JPH07509457A - Esterification method - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Esterification method Technical field The present invention relates to a method for esterifying hydroxyl compounds.

Background technology Esters, specifically phosphate esters, are widely distributed in nature and It occupies a central role in academic methods. Of particular interest are biosynthetic enzymes Carbohydrate phosphates and second cellular enzymes widely used in the study of reactions It is a phosphate salt of inositol that acts as a compound. However, these compounds are often obtained in low concentrations, and furthermore, they are usually difficult to isolate in pure form. Because they are difficult to synthesize, it is often necessary to synthesize them chemically.

Many pharmaceutical products have ester functionality. For example, it is used to treat asthma. Betamethacin used and haemorrhage control Menadiol is used. Both compounds are orthophosphate salts. Li Acid esters are a structural feature of various bacterial polysaccharides. Here it takes Polysaccharides are used in vaccines against diseases such as pneumonia and meningitis. of this type Synthetic antigens with the structure have recently been prepared for use as synthetic vaccines. Ta. Therefore, the preparation of products for many drugs requires the introduction of ester functionality. It is clear that it is necessary to

Other areas where esters are useful are in detailed biochemical research. Of course, this area also includes structural modifications related to the bioactivity of various compounds. This includes research on the effects of decoration. Research includes pharmaceutical trials for new and therapeutic drugs. It also includes research into the mechanisms of diseases such as cancer. In such research In particular, radioactive esters incorporating one atom of a radioactive isotope are used. This is often effective.

It is not possible to obtain a given ester compound by any other method other than chemical synthesis. It is often Noh. In fact, the chemical synthesis of esters has been extremely difficult in the past. It has been proven that this is difficult. Direct synthesis of esters is available, e.g. Method for esterifying hydroxyl compounds (HC) using phosphoric acid or polyphosphoric acid [MacDonald, The Carboh7drajes] , IA, 254 (1972) W, Pigman and D, nor +on (Eds), Academic Press, New York]. death However, the use of this method is limited. This is because many carbohydrates are Sensitive to acidic reaction conditions, often producing products such as cyclic esters or anhydrides This is because it undergoes a reaction that produces a modified compound. Therefore, this method is suitable for most Cannot be used for compounds. Indirect chemical synthesis methods were also invented and 'biochemically Synthesis method of important low molecular weight carbohydrate esters ['5ynthe+is of Some Low Mo1eculaI Carbohydrate E+ter s of Biological 51gn1ficance' by Lin dh, Chemical Communication+, University y of Stockholm, (1988), N.

8] etc. Furthermore, it is also described in the following document [0xaki el al, J, Chem, Soc, Perkin Trans, 1゜ (1992), 729-7371゜These documents contain information on how to synthesize phosphate esters. The complexity of known methods is shown. In fact, the latter involves a 12-step product synthesis method. is described, with various steps including chromatographic separation and It is stated that the total yield is less than 20%.

Therefore, existing methods of producing esters are far from ideal, and one important question remains. The problem is that the extreme reaction conditions required for direct esterification methods affect the starting materials and products. It is clear that both lead to undesirable side reactions. indirect chemical synthesis method Attempts have been made to eliminate this problem using Many steps to expose specific hydroxyl groups, multiple steps to introduce esters A number of steps and finally a series of deprotection steps are included. this war In short, although limited, the presence of functional groups that coexist within the molecule during synthesis is required. It will be done. Furthermore, the number of steps reduces the overall yield of the final product, often significantly Requires large amounts of expensive reagents.

Therefore, there is a need for a simple and cost-effective method to esterify hydroxyl groups. be done. The present invention provides that the ester formation reaction includes a hydroxyl compound and an oxyacid salt. It is based on the discovery that it is easily and significantly promoted in solutions containing

Apparently similar methods are described in U.S. Pat. 4412 and was previously applied to starch for food purposes. But long These proposed mills and their The applicability of the modification method to other hydroxyl compounds has been evaluated for 30-35 years. It seems that it was not valued.

Disclosure of invention According to the first aspect of the present invention, esters of hydroxyl compounds (HC) other than starch During the tellurization method or the amidation method of organic amines, HC or amines are acids, oxyacid anions or mixtures thereof, where the oxyacids or their anions are Can accept a lone pair of electrons from the oxygen of HC or the nitrogen of amine, and vice versa. It is possible to provide a method characterized in that the

In the present invention, "oxygen acid" includes, within its scope, one or more oxygen atoms. is replaced by a heteroatom, especially a nitrogen, sulfur or halogen atom, etc. Also included are hetero-oxyacids. Hetero-oxyacids include thiophosphates, halo Includes phosphates and phosphonitriles.

"Hydroxy compound" means hydroxyl group or alkoxy or phenoxy Refers to any compound containing an anion. Preferred hydroxyl compounds may contain inorganic compounds, such as oxyacids, but hydroxyl-containing Contains organic compounds. Examples of hydroxyl organic compounds include sugar, danpo, Glycoproteins, peptides, glycopeptides, sugar conjugates, and their Other molecules, amino acids, alditols, cyclitols, phosphate esters and carcinols Examples include bonic acid.

The conditions of the process of the invention are surprisingly mild, and a particular advantage of the invention is that the conditions of the process are surprisingly mild. Due to pH conditions, other functional groups on HC need to be protected (and subsequently deprotected) There is no. This reduces the total number of steps in the manufacturing process and also reduces the final The overall yield of the product can be increased, thereby increasing the cost effectiveness of the esterification process. It means that it can be added. Furthermore, mild reaction conditions can also be reaction is suitable for almost any starting material and does not lead to further undesired reactions. Guarantees that very little product is exposed.

The oxyacid may be an oxyacid of element M that can form a trimeric oxyacid of the following structure: M is an electron accepting element; X is a hetero-atom such as oxygen or sulfur, or a substituted nitrogen atom; Y is a heteroatom such as oxygen, hydrogen, or sulfur, or a substituted nitrogen atom; Depending on the valence of M, n is 0 or 1 and m is 0-2.

Elements M capable of forming trimeric oxyacids include phosphorus, boron and silicon.

Usually the nitrogen atom will be replaced with hydrogen or an alkyl group.

Phosphorus can form metaphosphate oxyacids. Due to the lack of electrons in the phosphorus atom, The ions tend to polymerize, forming trimers or trimers: An example of this is a chain structure.

Similarly, boron forms an oxyacid with the following structure: Additionally, silicon forms an oxyacid with the following structure: Forming oxyacids: However, the ability of elements to form this type of trimeric structure The force is merely an example of one or more oxygen acids accepting a lone pair of electrons.

Particularly preferred for use in the esterification reactions of the present invention is metaphosphoric acid, and the reaction mechanism of the esterification reaction using metaphosphoric acid is as follows. One suggestion is as follows: In this reaction mechanism, the reactive species is the metaphosphate monomer rather than the trimer. . However, the usefulness of the present invention depends on the precision or otherwise of this reaction mechanism. It does not exist.

Monomers equivalent to the oxygen anions of boron and silicon include: Preferably, it undergoes similar reactions with phosphoric oxyacids and anions.

It is not necessary to use salts of oxyacid anions that form monomer structures of the type described above. Nor. For example, in the case of phosphorus, metaphosphates are preferred, but orthophosphates are preferred; phosphates, diphosphates, triphosphates, polyphosphates, phosphonates, phosphines salts, peroxyphosphates and hypophosphates or other free acids can be used. Wear. If the reactive species for orthophosphate formation is a metaphosphate monomer, The reactivity of ortho-, di-, tri-, and polyphosphate oxyacids is explained as follows. It will be revealed. That is, in solution, these oxygen acids and anions are This means that it is equivalent to metaphosphate in which the reaction is thought to proceed. . Additionally, if these other phosphates are used, the metaphosphate is reacts with HC, so that the equilibrium with other phosphates becomes a means to continue the reaction. I would go for the talinate side. Similar methods apply to the other species mentioned above.

Other phosphorus-based oxyacids found to be effective in the present invention include , thiophosphates, halophosphates and phosphonitrile compounds, etc. - Oxygen acids.

The cation of the oxysalt is used to ensure that the salt is soluble in the solvent in which the reaction takes place. It is. In aqueous solutions, cations are alkaline or sodium, potassium or The most common are alkaline earth metals such as magnesium. For certain solvents, especially organic solvents, Large cations such as lanthanum, cesium or small cations such as lithium and ammonia. Small ionic species are more preferred. In water-soluble and other solvents, cations are Selected for its catalytic effect on the reaction. Prevent salts from exhibiting inappropriate pK values It is preferable to select a counter ion, especially keeping in mind the preferable pH operating conditions described below. should be kept at.

The reaction can be carried out both in aqueous and organic solvents. If organic solvents are used When used, highly polar solvents such as dimethyl sulfoxide (DMSO) are used. Preferably, it is a medium.

Generally, the reaction consists of the following steps: (a) HC or amine, HC oxygen or Or the lone pair from the nitrogen of the amine? In 8iT&, we can produce acceptable seeds. 0 to 30 (w/ w) providing a reaction mixture comprising water; (b) reacting the HC or amine with the oxygen acid species; to obtain a reaction mixture containing He or an oxyacid ester of an amine; Than (c) (i) at least partially recover the ester from the reaction mixture; or (i) i) Further reacting the ester as it is to form a predetermined compound or mixture Please do one of the following:

One method of preparing the preferred reaction mixture is to prepare the HC or amine and the oxyacid salt in water. A solution is prepared and then water is removed from the aqueous solution (that is, the water forms an ester reaction Therefore, if water is removed from the mixture based on Le Chatelier's principle, the reaction will normalize. This method of carrying out the reaction is particularly preferred as it shifts the equilibrium towards the production of the preferred ester. It's beautiful.

This method of forming the reaction mixture requires that the water in the HC/oxygen salt solution is initially excessively (for example, at least 2,5°10,20,50 or 100 times (by weight) )) works particularly well if present. In the water removal step, H Approximately 1 part (for example, 0°1 to 30%) or less is left based on the amount of C or amine. So much water except. As will be appreciated by those skilled in the art, convergence considerations, which are important for water While considering time and energy consumption in favor of volume removal and vice versa We should reach a compromise. Without a doubt, the best place to contribute to balance is Varies depending on the nature of the reactants and the operating conditions of the operator.

Water can be removed by suitable physical or chemical methods. preferred physical Examples of methods include, but are generally preferred, evaporation, evaporation under reduced pressure and freeze drying. There is dryness.

Considering energy consumption and time, it is often the best choice in a specific situation. are shown.

Other methods of preparing the reaction mixture include HC or amine and oxygen acid or Oxygen salts are added to HC or amine containing up to 30% (w/w) of water at the start of the reaction. There is a method of dissolving it in an organic solvent.

Oxylate salts are soluble in the chosen solvent and are therefore polar, such as dimethyl sulfoxide. It is important that the solvent should be used in general.

Although the reaction can be carried out at any pH, the preferred pH range is 1 to 9, and the best results are achieved when the pH is between 2 and 6. But long Therefore, one of the advantages of the reaction is that it can be carried out under mild pH conditions, e.g. pH 4.5-6. This may be the case if the HC or the ester produced is sensitive to highly acidic conditions. This is particularly important when For amine reactions, the pH is such that free amines react The number is preferably 7 or more to ensure its presence in the reaction mixture. Ami In some cases, a pH of 10 or higher is required for reactions involving However, generally the pH ranges from 7.5 to 9.

Hydroxyl compounds may be esterified or amines may be esterified by this method. However, this method is particularly preferred for the following esterification of organic compounds. Sugars, especially non-reducing sugars such as trehalose and sucrose, and lactose and Reducing sugars such as maltose; proteins; glycoproteins, peptides, glycopeptides and and sugar conjugates and other molecules with sugar functional groups; amino acids, especially serine and and threonine; and other organic compounds such as alditol and cyclitol; carboxylic acids, organic oxygen acids, especially phosphates and hydroxyl or alkoxy or phenolic acids. A compound containing an anion. The present invention relates to polysaccharides and oligosaccharides other than starch. (approximately 3-10 monosaccharide units), applicable to trisaccharides and monosaccharides.

The inorganic hydroxyl compounds esterified by the method of the present invention include oxygen acids themselves. However, the esterification reaction of the present invention is particularly applicable to di-, tri-, and poly-phosphorus. Useful in the synthesis of acid salts.

In general, esterification of tertiary derivatives, especially when the substituents are not too bulky. Although the reaction is possible, the reaction It is most effective for grade amines.

After formation of the starting mixture, it may be further processed to maximize the esterification reaction. . In some cases, the reaction mixture is heated to a temperature of 20 to 200°C, preferably 50 to 100°C. It is preferable to heat within a range of 0.1 hour to 40 days. Heating is especially If the temperature is high, the esterification reaction rate increases, so it is recommended to conduct the process in a closed system. preferable. Since water is a product of the esterification reaction, removal of water from the reaction system shifts the equilibrium of the reaction to form more esters. One way to remove water is , heating the mixture in an open system so as to evaporate the water.

Once the reaction is complete, the ester or amidate can be isolated by a suitable method. For example, by ion exchange chromatography. one or more reaction products are obtained Generally1, it is difficult to separate different products using chromatography. It's easy. Alternatively, the ester may remain in the resulting mixture; Further treatments or reactions may be performed to obtain compounds or mixtures.

The method of the present invention enables new esters and acetones not obtained by conventionally known methods. In particular, sucrose and trehalide, characterized by the provision of amidates It is now possible to prepare esters of acid-variable monosaccharides such as In a further embodiment of the invention, trehalose-2-phosphate, trehalose-3-phosphate phosphate, trehalose-4-phosphate and many sucrose mono-orthophosphates can be provided. These compounds are novel and require considerable difficulty and cost. It can be prepared by a conventionally known method.

The invention will be further explained based on the following examples. These examples are attached Refers to the drawings.

Figure 1 shows the trehalose-6-resolved product obtained from orthophosphate by the method of the present invention. This is an IHNMR spectrum of phosphate salt.

Figure 2 shows the trehalose-2-resolved product obtained from orthophosphate by the method of the present invention. This is an IHNMR spectrum of phosphate salt.

Figure 3 shows the trehalose-4-resolved product obtained from orthophosphate by the method of the present invention. This is an IHNMR spectrum of phosphate salt.

Figure 4 shows the trehalose-3-resolved product obtained from orthophosphate by the method of the present invention. This is an IHNMR spectrum of phosphate salt.

Figure 5 shows α,α′-trehalo treated with sodium phosphate according to the method of the present invention. HPLC ion-exchange chromatogram obtained from

Figure 6 shows trehalose-3-phosphorus obtained from metaphosphate by the method of the present invention. It is an IHNMR spectrum of an acid salt.

Figure 7 shows trehalose-6-phosphorus obtained from metaphosphate by the method of the present invention. The IH NMR spectrum of the acid salt shows the four isomers of α, α′-trehalose, mono-ortho. Phosphate preparation method α, α′ in sodium phosphate buffer solution (0.1 M, 100 ml) pH 5.5 - an aqueous solution of trehalose dihydrate (1.0 g, 2.6 mmol), where its There is approximately 100 times more water in the solution than sugar on a weight basis, at -78° C (solid C02) and further lyophilized to 4.5% for trehalose. Obtain a preparation with a moisture content (W/W) of . The preparation was sealed and heated at 56°C for 10 days, then washed with deionized exchanged water. (100 ml) and the solution was mixed with 1M sodium hydroxide, water, 1M acetic acid. Acetate, Bio-Rad which is continuously washed with water to form acetate Apply to AG1 resin, 120x2 cm anion-exchange resin. Bio-Ra dAG1 is a trademark name. The column is first washed with water to remove unreacted trehalo. (for recycling if necessary) and other unbound materials; After that, a 0.2-0.8M ammonium acetate aqueous solution gradient was used. Isomeric trehalose mono-ol separated from inorganic orthophosphate by elution with A fraction or fraction containing luthophosphate was obtained. trehalose phosphate The fractions containing . x BioLCPA 100), containing each of the four pure isomers. lyophilize the solution to make it pure for analysis. Trehalose monophosphate was obtained as an ammonium salt as an amorphous solid. . Di.

nex BioLCPA 100 is a trade name. Fraction 1.0.08 5g (6,6%), fraction 2.0.035g (2,7%), fraction fraction 3.0.041g (3.1%), fraction 4.0.027% (2°1%) ). Total amount: 0.188g (14.6%). 4 The product is the enzyme alkaline phosphate α,α-mono-trevalose (HPLC ion-exchange chromatography) ) and inorganic orthophosphates (identified using ammonium molybdate). (identified colorimetrically using the same method).

Elemental analysis data: Fraction 1, (actual value) C31, 55%, H6゜62%, H5, 81% , P6.45%.

Fraction 2, (actual value) C31.22%, H6°26%, H5.97% , P6.37%.

Fraction 3, (actual measurement) C31.62%, H6゜55%, H6.20% , P6.55%.

Fraction 4, (actual value) CB1.37%, H6゜32%, H5, 92% , P6.89%.

Cl2H29N2P1014 has CB1.58%, H6,40%, H6,1 4%, P6.79% is requested.

NMR data. Fraction 1. 2. Prototypes of products present in 3 and 4 The NMR spectra are shown in Figures 1-4 (6-.2-.4, respectively). -, and 3-phosphate, i.e. structure 1 as shown in the figure. 2. 3. and Matches 4. Figure 1 shows Sigma Chemical (SL gma Chemical) Proton NMR of trehalose-6-phosphate based on data from Co. Match the spectrum. These structures are similar to 13C and “P” NMR spectrum. It was also identified by spectroscopy.

Example 2 Based on conditions similar to Example 1, the six headings for Example 2 shown in Table 1 ) to (f) to convert α, α′-trehalose to α, α′ - A phosphoric acid ester of trehalose was prepared.

Example 3 The 8 isomer monoorthophosphate of sucrose was prepared based on the conditions shown in Table 1. It can be prepared by a method similar to Example 1. In this case, the main thing to be careful about is sucrose is a diclassic class that is extremely prone to becoming an acid, and as a result, direct phosphoric acid reaction using phosphoric acid This is something that is difficult to quantify. As with the 3-trehalose phosphate mentioned above, Most of the sucrose isomeric esters are novel compounds and, moreover, require existing methods. It was extremely difficult to prepare using

Examples 4 to 7 In a similar way, α-glycerophosphate; Serine phosphate; β-cyclodextrin thiosulfate; and serine thiophosphate, were similarly prepared using the conditions shown in Table 1.

Furthermore, we conducted experiments to study the effects of sodium phosphate buffer on various HCs. It was. Experiments were carried out in solutions with pH 5, 5, 7, 0 or 8.1, all with 56 After heating for several days at °C, carbohydrate monophosphates were isolated by ion-exchange chromatography. A product co-eluted with the salt ester. The results of these experiments are shown in Table 1.

Effects of other oxysalt buffers on various HCs at pH 2.0 to 6.0 A number of experiments were conducted to study as well. Heating for several days at temperatures above 56°C After that, the "ester-type" product is purified using ion-exchange chromatography. I observed it. The oxyacid buffers used included boric acid, thiophosphoric acid, phosphoric acid and Buffers derived from phosphinic acids are included.

In Table 1, is based on the Mitsubishi CA100 system (Karl Fischer) The values measured by Fischer titration are shown. Measurements include carbohydrates, amino It is based on the weight of acid or protein and does not include buffer salts.

In Table 1, is expressed as weight percent of saccharides, amino acids, or proteins. O Assuming that the same detection response factor for oligosaccharides and mannitol is the corresponding phosphate do. This tends to underestimate the esters present.

Glycerol phosphate was measured relative to alpha-glycerophosphate. in parentheses The number is the calculated average number of elemental phosphorus per molecule of In the case of mylose it is the average number of glucose residues per phosphorus element.

tr indicates the percentage (<0.1%).

Therefore, the esterification method of the present invention is extremely flexible and can be performed under relatively mild conditions. It turns out that it is possible to esterify a wide range of compounds with. moreover , the starting material can be recycled so that many products are obtained .

Example 8 Phosphate from α, α′-trehalose and sodium metaphosphate preparations Formation of a le α, α゛-trehalose dihydrate (1.0 g, 2.6 mmol) was added to sodium metaphosphate. The method of Example 1 was followed except that it was dissolved in a solution of thorium (0.1 M, 100 ml). repeated. The formulation was frozen to -78°C, lyophilized and sealed as described above. Heated at 6°C for 5 or 12 days.

The reaction was repeated at different pH and the results are shown in Table 2.

Table 2 pH (initial) Monophosphate Monophosphate 1.9 32 34 (7) 3.0 18 23 (6) 3.5 15 20 (4) 4.0 13 19 (4) 4.5 17 15 (4) 5.0 13 16 (4) 5.5 13 17 (4) 6.0 15 12 (3) In the table, indicates the results on day 7.

The number in parentheses is the percentage of diphosphate produced.

The phosphate percentages shown in Table 2 are determined from the detector response and are therefore Well, it's an underestimate, probably 1/2.

The resulting phosphate level depends on the water content and the temperature at which the reaction is carried out. It's hot Phosphate yields were tested in separate experiments conducted over short periods of time. An increase of about 40% based on launch response. Again, this is an underestimate and the actual value is It would be about twice the detector value.

Example 9 Reaction of α, α′-trehalose in DMSO a) Orthophosphate α, α-Trehalose dihydrate (1 part), disodium hydrogen orthophosphate and and sodium dihydrogen orthophosphate (4 parts) (so that the pH becomes 5.5 when dissolved in water). DMSO (100 parts) is dried. blend was heated at 80°C for 3 days, after which the DMSO was removed by lyophilization. Water the residue (100 parts) and analyzed by chromatography (ion exchange). blend contained approximately 1% trehalose phosphate. The relatively low yield is due to DM This may be due to the low solubility of sodium salts in SO.

b) Metaphosphate α,α′-trehalose dihydrate (1 part), sodium metaphosphate/metaphosphoric acid (4 parts), which is mixed to a pH of 2 in the case of an aqueous solution, is added. DMSO (100 parts) was dried and the mixture was heated at 80° C. for 3 days.

DMSO was removed and the residue was analyzed as above. The mixture contains 1.5% Contains haloose phosphate.

The relatively low astringency is probably due to the low solubility of the sodium salt in DMSO. It depends.

international search report -11----＾-・--、、、、PCT/GB　9】101545 Freon Continuation of top page (51) Int, C1, 6 identification symbol Internal office reference number // C07B 471 00 7419-4HCO7C2351089547-4H CO7F 7/21 8829-4H CO7K 1/13 8318-4H (81) Designated countries EP (AT, BE, CH, DE.

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Claims (23)

[Claims] 1. Esterification of hydroxyl compounds (HC) other than starch or organic amines During amidation, HC or amine is treated with oxygen acid, oxygen acid anions or mixtures thereof, where the oxyacid or oxyacid anion is HC It is characterized by reacting with oxygen or the nitrogen of an amine, which can accept a lone pair of electrons. Characteristic esterification or amidation method. 2. The claimed oxyacid is an oxyacid of element M capable of forming the following trimeric oxyacid structure: Methods described in Range 1: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, in the formula, M is an electron-accepting element; X is a hetero-atom such as oxygen or sulfur, or a substituted nitrogen atom; Y is a hetero atom such as oxygen, hydrogen, or sulfur, or a substituted nitrogen atom; Depending on the valence of M, n is 0 or 1 and m is 0 to 2. ) . 3. 3. The method according to claim 1 or 2, wherein M is phosphorus, boron or silicon. 4. The oxygen acid species is metaphosphate, orthophosphate, syphosphate, triphosphate, polyphosphate, phosphonate, phosphinate, peroxyphosphate, high poly phosphate, thiophosphate, halophosphate, phosphonitrilic derived from borates or silicates or their free acids 4. The method according to any one of claims 1 to 3. 5. (a) HC or amine; lone pair from oxygen of HC or nitrogen of amine an oxyacid or oxysalt capable of producing an acceptable species in solution; (b) providing a reaction mixture containing 0 to 30 (w/w) water relative to the weight of min; Oxygen acid esters of HC or amines are produced by reacting HC or amines with oxygen acid species. obtain a reaction mixture containing; optionally (c) (i) at least partially recover the ester from the reaction mixture; or (i) i) further reacting the ester as is to form the desired compound or mixture; The method according to any one of claims 1 to 4. 6. The reaction mixture forms an aqueous solution of HC or amine and oxyacid; claims made by removing water from said aqueous solution to form a starting mixture. The method described in item 5. 7. The water is initially at least 2 by weight based on the starting amount of HC or amine. 7. The method of claim 6, wherein the method is present in a two-fold excess. 8. Claims that the water is removed by evaporation, evaporation under reduced pressure or freeze drying The method according to item 6 or 7. 9. The reaction mixture is characterized in that the HC or amine and the oxyacid are dissolved in an organic solvent, where the The organic solvent contains water in an amount of 0 to 30% (w/w) based on the amount of the HC or amine. 6. The method according to claim 5, which is produced by dissolving in. 10. The method according to claim 9, wherein the solvent is dimethyl sulfoxide. . 11. The amount of water in the reaction mixture is greater than 15% (w/w) relative to the weight of the HC. 11. A method according to any one of claims 1 to 10, which is not numerous. 12. Any one of claims 1 to 11, wherein the pH of the mixture is 1 to 9. The method described in. 13. 13. The method according to claim 12, wherein the pH of the mixture is 2-6. 14. The HC contains sugars, proteins, glycoproteins, peptides, glycopeptides, Glycoconjugate, amino acid, alditol or cycloconjugate A method according to any one of the preceding claims, comprising toll. 15. 15. The method according to claim 14, wherein the sugar is a reducing sugar. 16. 15. The method according to claim 14, wherein the sugar is a non-reducing sugar. 17. Claim 14, wherein the amino acid is serine or threonine. the method of. 18. Heat the mixture for a period of 0.1 hour to 40 days at a temperature of 20° to 200°C. A method according to any one of claims 1 to 17, comprising a heating step. . 19. 19. A method according to claim 18, wherein the temperature is between 50<0>C and 100<0>C. 20. A product obtained by the method according to any one of claims 5 to 19. mixture. 21. A reaction product obtained by the method according to any one of claims 5 to 19. reaction mixture. 22. Hydroxyl compounds (HC) or organic amines that accept lone pairs of electrons in solution. Oxygen acid or oxyacid salt that can produce the oxyacid species that can be used; Reaction mixture containing from 0.1 to 30 (w/w) of water. 23. Trehalose-2-phosphate; Trehalose-4-phosphate; trehalose-3-phosphate; or Sucrose mono-orthophosphate.