Tocopherol manufacture by...

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2001-03-08

2002-04-09

Solola, T. A. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06369242

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a novel process for the manufacture of (all-rac.)-&agr;-tocopherol by the acid-catalyzed condensation of trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH) in a solvent. (All-rac.)-&agr;-tocopherol, (“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 most industrially 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 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., and 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), Bergel et al. and 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. From the work of Karrer et al. a technically interesting process 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) was developed in 1941. 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. The 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 and Nelan, 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 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 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 used 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
itro-methane, is given as 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). Among other disadvantages, it gives 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 Moroe et al., U.S. Pat. No. 3,459,773. However, the d,l-&agr;-tocopherol is not produced in satisfactory purity.
EP 603695 describes the manufacture of d,l-&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 Heinrich et al., 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 disadvantageous.
An interesting alternative for the condensation of TMHQ with IP to d,l-&agr;-tocopherol uses trifluoroacetic acid or its anhydride as the catalyst (EP 12824). Although in this process the avoidance of HCl is achieved, the catalyst is 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). 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 scandium, yttrium or lanthanide fluorosulphonate, nitrate or sulphate, e.g. scandium trifluoromethanesulphonate, as the catalyst for the condensation. 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 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 694 541, the condensation 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 condensation of TMHQ with IP can be performed using 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,l-&agr;-tocopherol from TMHQ and IP using bis(trifluoromethylsulphonyl)amine 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.
From the forgoing review it is evident that most of the previously known processes have considerable disadvantages. Thus, corrosion problems occur in all processes in which such acid catalysts 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.
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 condensation of trimethylhydroquinone with isophytol or phytol in the presence of a catalyst and in a solvent which does not have the disadvantages of previously known procedures. In this respect, it is nec

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