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Patented Dec. 3, 1946
2,411,970 _
~' .THE-PREBARATION‘OF THE'SAME- ~
'
'
' "Paul? Kar'réri Zurich, and cm _ Isler, Basel, 4‘
Switzerland, assignors to HoffmanmLaRoche;
i
v
'
‘
' "I
1" Inc.',"l\Tutiey, N._;J.','a corporationofNe
"
Jersey’: 1
' Now-Drawing‘. Application Augiistfié, ‘~19 f1" Serial
.1 80.406556, [Teri-Switzerland>March’$1,-71_93§’ "
z?io'joiaims. (c1.'260L-333§)'~
whichlis racemic at-theicarbonatom in; position 2
'The'present inventionarelates _to a novel'com
'pound,‘7,8-dimethyltocol‘o'f the formula;
of the ‘chroma'ne ‘ring, possesses ‘vitaminiactiv
" ‘ '
'ity. ‘Thisr'compound maybe prepared‘ by-iireaetirig
‘2,3édimethylhydroquinone
110m 8H2
.1130
with.‘ Iph'ytoly “ 'iso
phytol','for 'phytyl?h‘alidejs; underi'acid" conditions
cfcwHw.
‘ ,
.,
and preferably in thé'présence'bf acidicbndens'ing
agents; ‘The reaction? may, ‘for; examplegbe'fl-car
.
rie’d 'out'fin the‘presence of: anhydrous - zinc‘ chlo
“CH3
-
~
i
I
v
ride, formic 1 acid ior while? passing égaseous hydro
gen chloride ‘through; theirea‘ctioni mixture-.iiflt
has also been found particularly suitable 'to'zem
ploy a combination of zinc chloride and hydrogen
and'a
This process
application
‘for aprodu'cingthetsame';
is a continuation-'inl-part'of
- j
' ~our earlierapplicationliserial No.’f231_*,84l6_, ?led
September-'26,’
1938‘.
'
‘v
.
l
-
1
g
chloride.
'
~.
p
_. _.
p
-
The new compound is a light yellow, slightly
~ :Evans and collaborators ' (Memp-Univi: Califor;
viscous oil, theiallophanate of‘ which melts at
nia; vol. ‘8. year 1927) {discovered that ' a ‘ nutritive 15
factor which-is indispensable for ‘spermatoge'nesis
146° C. In the'cold, ‘the new "compound grad
ually reduces alcoholic silver nitrate solution; on
in’ male ‘rats andthe “successful ‘completion of an ‘
existing pregnancy in female? rats is1 contained
heating the reduction proceeds rapidly. The com
‘in wheat germ oil'and»variousfoodstuffsf'i'They
pound dissolves in concentrated sulfuric‘ acid with
named the new biological factor'vitaminE-{and 20 a yellow :color, and I the solution *fluoresces: inten
sivelyafteri a few hours’exposurej-to; ultraviolet
'idescribedia“ biological "method ‘of g determination
using female'riats.
light.‘ They 'solution'of' thev compound ‘in’ chloro
form yields a'dark. brown-coloration Von the-addi
'EvansiEmerson arid-Emer- - '
son (J. Biol. Chem., vol. 113, year 1936. page 319,
‘and vol.l'l22,' year 1937, page 99)‘l succeeded in
tion of ,tetranitromethane; _,Which gradually
isolating three distinct che'micalsub'stance‘s from :25 clears up. '
,
I
wheat germ oil and various 'other‘1vegetable3'oils
The new compound'l‘s'int'e‘nded to be used as a
which are responsible for the vitamin E action
pharmaceutical :preparationE-o'r as ‘aistartingilma
of the starting materials. These closely related
terial "for I the'f-manufacture-rilof ' pharmaceutical
compounds were named 11-, 18-,"and Y-tocopherols.
preparations.
Investigations by Fernholz (J .' Amer. Chem. §_Soc.,
vol. 59. year 1937, page 31154;vvol. 60, year 1938,
'
'
i 2 parts by weight of 2,3;dimethylhydroduinone,
page 700), Karrer and collaborators v(I-Ielvetica
Chimica Acta, vol. 20, year 1937, page 1422; vol. ‘
"6.5 parts'b'y' weight of phytyl bromide‘ or the
21, year 1938, page‘3Q9) ,1 BergelT'odd-‘arid comes: I
orators (Biochem. J.,' ‘v01. 31', year 1937, page
Emma"
l
.,
..
' oneon-‘gonmécnfwnoaéongcnagI‘,
_
'1CH3
iacHl'" ~ 1011a,.
.9113,“
2257; J. Chem.‘ Soc; year 1938,'page 253) ,7 as well
as John and collaborators (Zeitschrift ?ir physi
ologische Chemie, vol. 250, year 1937. page 11; vol.
:
‘1;.5 partsb'ylweight of ‘zinc'ch'l‘orideiiand 2o_ p1_;_r1;§
by weight of benzenea' biledjjigrf‘fqur"hdliits
under 'reflumThemreac on mixture'isjfthh
252. year 1938, pages 201, 208), con?rm and, sup
plement the knowledge of the ?rst-named inves
‘treated with water; the“ 'ligroin layer removed,
- tigators regarding tocopherols.
washed with potash solution, then with "water,
and the solvent evap6rated.:i_ The residue is dis
solved in asmall ( quantity of I low-boiling ,petro
Natural a-tocopherol was 'character‘ized'rby the
empirical formula 0291-15002, by an‘ allophanate ‘
melting at 158° C., by a p-n'itrophenylurethane
melting at 131° C., and a sublimate of durohydro- ‘_
quinone on thermaldecomposition. l8-Toc0pher0l '
possesses the impirical formula vC'zeHnaOz,‘yields
an allophanate melting at 143—144° C. and a sub
composition. ‘An allophenate melting at~135° C.
was produced from Y-tocopherol which has the 50
empirical formula C2aH4sO2. '
v
“
It has now been found that 7,8-dimethy1tocol of
the formula
'
.
.7 -v
~
row; brownish layer ‘the upper ‘part of th
_
foot therfsdfia ‘nearly 'cc1dr'1essjzQne, ‘Byi‘el me
the ‘brcwnishjlayer 'v 'ithda‘jmixtureqof‘ether and
~ 'sorption column‘; ‘then ‘a yellow ring,j and,
limate of trimethylhydroquinoneonthermal dee '
methanol, the‘f expected condensation productlof
the following
vmulai's, obtained. "
" ‘ ‘
‘
~
OH
'
l
CH:
H
n
60
'lltis a yilscousbi ‘which-‘has a strong reducing
2,411,970
3
4
action. ,Its analysis corresponds withthe formula
‘
C2sH4aO2. The compound possesses an active‘hy
drogen atom (calculated 0.24 per cent, found 0.24
Example 5 ,
4 parts by weight of 2,3-dimethylhydroquinone
are suspended in 50 parts by Weight of petroleum
ether, boiling point 80° 0., and 3 parts by weight
which had been kept on a Vitamin El-Iree diet, the .
compound proved fully active in a dose of 10 mg.‘ I of. anhydrous zinc chloride and 10 parts by weight
of a phytylhalide prepared by the addition of hy
Example 2
drogen bromide to phytyl bromide, are added, and
4 parts by weight of phytol', 2.5 parts :by'weight '1 the reaction product heated in the current of
per cent active hydrogen). ~When tested on rats. ' '
l0 nitrogen for four hours in an oil bath maintained
at 140° C. , Hydrogen bromide is evolved and
of 2,3-dimethylhydroquinone,' 1 part by weight of
anhydrous zinc chloride are heated to 180° C. for
finally, when .thishas ceased, the product is treat
one-half hour with stirring and-introducingcar
bon dioxide into the melt. The latter becomes
homogeneous. After cooling, the product is treat
’ ed with water, much petroleum ether is added,
and the benzine layer thoroughly washed with
15 Claisen’s solution, then with water, dried and ad
sorbed on an aluminiumoxide columnandeluted
ed with ether and water, the ether solution sepa
rated; washed withv potassium 1hydroxlde1-solu
in the manner described in the previous-examples.
The product so obtained is identical with the di
tion, th'en‘with water, and dried with sodium‘ sul
fate solution.
The ether ‘is removed and the
residue taken up in .low boiling "petroleum ether
and a chromatogram prepared on an aluminium 20
'ox‘ide column. The developed‘ vchromatogram
shows a narrow, brownish layerin the upper part
of the absorption column and then‘a yellow ring
and a principal zone that is nearly colorless. The
eluateof the brownish layera corresponds to the
formula:
'
'
'
.
"
‘
methyl-tocol previously obtained,
Example 6
1 part by weight of zinc chloride, 5 parts by
weight of isophytol and 2.5 parts by weight of 2,3
dimethylhydroquinone are dissolved in 20 parts by
volume of ether and 20 parts by volume of benzol
added, the mixture being warmed to a tempera
ture of 50—60° C. A rapid stream of dry hydro
gen chloride is passed through the solution which
is heated and stirred under re?ux for 4 hours un
til hydrogen chloride is evolved at the top of the
30 condenser. The cooled solution is poured into wa
‘It
ter, the ether-benzol layer washed with hydro
chloric acid, 10 per cent sodium-hydroxide, and
?nally several times with water containing sodium
chloride to ‘facilitate separation. After drying
a viscous oil possessing one active hydrogen
atom-as shown by the factfthat when submitted I
with sodium sulfate the solvents ‘are removedand
the residue is distilled in high vacuo.
to the Zerewitino?’ ‘determination 0.24 percent of
an active hydrogen atom is shown. When tested
We claim:
on rats kept on a vitamin-E-free diet, the com
pound was fully active‘infdo'ses of 10 mg. '
Eramplell
.
'
‘ 1. In a process for the manufacture of a to
40
I‘
cophero1 product, the steps of‘ producing a to
copherol of the formula
[1.5 parts by weight ‘of '2,3-dimethylhydroqui
none, 3 parts by weight of'isophytol of the for
mula
'
-
'
45
are heated in 10 parts of anhydrous formicacid
by condensing 2,3-dimethylhydroquin0ne with an
for six hours. The mixture is diluted with water,
aliphatic di-terpene derivative of the formula. .
extracted with ether, the ether layer washed with 50
sodium hydroxide solution, then with water, and
‘ cméoH-(Cth)Hie'-<0Hi>i¥eri—wmhéiii
dried over sodium'sulfate and the .solvent re
on;
(‘3113
CH3
I
moved. The residue is taken up with low boiling
‘wherein R’ represents one of the following radi
petroleum ether, is chromatogramed in the. man,
ner of the previous example to obtain the same 55
cals:
product.
I
.
.
i
.
V
'
,
I
-—C=CH—-CHZOH
‘
‘
‘
'
v
a
.
V
—CHa1—CHr-CHzHal
Example 4
Ha
4 parts by weight of phytol, 2.5 parts by weight
of 2,3-dimethylhydroquinone and 1 part by weight
,
H:
l-—-C=CH—CHzHa1
"
I
I
I
2
0H
H3
—(i1——CH=CHg ‘
of zinc chloride are suspended in 10 partsvby
is;
weight of decalin and heated to 150° C. and the
temperature is maintained while'passing carbon
under acid conditions, and recovering a tocoph
dioxide through the suspension. The solution be
erol
product from the reaction mixture thus ob
comes yellowish brown, the product is cooled, wa
ter and ether added'while stillstirring, and the
2. In a process for vthe'manufacture of a to
ether solution separated ofli, This solution is
copherol product, the steps of producing a‘ to
washed with water, potassium carbonate solution
copherol of the formula
r
'
and hydrochloric acid successively, then again
CH1
with water, separated from the aqueous layer,
dried with sodium sulfate and the ether removed.
The residue is then taken .up in low boiling .pe
CH?
'o-(onmcn(omiaomormloncm
troleum ether and a ‘chromatogram made as de
0 CH3‘
CH; "
OH;
on;
scribed in previous examples and the product iso
CH;
M
lated as in the previous examplesa 75
tained.
30W \(ljm
'
'
2,411,970
5
6
6. In a process for the manufacture of a to
by condensing 2,3-dimethy1hydroquinone with an
copherol product, the steps of producing gamma
aliphatic di-terpene derivative of the formula
tocopherol of the formula
01
wherein R’ represents one of the following radi
cals:
-C=CH—CH2OH
——Cl7Hal—C Hr-CHaHal
CH3
CH3
10
which comprises condensing, 2,3-dimethyl hydro
quinone with phytol in the presence of zinc chlo
ride, and recovering a tocopherol product from
the reaction mixture thus obtained.
7. In a process for the manufacture of a to
in the presence of zinc chloride, and recovering 15' copherol product, the steps of producing a to
a tocopherol product from the reaction mixture
copherol of the formula
thus obtained.
‘
»
HO
CH2
CH2
CH3)
0
3. In a process for the manufacture of a to
copherol product, the steps of producing gamma
tocopherol of the formula:
on,
E0
\ \CH2
CH3
CH3
CH3
CH3
CH3
CH3
CH3 ‘K /(llJ—(oH2)g(|JH(oHz)acmomnonom
0
<|3—(CH2)sCH(CH2)aCH(CH2)s?HCHa
CH3
CH3
CH3
which comprises condensing 2*,3-dimethyl hydro
25 quinone with isophytol under acid conditions,
and recovering a tocopherol product from the
reaction mixture thus obtained.
CH3
which comprises condensing 2,3—dimethylhydro¢
quinone with a phytylhalide under acid condi
tions, and recovering a tocopherol product from
the reaction mixture thus obtained.
_
8. In a process for. the manufacture of a to
copherol product, the steps of producing a to
30 copherol of the formula
CH2
4. Iri a process for the manufacture of a to
HO_/\H/ \(EHH
copherol product, the steps of producing gamma
tocopherol of the formula
CH2
CH3
C——(CH¢)@CH(OHz)3CH(OH2)aCHCHa
0 CH3
35
CH3
~CH3
CH3
CH3
which comprises condensing 2,3-dimethyl hydro
quinone with isophytol in the presence of zinc
chloride, and recovering a tocopherol product
CH3
40 from the reaction mixture thus obtained.
which comprises condensing 2,3-dimethylhydro
9. A completely racemic synthetic gamma to
quinone with phytyl bromide of the formula
copherol of the formula
under acid conditions, and recovering a tocoph
erol product from the reaction mixture thus ob
CH3
0
tained.
copherol product, the steps of producing gamma
tocopherol of the formula
CH3
CH3
,
7 chromane ring and of the formula:
OH:
CH3
} /
yo 0H3'
om
CH3
CH3
CH3
which comprises condensing 2,3-dimethyl hydro
recovering a tocopherol product from the reac
tion mixture thus obtained.
CH3
10. A synthetic gamma tocopherol which is
racemic at the carbon atom in position 2 of the
CH3
quinone with phytol under acid conditions, and
CH3
CH3
5. In a process for the manufacture of a to
60
PAUL KARRER.
O'T'I'O' ISLER.
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