RU2455296C2 - Method of producing aldonic acids and derivatives thereof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: described is a method of producing L-gluconic acid and salt thereof, which involves treatment of aqueous solution of 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone with a base at pH equal to at least 12 and temperature from 45 to 60°C to obtain aqueous solution of L-gluconic acid. The invention also describes methods of producing 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone by reacting 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone with a Lewis base in a ketone solvent in the presence of catalytic amounts of water.

EFFECT: methods have high output and are realised with less expenses and without anhydrous solvents.

11 cl, 5 ex

Description

BACKGROUND OF THE INVENTION

Natural glucose exists as a D-isomer and this isomer is preferred for most applications because it is a biologically active isomer. However, in some cases, the biological inactivity of the L-isomer is useful. For example, L-glucose can be used as a laxative or bowel cleanser, which can be useful, for example, if a scan of the colon and rectum is required.

However, since it is not widely distributed in nature, the synthesis of L-glucose and its analogues proved to be difficult and expensive. In previous methods for the synthesis of L-glucose, L-arabinose was usually used as the starting material. L-arabinose is a naturally occurring sugar that is available in large quantities from beet pulp according to the method described in Chemical Abstracts: 142135v, Vol. 75, 1971. In accordance with this method, dry beet pulp is treated with sulfuric acid to obtain an extract solution, which are subsequently fermented, evaporated and filtered. Then L-arabinose is crystallized from the resulting filtrate.

L-glucose can be obtained from L-arabinose according to the method of Sowden and Fischer, J.A.C.S., Vol. 69 (1947), pp. 1963-1965. In accordance with this method, L-arabinose is condensed with nitromethane in the presence of sodium methoxide to give sodium salts of nitro alcohols. Sodium salts are readily converted to the corresponding sugars through the Nef reaction.

Lundt et al. (I. Lundt, C. Pedersen, Synthesis , 7 , 669-672, (1992)) report that 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone can be obtained by the reaction of 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone with potassium fluoride under severely anhydrous conditions. The reaction described by Lundt et al. Is carried out using anhydrous potassium fluoride in anhydrous acetone, and the importance of anhydrous conditions is repeatedly emphasized.

A method for converting D-glucono-1,5 lactone or a salt thereof to 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone is described by Lundt et al. (I. Lundt, C. Pedersen, Synthesis , 7 , 669-672, (1992)). In this method, the starting material gluconolactone is stirred with ice-cold hydrogen bromide at room temperature for 18 hours, the reaction mixture is cooled and quenched with methanol, then, after settling overnight, the reaction mixture is concentrated to syrup, evaporated together with methanol and then water. After that, water is added and the product is extracted with ether.

SUMMARY OF THE INVENTION

The present invention relates to a method for the synthesis of L-gluconic acid, which has a higher yield and can be carried out at a lower cost than traditional methods. Specifically, the method relates to a method for converting 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone to L-gluconic acid. In addition, the method optionally includes additional steps for the preparation of the starting material, 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone from the readily available D-glucono-1,5-lactone compound. Additionally, it includes optional steps for converting L-gluconic acid to L-glucose and L-glucose analogs. The present invention may be extended to the preparation of epoxides from bromohydrins.

Definitions

Bromohydrin is an organic compound containing bromine and hydroxyl on adjacent carbon atoms.

An epoxide is an organic compound with a three-membered ring containing two carbon atoms and an oxygen atom. The chemical reaction in which the epoxide is formed is epoxidation.

Lactone is an organic compound with a ring containing a —O — C (O) - moiety.

α-Bromohydrinlactone is an organic compound that is both bromohydrin and lactone, and the bromohydrin bromine atom is located on the carbon atom adjacent to the carbonyl (i.e., C (O) fragment) of the lactone.

Aldonic acid is a compound of the formula HOOC- (CHOH) _n —CH ₂ OH, where n is from 1 to 7. Preferably, n is 3 or 4. Preferably, the aldonic acid is L- or D-gluconic acid.

Aldonolactone is an aldonic acid lactone, preferably containing from 3 to 9 carbon atoms, more preferably 5 or 6 carbon atoms.

α-Bromohydrinaldonolactone is an organic compound that is both bromohydrin and aldonolactone, and the bromohydrin atom is on the carbon atom adjacent to the carbonyl (i.e., C (O) fragment) of the lactone. Preferably, α-bromohydrinaldalolactone contains from 3 to 9 carbon atoms, more preferably 5 or 6 carbon atoms.

Epoxyaldonolactone is aldonolactone, which is an epoxide. α-Epoxyaldonolactone is an epoxyaldonolactone in which the oxygen atom of the epoxide is located on the carbon atom adjacent to the carbonyl (i.e., C (O) fragment) of the lactone. Preferably, epoxyaldonolactone contains from 3 to 9 carbon atoms, more preferably 5 or 6 carbon atoms.

An organic solvent is a solvent containing carbon.

A monosaccharide is a molecule with the chemical formula (CH ₂ O) _{n + m} , with the chemical structure H (CHOH) _n C = O (CHOH) _m H, where m and n are integers and m + n is at least to two. If either n or m is zero, then the monosaccharide contains an aldehyde group and is called an aldose; otherwise, it contains a ketone group and is called a ketose. At least half of the non-carbonyl carbon atoms of the monosaccharide have a hydroxyl substituent. Examples of monosaccharides include aldotetrosis, such as erythrose and threose; ketotetrosis, such as erythrulose; aldopentoses, such as arabinose, lyxose, ribose and xylose; ketopentoses, such as ribulose and xylulose; aldohexoses, such as allose, altrose, galactose, glucose, gulose, idose, mannose and talose; ketohexoses, such as fructose, psychosis, sorbose and tagatose; keto-heptoses, such as mannoheptulose and sedoheptulose; octoses such as octolose and 2-keto-3-deoxymethano-octonate; nonoses, such as sialose.

An oligosaccharide is a polymer containing from two to ten monosaccharide components. Examples of oligosaccharides include sucrose, lactose, maltose, trehalose and cellobiose.

A polysaccharide is a saccharide polymer containing more than ten monosaccharide components. Examples of polysaccharides include starch, cellulose and dextran.

A saccharide is a monosaccharide, oligosaccharide or polysaccharide and saccharides with one or more substituents, where the substituents can be, for example, a halide, amine, C ₁ -C ₅ alkyl, amino acid, protein, nucleoside, nucleotide, phosphate, sulfate and carboxy.

Detailed description

The present invention is based on the discovery of a new method for producing L-gluconic acid from D-glucono-1,5-lactone, which includes three different aspects of the present invention: obtaining 2,6-dibromo-2,6-dideoxy-D-mannono-1, 4-lactone from D-glucono-1,5-lactone (third aspect of the present invention); preparation of 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone from 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone (second aspect of the present inventions); and preparation of L-gluconic acid from 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone (first aspect of the present invention). This method can be further expanded by converting L-gluconic acid to L-gluconolactone and then converting L-gluconolactone to L-glucose.

The second aspect of the present invention can be expanded to obtain epoxides from bromohydrins. Specifically, the second aspect of the present invention takes advantage of the discovery that the preparation of epoxides from bromohydrins is particularly good if a catalytic amount of water is present in the reaction mixture. Shorter reaction times and higher yields are achieved compared to the harshly anhydrous conditions previously used to carry out the reaction, thereby obtaining better results without expensive anhydrous solvents.

The preparation of L-gluconic acid from 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone is known (I. Lundt, R. Madsen, Top. Curr. Chem., 215 , 177- 191, (2001)), but previously it was always carried out by adding an ice base to the starting material, followed by ensuring the course of the reaction for three days. In contrast, in the method of the present invention, the reaction usually proceeds to completion within no more than 6 hours. At this elevated temperature, one would expect that at the high pH required for the reaction, the starting material, 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone, will decompose, but unexpectedly discovered that this is not happening. Apparently, the possibility of losing the starting material was probably the reason that the reaction was carried out at 0 ° C before.

In the case of obtaining L-gluconic acid by the method according to the invention, the reaction proceeds to completion within no more than 6 hours, usually not more than 5 hours and, more preferably, not more than 4 hours. In contrast, the traditional method takes three days to flow to completion. This reduction in time provides significant cost savings and convenience of the method according to the invention in comparison with known methods. The inventors have found that the reaction temperature is important, with the preferred reaction temperature being 45-55 ° C and more preferably 45-50 ° C. The reaction can be carried out in an aqueous solvent, preferably in a mixture of an organic solvent and water. Suitable organic solvents are polar solvents such as ketones, for example acetone or methyl isobutyl ketone (MIBK).

The pH at which the reaction is carried out is also important, with a minimum value of pH 12. However, preferably, the pH of the reaction mixture is 12.5, more preferably 13, and most preferably about 13.5-14.

The base used in the method according to the invention is preferably an alkali or alkaline earth metal hydroxide, for example potassium, sodium or calcium hydroxide, although more favorable results are obtained using potassium and sodium hydroxide. The inventors have found that the best results are achieved using a molar ratio of hydroxide to 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone in the range between 1: 2 and 1: 4, but preferably 1 : 3. Using this amount of base ensures that the reaction mixture is sufficiently alkaline for the reaction to proceed.

The reaction product is a salt, the counterion of which depends on the base used in the method. However, if desired, the free acid can be obtained by acidification of the product mixture, preferably with a strong acid, such as hydrochloric acid, to a pH of about 1-2.5, or by size exclusion chromatography. If the acid method is used, the product can be isolated from the solution using conventional methods, for example, by evaporation of the solvent.

You can also get salts with alternative counterions from a solution of the free acid by neutralization to pH 7 using an aqueous solution of a base having a suitable counterion. For example, if a calcium salt is required, the acid solution may be treated with a base such as calcium carbonate or calcium acetate. The calcium gluconate salt is not particularly soluble and can be isolated by precipitation and filtration. Other more soluble salts, for example sodium and potassium salts, can be obtained by neutralizing the acidified solution, as noted above, followed by recrystallization of the desired salt.

The method may include isolating the product, L-gluconic acid or its salt, but for many applications, for example, if the product is intended to be used in another reaction, isolation is not necessary, and the mixture of products from the method can be used without further purification.

L-gluconic acid or its salt can, in turn, be converted to L-gluconolactone and, optionally, to L-glucose. Thus, the method optionally further includes:

(ai) converting L-gluconic acid or a salt thereof to L-gluconolactone; and optional

(aii) conversion of L-gluconolactone to L-glucose.

Stage (ai) and (aii) can be carried out by known methods. For example, a salt solution of L-gluconic acid can be converted to acid by acidification with a strong acid, as described above. The solution can be heated to a temperature of approximately 40-60 ° C and concentrated by removing most of the solvent. Then, an alcohol solvent may be added to form L-gluconolactone.

L-gluconolactone can be converted to L-glucose by treatment with a reducing agent, such as sodium borohydride. The reaction usually takes place at a temperature of from -10 to 5 ° C in an aqueous solvent, and the product can be purified by ion exchange followed by crystallization, usually from water and / or an alcohol solvent.

In a second aspect of the present invention, there is provided a process for preparing epoxides (such as 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone) by reacting bromohydrin (such as 2,6-dibromo-2, 6-dideoxy-D-mannono-1,4-lactone) with a Lewis base in the presence of a catalytic amount of water.

Unexpectedly, the author of the present invention found that the reaction does not proceed particularly well under harsh anhydrous conditions and that improvements in reaction time and yield are obtained if a catalytic amount of water is present in the reaction mixture. The fact that the reaction actually proceeds faster in the presence of a catalytic amount of water is an advantage since the need for expensive anhydrous reagents is eliminated.

Typically, the reaction is carried out in an organic solvent, usually in a ketone, such as acetone and / or methyl isobutyl ketone (MIBK). Other possible solvents include a non-polar solvent, for example hexane, benzene, toluene, diethyl ether, chloroform, ethyl acetate and dichloromethane; a polar aprotic solvent, for example dioxane, tetrahydrofuran, acetone, methyl isopropyl ketone, methyl isobutyl ketone, butanone, mesityl oxide, acetonitrile, dimethylformamide and dimethyl sulfoxide; and, less preferably, a polar protic solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, formic acid and acetic acid. Preferred solvents include ketones, for example acetone, methyl isopropyl ketone, methyl isobutyl ketone, mesityl oxide and butanone. Mixtures of two or more solvents are also contemplated.

The term “catalytic amount of water” refers to the water content in the reaction solvent, which may be from about 0.05 to 2 wt.%. However, it is preferred that the reaction solvent contains from about 0.2 to 0.8% or from 0.2 to 0.9% by weight, more preferably from about 0.4 to 0.6% or from 0.4 to 0 , 9 wt.%, And usually approximately 0.5 wt.% Or from 0.75 to 0.8 wt.%, For example 0.77 wt.% Water.

Any suitable Lewis base may be used, but examples of particularly suitable bases include alkali metal fluorides and carbonates, for example potassium fluoride, potassium carbonate, cesium carbonate and rubidium fluoride. Potassium fluoride is particularly suitable as it is inexpensive and readily available. The present inventors have found that the most favorable results are achieved using spray dried potassium fluoride as a Lewis base.

The reaction can be carried out with any suitable bromohydrin. Preferred bromohydrins include bromohydrins of aldonic acids and aldonolactones and lactones of α-bromohydrin. Particularly preferred bromohydrins include α-bromohydrin aldonolactones, for example, allonolactone, altronolactone, galactonolactone, gluconolactone, gulonolactone, idonolactone, mannolactone and talonolactone. The reaction product is preferably epoxyaldonolactone, such as α-epoxyaldonolactone.

The reaction is preferably carried out at a temperature of from 20 to 45 ° C, including room temperature, i.e. 20-25 ° C; more preferably 30-45 ° C, even more preferably 30-40 ° C. Typically, the reaction temperature is maintained at approximately 40 ° C. The reaction proceeds relatively quickly and usually ends within about 1 hour.

The method of the second aspect of the invention may be accompanied by conversion of the product in a subsequent reaction, for example, conversion of 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone to L-gluconic acid, which can be achieved using the method according to the first aspect of the invention.

In a third aspect of the present invention, a method for producing 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone is provided:

(ci) the interaction of D-glucono-1,5-lactone or its salt with hydrogen halide at a temperature of from 40 to 60 ° C;

(cii) adding methanol to the reaction mixture, bringing the temperature of the reaction mixture to 40-55 ° C and maintaining this temperature until the completion of the reaction.

Preferred hydrogen halides are hydrogen bromide, which can be used in a solvent such as acetic acid, and hydrogen chloride, which can be in solution or in gaseous form.

The desired temperature can be maintained by adjusting the temperature to 40-50 ° C after step (ci) and adjusting the rate at which methanol is added to the reaction mixture to ensure that the desired temperature is reached and maintained. After completion of the methanol addition, the reaction temperature is maintained at 45-55 ° C. until the reaction is complete.

It is possible to determine the completion of the reaction by monitoring at specific intervals. This can be done, for example, using thin-layer chromatography at certain time intervals by a method known to specialists in this field. The reaction is completed either when the entire starting material disappears, or when the amount of the starting material remains unchanged from one measurement to another.

The temperature at which the reaction is carried out is an important characteristic. If the reaction temperature is very low, the reaction will proceed at a rate that is unacceptably low, while if it is very high, large amounts of by-product are obtained from the side elimination reaction. The preferred temperature range for reaction step (ci) is from 50 to 60 ° C, with a range of 50-55 ° C or 53-57 ° C being more preferred, and most preferably, the temperature is kept as close as possible to 55 ° C. The reaction time for step (ci) is usually from 40 to 60 or 80 minutes, for example about 45 minutes or 60 minutes.

In step (cii), some cooling is usually required before the methanol is added, the reaction temperature being preferably brought to about 25-35 ° C, for example about 30 ° C. Further, methanol is preferably added at such a rate that the temperature reaches a peak below 55 ° C. It has been found that the addition of methanol over a period of about 12 to 20 minutes is usually satisfactory if the reaction temperature is brought to about 30 ° C. before the methanol is added. In this case, the exothermic reaction that occurs when methanol is added usually reaches a peak at about 40-45 ° C. After the addition of methanol, the preferred reaction temperature is 50-55 ° C. and, as a rule, the reaction proceeds to completion approximately 4 hours after the addition of methanol.

Once the reaction is complete, additional steps can be used to isolate and purify the product. A particularly effective optional process for isolating a product includes:

(ciii) distilling the product of step (cii);

(civ) dissolving the product of step (ciii) in methyl isobutyl ketone (MIBK) and washing the solution with sodium bicarbonate and water; and optional

(cv) product extraction by crystallization or evaporation of the solvent.

Methylisobutylketone (MIBK) is a particularly suitable solvent for isolating the product since it dissolves the desired product, 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone, but does not dissolve the more polar by-product.

If necessary, use the product, 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone, for the synthesis of 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4 -lactone, it is usually preferable to skip step (cv) and use the solution obtained in step (civ) directly in the next step, especially when the solvent used in step (civ) is methyl isobutyl ketone. However, in this case, it is useful to wash the product of step (civ) with a weak base, such as sodium bicarbonate, so as to bring the pH of the solution to 6-7 and bring the water content in the solution to about 0.5-2%, more typically 0, 7-1.5% and, as a rule, approximately 1 wt.%.

Using the first, second and third methods described above, it is possible to convert D-glucono-1,5-lactone to L-gluconic acid.

EXAMPLES

Example 1 - Synthesis of 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone

Scheme

Methodology

D-glucono-1,5-lactone (300 g) is loaded into a 6-liter jacketed reactor equipped with a mechanical stirrer mounted on top. Ice-cold 33% HBr (885 ml) was charged and the reaction mixture was heated to 50-55 ° C and kept at 50-55 ° C for 60 minutes. The solution was cooled to 30 ° C, then methanol (342 ml) was added over 13 minutes, while the exothermic reaction peaked at 42 ° C. The solution is heated to 50-55 ° C and maintained at this temperature for 4 hours. The solvent is removed under reduced pressure, with the reactor jacket temperature set at 40 ° C. until the product volume in the reactor reaches approximately 500 ml. MIBK (1000 ml) was added and the solution was cooled to 0 ° C. The cold solution is washed with saturated aqueous sodium hydrogen carbonate solution (1000 ml and 200 ml), then with water (200 ml). MIBK is distilled off in vacuo and the water content is checked to ensure that it is below 1%. The solution can be used for the next step.

Rf: 0.3 (toluene: acetone 4: 1)

Mp 133-135 ° C

¹ H NMR δ (CD ₃ CN): 4.94 (1H, d, J _2.3 4.40Hz, H-2), 4.57 (1H, dt, J _3.2 4.40Hz, J _{3, 4} 2.96Hz, H-3), 4.42 (1H, dd, J _4.3 2.96Hz, J _4.5 8.85Hz, H-4), 4.15 (1H, m, H-5 ), 4.12 (1H, d, J 5.80Hz, H-OH), 3.55 (1H, dd, J _rem 11.08Hz, J _6.5 2.8Hz, H-6), 3.5 ( 1H, d, 6.12 Hz, H-OH), 3.68 (1H, dd, J _hem 11.08 Hz, J _6.5 5.16 Hz, H-6).

Example 2 - Synthesis of 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone

Scheme

A solution of 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone (1100 g) in MIBK (2840 g) is loaded into a 6 L container equipped with a mechanical stirrer mounted on top. The water content in the solution was adjusted to 0.77%. The solution was then heated to 40 ° C, after which potassium carbonate (1009 g, 2.2 molar equivalents) was added, followed by potassium fluoride (636.5 g, 5 molar equivalents). The suspension is stirred for 1 hour at 40 ° C, after which time the reaction is complete. The suspension is filtered off and the filter cake washed with additional MIBK (4 x 400 ml). A solution containing 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone in MIBK was used for the next step without further purification.

Example 3 - Synthesis of L-gluconic acid

A solution containing 6-bromo-6-deoxy-2,3-anhydro-D-mannono-1,4-lactone in MIBK was charged into a 6 L container equipped with a mechanical stirrer mounted on top. Water (1 ml for every 4 ml of MIBK solution) was added to the stirred solution, followed by the addition of a 3N sodium hydroxide solution until a pH> 13 was reached. After 30 minutes, the stirrer was stopped and the aqueous layer was collected. The MIBK layer is washed with water (1 ml for every 4 ml of MIBK solution). The aqueous layers are combined and then heated at 45-50 ° C for 4-5 hours, after which time the reaction is complete. The pH was adjusted to 5-7 by the addition of aqueous HCl.

The formation and characterization of calcium salt is carried out as follows:

The solution from the rearrangement reaction (which contains 2.9 g of epoxide) is acidified to pH 2 by the addition of hydrochloric acid. Potassium carbonate was added to the acidified solution until pH 7 was reached. After 2 days, crystalline calcium-L-gluconate was isolated by filtration, washing the cold precipitate on the filter with cold aqueous methanol (7: 3, 5 ml). The product was dried in vacuo to give an off-white solid 1.42 g, 54% in two steps.

[α] _d ²² -5.5 ° (c = 3, water)

¹ H NMR δ (D ₂ O): 4.16 (1H, dd, J1.2Hz and J3.4Hz), 4.05 (1H), 3.79 (1H, dd), 3.76 (1H, m ), 3.73 (1H, dd), 3.64 (dd, J4.88Hz and 11.6Hz).

Example 4 - Synthesis of L-gluconolactone

Methodology

A stirred solution of crude potassium gluconate (0.24 mol) in water is acidified to pH 2.5 with concentrated HCl and then heated to approximately 50 ° C, approximately 80% of the water is removed under vacuum distillation. Isopropanol (800 ml) was added to the warm solution and the solution was heated at the boiling point under reflux, performing azeotropic drying to a final solution volume of 200 ml. This leads to the formation of 1,4-lactone (main product) and 1,5-lactone (minor product). The solution was cooled to room temperature and neutralized by the addition of triethylamine to give a pH of 7. Inorganic salts were removed by filtration and the filtrate was collected and used for the next step without further purification.

Example 5 - Synthesis of L-glucose

Methodology

A solution of lactone (100 ml) containing approximately 0.14 moles was cooled to -5 ° C and ice water (100 ml) was added thereto. Sodium borohydride (5.1 g) in 135 ml of water was added to the solution, while maintaining the temperature below 5 ° C. The solution was stirred for 20 minutes and then quenched with acetic acid (2 ml). The solution was concentrated to approximately 100 ml and then purified by ion exchange chromatography, passing through an acid column (Dowex 50-X4 ™, 100 ml) and then through a weakly basic column (Dowex MWA-2 ™, 200 ml), fractions containing L-glucose were collected and the product is concentrated to syrup. The product is crystallized from water, methanol and isopropanol to give 9 g of crystalline L-glucose showing an equal but opposite sign of rotation compared to D-glucose with the identical NMR spectrum.

LINKS

1. E. Fischer, Ber. Dtsch. Chem. Ges. 23, (1890), 2611-2624.

2. J.S. Sowden, Hol Fischer, J. Am. Chem. Soc. 69, (1947), 1963-1965.

3. R. Kuhn, P. Klesse, Chem. Ber., 91 , (1958), 1989-1991.

4. V. Bilik, Chem. Zvesti, 26, (1972), 187-189.

5. W. Sowa, Can. J. Chem., 47, (1969), 3931-3934.

6. J. Hajko, A. Liptak, V. Pozsgay, Carbohydrate Res., 321, (1999), 116-120.

7. WA Szarek, GW Hay, DM Vyas, ER Ison, LJJ Hronowski, Can. J. Chem., 62, (1984), 671-674.

8. M. Shiozaki. J. Org. Chem., 56, (1991), 528-532.

9. SY Co., AWM Lee, S. Masamune, LA Reed III, C.V. Sharpless, FJ Walker, Tetrahedron, 46, (1990), 245-264.

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12. I. Lundt, C. Pedersen, Synthesis, 7, 669-672, (1992).

13. Chemical Abstracts: 142135v, Vol. 75, (1971).

14. I. Lundt, R. Madsen, Top. Curr. Chem., 215, 177-191, (2001).

Claims (11)

1. The method of obtaining 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone, comprising: the interaction of 2,6-dibromo-2,6-dideoxy-D-mannono-1,4 -lactone with a Lewis base in a ketone solvent including a catalytic amount of water, where the Lewis base is alkali metal fluoride or carbonate, the catalytic amount of water is from 0.05 to 2% by weight of the solvent, and the process is carried out at a temperature of from 20 to 45 ° FROM. 2. The method according to claim 1, where the catalytic amount of water is from 0.75 to 0.8% by weight of the solvent. 3. The method according to claim 1, where the Lewis base is selected from potassium fluoride, cesium carbonate, rubidium fluoride, potassium carbonate, and combinations thereof. 4. A method for producing L-gluconic acid or a salt thereof, comprising: reacting 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone with a base at a pH of at least 13 and at a temperature of from 45 to 55 ° C for a period of not more than 6 hours, with the formation of L-gluconic acid, and, optionally, the conversion of L-gluconic acid to its salt. 5. A method for producing 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone, comprising:
(a) the interaction of D-glucono-1,5-lactone or its salt with hydrogen halide at a temperature of from 40 to 60 ° C with the formation of the reaction mixture; and
(b) adding methanol to the reaction mixture to form 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone,
(c) the interaction of 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone with a Lewis base in a ketone solvent comprising a catalytic amount of water, where the Lewis base is an alkali metal fluoride or carbonate, a catalytic amount water is from 0.05 to 2% by weight of the solvent, and stage (c) is carried out at a temperature of from 20 to 45 ° C. 6. The method according to claim 5, where after adding methanol, the reaction mixture is maintained at a temperature of from 40 to 55 ° C before stage (s). 7. The method according to claim 5, where the hydrogen halide is hydrogen bromide. 8. The method according to claim 5, where stage (a) is carried out at a temperature of from 50 to 60 ° C. 9. A method for producing L-glucose, including:
(a) the interaction of 2,6-dibromo-2,6-dideoxy-D-mannono-1,4-lactone with a Lewis base in a ketone solvent including a catalytic amount of water to form 6-bromo-6-deoxy-2,3 -anhydro-D-manno-1,4-lactone, where the Lewis base is an alkali metal fluoride or carbonate, a catalytic amount of water is from 0.05 to 2% by weight of the solvent, and step (a) is carried out at a temperature of from 20 to 45 ° C;
(b) the interaction of 6-bromo-6-deoxy-2,3-anhydro-D-manno-1,4-lactone with a base at a pH of at least 13 and at a temperature of from 45 to 55 ° C for a period of time not exceeding 6 hours, with the formation of L-gluconic acid;
(c) the conversion of L-gluconic acid to a salt of L-gluconic acid;
(d) reacting a salt of L-gluconic acid with an alcohol to form a lactone solution; and
(e) the interaction of a solution of lactone with a reducing agent in an aqueous solvent at a temperature of from -10 ° C to 5 ° C with the formation of L-glucose. 10. The method according to claim 9, where the alcohol is isopropanol. 11. The method according to claim 9, where the reducing agent is sodium borohydride.