Chromanylascorbic acid derivatives their preparation and use

Chromanylascorbic acid derivatives of the general formula I ##STR1## where R.sup.1 is an organic radical having 1 to 12 C atoms, in particular a methyl group, PA1 R.sup.2 is an organic radical having 8 to 30 C atoms, which is unsubstituted or substituted by functional groups, in particular the phytyl 30 radical, and PA1 R.sup.3 is the --PO.sub.3 H.sub.2 -- radical or a glycosidyl radical, PA1 R.sup.3, R.sup.4 and R.sup.5 are hydrogen, or an alkyl or acyl group having 1 to 20 C atoms, in particular hydrogen, and PA1 R.sup.6 is hydrogen or an acyl radical, their preparation by reacting the corresponding 5-chloromethyl- or 5-bromomethylchroman derivatives with the alkali metal or alkaline earth metal salts of ascorbic acid or the ascorbic acid derivatives corresponding to the formula I, and the use of the compounds according to the invention as pharmaceutical or cosmetic active compounds or food supplements, as bioantioxidants and for the stabilization of organic substances, in particular of foods, such as synthetic or natural fats and oils, or pharmaceutical preparations, but also of plastics, against the harmful action of oxygen, light and/or heat are described.

The invention relates to chromanylascorbic acid derivatives of the general 
formula I 
##STR2## 
where R.sup.1 is an organic radical having 1 to 12 C atoms, such as a 
branched or unbranched, saturated or unsaturated, aliphatic hydrocarbon 
radical having 1 to 12 C atoms, or a cycloalkyl group, aryl group or 
heterocyclic group having 4 to 12 C atoms, which is unsubstituted or 
substituted by one or more alkyl, alkoxy, hydroxyl, amino, monoalkylamino 
or dialkylamino groups, 
R.sup.2 is an organic radical having 8 to 30 C atoms, such as a branched or 
unbranched, saturated or unsaturated, aliphatic hydrocarbon radical having 
8 to 30 C atoms, preferably 12 to 24 C atoms, an alkyl radical having 1 to 
6 C atoms, which is unsubstituted or substituted by a carboxyl group, or a 
cycloalkyl group, aryl group or heterocyclic group having 4 to 20 C atoms, 
which is unsubstituted or substituted by one or more alkyl, alkoxy, 
hydroxyl, amino, monoalkylamino or dialkylamino groups, 
R.sub.3 is the --PO.sub.3 H.sub.2 -- radical or a glycosidyl radical, 
R.sup.3, R.sup.4 and R.sup.5 are each hydrogen or an alkyl, cycloalkyl, 
aryl, aralkyl or cycloalkylalkyl radical or a acyl radical of the formula 
--CO--R.sup.7 having 1 to 20 C atoms, 
or R.sup.4 and R.sup.5 together are an alkylene group which is 
unsubstituted or substituted by one or more alkyl groups, 
R.sup.6 is hydrogen or an acyl group of the formula --CO--R.sup.7 and 
R.sup.7 is a saturated or unsaturated aliphatic radical having 1 to 20 C 
atoms, or the phenylvinyl radical. 
Preferred chromanylascorbic acid derivatives of the general formula I are 
those where 
R.sup.1 is an aliphatic hydrocarbon radical having 1 to 4 C atoms, 
R.sup.2 is a linear or methyl-branched, saturated or unsaturated, aliphatic 
hydrocarbon radical having 12 to 24 C atoms 
and R.sup.3, R.sup.4 and R.sup.5 are hydrogen, or an alkyl or acyl group 
having 1 to 4 C atoms, and 
R.sup.6 is hydrogen or an acyl group having 1 to 20 C atoms, 
in particular the chromanylascorbic acid derivative of the general formula 
I, where R.sup.1 is a methyl group, 
R.sup.2 is the phytyl radical 
##STR3## 
and R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each hydrogen, ie. a product 
of the formula Ia coupled with ascorbic acid in the 5a-position of 
tocopherol 
##STR4## 
Both the chroman derivative .alpha.-tocopherol (vitamin E) and ascorbic 
acid (vitamin C) and ascorbic acid derivatives play an important part in 
biological systems on account of their oxidation-inhibiting and free 
radical-scavenging action and are employed in various manners for 
pharmaceutical or cosmetic purposes. Vitamin E in this case acts as a 
matter of priority as a free-radical scavenger in lipophilic phases and 
vitamin C and other ascorbic acid derivatives act as reductants in aqueous 
phases on account of their polar structure. Both compound classes are 
often employed jointly, as they complement each other synergistically in 
their action. The greatly different polarity of the chroman derivatives, 
such as vitamin E, on the one hand and the ascorbic acid derivatives, such 
as vitamin C, on the other hand however prevents an optimum interaction 
and the full display of the potential of action when using mixtures of 
both compounds. Physical phenomena such as diffusion processes, particle 
size and particle distribution can also greatly adversely effect the 
activity. Thus in commercial vitamin E preparations at present only a 
small fraction of the dose administered is used. 
The use of vitamin E for stabilizing plastics against the harmful actions 
of oxygen, heat and light is disclosed, for example, in DE-A 11 36 100 and 
DE-A 11 14 319 and EP-A 36 169. The stabilization of fats and oils in 
foods by vitamin E is also described (cf. Ullmanns Encyklopadie der 
technischen Chemie Ullmann's Encyclopedia of Industrial Chemistry!, 
Volume 23, page 649). 
The known chroman derivatives, however, still leave something to be desired 
with respect to activity, solubility in hydrophilic systems, distribution 
and dispersibility in vivo and also in volatility. 
The object of the present invention was therefore to make available novel 
chroman derivatives which do not have the abovementioned disadvantages of 
the known compounds or only have them to a relatively small extent. 
In particular, it was the object of the invention to make available a novel 
bodily tolerable vitamin E derivative with whose aid it is possible to 
improve the absorbability of vitamin E in the human and animal body. 
In the human body, vitamin E is absorbed in the intestinal tract. With 
commercial vitamin E preparations, at present only about 10% of the 
administered vitamin E dose is absorbed; the remainder is excreted 
unchanged. An important reason for this is the severe coagulation of the 
preparations in the basic intestinal medium. 
In the human body, there is a marked fall in pH between the stomach and 
intestinal tract. While the pH in the stomach is below 3, ie. in the 
acidic range, in the intestinal tract a basic medium (pH&gt;9) prevails. In 
order to increase the absorbability of vitamin E, the active compound must 
be present for at least a short time in finely dispersed form. As this is 
difficult to realize physically, it was a particular object of the 
invention to make available a vitamin E derivative from which vitamin E is 
released chemically in finely dispersed form in the intestinal tract, all 
substances involved or formed in this process, of course, having to be 
biologically acceptable. 
Surprisingly, we have succeeded in coupling vitamin E in the 5a-position to 
vitamin C. The resulting compound of the formula Ia is stable in acidic 
medium (eg. in the stomach). In basic medium (eg. in the intestinal 
tract), however, an ascorbate anion is eliminated with formation of an 
ortho-quinone methide from the compound of the formula Ia. The ascorbate 
anion then reduces the intermediate ortho-quinone methide to vitamin E, 
which is now resent in finely dispersed form and can therefore be readily 
absorbed. The yield of "precipitated" vitamin E is about 80%, based on 
compound of the formula Ia employed and can be further increased by 
addition of further vitamin C, ie. vitamin C in a form which is not bound 
to vitamin E. 
In this base-induced cleavage of the compound of the formula Ia, beside the 
compounds formed as main products: finely divided vitamin E and vitamin C 
in oxidized form, only para-tocopherylquinone and nonoxidized vitamin C 
are released. As para-tocopherylquinone also occurs normally in the body 
as a degradation product of vitamin E, all substances released from the 
coupling product of the formula Ia are biologically compatible. 
The preparation of the compound of the formula Ia and of the other 
chromanylascorbic acid derivatives of the general formula I is relatively 
uncomplicated. 
The invention also relates to a process for the preparation of 
chromanylascorbic acid derivatives of the general formula I, which 
comprises reacting a 5-halomethylchroman of the general formula II 
##STR5## 
where R.sup.1, R.sup.2 and R.sup.6 have the meanings indicated above and X 
is Br or Cl, with an alkali metal salt or alkaline earth metal salt of 
ascorbic acid itself or of an ascorbic acid derivative of the general 
formula III 
##STR6## 
where R.sup.3 to R.sup.5 have the meanings indicated above. 
Particularly advantageously, the process according to the invention for the 
preparation of the chromanylascorbic acid derivatives of the general 
formula I, in particular of the compound of the formula Ia, is carried out 
by preparing the alkali metal salts or alkaline earth metal salts of the 
ascorbic acid derivatives or of ascorbic acid itself in situ, ie. in the 
reaction mixture, by means of the presence of bases and then reacting 
them. 
The 5-halomethylchromans of the general formula II used as starting 
compounds for the process according to the invention are known compounds 
and can, for example, be prepared selectively by brominating or 
chlorinating the 5-methyl group of vitamin E or of the chroman derivatives 
in inert organic solvents, such as hexane, heptane, octane or toluene. 
Suitable 5-halomethylchromans of the general formula II where R.sup.6 is 
an acyl group are in particular the corresponding acetates, palmitates, 
sorbates, oleates, linoleates and cinnamates. 
To carry out the process according to the invention, a procedure is in 
general used in which ascorbic acid or an ascorbic acid derivative and an 
alkali metal or alkaline earth metal ascorbate or alkali metal or alkaline 
earth metal salt of an ascorbic acid derivative or alkali metal or 
alkaline earth metal hydroxide are dissolved in a universal solvent, such 
as dimethyl sulfoxide, with intensive mixing, the solution is cooled to 
room temperature and then treated with the solution of 
5a-bromo-.alpha.-tocopherol or one of its salts and the reaction mixture 
is heated under inert gas protection and with stirring for from 2 to 6 
hours, preferably from 2.5 to 3.5 hours, at from 40 to 60.degree. C. The 
reaction mixture is worked up in a customary manner, for example by 
extraction with n-hexane and water and subsequent chromatography on 
Al.sub.2 O.sub.3. Sodium ascorbate and 5a-halo-.alpha.-tocopherol or its 
salt are used in an approximately equimolar ratio. It has, however, proven 
to be advantageous additionally to add further ascorbic acid to the 
reaction mixture in order to prevent side reactions, such as the formation 
of tocopherylquinones. The additional amount of ascorbic acid is in 
general from 0.5 to 2 mol per mole of 5a-halo-.alpha.-tocopherol. 
The process turns out to be particularly advantageous if the 
5-halomethylchroman of the general formula II is employed immediately in 
the solution in which it was prepared. 
The invention furthermore relates to the use of the chromanylascorbic acid 
derivatives of the general formula I, in particular that of the compound 
of the formula Ia, as pharmaceutical or cosmetic active compounds or food 
supplements, or as bioantioxidants. 
The invention furthermore relates to the use of the chromanylascorbic acid 
derivatives of the general formula I, in particular of the compound of the 
formula Ia, for the stabilization of organic substances, in particular of 
foods, pharmaceutical or cosmetic preparations or plastics, against the 
harmful action of oxygen, heat and/or light. 
The use of the chromanylascorbic acid derivatives of the general formula I, 
in particular of the compound of the formula Ia, is particularly effective 
when they are employed as a mixture with ascorbic acid or ascorbic acid 
derivatives.