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Патент USA US2411968

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Patented Dec. 3, 1946
' 2,411,968
UNITED STATES PATENT oFl-"lcs
,
2,411,988
PROCESS FOR THE PREPARATION OF
SYNTHETIC DL-TOCOPHEROLS
‘Paul Karrer, Zurich, and 0m Isler, Basel, Swit
lerland, assignors to Ho?mann-La Roche Inc.,
Nutley, N. 1., a corporation of New Jersey
No Drawing. Application August 12, 1941, Serial
No. 406,554. In Switzerland March 31. 1938
10 Claims. (Cl. 260-333)
2
'It has now been found that by‘reacting tri
methylhydroquinone or dimethyihydroqulnone
with phytol under acid conditions, and Dreierably
in the presence of acid condensing agents, com
The present invention relates to a process for
the preparation oi synthetic tocopherols which
are racemic with respect to carbon atom 2 oi the
chromane ring.
This application is a continuation-in-part of 5 pounds can be obtained which contain a hetero
cyclic ring and which must be regarded as chro
' our application Serial No. 231,846, ?led Septem
mane derivatives of the general formula
ber 26, 193a.
CH.
CH:
—CHQCHICHQCHCH|CHgCH|CHCHsCH|CH|CHCHI
‘HO
0
vol. 59, year 1937, page 1154; vol. 60, year 1938,
page 700), Karrer and collaborators (Helvetica
Chimica Acta, vol. 20, year 1937; page 1422; vol.
21I year 1938. page 309), Bergel, Todd and collab
orators (Biochem. J., vol. 31, year 1937, page 2257;
Ha
Ha
tor example, be carried out in the presence of an
in male rats and the successful completion of an
existing pregnancy in iemale rats is contained in
wheat germ oil and various ioodstu?s. They
named the new biological i'actor vitamin E and
described a biological method oi'determination
using female rats. Evans, Emerson and Emer
son (J. Biol. Chem., vol. 113, year 1936, page 319,
and vol. 122, year 1937, page 99), succeeded in
isolating three distinct chemical substances from
wheat germ oil and various other vegetable oils
which are responsible for the vitamin E action oi’ 30
compounds were named ¢-, p- and ‘iv-tocopherols.
> Investigations by Fernholz (J. Amer. Chem. Soc.,
Ha
wherein two of the R radicals are methyl and the
other is methyl or hydrogen. The reaction may,
Evans and collaborators (Mem. Univ. Califor
nia, vol. 8, year 1927) discovered that a nutritive
factor which is indispensable for spermatogenesis
the starting materials. These closely related
Ha
hydrous zinc chloride, formic acid or while pass
ing gaseous hydrogen chloride through the reac
tion mixture. It has also been found particu
larly suitable to employ a combination of zinc
chloride and hydrogen chloride.
The new compounds are the racemates, with
respect to carbon atom 2 oi the chromane ring, of
tocopherols obtained from natural raw materials.
They are light yellow, slightly visco‘us oils which,
in the cold, gradually reduce alcoholic silver ni
trate solution. On heating the reduction pro
ceeds quickly. These oils dissolve in concen
trated sulphuric acid with a yellow color and
the solutions ?uoresce intensively alter a iew
hours’ exposure to ultra violet light. The solu
tion or the compounds in chloroform yields a deep
dark brown coloration on the addition of tetra
nitromethane, which gradually clears up. On
thermal decomposition the compounds form sub
iimates oi durohydroquinone or trimethylhydro
J. Chem. Soc., year 1938, page 253), as well as
John and collaborators (Zeitschriit i‘iir physiolo 40 quinone. When rats so far kept on a vitamin
E-iree diet were given these synthetic com
gische Chemie, vol. 250, year 1937. Page 11; vol.
pounds, it could be established that they ren
252, year 1938, Pages 201, 208) con?rm and sup
dered it possible for a litter 01' healthy young
plement the knowledge of the ?rst-named inves
rats to be born exactly as did tocopherols isolated
tigators regarding tocopherols.
Natural a-tocopherol was characterized by the 45 from natural products.
The new compounds are to be used as pharma
empirical formula CzsHsoOs, by an allophanate
ceutical preparations or as starting materials for
melting at 158° C., by a p-nitrophenylurethane
the manuiacture 0t pharmaceutical preparations.
melting at 131° C., and by a sublimate oi dum
hydrouuinone on thermal decomposition. p-To
Example 1
copherol possesses the empirical formula 50 "4 parts by weight of phytol, 2.5 parts by weight
Cal-14:02, yields an allophanate melting at 143
of trimethylhydroquinone and 1 part by weight
144" C. and a aublimate oi trimethylhydroquinone
on thermal decomposition. An allophanate
melting at 135° C. was produced from 'Y-toco
pherol which has the empirical formula CaHuOz.
. of anhydrous zinc chloride are heated to 180° C.
in a current of nitrogen for half an hour. The
suspended matter gradually gives a homogeneous
brown solution whereby a little hydrogen chloride
2,411,968
When the alcohol has been
distilled off, the crude dl-a-tocopherol is ex
tracted from the alkaline mixture with ether.
The ether solution is washed and dried. The
solvent is then evaporated and the residue trac
‘alcoholic potash.
escapes and a small quantity of trlmethylhydro
quinone sublimes. The product is now cooled,
precipitated with water, a lot oi ether added, the
ether solution washed with water, a solution of
caustic soda, and water, dried and the solvent
tionated in high vacuum at a pressure 0! 10-3
10-4 mm. A small preliminary fraction evapo
evaporated. The extract is dissolved in petro
leurn ether and adsorbed on an aluminium-oxide
rating at Bil-90° C. is separated; the principal
column. The chromatogram is developed with
quantity of the compound evaporates at 110-120’
much petroleum ether. The upper uniformly
C. It is identical with the compound obtained in
10
grey zone contains the condensation product.
accordance with Examples 1 and 2.
This is eluted by a mixture of methanol and ether
Example 4
and puri?ed by the preparation or a second chro
matogram. The following condensation product
4 parts by weight oi’ phytol, 2.5 parts by weight
is thereby obtained in a pure state:
15 of 3,5-dimethylhydroquinone and 1 part by
weight of anhydrous zinc chloride are heated to
180° C. for one-half an-hour while stirring and
CH:
CH!
03
~
on.
on
0
‘-C10Hu
H:
H:
introducing carbon dioxide. The suspended mat
ter gradually fuses giving a homogeneous brown
melt.
After cooling, the product is treated with
20
ether and water, the ether solution washed with
potash and water, and the ether residue adsorbed
The new compound from trimethylhydroqui
none and phytol contains 80.9 per cent of carbon
and 11.8 per cent oi hydrogen. The determina
tion according to Zerewitinofi indicates the pres
on an aluminium oxide column.
ence of one active hydrogen atom, i. e., a phenolic
hydroxyl group. The compound possesses a
characteristic absorption spectrum with a maxi
mum absorption at 294 pp. and a minimum ab
sorption at 256 all. It forms various crystalline
derivatives, such as a p-nitrophenyl-urethane
melting at 131° C., an allophanate melting at 172°
C., and a 3,5-dinitro benzoic ester melting at 63°
The chromato
gram is developed with much petroleum ether.
The whole of the lower part of the column is
whitish-grey. The top layer of aluminium oxide,
which is hardly colored, is removed and the whit
30
ish-grey principal zone eluted with a mixture of
methyl alcohol and ether (3:1). The solvent is
evaporated in vacuo and the residue distilled in a
molecular distillation apparatus. The compound
is a yellow, slightly viscous oil, nn'5=1.501. A
sublimate oi trimethylhydroquinone results on
thermal decomposition. An allophanate melting
C. On administering a dose of 3 mg. to a rat kept
on a vitamin E-iree diet, the full action of the
at 143° C, is obtained with cyanic acid in benzene
solution. A 5 mg. dose of this compound was bio
pure vitamin was observed.
logically fully active.
Example 2
4 parts by weight of phytol, 2.2 parts by weight
of trimethylhydroquinone and 1 part by weight
Example 5
4 parts by weight of phytol, 2.5 parts by weight
of 3,5-dimethylhydroqulnone and 1 part by
40
weight of zinc chloride are suspended in 10 parts
by weight of decaline and then heated to 150° C.
for one hour while heating and introducing car
of anhydrous zinc chloride are suspended in 10
parts by weight of decaline and then heated to
150-160“ C. for one hour while stirring and in
bon dioxide. The m-xylohydroquinone dissolves
completely. The ?uid becomes yellowish-brown.
troducing carbon dioxide. The trimethylhydro
quinone dissolves completely, whereby the liquid
becomes yellowish brown. The product is cooled,
water and ether added with stirring, the ether
solution washed successively with water, a solu
tion or caustic soda, hydrochloric acid, and water,
dried with sodium sulphate and the ether evapo
rated. The residue is adsorbed on an aluminium
oxide column. After development of the chro
matogram with a good deal of petroleum ether,
the column is uniformly grey. At the foot there
of there is a violet zone. The grey main zone is
eluted with a mixture of methyl alcohol and
ether (8:1), the solvent evaporated and the ex
tract iurther puri?ed by the preparation of a
second chrcmatogram. The product is then dis
tilled in a molecular distillation apparatus and
the compound described in the previous example
50
kept on a diet free from vitamin E. All the ani
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
four to ?ve hours under re?ux. The product is
then diluted with water, extracted with ether.
the ether evaporated and the residue saponi?ed
with an alcoholic solution of sodium ethylate or
The residue is adsorbed on an aluminium oxide
column. After developing the chromatogram
with much petroleum ether, the column appears
almost uniformly yellowish-grey. At the bottom
there is a small yellow zone. The yellowish-grey
principal layer is eluted, the solvent evaporated
and the residue puri?ed by the preparation or a
second chromatogram. The product is then dis
iii]
obtained. This compound was given in doses 0!
3 and 10 mg. each to four rats which had been
mals carried the pregnancy to term and brought
forth healthy young.
Example 3
The product is cooled, water and ether added
while stirring, the ether solution washed with
water, potash, hydrochloric acid and water, dried
with sodium sulphate and the ether evaporated.
65
tilled in a molecular distillation apparatus and
the compound described in Example 4 is obtained.
Example 6
4 parts by weight of phytol, 2 parts by weight
of 2,5-dimethyl hydroquinone and 1 part by
weight of zinc chloride are heated to 180° C. for
one-half hour while stirring and introducing car
bon dioxide. When the material has become ho
mogeneous, it is cooled, treated with ether and
water and the ether solution washed with potash,
then with water, the ether layer separated, dried,
and the ether removed by distillation. The resi
due is taken up in small volume of low boiling
petroleum ether and chromatogramed on an alu
minium oxide column. By eluting the yellowish
top zone with a mixture of ether and methanol,
8,41 1,908
5
.
wherein two of the R radicals represent a. methyl
an oil is obtained which reduces a neutral solu
tion of an alcoholic solution of-silver nitrate on
group and the third R radical a radical selected .
‘from the group consisting of hydrogen and
methyl radicals, by condensing a methyl substi
tuted hydroquinone of the formula
boiling. The material corresponds to the struc
ture:
CH:
CH1
‘
..
A
.
'
n
OH
Its aliophanate melts at 154° C.
wherein two of the R radicals represent a methyl
Example 7
group and the third R radical represents a radi
11 parts by weight of phytol. 5 parts by weight 16 cal selected from the group consisting of hydro
of 2,3-dimethyl hydroq'uinone; 60 parts by weight
gen and methyl radicals, with phytol under acid
of anhydrous formic acid are re?uxed together
conditions, and recovering a tocopherol product
for four to five hours. The product is then di
from the reaction mixture thus obtained.
luted in water, extracted with ether, the ether
2. In a, process for the manufacture of a to
evaporated, the residue saponi?ed with an alco 20 copherol product, the steps of producing a to
holic solution 01' sodium methylate or alcoholic
copherol of the formula
potash. when the alcohol has been distilled off,
the residual product is extracted with ether and
the ether solution washed and dried. The ether
is removed and the residue is taken up in a small
quantity of low boiling petroleum ether and chro
matogramed on an aluminium oxide column.
This gives a yellow-brownish layer in the upper
part of the absorption column which on elution
contains the expected condensation product con 30 wherein two of the radicals R represent a
group and the [third 8 radical represents
sisting of a viscous oil with strong reducing ac
cal selected from the group consisting of
tion. The analysis corresponds to the formula
gen and methyl radicals, by condensing a
CacHaOr. It possesses an active hydrogen atom
substituted hydroquinone of the formula
and corresponds to the structure:
on
35
CH:
CH:
‘
B
HO
47-01011”
c
o
methyl
a radi
hydro
methyl
OH
H:
40
H:
The allophanate thereof melts at 146° C. when
tested on rats which had been kept on a vitamin
E-i'ree diet, the compound was fully active in a
wherein two of the‘ R radicals represent a methyl
group and the third R radical represents a radical
selected from the group consisting 0! hydrogen
and methyl radicals, with phytoi in the presence
of zinc chloride, and recovering a tocopherol
product from the reaction mixture thus obtained.
dose oi’ 10 mg.
Example 8
2 parts by weight oi’ zinc chloride, 10 parts by
weight of phytol, and 5 parts by weight of tri
3. In a process for the manufacture of “a to
methyl hydroquinone are dissolved in a mixture
copheroi product, the steps of producing a to
of 20 parts by volume of ether and 20 parts by 50 copherol of the formula
volume of benzol, maintaining a temperature of
- 45-55? C.v Dry hydrochloric gas is passed through
1‘.
the mixture until complete saturation which re
Cal
quires from two to four hours. ‘ The reaction liq
7 Ho
uid is then washed with water, then with hydro 55
chloric acid, again with water, then with sodium
chloride solution and finally the ether-benzol so
lution is dried and the solvents removed, The
material is then worked up as in- previous exam
ples.
_
while we have‘ described herein some embodi
ments pf our‘ invention, we wish it to be known
that we do not intend to limit ourselves thereby;
except “within the scopeiof the "appended claims.
7
1. In a process for: the manufacture of a to
I
—(CH1)1CH(OHI)ICH(6HI)ICHCHJ
o
n.
on,
H.
H:
wherein two of then radicals represent a methyl
group and the third R radical represents a radi
cal selected from the group consisting of hydro
gen and methyl radicals, by condensing a methyl
substituted hydroquinone of the formula
'
We claim:
R
OH:
65
8.
copherol produyt,;tha steps .lof producing a to
coplierol of the formula
'
OH
0B:
7,0
CHE:
_
-wlmicmdnoucmcnmcncnl
' o/om
em
all
n,
wherein two of the it radicals represent a methyl
group and the third R. radical representsa radi
cal selected from the group consisting ‘of hydro
gen andmethylradicais. with phytol intheprea
_
ence of nine chloride. a solvent. while passins
.
gaseous hydrosen chloride through the mixture,
and recoverins a tocopherol product from the re
action mixture thus obtained.
,
producinl a to
copherol of the iormula
_
'
OH;
no
copherol product, the steps oi producing an e-to
copherol of the formula
Ks
- /b-(on|).cn(emncn(cnmcncm I
0 ts.
bin
in
m
which comprises condensing SJ-dimethrlhrdro
-—(CHs)sCH(OHl)sUB(GHQICHOHI
0
.
" 0
CH1
CH0
CH
OH!
em
‘
4. In a process for the manuiacture o! a to- v
no -_‘
8
oopherol product. ‘the steps 0!
Ha
Ha
quinone with phytol in the presence 0! zinc chlo
ride, and recovering a tocopherol product from
the reaction mixture thus obtained.
HI
Ha
8. In a process for the manufacture of a to
cophercl product, the steps oi- producing a to
copherol o! the formula
_
which comprises condensing trimethyihydro
quinone with phytol' under acid conditions, and
om
recovering a tocopherol product from the reac
tion mixture thus obtained.
'
CHI
no
He
5. In a process for the manufacture of a to
b-(onmomomhcn(camcncm
copherol product, the steps of producing an e-to
copherol oi the formula
0
Us
Kl
as
B!
B:
which comprises condensing 2,5-dimethylhydro
25 vquinone with phytol under acid conditions, and
recovering a tocopherol product from the reaction
mixture thus obtained.
- 9. In a process for the manuiacture of a to
copheroi product.‘the steps of producing a to
which comprises condensing trimethylhydro
30 copherol oi’ the formula
CK:
quinone with phytol in the presence of zinc chlo
ride, and recovering a tocopherol product from
‘
e. In a process for ‘the manufacture or a to
copherol product, the steps oi producing a. to
copherol oi' the formula '
OH:
HO
the reaction mixture thus obtained.
85
Kl
'
' hammer:(onmomonmcnon.
0
on.
m
n.‘
in
r
RI
em
-
‘
which comprises condensing iLo-dimethylhydro
’
OK:
quinoue with phytol in the presence oi zinc chlo
ride, and recovering a tocopheroi .product from
no
on.
,
.
the reaction mixture thus obtained.
OH
-(om).cmcmnomcnmoncn
10. A‘ process‘ tor producing a tocopherol-like
0
HI
H!
H:
H: '
chroman compound which comprises heating
trlmethyl 'hydroquinone and a solvent, in
which comprises condensing 3,5'-dimethyihydro 45 phytoi,
the presence of an acidic catalyst and in an at
quinone with phytol under acid conditions. and
mosphere of a substantially inert gas.
recovering. a tocopheral product from the reac
PAUL KARRER.
tion mixture thus obtained.
O'I'I‘O ISL-ER.
‘ 'I. In a process for the manufacture of a to
Certi?cate or Correction
PAUL KARRER ET AL.
to the above named
It is hereby certi?ai that error appears in the patent issued In the ant, upper
'
correction as follows:
inventors on December 3, 1946, requiring
the said
‘2412968”
read 2411968; and t at conform
right handoorner,
for
the
patent
number‘
should be read with ~thiscorrection therein that the same may
Letters Patent
to the record of the case in thePatent Oi?ce.
Signed and sealed this 25th day of February, A. D. 1947.
[sub]
LESLIE FRAZER,
First Assistant Commissioner of Patents.
_
ence of nine chloride. a solvent. while passins
.
gaseous hydrosen chloride through the mixture,
and recoverins a tocopherol product from the re
action mixture thus obtained.
,
producinl a to
copherol of the iormula
_
'
OH;
no
copherol product, the steps oi producing an e-to
copherol of the formula
Ks
- /b-(on|).cn(emncn(cnmcncm I
0 ts.
bin
in
m
which comprises condensing SJ-dimethrlhrdro
-—(CHs)sCH(OHl)sUB(GHQICHOHI
0
.
" 0
CH1
CH0
CH
OH!
em
‘
4. In a process for the manuiacture o! a to- v
no -_‘
8
oopherol product. ‘the steps 0!
Ha
Ha
quinone with phytol in the presence 0! zinc chlo
ride, and recovering a tocopherol product from
the reaction mixture thus obtained.
HI
Ha
8. In a process for the manufacture of a to
cophercl product, the steps oi- producing a to
copherol o! the formula
_
which comprises condensing trimethyihydro
quinone with phytol' under acid conditions, and
om
recovering a tocopherol product from the reac
tion mixture thus obtained.
'
CHI
no
He
5. In a process for the manufacture of a to
b-(onmomomhcn(camcncm
copherol product, the steps of producing an e-to
copherol oi the formula
0
Us
Kl
as
B!
B:
which comprises condensing 2,5-dimethylhydro
25 vquinone with phytol under acid conditions, and
recovering a tocopherol product from the reaction
mixture thus obtained.
- 9. In a process for the manuiacture of a to
copheroi product.‘the steps of producing a to
which comprises condensing trimethylhydro
30 copherol oi’ the formula
CK:
quinone with phytol in the presence of zinc chlo
ride, and recovering a tocopherol product from
‘
e. In a process for ‘the manufacture or a to
copherol product, the steps oi producing a. to
copherol oi' the formula '
OH:
HO
the reaction mixture thus obtained.
85
Kl
'
' hammer:(onmomonmcnon.
0
on.
m
n.‘
in
r
RI
em
-
‘
which comprises condensing iLo-dimethylhydro
’
OK:
quinoue with phytol in the presence oi zinc chlo
ride, and recovering a tocopheroi .product from
no
on.
,
.
the reaction mixture thus obtained.
OH
-(om).cmcmnomcnmoncn
10. A‘ process‘ tor producing a tocopherol-like
0
HI
H!
H:
H: '
chroman compound which comprises heating
trlmethyl 'hydroquinone and a solvent, in
which comprises condensing 3,5'-dimethyihydro 45 phytoi,
the presence of an acidic catalyst and in an at
quinone with phytol under acid conditions. and
mosphere of a substantially inert gas.
recovering. a tocopheral product from the reac
PAUL KARRER.
tion mixture thus obtained.
O'I'I‘O ISL-ER.
‘ 'I. In a process for the manufacture of a to
Certi?cate or Correction
PAUL KARRER ET AL.
to the above named
It is hereby certi?ai that error appears in the patent issued In the ant, upper
'
correction as follows:
inventors on December 3, 1946, requiring
the said
‘2412968”
read 2411968; and t at conform
right handoorner,
for
the
patent
number‘
should be read with ~thiscorrection therein that the same may
Letters Patent
to the record of the case in thePatent Oi?ce.
Signed and sealed this 25th day of February, A. D. 1947.
[sub]
LESLIE FRAZER,
First Assistant Commissioner of Patents.
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