JP2019006771A - Method for preparing a dinucleoside polyphosphate compound - Google Patents

Abstract

To provide a method of preparing dinucleoside polyphosphate, salt thereof, and a hydrate thereof.SOLUTION: The present invention provides a method for producing e.g. a compound of the following formula, including the step for the reaction between a nucleoside phosphate compound, a carbodiimide condensation agent and a metal ion in the presence of a solvent.SELECTED DRAWING: None

Description

  The present invention relates to a method for producing a dinucleoside polyphosphate compound, and more particularly to a method for producing a nucleoside phosphate compound and a salt thereof or a hydrate thereof in the presence of a metal halide.

  A nucleoside is a glycoside compound in which a nucleobase and a pentose sugar form an N-glycoside bond. When a phosphate group is bound to a nucleoside by a phosphorylase, it is a basic component of a DNA chain. It becomes a nucleotide (Nucleotide).

  It is known that dinucleoside polyphosphoric acid or a salt thereof, which is one of such nucleotides, is stable in the body similar to a substance in a living body, and has an effect on disease treatment corresponding thereto.

In particular, P ¹ , P ⁴ -di (uridine 5 ′-) tetraphosphate (hereinafter, referred to as “UP ₄ U”) or a salt thereof represented by the following chemical formula 1a is a dry eye disease or a decrease in tear secretion. It is a compound that is used as a therapeutic agent for keratoconjunctival epithelial disorder associated with infectious disease and has an effect of inducing sputum excretion, and is therefore expected to be developed as an expectorant or pneumonia therapeutic agent.

As a conventional synthesis method of UP ₄ U, Non-Patent Document 1 discloses uridine 5′-cyclic triphosphate and uridine produced by dehydration condensation reaction of uridine 5′-triphosphate (hereinafter referred to as UTP). A conventional production method in which 5′-monophosphate (hereinafter referred to as UMP) is reacted is reported, and Patent Document 1 reports on the improved production method.

In Patent Document 2, uridine, UMP, UDP or UTP and a salt thereof and a uridine nucleotide compound are dissolved in a polar, aprotic organic solvent and a hydrophobic amine, and a mono- or di-phosphorylating agent is used as a phosphorylating agent. A method for producing UP ₄ U using carbodiimide, active carbonyl or active phosphorus as an activator has been reported.

Patent Document 3 includes a group consisting of uridine 5′-diphosphate (UDP), UMP or pyrophosphate and imidazole, benzimidazole or 1,2,4-triazole which may have a substituent. A phosphate active compound synthesized by condensing with a selected compound and a phosphate compound selected from the group consisting of UMP, UDP, UTP and pyrophosphate or a salt thereof, in the presence of metal ions, water Alternatively, a method for producing UP ₄ U by reacting in a hydrophilic organic solvent has been reported.

However, the conventional UP ₄ U production method requires many troublesome process steps such as a metal salt exchange step reaction, resulting in a problem that the synthesis efficiency and purity of the final compound are lowered.

Specifically, in the conventional methods for producing UP ₄ U such as Patent Document 2 and Patent Document 1, a metal salt of a phosphoric acid compound must be reacted in the form of an amine salt such as tributylamine or triethylamine immediately before the reaction. Don't be. As a result, there is a troublesome process in which a metal salt such as a sodium salt of a uridine phosphate compound is generally converted to a phosphate compound in a free acid form by ion exchange resin column chromatography, and then a salt formation with an amine must be performed. is necessary. By performing such a process, the synthesis efficiency and purity of the final compound may be reduced. In particular, in the case of the synthesis reaction using UTP, which is known as a very unstable substance, the purity tends to decrease, and an organic salt such as a UTP amine salt sensitive to moisture has high hygroscopicity. There is a problem that storage and quality maintenance are very difficult.

Moreover, although the manufacturing method described in Patent Document 3 can synthesize UP ₄ U with a high yield of 45 to 94%, the salt exchange step reaction for preparing the phosphoric acid compound organic salt mentioned above And a dehydration process corresponding to it, and after synthesizing a phosphoric acid active compound in an organic solvent, the solvent is removed by a vacuum concentration step, and the pH is adjusted in the presence of water to react. Therefore, there is a problem that the purity of the compound is lowered.

  Therefore, for the reasons described above, a high yield of dinucleoside polyphosphate compound can be produced with high purity under environmentally friendly reaction conditions without troublesome process steps, and dinucleoside polyphosphate suitable for industrial mass production can be produced. There is a need for a manufacturing method.

International Publication No. 2008/012949 International Publication No. 1999/05155 International Publication No. 2014/103704

Bioorganic & Medicinal Chemistry Letters, 11, (2001), 157-160

  An object of the present invention is to provide a production method of dinucleoside polyphosphoric acid that is suitable and efficient for mass production and is harmless to the environment, and a production method capable of mass production of salts and hydrates thereof with high purity. It is in.

  The present invention provides a method for producing a dinucleoside polyphosphoric acid represented by the following chemical formula 1, a salt thereof and a hydrate thereof.

In one embodiment of the invention,
(S-1) a nucleoside phosphate compound represented by the following chemical formula 2, a salt thereof or a hydrate thereof;
Provided is a method for producing a dinucleoside polyphosphoric acid represented by the following chemical formula 1, a salt thereof or a hydrate thereof, comprising a step of reacting a condensing agent of carbodiimides; and a metal ion in the presence of a solvent.
In the chemical formula:
R ₁ and R ₂ are the same or different from each other and are each independently a pyrimidine base;
R ₃ is a pyrimidine base;
n is an integer from 2 to 6;
m is an integer of 1-3.

  In the present invention, the pyrimidine base may be selected from the group consisting of cytosine, uracil or thymine.

  In one embodiment of the invention, the base is uracil.

  In one embodiment of the present invention, n is 4.

In one embodiment of the present invention, the nucleoside polyphosphate represented by Formula 1 is represented by the following Formula 1a.

  According to the production method of the present invention, the chemical formula 2, which is commercially available, a salt thereof or a hydrate thereof can be used as it is without a separate conversion step, thereby reducing equipment necessary for production and using it in the conversion step. Time, effort, and cost can be saved, and the generation of impurities accordingly can be minimized.

In one embodiment of the present invention, the nucleoside phosphate compound represented by the chemical formula 2 is represented by any one of the following chemical formulas 2a to 2c.

  In one embodiment of the present invention, the salt of the nucleoside phosphate compound is a metal salt or an amine salt.

  The metal salt of the nucleoside phosphate compound may be selected from the group consisting of lithium, sodium, potassium, magnesium, calcium, barium, cerium, iron, nickel, copper, zinc and boron, preferably lithium, sodium or It may be an alkali metal salt of potassium and an alkaline earth metal salt of calcium or magnesium.

In one embodiment, the amine salt may be a tertiary amine, specifically, an alkyl such as trimethylamine, triethylamine, tributylamine, tripentylamine, trihexylamine, triethanolamine, pyridine or the like. The chain may be selected from the group consisting of trialkylamines composed of C _{1 to} C ₆ and cyclic trialkylamines.

  In the present invention, a condensing agent means a compound added as a reaction aid in a condensation reaction.

In one embodiment of the present invention, the carbodiimide condensing agent is represented by the following Formula 3.
In Formula 3,
R ₄ and R ₅ are the same or different from each other, and each independently represents a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and the alkyl group is an alkylamine group and is selectively May be substituted.

Specifically, R ₄ and R ₅ are the same or different from each other and are each independently ethyl, isopropyl, cyclohexyl or dimethylaminopropyl.

  The carboimide condensing agents include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) or a salt thereof, N, N′-diisopropylcarbodiimide (DIC) and N, N′-dicyclohexylcarbodiimide (DCC). Selected from the group consisting of

  In another embodiment of the present invention, the step (S-1) may further include a triazole additive. Specifically, the triazole additive may be hydroxybenzotriazole (HOBt) or 1-hydroxy-7-azabenzotriazole (HOAt). The triazole additive has the effect of increasing the efficiency of the condensing agent of the carbodiimides.

  In one embodiment of the invention, the metal ions are derived from the group consisting of metal chlorides, bromides, nitrates, sulfates and acetates.

In one embodiment of the present invention, the metal ion may be a metal ion selected from the group consisting of calcium, magnesium, cerium, iron, lithium, aluminum, titanium, and sodium.
In one embodiment of the present invention, the metal ion may be derived from a metal salt catalyst represented by the following chemical formula 4.
In Formula 4,
a is the number of moles of M;
b is the ionic valence of M;
M is calcium, magnesium, cerium, iron, lithium, aluminum, titanium or sodium;
c is the number of moles of X;
d is the ionic valence of X;
X is halogen, carbonate, acetate, nitrate, triflate, sulfate, carboxylate or derivatives thereof;
The value of the product of a and b is the same as the value of the product of c and d.

  In one embodiment of the present invention, the metal ions include calcium salts such as calcium chloride, calcium acetate, calcium carbonate, calcium sulfate, and calcium phosphate, magnesium salts such as magnesium chloride, magnesium carbonate, magnesium sulfate, and magnesium bromide, cerium chloride. Metal ions derived from cerium salts such as cerium fluoride, cerium iodide, cerium nitrate, cerium trifluoroacetate, etc., specifically, calcium chloride, cerium chloride, lithium iodide, magnesium chloride, iron chloride The metal ion may be derived from, but is not limited thereto, and may include all of the anhydrous form or the hydrate form.

  In the production method according to the present invention, by using inexpensive and harmless catalysts, the reaction time can be dramatically shortened and a high yield of dinucleoside polyphosphate can be provided. It can be applied to the present invention very suitably.

  In one embodiment of the present invention, the solvent is water, an organic solvent, or a mixed solvent of water and an organic solvent.

  In one embodiment of the present invention, water may be used alone as the solvent. Since the production method according to the present invention can use water alone, when it is applied to mass production industrially under environmentally friendly reaction conditions, there are problems of environmental pollution, costs generated by the use of organic solvents, and waste organics. It is economical and environmentally friendly because the processing costs of the solvent can be minimized.

  In one embodiment, a mixed solvent of water and an organic solvent can be used as the solvent.

In one embodiment, the organic solvent _is selected alcohol of C 1 -C _8, ketone C 3 _{-C 10,} 1,4-dioxane, acetonitrile, N, from the group consisting of N- dimethylformamide and dimethyl sulfoxide Is done.

  In one embodiment of the present invention, in the step (S-1), the equivalent of the condensing agent and the equivalent of the metal ion are the same or different, and each 1 mol of the nucleoside phosphate compound represented by the chemical formula 2 It reacts at 0.1 to 30.0 molar equivalents relative to equivalents. In particular, the equivalent of the condensing agent and the equivalent of the metal ion may be the same or different, and 1.0 mol to 10.0 mol equivalent to 1 mol equivalent of the nucleoside phosphate compound represented by the chemical formula 2, respectively. react.

  In one embodiment of the present invention, the reaction temperature in the step (S-1) can be carried out without difficulty within the range of reaction temperatures at which general pharmaceuticals can be synthesized. Specifically, 1) The reaction temperature in the step may be 0 ° C to 50 ° C, and more specifically, the reaction is performed at 5 ° C to 35 ° C.

  In one embodiment of the present invention, the method further includes (S-2) solidifying and purifying the product obtained from the step (S-1).

  The step (S-2) is a step of solidifying the reaction solution performed in the step (S-1) and then purifying it so that it can be used as a pharmaceutical using various methods.

  Specifically, in the step (S-2), after the step (S-1) is completed, a crude solid is produced by injecting or back-injecting an organic solvent, and the first step of filtering it. including.

In one embodiment of the present invention, the organic solvent in the step (S-2) may be a hydrophilic organic solvent. The hydrophilic organic solvent _is an alcohol of C 1 -C _8, ketone C 3 _{-C 10,} 1,4-dioxane, acetonitrile, N, is selected from the group consisting of N- dimethylformamide and dimethyl sulfoxide. Specifically, it can be selected from the group consisting of acetone, 1,4-dioxane, N, N-dimethylformamide, dimethyl sulfoxide, such as methanol, ethanol, propanol, and isopropanol.

  In one embodiment of the present invention, in the step (S-2), after the first step, the generated crude solid is dissolved in water, adsorbed on an anion exchange resin, and the target compound is eluted. A second step may be further included to convert to form to obtain the final compound.

  In the present invention, examples of the anion exchange resin include weakly basic anion exchange resins (Amberlite IRA67, Diaion SA-11A, etc.) and strong basic anion exchange resins (Amberlite IRA402, Diaion PA-312, etc.). ), Weakly acidic cation exchange resins (such as Diaion WK-30) or strong acidic cation exchange resins (such as Diaion PK-216, Dowex 50WX2) can be used. In particular, the target compound can be eluted with higher purity via a weakly basic anion exchange resin.

In one embodiment of the present invention, the nucleoside phosphate compound represented by the chemical formula 2, a salt thereof or a hydrate thereof; a condensing agent represented by the chemical formula 3; and a metal salt represented by the chemical formula 4 P ¹ , P ⁴ -di (uridine 5 ′-) tetraphosphate represented by the above chemical formula 1a, a salt thereof or a hydrate thereof, comprising a step of reacting a metal ion derived from a catalyst in the presence of a solvent The manufacturing method of can be provided.

  What has been mentioned above can be applied analogously as long as they do not contradict each other.

  As in the production method according to the present invention, by reacting the nucleoside phosphate compound represented by Chemical Formula 2 with water, which is an environmentally friendly solvent, together with a condensing agent and metal ions, a relatively simple process. Thus, the dinucleoside polyphosphoric acid represented by the above chemical formula 1, its salt or its hydrate can be produced with high efficiency and high purity.

  According to the present invention, dinucleoside polyphosphates can be obtained at high reaction conversion without complicated and troublesome conversion steps from commercially available forms of nucleoside phosphate compounds or metal salts thereof to the free acid or organic salt forms of nucleoside phosphate compounds. Can be synthesized. Thereby, since almost no side reaction product is produced, purification is very easy, and a high-quality compound to be used as a raw material for pharmaceuticals can be obtained. In addition, it is a very efficient and environmentally friendly synthesis method that can minimize environmental pollution during industrial mass production by using water alone or mixed with an organic solvent as a solvent. is there. Furthermore, it can be widely applied to the synthesis of substituted phosphate compound derivatives having various structures.

2 is a result of nuclear magnetic resonance analysis ( ¹ H NMR) of UP ₄ U (Diquafosol) synthesized in Example 1. FIG. 2 is the HPLC data of primary UP ₄ U (Diquafosol) obtained after completion of the reaction in Example 1. 2 is the HPLC data of UP ₄ U (Diquafosol) finally obtained after synthesis and purification in Example 1.

  The following examples are provided to help the understanding of the present invention. However, the following examples are provided only for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

The reagents and solvents mentioned below were purchased from a Chinese raw material manufacturer, Sigma-Aldrich Korea and TCI, HPLC was measured using Agilent Technologies 1200 Series, and ¹ H NMR was Measurements were made using a Bruker 400 ultraShield NMR Spectrometer. Purity was measured in area% of HPLC.

The HPLC conditions used in the present invention were as follows, and the purity of UP ₄ U (diquafosol) after the reaction or in the reaction mixture was measured.
Detector: UV spectrophotometer (measurement wavelength: 260 nm)
Column: YMC-Pack ODS-AQ (4.6 mm × 250 mm, 5 μm)
Mobile phase: 0.4% potassium dihydrogen phosphate aqueous solution Flow rate: 0.5 mL / min
Sample: UP ₄ U (Diquafosol) 10 mg / mobile phase 10 mL
Injection volume: 10 μL

Example 1. Synthesis of UP ₄ U from UDP · 2Na Dissolved UDP · 2Na salt (1000 g, 2.23 mol) in 3.0 L of purified water and stirred at 10 ° C., EDC · HCl (428 g, 2.23 mol) and CaCl _{2 · 2H 2 O (328g, 2.23mmol} ) was stirred successively added dropwise to 4 hours and 30 minutes at 10 ° C.. The reaction was monitored by HPLC.

After completion of the reaction, the compound obtained with 3.0 L of purified water and 12.0 L of EtOH was solidified and stirred at room temperature for about 1 hour. The produced solid was filtered and dried to obtain 1,038 g (purity 94.1%) of the desired UP ₄ U compound.

The obtained solid was dissolved in deionized water and adsorbed on a weakly basic anion exchange resin (Amberlite IRA series), then eluted sequentially with deionized water, a low concentration hydrochloric acid solution, and a sodium chloride solution, and concentrated under reduced pressure. Thereafter, a solid was precipitated with ethanol. The solid was filtered and dried to obtain the desired UP ₄ U · 4Na (780 g, yield 80%, purity 99.95%).

Experimental Example 1 Synthesis of UP ₄ U from UDP · 2Na: Effect on Metal Salt UDP · 2Na salt (500 mg, 1.12 mmol) was dissolved in 2 mL of purified water, and DIC (259 uL, 1.67 mmol) and various metal salts (1.67 mmol) were dissolved. ) Were added dropwise in order and allowed to react at room temperature.

The reaction solution was analyzed by HPLC, and determined the UP ₄ U purity of conversion and reaction solution of contrast to UDP · 2Na to UP ₄ U of interest.

From the results shown in Table 1, in the synthesis of UP ₄ U from UDP · 2Na salt, the conversion rate in the absence of metal salt is 2%, whereas 79% in the case of magnesium salt and 25 in the case of iron salt. When calcium was selected as the metal salt, a high conversion rate of 97% to 98% was exhibited, and the purity of the reaction solution was 83% to 84%, confirming a remarkable increase effect.

That is, from the above results, when the nucleoside phosphate compound represented by the chemical formula 2 of the present invention, a salt thereof or a hydrate thereof; a condensing agent; It was confirmed that UP ₄ U with high yield and high purity can be obtained.

Experimental Example 2. Synthesis of UP ₄ U from UDP · 2Na: Effect on condensing agent UDP · 2Na salt (500 mg, 1.12 mmol) was dissolved in 2 mL of purified water, and various condensing agents (1.67 mmol) and metal salt CaCl ₂ · 2H _2. O (247 mg, 1.67 mmol) was added dropwise in order and reacted at room temperature.

The reaction solution was analyzed by HPLC, and determined the purity of conversion and UP ₄ U of contrast to UDP to UP ₄ U of interest.

From the results of Table 2 above, when DIC, EDC.HCl, or DIC and HOBt are used as condensing agents in the synthesis of UP ₄ U from UDP · 2Na salt, the conversion rate to the target UP ₄ U is 98% or more. It was confirmed that the purity of UP ₄ U was 84% or more. In particular, when using a EDC · HCl as a condensing agent, the reaction time is significantly reduced, it was confirmed that the UP 4 is a high conversion rate and the target compound of the _U UP 4 _U can be synthesized in high purity.

Experimental Example 3. Synthesis of UP ₄ U from UDP · 2Na: Effect of reaction temperature, equivalent of condensing agent and metal salt UDP · 2Na salt (500 mg, 1.12 mmol) is dissolved in 2 mL of purified water, and the equivalent equivalent condensing agent and metal The salt CaCl ₂ .2H ₂ O was added dropwise in order to react.

The reaction solution was analyzed by HPLC, and determined the purity of conversion and UP ₄ U of contrast to UDP to UP ₄ U of interest.

From the results of Table 3 above, in the synthesis of UP ₄ U from UDP · 2Na salt, the starting material and the target compound are decomposed at a high reaction temperature of 40 ° C. or higher, and the purity in the reaction solution becomes 45% to 72%. It became low.

Experimental Example 4 Synthesis of UP ₄ U from UDP-organic salt: Effect on metal salt UDP-2TBA salt (1 g, 1.30 mmol) was dissolved in 10 mL of DMF, and DIC (240 uL, 1.55 mmol) and various metal salts (1.55 mmol). ) Were added dropwise in order and allowed to react at room temperature. The reaction solution was analyzed by HPLC, and the conversion rate and purity to the desired UP ₄ U were determined in comparison with UDP.

UDP · 2TEA salt (500 mg, 0.82 mmol) was dissolved in 5 mL of DMF, and DIC and various metal salts were added dropwise according to the following equivalents and reacted at room temperature. The reaction solution was analyzed by HPLC, and the conversion rate and purity to the desired UP ₄ U were determined in comparison with UDP.

From the results shown in Table 4, in the synthesis of UP ₄ U from a UDP organic salt (TBA salt or TEA salt), a high conversion rate of 83% to 99% was obtained in the presence of calcium, iron, magnesium, lithium, or cerium salt. confirmed.

It was confirmed that UP ₄ U can be obtained with a high purity of 71% to 83% when reacted in the presence of calcium salt or magnesium salt in the reaction solution having a high conversion rate.

That is, from the above results, when reacting the nucleoside phosphate compound represented by the chemical formula 2 of the present invention, a salt thereof or a hydrate thereof; a condensing agent; and a metal ion, UP ₄ U of high yield and high purity is obtained. Confirmed that you can get.

Experimental Example 5. Synthesis of UP ₄ U from cUTP: Effect on Metal Salt UTP · TBA salt (5 g, 9.10 mmol) was dissolved in 50 mL of DMF, and a cUTP solution was prepared with DIC (1.69 mL, 10.92 mmol) and quantified by HPLC. 1 ml (0.11 mmol) of the cUTP solution was taken, and a UMP / TBA salt solution (0.13 mmol) and various metal salts (0.132 mmol) were added dropwise in this order to react at room temperature.

The reaction solution was analyzed by HPLC, and determined the purity of conversion and UP ₄ U of contrast to UTP to UP ₄ U of interest.

From the results in Table 5, the synthesis of UP ₄ U from UTP / TBA salt showed a high conversion rate of 83% to 99% in the presence of calcium, iron, magnesium, lithium, or cerium salt. It can be confirmed that the conversion rate when there is no is as low as 41%.

From the above results, when the nucleoside phosphate compound represented by the chemical formula 2 of the present invention, a salt thereof or a hydrate thereof; a condensing agent; It was also confirmed that high-purity UP ₄ U can be obtained.

Comparative Example 1 Synthesis of UP ₄ U from UDP: International Publication No. 2014/103704 UDP · 2Na salt (50 g, 0.112 mmol) is dissolved in 400 mL of purified water and adsorbed on Dowex 50 w × 2-100 strongly acidic cation exchange resin. Thereafter, 1200 mL of purified water is passed at a rate of 30 mL / min to elute the UDP solution from which the Na salt has been removed. Tributylamine (80 mL, 0.336 mmol) was injected into the eluate, neutralized to pH 7 or higher, concentrated under reduced pressure at 60 ° C., and then concentrated azeotropically under reduced pressure with 1,4-dioxane several times to remove water. . The obtained residue was vacuum-dried at room temperature for 12 hours to obtain 75 g of UDP.2TBA salt (yield 87%, moisture 1.2%).

UDP · 2TBA (14.0 g, 18.1 mmol) in which Na salt is substituted with TBA salt in the above step is dissolved in 46 mL of propionitrile, and carbonyldiimidazole (8.8 g, 54.3 mmol) is added thereto at room temperature. For about 30 minutes and concentrated under reduced pressure to remove the solvent. 7 mL of purified water is poured into the obtained residue and cooled to about 5 ° C., and then UDP · 2Na (4.1 g, 9.1 mmol) is added. After titrating the reaction solution to pH 3.9 using 6N hydrochloric acid aqueous solution, 60% ferric chloride aqueous solution (75 μL, 0.36 mmol) was added and stirred at 10 ° C. for 27 hours. The reaction solution was titrated to pH 10 with 7.5N aqueous sodium hydroxide solution and stirred at 5 ° C. for 1 hour. 90 mL of ethanol was injected at the same temperature, allowed to stand at the same temperature for 12 hours, and filtered to obtain 13.8 g (purity 86.9%) of UP ₄ U compound in solid form.

  Based on the results of Experimental Examples 1 to 5, as in the production method according to the present invention confirmed in Example 1, the nucleoside phosphate compound represented by Chemical Formula 2, its salt or its hydrate; condensing agent It was confirmed that high yield and high purity dinucleoside polyphosphoric acid can be synthesized without a troublesome conversion step at a high reaction conversion rate when a metal ion is reacted. Compared with Comparative Example 1, which is the most effective experimental method of the prior art, this requires separate processing of a starting material in the form of a metal salt such as a commercially available sodium salt without a troublesome UDP salt replacement step. It was confirmed that the working time was also improved drastically by the reaction process which was available without using it and was greatly simplified.

  From the results as described above, it can be confirmed that the method for producing dinucleoside polyphosphoric acid, a salt thereof or a hydrate thereof according to the present invention is compatible with industry and usefully applied to mass production.

Claims (19)

(S-1) a nucleoside phosphate compound represented by the following chemical formula 2, a salt thereof or a hydrate thereof;
A method for producing a dinucleoside polyphosphoric acid represented by the following chemical formula 1, a salt thereof or a hydrate thereof, comprising a step of reacting a condensing agent of carbodiimides; and a metal ion in the presence of a solvent:
In the chemical formula:
R ₁ and R ₂ are the same or different from each other and are each independently a pyrimidine base;
R ₃ is a pyrimidine base;
n is an integer from 2 to 6;
m is an integer of 1-3.   The method for producing a dinucleoside polyphosphate, a salt thereof or a hydrate thereof according to claim 1, wherein the pyrimidine base is uracil. The method for producing a dinucleoside polyphosphate, a salt thereof or a hydrate thereof according to claim 1, wherein the nucleoside polyphosphate represented by the chemical formula 1 is represented by the following chemical formula 1a.
The method for producing a dinucleoside polyphosphate, a salt thereof or a hydrate thereof according to claim 1, wherein the nucleoside phosphate compound represented by the chemical formula 2 is represented by any one of the following chemical formulas 2a to 2c. :
  The method for producing a dinucleoside polyphosphate, a salt thereof or a hydrate thereof according to claim 1, wherein the salt of the nucleoside phosphate compound is a metal salt or an amine salt.   The dinucleoside polyphosphate according to claim 5, wherein the metal salt is selected from the group consisting of lithium, sodium, potassium, magnesium, calcium, barium, cerium, iron, nickel, copper, zinc and boron. A method for producing the hydrate. The amine salt, the alkyl chain is selected from the group consisting of trialkyl amines and cyclic trialkylamines comprised of C ₁ -C _6, dinucleoside polyphosphate, a salt thereof or a hydrated thereof according to claim 5 Manufacturing method.   The dinucleoside polyphosphoric acid according to claim 7, wherein the cyclic trialkylamine is selected from the group consisting of trimethylamine, triethylamine, tributylamine, tripentylamine, trihexylamine, triethanolamine, and pyridine. A method for producing the hydrate. The method for producing a dinucleoside polyphosphoric acid, a salt thereof or a hydrate thereof according to claim 1, wherein the carbodiimide condensing agent is represented by the following chemical formula 3:
In Formula 3,
R ₄ and R ₅ are the same or different from each other, and each independently represents a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and the alkyl group is an alkylamine group and is selectively May be substituted. 9. The dinucleoside polyphosphate, salt or hydrate thereof according to claim 8, wherein R ₄ and R ₅ are the same or different from each other and are each independently ethyl, isopropyl, cyclohexyl or dimethylaminopropyl. Manufacturing method.   The condensing agent for the carbodiimides is 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) or a salt thereof, N, N′-diisopropylcarbodiimide (DIC) and N, N′-dicyclohexylcarbodiimide (DCC). The manufacturing method of the dinucleoside polyphosphoric acid of Claim 1 selected from the group which consists of these, its salt, or its hydrate.   The method for producing dinucleoside polyphosphoric acid, a salt thereof or a hydrate thereof according to claim 1, wherein the metal ion is derived from the group consisting of metal chloride, bromide, nitrate, sulfate and acetate.   2. The dinucleoside polyphosphate, a salt thereof or a hydrate thereof according to claim 1, wherein the metal ion is a metal selected from the group consisting of calcium, magnesium, cerium, iron, lithium, aluminum, titanium and sodium. Production method. The method for producing a dinucleoside polyphosphate, a salt thereof or a hydrate thereof according to claim 1, wherein the metal ion is derived from a metal salt catalyst represented by the following chemical formula 4:
In Formula 4,
a is the number of moles of M;
b is the ionic valence of M;
M is calcium, magnesium, cerium, iron, lithium, aluminum, titanium or sodium;
c is the number of moles of X;
d is the ionic valence of X;
X is halogen, carbonate, acetate, nitrate, triflate, sulfate, carboxylate or derivatives thereof;
The value of the product of a and b is the same as the value of the product of c and d.   The method for producing a dinucleoside polyphosphoric acid, a salt thereof or a hydrate thereof according to claim 1, wherein the solvent is water, an organic solvent, or a mixed solvent of water and an organic solvent. The organic solvent _is an alcohol of C 1 -C _8, ketone C 3 _{-C 10,} 1,4-dioxane, acetonitrile, N, is selected from the group consisting of N- dimethylformamide and dimethyl sulfoxide, in claim 14 The manufacturing method of dinucleoside polyphosphoric acid of description, its salt, and its hydrate.   The equivalent of the condensing agent and the equivalent of the metal ion are the same or different, and each of them reacts at 0.1 to 30.0 molar equivalents with respect to 1 molar equivalent of the nucleoside phosphate compound represented by Chemical Formula 2. A method for producing a dinucleoside polyphosphoric acid, a salt thereof or a hydrate thereof according to claim 1.   The method for producing a dinucleoside polyphosphoric acid, a salt thereof or a hydrate thereof according to claim 1, wherein the reaction temperature is from 0C to 50C.   (S-2) The method for producing dinucleoside polyphosphoric acid, a salt thereof and a hydrate thereof according to claim 1, further comprising a step of solidifying and separating and purifying the product obtained from the step (S-1). .