Organic compounds -- part of the class 532-570 series – Organic compounds – Fatty compounds having an acid moiety which contains the...
Reexamination Certificate
2000-04-21
2002-04-09
Carr, Deborah D. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Fatty compounds having an acid moiety which contains the...
C554S206000
Reexamination Certificate
active
06369251
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for purification of a polyprenyl compound.
2. Related Art
(2E, 4E, 6E, 10E)-3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid, which is one of polyprenyl compounds, has been known to have suppressing effect on recurrence of hepatic carcinoma (New England Journal of Medicine, 334, 1516 (1996)).
Polyprenyl compounds are a known class of compounds as disclosed in Japanese Patent Publication (Kokoku) Nos. 63-32058, 63-34855 and the like. As described in the above patent publications, a purification method for polyprenyl compounds is known which comprises the step of subjecting crude crystals of polyprenyl compounds obtained by a reaction to crystallization and recrystallization in n-hexane.
SUMMARY OF THE INVENTION
The conventional purification of polyprenyl compounds using n-hexane fails to completely remove impurities produced during or after the reaction. The inventors of the present invention eagerly conducted researches on purification of polyprenyl compounds that are susceptible to oxidization with light, air and the like. As a result, they found that peroxides or oxides, which were not completely removable by the treatment using n-hexane, were perfectly removed by stirring a crude polyprenyl compound in an alcoholic solvent such as methanol for several hours with warming, and then carrying out recrystallization. They also found that a target polyprenyl compound of an extremely high purity was obtained by the above procedure. The present invention was achieved on the basis of these findings.
The present invention thus provides a method for purification of a polyprenyl compound, which comprises the step of recrystallizing a polyprenyl compound, preferably (2E, 4E, 6E, 10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid represented by Formula (I), by using a solvent comprising an alcohol.
According to preferred embodiments of the present invention, there are provided:
the aforementioned method for purification of a polyprenyl compound, wherein the polyprenyl compound is a polyprenylcarboxylic acid;
the aforementioned method for purification of a polyprenyl compound, wherein the polyprenyl compound is (2E, 4E, 6E, 10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid;
the aforementioned method for purification of a polyprenyl compound, wherein the solvent is an alcohol, preferably methanol; and
the aforementioned method for purification of a polyprenyl compound, wherein a purity of the polyprenyl compound after the purification step is 99.9% or higher.
PREFERRED EMBODIMENTS OF THE INVENTION
A particularly preferred example of the polyprenyl compound which can be purified by the method of the present invention includes (2E, 4E, 6E, 10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid whose chemical formula is shown above. Other examples of the polyprenyl compounds include conjugated polyprenylcarboxylic acids (polyprenoic acids) such as 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid and esters thereof disclosed in Japanese Patent Publication (Kokoku) No. 63-34855, more specifically, such as (2E, 4E, 6E, 10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid ethyl ester, which can be used as a raw material for the preparation of (2E, 4E, 6E, 10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid.
The polyprenyl compounds used in the present invention can be synthesized by a known method disclosed in Japanese Patent Publication (Kokoku) No. 63-32058 and Journal of Chemical society (C), 2154, 1966.
The recrystallization using a solvent comprising an alcohol is performed by recrystallizing crude crystals of a polyprenyl compound, or by recrystallizing crystals of a polyprenyl compound of a relatively high purity. As the alcoholic solvent used for the recrystallization, examples include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-methylpropanol, 3-methyl-1-butanol and the like, and among them, methanol is preferably used. In addition, a solvent containing an alcohol such as methanol and ethanol can also be used for the present invention. Examples of a solvent which can be used as a mixture or a suspension with an alcohol include, for example, halogenated solvents such as carbon tetrachloride, chloroform and dichloromethane, hydrocarbonic solvents such as n-pentane, n-hexane, n-heptane, isooctane, cyclohexane, methylcyclohexane, toluene, benzene and xylene, ether solvents such as diethyl ether, diisopropyl ether, t-butyl methyl ether, methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane, 1,1-diethoxypropane, 1,1-dimethoxymethane and 2,2-dimethoxypropane, ester solvents such as ethyl acetate and ethyl formate, other organic solvents such as acetonitrile, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, acetone, methyl ethyl ketone, methyl isopropyl ketone, petroleum ether, and water.
The recrystallization according to the present invention is performed by dissolving a polyprenyl compound in a solvent comprising an alcohol, preferably an alcoholic solvent such as methanol and ethanol, most preferably methanol, and then cooling the solution to allow precipitation of crystals.
Specifically, a solvent comprising an alcohol is added to a polyprenyl compound, and the mixture is stirred within a temperature ranging from room temperature to a boiling temperature of the solvent comprising an alcohol under heating. Then, the solution is left stand to allow precipitation of crystals.
More specifically, when methanol is used as the solvent comprising an alcohol, the solution is warmed to generally 50 to 70° C., preferably about 60° C. and stirred generally for about 1 hour or more, preferably about 3 hours. Then, the solution is left stand for cooling to allow precipitation of crystals.
By carrying out the purification of the present invention, a high purity of 99.9% or higher can be obtained for (2E, 4E, 6E, 10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid and the like. One of advantages of the high purity of the compound obtained by the present invention may include the following. Namely, for a government approval of the manufacture of a new drug, structural determination, and evaluation of toxicity and pharmacological action as well as normalization of a product are required for an impurity contained at a content ratio of 0.1% or more. Therefore, the process of obtaining a highly purified compound by the purification of the present invention is useful to obtain a drug with an excellent quality.
REFERENCES:
patent: 4655973 (1987-04-01), Yamatsu et al.
patent: 4757140 (1988-07-01), Deluca et al.
patent: 4841038 (1989-06-01), Deluca et al.
patent: 4917829 (1990-04-01), Yamatsu et al.
patent: 781809 (1957-08-01), None
patent: 63-32058 (1988-06-01), None
patent: 63-34855 (1988-07-01), None
patent: WO 94/22818 (1994-10-01), None
patent: 94/22818 (1994-10-01), None
344 New England Journal of Medicine 1561 (1996).
1966 Journal of Chemical Society 2154 (1966).
Patent Abstracts of Japan 56140949.
Patent Abstract of Japan 57106638.
K. Ashizawa et al., “The Crystal Structure of 3,7,11,15-tetramethy1-2,4,6,10,14-all trans-hexadecapentaenoic acid”, 33 Chem. Pharm. Bull. 7, 3062-64 (1985).
Gomi Noriaka
Takano Michika
Carr Deborah D.
Greenblum & Bernstein P.L.C.
Nikken Chemicals Co., Ltd.
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