Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-15
2001-05-29
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06239294
ABSTRACT:
DESCRIPTION
The present invention relates to a new recycling process for the production of &agr;-tocopherol acetate by condensation of trimethylhydroquinone diesters and isophytol in the presence of a catalyst system consisting of a zinc halide (Lewis acid) and of an aqueous protonic acid (Bronsted acid) and optionally of an elemental metal in a polar solvent/water mixture which is extractable or miscible in water, and subsequent recycling of the catalyst system.
&agr;-Tocopherol and its derivatives are of importance as feed additives, as antioxidants, as agents for stimulating the blood circulation, as agents for retarding cell ageing and for related applications. In particular, pulverulent formulations of alpha-tocopherol acetate (vitamin E acetate) together with a suitable silica are established on the market for use as feed additives.
Most well-known are processes for producing &agr;-DL-tocopherol, that is, the unesterified, light-sensitive vitamin E form which is not stable in storage. In these processes, alpha-tocopherol is first of all prepared by condensation of trimethylhydroquinone with isophytol, with condensation of water, and in a separate step is esterified with stoichiometric quantities of an acylating agent to form the vitamin E acetate. This procedure is outlined in the following diagram:
According to this prior art one generally commences from trimethylhydroquinone (TMHQ), which is reacted with isophytol using various catalyst systems. (DE-OS 4243464 (=U.S. Pat. No. 5,523,420,) DE-OS 19603142, EP 0694 541, DE 196 03 142, EP (0 949 255 A1).
On conclusion of the reaction, the product must subsequently be completely acetylated in order, for example, to obtain the usual commercial vitamin E acetate which is stable in storage. Common to all these processes is the fact that that they do not lead directly to tocopherol acetate, the usual commercial form of Vitamin E which is stable in storage.
There have also been attempts to react isophytol with trimethylhydroquinone esters as educt of the synthesis of tocopherols.
The main advantage of using the corresponding trimethylhydroquinone ester, for example, trimethylhydroquinone diacetate (TMHQ-DA), as the synthetic equivalent of TMHQ is that the acetyl group present in the vitamin E acetate end product is already present in the TMHQ-DA educt molecule and, by skilful control of the reaction, vitamin E acetate is attained directly by condensation of TMHQ-DA with isophytol, without the necessity of having subsequently to esterify with stoichiometric or even hyperstoichiometric quantities of acetic anhydride in a separate reaction step. Up to the present, however, there has been found no economic process which allows the condensation of the trimethylhydroquinone di- or monoesters used as educt with isophytol to be carried out with sufficiently high yields and vitamin E acetate to be obtained directly.
FR-A 2 259822 (DE-OS 2 404621) relates to the use of diacetylated trimethylhydroquinone TMHQ-DA. But the condensation with isophytol in the presence of a solid acid described in that document delivers a yield of only approximately 41% &agr;-DL-tocopherol (vitamin E) and does not lead to the corresponding esters.
The condensation of trimethylhydroquinone monoacetate (TMHQ-MA) with isophytol is described in DE-OS 2 160 103 (=U.S. Pat. No. 3,789,086). With the use of Fe (II) Cl
2
and hydrochloric acid and simultaneous removal of the water of reaction, only small quantities of &agr;-tocopherol acetate are obtained and it is necessary to acetylate subsequently with amine catalysis and addition of hyperstoichiometric quantities of acetic anhydride. The yields are unsatisfactory, the two-step procedure is expensive and the necessity of reacting with hyperstoichiometric quantities of acetic anhydride to obtain vitamin E acetate entails a high consumption of chemicals. The working-up of the catalyst phase obtained after the reaction is not dealt with.
According to JP-OS 51-80859 (Jul. 15, 1976), trimethylhydroquinone or its esters are reacted with isophytol in the presence of zinc chloride. The reaction leads to &agr;-tocopherol at temperatures of more than 100° C., in accordance with the set object.
A disadvantage of this process, which is quite economic as regards the yields achieved, is the problem of waste water which arises owing to the use of large quantities of zinc chloride. A simple recycling of these aqueous zinc chloride solutions obtained after extraction is not possible as, in the case of the condensation of TMHQ, in addition to the water required for the extraction, further water of reaction, which deactivates the catalyst solution, is formed during the reaction. (see Bull. Chem. Soc. Japan., 68, (1995), 3569 ff and Bull. Chem. Soc. Japan., 69, (1996), 137). Attempts to recycle the zinc halide phase extracted with water (approx. 20-60 wt. % ZnCl
2
) and to reuse it for the condensation result in a lowering of the reaction yield and in a poorer quality of product. In the Patent Application EP 0 850 937 A1, the reaction is carried out in a solvent which is immiscible or only slightly miscible with water, after the reaction the catalyst phase is extracted with water and, after concentration of the aqueous phase to about 60-90%, the catalyst solution thus obtained is returned to the reaction at 20-200° C. A disadvantage in this procedure is the fact that the zinc halide mixtures are in the form of a mash at room temperature and hence can only be delivered by pumps specifically intended for this field of application. To obtain a liquid form of catalyst, the mash has to be concurrently heated to an appropriate temperature, which likewise requires a considerable expense and is thus uneconomic.
A considerable disadvantage of this process is the high volatility of the protonic acid required for the reaction, in particular HCl during the removal of water by distillation in order to concentrate the Zn chloride solutions. Owing to this loss, in each case the quantity of HCl has to be added in the next batch, which complicates the process.
With regard to the yields, the hitherto most efficient process for the reaction of TMHQ-DA is described in DE-OS 197 57 124.7, in which a binary catalyst system consisting of a zinc halide and a protonic acid is used in various inert, aprotic solvents such as, for example, acetic ester or aromatics (toluene). Here the working-up is carried out by aqueous extraction of the entire catalyst phase after the condensation, a mixture of &agr;-tocopherol together with &agr;-tocopherol acetate being present in the product phase. In this procedure, for the subsequent esterification of the &agr;-tocopherol it is in addition necessary to add a catalyst for the acetylation and likewise to remove it again by aqueous extraction after the reaction. Where ester-containing solvents are used, the presence of water during the reaction gives rise to the further problem that, in addition to the saponification of the TMHQ-DA taking place in situ, there is also the resulting partial saponification of the solvent. In this way the ester used as solvent yields the corresponding organic acids and alcohols, which have to be removed from the product by means of expensive separation processes or accumulate in the recycling process during the return of the solvent.
2,3,5-trimethylhydroquinone diesters are prepared in known manner from ketoisophorone (4-oxoisophorone=KIP) in the presence of an acid catalyst and of an acylating agent such as carboxylic anhydride (in the simplest case, acetic anhydride with release of acetic acid) or acyl halides. The relevant processes are documented in several patent specifications (for example, DE 2 149 159, EP 0 808 815 A2, EP 0 850 910 A1, EP 0 916 642 A1). The formation of the TMHQ-DA conventionally used for the synthesis of vitamin E acetate in all cases takes place in the presence of an acid catalyst or a mixture of several suitable acids under appropriate conditions. On conclusion of the reaction, a mixture comprising TMHQ-DA, a few aromatic secondary products, in the
Huthmacher Klaus
Kretz Stephan
Krill Steffen
Degussa - AG
Owens Amelia
Smith , Gambrell & Russell, LLP
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