Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-04-24
2001-05-29
Gitomer, Ralph (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
Reexamination Certificate
active
06239311
ABSTRACT:
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to an improved process for preparation of 3,4-dihydroxybutanoic acid, glycolic acid and salts thereof from a D- or L-hexose source, particularly a D- or L-glucose source, containing glucose as a substituent. Further, the present invention relates to a process for preparing lactones derived from (S)-3,4-dihydroxybutanoic acid and salts thereof.
(2) Prior Art
During the course of the development by syntheses of naturally-occurring (R)-3-hydroxy long chain fatty acids, various synthetic routes to (S)-4-bromo-3-hydroxybutanoic acid methyl or ethyl esters were examined. The general approach was to carve out this chiral fragment from a suitably modified carbohydrate structure. Initial attempts involved selective protection and structural modification of methyl alpha-D-glucopyranoside followed by cleavage to yield a 4-carbon fragment containing the required functionalities. Although this approach proved to be quite viable, it proved not to be as direct as was believed.
A reaction in which some of the desired product is generated in fewer steps from inexpensive starting materials was considered. The treatment of cellobiose, a beta-1,4-linked glucose disaccharide, maltose (the alpha-1,4-linked isomer) and other related compounds with alkali has been shown to generate low yields of the desired material along with D,L-2,4-dihydroxybutanoic acid, glycolic acid, isosaccharinic acids, ketones, diketones, glyceric acids and a myriad of other degradation and condensation products (Corbett, W. M., et al., J. Chem. Soc., 1431-1435 (1955); Green, J. W., J. Amer. Chem. Soc. 78:1894-1897 (1956); and Rowell, R. M., et al., Carbohydr. Res. 11:17-25 (1969)). Starch and cellulose also yield similar compounds in what is known as the “peeling reaction”. This process was generally thought to have no synthetic potential. Most of the products formed in these reactions are formed from the intermediate dicarbonyl (diulose) compound F shown in
FIG. 1
according to a mechanism proposed by Isbell (Isbell, H. S., J. Res. Natl. Bur. Stand., 29:227 (1942)). The dicarbonyl compound F is rapidly attacked by alkali to yield a tarry mixture and the formation of 3,4-dihydroxybutanoic acid (1) and glycolic acid (4) as shown in
FIG. 1
in low yields and is slow and oxygen-dependent.
Alkaline hydrogen peroxide rapidly cleaves diketones to give carboxylic acids and treatment of diuloses and other carbohydrates with hydrogen peroxide in this manner has been described (Moody, G. J., Advances in Carbohydr. Chem. 19:149-180 (1964)). The reference does not describe the use of hydrogen peroxide to cleave a glucose source containing a 1,4-glucose linkage. Earlier work on the oxidation of maltose (Glattfield, J. W. E., et al., J. Amer. Chem. Soc. 40:973 (1918) using base and hydrogen peroxide yielded no 3,4-dihydroxybutanoic acid but gave glycolic acid, arabonic acid, D-erythronic acid, oxalic acid and formic acid. In this work, the reaction was conducted for a very prolonged period (13 days) at room temperature followed by an undefined period at 50° C. The molar proportions of base and hydrogen peroxide were both 8 to 9 fold of the sugar proportion. These conditions cause complete conversion of product to formic acid.
U.S. Pat. Nos. 5,292,939, 5,319,110 and 5,374,773 to the present inventor describe a significant improvement in the preparation of 3,4-dihydroxybutanoic acid and salts from a D- or L-hexose source using a base and a peroxide oxidizing agent. The preparation of the lactones is also described. The purpose of the present invention is to improve upon these processes.
The methods described for the preparation and isolation of optically active 3-hydroxy-&ggr;-butyrolactone by the alkaline oxidation of 4-linked hexoses have several drawbacks that limit their utility in commercial processes. One of the major limitation in the oxidation is that very low concentrations of peroxide and hydroxide and are typically used (Hollingsworth, R., U.S. Pat. Nos. 5,292,939; 5,319,110 and 5,374,773; Hollingsworth, R., J. Org. Chem. 64:7633-7634 (1999); and Huang, G. and R. I. Hollingsworth, Tetrahedron 54:1355-1360 (1998)). This limits the concentration of carbohydrate substrate that can be transformed to product to 0.02M or less. Because of this, the throughput of a commercial manufacturing system is severely limited. The concentrations of peroxide and hydroxide cannot be increased without the onset of unfavorable side reactions.
Another serious limitation is the necessity of removing all of the water from the acidified reaction mixture to effect lactonization of the 3,4-dihydroxy acid to the corresponding 3-hydroxy-&ggr;-butyrolactone product. It is estimated that 80% of the time spent in water removal is used in removing the last 20%. The time for water removal on a batch size of over 3,000 gallons is several days. There is also a tendency for the undesired acid catalyzed dehydration of the lactone to occur leading to the formation of 2(5H)-furanone. Another complication is that the syrup formed in the complete water removal stage is often too viscous to allow proper agitation. This leads to further dehydration because of local overheating. Yet another complication is the requirement for six or more extractions of the syrup with a suitable organic solvent for acceptable recovery of the lactone product. The resistance of the syrup to flow and the large number of extractions needed do not allow the implementation of a process where the reaction mixture can be concentrated and extracted in a continuous fashion. These drawbacks present a significant barrier to the efficient commercial utilization of this route to these important hydroxy acids and their corresponding lactones.
3,4-Dihydroxybutanoic and is a valuable chiral building block and the general strategies for obtaining it and its derivatives hinge upon the development of enzymatic systems utilizing beta-ketoesters as substrates (Nakamura, N., et al., Tetrahedron Letters, 30:2245-2246 (1989); Zhou, B., et al., J. Amer. Chem. Soc., 105:5925-5926 (1983); and Nakamura, N., et al., Tetrahedron Letters, 31:267-270 (1990)).
A chiral chemistry platform has been developed based on optically active 3,4-dihydroxybutyric acids and their gamma lactones. They allow access to other compounds ranging from alcohols, amines, halides, acids, esters, epoxides, acetals, tetrahydrofurans, pyrolidines, amides, nitrites and acid halides through much more complex structures in a stereospecific method. These compounds are important intermediates in the synthesis of a variety of chiral drug substances ranging from antiviral through broad spectrum antibiotics to cholesterol lowering drugs and drugs used for diabetes management. These uses are well documented in the literature (Corey, E. J., et al., J. Amer. Chem. Soc. 100 1942-1943 (1978); Uchikawa, O., et al., Bull. Chem. Soc. Jpn. 61 2025-2029 (1988); Hayashi, H., et al., J. Amer. Chem. Soc. 95 8749-8757 (1973); Danklmaier, J., et al., Liebigs. Ann. Chem. 1149-1153 (1988); Mori, Y., et al., Tetrahedron Letts. 29 5419-5422 (1988); Shieh, H. M., et al., Tetrahedron Letts 23 4643-4646 (1982); Mori, K., et al., Tetrahedron Letts 29 5423-5426 (1988); and Saito, S., et al., Chem. Letts 1389-1392 (1984)). They include the preparation of compounds such as eicosanoids (Corey, E. J., et al., J. Amer. Chem. Soc. 100 1942-1943 (1978)), modified nucleic acid bases (Hayashi, H., et al., J. Amer. Chem. Soc. 95 8749-8757 (1973)), the polyol function of macrolide antibiotics (Mori, Y., et al., Tetrahedron Letts. 29 5419-5422 (1988)), and (−) aplysistatin, an anti-cancer agent (Shieh, H. M., et al., Tetrahedron Letts 23 4643-4646 (1982)). The facile preparation of beta-lactams (an entire family of antibiotics) is also possible as is the preparation of the lactone ring of cholesterol lowering drugs such as Atorvastatin and Mevacor. More recently its use has been expanded into a variety of other areas, one important example of which is the synthesis of chiral substituted azetidinones
Board of Trustees operating Michigan State University
Gitomer Ralph
Khare D.
McLeod Ian C.
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