U.S. patent application number 09/802272 was filed with the patent office on 2001-10-04 for tocopherol manufacture by tris(perfluorohydrocarbylsulphonyl) methane or metal methides thereof.
This patent application is currently assigned to F. Hoffmann-La Roche AG. Invention is credited to Bonrath, Werner, Haas, Alois, Hoppmann, Eike, Netscher, Thomas, Pauling, Horst.
Application Number | 20010027255 09/802272 |
Document ID | / |
Family ID | 8168125 |
Filed Date | 2001-10-04 |
United States Patent
Application |
20010027255 |
Kind Code |
A1 |
Bonrath, Werner ; et
al. |
October 4, 2001 |
Tocopherol manufacture by tris(perfluorohydrocarbylsulphonyl)
methane or metal methides thereof
Abstract
A method of making (all-rac.)-.alpha.-tocopherol by the
acid-catalyzed condensation of trimethylhydroquinone with isophytol
or phytol wherein the condensation is carried out in the presence
of a tris(perfluoroalkanesulphonyl or
pentafluorobenzenesulphonyl)methane or a metal salt thereof as the
catalyst in an organic solvent. In addition to the metal salt, a
Bronsted acid, e.g. sulfuric acid, phosphoric acid or
p-toluenesulphonic acid, may be used as a co-catalyst. The product
of the method of making is the most active member of the vitamin E
group.
Inventors: |
Bonrath, Werner; (Freiburg,
DE) ; Haas, Alois; (Bochum, DE) ; Hoppmann,
Eike; (Leipzig, DE) ; Netscher, Thomas; (Bad
Krozingen, DE) ; Pauling, Horst; (Aesch, CH) |
Correspondence
Address: |
Mark E. Waddell, Esq.
Bryan Cave, LLP
245 Park Avenue
New York
NY
10167-0034
US
|
Assignee: |
F. Hoffmann-La Roche AG
|
Family ID: |
8168125 |
Appl. No.: |
09/802272 |
Filed: |
March 8, 2001 |
Current U.S.
Class: |
549/411 |
Current CPC
Class: |
C07D 311/72
20130101 |
Class at
Publication: |
549/411 |
International
Class: |
C07D 311/04 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 17, 2000 |
EP |
00105672.0 |
Claims
What is claimed is:
1. A method of making (all-rac.)-.alpha.-tocopherol comprising: a)
reacting trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol
(PH) in an organic solvent and in the presence of a
tris(perfluoroalkanesulpho- nyl)methane, a
tris(pentafluorobenzenesulphonyl)methane, a metal
tris(perfluoroalkanesulphonyl)methide, or a metal
tris(pentafluorobenzene- sulphonyl)methide catalyst of formula I:
[R.sup.1SO.sub.2).sub.3C].sub.x R.sup.2 I wherein R.sup.1 is a
perfluoroalkyl group C.sub.nF.sub.2n+1 or pentafluorophenyl,
R.sup.2 is a proton or a metal cation selected from the group
consisting of boron, magnesium, aluminium, silicon, scandium,
titanium, vanadium, vanadyl, manganese, iron, cobalt, nickel,
copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin,
lanthanum, cerium, praseodymium, neodymium, europium, dysprosium,
ytterbium, hafnium, platinum, and gold, n is an integer from 1 to
10, and x is the corresponding valency of the proton (1) or metal
cation (1, 2, 3, or 4); and b) isolating the
(all-rac.)-.alpha.-tocopherol.
2. A method according to claim 1 wherein the organic solvent is
selected from the group consisting of aliphatic ketones, cyclic
ketones, aliphatic esters, cyclic esters, aliphatic hydrocarbons,
and aromatic hydrocarbons.
3. A method according to claim 1 wherein the organic solvent is
selected from the group consisting of isobutyl methyl ketone,
diethyl ketone, cyclopentanone, isophorone, ethyl acetate,
isopropyl acetate, .gamma.-butyrolactone, ethylene carbonate,
propylene carbonate, hexane, heptane, octane, benzene, toluene, and
xylene.
4. A method according to claim 1 wherein the catalyst is present in
the reacting step at from about 0.1 mole % to about 2 mole % based
on the amount of TMHQ, IP, or PH present in the reacting step,
whichever is used in a lesser molar amount.
5. A method according to claim 1 wherein the reacting step further
comprises adding a Bronsted acid as a co-catalyst when the catalyst
is a metal tris(perfluoroalkanesulphonyl)methide or a metal
tris(pentafluorobenzenesulphonyl)methide.
6. A method according to claim 5 wherein the Bronsted acid is
selected from the group consisting of sulfuric acid, phosphoric
acid, and p-toluenesulphonic acid.
7. A method according to claim 1 wherein, in the reacting step,
about 10-100 ml of the organic solvent are present per 10 mmol IP
or PH.
8. A method according to claim 7, wherein about 30-60 ml of the
organic solvent are present per 10 mmol of IP or PH.
9. A method according to claim 1 further comprising carrying out
the reacting step at a temperature between about 60.degree. C. and
about 150.degree. C.
10. A method according to claim 9 wherein the temperature is
between about 100.degree. C. and about 120.degree. C.
11. A method according to claim 1 wherein the molar ratio of
TMHQ:IP or PH in the reacting step is from about 1.3:1 to about
2.5:1.
12. A method according to claim 11 wherein the molar ratio of
TMHQ:IP or PH is from about 1.5:1 to about 2.2:1.
13. A method according to claim 12 wherein the molar ratio of
TMHQ:IP or PH is about 2:1.
14. An acid-catalyzed process for producing (all-rac.)-.alpha.
tocopherol comprising: (a) forming a reaction mixture comprising
trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH), an
organic solvent, and a tris(perfluoroalkanesulphonyl)methane, a
tris(pentafluorobenzenesulphonyl)methane, a metal
tris(perfluoroalkanesul- phonyl)methide, or a metal
tris(pentafluorobenzenesulphonyl)methide catalyst of formula I:
[(R.sup.1SO.sub.2).sub.3C].sub.x R.sup.2 I wherein R.sup.1 is a
perfluoroalkyl group C.sub.nF.sub.2n+1 or pentafluorophenyl,
R.sup.2 is a proton or a metal cation selected from the group
consisting of boron, magnesium, aluminium, silicon, scandium,
titanium, vanadium, vanadyl, manganese, iron, cobalt, nickel,
copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin,
lanthanum, cerium, praseodymium, neodymium, europium, dysprosium,
ytterbium, hafnium, platinum, and gold, n is an integer from 1 to
10, and x is the corresponding valency of the proton (1) or metal
cation (1,2,3 or 4); and (b) isolating the
(all-rac.)-.alpha.-tocopherol.
15. A reaction mixture comprising: (d) trimethylhydroquinone
(TMHQ), (e) isophytol (IP) or phytol (PH) in an organic solvent,
and (f) a tris(perfluoroalkanesulphonyl)methane, a
tris(pentafluorobenzenesulphonyl- )methane, a metal
tris(perfluoroalkanesulphonyl)methide, or a metal
tris-(pentafluorobenzenesulphonyl)methide catalyst of formula I:
[(R.sup.1SO.sub.2).sub.3C].sub.x R.sup.2 I wherein R.sup.1 is a
perfluoroalkyl group C.sub.nF.sub.2n+1 or pentafluorophenyl,
R.sup.2 is a proton or a metal cation selected from the group
consisting of boron, magnesium, aluminium, silicon, scandium,
titanium, vanadium, vanadyl, manganese, iron, cobalt, nickel,
copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin,
lanthanum, cerium, praseodymium, neodymium, europium, dysprosium,
ytterbium, hafnium, platinum, and gold, n is an integer from 1 to
10, and x is the corresponding valency of the proton (1) or metal
cation (1,2,3 or 4), whereby (all-rac.)-.alpha.-tocop- herol is
formed in the reaction mixture by an acid-catalyzed condensation.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a novel process for the
manufacture of (all-rac.)-.alpha.-tocopherol by the acid-catalyzed
condensation of trimethylhydroquinone (TMHQ) with isophytol (IP) or
phytol (PH) in a solvent. (All-rac.)-.alpha.-tocopherol,
("d,l-.alpha.-tocopherol") is a diastereoisomeric mixture of
2,5,7,8-tetramethyl-2-(4',8',12'-trimethyl-tridecyl)-6-chromanol
(.alpha.-tocopherol), which is the most active and most
industrially important member of the vitamin E group.
BACKGROUND OF THE INVENTION
[0002] Many processes for the manufacture of d,l-.alpha.-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-.alpha.-tocopherol from TMHQ and phytyl bromide in
the presence of anhydrous zinc chloride (ZnCl.sub.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-.alpha.-tocopherol which was based on the
condensation of TMHQ with IP in the presence of the catalyst system
ZnCl.sub.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.sub.2 and a
Bronsted (protonic) acid, such as a hydrohalic acid, e.g. HCl,
trichloroacetic acid, acetic acid and the like, especially
ZnCl.sub.2/HCl, as the catalyst system. The disadvantages of these
and further published processes featuring ZnCl.sub.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.sub.2 required for the catalysis.
[0003] The manufacture of d,l-(.alpha.-tocopherol by the reaction
of TMHQ with phytyl chloride, PH or IP in the presence of boron
trifluoride (BF.sub.3) or its etherate (BF.sub.3.Et.sub.2O) is
described in German Patents 960720 and 1015446 and Nelan, U.S. Pat.
No. 3,444,213. However, BF.sub.3 also has corrosive properties.
[0004] Also, the condensation of TMHQ with IP or PH in the presence
of a Lewis acid, e.g. ZnCl.sub.2, BF.sub.3 or aluminum trichloride
(AlCl.sub.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.sub.2 and an acid is effected. In both
cases corrosion problems occur.
[0005] A further interesting method for the manufacture of
d,l-.alpha.-tocopherol from TMHQ and IP used an isolated
TMHQ-BF.sub.3 or -AlCl.sub.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-.alpha.-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.
[0006] The manufacture of d,l-.alpha.-tocopherol by the
condensation of TMHQ with IP using cation exchange resin complexes
of metal ions (Zn.sup.2+, Sn.sup.2+ and Sn.sup.4+) is disclosed in
Bull. Chem. Soc. Japan 50, 2477-2478 (1977). Among other
disadvantages, it gives the product in unsatisfactory yields.
[0007] The use of macroreticular ion exchangers, e.g.
Amberlyst.RTM. 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-.alpha.-tocopherol is not produced in satisfactory
purity.
[0008] EP 603695 describes the manufacture of
d,l-.alpha.-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.sub.2/HCl and ion exchangers. The reported
yields are unsatisfactory.
[0009] 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.sub.2/HCl.
However, corrosion problems and chloride contamination are
disadvantageous.
[0010] An interesting alternative for the condensation of TMHQ with
IP to d,l-.alpha.-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.
[0011] 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-.alpha.-Tocopherol could be
obtained, using various solvents, in about 90% yield.
[0012] A further process described in the literature (EP 658552;
Bull. Chem. Soc. Japan 68, 3569-3571 (1995)) for the synthesis of
d,l-.alpha.-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%.
[0013] 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)).
[0014] According to the Examples of EP 694 541, the condensation of
TMHQ with IP to .alpha.-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.sub.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.sub.2 used.
[0015] According to WO 97/28151, the acid-catalyzed condensation of
TMHQ with IP can be performed using a cyclic carbonate or
.alpha.-lactone as the solvent. The preferred catalyst is a mixture
of orthoboric acid and oxalic, tartaric or citric acid, or boron
trifluoride etherate.
[0016] WO 98/21197 describes the manufacture of
d,l-.alpha.-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.
[0017] 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
[0018] An object of the present invention is to provide a process
for the manufacture of (all-rac.)-.alpha.-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 necessary that the catalyst used has no, or at least a much
reduced, corrosive action, is non-toxic, does not contaminate the
environment and catalyzes the desired reaction as selectively as
possible and in high yields. Furthermore, the catalyst should
display its activity in small, catalytic amounts and should be
readily separable and reusable several times.
[0019] Another object of the invention is a method of making
(all-rac.)-.alpha.-tocopherol. This method includes: reacting
trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH) in
an organic solvent and in the presence of a
tris(perfluoroalkanesulphonyl)me- thane, a
tris(pentafluorobenzenesulphonyl)methane, a metal
tris(perfluoroalkanesulphonyl)methide, or a metal
tris(pentafluorobenzene- sulphonyl)methide catalyst of formula
I:
[(R.sup.1SO.sub.2).sub.3C].sub.x R.sup.2 I
[0020] wherein
[0021] R.sup.2 is a perfluoroalkyl group C.sub.nF.sub.2n+1 or
pentafluorophenyl,
[0022] R.sup.2 is a proton or a metal cation selected from the
group consisting of boron, magnesium, aluminium, silicon, scandium,
titanium, vanadium, vanadyl, manganese, iron, cobalt, nickel,
copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin,
lanthanum, cerium, praseodymium, neodymium, europium, dysprosium,
ytterbium, hafnium, platinum, and gold,
[0023] n is an integer from 1 to 10, and
[0024] x is the corresponding valency of the proton (1) or metal
cation (1, 2, 3, or 4);
[0025] and isolating the (all-rac.)-.alpha.-tocopherol.
[0026] Another embodiment of the invention is an acid-catalyzed
process for producing (all-rac.)-.alpha.-tocopherol. This process
includes forming a reaction mixture comprising
trimethylhydroquinone (TMHQ) with isophytol (IP) or phytol (PH), an
organic solvent, and a tris(perfluoroalkanesulphonyl)methane, a
tris(pentafluorobenzenesulphonyl- )methane, a metal
tris(perfluoroalkanesulphonyl)methide, or a metal
tris(pentafluorobenzenesulphonyl)methide catalyst of formula I:
[(R.sup.1SO.sub.2).sub.3C].sub.x R.sup.2 I
[0027] wherein
[0028] R.sup.1 is a perfluoroalkyl group C.sub.nF.sub.2n+1 or
pentafluorophenyl,
[0029] R.sup.2 is a proton or a metal cation selected from the
group consisting of boron, magnesium, aluminium, silicon, scandium,
titanium, vanadium, vanadyl, manganese, iron, cobalt, nickel,
copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin,
lanthanum, cerium, praseodymium, neodymium, europium, dysprosium,
ytterbium, hafnium, platinum, and gold,
[0030] n is an integer from 1 to 10, and
[0031] x is the corresponding valency of the proton (1) or metal
cation (1,2,3 or 4);
[0032] and isolating the (all-rac.)-.alpha.-tocopherol.
[0033] A further embodiment of the invention is a reaction mixture
containing:
[0034] (a) trimethylhydroquinone (TMHQ),
[0035] (b) isophytol (IP) or phytol (PH) in an organic solvent,
and
[0036] (c) a tris(perfluoroalkanesulphonyl)methane, a
tris(pentafluorobenzenesulphonyl)methane, a metal
tris(perfluoroalkanesul- phonyl)methide, or a metal
tris-(pentafluorobenzenesulphonyl)methide catalyst of formula
I:
[(R.sup.1SO.sub.2).sub.3C].sub.x R.sup.2 I
[0037] wherein
[0038] R.sup.1 is a perfluoroalkyl group C.sub.nF.sub.2n+1 or
pentafluorophenyl,
[0039] R.sup.2 is a proton or a metal cation selected from the
group consisting of boron, magnesium, aluminium, silicon, scandium,
titanium, vanadium, vanadyl, manganese, iron, cobalt, nickel,
copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin,
lanthanum, cerium, praseodymium, neodymium, europium, dysprosium,
ytterbium, hafnium, platinum, and gold,
[0040] n is an integer from 1 to 10, and
[0041] x is the corresponding valency of the proton (1) or metal
cation (1,2,3 or 4).
[0042] In this reaction mixture, (all-rac.)-.alpha.-tocopherol is
formed by an acid-catalyzed condensation.
DETAILED DESCRIPTION OF THE INVENTION
[0043] The objects of the present invention are achieved by
carrying out the condensation of trimethylhydroquinone with
isophytol or phytol in the presence of a so-called CH-acidic
compound or a metal salt thereof, which is more particularly a
tris(perfluoroalkanesulphonyl or
pentafluorobenzenesulphonyl)methane or a metal
tris(perfluoroalkanesulpho- nyl or
pentafluorobenzenesulphonyl)methide, in an organic solvent.
[0044] The condensation itself is represented in the following
Reaction Scheme, showing the reaction with IP only. 1
[0045] Accordingly, the process in accordance with the invention
for the manufacture of (all-rac.)-.alpha.-tocopherol by the
catalyzed condensation of trimethylhydroquinone with isophytol or
phytol, is characterized by carrying out the condensation in the
presence of a tris(perfluoroalkanesulphonyl or
pentafluorobenzenesulphonyl)methane or a metal
tris(perfluoroalkanesulphonyl or
pentafluorobenzenesulphonyl)methid- e, of the general formula
[(R.sup.1SO.sub.2).sub.3C].sub.x R.sup.2 I
[0046] wherein
[0047] R.sup.1 is a perfluoroalkyl group C.sub.nF.sub.2n+1 or
pentafluorophenyl,
[0048] R.sup.2 is a proton or a metal cation selected from the
group consisting of boron, magnesium, aluminium, silicon, scandium,
titanium, vanadium, vanadyl, manganese, iron, cobalt, nickel,
copper, zinc, yttrium, zirconium, rhodium, palladium, silver, tin,
lanthanum, cerium, praseodymium, neodymium, europium, dysprosium,
ytterbium, haffium, platinum and gold, each in the cationic
form,
[0049] n is an integer from 1 to 10 and
[0050] x is the corresponding valency of the proton (1) or metal
cation (1,2,3 or 4), as the catalyst in an organic solvent.
[0051] Some of the CH-acidic compounds and their metal salts of
formula I are known compounds. Thus, in Inorg. Chem. 27, 2135-2137
(1988) K. Seppelt and L. Turowsky describe for the first time the
preparation of tris(trifluoromethanesulphonyl)methane,
(CF.sub.3SO.sub.2).sub.3CH, and of four salts thereof, viz. the
potassium, rubidium, silver and cesium salts. The lithium and
further metal salts of (CF.sub.3SO.sub.2).sub.3CH and other
tris(perfluoroalkanesulphonyl)methides and their preparation are
described in Dominey, U.S. Pat. No. 5,273,840. Also developing the
original work of Seppelt and Turowsky, F. J. Waller et al. describe
in J. Org. Chem. 64, 2910 - 2913 (1999) the further preparation of
(CF.sub.3SO.sub.2).sub.3CH and its cesium salt, and also the
preparation of the corresponding scandium and ytterbium salts. In
Synlett 1999, No. 12, 1990-1992, J. Nishikido et al. describe the
preparation of scandium, yttrium and, in general, lanthanide (III)
tris(perfluorobutanesulphonyl)m- ethide complexes. Further
literature concerning the preparation of these and further metal
tris(perfluoroalkanesulphonyl)methides includes Lamanna et al.,
U.S. Pat. No. 5,554,664 and the many references mentioned in this
and in other aforementioned publications.
[0052] The tris(perfluoroalkanesulphonyl or
pentafluorobenzenesulphonyl)me- thanes or metal salts thereof
embraced by formula I and used as the catalysts in the process of
the present invention can be produced according to such published
methods, or in the case of those methanes or metal salts thereof
which may still not be known, according to analogous methods.
[0053] In the case of the metal tris(perfluoroalkanesulphonyl or
pentafluorobenzenesulphonyl)methides (the metal salts), this
catalyst can be used together with a strong Bronsted acid as a
co-catalyst in the process of the present invention. The Bronsted
acid present in such a catalyst system can be an inorganic or
organic acid, examples of which are sulfuric acid, phosphoric acid,
and p-toluenesulphonic acid. In the case of using a lithium salt as
the catalyst of formula I (R.sup.2 being the lithium cation), the
use of a Bronsted acid as a co-catalyst is particularly
preferred.
[0054] Solvents which can be used in the present invention are
polar or non-polar organic solvents. Suitable classes of polar
solvents include aliphatic and cyclic ketones, e.g. isobutyl methyl
ketone and diethyl ketone and, respectively, cyclopentanone and
isophorone; and aliphatic and cyclic esters, e.g. ethyl acetate and
isopropyl acetate, and, respectively, .gamma.-butyrolactone,
ethylene carbonate and propylene carbonate. Suitable classes of
non-polar solvents include aliphatic hydrocarbons, e.g. hexane,
heptane and octane, and aromatic hydrocarbons, e.g. benzene,
toluene and the xylenes. The condensation can be effected in a
single solvent phase, e.g. in toluene alone as the solvent, or in a
biphasic solvent system, e.g. in ethylene carbonate and hexane.
[0055] The method is conveniently effected at temperatures from
about 60.degree. C. to about 150.degree. C., preferably from about
100.degree. C. to about 120.degree. C.
[0056] Furthermore, the molar ratio of trimethylhydroquinone to
isophytol/phytol present in the reaction mixture is from about
1.3:1 to about 2.5:1, preferably from about 1.5:1 to about 2.2:1,
such as for example about 2:1.
[0057] The amount of catalyst of formula I used is such that the
molar ratio of catalyst to the educt (trimethylhydroquinone or
isophytol/phytol) which is in the lesser molar amount (generally
the isophytol or phytol) is from about 0.1:100 to about 2:100, i.e.
is from about 0.1 mole % to about 2 mole %.
[0058] Conveniently about 10 - 100 ml, preferably about 30 - 60 ml,
of organic solvent are used per 10 mmol of isophytol or phytol,
whichever is employed.
[0059] If the process reaction is carried out in a biphasic solvent
system, especially one consisting of a polar solvent, e.g. a cyclic
carbonate such as ethylene or propylene carbonate, and a non-polar
solvent, e.g. an aliphatic hydrocarbon such as hexane, then the
volume ratio of the non-polar solvent to the polar solvent is from
about 0.3:1 to about 5:1, preferably from about 1:1 to about
3:2.
[0060] Moreover, the process reaction may be carried out under an
inert gas atmosphere, preferably gaseous nitrogen or argon.
[0061] The reaction generally lasts for about 0.2 - 20 hours,
preferably about 0.5 - 1 hour.
[0062] The method in accordance with the invention can be carried
out batchwise or continuously. For example, isophytol or phytol may
be added, as such or in solution, portionwise to a suspension or
solution of the trimethylhydroquinone and the catalyst. The rate at
which the isophytol or phytol is added is not critical.
Conveniently, isophytol/phytol is added continuously over a period
0.5 to 5 hours. After completion of the isophytol/phytol addition
and an appropriate subsequent reaction period the working-up is
effected by procedures conventionally used in organic
chemistry.
[0063] If desired, the obtained (all-rac.)-.alpha.-tocopherol can
be converted into its acetate, succinate,
poly(oxyethylene)succinate, nicotinate and further known
application forms by standard procedures (See, for example, the 5th
Edition of Ullmann's Encyclopedia of Industrial Chemistry, Vol. A
27, pages 484-485 (VCH Verlagsgesellschaft mbH, D-69451 Weinheim,
1996)).
[0064] The process in accordance with the invention enables the
catalyst used to be separated readily and to be reused several
times.
[0065] Advantages in the use of the catalyst in the process in
accordance with the invention are, in addition to high yields of
(all-rac.)-.alpha.-tocopherol, the avoidance of corrosion, the
avoidance of waste water contamination with heavy metal ions, high
selectivity, and easy isolation of the
(all-rac.)-.alpha.-tocopherol product from the mixture after
reaction.
[0066] The following examples are provided to further illustrate
the process of the present invention. These examples are
illustrative only and are not intended to limit the scope of the
invention in any way.
EXAMPLES
Example 1
[0067] 5.23 g (33 mmol) of trimethylhydroquione (TMHQ) were
suspended/dissolved in 50 ml of toluene, whereafter 6.8 mg of
tris(trifluoromethanesulphonyl)methane were added and the mixture
was heated to about 100.degree. C. To the heated mixture with
stirring there was added portionwise 6 ml (16.5 mmol) of isophytol
over a period of about 60 minutes. Subsequently, the reaction
mixture is stirred for a further 30 minutes at 100.degree. C.,
after which the reaction was determined, by gas chromatography
(GC), to have been completed.
[0068] To isolate the crude (all rac.)-.alpha.-tocopherol formed in
the reaction the solvent was evaporated off under reduced
pressure.
[0069] This produced 6.52 g (91.7% theoretical yield) of
(all-rac.)-.alpha.-tocopherol, as analyzed by GC.
[0070] If desired, the crude product can be converted into its
acetate by standard procedures.
Example 2
[0071] 7.69 g (49.5 mmol) of trimethylhydroquione were
suspended/dissolved in a two-phase solvent system consisting 50 ml
of heptane and 40 ml of ethylene carbonate, whereafter 13.6 mg of
tris(trifluoromethanesulphonyl)- methane were added and the mixture
was heated to about 95.degree. C. To the stirred, heated mixture
11.88 ml (33 mmol) of isophytol were added over a period of about
20 minutes. Subsequently, the reaction mixture was stirred for a
further 30 minutes at 95.degree. C., after which the reaction was
determined by GC to have been completed.
[0072] To isolate the crude (all-rac.)-.alpha.-tocopherol formed in
the reaction, the heptane was evaporated off by concentration under
reduced pressure. The remaining ethylene carbonate phase was then
cooled to about 80.degree. C. and extracted with 50 ml of fresh
heptane. After the phase separation, the heptane phase containing
the product was evaporated under a reduced pressure of 20 mbar (2
kPa) at 40.degree. C. (The separated off ethylene carbonate phase,
containing the catalyst can be reused if desired).
[0073] This produced 13.27 g (96.6% theoretical yield) of
(all-rac.)-.alpha.-tocopherol, as analyzed by GC.
[0074] If desired, the crude product can be converted into its
acetate by standard procedures.
Example 3
[0075] (all-rac.)-.alpha.-tocopherol was produced according to the
method set forth in Example 2, with the exception that 40 ml of
propylene carbonate were substituted for 40 ml of ethylene
carbonate as the co-solvent. This produced 13.27 g (93.4%
theoretical yield) of (all-rac.)-.alpha.-tocopherol.
Example 4
[0076] 7.69 g (49.5 mmol) of trimethylhydroquinone were dissolved
in 40 ml of ethylene carbonate at 90.degree. C. After addition of
50 ml of heptane, 0.52 g (1.0 mmol) of silver
tris(trifluoromethanesulphonyl)methi- de
[(CF.sub.3SO.sub.2).sub.3Cag] were also added to the mixture. Over
a period of 20 minutes, 11.88 ml (33 mmol) of isophytol were
introduced into the mixture at 94.degree. C. After stirring for 30
minutes, the mixture was extracted with 50 ml of fresh heptane.
(After phase separation, the carbonate phase can be reused if
desired). The heptane phase was concentrated under a reduced
pressure of 20 mbar (2 kPa) at 40.degree. C., and the crude product
analyzed by GC. The yield of (all-rac.)-.alpha.-tocopherol was
12.79 g (90% theoretical yield).
Example 5
[0077] 7.69 g (49.5 mmol) of trimethylhydroquinone were dissolved
in 40 ml of ethylene carbonate at 90.degree. C. After addition of
50 ml of heptane, 0.17 g (0.33 mmol) silver
tris(trifluoromethanesulphonyl)methide was also added to the
mixture. Over a period of 20 minutes, 11.88 ml (33 mmol) of
isophytol were introduced into the mixture at 94.degree. C. After
stirring for 30 minutes, the heptane was distilled off, the
reaction mixture cooled to 80.degree. C., and the ethylene
carbonate phase extracted with 50 ml of fresh heptane. (After phase
separation, the ethylene carbonate phase can be reused if desired).
The heptane phase was concentrated under a reduced pressure of 20
mbar (2 kPa) at 40.degree. C. and the crude product analyzed by GC.
The yield of (all-rac.)-.alpha.-tocopherol is 12.43 g (87.5%
theoretical yield).
Example 6
[0078] 7.69 g (49.5 mmol) trimethylhydroquinone were dissolved in
40 ml of ethylene carbonate at 90.degree. C. After addition of 50
ml of heptane, 0.69 g (0.33 mmol) of zirconium
tris(trifluoromethanesulphonyl)methide
([(CF.sub.3SO.sub.2).sub.3C].sub.4Zr) was also added to the
mixture. Over a period of 20 minutes, 11.88 ml (33 mmol) of
isophytol were introduced into the mixture at 94.degree. C. After
stirring for 30 minutes, the heptane was distilled off, the
reaction mixture cooled to 80.degree. C., and the ethylene
carbonate phase extracted with 50 ml of fresh heptane. (After phase
separation, the ethylene carbonate phase can be reused if desired).
The heptane phase was concentrated under a reduced pressure of 20
mbar (2 kPa) at 40.degree. C. and the crude product analyzed by GC.
The yield of (all-rac.)-.alpha.-tocopherol was 12.8 g (90.06%
theoretical yield).
Example 7
[0079] 7.69 g (49.5 mmol) trimethylhydroquinone were dissolved in
40 ml of ethylene carbonate at 90.degree. C. After addition of 50
ml of heptane, 0.292 g (0.33 mmol) of copper
tris(trifluoromethanesulphonyl)methide
([(CF.sub.3SO.sub.2).sub.3C].sub.2Cu) were also added to the
mixture. Over a period of 20 minutes, 11.88 ml (33 mmol) of
isophytol were introduced into the mixture at 94.degree. C. After
stirring for 30 minutes, the heptane was distilled off, the
reaction mixture cooled to 80.degree. C., and the ethylene
carbonate phase extracted with 50 ml of heptane. (After phase
separation, the ethylene carbonate phase can be reused if desired).
The heptane phase was concentrated under a reduced pressure of 20
mbar (2 kPa) at 40.degree. C. and the crude product analyzed by GC.
The yield of (all-rac.)-.alpha.-tocopherol was 13.33 g (93.80%
theoretical yield).
Example 8
[0080] 4.4 g (28.3 mmol) trimethylhydroquinone were dissolved in 23
ml of ethylene carbonate at 90.degree. C. After addition of 30 ml
of heptane, 0.16 g (0.18 mmol) of vanadyl
tris(trifluoromethanesulphonyl)methide
([(CF.sub.3SO.sub.2).sub.3C].sub.2VO) were added. Over a period of
20 minutes, 6.8 ml (18.9 mmol) of isophytol were introduced into
the mixture at 94.degree. C. After stirring for 30 minutes, the
heptane was distilled off, the reaction mixture cooled to
80.degree. C., and the carbonate phase extracted with 30 ml
heptane. (After phase separation, the ethylene carbonate phase can
be reused if desired). The heptane phase was concentrated under a
reduced pressure of 20 mbar (2 kPa) at 40.degree. C. and the crude
product analyzed by GC. The yield of (all-rac.)-.alpha.-tocopherol
was 7.46 g (91.7% theoretical yield).
Example 9
[0081] 7.69 g (49.5 mmol) trimethylhydroquinone were dissolved in
40 ml ethylene carbonate at 90.degree. C. After addition of 50 ml
heptane, 0.582 g (0.33 mmol) of tin
tris(trifluoro-methanesulphonyl)methide
([(CF.sub.3SO.sub.2).sub.3C].sub.4Sn) were added. Over a period of
20 minutes, 11.88 ml (33 mmol) of isophytol were introduced into
the mixture at 94.degree. C. After stirring for 30 minutes, the
heptane was distilled off, the reaction mixture cooled to
80.degree. C., and the carbonate phase extracted with 30 ml of
heptane. (After phase separation, the ethylene carbonate phase can
be reused if desired). The heptane phase was concentrated under a
reduced pressure of 20 mbar (2 kPa) at 40.degree. C. and the crude
product analyzed by GC. The yield of (all-rac.)-.alpha.-tocopherol
was 12.74 g (89.67% theoretical yield).
[0082] The invention being thus described, it will be obvious that
the same may be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the invention
and all such modifications are intended to be included within the
scope of the following claims.
* * * * *