Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-29
2002-09-17
Solola, T. A. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S412000
Reexamination Certificate
active
06452023
ABSTRACT:
SUMMARY
The present invention is concerned with a novel process for the manufacture of d,1-&agr;-tocopherol by the acid-catalyzed condensation of trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH) in a solvent. As is known, d,1-&agr;-tocopherol is a diastereoisomeric mixture of 2,5,7,8-tetramethyl-2-(4′,8′,12′-trimethyl-tridecyl)-6-chromanol (&agr;-tocopherol), which is the most active and industrially most important member of the vitamin E group.
BACKGROUND OF THE INVENTION
Many processes for the manufacture of d,1-&agr;-tocopherol by the condensation of TMHQ with IP or PH in the presence of a catalyst or catalyst system and in a solvent or solvent system are described in the literature. These processes go back to the work of Karrer et al., Bergel et al., as well as, Smith et al. [see Helv. Chim. Acta 21, 520 et seq. (1938), Nature 142, 36 et seq. (1938) and, respectively, Science 88, 37 et seq. (1938) and J. Am. Chem. Soc. 61, 2615 et seq. (1939)]. While Karrer et al., carried out the synthesis of d,1-&agr;-tocopherol from TMHQ and phytyl bromide in the presence of anhydrous zinc chloride (ZnCl
2
; a Lewis acid), Bergel et al. and Smith et al. used TMHQ and PH as starting materials. In the following years many modifications, e.g., alternative solvents and Lewis acids, were developed. From the work of Karrer et al., a technically interesting process for the manufacture of d,1-&agr;-tocopherol was developed in 1941 that was based on the condensation of TMHQ with IP in the presence of the catalyst system ZnCl
2
/hydrochloric acid (HCl). See, U.S. Pat. No. 2,411,969. Later publications, e.g., Japanese Patent Publications (Kokai) 54380/1985, 64977/1985 and 226979/1987 [Chemical Abstracts (C.A.) 103, 123731s (1985), C.A. 103, 104799d (1985) and, respectively, C.A. 110, 39217r (1989)], describe this condensation in the presence of zinc and/or ZnCl
2
and a Bronsted (protonic) acid, such as a hydrohalic acid, e.g., HCl, trichloroacetic acid, acetic acid and the like, especially ZnCl
2
/HCl, as the catalyst system. Disadvantages of these and further published processes featuring ZnCl
2
in combination with a Bronsted acid are the corrosive properties of the acids and the contamination of the waste water with zinc ions as a result of the large amount of ZnCl
2
required for the catalysis.
The manufacture of d,1-&agr;-tocopherol by the reaction of TMHQ with phytyl chloride, PH or IP in the presence of boron trifluoride (BF
3
) or its etherate (BF
3
.Et
2
O) is described in German Patents 960720 and 1015446 as well as in U.S. Pat. No. 3,444,213. However BF
3
also has corrosive properties.
Also, the condensation of TMHQ with IP or PH in the presence of a Lewis acid, e.g., ZnCl
2
, BF
3
or aluminium trichloride (AlCl
3
), a strong acid, e.g., HCl, and an amine salt as the catalyst system is described in European Patent Publication (EP) 100471. In an earlier German patent publication (Deutsche Offenlegungsschrift: DOS), No. 2606830, the IP or PH is pretreated with ammonia or an amine before the condensation with TMHQ in the presence of ZnCl
2
and an acid is effected. In both cases corrosion problems occur.
A further interesting method for the manufacture of d,1-&agr;-tocopherol from TMHQ and IP comprises using an isolated TMHQ-BF
3
or -AlCl
3
complex and a solvent mixture featuring a nitro compound (DOS 1909164). This process avoids to a large extent the formation of undesired by-products because it involves mild reaction conditions. The yield of d,1-&agr;-tocopherol, based on IP and the use of the solvent mixture methylene chloride
itromethane, is given as 77%. However, these days the use of such a halogenated hydrocarbon as methylene chloride as a solvent is less tolerated than hitherto for ecological reasons.
The manufacture of d,1-&agr;-tocopherol by the condensation of TMHQ with IP using cation exchange resin complexes of metal ions (Zn
2+
, Sn
2+
and Sn
4+
) is disclosed in Bull. Chem. Soc. Japan 50, 2477-2478 (1977); amongst its disadvantages are that it produces the product in unsatisfactory yields.
The use of macroreticular ion exchangers, e.g., Amberlyst® 15, as the catalyst for the condensation of TMHQ with IP is described in U.S. Pat. No. 3,459,773. However, the d,1-&agr;-tocopherol could not be obtained in the requisite purity.
EP 603695 describes the manufacture of d,1-&agr;-tocopherol in liquid or supercritical carbon dioxide by the condensation of TMHQ with IP or PH in the presence of acidic catalysts, such as ZnCl
2
/HCl and ion exchangers. The reported yields are unsatisfactory.
The condensation in the presence of a catalyst system which consists of iron(II) chloride, metallic iron and HCl gas or aqueous solution is described in DOS 2160103 and U.S. Pat. No. 3,789,086. The formation of less by-products is advantageous compared with the aforementioned process using ZnCl
2
/HCl. However, corrosion problems and chloride contamination are equally disadvantageous.
An interesting alternative for the condensation of TMHQ with IP to d,1-&agr;-tocopherol comprises using trifluoroacetic acid or its anhydride as the catalyst, see, EP 12824. Although the avoidance of HCl is achieved in this process, the catalyst is relatively expensive.
The use of the heteropoly acid 12-tungstophosphoric or 12-tungstosilicic acid as the catalyst for the condensation of TMHQ with IP was described for the first time in React. Kinet. Catal. Lett. 47(1), 59-64 (1992). Following this procedure, d,1-&agr;-tocopherol could be obtained, using various solvents, in about 90% yield.
A further process described in the literature [EP 658552; Bull. Chem. Soc. Japan 68, 3569-3571 (1995)] for the synthesis of d,1-&agr;-tocopherol is based on the use of a scandium, yttrium or lanthanide fluorosulphonate, nitrate or sulphate, e.g., scandium trifluoromethanesulphonate. With up to about 10% excess of IP, this process gives yields up to 98%.
The use of ion-exchanged bentonite, montmorillonite or saponite through treatment with, e.g., scandium chloride and other metal salts (yttrium, lanthanum, etc.) as the catalyst for the condensation of TMHQ with IP or PH is disadvantageous because of the need for a large amount of catalyst [EP 677520; Bull. Chem. Soc. Japan 69, 137-139 (1996)].
According to the Examples of EP 694 541, the condensation of TMHQ with IP to &agr;-tocopherol can be achieved in high yields and with a high product purity when solvents such as carbonate esters, fatty acid esters and mixed solvent systems are employed with catalysis being effected by ZnCl
2
/HCl. Disadvantages in this process include the contamination of the waste water by zinc ions and the usual large “catalyst amount” of ZnCl
2
used.
According to WO 97/28151, the acid-catalysed condensation of TMHQ with IP can be performed in a cyclic carbonate or &agr;-lactone as the solvent. The preferred catalyst is a mixture of ortho boric acid and oxalic, tartaric or citric acid, or boron trifluoride etherate.
From the foregoing, it is evident that most of the previously known processes have considerable disadvantages. Corrosion problems occur in all processes in which acid catalysts such as boron trifluoride are used. Toxicity problems with the boron trifluoride adducts also occur, and, when iron or zinc is used, there is a contamination of the waste water with the metal ions that is no longer acceptable. In some processes, the formation of undesired by-products, e.g., phytyltoluene and chlorophytols, is an especially serious problem.
DETAILED DESCRIPTION OF THE INVENTION
An object of the present invention is to provide a process for the manufacture of d,1-&agr;-tocopherol by the condensation of trimethylhydroquinone with isophytol or phytol in the presence of a catalyst and in a solvent without the disadvantages of previously known procedures. In this respect, it is necessary that the catalyst used has no, or at least a much reduced, corrosive action, is non-toxic, does not contaminate the environment and catalyzes the desired reaction as selectively as possi
Aquino Fabrice
Bonrath Werner
Bryan Cave LLP
Roche Vitamins Inc.
Solola T. A.
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