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Patented Dec. 3, 1946
2,411,967 -
i
pairao STATES ‘PATENT OFHCE ~
DL-TOCOPHERQLS AND PROCESS FOR THE ‘
MANUFACTURE OF SADIE
'
Paul Karrer, Zurich, and Otto Isler, Basel, Swit
zen-land, assi'gnors to Hoffman-La Roche Inc.,
Nutley, N. J., a corporation of New Jersey
no Drawing. Application ‘September 26, 1938,
Serial No. 231,846. In Switzerland March 31,
'1938
>
23 Claims. (Cl. 260-333)
2
Evans ‘and collaborators (Mem. Univ. Califor
The new compounds are the racemates with re
nia, vol. 8, year 1927) discovered that a nutritive
factor" which is indispenable for spermatogenesis
spect to carbon atom 2 of the chromane ring of
tocopherols obtained from natural raw materials.
in male rats and the successful completion of an
existing pregnancy in female rats is contained in
They are light yellow, slightly viscous oils which,
in the cold, gradually reduce alcoholic silver ni
wheat germ oil and various foodstuffs. They
named the new biological factor vitamin E and
trate solution. On heating the reduction pro- .
ceeds quickly. These oils dissolve in concentrat
ed sulphuric acid with a yellow colour and the
described a biological‘ method of determination
solutions ?uoresce intensively after a few hours
using female rats. Evans, Emerson and Emerson
(J. Biol. Chem, vol. 113, year 1936, page 319, and 10 exposure to ultra ,violet light. The solution of
the compounds in chloroform yields a deep dark
vol. 122, year 1937, page 99) succeeded in isolat
brown colouration on the addition of tetranitro
ing three distinct chemical substances from
methane, which gradually clears up‘. On thermal
wheat germ oil and various _other.vegetab1e oils
decomposition the compounds form sublimates
which are responsible for the vitamin E action or
the starting materials. These closely related com 15 of durohydroquinone or trixnethylhydroquinone.
When rats so far kept on a vitamin E-free diet
pounds were named a-, B- and 'y-lIOCODhGI‘OlS.
were given these synthetic compounds it could be
Investigations by Fernholz (J. -Amer. Chem. Soc.,
established that they enabled a litter of healthy
vol. 59, year 1937, page 1154; vol. 60, year 1938,
young rats to be born exactly as did tocopherols
page 700), Karrer and collaborators (Helvetica
Chimica Acta, vol. 20, year 1937, page 1422; vol. 20 isolated from natural products.
The new compounds are to be used as pharma
21, year 1938, page 309), Bergel, Todd and col
ceutical preparations or as starting materials for
iaborators (Biochem. J., vol. 31, year 1937, page
the manufacture of pharmaceutical preparations,
2257; J. Chem. 800., year 1938, page 253), as well
as John and collaborators (Zeitschrift fiir physi
Erample 1
oiogische Chemie, vol 250, year 1937, page 11; vol. 25
252, year 1938, pages 201, 208) con?rm and sup
1.7 parts by weight of trimethylhydroquinone
plement the knowledge of the ?rst named inves
are covered with 10 parts by weight of dry ben
zine (boiling point 80-100° C). 1.0 part by weight
of anhydrous zinc chloride‘ and 4.8 parts by
cal formula CznHsoOa, by an allophanate melting 30 weight of phytyl bromide of the formula
at 158° C., by a p-nitr'ophenylurethane melting at
131° (3., and by a sublimate of durohydroquinone
tigators regarding tocopherols.
‘
I
cz-TOCODhGl‘Ol was characterized by the empiri
on ' thermal decomposition.
B-Tocopherol pos
sessesthe empirical formula C2aH4aO2, yields} an
allophanate melting at 143-144“ C. and a sub
limate of trimethylhydroquinone on thermal de
composition. ‘An allophanate melting at 135° C.
was produced from 'y-tocopherol which has the
empirical formula C2aH4aO2. -
35
prepared by the action of phosphorous trlbro
mide on phytol, are added and the reaction prod
uct heated to 80° C. in a current of nitrogen for
two hours. The product is then decomposed by
water, the benzine layer washed with dilute so
It has now been found that by the action of 40 dium hydroxide and water, dried, and, following
this, a chromatogram prepared on aluminium
oxide. The chromatogram consists of two lay
phytylhalides, suitably in presence of acid con
ers: an upper‘ layer which is grey, and a lower
densing agents, compounds can be obtained
which contain a heterocyclic ring and which 45 layer which is light yellowish. The upper main
layer is eluted by a mixture of methanol and
must be regarded as chromane derivatives of the
ether and puri?ed by the preparation of a sec
general formula
‘
trimethylhydroquinone or dimethylhydroquinone
on phytol, phytylhalides, of 3-halogeno-dihydro
R
HO
'
CE:
CH9
-—CHnCHnCHgCHCHsCHnCHgCHCKaCHgCHaCHCH;
R
0
En
H9
R
wherein R is methyl or hydrogen.
H5
H8
2,411,9a7 '
3
4
‘0nd chromatogram. The following condensation
brown solution whereby a little hydrogen‘ chloride
product is thereby obtained in a pure-state:
escapes and a small quantity oftrimethylhydro- ,' I
quinone sublimes. The product is now cooled,
precipitated with water, a lot of ether added, the
ether solution washed with water, a solution of
caustic soda, and water, dried and the solvent
evaporated. The extract is dissolved in petroleum
CH;
OH
/C\Iia
‘
CH:
6-0153“
on,
-
o
H,
ether and adsorbed on an aluminium-oxide col
’
umn.
H:
The new compound from trimethylhydroqui
none and phytyl bromide contains 80.9 percent
of carbon and 11.8 percent of hydrogen. The de
termination according to ,Zerewitinoff indicates
10
The chromatogram is developed‘ with
much petroleum ether.
The upper ‘ uniformlyv
grey zone contains the condensation product
which has-the same properties as the productob
tained in accordance with Examples 1 and 2.
Example 4
the presence of one active hydrogen atom, i. e., a
.phenolic hydroxyl group. The compound pos .15
4 parts by weight of phytol, 2.2 parts by weight
sesses a characteristic absorption spectrum with
of trimethylhydroquinone and 1 part by weight
a maximum absorption at 294/4]!- and a minimum
of anhydrous zinc chloride are suspended in 10
absorption at 256/.L/L. It forms various crystalline
parts by weight of decaline and then heated to
derivatives, such as a p-nitrophenyl-urethane 20 150—160° C. for one hour while stirring and pass
' melting at 131° C., an allophanate melting at
ing carbon dioxide. The trimethylhydroquinone
172° C., and a 3,5-dinitro benzoic ester melting at
dissolves completely, whereby the liquid becomes
63° C. On administering a dose of 5 mg to ‘a
'yellowish brown. The product is cooled, water
rat kepton a vitamin E-free diet the full action of
and ether added with stirring, the ether solution
the pure vitamin was' observed.
25 washed successively with water, a solution of
Example‘ 2
caustic soda, hydrochloric acid, and‘water, dried
_' 4 parts by weight of trimethylhydroquinone are
covered with 50 parts by weight of petroleum
ether (boiling point 80-105" C). 3 parts by weight
with, sodium sulphate and the ether evaporated.
‘The residue is adsorbed on an aluminium-oxide '
column. After development of the chromato
gram with a good deal of petroleum ether, the
of anhydrous zinc chloride and 10 parts by weight 30 column is uniformly grey. At the foot thereof
of 3-bromo-dihydrophytylbromide of the for
there ‘is a violet zone. The'grey main zone is
mula
v
-
eluted with a mixture‘ of methyl alcohol and ether
_
cinch.(Clinton.(c11,)=.0H.(oH5),.CBi-.cH.cHiBr
H,
.
H;
in
H.
'
(3:1), the solvent evaporated and the extract.
35 further puri?ed by the preparation of a second
prepared by the addition of hydrogen bromide
to phytyl bromide, are added and the reaction
chromatogram. The product is then-‘distilled in
a molecular distillation apparatus and the com
pound described in the. previous examples ob
product heated in a current of nitrogen for 4
tained. This compound was given in doses of
hours at a bath temperature of 140° C. The re
action product becomes brown with a vigorous 40 3 and 10 mg. each to four rats which had been
kept on a diet free from vitamin E. All the
evolution of hydrogen bromide. Finally, the
_ product is treated with water, much petroleum
ether added, the benzine layer thoroughly
washed with Claisen’s solution (a solution of 350
grams of potassium hydroxide in 250 grams of ' ‘
water and su?icient methyl alcohol to prepare one
liter, see "Annalen der Chemie” vol. 418 {1919],
page 96) and water, dried, adsorbed on alumin
ium oxide and-developed with petroleum ether. '
The chr'omatogram shows an upper zone which ‘
is grey, and a lower zone which is light yellow.
' The product is eluted with a mixture of methyl
alcohol and ether, the extract boiled in an at
mosphere of nitrogen with 4‘ percent methyl
animals became pregnant and brought forth
healthy young.
_ '
_
Example 5
11 parts by weight of phytol, 5 parts by weight
of trimethylhydroquinone and 60 parts by weight
of anhydrous formic acid are boiled together for
4-5 hours under re?ux. The product is then
diluted with water, extracted with ether, the
ether evaporated and the residue saponified with
an alcoholic solution of sodium ethylate or alco
holic potash. When the alcohol- has been dis
tilled o?, the crude dl-a-tocopherol is extracted
, from the alkaline mixture with ether.
The ether
alcoholic potash in order to remove adhering
bromine. For the preparation of the pure com
solution is washed and dried“ The solvent is
then evaporated and the residue fractionated in
pound, another chromatrogram is prepared from
high vacuum at a pressure of 10-3-10“ mm. A
small preliminary fraction evaporating at
80-90° C. is separated; the principal quantity of
(it) the compound evaporates at 110-120° C. It is
ether.
.
identical with the compound obtained in accord
The new compound is a yellowish oil. It yields
‘ ance with Examples 1-4.
a white, crystalline p-nitrophenylurethane melt
ing at 131° C. (found N 4.69 percent, calculated
Example 6
. the product obtained by the extraction of the
alkaline-aqueous methyl-alcoholic solution with
-
4.71 percent) , If mixed with the p-nitrophenyl
urethane of a-tocopherol melting at 131° C., the
mixture melts without depression. A sublimate
of durohydroquinone isgformed on thermal de
composition.
.
-
'
Example 3
v 4 parts by weight of phytol, 2.5 parts by weight
of trimethylhydroquinone and 1 part by weight '
of anhydrous zinc chloride are heated to 180° C.
in a current of .nitrogen for half whom. The
suspended matter gradually gives a homogeneous
1 part by weight of 2,5-dimethylhydroquinone
is heated on a boiling water-bath for three hours
with 3 parts by weight of phytyl bromide, 1 part
by weight of anhydrous zinc chloride and 10
parts by weight of benzine boiling at 80-100“ C.
The reaction ‘mixture ‘is then decomposed by
the addition of water, the benzine layer removed,
'washed, ?rst with potash solution, then with
water, and the solvent evaporated. The remain
ing residue is dissolved in a little low-boiling
petroleum ether, ?ltered from a small quantity
f 2,411,907
for one hour-'while‘heating and introducing car
,
.
.
.
Example
1.1v
bon dioxide. The m-xy'lohydroquinone dissolves
1.5 ‘parts by weight or trimethylhydroquinone
completely. The ?uid'becomes yellowish-brown. _. (‘and 3.0 parts by weight of .isophytol of the ior- -
The product ‘is cooled, water and ether added
while stirring, the ether solution washed with
water, potash, hydrochloric acid and water, dried
mula
,
.
_
omomonmon(onmomomnown).on=om
with sodium sulphate and the ether evaporated.
H;
.
B1
1.1;
HI ‘
- are heated with 10 parts by weight oi’ anhydrous
column. Alter developing the chromatogram
formic acid ior 6. hours. The mixture is diluted
with much petroleum ether, the column appears. 10 _ with water, extracted with'ether, the ether layer
The residue is adsorbed on an aluminium oxide
almost uniformly yellowish-grey. At the bottom
washed with sodium hydroxide, then with water
there is a small yellow zone. The yellowish-grey
'
and the solvent evaporated.
The condensation
principal layer is eluted, the solvent evaporated‘
product remains as a viscous oil which readily re
and the residue puri?ed by ‘the preparation of a .
duces methyl-alcoholic silver nitrate solution. Its
'
second chromatogram. ‘The product is then dis- .15 absorption spectrum hasa maximum at 294m;
The compound forms a crystalline allophanate
tilled in a'molecular distillation apparatus and
of melting point‘172-173° C. It is identical with
the compound described in Example 9 is ob- _
dl-a-tOCOPhBIOl.
‘
1
tained.
Example 11v
We
20
2.5 parts by weight or 3,5-dimethylhydroqui
none, 4 parts by weight of 3-bromo-dihydro
claim:
_
r
of the formula
phytylbromide and 1.5 parts by weight of anhy
,
-
1. A synthetic tocopherol, which is racemic at
the C‘ atom in position 2 or the chromane ring.
'
drous zinc chloride are disolved in 20v parts by
weight of petroleum ether (boiling point 80-105"
C.) and then heated to 100° C. for two hours while
stirring. The solution evolves a considerable
quantity of hydrogen bromide and becomes brown.
Finally, water and ether are added, the ether
solution is then washed with potash and water, 30 wherein two of the R radicals represent a methyl
dried, and the solvent evaporated. The residue is
group and the third R radical represents a radi
dissolved in petroleum ether and adsorbed on
calselected from the group consisting of hydrogen
- an aluminium oxide column. After development
and methyl radicals.
of the chromatogram with petroleum ether it
'
'
2. A synthetic tocopherol, which is racemic at
shows a nearly colourless principal zone‘ and a 35 the O atom in position 2 of the chromane ring,v or
‘yellow ring at the bottom. The principal zone is
the formula
eluted with a mixture of methyl alcohol and ether,
with methyl alcoholic potash for the removal of
adhering bromine. The alkaline aqueous methyl
.
40
alcoholic solution is extracted with ether and an
.
cm
/ —(CH:):CH(CH|):CH(CH:);CHCH2
0 (EH;
H:
H]
H3
2 parts by weight of 2,3-dimethylhydroquinone,
CH;
by weight. of zinc chloride and 20 parts by weight
50
H0
of benzene are boiled for‘ 4 hours under re?ux.
'
HI
tains the expected condensation product of the
CH;
_ 6o
CH:
H;
I
65
'
-(crn)i0H(oH,).cH(crnhcncnl'
H7‘ 0
H3
/
H;
I
HI
.
HI
I
5., A synthetic, optically inactive tocopherol, o1 - >
_Hi
It is a viscous oil which has a strong reducing
the formula
action. Its analysis corresponds with the for
mula Casi-14802. The compound possesses an ac 70
tive hydrogen atom (calculated 0.24 per cent,
found 0.24 per cent active hydrogen). When
tested on rats-which had been kept on a vitamin
'
76
.
'
R
CH:
Ho
R
CE:
I
I
.
o-(olimicmcm).cmcnmcncm
0
E-free diet, the compound proved fully active in
a dose of 20 mg.
\CHs -
- c'
—CIIHIS
_-o
CHr
Ho
OH:
c’
’
4. A synthetic tocopherol, theyallophanate of
which melts at about 172° C. and which is racemic
at the C atom in position 2 of the chromane ring,
of the formula
low ring, and, at the foot thereof, a nearly colour- _
less zone. The 'eluate of the brownish layer con
.
'
“(CHI):CH(CH:):CH(CH:)ICHCH;
Ha
Ha
Ha
HI
O
upper part of the absorption column, then a yel
OH
CH1
/
The preparation of a chromatogram of the
product gives a narrow brownish layer in the ‘>55
'
'
H
The working up of the reaction product is carried
.
Y
CHI
' 6.5 parts by weight of phythyl bromide, 1.5 parts
.'
i
3. A synthetic tocopherol, which is racemic at
the C atom in position 2 of the chromane ring. 01.’
the formula
Example 12
following formula:
em
H:
45
product described in Example 8_.
out as described in Example '7.‘
.
'
H0
(33'
other chromatogram prepared from the extrac
tion-residue. in order to obtain the pure com
pound which is of the same structure as the ?rst
"
CHI
the extract boiled in an atmosphere of nitrogen ._
m
'
m
m
-
a.
.
2,411,987
6
of solid matter and the solution poured through
.
Example, 8_ -
a column of aluminium oxide for the preparation
of a chromatogram.- The reaction product is
rather ?rmly held by the adsorbent. The ad
sorption column is then'divided into three parts
and the separate parts .eluted‘by a mixture of
methanol and ether. The extract from the top
1.5 g. of 3,5-dimethylhydroquinone, 5 ‘g. of
phytyl bromide, 1.2 g. -of zinc chloride and 30
cc. of ligroin are boiled for 2 hours under re
(?ux. The treatment of the reaction product is.
effected as described in Example '7. The prepa
ration of a chromatogramon aluminium oxide
gave at the top of the column a narrow, dark
compound contained therein is of the following
brown zone which is neglected, while the re
formula
'
10
mainder of the column was of a light brownish
zone possesses vitamin E activity.
The active
colour. From the upper half of this part of the
CH:
CH|
CH:
Yo/Eih
column an oil could be elutedv which reducesa
neutral solution of silver nitrate already on
standing at room temperature; the reduction
15 proceeds more quickly on heating. The analysis
gave ?gures which show that the compound is
of the following composition:
CH:
' From the second and third layers viscous oils are
obtained after evaporation of the solvent which 20
do not possess vitamin E activity.
‘ Example 7
CH:
OH
I
CH: _
CH
1.5 parts by weight of 2,5-dimethylhydro
O
—CuHu
E]
' quinone, 5.5 parts by weight of phytyl bromide, 25
1.2 parts by weight of zinc chloride'and 35 parts
This compound possesses vitamin E activity.
The oil obtained from the lowest part of the
by volume of ligroin are boiled for 2 hours under
a re?ux condenser. The reaction mixture is
tube also reduces a solution of silver nitrate and
then decomposed with water, the ligroin layer
an allophanate can be prepared therefrom which,
removed, washed with potash solution, then 30 when analysed, gave ?gures which agree with
with water, and the solvent evaporated. The
the formula C5oHaaO4N2.
residue is dissolved in a small quantity of low
Consequently, the oil probably has the follow
boiling petroluem ether and a chromatogram
ing constitution:
prepared on an aluminium oxide column. By
eluting the yellowish-brown top zone with a 35
mixture of ether and methanol,'an oil is obtained
which reduces a neutral methyl alcoholic solu
tion of silver nitrate on boiling, and contains 0.2
per' cent of active hydrogen according to the
Zerewitino?’ determination. These properties 40
indicate that the oil isolated from the yellow
CH
Yo/om
'
ish-brown upper zone is a compound of the fol
lowing formula:
2011"
Example 9
4 parts by weight of phytol, 2.5 parts by weight
of 3,5-dimethylhydroquinone and 1 part by
CH:
CE]
OH
weight of anhydrous zinc chloride are heated to
180° C. for 1/2 hour while stirring and introduc
ing carbon dioxide. The suspended matter grad
0- Ha.
ually fuses giving a homogeneous brown melt.
Hz
After cooling, the product is ‘treated with ether
and water, the ether solutionwashed with potash
This compound possesses vitamin E activity and
and water, and the ether residue adsorbed on an
is the same compound as is obtained in Ex
aluminium oxide‘ column. The .chromatogram is
ample. 6.
'
From the lower part of the aluminium oxide 55 developed with much petroleum ether. The
whole of the lower part of the column is whitish
column an oil can be eluted by means of a mix
grey. The top layer of aluminium oxide, which
ture of ether and methanol the analysis of which
is hardly coloured, is removed and the whitish
reveals that it has the formula C4sHaoO2. The
grey principal zone eluted with a mixture of
compound contains no active hydrogen (Zere
witino? determination), and it does not reduce 60 methyl alcohol and ether (3:1). The solvent is
on boiling. An allophanate cannot be prepared
evaporated in vacuo and the residue distilled in
a molecular distillation apparatus. The com
therefrom.
pound is a yellow, slightly viscous oil, nD25=-1.501,
a methyl alcoholic solution of silver nitrate even
This indicates that the compound
and is identical with the ?rst product described
does not contain a free hydroxyl group and that
65 in Example 8. A sublimate of trimethylhydro
it probably has the following constitution: ‘
on,
0
\' / \
CH3
l
quinone results on thermal decomposition.
cyanic acid in benzene solution. A 10 mg. dose
of this compound was biologically fully active.
CE’
clan-Ces: W C-CxaR-n
(13H:
/|
CH;
An .
allophanate melting at 143° C. is’ obtained with
O CH:
Its absorption spectrum shows a maximum at
296 pa and a minimum at 260 1141..
70
Example 10
4 parts by weight of phytol, 2.5 parts by weight
of 3,5-dimethylhydroquinone and 1 part by
weight of zinc chloride are suspended in 10 parts
75 by weight of decaline and then heated to 150° C.
2,411,967
~
9
10
,
wherein two of the R radicals represent a methyl
' erol product from the reaction mixture thus oh
tained.
group and the third R radical represents, a radi
cal selected from the group consisting of hydro
10. In a process for the manufacture of a to
copherol product, the steps of producing ‘a to
6. A synthetic, optically inactive tocopherol, of 5. copherol of the formula
the formula
R
gen and methyl radicals.
'
CH3
-
CH3
.
H0.
CH1
CH:
H0
CH
/
0
l0
'
R
-—(CH:)3CH(CH:)3CH(CHghCHCHt
o
_
Ha
Ha
Ha
Ha
,
H:
R
wherein two of the R radicals represent a methyl
.
7. A synthetic, optically inactive tocopherol, of 15 group and the third R radical a radical selected
the formula
‘
I
from the group consisting of hydrogen and meth~=
'
yl radicals, by condensing a methyl substituted . .
CH:
hydroquinone of the formula
CH:
H0
12
20
HO
H
R
OE
8. A synthetic tocopherol, which is racemic at
the C atom in position 2 of the chromane ring, 25
wherein two of the R radicals represent a methyl
of the formula
group and the third R radical represents a radical
CH3
selected from the group consisting of hydrogen
and methyl radicals, with an aliphatic di-terpene
HO
30 derivative of the formula
'
CH3
OZJIH:
_H3
Ha
Ha
H:
9. In a process for the manufacture of a to- 35
copherol product, the steps of producing a to‘
H:
cals:
'
—C=CH~CHIOH
copherol of the formula
H8
—CHal—CHa—-CH2Hal
a.
H!
40
O
‘
'
—o=cn-crnna1
E
w
.m
H:
wherein R’ represents one of the following radii»,
-
on
~<.'l—-CH=CE5
H0
0-
H:
wherein two of the R radicals represent a methyl
in the presence of zinc chloride, and recovering
a tocopherol product from the reaction mixture
45 thus obtained.
11. In a process for the manufacture of a
group and the third R radical a radical selected
tocopherol product, the steps of producing an
from the group consisting of hydrogen and meth
a-tOCOPhEl‘Ol of the formula
~yl radicals, by condensing a methyl substituted
cm
hydroquinone of the formula
50
B0
’
C5:CH9
I
CH
_
—'-(CH1);CH(CHMCIHCHahCHCHn
_
0
Ha
H3
H3
H; I
H:
which comprises condensing. trimethylhydroqui=
none with analiphatlc di-terpene derivative of
wherein two of the R radicals represent a methyl
the formula
'
group and the third R radical represents a radi
cal selected from the group consisting of hydro 60
gen and ‘methyl radicals, with an aliphatic di
terpene derivative of the formula
wherein R’ represents one of the following radi
CHr-—CH—(CH2)a—CH—(CH2)s—-CH—(CHz);-—R'
cals:
H:
H:
CH1;
wherein R’ represents one of the following radi
cals:
—,o=cH—cH,on' _
CH;
—C=CH—CHzHal
Ha‘
—CHal—CHz—CHzHal
(‘3H5
70
OH
-—(|J—CH=CH2
Ha
under acid conditions, and recovering a tocoph
under acid conditions, and recovering a tocoph
erol product from the reaction mixture thus ob-»
tained.
'
12. In a process for the manufacture of a tow
2,41 1,967
'
1l
12
.
‘ which-comprises condensing trimethylhydroqui
copherol product, the steps of producing an a-tO
none with phytyi bromide of the formula _
copherol of ‘the formula _
CHz-OH-(CH?a-CH-(OHz):—-CH-—(CH:):—C=CH-CHzBr
CHi
' H0
CH1
‘ CH!
l
C
H:
Ha
Ha
H:
thus obtained.
H:
H:
which comprises condensing trimethylhydroqui
10 copheroi product, the'steps of. producing tocoph
erol of the formula
none with an aliphatic di-terpene derivative of
the formula
'
.
7
16. In a process for the manufacture of a to
H:
v
Ha
a tocopherol product from the reaction mixture
JJ-(CHz)|CH(CH|)|CH(CHa)aCHCH'
0
H:
in the presence of zinc chloride, and recovering
_ '
CH:
'
oHi-c'H-(cm)rcn-(cnnr-cn-(oncr-n'
Ha
Ha
H:
15
,
wherein R’ represents one of the following rad
v
icals:
.
-
,
'
0
H:
~
20.
which comprises condensing 3,5-dimethylhydro
quinone with an- aliphatic di-teprpene derivative
of the formula
CHPCHF-(CHQ):—-CHf—(CHi)i—-CH—(CH:)a-'R'
Ha
HI
Ha
wherein R’ represents one of- the following radi
in the presence of zinc chloride, and recovering 25
a tocopherol product from the reaction mixture
thus obtained.
cals:
'
'
13. In a process for the manufacture of a to
copherol product, the steps of producing an a-tO
copheroi of the formula:
-
30
.
CH1
under acid conditions; and recovering a tocoph
CH1
H0
'
_ CH
erol product from the reaction mixture thus ob
CH2
35 tained.
,17. In a process for the manufacture of a to
éI-(CHQMCHUJHQMCH(CHghCHCH:
0 I
Ha
Ha
.Ha
copherol'product, the steps of producing a'tocoph
Ht
H:
erol of the formula
'
.
which comprises condensing trimethylhydroqui
none with phytyi halide of the formula
-
40
01.1:
'\CH:
.110
wherein Hal represents a halogen radical, under
acid conditions, and recovering a tocopherol prod
uct from the‘reaction mixture thus obtained.
0
which comprises condensing 3,5-dimethylhydro
quinone with a phytyi halide under acid condi~
14. In a process for the manufacture of a to
copherol product, the steps of producing an a-to
copherol of the formula
CH;
.
.
tions, and recovering a tocopherol product from
> the reaction mixture thus obtained.
18. In va. process for the manufacture of a to
50 copherol product,- the steps of producing a to
copherol of the formula
Cg:
, H0
‘
CH,
CH
o
’
CH:
Acumen(cmhomonmcncm
H,
H.
H.
.n
CH:
no
HI
CHz—-CH—-(CHz)x-CH—(CHz)r-CH—-(CH:)x—C=CHfCH:Br
H;
H,
H:
H:
,
CH,
CH
I which comprises condensing trimethylhydroquip
none with phytyi bromide of the formula.
~
u
é—(CH2)xCH(CH:)aC-H(CH1)aCHCHi
.
04:11,
_
H;
>
' Ha
H:
which comprises condensing 3,5-_dimethyl hydro
quinone with phytyl bromide of the formula
‘
60
‘
4- under acid conditions, and recovering a tocoph
eroi product from the reaction mixture thus ob
tained.
15‘. In a process for the manufacture of a to
under acid conditions, and recovering a tocoph
erol product from‘ the reaction mixture thus ob
65
copherol product, the steps of producingan a-tO
tained.
'
>
-
19; In a process for the manufacture’ of a to
copherol product, the steps of producing a to
copheroi of the formula
copherol of the formula
CH3
70
on,
. HO
\CH:
CH
75
-
on.
c-(cnmon(ormrcmonmcncna
,0,
H.
IH;
'
Hz
CHE
2,41 1,967
14
which comprises condensing 2,5-dimethy1 hydro
which comprises condensing 3,5-dimethylhydro
quinone with phytyl bromide of ‘the-formula
vquinone with a phytyl halide under acid‘ condi
tions, and recovering a tocopherol product from
the reaction mixture thus obtained.
22. In a process for the manufacture of a to
copherol product, the steps of producing a to
copherol of the formula
in the presence of zinc chloride, and recovering
a tocopherolproduct from the reaction mixture
thus obtained.
CH:
20. In a process for the manufacture of a to
copherol product, the steps of producing a‘ to 10
copherol of the formula
Ho W011,
\CH:
H
CH:
c-rcnoicmcm)lcmcnmoncm
OH:
HO
0
CH:
H
’
15
'
Ha
Ha,
Ha
which comprises condensing 2,5-dimethylhydro
c-(onznomcm)somcmhcném
H3
H;
CH3
quinone with phytyl bromide of the formula
O CH:
CH3
H3
Ha
'
which comprises condensing 2,5-dimethylhydro
quinone with an aliphatic di-terpene derivative
of the formula
.
under acid conditions, and recovering a, tocoph
erol product from the reaction mixture thus of
tained.
CHz-CH-(CHz)a——GH—tCHz):r—CH¥(CH2)s—~R’
Ha
,
H3
7
CH:
23. In a process for the manufacture of a. to
wlierein R’ represents one of the following radi—
ca s:
'
Ha
—C=CH—CHzHal
Hz
copherol product, the steps of producinge~ t0
-
copherol of the formula
Ha
OH
.
30
~é-C H==CH2
CH;
H0
7
‘
on,
'- H
Ha
0
under acid conditions, and recovering ‘a tocoph
eroi product from the reaction mixture thus ob 35
tained.
‘
OH:
v
—(CH2)|CH(CH2)aQH(CH2)aCHCHi
Ha
Ha
Ha
H8
Ha
' which comprises condensing 2,5-dirnethylhydro
'
quinone with phytyl bromide of the formula
21. In a process for the manufacture of a to- ‘
copherol product, the steps of producing a to
copherol of the formula
40
. in the presence of zinc chloride, and recoveringa
tocopherol product from the reaction mixture' thus
obtained.
‘
PAUL KARRER.
H:
OTTO ISLER.
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