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Патент USA US2407727

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Patented Sept. 17, 1946 r
2,407,726
UNITED STATES‘ PATENT‘ OFFICE
- METHODS OF‘PREPARING ‘CHEMICAL
‘
PRODUCTS
‘
Lee Irvin Smitli,.Minneapo1is;Minn., and‘William.
B.'Renfr0w; 51a, Charlotte, N; 0;,‘ assignors'to
. Reg'ent‘s-of‘the ‘University ofiMinnesota; Minne
apolis, Minn, a corporation-ofr‘Minnesotav
N0 Drawing. ApplicationAugustZ,1941,
Serial ‘No. 405,796‘
7 3 Claims.
1
(01. 260-333)‘
2'
The present’ invention relates to'derivatives of
theto'copherols'and related substances and to the
method of preparing such derivatives.
Contemporary advances in the knowledge of
nutrition and‘medicine in'th‘e medical and vet
erinary ?elds have developed the importance of
.
enttinvention' so as to‘ furnish-,after the‘?rst"rej—
action, an acid. group capable. oi'reaction with a
metal ‘ion to form a salt.
In this present‘ invention;. it‘ has been‘ found?
' that the‘ desired compound can be prepared by
?rst proceeding through an. intermediate step, by
treating a selected tocopherol‘ with a Grignard‘
reagent. such as methyl, ethyl or isopropyl maga
substances having biological activity. Substances
designated“ as the “tocopherols” have beenshown
tube the primary compoundsexhibiting vitamin
nesium iodide, bromide or chloride. .The; alkyl
E activity and much WOI‘k' has been carried out 10 group of the Grignard reagent is preferably
to ‘increase‘the' knowledge concerning these com
chosen so that the alkane subsequently generated
pounds for clinical and veterinary uses; To ac
_ in the reaction will be volatilized at thetemperar
celerate‘ the" accumulation of this‘ knowledge,
standard‘test conditions-have been’ established to
Thus, where the'methyl-Grignard reagent‘ is used‘, '
evaluate the‘ comparative strengths '- or V potencies 15
methane‘is liberated, similarly, Where'tlie‘ethyl‘
tures. used, and therefore‘ readily separated;
of‘ test‘ materials‘by the use'of “standard” ani
G-rignard is used,.ethaneiis liberated: If, the hy
mals, usually white‘ rats; It has been'established
drocarbon‘ liberated is‘ not readily volatilized',‘ it
that results thus obtained on “standard” testtani
mayineyertheless- be separated by’ use of. appro=
mals may'normally' be projected‘ and applied to
priate procedures‘.
,
other mammals” and’ to ‘ human beings ‘by‘ the ap 20
After reaction of. the tocopherol with the G'rig
plication" of factors established by‘clinica‘l tests
nardireagent; thereacti'on product is 'treated’iwith.
the anhydride of‘ thepolybasic acid, which; re
acts with the halo-magnesium derivative of‘ the
relating“ torcompositions other than' those ex‘
hibiting vitamin E activity. .
‘
Extended clinical tests on human beings re
tocopherol‘to thus form an ester salt. Thus, suc
quire relatively long periods of'time and therefore
the-mode of'utilization of" any medical‘or dietary
improvement; whether- in the vitamin-?eld or'in
other ‘medical or ‘dietary ?elds, maybe developed‘
only‘ after years of» study; but'this does ‘not‘pre
cinic anhydride reacts with the halo-magnesium
derivative of‘ the, t'ocopherol, inserting; itself‘ be.
tween the magnesium halide and‘ the oxygen to
which it is attached. By acidifying this product,
such, as the' tocopherolsv and‘ their‘ derivatives
formed in place of the magnesium halide. The
free acidphaving ‘one group esteri?edwith theselected tocopherol', other hydroxy chroman or hy-‘
a1 free acidfhaving one acid group of the starting '
cl'ude- valuable ‘utilization of" speci?c ' materials 3 U (ii-basic acid- esteri?ed with the tocopherol is
within" the purview‘ of. available information.
Therefore, it is’ logical and proper't‘hat‘ considi
erable Weight be given to ?ndings‘developed‘ih‘
the tests with “standardized” test" animals.
‘Co-pending application Serial No. 211,077,
Patent 2.2452054; and"otherapplications, describe
processesfor'synthesizingtocopherols; A further.
droxy coumaran, is a new and useful interme
' diate which may be‘used-for. the‘ formation-of a
invention, as described in this application, resides
in: the-process‘ for making stableand' useful de
rivatives of the‘tocopherols.
It‘ is‘a'n object of the invention to prepare de
rivatives‘of‘ the’tocopherols, which derivatives re
tain' the biological activity of the primary
t‘ocopherol‘itself, and yet assume various desirable
physical characteristics which‘ assist in' utiliza
tion of the compositions;
A‘ further object'is to prepare a nonetoxiere
action product‘ which is suitable for. clinical‘ use
wide variety of further'compounds. Thus, it may
bereacted with alkali metal salts orbases toform
an ester'salt" of the polybasic acid, in which one,
acid group has been. esteri?ed with tocopherol',
and ‘the other converted to a salt.
.
This invention is illustrated by the'following
example which, however, must. not be taken asv
any limitation upon the. invention describediand
claimed.“
Eztampl'e
a-tocopherol‘ (4:91‘ g.) was dissolved in: ethyl
ether" (50 c0‘.)1 and’. al 5:%- excess; based‘ on‘ the:
tocopherol, of, propyl magnesium chloride‘in ethyl
and‘ has" vitamin E activity substantially equiva
ether" (5.3 cc., ZIOG‘N.) was added; After thor-A
lentto the a-tocopherol‘content, on the molecu
lar basis; but which has modi?ed chemicaLand
physical‘ properties, particularly. that. of being a
solid‘rather than a liquid.
A further object is to provide a process for pre7 1.!
ough- mixing of theforegoing reaction’ mixture,
paring di-basic'l-acid anhyd'ride-reaction products
of the tocopherol'sl
~
More speci?cally, one object is to prepare a
at“ roomItemp'erature, a- solution of'su'ccinic an
hydride-(Llllg, 10%excess) in dioxane; (1000:)“
Was- added‘la-nd' the ?'askl r-ins'ed’with anad‘diti‘onal .
1000; of di'oxane; The‘ reaction ‘mixture was then;
stoppered and? allowed‘ to“ stand5 overnight; at’
room ‘ temperature, after which“ it‘ was‘ heated-ion
a steam bath for four hours. 'It was then poured “ '
calcium salt of the acid succinate of a-tOCOphEI‘Ol,
into water, the reaction mixture acidi?ed with
A polybasic anhydride is required in the pres 60 dilute hydrochloric acid, extracted with ethyl
2,407,726
3
4
.
groscopic solid that latherswhen shaken with
water but is only very slightly soluble in water.
The salts of ammonium, potassium, and chloro
magnesium yield oils by a similar process. The
ether and the ether solution dried, by introducing
thereinto a solid drying agent. . The solution
was then ?ltered to remove the drying agent
and the ether evaporated from the ?ltrate.
There remained 5.88 grams (97.2% yield) of
barium salt is a solid.
.
the acid succinate of ‘it-tocopherol.
This was then dissolved in methanol (25 cc.)
Maleic
anhydride,, phthalic
anhydride,
and '
glutaric anhydride form derivatives that closely
resemble in physical properties the derivative
and concentrated ammonia (1 cc.) was added,
from succinic acid.
.
followed by the addition of a solution of calcium
The invention is applicable to such raw ma
chloride in methanol (13 00., 10%, 100% excess). 10
terials as the natural 11-, c- or gamma-tocoph
A voluminous precipitate formed. The mixture
erols, or to synthesized a-tOCODheI‘O], or xylol
was thoroughly stirred for ten minutes and more
tocopherols, or to other hydroxy chromans or hy
concentrated ammonia (3 cc.) added. After fur
- droxy coumarans and similar compounds.’
ther stirring, the precipitate was allowed to settle,
Many obvious variations may be made in the
the liquid decanted off and the precipitate 15
invention herein illustrated and described with
washed with acetone. The solid is dried for a
out departing from the spirit of the invention
short time at 100° C. in a vacuum, after which
claimed.
1
.
it was dissolved in hot dioxane (100 cc.) and re
We claim:
precipitated by pouring the solution into water
1. The process comprising reacting a com
(150 cc.). The liquid was decanted off, the solid
pound selected from the group consisting of ,hy
washed with acetone and dried in a vacuum
droxy chromans and hydroxy coumarans with a ‘
desiccator. The solid was dissolved in a mini
Grignard reagent, reacting the resultant mix
mum amount of hot dioxane and the hot solution
ture with a polybasic acid anhydride, and acidi_-.
?ltered, after which the ?ltrate was cooled. A
.
voluminous precipitate formed. Two volumes of 25, fying the reaction mixture.
com- '
> 2. The process comprising reacting
acetone were then added, mixed thoroughly and
pound selected from the group consisting of hy
the liquid decanted off. The solid remaining
after decanting was washed with acetone and
, droxy chromans and hydroxy coumarans with
a Grignard reagent, reacting the resultant mix,
dried for a short time in a vacuum at 100° C.,
dissolved again in a minimum amount of hot di 30 ture with a polybasic acid anhydride, acidifying
oxane and allowed to crystallize from the cooled
the reaction mixture, and recovering. the’ 'acid
polyhydric acid ester of the selected starting ma-"
liquid. The solid was then washed with acetone ‘
and dried at 100° C. underreduced pressure.
3, The process comprising reacting a com
weighed 44 grams (‘71% yield) and melted at
214-215” C.
35 pound selected from the group consisting of hy
terial.
I
a
droxy chromans, and hydroxy coumarans witha
The product is a white solid, readily soluble
Grignard reagent, reacting the resultant mixture
in ethyl ether and ligroin; moderately soluble in
with a polybasic acid anhydride, acidifying the
alcohol; soluble in hot dioxane and sparingly
reaction mixture, and reacting the acidi?ed prod
soluble in cold dioxane; insoluble in water and
'
acetone. Combustion analysis shows good cor 40 uct with a metallic base.
4.‘The process comprising reacting a. com
relation between theoretical and observed analy
pound selected from the group consisting of hy-'
sis, as shown in the following table:
Carbon
,
Per cent
Calculated for (CaaHsaOshC? _____ .._
72. 10
Hydro-
-
gen
Calomm
Per cent
9. 75
Per cent
3.
45
droxy chromans, and hydroxy coumarans witha
Grignard reagent, reacting the resultant mixture
with a. polybasic acid anhydride, acidifying the
reaction mixture, reacting the acidi?ed product
with a metallic base, and recovering the salt 01'‘
the acid polyhydric acid ester- of theselected
starting material.
Rigorously conducted vitamin E assays with 50 5. The process comprising reacting a tocoph-v
Found ____________________________ __
72. 27
9. 70
,3. 37
,
rerol with a Grignard reagent, reacting the re-,
“standard” test animals shows that the com
‘sultant mixture with succinic anhydride, and
pound is fully equivalent to a-tocopherol on a
acidifying to form the acid succinate of the’
molecular basis, and the compound is effective in
tocopherol.
_
increasing reproduction when used as a dietary
6.
The
process
comprising
reacting
a
tocoph
55
supplement in the food mixtures fed to fowls
ero1 with a Grignard reagent, reacting the re
such as chickens, ducks, turkeysand the like and
sultant mixture with succinic ahydride, acidify- .
food mixtures for fur bearing animals such as
ing, and reacting the resultant product with
foxes and mink. For such uses, the calcium suc
compound presenting an available reactive cal—_
cinate ‘salt of tocopherol is especially desirable in
cium ion, to form the calcium salt of the acid ,
that, it is stable in air, soluble in fats and in
succinate of the tocopherol.
soluble in water.
Other metallic‘salts of any of the metals may
be prepared in an ahalogous fashion by neutraliz
ing the polybasic acid ester of the selected tocoph
erol by the appropriate metal base or by treat
ing the ester with selected salts of'appropriate
' metals.
Where the ?nished product is used for
medical or dietary purposes, the metal selected
for formationrof the salt is, of course, non-toxic.
7. The process comprisingreacting izr-tocoph}
erol with an valkyl magnesiumv halide wherein the‘
alky1 group corresponds to an easily volatilized
-. alkane, reacting the resultant mixture with suc
cinic anhydride, acidifying the mixture, and re?
acting the resultant acid succinate ester of a
tocopherol with calcium halide under alkaline
conditions to form the corresponding calcium
For other purposes where the matter of toxicity 70 salt of the acid succinate of u-tocopheroh
is unimportant, other metals may be used.
LEE IRVIN SMITH;
The sodium salt so prepared is a slightly hy
WILLIAM
RENFROW, JR.‘ "
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