| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | March 8, 1994 |
| PATENT TITLE |
Process for the preparation of 3,4-dihydroxybutanoic acid and salts thereof |
| PATENT ABSTRACT | A process for the preparation of 3,4-dihydroxybutanoic acid (1) and salts thereof from a glucose source containing 1,4-linked glucose as a substituent is described. The process uses an alkali metal hdyroxide and hydrogen peroxide to convert the glucose source to (1). The compound (1) is useful as a chemical intermediate to naturally occurring fatty acids and is used to prepare 3,4-dihydroxybutanoic acid-gamma-lactone (2) and furanone (3), particularly stereoisomers of these compounds |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | October 26, 1992 |
| PATENT REFERENCES CITED |
Rowell et al., Carbohydr. Res., 11, 17-25 (1969). Moody, Advances in Carbohydr. Chem., 19, 149-179 (1964). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
I claim: 1. A process for the conversion of a hexose source containing D-hexose as a substituent and another sugar attached to the D-hexose substituent in the 4 position to 3,4-dihydroxybutyric acid and glycolic acid which comprises: (a) reacting in a reaction mixture the hexose source with a base selected from the group consisting of an alkali metal hydroxide and an alkaline earth metal hydroxide and a peroxide oxidizing agent until 3,4-dihydroxybutyric acid and glycolic acid are formed as essentially the only products, wherein the peroxide and the base are present in a range up to a 4 molar excess over the D-hexose and wherein the D-hexose is between about 0.05 to 80% by weight per volume of the reaction mixture. 2. The process of claim 1 wherein the D-hexose source is selected from the group consisting of maltose, lactose and maltodextrans. 3. The process of claim 1 wherein the D-hexose source is selected from the group consisting of starch and starch hydrolysates. 4. The process of claim 1 wherein the D-hexose source is cellulose. 5. The process of claim 1 wherein the base is between about 0.005M and 0.2M and wherein the hydrogen peroxide is between about 0.05M and 0.2M. 6. The process of claim 1 wherein the glycolic acid is separated from the reaction mixture by distillation. 7. The process of claim 1 wherein the peroxide oxidizing agent is selected from the group consisting of alkali metal peroxides, alkaline earth metal peroxides and hydrogen peroxide. 8. The process of claim 1 wherein the 3,4-dihydroxy butyric acid is separated from the reaction mixture. 9. A process for the conversion of a glucose source containing glucose as a substituent and another sugar attached to the glucose substituent in the 4 position to 3,4-dihydroxybutyric acid and glycolic acid which comprises: (a) reacting in a reaction mixture the glucose source with a base selected from the group consisting of an alkali metal hydroxide and an alkaline earth metal hydroxide and hydrogen peroxide until 3,4-dihydroxybutyric acid and glycolic acid are formed as essentially the only products, wherein the peroxide and the base are present in a range up to a 4 molar excess over the glucose and wherein the glucose is between about 0.05 to 80% by weight per volume of the reaction mixture. 10. The process of claim 9 wherein the 3,4-dihydroxybutyric acid is (S)-3,4-dihydroxybutanoic acid. 11. The process of claim 9 wherein the glucose source is selected from the group consisting of maltose, hexose and maltodextrans. 12. The process of claim 9 wherein the glucose source is selected from the group consisting of starch and starch hydrolysates. 13. The process of claim 9 wherein the glucose source is cellulose. 14. The process of claim 9 wherein the base is sodium hydroxide, wherein the sodium hydroxide is between about 0.005M and 0.2M and wherein the hydrogen peroxide is between about 0.05M and 0.2M. 15. The process of claim 9 wherein the glycolic acid is separated from the reaction mixture by distillation. 16. The process of claim 9 wherein the reaction is conducted at between about 25.degree. and 80.degree. C. for at least about 4 hours. 17. The process of claim 16 wherein the reaction is conducted at about 70.degree. C. for between about 14 and 24 hours. 18. The process of claim 10 wherein the 3,4-dihydroxy butyric acid is separated from the reaction mixture. |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for preparation of 3,4-dihydroxybutanoic acid and salts thereof from a D-hexose source, particularly a glucose source containing glucose as a substituent. In particular, the present invention relates to a process for preparing (S)-3,4-dihydroxybutanoic acid and salts thereof. 2. Prior Art During the course of the development by syntheses for 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 we had envisioned. A reaction in which some of the desired product is generated in a 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 is, 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 (Glattfeld, 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 glycollic 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.degree. 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. 3,4-Dihydroxybutanoic 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)). OBJECTS It is therefore an object of the present invention to provide a process for preparing a 3,4-dihydroxybutanoic acid from a D-hexose source. It is further an object of the present invention to provide a process which is simple, economical and inexpensive. These and other objects will become increasingly apparent by reference to the following description and the drawings. IN THE DRAWINGS FIG. 1 shows the mechanism of alkaline peroxide degradation of a 4-linked glucose. FIG. 2 shows 300 MHz .sup.1 H-NMR spectrum of a crude reaction mixture after treatment of maltose with 0.16M sodium hydroxide at 70.degree. C. for 24 hours. FIG. 3 shows 300 MHz .sup.1 H-NMR spectrum of a crude reaction mixture after treatment of maltose with 0.16M sodium hydroxide and 1.3 equivalents of hydrogen peroxide for 24 hours at 70.degree. C. FIG. 4 shows .sup.13 C-NMR spectrum of a crude reaction mixture after treatment of maltose with 0.16M sodium hydroxide and 1.3 equivalents of hydrogen peroxide for 24 hours at 70.degree. C. FIG. 5 shows 300 MHz .sup.1 H-spectrum of (S)-3-hydroxybutyrolactone. FIG. 6 shows 300 MHz .sup.1 H-NMR spectrum of crude reaction mixture after treatment of starch with 0.16M sodium hydroxide and 1.3 equivalents of hydrogen peroxide for 24 hours at 70.degree. C. Note the signals between 2 and 2.5 ppm due to the C-2 methylene group of the 3,4-dihydroxybutanoic acid (1). GENERAL DESCRIPTION The present invention relates to a process for the conversion of a hexose source containing D-hexose as a substituent and another sugar attached to the D-hexose substituent in the 4 position to 3,4-dihydroxybutyric acid and glycolic acid which comprises: reacting in a reaction mixture the glucose source with a base selected from the group consisting of an alkali metal hydroxide and an alkaline earth metal hydroxide and a peroxide oxidizing agent until 3,4-dihydroxybutyric acid and glycolic acid are formed; and separating the 3,4-dihydroxybutyric acid and glycolic acid from the reaction mixture. The present invention particularly relates to a process for the conversion of a glucose source containing glucose as a substituent and another sugar attached to the glucose substituent in the 4 position to 3,4-hydroxybutyric acid and glycolic acid which comprises: reacting in a reaction mixture the glucose source with a based selected from the group consisting of an alkali metal hydroxide and an alkaline earth metal hydroxide and hydrogen peroxide until 3,4-dihydroxybutyric acid and glycolic acid are formed; and separating the polypeptide from the reaction mixture. The preferred glucose source is starch or maltose. The hexoses in the hexose source can be any D-hexose such as galactose, mannose, glucose and the like. These sugars will produce the 3,4-dihydroxybutyric acid by the process of the present invention. The reaction can also be applied to cellulose. Both cellulose and starch are among the most abundant materials on earth. The process of the present invention transforms these and similar abundant, renewable resources to otherwise inaccessible intermediates which can be used in the pharmaceutical, chemical and polymer industries and reduce our dependence on petrochemicals. The peroxide oxidizing agent can be any peroxide which will produce the 3,4-dihydroxybutyric acid. These include alkaline earth metal peroxides such as barium peroxide, the alkali metal peroxides such as sodium peroxide and hydrogen peroxide. The selection of the peroxide is within the skill of the art. The base is selected from alkali metal and alkaline earth metal peroxides. These include zinc hydroxide, calcium hydroxide (lime), potassium hydroxide, sodium hydroxide and the like. The selection of the base is with the skill of the art. Preferably the sodium hydroxide or potassium hydroxide and the hydrogen peroxide molar concentration is between 1 to 2 fold of the total 4-linked hexose. The concentration up to 4 fold can be used but with increasing degradation of the desired product. The D-hexose source is preferably at least about 0.05 percent up to about 80% by weight per volume of the reaction mixture. Preferably the reaction of the base with the glucose source is conducted for at least about 4 hours, preferably between about 14 and 24 hours. The reaction is conducted at a preferred temperature between about 25.degree. and 80.degree. C. The preferred reactions are shown in Schemes I, II and III as follows: ##STR1## Scission of the bond between the two carbonyl groups of the diulose F resulting from the degradation of the glucose source occurs in the presence of alkaline hydrogen peroxide before any competing reactions to yield the required (1) which is stable to further reaction. On acidification of the reaction mixture, (1) undergoes spontaneous cyclization to yield the gamma-lactone (2) which is dehydrated, on heating in the presence of acid, to yield the unsaturated lactone (3). Treatment of the lactone (2) with hydrogen bromide in acetic acid in the presence of ethanol should readily yield (S)-4-bromo-3-hydroxybutanoic acid ethyl ester, the key fragment in our chiral 3-hydroxy fatty acid syntheses. (S)-3,4-dihydroxybutanoic acid (1) and glycolic (4) acid were the only products formed from the 4-substituted glycosyl residues of maltose or starch when these compounds were treated with alkaline hydrogen peroxide at 70.degree. C. for 24 hours. Acidification of the reaction mixture and concentration to dryness led to complete conversion of the hydroxybutanoic acid to the gamma-lactone (2). This could be isolated by chromatography on silica gel or converted to the 2(5H)-furanone (3) by distillation of the acidic reaction mixture under reduced pressure. The reaction of maltose or starch under these conditions is thought to proceed by cleavage between the two carbonyl groups of an intermediate 4-deoxy-D-glycerohex-2,3-diulose (F) as in FIG. 1. In the absence of hydrogen peroxide, a complex reaction mixture is formed in which the desired products do not predominate. This reaction opens the way to the preparation, in high yield, of large quantities of valuable chiral building blocks from a cheap, renewable, natural resource |
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| PATENT PHOTOCOPY | Available on request |
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