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Патент USA US2411969

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Patented Dec. 3, 1946
-
j
j. Y
UNITED STATES PATENT OFFICE
rnoouss FOR THE PREPARATION .joF ,
_ SYNTHETIC DL-TOCOPHEROLS -, ~ '
Paul Karrer, Zurich, and Otto Isler, Basel,
Switzerland, assignors to Hoffmann-La Roche
Inc., Nutley, N. J ., a corporation of New Jersey
No Drawing. Application August 12, 1941, Serial
No. 406,555. In Switzerland March 31, 1938
14 Claims. (Cl. 260-333A)
~
1
.
.
The present invention relates to a process
for the preparation of synthetic tocopherols
which are racemic with respect to carbon atom 2
of the chrom'ane ring.
‘
. _
2
methylhydroquinone
This application is a continuation-in-part of
.
~
or
dimethylhydroquinone
5 with isophytol of the formulav
our application Serial No. 231,846, ?led September 26, 1938.
Evans and collaborators (Mem. Univ. California, vol. 8, year 1927)
.-
at 135° C. was produced from v-tocopherol which
has the empirical formula C28H4802.
It has now been found that by reacting tri
f '
' '
‘.
CH3CH(CH2)3CH(CH2)3CH(CH2)3C(OH).CH=CH2 ’
CH5
CH3
CH3
CH3
'
discovered that a nutri-
,
.
'
'
tive factor which is indispensable for spermato- 10 under acid conditions, and preferably in the pres
genesis in male rats and the successful compleence of acid condensing agents, compounds can
tion of an existing pregnancy in female rats is
be obtained which contain a heterocyclic ring
contained in wheat germ oil and various foodwhich must be regarded as chromane derivatives
stu?s.
They named the new biological factor
of the general formula
'
'
'
'
'
R
OH,
HO ,
1
(IJHQ
_
_
v
.
Ryo
I /o-oH2omcmcnoHiomomcucmomomeuom
CH3
om ~ CH3
- OH:
R
V
..
g
.
vitamin E and described a biological method of 25 wherein two of the R radicals are methyl and the
determination using female rats. Evans; Emerother is methyl or hydrogen. The reaction may,
son and Emerson (J. Biol. Chem., vol. 113,year
for example, be carried out in the presence of
1936, page 31-9, and vol. 122,, year 1937, page 99)
anhydrous zinchchloride, formic acid or while
succeeded in isolating three distinct» chemical
passing gaseous‘ hydrogen chloride through the
substances from wheat germ oil and various 30 reaction mixture. It has also been found particu
other vegetable oils which are responsible for the
larly suitable to employ a ‘combination of zinc
vitamin E action of the starting materials. These
closely related compounds were named 00-, 13-
chloride and hydrogen chloride...
_
1.
The new compounds are the racemates, with
and 'y-tocopherols. Investigations by Fernholz
respect to carbon atom 2 of the chromane ring,
(J. Amer. Chem. Soc.; vol. 59, year 1937, page 35 of tocopherols obtained from natural raw mate
1154; vol. 60, year 1938, page 700), Karrer and
rials. They are light yellow, slightly visnous oils
collaborators (Helvetica Chimica Acta, vol. 20,
which, in the cold, gradually reduce alcoholic
year 1937, page 1422; vol. 21, year 1938, page 309),
silver nitrate solution. On heating the reduction
Bergel, Todd and collaborators (Biochem. J ., vol.
proceeds quickly. These oils dissolve in concen
31, year 1937, page 2257; J. Chem. 800., year 40 trated sulfuric acid vwith'a yellow color, and the
1938, page 253), as well as John and collaborators
solutions ?uoresce intensively after afew hours’
(Zeitschrift fiir physiologische Chemie, vol. 250,
exposure to ultra violet light. The solution of
year 1937, page 11; vol. 252, year 1938, pages 201,
the compounds in chloroform yields a deepdark
208) con?rm and supplement the knowledge of
brown coloration on the addition of tetranitrothe ?rst-named investigators regarding tocoph- 45 methane,_which gradually clears up. On thermal.
erols.
Natural a-tOCODhEI‘Ol was characterized by the
decomposition the compounds form, sublimates of
durohydroquinone or trimethylhydroquinone.
empirical formula C29H5002, by an allophanate
When rats so far kept on a vitamin E-free diet
melting at 158° C., by a p-nitrophenylurethane
were giv'en'these synthetic compounds, it could
melting at 131° 0., and by a sublimate of duro- 50 beiestablished that ‘they rendered it possible‘ for
hydroquinone on thermal decomposition. sé-To;
a'litt'er 'of healthy young rats to be born exactly
cop'herol possesses the empirical formula 028114802,
and yields an allophanate melting at 143-1440 C.
_ as did tocopherols isolated from natural products-i
i The new compounds are to be used as pharma
and a sublimate of trimethylhydroquinone on
ceutical preparations or as starting materials for
thermal decomposition. } An allophanate melting 55 the ‘manufacture of pharmaceutical preparations.
2,411,969
4
3
Example 4
Example 1
1.5 parts by weight of trimethylhydroquinone
1.5 parts by weight of 2,3-dimethylhydroqui
none and 3 parts by weight of isophytol are heated
with 10 parts by weight of anhydrous formic acid
for six hours. The mixture is then cooled, diluted
with water, extracted with ether and the ether
and 3.0 parts by weight of isophytol are heated
with 10 parts by weight of anhydrous formic acid
for six hours. The mixture is diluted with water,
extracted with ether, the ether layer washed with
sodium hydroxide, then with. water, and the
layer washed with sodium hydroxide solution,
then with water and the ether solution dried with
remains as a viscous oil which readily reduces; lo: sodium sulfate. After ?ltering from the sodium
sulfate, a solvent is evaporated, taken up in a
methyl-alcoholic silver nitrate. solution. Afterv
solvent evaporated.
The condensation product
puri?cation, preferably by distillation below: 1 mm.
small“ quantity of low boiling petroleum ether
pressure, its absorption spectrum has a maximum
at 294 ,u,u.. The compound forms. a. crystalline.
and‘ a chromat'ogram prepared on an aluminium
oxide column. The upper layer of the column is
I a yellow‘ brown layer which, when eluted, con
allophanate of melting point 172~1-73""C.
product is dl-a-tocopherol of» the formula
The
tains the expected‘ condensation product of the
following formula:
CH:
CE:
011W
(‘3H,
.
01-01011“
CHa
20'
yo/ém
CH3
It is a viscous oil with a strong reducing action
and contains one active hydrogen atom as shown
Example 2
4 parts by weight of isophytol‘, 2'parts by weight‘
of 2,5-dimethyl hydroquinone and 2 parts by
by the Zerewitino? determination.
point is at 146° C.
weight of Zinc chloride are’ suspended in. 1‘0‘v parts
of decalin and heated. to 150° C. for one hour
while passing carbon dioxide through the melt. 30
The reaction product is cooled and water and‘
ether added while stirring. The ether‘ layer is
separated, washed with water and potassium car
bonate solution, then with hydrochloric acid,
then with water, and ?nally dried with sodium.
sulfate. The ether ‘is removed, the residue dis
Its. melting
It is fully active, when tested on rats kept on
a vitamin E-free diet in doses of 10 mg.
Example 5
2 parts by weight of zinc chloride. 10 parts by
weight of isophytol, 5 parts by‘ weight of trimeth
ylhydroquinone- are dissolved in a. mixture of 20
parts by volume of ether and 20 parts by volume
of benzol, maintaining a temperature of 45-55°
solved in low boiling petroleum ether and ab
C,
Dry hydrochloric gas is passed through the
sorbed on the aluminium oxide column. By elut
mixture
until complete saturation, which requires
ing the yellowish brown upper zone, an oil is’ ob
tained. which reduces an alcoholic solution. of. sil 40 from two to four hours. The reaction liquid is
then washed with water, then with hydrochloric
ver nitrate on boiling and contains 0.2 per cent
acid, again with water, then with sodium chloride
of active hydrogen by the Zerewitinof‘f determi
solution and ?nally the ether-benzol solution is
nation. The product has the constitution
dried and the solvents removed, The material
is then worked up as in previous examples.
We claim:
1. In a process for‘ the manufacture of a to
\ClEl'é'
on
(Ii-Giulia;
.
'
0
copherol product, the steps of producing a tocoph
erol of the formula
on.
CH:
50
and shows a melting point of 154° C.
Example‘ 3
4 parts ‘by weight of isophytol, 3.5 parts by
weight of 3,5-dimethylhydroquinone and 1 part
by weight of‘ anhydrous zinc chloride are heated
to 180° C. for one-half hour with stirring and‘
introducing carbon dioxide into the melt, The
R
-
-/|
0 CH3
CH3
CH3
CH5
R
wherein two of the R‘ radicals represent a methyl
group and the third R radical represents a radi
cal selected from the group consisting of hydro
solution becomes homogeneous and after cooling
is extracted with water and ether. The ether 60 gen and methyl radicals, by condensing a methyl
substituted hydroquinone of the formula
solution is washed with potash solution and then
with water and the ether residue absorbed in an
aluminium oxide column from low boiling pe
troleum ether. The chromatogram is developed
with‘ much petroleum ether, the whole of the 65
lower part of the column becoming a whitish grey.
R
|
RQ-OH
The top layer of- the aluminium; oxide column
R
which carries very little color is removed and
wherein two oftthe- R radicals represent a methyl
the lower zone extracted with 3 parts of'methyl
alcohol and 1 part of ether. The solvent is evap 70 group and the third R radicalrepresents a radical
selected from the group consisting of hydrogen
orated in vacuo and the residue ‘distilled on a
and methyl radicals, with isophytol under acid
molecular distillation apparatus. The compound
conditions, and recovering a tocopherol product
is a yellow, slightly viscous oil, n/25D=1.501. It
fromthe reaction mixture thus obtained.
yields an allophanate. melting at 143° C. and is»
2. In a process for the manufacture of a to
75
active biologically in doses of 5 mg.
2,411,969
6
5
copherol product, the steps of producing a tocoph
5. In a process for the manufacture of a to
copherol. product, the steps of producing an
a-tOCOPhGl‘Ol of the formula
erol of the‘ formula
R
|
on,
\CHu
_
>
,
'. (‘J-(oH1)zomcmnomomnonom
o CH3:
CH3
CH3
CH3
wherein two of the R radicals represent a methyl
group and the third R radical represents a radical
selected from the group consisting of hydrogen
which comprises condensing trimethylhydroqui
none with isophytol in the presence of zinc chlo
ride, and recovering a tocopherol product from
and methyl radicals, by condensing a methyl
the reaction mixture thus obtained.
.
substituted hydroquinone of the formula
15
6. In a process for the manufacture of a to
R
copherol product, the steps of producing a to
copherol of the formula
H0
I
R
CH3
OH
CH:
20
H0
CH:
R
wherein two of the R radicals represent a methyl
group and the third R radical represents a radi
cal selected from the group consisting of hydro
25
gen and methyl radicals, with isophytol in the '
quinone with isophytol under acid conditions, and
recovering a tocopherol product from the reaction
mixture thus obtained.
presence of zinc chloride, and recovering a to
copherol product from the reaction mixture thus
obtained.
3. In a process for the manufacture of a to
copherol product, the steps of producing a tocoph
erol of the formula
_
which comprises condensing 3,5-dimethylhydro
7. In a process for the manufacture of a to
30 copherol product, the steps of producing a to
copherol of the formula
.
CHa
R
|
I
CE:0 H:
35
/I
W0 CH3
CH3
OH;
on;
which comprises condensing 3,5-dimethylhydro
quinone with isophytol in the presence of zinc
wherein two of the R radicals represent ‘a methyl 40 chloride, and recovering a tocopherol product
group and the third R radical represents a radi
I from the reaction mixture thus obtained.
cal selected from the group consisting of hydro
8. In a process for the manufacture of a to
gen and methyl radicals, by condensing a methyl
copherol product, the steps of producing a to
substituted hydroquinone of the formula
45 copherol of the formula
R
CH:
CH)
no
lax/L0H
HO
(EB,
50
C—-(GH|):CH(CH2):CH(CH2):CHCH3
0 011,
R
cm
on,
cm
H:
wherein two of the R radicals represent a methyl
group and the third R radical represents a radical
which comprises condensing 2,5-dimethylhydro
55
quinone with isophytol under acid conditions, and
selected from the group consisting of hydrogen
recovering a tocopherol product from the reaction
and methyl radicals, with isophytol in the pres
mixture thus obtained.
'
ence of zinc chloride, a solvent, while passing
9. In a process for the manufacture of a to
gaseous hydrochloric acid through the mixture,
copherol product, the steps of producing a to
and recovering a tocopherol product from the
“ copherol of the formula
reaction mixture thus obtained.
4. In a process for the manufacture of a to
CH3
copherol product, the steps of producing an a-to
copherol of the formula
’
65
CH3
I
CE:
'
CH:
e-komhomcm),omomnoncn.
5H:
CH:
H:
CHI
/cli-(cn,>acn(om)acn(onmonona
0 on:
l
VO/(E H:
new (‘1H,
CH3
CH2 a
H0
‘on;
CH3
om
which comprises condensing 2,5-dimethylhydro
70 quinone with'isophytol in the presence of zinc
CH3
chloride, and recovering a tocopherol product
which comprises condensing trimethylhydro-.
from the reaction mixture thus obtained.
10. A process for the manufacture of a to
quinone with isophytol under acid conditions, and
copherol product which comprises reacting iso
recovering a tocopherol product from the reaction
75 phytol with an alkyl substituted para dihydroxy
mixture thus obtained.
'
2,411,969
7
benzene having an unsubstituted position ortho
to said‘hydroxyi, under acidic conditions.
8
phytol with a methyl substituted para dihydroxy
benzene in the presence of an acidic catalyst;
' 14. A process for the manufacture of a to
11. The process of claim 10 in which the re
copherol product which comprises reacting iso
action is conducted in the presence of zinc chlo
in phytol with trimethyl hydroquinone in- the pres
ride.
ence of formic acid.
'
12. The process of claim 10 in which they re
PAUL KARRER.
action is conducted in the presence of formic acid.
13,, A process for the manufacture of a to
copherol product, which comprises’ reacting iso
OTTO ISLER.
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