Note: Descriptions are shown in the official language in which they were submitted.
1~a'7~8~
Preparation of tocopheryl acetate and tocopheryl
propionate
The present invention reLates to an improved pro-
cess for the preparation of tocopheryL acetate
c~3 co-o~'J `l ~ ~ ~
by reacting trimethylhydroquinone with phytol or isophytol
in the presence of a proton donor and zinc chloride and
then esterifying the tocopherol ~ith acetic anhydride or
propion;c anhydride.
Apart from the improvement according to the inven-
tion, this process is kno~n in principle and in many
variants, but the embodiments known hitherto are unsatis-
factory.
According to ExampLe 1 of U.S. Patent 3,444,213,
trimethylhydroquinone is condensed with isophytol in the
presence of 3lacial acetic acid and BF3 etherate, the
volat;le constituents are substantially separated off from
the reaction mixture, and the crude tocopherol is heated
~ith acetic anhydride and pyridine. This procedure is
relatively troubLesome and consumptive of energy, requires
the presence of pyr;dine and in spite of this g;ves a
yield of ~ocopheryl acetate of only 87X, uhich is unsatis-
factory in view of the expensive starting materials.
A sinilar situation is found in the case of the
~.
l~t7~
prDcess described in U.5. Patent 3,708,505, in ~hich tri-
~ethyihydroquinone is condensed ~ith isophytol in the
presence of an scid and zinc chLoride ~nd of benzene as
the diluent, and the reaction mixture is then subjected,
at the boil, to an esterification reaction ~ith acetic
anhydrideO Depending on the type of acid used, crude
yieLds of tocopheryl acetate of from ~8 to 93.6Z are
obtained in this c~se. Ho~ever, when the purities, ~hich
~re from b4 to 89.5X, ~re taken into account~ the yields
of pure product are correspondingly lo~er. Moreover, the
fact that the estcrification takes 6 hours at the boiling
point constitutes a d;sadvantage.
~ apanese Patent 149,984 further~ore discloses
that tocopheryl acetate ~ay ~e prepared by reacting toco-
pherol uith acetic anhydride in the presence of hydrogen
chloride ~nd zinc dust or cf zinc chloride. This reaction
proceeds adiabatically, the temperature of the reaction
~ixture increas;n~ from room temper3ture to ~bo~t 60C~
takes about 1-2 hours ~nd gives a yield of ester of 96X~
b~sed on the d,l-a-tocopherol employed.
It is an object of the present invention to pre-
p~re tocopheryl acetate fro~ triMe~hylhydroquinone and
phytol or isGphytol in ~ ~anner ~hich is simpler and nore
econo~ic~l than hitherto~
~ e h~ve found that ~hi~ object ~ aehieved ~nd
that, surprisingly, the ~cetylation of tocopherol ~ith
acetic anhydride in the presence of hydro~en chloride and
2inc dust or z;nr. ehloride ~lso proceeds virtuallr to com-
pletion ~n ~ short ti~e ~nd ~ithou~ exterr~l heatin~ if,
~ 2 ~
3~
instead of using isolated and dry ~-tocopherol as a starting
material, the two-phase dark mixture obtained in the reaction
of trimethylhydroquinone with phytol or isophytol in the
presence of a proton donor, preferably hydrogen chloride, and
zinc chloride and of a liquid hydrocarbon is cooled and then
reacted with acetic anhydride. After the addition of acetic
anhydride has ended, the acetylation is virtually complete.
In this process, the tocopheryl acetate is obtained in good
yield and, surprisingly, in very pure form.
Equally successful results were obtained in the
preparation of tocopheryl propionate when the reaction mixture
described was reacted with propionic anhydride.
The present invention accordigly relates to a
process for the preparation of tocopheryl acetate or tocopheryl
propionate by reacting trimethylhydroquinone with phytol or
isophytol in the presence of a proton donor, zinc dust or
- zinc chloride, and a liquid hydrocarbon as the solvent, esteri-
fying the tocopherol obtai.ned and working up the esterification
mixture to give tocopheryl acetate or tocopheryl propionate,
wherein the mixture obtained in the reaction of trimethylhydro-
quinone with phytol or isophytol is cooled and then reacted
with acetic anhydride or propionic anhydride at from 0 to 60C.
In a particu].arly advantageous embodiment of the
novel process, a mixture obtained by reacting trimethylhydro-
quinone with phytol or is.ophytol while separating off water is
reacted with acetic anhydride or propionic anhydride, at from
0 to 60C.
1~'7~3~
~he first step is advantageously carried out by
~radually adding phytol or isophytol to a mixture of tri-
~ethylhydroquinone, the proton donor, z;nc chLor;de and
the hydrocarbon at from 80 to 130C, and keeping the mix-
ture uithin this temperature range for about 1-10 hours,
uhiLe mixing thoroughly.
$n this process, the molar ratio of trimethyL-
hydroquinone to phytol or isophytol is preferably from
0.9:1 to 1.1:1, and that of trimethylhydroquinone to zinc
chloride is from 20:1 to 1:1.
About 0.5-2 liters of the hydrocarbon solvent are
advantageously employed per moLe (152 9) of trimethyL-
hydroquinone.
SuitabLe proton donDrs are strong mineraL acids,
eg. hydrochloric acid, hydrogen chLor;de or suLfuric ac;d,
strong acid saLts, eg. sodium hydrogen sulfate, and
strong organic acids, eg. p-toluenesulfonic acid or tri-
fluoroacetic acid, but hydrochloric acid or hydrogen
chloride is preferably empLoyed.
Suitable solvents are hydrocarbons, eg. hexane,
heptane, cyclohexane, benzene or toluene.
Since uater is split off in the condensation of
trimethylhydroquinone ~ith phytol or isophytol, it is
advisable to separat~ off continuously the ~ater formed and
that already present in the reaction mixture. Although
this is not absolutely netessary since the reattion proceeds
smoothly even ~hen ~ater is not separated off, if this is
not done a relatively large amount of carboxy~ic acid
anhydride is required in the subsequent acylation step.
1~7;~
Furthermore, it may be advisable to carry out the
reaction in a conventional manner in the presence of a
small amount of a nitrogen base, such as ammonia or an
organic amine, eg. stearylamine, or ~ith a phytol or iso-
phytol ~h;ch has been treated at from 20 to 120C ~ith
ammonia or an organic amine tcf. U.S. Patent 4,191,692 and
German Patent 2,606,830).
After the condensat;on is complete, the reaction
mixture obtained ;s cooled~ acetic anhydride or propionic
anhydride is added at from 0 to 6ûC and if necessary the
mixture is allo~ed to contin~e reacting for a further
0.5-3 hours at from 0 to 60C. ~orking up to give toco-
pheryl acetate or tocopheryl propionate is then carried
out in a convent;onal manner by extracting the mixture,
for example ~ith water or aqueous methanol, and isolating
the tocopheryl salt from the remaining hydrocarbon phase.
The acylation is exothermic, so that external heating of
the reaction mixture is in general not necessary.
The carboxylic acid anhydride is advantageously
added at from 20 to 50C, ~hile cooling ~ith ~ater. The
acylation may also be carried out at a lo~er temperature,
eg. ûC, but in ~eneral this has no substantial advan-
tages, and the reaction nixSure must be cooled beforehand
to the ~o~er temperature.
For the acylation step also, it is, surprisingly,
not absolutely necessary that the ~ater formed in the con-
densation of trimethylhydroquinone ~ith phytol or isophytol
be removed from ~he reaction mixture either dur;ng or after
the condensation. It ;s only necessary to add to the
~ ~'7~
reaction mixture a further molar amount of carboxylic acid
anhydride equivaLent to the a~ount of ~ater present. For
dry reaetion mixtures, in general from 1 to 1.5, preferably
from 1.1 to 1.3, moles of carboxylic acid anhydride are
required per mole of initially used trimethylhydroquinone,
~hereas for reaction mixtures for ~hich the ~ater of con-
densation has not been remcved, from Z to 3, preferably
from 2.1 to 2.5, moles are accordingly required. It is
possible to use larger amounts of carboxylic acid anhy-
dride, but this is of no further economic advantage. Even~hen ~ater of condensat;on is present in the reaction
mixture, the acylation is virtually complete directly
after the final amount of anhydride has been added, ie.
the content of free tocopherol is less than 0.1X (measured
by high pressure column chromatography).
~ urthermore, essent;al features of the novel pro-
cess are that the tocopherol formed in the condensation
does not require to be isola~ed, and that the reaction
mixture ob~ained in the condensation can be subjected to
esterification, ~ithout further purification or process
steps. In spite of this, the tocopheryl salt obtained in
the novel process is, surprisingly, very pure. ~he car-
boxylic ac;d anhydride residues ~hich in prior processes
~ere usually present in the product and ~ere difficult tv
separate off are absent. Even from reaction mixtures in
heptane, ~here the condensation has been carried out
us;ng an excess of trimethylhydroquinone, a pure toco-
pheryl saLt is obtained since the trimethyLhydroquinone
is completely converted, for example in the reaction w;th
-- 6 --
~IL7.~8~2
acetic anhydride, to trimethylhydroquinone diacetate,
which can be readily extracted from the heptane solut;on
using aqueous ~ethanol. This is very important since
separation of tocopheryl acetate and trimethylhydroquinone
diacetate by distillation ~ould be extremel~ difficult
technically.
The process according to the invention gives very
good quality tocopheryl acetate in a simple manner and in
a yield of from 94 to 98X. ~he content of f ree tocopherol
is less than 0.1X~
EXAMPLE 1
a) A mixture which contained 33.4 9 ~0.2 mole) of
trimethylhydroquinone, 5 9 of zinc chloride, 0.5 9 of
stearylamine and 250 ml of heptane and ~as saturated with
hydrogen chloride gas ~as heated at the boil (98C~ while
the HCl saturation uas ~aintained, 62.8 9 (0.21 mole) of
isophytoL uere added in the course of one hour, and the
mixture ~as kept at this temperature for a further hour.
b) The very dark, tvo-phase reaction mixture thus
obtained ~as cooled to room temperature and 47 9
(û.46 mole) of acetic anhydride ~ere then added, the tem-
perature being kept at 40C by ~ooling. The reaction
mixture was cooled to room temperature and then extracted
~ith three times 200 ~l of a ~ixture of methano~ and ~ater
~1 1 V/V)r The remainin~ heptane phase ~as evaporated to
dryness, and 96~1 ~ of pale yellow d~l-a-tocopheryl a~etate
~ith 8 purity of 93.0X ~ere obtained (USP XX), corres-
pondin~ to a ~ieLd of 9~.5%, based on ~rimethylhydro-
quinon~. The con~ent of free tocopherol was less than
1~7;~ 2
0.1% by veight according to HPLC. Distillation of the
product gave 98Z pure tocophery~ acetate (USP X%).
EXAMPLE 2
~he procedure described in Example 1 ~as followed,
except that the ~ater of reaction formed was additionally
separated off in the first stage. Acetylation ~as
carried out by adding 27 9 tO.27 mole) of acetic anhydride
instead of 47 9 as stated in Example 1. The tocopheryl
acetate ~as obtained in a purity of 94X and in a yield of
98Z (USP-XX).
EXAMPLE 3
The procedure descr;bed ir, Example 1a) was
followed~ and the reaction mixture obta;ned was then
cooled to ûC instead of room temperature. 47 9
(0.46 mole) of acetic anhydride ~ere then added at 0C in
the course of 20 m;nutes, ~hile stirring, the mixture was
extracted ~ith three times 20û ml of a 1:1 m;xture of
~ethanol and ~ater, and the remaining heptane phase ~as
then evaporated to dryness. 96 9 of 94% pure tocopheryl
acetate ~ere obtained, corresponding to a yield of 95%.
The purity of the distilled product ~as 97X.
EXAMPLE 4
The procedure descr;bed in Example 1a) ~as
follo~ed, except Shat 38 ~ ~0.25 mole) of trimethylhydro-
quinone were employed ins~ead of 30.4 ~ S0.2 mole).
57.2 9 (0.56 moLe) of acetic anh~dride were edded at room
temperatur~ to the reaction mixture obtained, the tempera-
ture increasin~ to 55C, and the mixture ~as then
extracted three t;mes with 90% strength aqueous methanol
-- 8 --
3~
and once ~ith 75Z strength methanoL. 95.8 9 of 94.9% pure
tocopheryl acetate ~ere obtained, corresponding to a yield
of 96.2X, based on the 97X strength isophytol employed.
It ~as possible to distil the tocopheryl acetate without
difficuLty~ since the product obtained no longer conta;ns
any trimethylhydroquinone diacetat 2 . The purity of the
distilled product was 97.2X 5USP XX).
EXAMPLE 5
The procedure described in Example la) ~as
follo~ed. The dark t~o-phase reaction mixture obtained
in this condensation uas cooled to room temperature, after
~hich 59.9 9 (0.46 mole) of propionic anhydride ~ere
added, the temperature increasing to 50C. The reaction
mixture was allo~ed to cool to room temperature and then
extracted with three times 200 ml of a methanol/uater mix-
ture (1:1 v/v), and the remaining heptane phase ~as
evaporated to dryness. 101.Z g of paLe ~ello~ d,l-~-toco-
pheryl propionate u;th a purity of 90.5X ~gas chroma-
tosraphy) uere obtained, corresponding to a yield of 94.1%,
based on trimethylhydroquinone employed. The content of
free tocopherol ~as less than 0.1X by ~eight according to
HPLC. Distillation of the product gave 95.2% pure toco-
pheryl propionate.
g _
