Continuous process for preparing optically pure...

Details Continuous process for preparing optically pure... Continuous process for preparing optically pure...

1999-07-23

2001-09-11

Killos, Paul J. (Department: 1623)

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

Organic compounds

Carboxylic acids and salts thereof

C562S515000, C560S186000, C435S064000, C435S072000, C435S075000

Reexamination Certificate

active

06288272

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a continuous process for preparing optically pure (S)-3,4-dihydroxybutyric acid derivatives expressed by the following Formula 1 and more particularly, to the continuous process which enables preparing optically pure (S)-3,4-dihydroxybutyric acid derivatives economically in large quantities, by:
(a) Preparing &agr;-(1,4) linked oligosaccharide having adequate sugar distribution by reacting amylopectin which is easily available from natural product with enzyme under a specific condition; and
(b) Performing oxidation by running basic anion exchange resin with an oxidant to give (S)-3,4-dihydroxybutyric acid-anion exchange resin complex, dissociating the (S)-3,4-dihydroxybutyric acid from anion exchange resin complex and esterification sequentially under a specific condition.
 wherein, R represents linear or branched alkyl group with 1~5 carbon atoms.
Description of the Related Arts
(S)-3,4-Dihydroxybutyric acid derivatives and (S)-3-hydroxy-&ggr;-butyrolactone are used as synthetic intermediates for preparing various chiral compounds. For example, it is well known that they act as key intermediates for preparing neuromeidator (R)-GABOB [Tetrahedron, 46, 4277(1990)], treatment for hyperlipemia (Atorvastatin; HMG-CoA reductase inhibitor) [Tetrahedron Lett., 33, 2279(1992)], (S)-oxiracetam which is improvement agent in brain metabolism [International patent publication WO93/06,826], L-carnitin which is health supplement agent [International patent publication WO99/05,092], (S)-3-hydroxytetrahydrofuran [
J Am. Chem. Soc
., 117, 1181(1995); International patent publication WO94/05,639] which is an essential intermediate of AIDS drug (Agenerase; HIV protease inhibitor), (S)-mono-betalactam [Japanese patent publication 64-13,069(1989)], ester of (S)-3-hydroxy-4-bromobutyric acid [Japanese patent publication 4-149,151(1992); Japanese patent publication 6-172,256(1994)], potentiating intermediate of satiety agent [
Bull. Chem. Soc. Jpn
., 61, 2025(1988)] and neuroleptic drug [USP 4,138,484] and useful intermediates in synthetic efforts towards natural products [
J. Org. Chem
., 50, 1144 (1985),
Can. J. Chem
., 65, 195 (1987),
Tetrahedron Lett
., 507 (1992)]. Optical purity is the most important factor in preparing these chiral compounds.
The conventional techonologies for preparing (S)-3,4-dihydroxybutyric acid derivatives and (S)-3-hydroxy-&ggr;-butyrolactone, which are useful for preparing the said chiral compounds, are explained in detail hereunder.
Methods of preparing (S)-3-hydroxybutyric acid derivatives from the enzymatic or catalytic reduction of &bgr;-ketoester were known [
J. Am. Chem. Soc
., 105, 5925~5926(1983);
Teterahedron Lett
., 31, 267~270(1990); European patent publication 452,143A2]. These methods have difficulty in that the prochiral center should be reduced to one-side to generate chiral center and expensive metal catalyst should be used.
A technology preparing ester of (S)-3,4-dihydroxybutyric acid and (S)-3-hydroxy-&ggr;-butyrolactone by selective reduction of (L)-malic acid ester was known [
Chem. Lett
., 1389~1392(1984); U.S. Pat. No. 5,808,107]. This technology has disadvantage in that reduction should be performed selectively to only one of the two ester functional groups.
Many methods of preparing (S)-3,4-dihydroxybutyric acid derivatives and (S)-3-hydroxy-&ggr;-butyrolactone from carbohydrate have been reported.
A technology preparing isosaccharinic acid (B) or (S)-3,4-dihydroxybutyric acid (C) is reported [
J. Chem. Soc
., 1924~1931(1960)] by alkaline degradation of carbohydrate containing glucose substituent in the 4-position, such as 4-O-methyl-(D)-glucose, maltose, amylose and cellulose, elimination of C-4 substituent as leaving group, forming dicarbonyl compound (A; 4-deoxy-2,3-hexodiulose), and reacting the formed dicarbonyl compound with base as shown in Scheme 1. However, the yield of (S)-3,4-dihydroxybutyric acid is low.
Also, it has been reported that (S)-3,4-dihydroxybutyric acid (C) and glycolic acid (D) were obtained as major products by forming dicarbonyl compound (A) from alkaline degradation of carbohydrate containing glucose substituent in the 4-position, and separating the formed dicarbonyl compound (A) and reacting it with hydrogen peroxide[
J. Chem. Soc
., 1932~1938(1960)]. This method has a serious problem that the product exists as small amounts of isomers due to tautomerization and a mixture of cyclic compounds and hydrates derived from dicarbonyl compound (A). So, the dicarbonyl compound (A) cannot be separated in good yields from the reaction mixture. Another problem is that the prepared (S)-3,4-dihydroxybutyric acid is degraded to formic acid and glycolic acid due to the overoxidation.
A similar technology for preparing (S)-3,4-dihydroxybutyric acid from carbohydrate either using base only or using oxygen in base was known. It proposed that the dicarbonyl compound (A) was a synthetic intermediate for (S)-3,4-dihydroxybutyric acid as shown in the Scheme 1. But the yield was reported to be as low as about 30% [
J. Res. Natl. Blir. Stand
., 32, 45(1944);
J. Am. Chem. Soc
., 2245~2247(1953);
J. Am. Chem. Soc
., 1431~1435(1955);
Carbohyd. Res
., 11, 17~25(1969);
J. Chromatography
, 549, 113~125(1991)]. In these methods, (S)-3,4-dihydroxybutyric acid is produced with various kind of mixtures including glycolic acid (D), isosaccharinic acid (B), formic acid, ketone, diketone and glyceric acid. Since the yield of (S)-3,4-dihydroxybutyric acid is very low, these methods are also considered as not suitable for industrial use.
A method for preparing (S)-3,4-dihydroxybutyric acid from disaccharide (lactose) using base and oxidant has been reported [International patent publication WO98/04543]. In this work, (S)-3,4-dihydroxybutyric acid was cyclized to (S)-3-hydroxy-&ggr;-butyrolactone under the reaction condition and purified by protection of the two hydroxy groups to acetonide ester compound, methyl (S)-3,4-O-isopropylidene-3,4-dihydroxybutanoate, which was recyclized to (S)-3-hydroxy-&ggr;-butyrolactone under acidic media.
Preparing methods of (S)-3,4-dihydroxybutyric acid including the process of alkaline oxidation of carbohydrate containing glucose substituent in the 4-position have been known [U.S. Pat. No. 5,292,939, 5,319,110 & 5,374,773(1994)]. In these methods, dicarbonyl compound (A) intermediate is formed at first, oxidized to (S)-3,4-dihydroxybutyric acid (C) and glycolyic acid (D). However, optical purity, the most important physical property of chiral compounds, is not mentioned at all. Also, purification of target compounds is very difficult, considering the reaction mechanism. In the case of disaccharides such as maltose or lactose, only one sugar unit in the disaccharide forms (S)-3,4-dihydroxybutyric acid and the other sugar unit functions as leaving group, so that the target product and leaving group coexist as 1:1 mixture. Accordingly, it is very difficult to separate and purify (S)-3,4-dihydroxybutyric acid or (S)-3-hydroxy-&ggr;-butyrolactone from the reaction mixture. The theoretical mass conversion obtainable is 28.3 wt %. In other words, 28.3 g of (S)-3-hydroxy-&ggr;-butyrolactone can be obtained from 100 g of disaccaride. For polysaccharides, such as maltodextrin, starch and cellulose, mentioned in the above patents, the (1,4) and/or (1,6) glucose units are linked complexly like nets. The problem is that the step-by-step oxidation proceeding from the reducing end units comprising (1,4) linkage terminates at (1,6) linkage unit. Therefore no more target product is formed. Also, the polysaccharides are degraded by overoxidation of reducing end units to complex acid mixtures containing formic acid, oxalic acid, glycolic acid and erythronic acid [
J. Am. Chem. Soc
., 81, 3136(1959); Starch 41 Nr. 8, S. 303~309(1989);
Synthesis
, 597~613(1997)].
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