The method of obtaining d-glucuronic acid

 

The invention relates to a method for producing D-glucuronic acid by heating salts 1,2-D-isopropylidene - D-glucuronic acid in aqueous solution in the presence of acid agents. As acidic agents used sulfoxide cation exchange resin having an exchange capacity of not less than 4 mgmEq/g, in an amount not less than 0.5 g of 0.001 mol of salts of 1,2-O-isopropylidene-D-glucuronic acid. Heating salts of 1,2-O-isopropylidene-D-glucuronic acid is carried out at a temperature 40-95oC. as an aqueous solution using an aqueous solution of ethanol with a concentration of not more than 50%. As salts of 1,2-O-isopropylidene-D-glucuronic acid use salts with alkali or alkaline earth metals or ammonium salt. The technical result - the ecological security of the method and improve the purity of the product. 4 C.p. f-crystals.

The invention relates to methods for D-glucuronic acid. D-glucuronic acid (ha) and its derivatives (lactone, salts, amides and other) are biologically active compounds, which find wide application in medicine and pharmaceutical chemistry for the synthesis of modificationsto ways to get D-glucuronic acid come from 1,2-isopropylidene-D-glucose, during oxidation which emit 1,2-isopropylidene-D-glucuronic acid (IPHC) or more of its salts (Na, K, CA, BA and others). For making the last connection in the General Ledger should be implemented stage neutralization salts and acid hydrolysis of 1,2-isopropylidene group, which can be illustrated by the scheme (for example sodium salt IPHC) that are listed at the end of the description.

D-glucuronic acid has a very high chemical lability and capable-to-many transformations under mild conditions. Normal monosaccharides tautomeric transformations in solutions (mutarotation) if GK is complicated by the formation of D-glucofuranose-6,3-lactone (GL-lactone). The ratio of components in the balance of 60% ha and 40% GK-lactone at room temperature. The increase of temperature, and the presence of acid catalysts accelerates the achievement of this balance. When heated D-glucuronic acid in the presence of strong acids is easy and decarboxylation with the formation of carbon dioxide, furfural and other degradation products. In acidic, neutral and alkaline environments Ledger turns in the epimer at C-2 and then into the corresponding keto-acid and isomeric CC allegedely. These circumstances are extremely of Sartana, or CC salt.

The known method for producing 1,2-isopropylidene-D-glucuronate, sodium (description of the invention and to.with. The USSR 883054, M. CL.307 N 7/02) used as an intermediate in the synthesis of D-glucuronic acid, its lactone (glucurono) and their derivatives by catalytic oxidation of 1,2-isopropylidene-D-glucose by oxygen in alkaline medium at elevated temperature and stirring, in which the catalyst is used, the palladium catalyst containing 1.8% Pd on charcoal, promoted potassium salt (0.8%) and sodium (0,2%), with a ratio of oxidizable compounds and catalyst 1: 0,45-of 0.91, a temperature of 65-70oC, pH 7.5-8.0 and the concentration of the original substance 1-10%.

However, in this way it is impossible to get D-glucuronic acid and GK-lactone.

A method of obtaining D-glucuronic acid (C. L. Mehltretter, Alexander B. H., R. L. Mellies et al. A Practical Synthesis of D-Glucuronic Acid through the Catalytic Oxidation of 1,2-Isopropylidene-D-glucose. // J. Am. Chem. Soc. - 1951. - V. 73. - 6. - P. 2424-2427), in which an aqueous solution of CA-IPGC heated at 90-100oWith equimolecular amount of the dihydrate of oxalic acid for 1.75 h and filtered insoluble and precipitated calcium oxalates. After removal of water and processing of the reaction mixture with ethanol p is the CIO in GK-lactone.

This method has limited functionality, as it applies only to calcium (or bereavem) salts of 1,2-O-isopropylidene-D-glucuronic acid neutralization and hydrolysis of which leads to insoluble oxalates of calcium or barium), which can be easily separated from the solution GK and GK-lactone by filtration. Other salts of 1,2-O-isopropylidene-D-glucuronic acid (e.g. sodium or potassium) give soluble oxalates, which cannot be separated from the desired products by known methods.

The closest in technical essence and the tasks of the present invention is a method of obtaining D-glucuronic acid, and excreted in the form of Na-salt (Feldman, D. P., Voitenko A. D., Shimanskaya M Century. etc. / Method of obtaining D-glucuronate sodium. // Chem-Pharm. Journal, 1984. - 11. - S. 1356-1360), which conduct acetominoven D-glucose in the presence of sulphuric acid with the formation of a mixture of two major products - 1,2-O-isopropylidene-D-glucose and 1,2;5,6-di-O-isopropylidene-D-glucose, the last connection turn by acid hydrolysis of 1,2-O-isopropylidene-D-glucose, catalytic oxidation which get 1,2-O-isopropylidene-D-glucuronate sodium. The implementation of hydrolysis when nagrevaniya by neutralization with sodium hydroxide and evaporation of the solution to dryness receive a mixture of D-glucuronate, sodium and sodium chloride. The allocation of D-glucuronate sodium from the mixture are repeated extraction with hot dimethyl sulfoxide and then adding to the extract of acetone and filtering precipitated D-glucuronate sodium.

The functionality of this method is limited by the necessity of using only those salts of 1,2-O-isopropylidene-D-glucuronic acid with metals, which give insoluble in dimethyl sulfoxide chlorides, for example, NaCl. If the resulting chlorides soluble in dimethyl sulfoxide, cleaning salt of D-glucuronic acid by extraction with hot dimethyl sulfoxide becomes impossible.

The disadvantage of this method is that when carrying out the neutralization and hydrolysis of salts of Na-IPGC using hydrochloric acid in the lability of D-glucuronic acid occur side transformations, which reduce the yield and complicate the purification processes of target products. In addition, the cleaning process of the Na-salt of D-glucuronic acid requires costly and polluting procedures extraction with dimethyl sulfoxide and the subsequent precipitation of the product with acetone.

The main task to be solved by the invention, the two the national capabilities.

This task is solved in that in a method of producing D-glucuronic acid by heating salts of 1,2-O-isopropylidene-D-glucuronic acid in aqueous solution in the presence of acid agents, as acidic agents used sulfoxide cation exchange resin.

Best is to use sulfanilic cation exchange resin having an exchange capacity of not less than 4 mgmEq/g of at least 0.5 g to 0.001 mol of salts of 1,2-O-isopropylidene-D-glucuronic acid.

Preferably the heating of the salts carried out at a temperature 40-95oC. lower the temperature of the heating significantly lengthens the process of hydrolysis, and too high leads to lower output of the D-glucuronic acid because of its lability.

Suitable as an aqueous solution to use an aqueous solution of ethanol with a concentration of not more than 50% due to the poor solubility of salts IPGC in ethanol.

As salts of 1,2-O-isopropylidene-D-glucuronic acid optimal use of alkaline, alkaline earth or ammonium salts, the cations of which are able to bind cation exchange resins, for example, Li, Na, K, Rb, Cs, Ca, Ba, Mg, Al, NH4and other

Currently the car is retene.

The proposed method is environmentally friendly and provides a cleaner product. The absence in the solution of the homogeneous acid catalyst (Hcl, oxalic acid and other acids) prevents the flow of processes side transformations of D-glucuronic acid pollutants targeted products and require treatment with expensive and polluting technologies. Sulfoxide cation exchange resin is used as the acidic agents, can be readily separated from the reaction mixture by simple filtration and easily regenerated by known methods.

The broad functionality of the proposed method is provided because it may use any salt of 1,2-O-isopropylidene-D-glucuronic acid cations which are able to bind cation exchange resin (alkali, alkaline earth or ammonium, for example, Li, Na, K, Rb, Cs, Ca, Ba, Mg, Al, NH4and others).

The ability of the proposed method in aqueous solution (mostly water-alcohol) facilitates the Stripping of solvents in the process of selection of GC and GC-lactone, as adding more low-boiling alcohol lowers the overall temperature of the boiling mixture of alcohol and water.

The use of cation exchange resins in the production of D-glucuronic acid is known (U.S. Pat. Japan 15119, 1962 Chem.Abstr., 1963, v.59, N a; U.S. Pat. Japan 1366, 1963 Chem. Abstr. , 1964, v.60, N 651a; Imai Y., Hirasaka Y. //Yakugaku Zasshi, I960, v.80, p. 1139-1142). However, they are used only in the processes of neutralization salts of D-glucuronic acid. According to the present invention sulfoxide cation exchange resin, in addition to neutralizing salts of 1,2-O-isopropylidene-D-glucuronic acid provide when heated cleavage (hydrolysis) protective isopropylidene group from these compounds.

Last hydrolytic function sulfanilic cation exchange resins in relation to the salts of 1,2-O-isopropylidene-D-glucuronic acid is not obvious and, as far as we know from sources not previously been used to obtain D-glucuronic acid.

When the neutralization and hydrolysis of the salts of Na-IPGC with hydrochloric acid produces sodium chloride. In the case of sulfanilic cation exchange resin sodium chloride (or other salts) are not available, therefore, these solutions can be isidia industry and others) as a direct source of D-glucuronic acid.

The present invention is as follows.

Heat the mixture consisting of salts of 1,2-O-isopropylidene-D-glucuronic acid, for example, the calcium salt of 1,2-O-isopropylidene-D-glucuronic acid pentahydrate, aqueous solution and sulfonyloxy cation-exchange resin, for example Amberlite-IR or KU-2 cation exchanger universal) produced Kemerovo plant "Azot". Use sulfoxide kationoobmennika resin having an exchange capacity of not less than 4 mgmEq/g, in an amount not less than 0.5 g per 0.001 mol of salts of 1,2-O-isopropylidene-D-glucuronic acid.

The heating is carried out at a temperature 40-95oC. After the reaction sulfanilyl cation exchange resin is filtered off, washed with water. The filtrate contains a mixture of D-glucuronic acid and D-glucurono (lactone D-glucuronic acid). In the specified temperature range the reaction is held for 1-5 h without side processes of degradation of the HS, so the overall yield of the reaction products (the amount of GC and GC-lactone) quantitative. The ratio of GC and GC-lactone in the product is determined only by the conditions of thermodynamic equilibrium between them (temperature and duration). As the aqueous solution using sadalsuud alkaline, alkaline earth or ammonium salts, the cations of which are able to bind cation exchange resins, for example Li, Na, K, Rb, Cs, Ca, Ba, Mg, Al, NH4and other

Removing the D-glucuronic acid from the resulting aqueous or aqueous-organic solution is possible in many known ways. For example, by neutralizing solutions of hydroxides of alkali metals and receiving the corresponding salts of D-glucuronic acid, which, in turn, can be transformed into a free D-glucuronic acid neutralization on cation-exchange resins (U.S. Pat. Japan 15119, 1962; Chem.Abstr., 1963, v.59, N a, Pat. Japan 1366, 1963; Chem. Abstr., 1964, v.60, N 651a) or processing triperoxonane acid (and.with. The USSR 1089957, 1984), or (in the case of calcium and barium chloride salts ha) by treatment with sulfuric acid (C. L. Mehltretter, Alexander B. H., R. L. Mellies et al. A Practical Synthesis of D-Glucuronic Acid through the Catalytic Oxidation of 1,2-Isopropylidene-D-glucose. // J. Am. Chem. Soc. - 1951. - V. 73. - 6. - P. 2424 - 2427; Zervas L, Sessler P. // Ber. 1933, Bd.66, S. I 326-1329; Ehrlich F., Rehorst K. // Ber., 1929, Bd. 62A, S. 628-634).

However, it is possible the direct use obtained according to this invention an aqueous or aqueous-organic solutions of GK and GK-lactone as biologically active compounds in those cases when it is necessary without the direct allocation of D-glucuronic acid and the Oli 1,2-O-isopropylidene-D-glucuronic acid pentahydrate, 75 ml of water and 14.8 g of cation-exchange resin KU-2. Cation-exchange resin is filtered off, washed with 10 ml of water. The filtrate contains a mixture of D-glucuronic acid and D-glucurono (lactone D-glucuronic acid) in approximately equal proportions. To the resulting solution at room temperature is added dropwise under peremeshivanii solution of 1N sodium hydroxide to pH 6.5-7. From the resulting solution of sodium salt of D-glucuronic acid removes water at a temperature not exceeding 30oC. the Residue is crystallized from a mixture of ethanol-water (6:5). Obtain 1.23 g of sodium salt of D-glucuronic acid. The dilution of the stock solution of 96% ethanol gives another 0.33 g of the product. Total yield 1.56 g (52%) of pure sodium salt of D-glucuronic acid hydrated with so pl. 147-149oC.

Dissolving 1.56 g of sodium salt of D-glucuronic acid hydrated in 10 ml of water, passed through a column Packed with 10 g of cation-exchange resin KU-2. Wash the column with water until neutral wash water. From the resulting solution of D-glucuronic acid removes water at a temperature not exceeding 20oC. Obtain 1.26 g of crystalline D-glucuronic acid (50% in terms of calcium salt of 1,2-O-isopropylidene-D-glucuronic acid pentahydrate).

Example 3. Heated for 3 h at 75oWith a mixture of 3.88 g (0.00641 mol) calcium salt of 1,2-O-isopropylidene-D-glucuronic acid pentahydrate, 40 ml of water, 40 ml of 96% ethanol and 14.8 g of cation-exchange resin KU-2. Cation-exchange resin is filtered off, washed with 10 ml of water. To the resulting solution at room temperature is added dropwise under peremeshivanii solution of 1N sodium hydroxide to pH 6.5-7. From the resulting solution of sodium salt of D-glucuronic acid removes water and ethyl alcohol at a temperature not exceeding 30oC. the Residue is crystallized from a mixture of ethanol - water (6:5). The resulting sodium salt of D-glucuronic acid are dissolved in 10 ml of water, passed through a column Packed with 10 g of cation-exchange resin KU-2. Wash the column with water until neutral wash water. From the resulting solution of D-glucuronic acid removes water at a temperature not exceeding 20oC. Obtain 1.23 g of crystalline D-glucuronic acid (49% in terms of calcium sales, consisting of 3.28 g (0.0128 mol) of sodium salt of 1,2-O-isopropylidene-D-glucuronic acid, 75 ml of water and 14.8 g of cation-exchange resin KU-2. Cation-exchange resin is filtered off, washed with 10 ml of water. The filtrate contains a mixture of D-glucuronic acid and D-glucurono (lactone D-glucuronic acid) in approximately equal proportions. The resulting solution was treated as in example 1, obtaining 1.28 g of crystalline D-glucuronic acid (51.5% in terms of sodium salt of 1,2-O-isopropylidene-D-glucuronic acid).

Example 5. Heated for 3 h at 75oWith a mixture of 3.88 g (0.00641 mol) calcium salt of 1,2-O-isopropylidene-D-glucuronic acid pentahydrate, 75 ml of water and 15 g of cation-exchange resin Amberlite - IR 120. Cation-exchange resin is filtered off, washed with 10 ml of water. The filtrate is treated analogously to example 1. Obtain 1.14 g of crystalline D-glucuronic acid (46% in terms of calcium salt of 1,2-O-isopropylidene-D-glucuronic acid pentahydrate).

Example 6. Heated for 4 h at 75oWith a mixture of 3.88 g (0.00641 mol) calcium salt of 1,2-O-isopropylidene-D-glucuronic acid pentahydrate, 75 ml of water, cation-exchange resin KU-2 in an amount not less than double exchange capacity (the account on the calcium salt of 1,2-O-isopropylidene-D-glucuronic acid pentahydrate).

The proposed method has been successfully tested in pilot scale using download reagents in quantities of several hundred grams.

Thus, the proposed method of producing D-glucuronic acid is environmentally safe and has a wide functionality.

Claims

1. The method of obtaining D-glucuronic acid by heating salts of 1,2-O-isopropylidene-D-glucuronic acid in aqueous solution in the presence of acid agents, characterized in that as acidic agents used sulfoxide cation exchange resin.

2. The method of obtaining D-glucuronic acid on p. 1, characterized in that as sulfanilic cation exchange resins used sulfoxide cation exchange resin having an exchange capacity of not less than 4 mgmEq/g, in an amount not less than 0.5 g of 0.001 mol of salts of 1,2-O-isopropylidene-D-glucuronic acid.

3. The method of obtaining D-glucuronic acid on p. 1, characterized in that the heating salts of 1,2-O-isopropylidene-D-glucuronic acid is carried out at a temperature 40-95oC.

4. The method of obtaining D-glucuronic acid on p. 1, characterized in that the method for obtaining D-glucuronic acid in p. 1, characterized in that salts of 1,2-O-isopropylidene-D-glucuronic acid use salts with alkali or alkaline earth group of metals or ammonium salt.

 

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