Alkali metal salt of thiazolidine-2,4-dione derivative

Details Alkali metal salt of thiazolidine-2,4-dione derivative Alkali metal salt of thiazolidine-2,4-dione derivative

2002-07-25

2004-11-16

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06818776

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a purifying application and purifying method, using alkali metal salt of 5-[2,4-dioxothiazolidin-5-yl]methyl)-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide (herein after abbreviated as KRP-297) that improve the diabetes mellitus and hyperlipidemia in the medical field or hydrate of that salt.
BACKGROUND TECHNOLOGIES
The thiazolidine-2,4-dione-based compounds are utilized widely as core element of drugs, and, for the purification thereof, means such as repeated recrystallization with organic solvent and silica gel column chromatography are used. For preparing these compounds in the industrial scale, however, conventional methods have had such difficulties that the yield is low, the removal of impurities is insufficient, or such as harmful solvent must be used in a large quantity.
5-[(2,4-Dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide (KRP-297) represented by a following chemical formula
is a compound disclosed in Japanese Unexamined Patent Publication No. Hei 9-48771 as a therapeutic agent of diabetes mellitus and therapeutic agent of hyperlipidemia. It is reported that it has an excellent antihyperglycemic activity (M. Nomura et al,
Bioorg. Med. Chem. Lett.,
1999, 9, 533), and it has an agonistic action against human peroxisome proliferator-activated receptor (PPAR) (K. Murakami et al,
Diabetes.
1998, 47, 1841).
Currently, KRP-297 is under clinical trials as a promising therapeutic agent of diabetes mellitus and therapeutic agent of hyperlipidemia.
Hereafter, for massively and continuously preparing KRP-297 with high quality as a drug and high safety containing less impurities, it is required to solve the subjects of improved yield, removal of impurities and reduction of harmful solvents. In particular, the establishment of purifying method of KRP-297, wherein the impurities can be removed efficiently with good reproducibility, will become necessary and indispensable.
DISCLOSURE OF THE INVENTION
As a result of diligent studies to solve the subjects in the industrial preparation of KRP-297 that is promising as a drug, the inventors have found that, by once forming alkali metal salt of KRP-297 after completion of final reaction and by separating and purifying this, followed by freeing, high-purity KRP-297 can be obtained rapidly with good reproducibility, leading to the completion of the invention.
The inventive alkali metal salt of KRP-297 is a novel compound not described in the literatures, and also its usefulness has not yet been known. So far, since it has been known that the thiazolidine-2,4-dione ring is unstable to alkali and the decomposition proceeds in the presence of base, separation of alkali metal salt and industrial application such as purification using it have not been found.
In the invention, upon preparing KRP-297, its alkali metal salt is formed in the reaction system, it is separated and purified, and then freed from that alkali metal salt, thereby high-quality KRP-297 can be prepared in high yield.
The formation of alkali metal salt is conducted by adding aqueous solution or alcoholic solution such as methanol or ethanol of sodium hydroxide or potassium hydroxide to organic solvent such as methylene chloride, isopropyl alcohol or ethyl acetate, in which KRP-297 is dissolved, in a range from 0° C. to 60° C. Immediately after the addition of alkali solution, the sedimentation of salt starts and, thereafter, if stirring for 30 minutes to overnight, the formation and deposition are completed. Then, the precipitates of salt obtained are filtered and washed with small quantity of organic solvent such as isopropyl alcohol or ethyl acetate under suction, thereby obtaining alkali metal salt of KRP-297. The alkali metal salt of KRP-297 can be separated as its hydrate depending on the conditions, or, as the case may be, as its solvating medium. Usually, it can be used even without such separation and purification. Then, this alkali metal salt is dissolved into water or water-containing alcohol and acidic neutralizer such as hydrochloric acid or acetic acid is added to adjust the pH value to a range from 2 to 6, thus making it possible to free KRP-297 as precipitates. The precipitates of KRP-297 obtained are collected by filtration and washed with small quantity of water-containing alcohol, thereby KRP-297 with high purity can be obtained in high yield. Thereafter, if needed, by performing the recrystallization for the purposes of adjustment of crystal form etc., KRP-297 with high quality can be obtained.
According to the method of the invention, because of unnecessity for repeated recrystallization with organic solvent, the complexity of procedure, decrease in yield and, additionally, massive use of recrystallizing solvent and its disposal problems can be solved, hence, not only KRP-297 can be advantageously prepared industrially, but also it is provided as a drug with high purity and high quality.
The inventive alkali metal salt of KRP-297 can be separated as its hydrate depending on the conditions, or, as the case may be, as its solvating medium, which are all included in the invention. Moreover, since KRP-297 has one asymmetric carbon atom on the thiazolidine-2,4-dione ring, it can form two optical isomers, but it goes without saying that the optical isomers and their mixtures are included in that alkali salt.


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