxidation of &bgr;-IP by reaction with aqueous hydrogen peroxide in the presence of formic acid to give HIP, with simultaneous back-isomerization of &bgr;-IP to alpha-isophorone.
The object of the present invention is to find alternative aliphatic initial reactants for TMHQ-DA synthesis which are readily obtainable, and to find a process for the efficient reaction of this alternative initial reactant to give TMHQ diesters.
SUMMARY OF THE INVENTION
The present invention relates to the use of dihydro-ketoisophorone (DH-KIP) as an alternative initial reactant for the synthesis of TMHQ-DA. The invention relates also to an economically viable process for this reaction. It is intended that both the requisite oxidation reaction as well as the rearrangement reaction involving aromatization be performed in a single process step.
DETAILED DESCRIPTION OF THE INVENTION
The present invention thus relates to a process for preparing trimethylhydroquinone diesters of the general formula (2)
wherein R represents an optionally substituted aliphatic, alicyclic or aromatic hydrocarbon group,
and to a process for preparing 2,3,5-trimethyl-hydroquinone of the general formula (3)
by reacting 2,2,6-trimethyl-cyclohexane-1,4-dione of the general formula (1)
with an acylating agent, the reaction being performed under oxidative conditions, with a sulfonating agent, and in the presence of a proton acid and/or a Lewis acid, at a temperature between −50° C. and 200° C., wherein the ratio between acylating agent and 2,2,6-trimethyl-cyclohexane-1,4-dione is at least 1.
The reaction of DH-KIP as an initial reactant in the preparation of TMHQ-DA has not heretofore been used because the saturated 1,4-diketone does not have the appropriate oxidation state to ensure successful reaction by a simple rearrangement to TMHQ-DA.
By means of the process according to the invention, however, it is now possible to use DH-KIP as an initial reactant for the synthesis of trimethylhydroquinone diesters and trimethylhydroquinone. The reaction according to the invention is shown in the following diagram:
As shown in the reaction scheme given above, the reaction also leads to trimethyl-pyrocatechol diacetate (TMBC-DA) and to 3,4,5-trimethylphenol acetate (TMP-Ac), in addition to trimethylhydroquinone diacetate, depending on the reaction conditions.
The invention provides a new process for preparing 2,3,5-trimethylhydroquinone diesters, and trimethylhydroquinone, by the rearrangement of 2,2,6-trimethyl-cyclohexane-1,4-dione (dihydroketoisophorone=DH-KIP) by reaction with an acylating agent in the presence of an acid proton-containing catalyst w
Huthmacher Klaus
Krill Steffen
Degussa - AG
Killos Paul J.
Smith , Gambrell & Russell, LLP
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