Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-05-02
2001-11-27
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
Reexamination Certificate
active
06323359
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a process for the preparation of derivatives of the antioxidant probucol. More particularly, the present invention relates to a process for preparing water-soluble derivatives of probucol compounds by reaction of the salts of such compounds with carboxylic acid anhydrides.
BACKGROUND OF THE INVENTION
Probucol is a well-known antioxidant that is chemically related to 2-[3]-tert-butyl4-hydroxyanisole, 2,6-di-tert-butyl4-methylphenol and the like. These materials are commonly used in foods to prevent oxidative deterioration. The compound probucol, 4,4′-(isopropylidenedithio) bis(2,6-di-tert-butylphenol), is represented by the following structural formula
The preparation of this compound is a multistep process, starting by reacting a solution of the appropriately-substituted 4-mercaptophenol with acetone, in the presence of a catalytic amount of hydrochloric acid. Probucol precipitates from the reaction mixture and is readily separated and purified. The reaction is described in detail in U.S. Pat. No. 3,862,332 (Barhhart et al).
Similarly, probucol and certain of its derivatives is also described in U.S. Pat. No. 3,485,843 (Wang), U.S. Pat. No. 3,576,833 (Neuworth) and U.S. Pat. No. 4,985,465 (Handler).
As noted above, probucol is related to antioxidants found useful as food additives. However, this compound has also proven effective as a serum cholesterol-lowering agent for treating patients suffering from hypercholesterolemia. Further, probucol has been suggested as an effective antiviral compound (see U.S. Pat. No. 4,985,465 cited above) as well as a compound that may be active in treating arrhythmia (see U.S. Pat. No. 4,719,273 to McCaughn).
Administration of probucol itself into the human body is difficult because of its lack of solubility in aqueous solutions. While it cannot be injected intravenously and is poorly miscible in buffered solutions, solid dosage forms such as tablets or capsules are commercially available for administration. Unfortunately, even this route is subject to problems, since uptake by the body is poor. It appears that patients administered the same concentration of probucol obtain sera levels of the compound that differ by as much as 20 times. In order to avoid the low water solubility problems associated with probucol utilization in the body, water-soluble derivatives have been prepared that spontaneously hydrolyze in aqueous environments to probucol. Thus, U.S. Pat. No. 5,262,439 (Parthasarathy), incorporated herein in its entirety by reference, disclose a class of water-soluble probucol derivatives having one or more ester groups replacing the phenolic hydroxyl group of the probucol molecule. Some of the compounds disclosed in this reference have polar or charged functionalities attached to the ester group, e.g., the groups carboxylic acid, amide, amino, and aldehyde. The method for preparing these water-soluble probucol compounds involves the treatment of a solution of probucol with the carboxylic acid anhydride compound bearing the desired polar or charged functionality in the presence of a catalyst. The catalyst is disclosed to be 4-(dimethylamino)pyridine. While the reaction is relatively simple in concept, the isolation of the desired derivative is complex to the point that economically acceptable yields of these water-soluble derivatives is not possible.
Accordingly, there is a need for a method to prepare water-soluble derivatives of probucol that is simple and provides the di sired compound in good yields.
SUMMARY OF THE INVENTION
A method is described for the preparation of water-soluble derivatives of probucol compounds having the following formula
where R
1
and R
2
are the same or different and are alkyl, alkenyl or aryl having from 1 to 8 carbon atoms, R
3
, R
4
, R
5
and R
6
are the same or different and are alkyl having from 1 to 4 carbon atoms and X and Y are the same or different and are hydrogen or the groups saturated acyl or unsaturated acyl having from 1 to 8 carbon atoms said saturated or unsaturated acyl groups containing a polar or charged functionality. The method for preparation of such compounds
where R
3
, R
4
, R
5
and R
6
are as previously defined with a compound selected from the group consisting of alkali metal hydride, alkali metal hydroxide, alkali metal alkoxide, alkyl ammonium alkoxide, alkyl ammonium hydroxide and mixtures thereof. The reaction forms a solution of the ammonium or alkali metal salt of the probucol compound, which may be separated from the reaction mass and further reacted or, more conveniently, used “as is” in the subsequent, second, reaction step. In such second step, the salt (or the “as is” reaction solution) is reacted with a carboxylic acid anhydride selected from the group consisting of succinic acid anhydride, glutaric acid anhydride, adipic acid anhydride, suberic acid anhydride, sebacic acid anhydride, azelaic acid anhydride, phthalic acid anhydride and maleic acid anhydride. The water-soluble probucol compound is then separated from the resulting reaction mixture.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides a process for preparing water-soluble probucol compounds that is an improvement over the prior art processes.
The process of the present invention utilizes a starting material that is a probucol compound having the following formula
where R
1
and R
2
are the same or different and are alkyl, alkenyl or aryl having from 1 to 8 carbon atoms and R
3
, R
4
, R
5
and R
6
are the same or different and are alkyl having from 1 to 4 carbon atoms.
Preferably, R
1
and R
2
are the same and are alkyl having from 1 to 8 carbon atoms, most preferably methyl.
Preferably, R
3
, R
4
, R
5
and R
6
are the same and are alkyl having from 1 to 4 carbon atoms, most preferably tert-butyl.
As a first step in the method for preparing water-soluble probucol compounds according to the present invention, the hydroxyl groups of probucol compounds illustrated above are reacted with a compound that forms an alkali metal or ammonium salt of such probucol compounds. These materials are highly basic reactants and are selected from the group consisting of alkali metal hydride, alkali metal hydroxide, alkali metal alkoxide, alkyl ammonium alkoxide, alkyl ammonium hydroxide and mixtures thereof.
The alkyl group as disclosed herein, such including the alkyl group of alkoxides, is C
1
to C
8
alkyl and includes the moiety's methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylpentyl, n-octyl and the like.
Preferably the alkali metals of these reactants are lithium, sodium, potassium and cesium, most preferably sodium or potassium with potassium being especially preferred.
A particularly preferred reactant used to produce the salt of the probucol compounds are sodium or potassium butoxide.
The salt of the probucol compound prepared in the first step as set forth above is next reacted with a compound that contains a group reactive with the ammonium or alkali metal phenoxide formed at the 4- and 4′-positions of the bisphenol moiety. Such compounds may be described as those that are saturated or unsaturated acyl that have attached to them groups that bear a polar or charged functionality. Illustrative classes of compounds of this nature are saturated or unsaturated dicarboxylic acids, amines, amides, aldehydes or salts of such compounds.
In the most preferred embodiment, second step of the above class of reactants with the salt of probucol compounds formed in the first step of the process of the invention are dicarboxylic acids, dicarboxylic acid anhydrides and the salts thereof such compounds having from 2 to 8 carbon atoms, the salts including the alkali metal salts, alkaline earth metal salts, ammonium salts, the transition metal salts, the noble metal salts and the heavy metal salts of such dicarboxylic acids or acid anhydrides.
Particularly preferred reactants with the salt of the probucol compounds formed in the first step of the process of the present invention are
Hammond Richard J.
Killos Paul J.
Salsbury Chemicals, Inc.
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