Process for the preparation of L-carnitine

Details Process for the preparation of L-carnitine Process for the preparation of L-carnitine

2000-01-27

2002-01-29

Geist, Gary (Department: 1623)

Harvesters

Reexamination Certificate

active

06342034

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the process for the preparation of L-carnitine expressed by the following formula 1, which is useful in industrial mass production due to the fact that each reaction in the aqueous solution phase is continuously carried out in a reactor without separate purification process. More particularly, this invention relates to such process, wherein (S)-3-activated hydroxybutyrolactone is utilized as a raw material so as to undergo the following chemical reactions under the specific conditions: a ring-opening reaction, epoxydation where the chiral center is inversely converted, and nucleophilic substitution of trimethylarmine.
2. Description of the Prior Art
Carnitine occurs as two enantiomers, L- and D-isomers, in terms of its stereostructural characteristics although naturally-occurring carnitine in vivo is almost exclusively the L-isomer.
L-carnitine, also known as vitamin B
T
, is present in the body tissues of animals including human and serves several vital roles. Thus, researchers have systematically focused on the physiological roles of L-carnitine. In particular, L-carnitine in vivo reacts with fatty acids with long chains which cannot pass through the mitochondria membrane. After such reaction, said fatty acids are converted into the membrane-permeable derivatives. In this pathway, L-carnitine plays a vital role in degrading the fatty acids in mitochondria via oxidation for energy source.
Meanwhile, the D,L-carnitine racemate has been used as a pharmaceutical drug or food additive in the past, but D-carnitine has been reported to have a competitive interference effect against the physiological roles of L-carnitine in vivo [Fritz, I. B., Schultz, S. K., J. Biol. Chem. (1965) 240 2188; Roe, C. R., Bohan, T. P., Lancet (1982) 1411]. Recently, there has been a trend of selectively using the optically pure L-carnitine instead of the D,L-carnitine racemate. Therefore, many of the references or patents include active research on the topic of obtaining an optically pure L-carnitine.
The conventional methods relating to the preparation of the optically pure L-carnitine are as follows:
First, according to the chemical optical resolution method, D,L-carnitine or the racemate of its derivatives is reacted with an optically pure chiral optical resolution agent to yield diastereoisomers. Then, the target diastereoisomer is obtained by resolution using the difference of solubility in an appropriate solvent. The above compound is again hydrolyzed so as to yield the target L-carnitine. The commonly used optical resolution agent includes D-camphoric acid [U.S. Pat. No. 4,254,053 (1981)], L-tartaric acid [European Patent 157,315 (1985)], dibenzoyl-D-tartaric acid [U.S. Pat. No. 4,933,490 (1990)], dibenzoyl-L-tartaric acid [U.S. Pat. No. 4,610,828 (1986)], D-mandelic acid [Japanese Unexamined Patent Publication Sho 59-231,048 (1984)], and N-acetyl-D-glutamic acid [Japanese Unexamined Patent Publication Hei 1-131,143 (1989)]. However, the aforementioned chemical optical resolution method has recognized disadvantages in that a) high-priced optical resolution agent would be inevitably used, b) the process of recovering such agent would be essential, c) the optical resolution is extremely difficult during the re-crystallization step for the formation of the diastereoisomer.
Second, there is a biological method for preparing L-carnitine using microorganisms or enzymes. L-carnitine is produced from butyrobetaine as a raw material by means of stereo-selective hydroxylation with pertinent enzymes [U.S. Pat. No. 4,371,618 (1983), U.S. Pat. No. 5,187,093 (1993)], or from crotonobetaine as a raw material by means of stereoselective hydration with appropriate enzymes [U.S. Pat. No. 4,650,759 (1987), U.S. Pat. No. 5,248,601 (1993), European Patent 457,735 (1991)]. However, these methods also have recognized disadvantages in that a) a longer reaction time of 2~3 days is required, and b) unlike the chemical reaction, the reaction concentration is extremely low as is the characteristic of the biological reactions.
Further, there is another biological method for preparing L-carnitine via the reaction between (R)-3,4-epoxybutyric acid and trimethylamine [Helvetica Chimica Acta, vol. 70, 142~152 (1987); European Patent 237,983 (1987)]. (R)-3,4-epoxybutyric acid as a main raw material undergoes a chemical reaction to yield a racemic 3,4-epoxybutyric acid ester. Based on the biological method, such ester undergoes optical resolution to yield (R)-3,4-epoxybutyric acid ester selectively, which is again hydrolyzed to produce the target compound. This method has proven to have an excellent stereo-selectivity although a careful modulation of reaction is required as is typical of the biological reaction with a prolonged reaction time of approximately 24 hours.
Third, there is the method of preparing L-carnitine by means of utilizing chiral material from the natural source. According to such method, D-mannitol is employed as a raw material. Then, via various reaction steps, L-carnitine is prepared [European Patent 60,595 (1982)]. However, this method also has recognized disadvantages in that a) the reaction steps are very complicated, and b) heavy metal compounds such as tetraacetyl lead must be employed. Further, the process of preparing L-carnitine from D-(R)-tartaric acid has been reported in the literature [Tetrahedron Letters, vol.31, 7323~7326 (1990)], but in such case, many complicated manufacturing steps are required.
Another method of preparing L-carnitine from (S)-3-activated hydroxybutyrolactone has been disclosed [U.S. Pat. No. 5,473,104 (1995)]. According to this method, (S)-3-methanesulfonyl hydroxybutyrolactone of 1.0 equivalent, and 25% trimethylarmine solution of 2.0 equivalent are mixed. Then, the mixture in a closed container is stirred at room temperature for 1 hour. In addition, the mixture is reacted at 100° C. for 16 hours to produce pure L-carnitine, but the yield is not mentioned. The above method has disclosed that as the assumed reaction routes, the following successive reactions may be implemented: A ring-opening reaction, epoxydation where the chiral center is inversely converted, and nucleophilic substitution by trimethylamine.
However, reproduction of the results therefrom could not be confirmed since L-carnitine was not obtainable based on the examples herein. To examine the method in a more accurate manner, the reaction solution was analyzed with nuclear magnetic resonance and a results showed very little amount of L-carnitine.
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 the intensive studies to overcome the problems associated with the process of preparing L-carnitine, the invention herein has been devised based on the fact that the following reactions can be carried out with (S)-3-activated hydroxybutyrolactone as a raw material under the specific conditions: a ring-opening reaction, epoxydation where the chiral center is inversely converted, and nucleophilic substitution of trimethylamine. Where reaction conditions are duly designated under said invention, the purity and yield at each reaction step are relatively high to the point that separate purification process is not required with the result of achieving the one-pot reaction herein.
Therefore, the objective of this invention is to provide a

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