Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-17
2002-07-23
Stockton, Laura L. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06423851
ABSTRACT:
FIELD OF THE INVENTION
The present invention is concerned with a novel process for the manufacture of d,l-&agr;-tocopherol by the catalyzed condensation of trimethylhydroquinone with isophytol in a solvent. As is known, d,l-&agr;-tocopherol is a diastereomer 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,l-&agr;-tocopherol by the condensation of trimethylhydroquinone (TMHQ) with isophytol (IP) in the presence of various catalysts or catalyst systems and in various solvents 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, 520-525 (1938), Nature 142, 36 (1938) and, respectively, Science 88, 37-38 (1938) and J. Am. Chem. Soc. 61, 2615-2618 (1939)). While Karrer et al. carried out the synthesis of d,l-&agr;-tocopherol from TMHQ and phytyl bromide in the presence of anhydrous zinc chloride (ZnCl
2
; a Lewis acid), not only Bergel et al., but also Smith et al used TMHQ and phytol as starting materials.
In the following years modifications, such as alternative solvents and Lewis acids, were developed. From the work of Karrer et al. a process was developed in 1941 for the manufacture of d,l-&agr;-tocopherol which was based on the condensation of TMHQ with IP in the presence of the catalyst system ZnCl
2
/hydrochloric acid (HCl) (Karrer et al., 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)), disclose this condensation in the presence of zinc and 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 relatively large amount of ZnCl
2
required for the catalysis.
The manufacture of d,l-&agr;-tocopherol by the reaction of TMHQ with phytyl chloride, phytol or isophytol in the presence of boron trifluoride (BF
3
) or its etherate (BF
3
.Et
2
O) is disclosed in German Patents 960720 and 1015446 as well as in Nelan et al., U.S. Pat. No. 3,444,213, and Finnan, U.S. Pat. No. 4,634,781. However, BF
3
also has corrosive properties.
The condensation of TMHQ with IP or another phytyl derivative in the presence of a Lewis acid, e.g. ZnCl
2
, BF
3
or aluminum trichloride (AlCl
3
), a strong acid, e.g. HCl, and an amine salt as the catalyst system is disclosed in EP100471. In an earlier patent publication (DOS 2606830), the IP or phytol 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,l-&agr;-tocopherol from TMHQ and IP includes using an isolated TMHQ-BF
3
or -AlCl
3
complex as the catalyst and a solvent mixture featuring a nitro compound (see, DOS 1909164). This process avoids to a large extent the formation of undesired byproducts because it involves mild reaction conditions. The yield of d,l-&agr;-tocopherol, based on IP and the use of the solvent mixture methylene chloride
itromethane, is reported to be 77%. However, the use of such a solvent mixture is disadvantageous.
The manufacture of d,l-&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). One of the disclosed disadvantages is that the product is formed in unsatisfactory yields.
The use of macroreticular ion exchangers, e.g. AMBERLYST® 15, as the catalyst for the condensation of TMHQ with IP is disclosed in Moroe et al., U.S. Pat. No. 3,459,773. EP 603 695 discloses the manufacture of d,l-&agr;-tocopherol in liquid or supercritical carbon dioxide by the condensation of TMHQ with IP in the presence of acidic catalysts, such as ZnCl
2
/HCl and ion exchangers.
The condensation in the presence of a catalyst system which consists of iron(II) chloride, metallic iron and HCl gas is disclosed in DOS 2160103 and Frick et al., U.S. Pat. No. 3,789,086. The formation of fewer byproducts is an advantage of this process compared with the aforementioned process using ZnCl
2
/HCl. However, corrosion problems and chloride contamination are equally disadvantageous.
An alternative for the condensation of TMHQ with IP to d,l-&agr;-tocopherol including using trifluoroacetic acid or its anhydride as the catalyst is disclosed in EP 12824. Although this process avoids the use of HCl, the alternative catalyst is relatively expensive.
The use of heteropolytungsten acids as catalysts for the condensation of TMHQ with IP is disclosed in React. Kinet. Catal. Lett. 47(1), 59-64 (1992). d,l-&agr;-Tocopherol was reportedly obtained with about 90% yield using this process and various solvents. A further process disclosed in the literature (EP 658 552; Bull. Chem. Soc. Japan 68, 3569-3571 (1995)) for the synthesis of d,l-&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 reportedly achieves 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 has as a disadvantage the need for a large amount of catalyst (EP 677 520; Bull. Chem. Soc. Japan 69, 137-139 (1996)). According to the Examples of EP 694 541, the condensation of TMHQ with IP to form &agr;-tocopherol may 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, wherein catalysis is effected by ZnCl
2
/HCl. Disadvantages in this process include, in addition to the contamination of the waste water by zinc ions, the usual large “catalyst amount” of ZnCl
2
used.
According to WO 97/28151, the acid catalyzed condensation of TMHQ with IP may 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.
Finally, WO 98/21197 discloses the manufacture of d,l-&agr;-tocopherol from TMHQ and IP using bis(trifluoromethylsulphonyl)amine or a metal salt thereof optionally with a strong Bronsted acid as catalyst in a variety of aprotic solvents such as aliphatic and cyclic ketones or esters, and aromatic hydrocarbons.
From the foregoing explanations it is evident that most of the previously known processes have considerable disadvantages. Thus, corrosion problems occur in the case of all processes in which acid catalysts such as boron trifluoride are used. Toxicity problems with the boron trifluoride adducts also occur. When iron or zinc is used, there is a contamination of the waste water with the metal ions which today is no longer acceptable. In some of the prior art processes, formation of undesired byproducts, e.g. phytyltoluene and chlorophytols, is an especially serious problem. Furthermore, the use of organic solvents requires complicated procedures for their removal or recycling during the product isolation.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a process for the preparation of d,l-&agr;-tocopherol by the condensation of trimethylhydroquinone with isophytol in the presence of a catalyst and in a solvent which does not have the disadvantages of previously known procedure
Bonrath Werner
Wang Shaoning
Bryan Cave LLP
Roche Vitamins Inc.
Stockton Laura L.
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