Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-10-17
2002-12-24
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S512000, C562S523000, C562S527000, C562S540000, C536S018200
Reexamination Certificate
active
06498269
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to methods for the oxidation of aldehydes, hemiacetals, and primary alcohols. The method finds particular utility in the production of monosaccharide aldaric acids and polyuronic acids.
BRIEF DESCRIPTION OF THE RELATED ART
Carbohydrates, or saccharides, have great promise as a renewable resource in the large-scale production of chemicals for industrial, pharmaceutical, and home use. Not only is the promise of tapping a renewable resource of great economic interest, but a number of carbohydrate-based polymers have been shown to be biodegradable. These materials may therefore also satisfy growing environmental concerns. This appealing combination of advantages is, however, often offset by the unavailability of economical processes for the production of carbohydrate-based raw materials.
D-glucose (also known as dextrose) is the building block of starch, cellulose, and maltose, and is widely used in the food industry, as a feedstock for sorbitol production, and as a carbon source in industrial fermentations. It is currently produced on large industrial scale by the enzymatic hydrolysis of starch. However, broader industrial use of the oxidized forms of D-glucose is hampered by a number of problems, including reaction selectivity. Use of oxidized forms of oligocarbohydrates and polycarbohydrates (as phosphate-free detergent builders, metal chelators, and additives for glues, inks, and the like) is similarly limited by lack of reaction selectivity.
Glucaric acid, a diacid in which both terminal ends of the glucose molecule are in the forms of acid finctionalities, is an especially useful oxidation product of glucose. Not only glucaric acid, but carbohydrate-based acids (e.g. aldaric acids, polyuronic acids) in general show great promise as raw materials for the formation of biodegradable detergents, metal complexation agents (special sequestrants/preservatives in, for instance, cooling fluids and or foods), biodegradable polymers for high tensile strength fibers, films, adhesives and plant fertilizers. Glucaric acid has also been shown to have anti-tumor and chemopreventive properties, cholesterol-lowering effects, and has been shown to be a viable chelating agent for radioisotopes of biomedical interest such as
99m
Tc. This isotope is used for the radioimaging of tumors, bone structures and the early detection of myocardial infarction.
D-glucaric acid is generally made by direct oxidation of D-glucose as shown below:
The current difficulty in obtaining D-glucaric acid on a commercial scale is reflected in its price, which is more than 100-fold that of glucose. Classic prior art methods for the production of glucaric acid from glucose use strong oxidants such as nitric acid or nitrogen oxides. These methods are characterized by low overall yields due to poor selectivity of these oxidations and large quantities of undesired degradation products formed. The number of side products and decomposition products formed require economically inefficient separation steps for the isolation of the glucaric acid or its salts. Other oxidation methods require use of expensive precious metal catalysts such as platinum, palladium, ruthenium or their oxides, or have other requirements, which render them less suitable for large-scale industrial processes, such as expensive and/or environmentally unfavorable solvents or reaction conditions.
Hypochloride (M
+
OCl
−
, bleach) and hypbromide (M
+
OBr
−
) are known to oxidize carbohydrates, but the reaction is characterized by long reaction times, destruction of the backbone of polymeric saccharides and thus low yields, on the order of 12% based on the starting material (Mehltretter, et al., Adv. Carbohydr. Chem. Vol. 8, pp. 231-249 (1953).
As reviewed by de Nooy et al. in Synthesis, Vol. 10, pp. 1153-1174 (1996), addition of a nitroxide-based catalyst to a sodium hypochloride solution results in improved yields, such that up to quantitative yields of oxidation product can be observed. The outcome of these oxidation reactions is strongly dependent on the particular reaction conditions chosen, as detailed by de Nooy, et aL in
Tetrahedron
, Vol. 51, pp. 8023-32 (1995). Oxidations using bleach are only possible with solutions containing no more than 15 weight percent of total dissolved solids, and addition of commercial bleach solution results in further dilution of the reaction mixture. Scale-up of this process is accordingly difficult, requiring larger and more expensive equipment, more space, and more energy, and generating more waste. Product isolation from dilute solutions is also more difficult.
Yamaguchi et al., in Bull. Chem. Soc. Jpn., Vol. 63, 947-948 (1990) disclose the oxidation of primary and secondary alcohols to using a nitroxide/chlorine system in organic solvents in yields in the range from bout 60 to 70%. The reported oxidation is non-selective, and thus unsuitable for use in oxidations of carbohydrate substrates such as glucose to the corresponding acids.
There accordingly remains a need in the art for efficient, environmentally favorable methods for the high yield production of carbohydrate diacids suitable for large-scale industrial production. It would be a further benefit if the method were generally applicable for the oxidation of aldehydes, hemiacetals, and primary alcohols in the presence of other functional groups.
SUMMARY OF THE INVETION
The above described drawbacks and disadvantages are alleviated by a method for the oxidation of substrates comprising treating an aqueous, basic solution of a substrate having an oxidizable functionality using an elemental halogen as terminal oxidant in the presence of an oxoammonium catalyst/halide co-catalyst system. In contrast to the prior art, use of elemental halogen, preferably chlorine gas or elemental bromine, unexpectedly allows selective oxidation without significant degradation of the substrate. The substrate is preferably a monosaccharide, oligosaccharide, or polysaccharide, and the oxidizable functionality is preferably an aldehyde, hemiacetal, or a primary alcohol. An effective source of the oxoammonium catalyst is based on 2,2,6,6-tetrarnethylpiperidinyl-1-oxy (TEMPO) and a particularly economical and effective catalyst is 4-acetylamnino-2,2,6,6-tetramethylpiperidinyl-1-oxy.
In a particularly preferred embodiment, a 5- or 6-carbon monosaccharide is oxidized to the corresponding aldaric acid, without substantial degradation of the backbone. The oxidized product may be isolated by filtration of the corresponding salts, or by acidification and extraction. The oxidation is highly selective for terminal groups, such that direct isolation of the product alkaline or alkaline metal salt from the reaction mixture yields analytically pure product.
This straightforward process produces highly desirable products in high yield and with high selectivity. Use of an inexpensive oxidant such as chlorine in an aqueous solvent allows for scaling up of the oxidation method to industrially relevant scales, thus providing significant advantages over other prior art methods. The above discussed and other features and advantages of the present invention will be appreciated and understood by those skilled in the art from the following detailed description.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
A high-yield, selective method for the oxidation of functional groups such as aldehydes, hemiacetals, and primary alcohols comprises treating an aqueous, basic solution of a substrate having an oxidizable functional group with an elemental halogen in the presence of a catalytic quantity of an oxoammonium catalyst/halide co-catalyst system. In an important and unexpected feature, use of elemental halogen does not result in the degradation of the substrate. In the case of the oxidation of D-glucose to D-glucaric acid, the reaction may result in the production of high yields (>90%) of analytically pure potassium salts, or the glucaric acid may be isolated by acidification and extraction.
Substrates suitable for oxidation have
Bobbitt James M.
Brückner Christian
Merbouh Nabyl
Cantor & Colburn LLP
Dentz Bernard
The University of Connecticut
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