Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-14
2001-05-15
Keys, Rosalynd (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S518000
Reexamination Certificate
active
06232478
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the process for the preparation of chiral 3,4-epoxybutyric acid and the salt thereof expressed by the following formula 1, wherein (S)-3-activated hydroxybutyrolactone as a raw material and other inexpensive reactants are utilized so as to undergo an efficient ring-opening reaction and epoxydation with an inversion of chiral center.
2. Description of the Prior Art
Chiral 3,4-epoxybutyric acid of formula 1 or the ester compound thereof is an useful raw material for the preparation of various chiral compounds due to the synthetic utility of the epoxy group. For example, (R)4-amino-3-hydroxybutyrolactone (GABOB) prepared from (R)-3,4-epoxybutyric acid is widely known for its use as an anti-epileptic or hypotensive drug [Otsuka, M., Obata. K., Miyata, Y., Yaneka, Y., J. Neurochem. (1971) 18, 287; Buscaino, G., A., Ferrari, E., Acta Neurol. (1961) 16, 748; DeMaio, D., Madeddu, A., Faggioli, L., Acta Neurol. (1961) 16, 366; Ushinkoba, K., Nippon Seirigaku Zassni (1959) 21, 6161.
The examples for the preparation of chiral (R)-3,4-epoxybutyric acid in the prior art are as follows: In the case of the process through the oxidation reaction after stereo-selectively introducing the epoxy group via asymunetric epoxydation reaction U. Org. Chem., vol. 49, 3707~3711(1984)], the low yield of 11~25% and stereo-selectivity of 55% ee result therefrom, which is rather problematic for the industrial purpose.
Another method is selectively obtaining (R)-3,4-epoxybutyric acid ester with the target chiral center by performing a biological optical resolution on the racemic 3,4-epoxybutyric acid ester, which in turn can be obtained via chemical method [Helvetical Chimica Acta, vol. 70, 142~152(1987); Europe Patent 237,983(1987)]. In the case above, the stereo-selectivity is superior. However, the reaction time of approximately 24 hours is required, and the yield of more than 50% cannot be expected as is the characteristic of the biological optical resolution reaction.
On the other hand, the method of preparing (S)-3,4-epoxvbutyric acid ethyl ester from (S)-3-hydroxybutyrolactone, or preparing (R)-3,4-epoxybutvric acid ethyl ester from (R)-3-hydroxybutyrolactone is well known [Larcheveque, M., Henrot, S., Tetrahedron Letters, (1987) 28, 1781; Larcheveque, M., Henrot, S., Tetrahedron, (1990) 46, 4277]. However, iodotrimethyl silane and silver oxide are rather expensive, and difficult anhydrous condition is required therein.
The optically pure 3-hydroxybutyrolactone has seldom been utilized as a chiral raw material in the past due to the difficulty in its preparation. But, recently, the very inexpensive and facile method of preparing (S)-3-hydroxybutyrolactone through oxidation and successive cyclization from inexpensive natural D-carbohydrates and hydrogen peroxide has been developed (U.S. Pat. Nos. 5,292,939, 5,319,110, 5,374,773). As a result, (S)-3-hydroxybutyrolactone is being utilized as a pivotal raw material in the preparation of various chiral compounds, and the extent of its use will be expanded.
SUMMARY OF THE INVENTION
As a result of intensive studies, the present invention has been devised in which (R)-3,4-epoxybutyric acid and the salt thereof can be economically prepared with inexpensive reagents. Under said invention, (S)-3-activated hydroxybutyrolactone as a raw material undergoes an inversion of the chiral center via ring-opening and epoxydation reactions. The inversion reaction of the chiral center with respect to the preparation of chiral 3,4-epoxybutyric acid has not been mentioned in the references. Generally, in the case of the chiral compound, both (S)- and (R)-types are useful as shown in [Larcheveque, M., Henrot, S., Tetrahedron Letters, (1987) 28, 1781; Larcheveque, M., Henrot, S., Tetrahedron, (1990)46, 4277]. In this respect, the above method is an useful reaction in which both (S)- and (R)-types of derivatives can be easily and efficiently prepared from (S)-3-hydroxybutyrolactone.
Consequently, the objective of the present invention is to prepare pure chiral 3,4-epoxybutyric acid with high yield, using relatively inexpensive and easily-handled compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the process of preparing 3,4-epoxybutyric acid of the following formula 1, wherein
(S)-3-activated hydroxybutyrolactone of the following formula 2 is subjected to a ring-opening reaction in the aqueous solvent, based on the above reaction, 4-hydroxy-3-activated hydroxybutyric acid of the following formula 3 is prepared therefrom, and
4-hydroxy-3-activated hydroxybutyric acid of said formula 3 is subjected to an inverse conversion reaction at the chiral center in the presence of a base for the preparation of 3,4-epoxybutyric acid of the following formula 1.
where R is introduced for the purpose of activating the hydroxy group and can be an alkylsulfonyl, arylsulfonyl, acyl, or phosphoryl group.
The present invention is explained in more detail as set forth hereunder. The present invention relates to the economical and inventive method of preparing highly pure chiral (R)-3,4-epoxybutyric acid and the salt thereof with -high yield by means of inverting the chiral center from (S)-3-activated hydroxybutyrolactone.
The following scheme 1 shows the preparation method of chiral (R)-3,4-epoxybutyric acid and the salt thereof according to this invention:
where R is introduced for the purpose of activating the hydroxy group and includes an alkyl, sulfonyl, arylsulfonyl, acyl group, or phosphoryl group.
(S)-3-activated hydroxybutyrolactone of formula 2 as the starting material of the present invention is a compound, which is activated for the purpose of the nucleophilic substitution of the hydroxy group in (S)-3-hydroxybutyrolactone.
Various chemical methods designed to activate the hydroxy group have been disclosed including sulfonylation, acylation and phosphorylation. Among these methods, the sulfonylation is typically used. The sulfonylation agent includes an alkylsulfonic acid anhydride, alkylsulfonyl chloride or aryisulfonyl chloride. Hence, alkylsulfonyl refers to alkylsulfonyl or haloalkylsulfonyl of C
1~12
, or more specifically includes methanesulfonyl, ethanesulfonyl, isopropanesulfonyl, chloromethanesulfonyl, trifluoromethanesulfonyl and chloroethanesulfonyl. Arylsulfonyl includes benzenesulfonyl, toluenesulfonyl, haloarylsulfonyl such as chlorobenzenesulfonyl or bromobenzenesulfonyl, naphthalenesulfonyl, alkoxyarylsulfonyl of C
1~4
such as methoxybenzenesulfonyl and nitroarylsulfonyl. The compound expressed by formula 2, prepared via said activation reaction, includes (S)-3-alkylsulfonylhydroxybutyrolactone, (S)-3-arylsulfonyl hydroxybutyrolactone, and so on. For this purpose, (S)-3-methanesulfonyl hydroxybutyrolactone is generally used.
The first reaction step is a ring-opening reaction of (S)-3-activated hydroxybutyrolactone expressed by formula 2. The ring-opening reaction of this invention is similar to the reaction in which the ester group is hydrolyzed. However, in view of the reaction mechanism, the general hydrolysis method cannot work due to the presence of the 3-activated hydroxy group which is easily detachable at the 8-position of the carbonyl group of the compound of formula 2. In this regard, several commonly known hydrolysis methods have been implemented, but the ring-opening reaction did not occur with respect to the compound of formula 2. Therefore, the target compound of formula 3 under this invention could not be obtained. For example, the hydrolysis of the esters using water as a solvent in the presence of sodium hydroxide is known to be irreversible and quantitative. However, when the ring-opening reaction of 3-methanesulfonylhydroxybutyrolactone was attempted among the compounds of formula 2, the compounds without the sulfonylhydroxy group(-OR) were mainly obtained. In addition to sodium hydroxide, various types of bases (e.g., inorganic bases such as potassium hydroxide, or organic amines such as trieth
Byun Il Suk
Choi Yoon Hwan
Kim Kyung Il
LandOfFree
Process for the preparation of chiral 3,4-epoxybutyric acid... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Process for the preparation of chiral 3,4-epoxybutyric acid..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of chiral 3,4-epoxybutyric acid... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2477163