WO2025018615A1 - Method for producing allulose dimer - Google Patents

Abstract

The present application relates to a method for producing an allulose dimer of chemical formula 1a or chemical formula 1b, a salt thereof, a solvate thereof, a hydrate thereof, or crystals thereof, the method comprising: a step for preparing a compound represented by chemical formula 3 and a compound represented by chemical formula 4 by protecting hydroxyl groups of a compound represented by chemical formula 2a and a compound represented by chemical formula 2b by using a solvent and a protecting group reagent; a step for linking the compound of chemical formula 3 and the compound of chemical formula 4 through a linker; a step for preparing a dioxane ring compound by forming a dioxane ring through an intramolecular reaction in a complex of the compound of chemical formula 3 and the compound of chemical formula 4 linked through the linker; and a step for removing the protecting groups and linker from the dioxane ring compound.

Description

Method for producing allulose dimer

The present application relates to a method for producing allulose dimer.

Allulose, an epimer of fructose, is a stereoisomer of fructose with a chiral center at carbon 3 and different configurations of alcohol groups. Allulose is a rare substance produced from fructose by a specific enzyme. It has a similar sweetness to fructose but almost no calories, so it can be usefully used as a functional food material and pharmaceutical raw material for preventing diabetes, preventing tooth decay, promoting the growth of bifidobacteria, and reducing blood pressure and blood cholesterol levels.

One example of the present application provides a method for producing high-purity allulose dimer, thereby providing a manufacturing method capable of industrially producing allulose dimer crystals.

One example of the present application can provide a method for producing an allulose dimer by protecting primary and secondary alcohols, which are active functional groups of allulose, respectively, then combining two allulose molecules using a linker, forming a ring through an intramolecular reaction, and then removing the protecting group and linker.

The present application is specifically described as follows, and each description and embodiment described in the present application can also be applied to each other description and embodiment. In addition, the scope of the present application is not limited by the specific description described below.

A method for producing allulose dimer, a salt thereof, a hydrate thereof, or a crystal thereof according to an example of the present application is a process for obtaining a high-purity allulose dimer crystal of the following chemical formula 1A or the following chemical formula 1B from allulose.

In a method for manufacturing allulose dimer according to an example of the present application, the solvent used in each step may be a solvent selected from among acetone, ethyl acetate, ethyl ether, tetrahydrofuran, N,N-dimethylformamide, dichloromethane, dimethylsulfoxide, acetonitrile, methanol, ethanol, propanol, isopropanol, dioxane, n-hexane, and water, and each step may be reacted at a reaction temperature of 0 to 40°C or 35 to 60°C.

In addition, the intermediates generated at each stage are crystallized in a single solvent or in a mixture of two or more solvents, and purification, etc. can be performed as needed to increase the purity of the intermediates.

A method for producing allulose dimer, a salt thereof, a hydrate thereof, or a crystal thereof according to an example of the present application may include the following four steps (1) to (4):

(1) A step of protecting the hydroxyl group of the compound of the following chemical formula 2A and the compound of the following chemical formula 2B to prepare the compound of the following chemical formula 3 and the compound of the following chemical formula 4;

(2) A step of combining a compound of the following chemical formula 3 and a compound of the following chemical formula 4 via a linker;

(3) a step of producing a dioxane ring compound by forming a dioxane ring through an intramolecular reaction in a complex of a compound of the following chemical formula 3 and a compound of the following chemical formula 4, which are combined through the linker; and

(4) Step of removing the protecting group and linker from the above dioxane ring compound:

[Chemical Formula 2A]

[Chemical Formula 2B]

[Chemical Formula 3]

[Chemical Formula 4]

An allulose dimer according to an example of the present application may be an allulose dimer of the following chemical formula 1A or the following chemical formula 1B:

[Chemical Formula 1A]

[Chemical Formula 1B]

The compound of the above chemical formula 1A may be, for example, a compound of the following chemical formula 1A-1:

[Chemical Formula 1A-1]

The compound of the above chemical formula 1B may be, for example, a compound of the following chemical formula 1B-1:

[Chemical Formula 1B-1]

The step of preparing the above dioxane ring compound may include a step of replacing the PG1, PG2, PG5 and PG6 protecting groups of the conjugate linked through the linker with different protecting groups; and a step of forming a dioxane ring by an intramolecular reaction.

The step of replacing the above different protecting groups may be replacing the PG1, PG2, PG5, and PG6 protecting groups with protecting groups that are removed or deprotected under different conditions than the PG3, PG4, PG7, and PG8 protecting groups.

The step of replacing the above different protecting groups may be replacing the PG1, PG2, PG5, and PG6 protecting groups with protecting groups that are removed or deprotected en bloc with the linker.

A method for producing allulose dimer, a salt thereof, a hydrate thereof, or a crystal thereof according to an example of the present application may specifically include a total of seven steps of the following (a) to (g), and as an example, may include a process included in the following reaction scheme 1:

(a) a step of preparing a mixture of a compound of the following formula 3 and a compound of the following formula 4 by protecting the hydroxy groups of the compound of the following formula 2A and the compound of the following formula 2B in a mixture of a compound of the following formula 2A and a compound of the following formula 2B, crystallizing and separating the compound of the following formula 3, and separating the compound of the following formula 4;

(b) a step of preparing a compound of the following chemical formula 6A by reacting a compound of the following chemical formula 5 with a compound of the following chemical formula 3;

(c) a step of reacting a compound of the following chemical formula 6A with a compound of the following chemical formula 4 to produce a compound of the following chemical formula 7;

(d) a step of selectively deprotecting the PG1, PG2, PG5, and PG6 protecting groups of the compound of the following chemical formula 7 to prepare a compound of the following chemical formula 8;

(e) a step of protecting the hydroxy group of the compound of the following chemical formula 8 with a protecting group different from the PG3, PG4, PG7, and PG8 protecting groups to prepare a compound of the following chemical formula 9;

(f) a step of treating the compound of the following chemical formula 9 with a strong acid to synthesize the compound of the following chemical formula 10-A and the compound of the following chemical formula 10-B as isomers; and

(g) A step of removing the linker of the compound of formula 10A or formula 10B below and deprotecting the protecting group.

[Reaction Formula 1]

The method for manufacturing allulose dimer according to an example of the present application is described in more detail step by step as follows:

(1) A step of protecting the hydroxyl group of the compound of the following chemical formula 2A and the compound of the following chemical formula 2B to prepare the compound of the following chemical formula 3 and the compound of the following chemical formula 4.

(a) a step of preparing a mixture of a compound of the following formula 3 and a compound of the following formula 4 by protecting the hydroxyl group of the compound of the following formula 2A and the compound of the following formula 2B in a mixture of the compound of the following formula 2A and the compound of the following formula 2B, crystallizing and separating the compound of the following formula 3, and separating the compound of the following formula 4

[Reaction Formula 2-1]

[Reaction Formula 2-2]

The above reaction schemes 2-1 and 2-2 are protection reactions that protect the hydroxyl groups at carbon numbers 1, 2, 4, and 5 of the compound of chemical formula 2A, and the hydroxyl groups at carbon numbers 1, 2, 3, and 4 of the compound of chemical formula 2B. For example, the reaction solvent may be acetone or tetrahydrofuran.

The above protecting reagent may be at least one selected from the group consisting of acetone, 2,2-dimethoxypropane, 2-methoxyprofen, and camphorsulfonic acid.

In the above chemical formula 3, PG1 to PG4 are protecting groups, and in the above chemical formula 4, PG5 to PG8 are protecting groups.

For example, in the chemical formula 3, PG1 and PG2 can be connected to each other to form a protecting group, and PG3 and PG4 can be connected to each other to form a protecting group.

For example, in the chemical formula 3, PG1 and PG2 can be linked to each other to form an acetonide protecting group, and PG3 and PG4 can be linked to each other to form an acetonide protecting group.

For example, the compound of the above formula 3 may be a compound of the following formula 3A:

[Chemical Formula 3A]

For example, in the chemical formula 4, PG5 and PG6 can be connected to each other to form a protecting group, and PG7 and PG8 can be connected to each other to form a protecting group.

For example, in the chemical formula 4, PG5 and PG6 can be linked to each other to form an acetonide protecting group, and PG7 and PG8 can be linked to each other to form an acetonide protecting group.

For example, the compound of the above chemical formula 4 may be a compound of the following chemical formula 4A:

[Chemical Formula 4A]

The step of obtaining the compound of the above chemical formula 3 and the compound of the above chemical formula 4 may be performed in the presence of an acid catalyst. The acid catalyst may be at least one selected from the group consisting of methanesulfonic acid, sulfuric acid, hydrochloric acid, nitric acid, and acetic acid.

In the above reaction formulas 2-1 and 2-2, water (H ₂ O) is generated as a byproduct, which acts as a reverse reaction under an acid catalyst, and the solvent may be diluted, thereby delaying the reaction rate. Accordingly, a moisture absorbent may be added after a certain period of reaction or during the reaction (for example, at the beginning of the reaction) to suppress the reverse reaction. The moisture absorbent may be, for example, magnesium sulfate (MgSO ₄ ) and/or sodium sulfate (Na ₂ SO ₄ ).

For example, the compound of Chemical Formula 3 and the compound of Chemical Formula 4 can be prepared by adding allulose and an acid catalyst to acetone. The acetone can participate in the reaction as a reaction solvent and an alcohol group protecting reagent of allulose. The amount of acetone used as a reaction solvent and a protecting reagent for the preparation of Chemical Formula 3 and Chemical Formula 4 can be 7 to 40 times (v/w), 7 to 20 times (v/w), 7 to 15 times (v/w), 8 to 40 times (v/w), 8 to 20 times (v/w), 8 to 15 times (v/w), 10 to 40 times (v/w), 10 to 20 times (v/w), or 10 to 15 times (v/w) the volume of allulose as a starting material.

As a protecting reagent, 2,2-dimethoxypropane, 2-methoxypropene, etc. can be used in an amount of 2 equivalents or more, for example, 2 to 3 equivalents or 2.5 to 3 equivalents, relative to the starting material allulose.

The reaction temperature of the above reaction schemes 2-1 and 2-2 may be 0 to 35°C. For example, when using acetone solvent and/or a protecting reagent, if the reaction temperature is low, the reaction time becomes long, and if the reaction temperature is too high, unknown impurities may be generated, so the reaction may be performed at a temperature of 20 to 30°C. For example, when using a protecting reagent such as 2,2-dimethoxypropane or 2-methoxypropene, the reaction time is appropriate and the yield is the best at a reaction temperature of 0 to 5°C.

After the reaction and work up of the above reaction schemes 2-1 and 2-2, a step of crystallizing the compound of the above chemical formula 3 may be additionally included. The crystallization step may be crystallized in a single solvent or in a mixed solvent of two or more. The crystallization solvent may be, for example, a solvent selected from the group consisting of ethyl ether (diethyl ether), ethyl acetate, n-hexane, and isopropyl alcohol, and the compound of the above chemical formula 3 may be crystallized to separate it into white crystals, and then the compound of the above chemical formula 4 may be obtained.

For example, the compound of chemical formula 3 can be obtained with 99.2% purity by crystallization using diethyl ether as a sole solvent.

(2) A step of combining a compound of the following chemical formula 3 and a compound of the following chemical formula 4 through a linker.

(b) a step of producing a compound of the following chemical formula 6A by reacting a compound of the following chemical formula 5 with a compound of the following chemical formula 3

[Reaction Formula 3]

The above reaction scheme 3 is a step for producing a compound of formula 6A by reacting a compound of formula 3 and a compound of formula 5. This is a reaction for producing a compound of formula 2A and a compound of formula 2B as a single molecule, using the compound of formula 5 as a linker, as a strategy for producing an allulose dimer according to one example of the present application. A hydroxyl group that is not protected by a protecting group in the compound of formula 3 and the compound of formula 5 can be combined to produce a compound of formula 6A.

In the above chemical formula 5, X ₁ and X ₂ each independently represent a leaving group such as chloro (Cl), bromo (Br), iodine (I), methanesulfonyl (OMs), or p-toluenesulfonyl (p-TS).

The compound of the above chemical formula 5 may be a bishalomethylbenzene, for example, 1,2-dihalomethylbenzene, 1,3-dihalomethylbenzene, or 1,4-dihalomethylbenzene.

In the above chemical formula 6A, PG1 to PG4 are protecting groups, and in the above chemical formula 6B, PG1 to PG4 are protecting groups.

For example, in the chemical formula 6A, PG1 and PG2 can be connected to each other to form a protecting group, and PG3 and PG4 can be connected to each other to form a protecting group.

For example, in the chemical formula 6A, PG1 and PG2 can be linked to each other to form an acetonide protecting group, and PG3 and PG4 can be linked to each other to form an acetonide protecting group.

For example, the compound of formula 6A may be a compound of formula 6C:

[Chemical formula 6C]

In the above chemical formula 6C, X is Br, Cl, I, methanesulfonyl (Oms), or p-toluenesulfonyl (p-Ts).

For example, in the chemical formula 6B, PG1 and PG2 can be connected to each other to form a protecting group, and PG3 and PG4 can be connected to each other to form a protecting group.

For example, in the chemical formula 6B, PG1 and PG2 can be linked to each other to form an acetonide protecting group, and PG3 and PG4 can be linked to each other to form an acetonide protecting group.

For example, the compound of formula 6A may be a compound of formula 6D:

[Chemical Formula 6D]

The reaction solvent that can be used in the above reaction scheme 3 may be selected from ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, methylene chloride, acetone, dimethyl sulfoxide, and N,N-dimethylacetamide. For example, the reaction solvent is N,N-dimethylformamide or tetrahydrofuran, and the amount of the reaction solvent used may be 7 to 5 v/w relative to the compound of chemical formula 3.

The base used in the above reaction scheme 3 may be a base selected from among amine bases such as trimethylamine, triethylamine, N,N-dimethylpyridine, pyridine, N,N-dimethylaniline, and the like; inorganic bases such as potassium t-butoxide, sodium t-butoxide (t-BuONa), t-butoxide (t-BuOK), sodium hydride (NaH), and the like.

When preparing chemical formula 6A of the above reaction scheme 3, the production of the compound of chemical formula 6B, which is a byproduct, can be suppressed by the amount used, the order of addition, and the speed of addition of the compound of chemical formula 3 and the compound of chemical formula 5.

Specifically, at a reaction temperature of -10 to 25°C, under a reaction solvent, 0.5 to 1.3 equivalents, 0.5 to 1 equivalents, 0.8 to 1.3 equivalents, or 0.8 to 1 equivalents of the compound of formula 5 relative to the compound of formula 3 are dissolved in the reaction solvent, 0.9 to 2 equivalents or 1 to 1.5 equivalents (for example, 1.2 equivalents) of a base are added, and then the solution of the compound of formula 3 is slowly added, thereby producing the compound of formula 6A without producing the compound of formula 6B as a byproduct. For example, after the completion of the reaction by adding the solution of the compound of the chemical formula 3, the content of the compound of the chemical formula 6B in the reaction solvent is 100% (mol/mol) or less, less than 100% (mol/mol), 90% (mol/mol) or less, 80% (mol/mol) or less, 70% (mol/mol) or less, 60% (mol/mol) or less, 50% (mol/mol) or less, 40% (mol/mol) or less, 30% (mol/mol) or less, 25% (mol/mol) or less, 20% (mol/mol) or less, 15% (mol/mol) or less, 10% (mol/mol) or less, 9% (mol/mol) or less, 8% (mol/mol) or less, 7% (mol/mol) or less, 6% (mol/mol) or less, 5% (mol/mol) or less, 4% (mol/mol) or less, It can be less than or equal to 3%(mol/mol), less than or equal to 2%(mol/mol), or less than or equal to 1%(mol/mol).

The step of binding the linker to the compound of the above chemical formula 3 may be performed at a temperature of -10 to 10°C, -10 to 5°C, -5 to 10°C, -5 to 5°C, -3 to 3°C, -2 to 2°C, -1 to 1°C, or, for example, 0°C.

For example, the reaction scheme 3 may be a method in which the compound of chemical formula 3 is slowly added to a reactant of 0.9 to 2.0 equivalents of a basic compound such as sodium hydride or an amine base and 0.8 to 1.3 equivalents of a 1,2-, 1,3-, 1,4-dihalo compound in a reaction solvent.

(c) a step of reacting a compound of the following chemical formula 6A with a compound of the following chemical formula 4 to produce a compound of the following chemical formula 7.

[Reaction Formula 4]

The above reaction scheme 4 is a step for producing the above chemical formula 7 by coupling the above chemical formula 6A compound with the chemical formula 4 compound. The compound of the above chemical formula 7 can be produced by coupling reaction of the compound of the above chemical formula 6A in which four alcohol groups are protected and the compound of the above chemical formula 4 in which four alcohol groups are protected.

In the compound of the above chemical formula 7, PG1 to PG8 are protecting groups, for example, PG1 and PG2 can be connected to each other to form a protecting group, PG3 and PG4 can be connected to each other to form a protecting group, PG5 and PG6 can be connected to each other to form a protecting group, and PG7 and PG8 can be connected to each other to form a protecting group.

For example, the compound of the above chemical formula 7 may be a compound of the following chemical formula 7A:

[Chemical Formula 7A]

The reaction solvent that can be used in the above reaction scheme 4 may be selected from ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, methylene chloride, acetone, dimethyl sulfoxide, N,N-dimethylacetamide, and diethyl ether, and may be, for example, tetrahydrofuran or N,N-dimethylformamide.

The base that can be used in the above reaction scheme 4 can be selected from among amine bases such as trimethylamine, triethylamine, N,N-dimethylpyridine, pyridine, N,N-dimethylaniline, and the like, and inorganic bases such as potassium t-butoxide, sodium t-butoxide, and sodium hydride.

Specifically, the compound of the chemical formula 4 is dissolved in a reaction solvent of 7 to 10 v/w, cooled to 0 to 20°C, 1 to 2 equivalents of sodium hydride are added relative to the compound of the chemical formula 4, and 1 to 1.3 equivalents of the compound of the chemical formula 6 are added to cause a reaction.

The step of binding the compound of the chemical formula 4 to the compound of the chemical formula 6A may be performed at a temperature of -10 to 10°C, -10 to 5°C, -5 to 10°C, -5 to 5°C, -3 to 3°C, -2 to 2°C, -1 to 1°C, or, for example, 0°C.

For example, the reaction solvent for producing the compound represented by the chemical formula 7 is N,N-dimethylformamide or tetrahydrofuran, and the amount of the reaction solvent used is 7 to 15 times (v/w) compared to the compound represented by the chemical formula 6. In addition, 0.9 to 2.0 equivalents of a base such as sodium hydride or an amine base and 0.8 to 1.3 equivalents of the compound represented by the chemical formula 4 may be added under the reaction solvent.

As a post-process after the reaction, a step of crystallizing the compound of formula 7 may be additionally included. The crystallizing step may use a single or mixed solvent from among ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, methylene chloride, acetone, dimethyl sulfoxide, N,N-dimethylacetamide, diethyl ether, methanol, ethanol, and isopropanol to crystallize the compound of formula 7.

(3) A step of producing a dioxane ring compound by forming a dioxane ring through an intramolecular reaction in a complex of the compound of the chemical formula 3 and the compound of the chemical formula 4 combined through the linker.

(d) a step of selectively deprotecting the PG1, PG2, PG5, and PG6 protecting groups of the compound of the following chemical formula 7 to prepare the compound of the following chemical formula 8.

[Reaction Formula 5]

The above reaction scheme 5 is a deprotection reaction step of the compound of chemical formula 7, which is a step of selectively removing the PG1, PG2, PG5, and PG6 protecting groups from the compound of chemical formula 7 to prepare the compound of chemical formula 8.

In the compound of the above chemical formula 8, PG3, PG4, PG7, and PG8 are protecting groups.

For example, in the chemical formula 8, PG3 and PG4 can be connected to each other to form a protecting group, and PG7 and PG8 can be connected to each other to form a protecting group.

For example, in the chemical formula 8, PG3 and PG4 can be linked to each other to form an acetonide protecting group, and PG7 and PG8 can be linked to each other to form an acetonide protecting group.

For example, the compound of the above chemical formula 8 may be a compound of the following chemical formula 8A:

[Chemical Formula 8A]

The reaction solvent that can be used in the above reaction scheme 5 is 10 to 20 v/w of a single solvent or a mixture of two or more solvents selected from acetic acid, methanol, ethanol, acetone, tetrahydrofuran, and purified water.

The deprotecting reagent that can be used in the above reaction scheme 5 may be an organic acid deprotecting reagent, and for example, one or more deprotecting reagents selected from the group consisting of acetic acid, hydrochloric acid, phosphoric acid, and formic acid may be used.

For example, the reaction scheme 5 can be used to prepare the compound of formula 8 by adding diluted hydrochloric acid or diluted acetic acid in a solvent and stirring at -10 to 10° C. or 40 to 70° C. to selectively remove the PG1, PG2, PG5, and PG6 protecting groups.

When using the above diluted hydrochloric acid (for example, hydrochloric acid having a concentration of 1 to 4 N or 1 to 3 N), the reaction temperature may be -10 to 30°C, -10 to 10°C, -10 to 5°C, -5 to 10°C, -5 to 5°C, -3 to 3°C, -2 to 2°C, -1 to 1°C, or, for example, 0°C.

When the diluted acetic acid (for example, acetic acid having a concentration of 30 to 70%) is used, acetic acid can participate in the reaction as a reaction solvent and a deprotecting reagent. 5 to 10 v/w of diluted acetic acid having a concentration of 30 to 70% relative to the compound of the chemical formula 7 as a starting material is added, and stirred at 30 to 80° C. or 40 to 70° C., selectively deprotecting only the PG1, PG2, PG5 and PG6 protecting groups among the protecting groups can be prepared to produce the compound of the chemical formula 8. When the solvent used is acetic acid, an organic solvent and a mixed solvent can also be used, but diluted acetic acid can be used alone, preferably.

When using the above diluted acetic acid, the reaction temperature may be 40 to 70°C, 40 to 60°C, 50 to 70°C, 50 to 60°C, or, for example, 55°C for deprotection.

(e) a step of preparing a compound of the following chemical formula 9 by protecting the hydroxyl group of the compound of the following chemical formula 8 with a protecting group different from the PG3, PG4, PG7, and PG8 protecting groups.

[Reaction Formula 6]

The above reaction scheme 6 is a step for preparing the compound of the formula 9 by protecting the four secondary alcohol groups of the compound of the formula 8 with a protecting group different from the PG3, PG4, PG7, and PG8 protecting groups. Specifically, the compound of the formula 8 may be treated with a protecting group reagent different from the protecting group reagent used in the above reaction scheme 2. That is, the protecting groups of PG9 to PG12 in the formula 9 are different from the protecting groups of PG3, PG4, PG7, and PG8. The different protecting group reagent may introduce a protecting group that is removed under different conditions from the protecting groups of PG3, PG4, PG7, and PG8 of the compound of the formula 8.

The protecting group reagent used in the above reaction scheme 6 is a protecting group reagent that introduces a different protecting group from the protecting groups of the compound of the above chemical formula 3 and the compound of the above chemical formula 4, and may be, for example, at least one protecting group reagent selected from the group consisting of a benzyl group compound, a benzoyl group compound, a trimethysilyl group compound, and an ortho ester group compound, for example, benzyl halide. The different protecting group may be deprotected under different conditions from the protecting groups of the compound of the above chemical formula 3 and the compound of the above chemical formula 4.

For example, in the chemical formula 9, PG3 and PG4 may be connected to each other to form an acetonide protecting group, PG7 and PG8 may be connected to each other to form an acetonide protecting group, and PG9 to PG12 may be a benzyl group (Bn).

For example, the compound of the above chemical formula 9 may be a compound of the following chemical formula 9A:

[Chemical Formula 9A]

The reaction solvent that can be used in the above reaction scheme 6 can be selected from ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, acetonitrile, methylene chloride, acetone, dimethyl sulfoxide, N,N-dimethylacetamide, and diethyl ether, and by adding 4 equivalents or more of a base and benzyl halide, benzyl chloride, or benzyl bromide under the reaction solvent, the compound of chemical formula 9 can be prepared.

The base that can be used in the above reaction scheme 6 is an amine base such as a metal alkoxide of an alkaline earth metal such as sodium hydride, potassium, or sodium, pyridine, substituted pyridine, aniline, or N,N-dimethylaryl, in an amount of 4 to 6 equivalents.

The reprotection with the different protecting group may be performed by pretreatment at a temperature of -10 to 10°C, for example, 0°C, and then raising the temperature to room temperature. Specifically, the compound of the formula 8 may be added to a solvent (e.g., tetrahydrofuran or N,N-dimethylformamide), cooled to a temperature of -10 to 10°C, for example, 0°C, adding a base (e.g., 4 to 6 equivalents of sodium hydride), first adding a protecting reagent different from the protecting reagent used in the reaction scheme 2 (e.g., a benzyl compound, for example, benzyl halide), and then raising the temperature to room temperature, and then second adding the different protecting reagent. The amount of the reaction solvent used may be 7 to 15 v/w relative to the compound of the formula 8. The reprotection with the above different protecting group may be, in the step (4) of removing the protecting group and linker from the dioxane ring compound, reprotection with a protecting group that can be removed together with the linker. For example, the above different protecting group reagent may be, for example, 4 to 8 equivalents of benzyl halide, and the benzyl halide may be substituted with methane, nitro, etc.

After the reaction is complete, the reactants are cooled to 0℃, and the base is deactivated with saturated ammonium chloride (sat-NH4Cl), after which the post-process can be performed.

(f) A step of treating the compound of the following chemical formula 9 with a strong acid to synthesize the compound of the following chemical formula 10-A and the compound of the following chemical formula 10-B as isomers.

[Reaction Formula 7]

The above reaction scheme 7 is a step of selectively deprotecting the PG3, PG4, PG7, and PG8 protecting groups of the compound of formula 9 having a protected hydroxy group in the presence of a strong acid catalyst such as trifluoromethanesulfonic acid (TfOH), and forming a dioxane ring through an intramolecular reaction to prepare the compound of formula 10A and the isomeric compound of formula 10B. The compound of formula 10A and the compound of formula 10B are alpha, beta (α, β) and beta, alpha (β, α) isomers of the allulose dimer intermediate.

In the above chemical formula 10A, PG9 to PG12 are protecting groups, and in the above chemical formula 10B, PG9 to PG12 are protecting groups.

For example, in the chemical formula 10A, PG9 to PG12 may be benzyl groups (Bn).

For example, in the chemical formula 10B, PG9 to PG12 may be benzyl groups (Bn).

For example, the reaction scheme 7 may selectively deprotect PG3, PG4, PG7, and PG8 of the compound of formula 9, and form a dioxane ring through an intramolecular reaction to prepare the compound of formula 10A and the compound of formula 10B.

For example, the above reaction scheme 7 can selectively deprotect the acetonide protecting group of the compound of formula 9A, and form a dioxane ring through an intramolecular reaction of the primary alcohol group of the five-membered ring, the secondary alcohol group of the six-membered ring, and the primary alcohol group of the six-membered ring and the secondary alcohol group of the five-membered ring, respectively, to produce a compound in which PG9 to PG12 in formula 10A are benzyl groups (Bn) and a compound in formula 10B in which PG9 to PG12 are benzyl groups (Bn).

Specifically, the compound of the chemical formula 10A and the compound of the chemical formula 10B can be prepared by adding 0.8 to 2 equivalents of trifluoromethanesulfonic acid (TfOH) at a reaction temperature of -70 to -45°C in a reaction solvent of 7 to 10 v/w of tetrahydrofuran (THF).

As an example, the compound represented by the chemical formula 9 may be prepared using 0.5 to 2 equivalents of trifluorosulfonic acid in a 7 to 15 v/w methylene chloride solvent.

The step of forming the above dioxane ring may be performed by cooling to a temperature range of -85 to -65°C (for example, -78°C) and then heating to a temperature range of -60 to -40°C (for example, -50°C).

(g) a step of removing the linker of the compound of chemical formula 10A or chemical formula 10B and deprotecting the protecting group;

[Reaction Formula 8-1]

[Reaction Formula 8-2]

The above reaction schemes 8-1 and 8-2 are steps for producing allulose dimer isomers of chemical formula 1A or 1B by removing linkers and deprotecting protective groups of compounds of chemical formula 10A and 10B under a 10%-palladium (10%-Pd/C) catalyst.

Specifically, by adding 10 to 30 equivalents of formic acid (HCO 2 H) or ammonium formate (HCO 2 NH 4 ) as a hydrogen source in the presence of a 10% palladium catalyst in a single solvent or a mixed solvent selected from methanol, ethanol, acetone, tetrahydrofuran, _ethyl acetate, and purified water to the compound of formula _10A or formula _10B , and stirring at normal pressure to deprotect the protecting group, a high-purity allulose dimer of formula 1A or formula 1B having a purity of 90% or more, 95% or more, 99% or more, or 99.5% or more can be prepared.

For example, a deprotection reaction of a benzyl group may be performed in the presence of 0.1 to 1 equivalent of a palladium carbon catalyst and 1 to 10 equivalents of formic acid (HCO ₂ H) or ammonium formic acid (HCO ₂ NH ₄ ) in the presence of a compound represented by the chemical formula 10A or 10B.

The step of removing the linker may be performed at a temperature of -10 to 10°C, -10 to 5°C, -5 to 10°C, -5 to 5°C, 0 to 10°C, or 0 to 5°C.

After the reaction of the above reaction scheme 8-1 or the above reaction scheme 8-2, a step of crystallizing the allulose dimer of the above chemical formula 1A or the above chemical formula 1B may be additionally included.

The moisture content of the hydrate can be, for example, 1 to 15 wt%, 1 to 13 wt%, 1 to 12 wt%, 5 to 10.5 wt%, 3 to 15 wt%, 3 to 13 wt%, 3 to 12 wt%, 3 to 10.5 wt%, 5 to 15 wt%, 5 to 13 wt%, 5 to 12 wt%, or 5 to 10.5 wt%.

Another example of the present application relates to a compound of Formula 6A below, Formula 6B below, Formula 7 below, Formula 10A below, or Formula 10B below, a salt thereof, a solvate thereof, a hydrate thereof, or a crystal thereof:

[Chemical Formula 6A]

In the above chemical formula 6A,

PG1 to PG4 are protecting groups,

X is Br, Cl, I, methanesulfonyl (Oms), or p-toluenesulfonyl (p-Ts),

[Chemical Formula 6B]

In the above chemical formula 6B, PG1 to PG4 are protecting groups,

[Chemical formula 7]

In the above chemical formula 7, PG1 to PG8 are protecting groups,

[Chemical Formula 10A]

In the above chemical formula 10A, PG9 to PG12 are protecting groups,

[Chemical Formula 10B]

In the above chemical formula 10B, PG9 to PG12 are protecting groups.

The present application provides a method for producing allulose dimer, a rare substance, thereby enabling industrial production of high-purity allulose dimer.

Hereinafter, the present invention will be described in more detail by the following examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example 1. Preparation of compound of chemical formula 3A

[Reaction Formula 2-1A]

(1) Manufacturing using acetone and sulfuric acid catalyst

100 g (0.555 mol) of D-allulose, 1,200 mL of acetone, and 0.5 mL of sulfuric acid were added to a reaction vessel and stirred at room temperature for more than 12 hours. When the reaction solution became a clear solution, the reaction solution was cooled to 0°C, the acid was neutralized with 2.7 mL of triethylamine, and then concentrated under reduced pressure. 1,000 mL of methylene chloride and 300 mL of purified water were added to the concentrate, stirred for 30 minutes, and then the layers were separated.

The methylene chloride layer was washed with 300 mL of purified water, the remaining moisture was removed with salt water, treated with magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in 300 mL of ethyl ether, and crystallization was induced by cooling from 40°C to 0°C using a crystallization method to obtain crystals, and the resulting crystals were filtered to obtain 46.2 g of a compound of chemical formula 3A as white crystals. The crystals were used as seed crystals in (2) and (3) of Example 1 thereafter.

H-NMR (CDCl3): δ 1.3~1.5(12H),3.1(1H), 3.6(1H), 3.7(1H), 4.0(1H), 4.2~4.3(2H),4.6(1H), 4.9(1H) )

(2) Manufacturing using acetone and methanesulfonic acid catalysts

100 g (0.555 mol) of D-allulose, 1,200 mL of acetone, and 0.5 mL of methanesulfonic acid were added to a reaction vessel and stirred at room temperature for more than 12 hours. When the reaction solution became a clear solution, the reaction solution was cooled to 0°C, quenched with 2.7 mL of triethylamine, and concentrated under reduced pressure. 1,000 mL of methylene chloride (DCM) and 300 mL of purified water were added to the concentrate, stirred for 30 minutes, and then the layers were separated.

After washing the DCM layer with 300 mL of purified water, the remaining moisture was removed with salt water, treated with MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in 300 mL of ethyl ether, cooled to 0°C, and the crystals obtained in (1) of Example 1 were added as seed, stirred for 1 hour, and the resulting crystals were filtered to obtain a compound of chemical formula 3A as white crystals.

H-NMR (CDCl3): δ 1.3~1.5(12H),3.1(1H), 3.6(1H), 3.7(1H), 4.0(1H), 4.2~4.3(2H),4.6(1H), 4.9(1H) )

(3) Manufacturing using 2,2-dimethoxypropane

100 g (0.555 mol) of D-allulose, 800 mL of dry tetrahydrofuran (Dry-THF), and 0.5 mL of methanesulfonic acid were added to a reaction vessel and cooled to 0°C. 149 mL (1.22 mol) of 2,2-dimethoxypropane as a protecting reagent was slowly added, and the mixture was stirred for 3 hours while maintaining the temperature. After concentrating the reactant under reduced pressure, 1000 mL of methylene chloride (DCM) and 300 mL of purified water were added to the concentrate, stirred for 30 minutes, and then the layers were separated.

After washing the DCM layer with 300 mL of purified water, the remaining moisture was removed with salt water, treated with MgSO ₄ , filtered, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in 300 mL of ethyl ether, cooled to 0°C, and the crystals obtained in (1) of Example 1 were added as seed, stirred for 1 hour, and the resulting crystals were filtered to obtain 46.2 g of a compound of chemical formula 3A as white crystals.

H-NMR (CDCl3): δ 1.3~1.5(12H),3.1(1H), 3.6(1H), 3.7(1H), 4.0(1H), 4.2~4.3(2H),4.6(1H), 4.9(1H) )

Example 2. Preparation of compound of chemical formula 4A

[Reaction Formula 2-2A]

The white crystals of the compound of chemical formula 3A prepared in (1) of the above Example 1 were filtered, and the filtrate was concentrated and then purified by column chromatography with EtOAc/Hex = 1/3 to obtain 22 g of the compound of chemical formula 4A.

H-NMR (CDCl3): δ 1.2~1.5(12H), 3.1(1H), 3.6(1H), 3.7(1H), 4.0(1H), 4.2~4.3(2H), 4.6(1H), 4.9(1H) )

Example 3. Preparation of compound of chemical formula 6C

[Reaction Scheme 3A]

(1) Manufacturing using tetrahydrofuran (THF)

11.57 g (40.36 mmol) of 1,3-Bis(bromomethyl)benzene was added to 150 mL of THF, cooled to 0°C, 2.5 g (57.66 mmol) of 60%-NaH was added, and stirred for 10 minutes.

A solution of 10 g (38.4 mmol) of the compound of chemical formula 3 obtained in Example 1 dissolved in 50 mL of tetrahydrofuran (THF) was slowly added to the reaction mixture, stirred at 0°C for 30 minutes, and then stirred at room temperature for 24 hours.

The reaction product was quenched with Sat-NH ₄ Cl, extracted with 200 mL of EtOAc and 100 mL of purified water, treated with Brine and MgSO ₄ , and purified by column with Hexane/EtOAc = 9/1 to obtain 10.3 g of a compound of chemical formula 6C.

H-NMR (CDCl3): δ 1.3~1.4(12H), 3.5~3.6(2H), 4.0(1H), 4.2~4.3(2H), 4.4~4.6(5H), 4.7(1H), 7.2~7.3( 4H)

(2) Manufacturing using dimethylformamide (DMF)

Using 80 mL of dimethylformamide (DMF) as a reaction solvent, 10.3 g of compound of chemical formula 6C was obtained in the same manner as in (1) of Example 3.

H-NMR (CDCl3): δ 1.3~1.4(12H), 3.5~3.6(2H), 4.0(1H), 4.2~4.3(2H), 4.4~4.6(5H), 4.7(1H), 7.2~7.3( 4H)

Example 4. Preparation of compound of chemical formula 7A

[Reaction Scheme 4A]

(1) Manufacturing using dimethylformamide (DMF)

50 g (0.192 mol) of the compound of chemical formula 4A obtained in Example 2 was dissolved in 400 mL of dimethylformamide (DMF), cooled to 0°C, 11.5 g (0.289 mol) of 60%-NaH was added, and stirred for 20 minutes.

A solution of 102.1 g (0.230 mol) of the compound of chemical formula 6C obtained in Example 3 dissolved in 250 mL of dimethylformamide (DMF) was slowly added to the reaction mass over 30 minutes, and the mixture was heated to room temperature and stirred for 5 hours.

After cooling the reaction to 0℃, the mixture was quenched with sat-NH4Cl solution, and extracted with 1100 mL of EtOAc and 500 mL of purified water.

The organic layer was washed with 300 mL of purified water, treated with Brine and MgSO ₄ , and then concentrated under reduced pressure.

The concentrate was purified by column chromatography using Hex/EtOAc=6/1 to obtain 112 g of a compound of chemical formula 7A.

H-NMR (CDCl3): δ 1.1~1.3(24H), 3.4~3.5(4H), 4.0(2H), 4.2~4.3(4H), 4.4~4.6(6H), 4.7(2H), 7.2~7.3( 4H)

(2) Manufacturing using tetrahydrofuran (THF)

Using 600 mL of tetrahydrofuran (THF) as a reaction solvent, 112 g of compound of chemical formula 7A was obtained in the same manner as in (1) of Example 4.

H-NMR (CDCl3): δ 1.1~1.3(24H), 3.4~3.5(4H), 4.0(2H), 4.2~4.3(4H), 4.4~4.6(6H), 4.7(2H), 7.2~7.3( 4H)

Example 5. Preparation of compound of chemical formula 8A

[Reaction Scheme 5A]

(1) Manufacturing using acetic acid

In Example 4, 24.5 g (39 mmol) of the compound of chemical formula 7A obtained was added and dissolved in 350 mL of 60%-AcOH, and stirred at 55°C for 6 hours. After cooling the reaction mass to room temperature, 800 mL of purified water and 800 mL of EtOAc were added and extracted. The aqueous layer was re-extracted with 500 mL of EtOAc. The organic layer was washed three times with 500 mL of purified water, and again with sat-NaHCO ₃ , treated with MgSO ₄ , concentrated under reduced pressure, and then purified by column chromatography with EtOAC /Hex = 1/1 to obtain 13.8 g of the compound of chemical formula 8A.

H-NMR (DMSO): δ 1.1~1.3(12H), 3.3~3.4(4H), 3.9~4.0(2H), 4.1~4.3(4H), 4.3~4.6(6H), 4.6~4.7(2H), 7.2~7.3(4H)

(2) Manufacturing using methanol

In Example 4, 5 g (7.96 mmol) of the compound of chemical formula 7A obtained was added to 40 mL of methanol, cooled to 0°C, 10 mL of 3-HCl was added, and stirred for 4 hours. 40 mL of purified water was added to the reaction mixture, and extraction was performed with 200 mL of EtOAc. The aqueous layer was re-extracted with 100 mL of EtOAc, and the organic layer was washed with 50 mL of purified water, treated with MgSO ₄ , concentrated under reduced pressure, and then purified by column chromatography with EtOAC /Hex = 1/1 to obtain 2.1 g of the compound of chemical formula 8A.

H-NMR (DMSO): δ 1.1~1.3(12H), 3.3~3.4(4H), 3.9~4.0(2H), 4.1~4.3(4H), 4.3~4.6(6H), 4.6~4.7(2H), 7.2~7.3(4H)

Example 6. Preparation of compound of chemical formula 9A

[Reaction Scheme 6A]

(1) Manufacturing using dimethylformamide

38 g (70.0 mmol) of the compound of chemical formula 8A prepared in Example 5 was added to 380 mL of dimethylformamide (DMF), cooled to 0°C, 14.0 g (0.35 mol) of 60%-NaH was added, and stirred for 20 minutes.

50.0 mL (0.42 mol) of benzyl bromide was slowly added to the reaction mixture, stirred at 0°C for 2 hours, warmed to room temperature and stirred for 3 hours, and 10 mL of benzyl bromide was added to the reaction mixture and stirred at room temperature for 3 hours.

After cooling the reaction to 0℃, the solution was quenched with sat-NH ₄ Cl solution, and extracted with 1100 mL of EtOAc and 500 mL of purified water.

The organic layer was washed with 300 mL of purified water, treated with Brine and MgSO ₄ , and then concentrated under reduced pressure.

150 mL of isopropyl alcohol was added to the concentrate, stirred at 40°C for 30 minutes, cooled to 0°C, and the resulting crystals were filtered and dried to obtain 46.2 g of a compound of chemical formula 9A.

H-NMR (DMSO-d6): δ,1.2~1.3(12H), 3.3~3.4(9H), 3.6~4.2(9H), 4.4~4.8(8H),7.2~7.4(24H)

(2) Manufacturing using tetrahydrofuran (THF)

5.0 g (9.2 mmol) of the compound of chemical formula 8A prepared in Example 5 was added to 50 mL of tetrahydrofuran (THF), cooled to 0°C, 14.0 g (0.35 mol) of 60%-NaH was added, and stirred for 20 minutes.

6.5 mL (55.2 mmol) of benzyl bromide was slowly added to the reaction mixture, stirred at 0°C for 2 hours, warmed to room temperature and stirred for 3 hours, and 2 mL of benzyl bromide was added to the reaction mixture and stirred at room temperature for 3 hours.

After cooling the reaction to 0℃, the solution was quenched with sat-NH ₄ Cl solution, and extracted with 100 mL of EtOAc and 30 mL of purified water.

The organic layer was washed with 30 mL of purified water, treated with Brine and MgSO ₄ , and then concentrated under reduced pressure.

10 mL of isopropyl alcohol was added to the concentrate, stirred at 40°C for 30 minutes, cooled to 0°C, and the resulting crystals were filtered and dried to obtain 5.4 g of a compound of chemical formula 9A.

H-NMR (DMSO-d6): δ,1.2~1.3(12H), 3.3~3.4(9H), 3.6~4.2(9H), 4.4~4.8(8H),7.2~7.4(24H)

Example 7. Preparation of compounds of chemical formula 10C and 10D

[Reaction Scheme 7A]

21 g (27.5 mmol) of compound of chemical formula 9A prepared in Example 6 was added to 200 mL of methylene chloride, cooled to -78°C, 3.6 mL (41.2 mmol) of CF ₃ SO ₃ H was added, and the mixture was stirred for 2 hours while maintaining the temperature. The temperature was gradually increased, stirred at -50°C for 3 hours, quenched with triethylamine, and then heated to room temperature.

After the reactant was separated into layers using 300 mL of methylene chloride and 300 mL of purified water, the organic layer was washed with 200 mL of purified water, then treated with Brine and MgSO ₄ and concentrated under reduced pressure, and then purified by column with Hex/EtOAc=1/1. Spot impurities with Rf 0.2 or higher during the column were removed by Hex/EtOAc=1/1, and then purified by column with EtOAc/MeOH=10/1, to obtain 13.2 g of a mixture of a compound of chemical formula 10C and a compound of chemical formula 10D.

H-NMR(CDCl3): δ 3.3~4.2(15H), 4.4~4.8(12H),7.2~7.4(24H)

Example 8. Preparation of allulose dimer

[Reaction Formula 8-1A]

[Reaction Formula 8-2A]

(1) Manufacturing using formic acid

18 g of a mixture of compounds of chemical formula 10C and 10D obtained in Example 7 was added to 320 mL of EtOAc-320 mL of MeOH, 600 mg of 10%-Pd/C and 80 mL of HCO ₂ H were added, and the mixture was stirred at room temperature for 16 hours.

The removal of the starting material was confirmed by TLC and HPLC, and the reaction product was filtered under a celite pad and concentrated under reduced pressure.

100 mL of purified water and 50 mL of EtOAc were added to the concentrate, and the layers were separated. The aqueous layer was extracted twice with 50 mL of EtOAc to remove impurities. The aqueous layer was cooled from 40°C to 0°C to induce crystallization, and filtered to obtain 5.1 g of the compound of chemical formula 1A and the compound of chemical formula 1B as white crystals with a purity of 99.52%.

H-NMR(D ₂ O): δ 3.4~3.5(1H), 3.6~3.9(8H), 4.1~4.15(1H),4.6~4.7(4H)

C-NMR(D ₂ O): δ 104.8, 96.3, 82.5, 71.2, 70.7, 70.6, 68.6, 65.0, 64.59, 64.57, 62.3, 58.1

(2) Manufacturing using ammonium formate

10 g of a mixture of the compound of chemical formula 10C and the compound of chemical formula 10D obtained in Example 7 was added to 200 mL of EtOAc-200 mL of MeOH, 400 mg of 10%-Pd/C and 8 g of HCO ₂ NH ₄ were added, and the mixture was stirred at room temperature for 16 hours.

The removal of the starting material was confirmed by TLC and HPLC, and the reaction product was filtered under a celite pad and concentrated under reduced pressure.

40 mL of purified water and 50 mL of EtOAc were added to the concentrate, and the layers were separated. The aqueous layer was extracted twice with 50 mL of EtOAc to remove impurities. The aqueous layer was cooled from 40°C to 0°C to induce crystallization, and filtered to obtain 2.8 g of the compound of chemical formula 1A and the compound of chemical formula 1B as white crystals with a purity of 99.64%.

H-NMR (DO): δ 3.4~3.5(1H), 3.6~3.9(8H), 4.1~4.15(1H),4.6~4.7(4H)

C-NMR(D ₂ O): δ 104.8, 96.3, 82.5, 71.2, 70.7, 70.6, 68.6, 65.0, 64.59, 64.57, 62.3, 58.1

Example 9. Preparation of allulose dimer hydrate

10 g of the compound of chemical formula 10 obtained in Example 7 was added to 200 mL of EtOAc-200 mL of MeOH, 400 mg of 10%-Pd/C and 8 g of HCO ₂ NH ₄ were added, and the mixture was stirred at room temperature for 16 hours.

The removal of the starting material was confirmed by TLC and HPLC, and the reactant was filtered through a celite pad and concentrated under reduced pressure.

40 mL of purified water and 50 mL of EtOAc were added to the concentrate, the layers were separated, and the aqueous layer was extracted twice with 50 mL of EtOAc to remove impurities. The aqueous layer was concentrated under reduced pressure to remove residual organic solvent, and the concentrate of the aqueous layer was cooled to 0 to 5°C to induce crystallization, filtered and dried to obtain 1.3 g of a hydrate of the compound of formula 1A and a hydrate of the compound of formula 1B as white crystals with a purity of 99.83%.

H-NMR(D ₂ O): δ 3.4~3.5(1H), 3.6~3.9(8H), 4.1~4.15(1H),4.6~4.7(4H)

C-NMR(D ₂ O): δ 104.8, 96.3, 82.5, 71.2, 70.7, 70.6, 68.6, 65.0, 64.59, 64.57, 62.3, 58.1

Moisture content: 5.2 to 10.6 wt%

Claims (21)

A step of protecting the hydroxyl group of the compound of the following chemical formula 2A and the compound of the following chemical formula 2B using a solvent and a protecting reagent to prepare the compound of the following chemical formula 3 and the compound of the following chemical formula 4; A step of combining a compound of the following chemical formula 3 and a compound of the following chemical formula 4 via a linker; A step of producing a dioxane ring compound by forming a dioxane ring through an intramolecular reaction in a complex of a compound of the following chemical formula 3 and a compound of the following chemical formula 4, which are combined through the linker; and Comprising a step of removing a protecting group and a linker from the above dioxane ring compound, A method for producing an allulose dimer of the following chemical formula 1A or the following chemical formula 1B, a salt thereof, a solvate thereof, a hydrate thereof, or a crystal thereof: [Chemical Formula 1A]

[Chemical Formula 1B]

[Chemical Formula 2A]

[Chemical Formula 2B]

[Chemical Formula 3]

In the above chemical formula 3, PG1 to PG4 are protecting groups, [Chemical Formula 4]

In the above chemical formula 4, PG5 to PG8 are protecting groups. In the first paragraph, the step of preparing the dioxane ring compound comprises: A step of replacing the PG1, PG2, PG5 and PG6 protecting groups of the complex linked through the above linker with different protecting groups; and A method comprising the step of forming a dioxane ring by an intramolecular reaction. In the first paragraph, the compound of the chemical formula 3 is a compound of the following chemical formula 3A, and the compound of the chemical formula 4 is a compound of the following chemical formula 4A, the method: [Chemical Formula 3A]

[Chemical Formula 4A]

In the first aspect, the linker is a compound represented by the following chemical formula 5, preferably bishalomethylbenzene, the method: [Chemical Formula 5]

X ₁ and X ₂ are each independently Br, Cl, I, methanesulfonyl (Oms), or p-toluenesulfonyl (p-Ts). In the first paragraph, the complex bonded through the linker is a compound of the following chemical formula 7, the method: [Chemical formula 7]

In the third paragraph, the complex bonded through the linker is a compound of the following chemical formula 7A, the method: [Chemical Formula 7A]

A method in claim 1, wherein the step of obtaining the compound of chemical formula 3 and the compound of chemical formula 4 is performed in the presence of an acid catalyst. A method in claim 1, wherein the step of obtaining the compound of formula 3 and the compound of formula 4 comprises a step of adding a moisture absorbent during or after the reaction. A method in which, in the step of obtaining the compound of the chemical formula 3 and the compound of the chemical formula 4 in the first paragraph, the total volume of the solvent and the protecting reagent is used in a volume (mL) that is 7 to 40 times the weight (g) of the compound of the chemical formula 2A and the compound of the chemical formula 2B. A method in claim 1, wherein the step of combining via the linker comprises combining the compound of chemical formula 3 with the linker and then combining the compound of chemical formula 4. In claim 10, the method for combining the compound of formula 3 and the linker comprises dissolving 0.5 to 1.3 equivalents of the linker relative to the compound of formula 3 in a reaction solvent, adding 0.9 to 2 equivalents of a base to the reaction solvent, and adding a solution of the compound of formula 3 to the reaction solvent to combine the linker. In the 11th paragraph, the method wherein, after the completion of the reaction by adding the solution of the compound of the chemical formula 3, the content of the compound of the chemical formula 6B below in the reaction solvent is 10% (mol/mol) or less of the content of the compound of the chemical formula 6A below: [Chemical Formula 6A]

In the above chemical formula 6A, PG1 to PG4 are protecting groups, X is Br, Cl, I, methanesulfonyl (Oms), or p-toluenesulfonyl (p-Ts), [Chemical Formula 6B]

In the above chemical formula 6B, PG1 to PG4 are protecting groups. A method according to claim 1, wherein the step of binding through the linker is performed at a temperature of -10 to 10°C, preferably at a temperature of 0°C. A method in claim 1, wherein the step of forming the dioxane ring is performed by cooling to a temperature range of -85 to -65°C and then raising the temperature to a temperature range of -60 to -40°C. In the second paragraph, the step of replacing the protector with a different protector is to remove the protector and reprotect with a different protector. A method according to claim 1, wherein removing the protective group is performed at a temperature of -10 to 10°C, preferably at a temperature of 0°C, or at a temperature of 50 to 60°C, preferably at a temperature of 55°C. In the second paragraph, the step of replacing the protector with a different protector is to remove the protector and reprotect with a different protector. A method according to claim 1, wherein reprotecting with the different protecting groups is performed at a temperature of -10 to 10°C, preferably at a temperature of 0°C. A method according to claim 2, wherein the step of removing the linker is performed at a temperature of -10 to 10°C. A method in claim 1, wherein the solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, propanol, water (H ₂ O), dichloromethane, acetonitrile, acetone, ethyl acetate, ethyl ether, tetrahydrofuran, N,N-dimethylformamide, dioxane, and n-hexane. A method in claim 1, wherein the protecting reagent is at least one selected from the group consisting of acetone, 2,2-dimethoxypropane, 2-methoxyprofen, and camphorsulfonic acid. In the second paragraph, the step of replacing the different protector is: Using one or more solvents selected from the group consisting of acetic acid, methanol, ethanol, acetone, tetrahydrofuran, and water, or Using one or more deprotecting reagents selected from the group consisting of organic acid deprotecting reagents, for example, acetic acid, hydrochloric acid, phosphoric acid, and formic acid, or A method comprising: using a protecting group reagent that introduces a protecting group different from the protecting groups of the compound of the above formula 3 and the compound of the above formula 4, specifically a protecting group that is removed under different conditions from the protecting groups of the compound of the above formula 3 and the compound of the above formula 4 and/or a protecting group that can be removed together with the linker, for example, at least one protecting group reagent selected from the group consisting of a benzyl group compound, a benzoyl group compound, a trimethysilyl group compound, and an ortho ester group compound, for example, a benzyl halide. A compound of the following chemical formula 6A, the following chemical formula 6B, the following chemical formula 7, the following chemical formula 10A, or the following chemical formula 10B, a salt thereof, a solvate thereof, a hydrate thereof, or a crystal thereof: [Chemical Formula 6A]

In the above chemical formula 6A, PG1 to PG4 are protecting groups, X is Br, Cl, I, methanesulfonyl (Oms), or p-toluenesulfonyl (p-Ts), [Chemical Formula 6B]

In the above chemical formula 6B, PG1 to PG4 are protecting groups, [Chemical formula 7]

In the above chemical formula 7, PG1 to PG8 are protecting groups, [Chemical Formula 10A]

In the above chemical formula 10A, PG9 to PG12 are protecting groups, [Chemical Formula 10B]

In the above chemical formula 10B, PG9 to PG12 are protecting groups.