Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-01-26
2002-04-02
Owens, Amelia (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06365758
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a process for preparing tocopheryl esters or tocotrienyl esters by acid-catalyzed esterification of a tocopherol or a tocotrienol in a solvent at elevated temperature with the appropriate carboxylic acid, in particular with sorbic acid.
A tocopherol means according to the invention a compound of the formula I
where R
1
to R
3
are H or methyl, and the side chain is saturated, and a tocotrienol is a corresponding compound in which the dotted lines denote another bond.
The process is of particular interest for preparing carboxylic esters of &agr;-tocopherol, i.e. a compound where R
1
to R
3
are each methyl, and the side chain is saturated. &agr;-Tocopherol has the highest vitamin E activity.
&agr;-Tocopherol (vitamin E; VE) has recently attained great importance in livestock nutrition and as food supplement since it is the principal lipid-soluble biological antioxidant, and because of its additional biological effect. Since free tocopherols are very readily oxidized in air, they are preferably used in the form of their esters with carboxylic acids, which are relatively stable to atmospheric oxygen at room temperature. As is evident from formula I, tocopherols are compounds with a sterically hindered phenolic hydroxyl group and thus a hydroxyl group which is extremely difficult to esterify.
It is known about phenols themselves that although they react well with acid chlorides or anhydrides they do not react with carboxylic acids to give phenol esters (cf. Brockhaus Chemie, VEB F. A., Brockhaus Verlag Leipzig, 5th edition, 1987, Volume 2/L-Z, page 846-847, left-hand column, paragraph 3 or DBP 10 35 960). The same applies a fortiori to topopherols and tocotrienols with their sterically hindered OH group. Thus, the most important tocopheryl ester, tocopheryl acetate, is prepared industrially exclusively by reacting tocopherol with acetic anhydride.
A review of processes for preparing esters of &agr;-tocopherol with aliphatic or aromatic carboxylic acids is to be found in Izvestiya vysshikh uchebnykh zavedenii, Khimiya i khimicheskaya tekhnologiya, 1991, 34(11), 3-26, in particular 4-9. According to pages 4-5 of loc. cit., alkyl carbonates are prepared by reacting VE with phosgene and subsequently with alkanols in the presence of pyridine or by reacting VE with acid chlorides of the alkylcarboxylic acids. According to page 5 of loc. cit., the palmitate, stearate, propionate, caprate and p-nitrobenzoate are also prepared by reacting VE with the appropriate acid chlorides in the presence of pyridine at 50 to 62° C. Although, according to page 5 of loc. cit., the palmitate and stearate can also be prepared by reacting VE with palmitic acid or stearic acid, this is only in the presence of costly exotic condensing agents such as carbonyldiimidazoles or thionyldiimidazoles. According to the foot of page 5 of loc. cit., succinates, malonates, glutarates and phthalates are prepared by reacting VE with a Grignard reagent and subsequently with anhydrides of the appropriate acids. According to page 6 of loc. cit., the malonate and phthalate are prepared by reacting VE with malonic anhydride and phthalic acid, respectively, in the presence of large amounts of ZnCl
2
as dehydrating agent. According to page 8 of loc. cit., &agr;-tocopheryl methoxypolyoxyethyleneacetate is prepared by reacting VE with methoxypolyoxyethyleneacetic anhydride in the presence of p-toluenesulphonic acid (6 h) or in pyridine (6 days). According to page 8 of loc. cit., &agr;-tocopheryl p-chlorophenoxyisobutyrate, which has antiatherosclerotic activity, is prepared by reacting VE with p-chlorophenoxybutyric acid in the presence of costly carbonyldiimidazoles or with the appropriate acid chloride in the presence of pyridine or else by reacting VE with sodium methoxide in methanol and reacting the resulting sodium salt of VE with p-chlorophenoxyisobutyryl chloride. According to page 8 of loc. cit., &agr;-tocopheryl pivalate is prepared by condensing VE with pivalic acid in the presence of large amounts of pyrophosphate or under the influence of enzymes. According to the foot of page 8 of loc. cit., tocopheryl salicylate is prepared by condensing VE with salicylic acid in the presence of large amounts of tetraalkyl pyrophosphate. According to the top of page 9 of loc. cit., &agr;-tocopheryl cinnamate and &agr;-tocopheryl ferulate are prepared by reaction of the appropriate acid chlorides.
According to page 9 of loc. cit., the &agr;-tocopheryl esters of linoleic acid, oleic acid and arachidonic acid, which are in demand as compounds with antiatherosclerotic effect, are prepared by reacting VE with said acids and acid chlorides or anhydrides of said acids in the presence of large amounts of tetraalkyl pyrophosphate or other acid scavengers or else recently by reacting VE with the appropriate acids in the presence of costly carbonyldiimidazoles or thionyldiimidazoles.
Another &agr;-tocopheryl derivative of medical interest is &agr;-tocopheryl sorbate which is of interest as sunscreen agent. It is prepared as disclosed in EP 313 303 B1 by reacting 1 mol of VE with 4.3 mol of a polyphosphate ester and subsequently stirring with 1 mol of sorbic acid for 16 hours.
Another application described for tocopheryl sorbate is its use as ingredient of dermatological compositions for antiacne treatment (cf. U.S. Pat. No. 5,545,407).
As is evident from the cited prior art, &agr;-tocopheryl esters are mostly prepared in the prior art by reacting VE with carbonyl chlorides or carboxylic anhydrides. The disadvantages of this are that the acid chlorides or anhydrides must previously be prepared in an elaborate manner, that working with acid chlorides industrially is rather costly, and that it is necessary in many cases to operate in pyridine, which is not advantageous for vitamin derivatives because of its unpleasant properties (inter alia the odor).
In the cases where VE is esterified with the carboxylic acids themselves in the prior art, it is necessary also to use multiple molar amounts of dehydrating agents such as polyphosphate esters, tetraalkyl pyrophosphate or zinc chloride or else to have costly condensing agents such as carbonyldiimidazoles or thionyldiimidazoles present. The use of polyphosphate esters and tetraalkyl pyrophosphate is unsuitable on an industrial scale because of the costly preparation thereof. As is evident from EP 313 303, for example, there are technical problems in preparing polyphosphate esters owing to the use of the very hygroscopic P
2
O
5
, the hazardous diethyl ether and chloroform, and the long reaction time of 48 hours. Use of zinc chloride and the imidazoles containing chloride ions from their preparation makes severe demands on the reactor material and results in high costs.
It is an object of the present invention to develop a process for esterifying tocopherols and tocotrienols in which the tocopherols or tocotrienols can be esterified with the appropriate carboxylic acids in a simple and industrially worthwhile manner without the need also to use a large excess of dehydrating agent or else costly exotic condensing agents such as carbonyldiimidazole or thionyldiimidazoles.
SUMMARY OF THE INVENTION
We have found that this object is achieved by a process for preparing tocopheryl esters or tocotrienyl esters by acid-catalyzed esterification of a tocopherol or a tocotrienol in a solvent while stirring at elevated temperature, which comprises
a) carrying out the esterification with the appropriate carboxylic acid,
b) carrying out the esterification with from 2.5 to 6 mol. preferably 3 to 5 mol. of the carboxylic acid in an aliphatic, cycloaliphatic or aromatic hydrocarbon boiling in the range from 80 to 200° C., preferably 110 to 130° C., or else with from 1.0 to 2.5 mol, preferably 1 to 1.5 mol, of the carboxylic acid in a mixture consisting of an aliphatic or cycloaliphatic hydrocarbon boiling in the range from 80 to 200° C. and a cyclic carbonate of the formula II or a &ggr;-lactone of the formula III
where R
1
, R
2
and R
3
are each H or C
Harms Guido
Jaedicke Hagen
Laas Harald
von dem Bussche-Hünnefeld Joanna Linda
BASF - Aktiengesellschaft
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Owens Amelia
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