Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-01-17
2004-03-02
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06700002
ABSTRACT:
FIELD OF THE INVENTION
The present invention is concerned with a novel process for the manufacture of (all-rac)-&agr;-tocopherol by the acid-catalyzed reaction of trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH) in a solvent.
BACKGROUND OF THE INVENTION
As is known, (all-rac)-&agr;-tocopherol (or as it has mostly been denoted in the prior art, “d,l-&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.
Many processes for the manufacture of “d,l-&agr;-tocopherol” by the reaction 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,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 PH as starting materials. In the following years alternative solvents and Lewis acids were developed. From the work of Karrer et al. there was developed in the year 1941 a technically interesting process for the manufacture of d,l-&agr;-tocopherol which was based on the reaction of TMHQ with IP in the presence of the catalyst system ZnCl
2
/hydrochloric acid (HCl) (U.S. Pat. No. 2,411,969, which is hereby incorporated by reference as if recited in full herein). 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 reaction 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,l-&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, which is hereby incorporated by reference as if recited in full herein. However BF
3
too has corrosive properties.
Also, the reaction of TMHQ with IP or PH 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 described in European Patent Publication (EP) 100471. In an earlier patent publication, DOS 2606830, the IP or PH is pretreated with ammonia or an amine before the reaction 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 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,l-&agr;-tocopherol, based on IP and the use of the solvent mixture methylene chloride
itromethane, is reported as 77%. However, the use of such a solvent mixture is disadvantageous because nitro compounds tend to be unstable when excessively heated, so that difficulty is encountered in the product isolation, solvent separation and recycling procedures.
The manufacture of d,l-&agr;-tocopherol by the reaction 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 other disadvantages the reaction produces the product in unsatisfactory yields.
The use of macroreticular ion exchangers, e.g. Amberlyst® 15, as the catalyst for the reaction of TMHQ with IP is described in U.S. Pat. No. 3,459,773, which is hereby incorporated by reference as if recited in full herein. However, the d,l-&agr;-tocopherol could not be obtained in the requisite purity.
EP 603695 discloses the manufacture of d,l-&agr;-tocopherol in liquid or supercritical carbon dioxide by the reaction 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 reaction 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, which is hereby incorporated by reference as if recited in full herein. 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 alternative for the reaction of TMHQ with IP to form d,l-&agr;-tocopherol includes using trifluoroacetic acid or its anhydride as the catalyst (EP 12824). Although in this process the avoidance of HCl is achieved, the catalyst is also corrosive, and relatively expensive.
The use of a heteropoly acid such as 12-tungstophosphoric or 12-tungstosilicic acid as the catalyst for the reaction of TMHQ with IP was described in React. Kinet. Catal. Lett. 47(1), 59-64 (1992). d,l-&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,l-&agr;-tocopherol is based on the use of a various lanthanide trifluoromethanesulphonates (triflates), e.g. scandium trifluoromethane-sulphonate, as the catalyst for the reaction. 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 reaction of TMHQ with IP or PH has as a disadvantage the need for a large amount of catalyst (EP 677520; Bull. Chem. Soc. Japan 69, 137-139 (1996)).
According to the Examples of EP 694541, the reaction of TMHQ with IP to &agr;-tocopherol can be achieved in high yields and with a high product purity when such solvents as carbonate esters, fatty acid esters and certain mixed solvent systems are employed, the exemplified catalysis being effected by ZnCl
2
/HCl. Disadvantages in this process are, 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 reaction of TMHQ with IP can be performed in a cyclic carbonate or &agr;-lactone as the solvent. The preferred catalyst is a mixture of orthoboric acid and oxalic, tartaric or citric acid, or boron trifluoride etherate.
In EP 784042, there is disclosed the use of hydrogen bis(oxalato)borate as a protonic acid catalyst in various condensation reactions, e.g. Friedel-Crafts condensations, including the acid-catalyzed reaction of TMHQ with IP to produce d,l-&agr;-tocopherol.
WO 98/21197 discloses the manufacture of d,l-&agr;-tocopherol from TMHQ and IP using bis(trifluoromethylsulphonyl)imide or a metal salt thereof optionally together with a strong Bronsted acid, as catalyst in such types of aprotic solvents as aliphatic and cyclic ketones or esters, and aromatic hydrocarbons.
Using the same kind of bis(trifluoromethylsulphonyl)imide catalyst it has been shown in EP 1000940 that the dl-&agr;-tocopherol manufacturing process can also be realized
Bonrath Werner
Netscher Thomas
Wietelmann Ulrich
Bryan Cave LLP
McKane Joseph K.
Roche Vitamins Inc.
Sackey Ebenezer
LandOfFree
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