Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-20
2001-12-11
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C560S079000, C568S341000, C568S772000
Reexamination Certificate
active
06329535
ABSTRACT:
INTRODUCTION AND BACKGROUND
The present invention provides a process for preparing esterified chroman compounds from technical grade purity 2,6,6-trimethyl-cyclohex-2-ene-1,4-dione (4-oxo-isophorone, KIP), wherein the esterified intermediate is reacted directly to give the desired chroman compounds without an additional purification step.
The most important compound in this group of substances is vitamin E which is mostly marketed as an ester. Chroman compounds are generally important for use as pharmaceuticals, animal food additives and antioxidants.
The reaction to give vitamin E acetate proceeds as follows:
This shows that 2,3,5-trimethylhydroquinone diesters are valuable intermediates for the production of chroman compounds.
PRIOR ART
The production of KIP, the precursor for trimethylhydroquinone diester synthesis is achieved by known processes, e.g. by the oxygen-oxidation of &bgr;-isophorone followed by distillation (U.S. Pat. No. 5,874,632).
Varying amounts of secondary products are present in the technical grade product, depending on the isolation procedure used. In addition to small amounts of &agr;-isophorone, these are mainly 4-hydroxy-isophorone (HIP) and lanierone. HIP and lanierone are not inert in the acylating aromatization reaction, but produce secondary products. Thus a variety of acylated aromatic compounds are produced under the conditions of TMHQ DA synthesis. The main product among the group of products found under the reaction conditions has been identified as the 2,3,5-trimethyl-phenol ester. The production of the secondary product is illustrated in the following reaction scheme:
Lanierone, another secondary product of &bgr;-IP oxidation, which can only be separated from KIP in a costly distillation process or by basic reactive extraction, reacts, under the conditions of aromatization, to give a mixture consisting of the 3,4,5-trimethylpyrocatechol diester (3,4,5-TMPC diester) and the 3,4,6-trimethylpyrocatechol diester (3,4,6-TMPC diester), wherein the 3,4,5-isomer is the main reaction product. The reaction scheme given below illustrates this aromatization of lanierone with an acylating agent in the presence of an acid catalyst (homogeneous or heterogeneous) using the reaction with acetanhydride as an example:
When aromatizing KIP which does not contain any lanierone, only the 3,4,5-TMPC diester is produced as a secondary product, along with the TMHQ diester, in the presence of suitable catalysts.
All in all, therefore, when using technical grade KIP (either from &bgr;-isophorone or by direct oxidation from alpa-isophorone) as the reactant during the synthesis of trimethylhydroquinone esters, a reaction product is obtained which contains a variety of phenols and pyrocatechols, in the form of their esters, as described above, in addition to the desired product. Use of this crude reaction mixture in the following condensation stage with isophytol with the objective of synthezising pure vitamin E esters is impossible. The secondary products described are not inert under the conventional reaction conditions used for condensation, but also react with isophytol with the elimination of water. The vitamin E ester formed in this way is then contaminated with a variety of secondary products which can be separated only in a costly manner.
Given this situation, it appears to be advantageous to separate the secondary products at the trimethylhydroquinone diester stage. Hitherto, this separation of the secondary products (TMPC diesters and TMP esters) has been possible only by expensive chemical engineering operations the disadvantages of which are explained in detail in the following.
The preparation of 2,3,5-trimethylhydroquinone diesters (TMHQ diesters) from ketoisophorone (4-oxo-isphorone=KIP) in the presence of an acid catalyst and an acylating agent such as carboxylic anhydrides or acyl halides is known from the prior art (e.g. DE-A 2 149 159, EP 808 815 A2, EP 0 850 910 A1, EP 0 916 642 A1). The production of the TMHQ diester from KIP and an acylating agent takes place in all cases in the presence of an acid catalyst or a mixture of several strong acids under suitable conditions. The reaction itself is advantageously performed in such a way that the catalyst and acylating agent are initially introduced and then KIP is added at moderate temperatures. After completion of the reaction, a mixture of the corresponding trimethylhydroquinone diester, the secondary products specified above, substantially aromatic compounds, excess acylating agent, the catalyst and carboxylic acid is obtained, which has to be worked up in an appropriate manner to isolate the TMHQ diester.
Normally, the reaction is not performed in an additional solvent, but a mixture (in the case where acetanhydride is used as the acylating agent) of acetanhydride and acetic acid is used. Acetanhydride, which is usually used in excess, is a reactive solvent in this case.
Isolation from the reaction solution and the removal of secondary products is performed by a variety of methods.
DE-A-2 149 159 discloses a process in which the reaction solution is extracted with benzene and allowed, after dilution with ether, to crystallize from hexane with significant losses. This means that at least 3 additional solvents are introduced and these have to be recovered again in extra steps.
It is also known that the desired TMHQ diester can be crystallized out of the reaction solution, after neutralization of the strongly acid catalyst, by adding water or a mixture of water and a solvent, preferably a carboxylic acid (EP-A 808 815). Following this mode of operation, re-use of the catalyst is costly or impossible. Also, the recovery or recycling of unconsumed acylating agent, which is always used in excess in the prior art, is impossible because it is hydrolyzed under these conditions. TMHQ is produced during optionally occurring hydrolysis of the diester and since this is the equivalent of 2,3,5-trimethylhydroquinone diacetate (TMHQ DA) it can be used for the preparation of vitamin E acetate by condensation with isophytol. However, the acyl units present in vitamin E acetate (essential for the storage stability of this commercial form of vitamin E) have to be introduced at a later stage when using TMHQ instead of TMHQ DA. The isolation of TMHQ DA in aqueous media is therefore not desirable and ultimately is not economically viable.
An object of the present invention is to simplify the costly procedure outlined above and thus to find an economically viable process.
In particular an object of the invention is to find a process with which a TMHQ diester can be prepared from KIP in the status in which it is available as a technical grade product and to isolate the TMHQ diester, without further process steps such as purification and drying, so that it is suitable for use in the synthesis of chroman compounds.
SUMMARY OF THE INVENTION
The above and other objects can be achieved according to the presnet invention by a process for preparing esterified chroman compounds, in which
1.1 ketoisophorone (KIP), present with technical grade purity, is reacted with an acylating agent in the presence of a proton acid to give a trimethylhydroquinone ester (TMHQ ester) and
1.2 this ester is then reacted with an allyl alcohol derivative or an allyl alcohol in the presence of zinc halides and proton-producing acids,
1.2.1 the solution obtained in reaction step 1.1 is cooled to a temperature between 5 and 40° C.,
1.2.2 the product which crystallizes out is separated and optionally washed,
1.2.3 the filtrate obtained during separation and optionally washing is used as the solvent for the next reaction mixture in accordance with reaction step 1.1,
1.2.4 the optionally washed product is used in the reaction in accordance with 1.2 without being dried and
1.2.5 the desired product is isolated, optionally after further acylation.
After completion of reaction, some of the TMHQ diester produced crystallizes from the reaction solution of KIP and an acylating agent, during cooling of the reaction solution, in high purity without the addit
Hasselbach Hans Joachim
Huthmacher Klaus
Krill Steffen
Weigel Horst
Covington Raymond
Degussa Dental GmbH & Co. KG
Rotman Alan L.
Smith , Gambrell & Russell, LLP
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