WO2003070718A1

WO2003070718A1 - MANUFACTURE OF (ALL-RAC)-α-TOCOPHEROL

Info

Publication number: WO2003070718A1
Application number: PCT/EP2003/001556
Authority: WO
Inventors: Werner Bonrath; Simone Gockel; Alois Haas; Thomas Netscher; Horst Pauling
Original assignee: Roche Vitamins AG; DSM IP Assets BV
Current assignee: DSM Nutritional Products AG; DSM IP Assets BV
Priority date: 2002-02-25
Filing date: 2003-02-17
Publication date: 2003-08-28
Anticipated expiration: 2004-08-25
Also published as: AU2003210291A1

Abstract

A process for the manufacture of (all-rac)-α-tocopherol by the acid-catalyzed reaction of trimethylhydroquinone with isophytol or phytol is characterized by carrying out the condensation in the presence of a bis (perfluoroalkylsulphonyl) methane as the catalyst in an organic solvent. The product of the process is the most active member of the vitamin E group.

Description

Manufacture of (all-mc -(X-Tocopherol

The present invention is concerned with a novel process for the manufacture of (all- rac) - (X-tocopherol by the acid- catalyzed reaction of trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH) in a solvent. As is known, (all-r c)-(X-tocopherol (or as it has mostly been denoted in the prior art, "d,l-(X-tocopherol") is a diastereoisomeric mixture of 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyl-tridecyl)-6-chromanol ((X-tocopherol), which is the most active and industrially most important member of the vitamin E group.

Many processes for the manufacture of "dJ-fX-tocopherol" (referred to as such in the literature reviewed hereinafter) 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-(X-tocopherol from TMHQ and phytyl bromide in the presence of anhydrous zinc chloride (ZnCl₂; 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. From the work of Karrer et al. there was developed in the year 1941 a technically interesting process for the manufacture of d,l- (X-tocopherol which was based on the reaction of TMHQ with IP in the presence of the catalyst system ZnCl /hydrochloric acid (HCl) (US Patent 2,411,969). Later publications, e.g. Japanese Patent Publications (Kokai) 1985/054380, 1985/064977 and 1987/226979 [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 ZnCl₂ and a Brδnsted (protonic) acid, such as a hydrohalic acid, e.g. HCl, trichlo- roacetic acid, acetic acid and the like, especially ZnCl₂/HCl, as the catalyst system. Disadvantages of these and further published processes featuring ZnCl in combination with a Brδnsted 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 ZnCl₂ required for the catalysis.

The manufacture of d,l-(X-tocopherol by the reaction of TMHQ with phytyl chloride, PH or IP in the presence of boron trifluoride (BF₃) or its etherate (BF₃ ^*Et₂O) is described in German Patents 960,720 and 1,015,446 as well as in US Patent 3,444,213. However BF₃ too has corrosive properties.

Also, the reaction of TMHQ with IP or PH in the presence of a Lewis acid, e.g. ZnCl₂, BF₃ or aluminium trichloride (A1C1₃), a strong acid, e.g. HCl, and an amine salt as the catalyst system is described in European Patent Publication (EP) 100,471. In an earlier patent publication, DOS 2,606,830, the IP or PH is pretreated with ammonia or an amine before the reaction with TMHQ in the presence of ZnCl and an acid is effected. In both cases corrosion problems occur.

A further interesting method for the manufacture of d,l-(X-tocopherol from TMHQ and IP comprises using an isolated TMHQ-BF₃ or -AICI₃ complex and a solvent mixture featuring a nitro compound (DOS 1,909,164). This process avoids to a large extent the formation of undesired by-products because it involves mild reaction conditions. The yield of d,l- (X-tocopherol, based on IP and the use of the solvent mixture methylene chloride/nitro- methane, is given as 77%. However, the use of such a solvent mixture is disadvantageous.

The manufacture of d,l- (X-tocopherol by the reaction of TMHQ with IP using cation exchange resin complexes of metal ions (Zn²⁺, Sn²⁺ and Sn ⁺) is disclosed in Bull. Chem. Soc. Japan 50, 2477-2478 (1977); amongst other disadvantages it gives 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 US Patent 3,459,773. However, the d,l-(X- tocopherol could not be obtained in the requisite purity.

EP 603,695 describes the manufacture of d,l-(X-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 /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 2,160,103 and US Patent 3,789,086. The formation of less by-products is advantageous compared with the aforementioned process using ZnCl₂/HCl. However, corrosion problems and chloride contamination are equally disadvantageous. An interesting alternative for the reaction of TMHQ with IP to d,l- (X-tocopherol comprises using trifluoroacetic acid or its anhydride as the catalyst (EP 12824). Although in this process the avoidance of HCl is achieved, the catalyst is relatively 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,l-(X-Tocopherol could be obtained, using various solvents, in about 90% yield.

A further process described in the literature [EP 658,552; Bull. Chem. Soc. Japan 68, 3569-3571 (1995)] for the synthesis of d,l- (X-tocopherol is based on the use of a various lanthanide trifluoromethanesulphonates (inflates), e.g. scandium trifluoromethanesul- phonate, 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. salts) 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 677,520; Bull. Chem. Soc. Japan 69, 137-139 (1996)].

According to the Examples of EP 694,541 the reaction of TMHQ with IP to (X-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 /HCl. Disadvantages in this process are, in addition to the contamination of the waste water by zinc ions, the usual large "catalyst amount" of ZnCl₂used.

According to WO 97/28151 the acid-catalysed reaction of TMHQ with IP can be performed in a cyclic carbonate or (X-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-(X-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 1,000,940 that the dl- (X-tocopherol manufacturing process can also be realized in supercritical carbon dioxide or nitrous oxide as the solvent. From the foregoing 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, chlorophytols, and products of the dehydration of IP or PH, i.e. so-called phytadienes, is an especially serious problem: the selectively of the reaction is unsatisfactory. In most cases the yields are unsatisfactory.

The object of the present invention is to provide a process for the manufacture of (all- rac) -(X-tocopherol by the reaction 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 necessary that the catalyst used has no, or at least a much reduced, corrosive action, is non-toxic, does not contaminate the environment, e.g. with chlorinated by-products or heavy metal ions, and catalyzes the desired re- action as selectively as possible, with as little as possible co-production of such by-products as phytadienes, and in high yields. Furthermore, the catalyst should display its activity in small, really catalytic, amounts and should be readily separable and re-usable several times.

This object of the present invention is achieved by carrying out the reaction of trimethylhydroquinone with isophytol or phytol in the presence of a so-called "CH₂-acidic compound", more particularly a bis(perfluoroalkylsulphonyl)methane, as will be defined hereinafter, as the catalyst in an organic solvent.

The reaction itself is represented in the following Reaction Scheme, showing the reaction with IP only.

Reaction Scheme

isophytol trimethylhydroquinone

catalyst -H,0

(all-r c)-(X-tocopherol

Accordingly, the process in accordance with the present invention for the manufacture of (all-r c)-(X-tocopherol by the acid-catalyzed reaction of trimethylhydroquinone with isophytol or phytol is characterized by carrying out the reaction in the presence of a bis(perfluoroalkylsulphonyl)methane of the general formula

(RSO₂)₂CH₂ I

wherein

each R, independently, signifies a perfiuoroalkyl group C_nF_{2n +} 1 and

n signifies an integer from 1 to 4,

as the catalyst in an organic solvent.

In the catalyst of the formula I the perfiuoroalkyl group R with 3 or 4 carbon atoms, i.e. heptafluoropropyl or nonafluorobutyl, respectively, maybe straight chain or branched.

Some of the bis(perfluoroalkylsulphonyl)methanes of formula I used as the catalysts in the process of the present invention are known compounds, of which the production is disclosed in R. J. Koshar et al, J Org. Chem. 38(19), 3358-3363 (1973); F. J. Waller et al., J. Org. Chem. 64, 2910-2913 (1999); US Patent 3,776,960; and Japanese Patent Publication (Kokai) 2001/039942 A2. Those bis(perfluoroalkylsulphonyl)methanes which may still not be known can be produced according to analogous methods to the disclosed methods. Solvents which can be used in the process of the present invention are polar or non- polar organic solvents, particularly the former or mixtures of both types. Suitable classes of polar solvents include aliphatic and cyclic esters, e.g. ethyl acetate and isopropyl acetate, and, respectively, γ-butyrolactone; and aliphatic and cyclic carbonates, e.g. ethylene carbonate, propylene carbonate and 1,2-butylene carbonate. Suitable non-polar solvents are aliphatic hydrocarbons, e.g. hexane, heptane and octane. As indicated above, non- polar solvents are preferably used in combination with polar solvents rather than as sole solvents, giving biphasic solvent systems. When the reaction is effected in such a biphasic solvent system, preferred polar solvents are ethylene carbonate, propylene carbonate, 1,2- butylene carbonate, γ-butyrolactone and mixtures of two or more of these, and preferred non-polar solvents are hexane, heptane and octane.

The process is conveniently effected at temperatures from about 80°C to about 150°C, preferably from about 90°C to about 130°C, especially preferred from about 100°C to about 125°C.

Furthermore, the molar ratio of trimethylhydroquinone to isophytol or phytol is conveniently about 1.25 : 1 to about 2.2 : 1, preferably about 1.5 : 1 to about 2 : 1.

The amount of catalyst, i.e. bis(perfluoroalkylsulphonyl)methane of the formula I, used is such that the molar ratio of the catalyst to the educt (trimethylhydroquinone or isophytol/phytol) which is in the lesser molar amount, generally the isophytol or phytol, is conveniently about 0.08 : 100 to about 2.0 : 100, preferably about 0.10 : 100 to about 0.25 : 100, i.e. the relative amount of the catalyst to the trimethylhydroquinone or isophytol/phytol, whichever is in the lesser molar amount, is about 0.08 mole % to about 2.0 mole %, preferably about 0.10 mole % to about 0.25 mole %.

Conveniently about 0.5 - 2 ml, preferably about 0.75 - 1.25 ml, most preferably about 0.9-1.1 ml, of a polar solvent are used per mmol of trimethylhydroquinone.

If the process is carried out with a biphasic solvent system, especially one consisting of a polar solvent, e.g., and as preferred, a cyclic carbonate such as ethylene carbonate, propylene carbonate, 1,2-butylene carbonate or a mixture of two or all three of these cyclic carbonates, and a non-polar solvent, e.g. an aliphatic hydrocarbon such as hexane, heptane or octane, then the volume ratio of the non-polar solvent to the polar solvent is conveniently in the range from about 1 : 3 to about 5 : 1, preferably from about 1 : 1.25 to about 2 : 1.

Moreover, the process is conveniently carried out under an inert gas atmosphere, preferably gaseous nitrogen or argon. The actual reaction generally lasts for about 0.5 to about 2.5 hours, preferably about 0.75 to 1.5 hours.

The process in accordance with the invention can be carried out batchwise or continuously, and in general operationally in a very simple manner, for example by adding isophytol or phytol, as such or in solution, portionwise to a mixture of the catalyst, the trimethylhydroquinone and the solvent. The rate at which the isophytol or phytol is added is not critical. Conveniently, isophytol or phytol, preferably as such, is added continuously over a period from about 5 minutes to about 1 hour, preferably from about 10 to 30 minutes. After completion of the isophytol/phytol addition and an appropriate subsequent reaction period the working-up can be effected by procedures conventionally used in organic chemistry.

If desired, the obtained (all-rac)-(X-tocopherol can be converted into its acetate, suc- cinate, poly(oxyethylene)succinate, nicotinate and further known application forms by standard procedures [see, for example, the 5 Edition of Ullmann's Encyclopedia of In- dustrial Chemistry, Vol. A 27, pages 484-485 (VCH NerlagsgeseUschaft mbH, D-69451 Weinheim, 1996)].

The process in accordance with the invention enables the catalyst used to be separated readily and to be reused several times.

Advantages in the use of the catalyst in the process in accordance with the invention are, in addition to high yields of (all-røc)-(X-tocopherol, the avoidance of corrosion, the avoidance of waste water contamination with heavy metal ions, the high selectivity as well as the enabled ready isolation of the produced (all- rac) -(X-tocopherol from the mixture after reaction.

The process in accordance with the invention is illustrated by the following Example:

Example

7.56 g (49.5 mmol) trimethylhydroquinone (TMHQ), the catalyst of formula (RSO₂)₂CH₂, 50 ml of cyclic carbonate/ester solvent [either ethylene carbonate (EC), propylene carbonate (PC), a 1 : 1 mixture of EC and PC (EC/PC) or γ-butyrolactone (BL)] and 50 ml of non-polar organic solvent (heptane) were introduced into a 200-ml four- necked flask equipped with a reflux condenser, a water separator, a mechanical stirrer and argon gasification means. The reaction mixture was heated to 110°C (boiling point of heptane) under an argon atmosphere, and 12 ml (33 mmol) of isophytol (IP) were added dropwise at a rate of 1.2 ml/minute. After completion of the isophytol addition the heptane component of the solvent mixture was distilled off and the remaining liquid mixture in the flask stirred at 140°C for 30 minutes. Thereafter the mixture was cooled to 80°C and 50 ml heptane were added. After phase separation the heptane phase was concentrated under reduced pressure [40°C, 25 bar (2.5 kPa)]. The crude product was analysed by gas chromatography (with an internal standard) to establish the yield, based on the amount of IP used, of (all-rac)-α-tocopherol. The results are summarized in the following Table:

Table: Reaction of TMHQ and IP in various solvents using the catalyst I, (RSO^^CH?

If desired, the crude product can be converted into its acetate by standard procedures.

Claims

1. A process for the manufacture of (all-rac)-(X-tocopherol by the acid- catalyzed reaction of trimethylhydroquinone with isophytol or phytol, which process is characterized by carrying out the reaction in the presence of a bis(perfluoroall ylsulphonyl)- methane of the general formula

(RSO₂)₂CH₂ I

wherein

each R, independently, signifies a perfiuoroalkyl group C_nF_{2n + 1}, and

n signifies an integer from 1 to 4,

as the catalyst in an organic solvent.

2. A process according to claim 1, wherein an aliphatic or cyclic ester, an aliphatic or cyclic carbonate or an aliphatic hydrocarbon is used as the organic solvent.

3. A process according to claim 2, wherein the solvent is ethyl acetate, isopropyl acetate, γ-butyrolactone, ethylene carbonate, propylene carbonate, 1,2-butylene carbonate, hexane, heptane, octane, benzene, toluene or xylene or a mixtures of two or more of such solvents.

4. A process according to claim 3, wherein a biphasic solvent system of a non-polar solvent and a polar solvent is used, the non-polar solvent being ethylene carbonate, propylene carbonate, 1,2-butylene carbonate, χ-butyrolactone or a mixture of two or more of such solvents, and the non-polar solvent is hexane, heptane or octane.

5. A process according to any one of claims 1 to 4, wherein the molar ratio of trimethylhydroquinone to isophytol or phytol present in the reaction mixture is about 1.25 : 1 to about 2.2 : 1, preferably about 1.5 : 1 to about 2 : 1.

6. A process according to any one of claims 1 to 5, wherein the relative amount of the catalyst bis(perfluoroalkylsulphonyl)methane of the formula I to the amount of trimethylhydroquinone or isophytol/phytol, whichever is in the lesser molar amount, is about 0.08 mole % to about 2.0 mole %, preferably about 0.10 mole % to about 0.25 mole %.

7. A process according to any one of claims 1 to 6, wherein the reaction is effected at temperatures from about 80°C to about 150°C, preferably from about 90°C to about 130°C, especially from about 100°C to about 125°C.

8. A process according to any one of claims 1 to 7, wherein about 0.5 - 2 ml, preferably about 0.75 - 1.25 ml, most preferably about 0.9 - 1.1 ml, of a polar solvent are used per mmol of trimethylhydroquinone.

9. A process according to any one of claims 1 to 8, wherein a biphasic solvent system of a polar solvent and a non-polar solvent is used, the volume ratio of the non-polar solvent to the polar solvent being in the range from about 1 : 3 to about 5 : 1, preferably from about 1 : 1.25 to about 2 : 1.

10. A process according to any one of claims 1 to 9, wherein isophytol or phytol, as such or in solution, is added portionwise to a mixture of the catalyst, the trimethylhydro- quinone and the solvent.