Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-08-16
2002-11-19
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
06482961
ABSTRACT:
FIELD OF THE INVENTION
The present invention is a method of making (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
(All-rac)-&agr;-tocopherol (or, as it is generally 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 most industrially important member of the vitamin E group.
Many processes for the manufacture of “d,1-&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 etseq. (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), not only Bergel et al. but also Smith et al. used TMHQ and PH as starting materials. In the following years mainly modifications, e.g. alternative solvents and Lewis acids, were developed. In 1941, a process for the manufacture of d,1-&agr;-tocopherol which was based on the reaction of TMHQ with IP in the presence of the catalyst system ZnCl
2
/hydrochloric acid (HCl) was developed from the work of 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)), 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. The disadvantages of these and further published processes featuring ZnCl
2
in combination with a Bronsted acid are the corrosive properties of the acid 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 Nelan, U.S. Pat. No. 3,444,213. However, BF
3
also 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 carried out. In both cases corrosion problems persist.
A further interesting method for the manufacture of d,1-&agr;-tocopherol from TMHQ and IP uses 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
itro-methane, is given as 77%. Accordingly, the use of such a solvent mixture is disadvantageous.
The manufacture of d,1-&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), among other disadvantages, it 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 Moroe et al., 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 reaction of TMHQ with IP or PH in the presence of acidic catalysts, such as ZnCl
2
/HCl and ion exchangers. However, 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 Heinrich et al., U.S. Pat. No. 3,789,086. Although this method forms less by-products, corrosion problems and chloride contamination remain as disadvantages.
An interesting alternative for the reaction of TMHQ with IP to d,1-&agr;-tocopherol uses trifluoroacetic acid or its anhydride as the catalyst (EP 12824). Although no HCL is used in this process, the catalyst is expensive.
The use of the heteropoly acid 12-tungstophosphoric or 12-tungstosilicic acid as the catalyst for the reaction of TMHQ with IP was described for the first time in React. Kinet. Catal. Lett. 47(1), 59-64 (1992). d,1-&agr;-Tocopherol was 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 various lanthanide trifluoromethanesulphonates (triflates), e.g., scandium trifluoromethanesulphonate, as the catalyst for the reaction. With up to about 10% excess of IP this process produces yields of 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 the disadvantage of requiring 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. The disadvantage in this process, in addition to the contamination of the waste water by zinc ions, is the usual large “catalyst amount” of ZnCl
2
required.
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.
WO 98/21197 describes the manufacture of d,1-&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 (EP 1000940) that the d,1-&bgr;-tocopherol manufacturing process can also be realized when supercritical carbon dioxide or nitrous oxide is used as the solvent.
From the forgoing review 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 which is today no longer acceptable. In some processes the formation of undesired by-products, e.g., phytyltoluene and chlorophytols, is an especially serious problem. Finally, in most cases the product yields are unsatisfactory.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a process for the manufacture of (all-rac)-&agr;-tocopherol by the reaction of trimethylhydroquinone wit
Bonrath Werner
Haas Alois
Hoppmann Eike
Pauling Horst
Bryan Cave LLP
Owens Amelia
Roche Vitamins Inc.
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