Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-08
2002-08-27
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C544S410000
Reexamination Certificate
active
06441199
ABSTRACT:
CROSS-REFERENCE TO RELATED APPLICATION
This application is based on German Application DE 100 11 403.2, filed Mar. 9, 2000, which disclosure is incorporated herein by reference.
FIELD OF THE INVENTION
This invention relates to an improved process for the production of alpha-tocopherol acetate by condensation of trimethylhydroquinone and isophytol in the presence of a catalyst system of a zinc halide and an aqueous Brønsted acid and optionally an elemental metal as a third component, wherein the reaction is performed in a polar, protic solvent extractable or miscible with water, preferably acetic acid. After the condensation to yield alpha-tocopherol (&agr;-tocopherol), a phase separation is performed to separate an acetic, aqueous catalyst phase and the resultant product solution separated from water is then esterified at moderate temperatures with an acylating agent, in the presence of the remaining catalyst components, Lewis acid/protonic acid, present in the product phase, and the solution of the catalysts obtained after working up by aqueous extraction after condensation, and acylation is regenerated by suitable methods and returned to the reaction as an acetic catalyst solution.
TMHQ=trimethylhydroquinone
Ac
2
O=acetic anhydride
AcOH=acetic acid
LM=solvent
X=halide, hydroxide, oxide
Y=anion of a Brønsted acid.
&agr;-Tocopherol and the derivatives thereof are of significance as feed additives, antioxidants, circulatory stimulants, agents for reducing cell aging and for associated applications. Pulverulent formulations of &agr;-tocopherol acetate (vitamin E acetate) with a suitable silica are commercially known for feed additive applications.
BACKGROUND OF THE INVENTION
The processes which have primarily been described in the prior art are for the production of &agr;-DL-tocopherol, i.e. the unesterified, non-storage-stable, photosensitive form of vitamin E. According to these processes, &agr;-tocopherol is initially produced by condensation of trimethylhydroquinone with isophytol with condensation of water, and is esterified in a separate step with stoichiometric quantities of an acylating agent to yield vitamin E acetate. This method is illustrated in the following reaction scheme:
According to this prior art, the starting material is generally trimethylhydroquinone (TMHQ), which is reacted with isophytol using various catalyst systems. (U.S. Pat. No. 2,411,969, Hoffmann LaRoche; DE 3 203 487, BASF; U.S. Pat. No. 3,708,505, Diamond Shamrock, U.S. Pat. No. 4,239,691, Eastman Kodak; as well as DE-OS 42 43 464. U.S. Pat. No. 5,523,420, DE-OS 4243464, EP 0 694 541, and DE 196 03 142). The catalysts used for the reaction are generally combinations of Lewis acids, in particular zinc halides, and protonic acids, in particular hydrochloric acid or hydrobromic acid. A mixture of zinc chloride and gaseous hydrogen chloride is advantageously used as a conventional condensation catalyst system, wherein the water arising during the reaction is removed with the solvent by azeotropic distillation or as aqueous acid by distillation. Particularly good yields are achieved, according to EP 0 100 471 and DE 26 06 830 by adding an amine or quaternary ammonium salt as a third catalyst component. EP 0 850 937 A1 also describes the additional use of an amine, in particular tridecylamine (TDA×HCl), which, in its protonated state, may also assume the form of a quaternary ammonium salt.
Once the reaction is complete, the product must then be acetylated in order to obtain the storage-stable vitamin E acetate usual in commerce.
One disadvantage of this process, which is highly economic with regard to the yields achieved, is the issue of wastewater caused by the use and extractive separation of large quantities of zinc chloride. The catalyst components are conventionally extracted after the condensation with water or with a mixture of water and methanol. In this manner, it is possible to remove both the mixture of protonic acid/Lewis acid and the phase transfer catalyst from the crude tocopherol phase but, after such working up, the crude tocopherol phase may no longer be acylated at moderate temperatures, as the presence of a catalyst is required for mild, selective acylation with acetic anhydride.
In the stated patent literature, the acylation with acetic anhydride is either performed at elevated temperatures of >100° C., or, alternatively, a catalyst is added again. In this connection, both organic bases and Lewis or protonic acids have been described as catalysts for acylating the crude tocopherol. Once the reaction is complete, the catalyst and the acetic acid formed must be separated by extraction with water and a suitable organic extracting agent. The process accordingly comprises in total two complex extraction steps, if esterification is to be performed at moderate temperatures. If the subsequent acetylation is performed purely thermally in the presence of a catalyst by refluxing with acetic anhydride, a corresponding energy input is required.
It is not possible simply to recycle these aqueous zinc halide solutions arising after extraction because, in the case of condensation of TMHQ with isophytol, water, which deactivates the catalyst solution, is also formed during the reaction, in addition to the water required for extraction (c.f. Bull. Chem. Soc. Jpn., 68, (1995), pp. 3569 et seq. and Bull. Chem. Soc. Jpn., 69, (1996), p. 137, left hand column). Attempts to recycle the zinc halide phase extracted with water (approx. 20-60 wt. % ZnCl
2
) and to reuse it for condensation, result in a reduction in reaction yield and poorer product quality. Evaporating this aqueous catalyst solution to regenerate pulverulent zinc halide involves complex solids handling and is not economic.
In EP 0 850 937 A1, Baldenius et al., the reaction is performed in a solvent which is immiscible or only slightly miscible with water, the catalyst phase is extracted with water after the reaction and, once the aqueous phase has been concentrated to approx. 60%-90%, the resultant catalyst solution is returned to the reaction at 20° C.-200° C. The disadvantage of this process is the fact that the zinc halide mixture assumes mash form at room temperature and may thus only be conveyed by special pumps designed for this purpose. In order to obtain the catalyst in liquid form, the mash must be heated to an appropriate temperature, which also entails considerable costs.
It is moreover necessary in this process to introduce the protonic acid, preferably hydrochloric acid, as a pure substance in gaseous form during the reaction. The water entering the reaction system due to the recycling of the catalyst mash and the water arising during the reaction are continuously removed during the reaction by azeotropic distillation. It should be noted that, once 1.5 mol of H
2
O/mol of ZnCl
2
have been introduced, azeotropic removal of water may not occur. Larger quantities of water, however, deactivate the catalyst completely.
Another considerable disadvantage is the fact that the acylation catalyst is also removed from the organic phase during aqueous extraction of the catalyst solution. When this process is used, there is no option but either to add fresh catalyst in an additional step or alternatively to perform acylation thermally, which is costly in terms of energy. This disadvantage gave rise to the object to be achieved by the invention of providing a catalyst/solvent matrix which permits both the condensation and the post-acetylation to be performed at moderate temperatures without the necessity of costly addition of fresh catalyst after the condensation.
The selection of the solvent is of particular significance because the condensation solvent also predetermines the subsequent working up and ultimately the catalyst recycling medium.
Using solvents containing esters gives rise to a further difficulty, due to the presence of water during the reaction, in particular if it is economically essential to recycle the catalyst in the form of an aqueous solution. The concentration of wat
Huthmacher Klaus
Kretz Stepahn
Krill Steffen
Covington Raymond
Degussa - AG
Pillsbury & Winthrop LLP
Rotman Alan L.
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