JP6819457B2 - 1,2; 4,5-Inositol derivative production method - Google Patents

Description

The present invention relates to a method for producing a 1,2; 4,5-inositol derivative.

Inositol is a 6-membered alicyclic compound having 6 hydroxyl groups, and by introducing an organic group into the hydroxyl group, various inositol derivatives can be synthesized. Specifically, an inositol derivative having an organic group introduced into one hydroxyl group (pentaol), an inositol derivative having an organic group introduced into two hydroxyl groups (tetraol), and an inositol derivative having an organic group introduced into three hydroxyl groups (triol). ), Inositol derivatives with organic groups introduced into 4 hydroxyl groups (diols), inositol derivatives with organic groups introduced into 5 hydroxyl groups (monool), and inositol derivatives with organic groups introduced into all hydroxyl groups have been reported. There is. Among them, 1,2; 4,5-inositol derivatives having two hydroxyl groups and having the hydroxyl groups located facing each other are desired to be developed as useful monomers for realizing a highly heat-resistant resin.

As a method for producing a 1,2; 4,5-inositol derivative, a method of reacting inositol with a carbonyl compound or an acetal compound in the presence of an acid catalyst is known. As inositol, a method using myo-inositol (Non-Patent Document 1), a method using epi-inositol (Non-Patent Document 2), and the like are known. As the carbonyl compound or acetal compound, a method using cyclohexanone (Non-Patent Document 1), a method using dimethoxycyclohexane (Non-Patent Document 3), and a method using 2,2-dimethoxypropane (Non-Patent Document 4). and so on. Although these methods do not describe the reaction yields of 1,2; 4,5-inositol derivatives, for example, according to Non-Patent Document 3, crystallization is performed from acetone and petroleum ether after the reaction, and an isolated yield of 14% is obtained. We have obtained 1,2; 4,5-inositol derivatives at a rate. Regarding other documents, the isolated yield of 1,2; 4,5-inositol derivatives isolated by silica gel column chromatography or the like was about 20%.

On the other hand, attempts have been made to increase the yield of 1,2; 4,5-inositol derivatives by performing crystallization (Non-Patent Document 5). In this method, 1,2; 4,5-inositol derivatives are obtained in a total yield of 75% by repeating the steps of treating the filtrate after crystallization with p-toluenesulfonic acid.
Further, in a method for producing a furanose derivative in which a hydroxyl group at the anomer position is acylated, a method for efficiently producing a furanose derivative by increasing the amount of β-anomer produced by crystallizing β-anomer in a reaction system is known. (Patent Document 1).

J. Chem. Soc., 1961, 4116-4122 Carbohyd. Res., 20 (1971) 97-104 J. Org. Chem., 2002, 67, 2874-2880 Carbohyd. Res., 142 (1985) 132-134 Tetrahedron (1991), 47, (26), 4709

Patent No. 5550234

In the methods described in Non-Patent Documents 1 to 4, all of the methods include 1,2-inositol derivatives, 1,2; 3,4-inositol derivatives, 1,2; 3,4; 5,6-inositol derivatives, and the like. There is a problem that the production of by-products cannot be suppressed and the yield is low because the selectivity of the target 1,2; 4,5-inositol derivative is low.
Further, in the method described in Non-Patent Document 5, reaction-generated 1,2; 4,5-inositol derivatives are obtained by crystallization in a yield of 25%, and then crystallized from the filtrate after crystallization. The analysis solvent was distilled off, DMF and an extremely small amount of p-toluenesulfonic acid were added, the mixture was heated at 95 ° C., and further post-treatment and crystallization were performed to obtain 1,2; 4,5-inositol derivatives again. I have acquired 18%. By repeating this, the yield of the 1,2; 4,5-inositol derivative finally reached 75%, but after distilling off the solvent from the filtrate after crystallization or after the reaction with an acid catalyst. Various post-treatment steps are required, a huge amount of solvent is used, and the operation is complicated, so that it is not suitable for industrialization by mass production.

Further, in Patent Document 1, a necessary three-dimensional β-anomer is precipitated in the reaction system, but the reagent, solvent, type and amount of acid catalyst used, reaction temperature and time are described in the sugar described in the document. The conditions of Patent Document 1 cannot be applied to the production of 1,2: 4,5-inositol derivatives because they are optimized for the derivative. As described above, there has been a problem in finding a reaction system capable of precipitating a 1,2: 4,5-inositol derivative as a target product.

Therefore, it is an object of the present invention to provide a production method for improving the yield of the target 1,2; 4,5-inositol derivative by a simple method.

As a result of diligent studies to solve the above problems, the present inventors proceeded with the reaction while crystallizing the 1,2; 4,5-inositol derivative in the process of producing the 1,2; 4,5-inositol derivative. The present invention was completed by finding that the desired 1, 2; 4,5-inositol derivative can be produced in good yield.
That is, the gist of the present invention is as follows.
[1] A method for producing an inositol derivative represented by the following formula (2) by a reaction of introducing and / or removing a cyclic protecting group into the inositol derivative represented by the following formula (1) in the presence of a catalyst. A method for producing an inositol derivative, which proceeds with the reaction of introducing and / or removing the cyclic protecting group while crystallizing the 1,2; 4,5-inositol derivative represented by the following formula (2).

(R ^{1 to} R ⁶ in the above formula (1) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups may have an arbitrary substituent. Further, any two of R ^{1 to} R ⁶ may be bonded to each other to form a ring.)

(R ^{7 to} R ¹⁰ in the above formula (2) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups may have an arbitrary substituent. Further, R ⁷ and R ⁸ and R ⁹ and R ¹⁰ may be coupled to each other to form a ring.)
[2] The inositol derivative represented by the formula (1) is myo-inositol or my.
The method for producing a 1,2; 4,5-inositol derivative according to [1], which comprises a derivative of o-inositol.
[3] The 1, according to [1] or [2], wherein the inositol derivative represented by the formula (1) contains the 1,2; 3,4-inositol derivative represented by the following formula (3). 2; Method for producing 4,5-inositol derivative.

(R ^{11 to} R ¹⁴ in the above formula (3) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups may have an arbitrary substituent. In addition, R ¹¹ and R ¹² , and R ¹³ and R ¹⁴ may be coupled to each other to form a ring.)
[4] The 1,2,4,5-inositol derivative according to [3], wherein 10% or more of the total amount of the inositol derivative represented by the formula (3) is converted into 1,2; 4,5-inositol derivative. A method for producing an inositol derivative.
[5] The inositol derivative represented by the formula (1) is a 1,2-inositol derivative represented by the following formula (4) and / or 1,2; 3, represented by the following formula (5). 4; The method for producing a 1,2; 4,5-inositol derivative according to any one of [1] to [4], which comprises a 5,6-inositol derivative.

(Rs ^{15 to} R ²² in the above formulas (4) and (5) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups have an arbitrary substituent. R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , and R ²¹ and R ²² may be coupled to each other to form a ring.)
[6] In the reaction for introducing and / or eliminating the cyclic protecting group, the solubility of the 1,2; 4,5-inositol derivative represented by the above formula (2) at 0 to 10 ° C. is 0 to 20% by weight. The method for producing a 1,2; 4,5-inositol derivative according to any one of [1] to [5], wherein the reaction is allowed to proceed using the following solvent.
[7] Any of [1] to [6], wherein the reaction is carried out using a hydrocarbon solvent, an ester solvent and / or an ether solvent in the reaction for introducing and / or removing the cyclic protecting group. The method for producing a 1,2; 4,5-inositol derivative according to item 1.
[8] The 1,2; 4,5- according to any one of [1] to [7], wherein the reaction proceeds at 50 ° C. or lower in the reaction for introducing and / or removing the cyclic protecting group. A method for producing an inositol derivative.
[9] (A) Condensation reaction step in which inositol and a carbonyl compound and / or an acetal compound are condensed in the presence of an acid catalyst.
(B) Reaction products other than the 1,2,4,5-inositol derivatives of the following formula (2) contained in the solution obtained in the condensation reaction step are represented by the following formula (2) under an acid catalyst. 1,2; 4,5-Reaction step to convert to inositol derivative,
(C) A separation step of separating 1,2,4,5-inositol derivatives of the following formula (2) from the reaction solution after the reaction step.
A method for producing a 1,2; 4,5-inositol derivative having the above, in which the 1,2; 4,5-inositol derivative represented by the following formula (2) is crystallized in the reaction step (B). A method for producing a 1,2; 4,5-inositol derivative, wherein the reaction proceeds while allowing the reaction to proceed.

(R ^{7 to} R ¹⁰ in the above formula (2) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups may have an arbitrary substituent. Further, R ⁷ and R ⁸ and R ⁹ and R ¹⁰ may be coupled to each other to form a ring.)
[10] The solution obtained in the step (A) is inositol, 1,2; 3,4-inositol derivative represented by the following formula (3), 1,2-represented by the following formula (4). 1, 2, 4 according to [9], which comprises an inositol derivative, one or more compounds selected from the group consisting of 1,2; 3,4; 5,6-inositol derivatives represented by the following formula (5). , 5-Method for producing inositol derivative.

(In the above formulas (3) to (5), R ^{11 to} R ²² each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups have arbitrary substituents. R ¹¹ and R ¹² , R ¹³ and R ¹⁴ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , and R ²¹ and R ²² are coupled to each other and ring. May be formed.)
[11] In the step (B), the reaction was carried out using a solvent having a solubility of the 1,2; 4,5-inositol derivative represented by the formula (2) at 0 to 10 ° C. of 0 to 20% by weight or less. The method for producing a 1,2; 4,5-inositol derivative according to [9] or [10]. [12] The 1, 2, 4 according to any one of [9] to [11], wherein the reaction is allowed to proceed in the step (B) using a hydrocarbon solvent, an ester solvent and / or an ether solvent. , 5-Method for producing inositol derivative.
[13] The method for producing a 1,2; 4,5-inositol derivative according to any one of [9] to [12], wherein the reaction proceeds at 50 ° C. or lower in the step (B).
[14] After the step (A), the 1,2; 4,5-inositol derivatives of the formula (2) are separated, and the remaining solution is subjected to the step (B), [9] to [13]. ] A method for producing a 1,2; 4,5-inositol derivative according to any one of.

According to the method for producing an inositol derivative of the present invention, it is possible to utilize the by-product produced when the 1,2; 4,5-inositol derivative is synthesized, and the yield of the desired inositol derivative can be obtained by a simple method. The rate can be expected to improve.

6 is an NMR chart of DCMI obtained in Example 1. 6 is an NMR chart of DHMI obtained in Comparative Example 2. 6 is an NMR chart of DAMI obtained in Comparative Example 3.

Hereinafter, the present invention will be specifically described, but the present invention is not limited to the following embodiments, and various modifications can be made within the scope of the gist of the present invention. In the present specification, in the "X, Y-inositol derivative (X, Y is any of 1 to 6)", two adjacent hydroxyl groups bonded to the 1st to 6th carbons of cyclohexane in the inositol skeleton are cyclically protected. It means that it is protected by the group. Here, any carbon in the inositol skeleton may be set to the 1st position, and adjacent carbons may be set to the 2, 3, 4, 5, 6 positions in order. Since the carbon atom number is uniquely determined in the IUPAC nomenclature, for example, the inositol 1 protector is expressed as a 1,2-inositol derivative in the present invention, but the 1,2-inositol derivative, 2, 3 in the IUPAC nomenclature is used. Includes −-inositol derivatives, 3,4-inositol derivatives, 4,5-inositol derivatives, 5,6-inositol derivatives, and 1,6-inositol derivatives. Similarly, in the present invention, there are two types of inositol 2 protectors, 1,2; 3,4-inositol derivatives and 1,2; 4,5-inositol derivatives, each containing a plurality of isomers. That is, 1,2; 3,4-inositol derivatives are 1,2; 3,4-inositol derivatives, 1,2; 5,6-inositol derivatives, 2,3; 4,5-inositol derivatives in the IUPAC nomenclature. , 2,3; 6,1-inositol derivative, 3,4; 5,6-inositol derivative, 4,5; 6,1-inositol derivative, 1,2; 4,5-inositol derivative is IUPAC. 1,2; 4,5-inositol derivative, 2,3; 5,6-inositol derivative, 3,4; 6,1-inositol derivative in the nomenclature. The inositol 3 protectant is 1,2; 3,4; 5,6-inositol derivative and 2,3; 4,5; 6,1-inositol derivative.

Further, the 1,2; 4,5-inositol derivative produced by the present invention is any one of a plurality of possible isomers, and in particular, the 1,2; 4,5-inositol derivative in the IUPAC nomenclature. Is desirable.
In the method for producing a 1,2; 4,5-inositol derivative according to the first aspect of the present invention, a cyclic protecting group is introduced and / or eliminated from the inositol derivative represented by the following formula (1) in the presence of a catalyst. This is a method for producing an inositol derivative represented by the following formula (2) by the above reaction, and the cyclic protecting group while crystallizing the 1,2; 4,5-inositol derivative represented by the following formula (2). It is characterized by advancing the reaction of introducing and / or desorbing.

(R ^{1 to} R ⁶ in the above formula (1) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups may have an arbitrary substituent. Further, any two of R ^{1 to} R ⁶ may be bonded to each other to form a ring.)

(R ^{7 to} R ¹⁰ in the above formula (2) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups may have an arbitrary substituent. Further, R ⁷ and R ⁸ and R ⁹ and R ¹⁰ may be coupled to each other to form a ring.)
In addition, the method for producing 1,2; 4,5-inositol derivatives according to the second aspect of the present invention has the following steps (A) to (C), and the above formula (B) in the reaction step (B). It is characterized in that the reaction proceeds while crystallizing the 1,2; 4,5-inositol derivative represented by 2).

(A) Condensation reaction step in which inositol and a carbonyl compound and / or acetal compound are subjected to a condensation reaction in the presence of an acid catalyst (B) 1, 1 of the above formula (2) contained in the solution obtained in the condensation reaction step. 2; Reaction step of converting a reaction product other than the 4,5-inositol derivative into the 1,2; 4,5-inositol derivative represented by the above formula (2) under an acid catalyst (C) After the reaction step Separation step of separating 1,2; 4,5-inositol derivative of the above formula (2) from the reaction solution of the following, 1,2; 4,5-inositol derivative of the first aspect and the second aspect of the present invention. Are collectively referred to as "the production method of the present invention". The production method of the present invention is characterized in that the reaction proceeds while crystallizing the 1,2; 4,5-inositol derivative represented by the above formula (2), which is the target compound. That is, by crystallizing the target compound under equilibrium reaction conditions, the target compound is removed from the reaction system, whereby the target compound is supplied again by reaction equilibrium, and the target compound is crystallized again. By continuously performing this reaction and crystallization, it is a method that can efficiently produce and obtain the target compound.
In the production method of the present invention, the 1,2; 4,5-inositol derivative represented by the above formula (2), which is the target compound, is produced by the reaction of introducing and / or removing the cyclic protecting group of the inositol derivative. Therefore, it does not necessarily include the isomerization of the inositol 2 protector, which will be described later, but also the reaction of obtaining the target compound from inositol, the inositol 1 protector, the inositol 3 protector, etc., but in the present specification, it is cyclically protected while being crystallized. The reaction of introducing and / or removing a group to convert it into a 1,2; 4,5-inositol derivative is referred to as "isomerization crystallization".

The inositol derivative represented by the above formula (2) obtained by the production method of the present invention is not particularly limited as long as it is a compound satisfying the formula (2), and R ^{7 to} R ¹⁰ in the formula (2) will be described later. It suffices if it satisfies the preferable range, and specific examples thereof include those represented by the following structural formulas.

1. 1. The first aspect of the present invention The method for producing the 1,2; 4,5-inositol derivative of the first aspect of the present invention is to add a cyclic protecting group to the inositol derivative represented by the above formula (1) in the presence of a catalyst. When producing the inositol derivative represented by the above formula (2) by the reaction of introducing and / or eliminating
2; It suffices if the reaction can proceed while crystallizing the 4,5-inositol derivative.

Examples of the inositol derivative represented by the above formula (1) include inositol, an inositol 2 protectant such as a 1,2; 3,4-inositol derivative represented by the following formula (3), and a formula (4) below. Examples thereof include an inositol 1 protectant such as a 1,2-inositol derivative and an inositol 3 protectant such as a 1,2; 3,4; 5,6-inositol derivative represented by the following formula (5). In particular, since the number of cyclic protecting groups does not change, the inositol 2 protecting body such as 1,2; 3,4-inositol derivatives represented by the following formula (3) is used because there is no waste of cyclic protecting groups. 2 is generated when a cyclic protecting group is introduced into 1 protective body, and 2 protective bodies are generated when the cyclic protecting group is removed from 3 protective bodies. -Inositol 1-protecting group such as 1,2-inositol derivative represented by the following formula (4) or 1,2; 3, represented by the following formula (5) because the yield of the inositol derivative increases. 4; It is preferably an inositol 3-protecting group such as a 5,6-inositol derivative.

(In the above formulas (3) to (5), R ^{11 to} R ²² each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups have arbitrary substituents. R ¹¹ and R ¹² , R ¹³ and R ¹⁴ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , and R ²¹ and R ²² are coupled to each other and ring. May be formed.)

In the above formulas (2) to (5), examples of the organic group having 1 to 30 carbon atoms represented by R ^{7 to} R ²² include a methyl group, an ethyl group, a normal propyl group, a normal butyl group and a normal group. Substituentally substituted or unsubstituted linear alkyl group having 1 to 30 carbon atoms such as pentyl group, normal hexyl group, normal heptyl group, normal octyl group, trifluoromethyl group and benzyl group; isopropyl group, isobutyl group, sec- Substituent or unsubstituted branched or cyclic alkyl group having 1 to 30 carbon atoms such as butyl group, tert-butyl group and cyclohexyl group; phenyl group, naphthyl group, 4-methylphenyl group, frill group, thienyl group and the like. Substituted or unsubstituted aryl groups having 4 to 30 carbon atoms which may be substituted; and the like can be mentioned. A branched or cyclic alkyl group or aryl group that can impart high heat resistance to the resin when used as a resin raw material is preferable, while a linear alkyl group or branched group can be imparted from the viewpoint of imparting high weather resistance. Alternatively, a cyclic alkyl group is preferable. Methyl group, ethyl group, isopropyl group, normal propyl group, normal butyl group, isobutyl group, sec-butyl group, tert-butyl group, normal pentyl group, because the raw materials are easily available and synthesized. A linear or branched alkyl group having 1 to 8 carbon atoms such as a normal hexyl group, a normal heptyl group, and a normal octyl group is preferable, and an isopropyl group, an isobutyl group, and sec-butyl that can impart heat resistance and weather resistance in a well-balanced manner are preferable. A branched alkyl group having 3 to 4 carbon atoms such as a group is more preferable.

Here, R ^{7 to} R ²² may be independently different organic groups or a combination of a hydrogen atom and an organic group, but are groups derived from a single carbonyl compound and / or an acetal compound. This is preferable from the viewpoint of synthesis, and the fact that R ^{7 to} R ²² are the same reduces the number of isomers and increases the yield of the desired 1,2; 4,5-inositol derivative. More preferred.

R ⁷ and R ⁸ , R ⁹ and R ¹⁰ , R ¹¹ and R ¹² , R ¹³ and R ¹⁴ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , R ²¹ and R ²² are mutual. When a ring is formed by being bonded to, examples of the ring formed by the acetal carbon and each R include a substituted or unsubstituted cycloalkyl group having 3 to 30 carbon atoms, and even a monocyclic type is often used. It may be ring-shaped. Specifically, monocyclic cycloalkylidene groups such as cyclopropylidene group, cyclobutylidene group, cyclopentylidene group, cyclohexylidene group, cycloheptilidene group, cyclooctylidene group, 9,9-fluorenylidene; Polycyclic cycloalkylidene groups such as an adamantylidene group, a norbornylidene group, and a camphanilidene group; can be mentioned. Among these, the reason is that the number of isomers is reduced and the yield of the target 1,2; 4,5-inositol derivative is increased, and the raw materials are easily available and synthesized. , Cyclopentylidene group, Cyclohexylidene group, Cycloheptylidene group, Cyclooctylidene group, Adamanthylidene group, Norbornylidene group are preferable, and the target 1,2; 4,5-inositol derivative is more preferable. Examples thereof include a cyclopentylidene group, a cyclohexylidene group, and an adamantilidene group, which can impart heat resistance and weather resistance to a resin in a well-balanced manner when used as a resin raw material.
Here, R ^{7 to} R ²² may be independently different organic groups, but it is preferable from a synthetic point of view that they are groups derived from a single carbonyl compound and / or an acetal compound.

As the inositol used in the present invention, those having arbitrary steric chemistry can be used, and cis-inositol, epi-inositol, allo-inositol, muco-inositol, neo-inositol, sillo-inositol, D-chiro can be used. -Inositol, L-chiro-inositol can be mentioned. Any two or more of the above inositols may be used in combination, but the stereochemistry of inositol causes differences in the solubility and crystallinity of the target 1,2; 4,5-inositol derivatives, which makes control difficult. It is preferable to use inositol having one stereochemistry. Of these, myo-inositol, which is available at a relatively low cost, is preferable.

Examples of the raw material of the cyclic protecting group to be introduced in the reaction for introducing and / or eliminating the cyclic protecting group in the production method of the first aspect of the present invention include a carbonyl compound and an acetal compound. By reacting these compounds with the above-mentioned inositol, the inositol derivatives represented by the above formulas (2) to (5) can be obtained. The carbonyl compound and / or acetal compound forming the cyclic protecting group of R ^{7 to} R ²² described above is the same as that used in the step (A) of the second aspect of the present invention described later.

The acid catalyst used in the reaction for introducing and / or desorbing a cyclic protecting group in the production method of the first aspect of the present invention is not particularly limited as long as the reaction proceeds, and is either an inorganic acid or an organic acid. Can also be used. Examples of the inorganic acid include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid; heteropolyacids such as phosphomolybdic acid, silicate molybdic acid, phosphotungstic acid and silicate tungstic acid; zeolite, cation exchange resin and the like. Solid catalyst; Examples of the organic acid include carboxylic acids such as formic acid, acetic acid and trifluoroacetic acid; methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and 10-campersulfonic acid and the like. Acids; onium salts obtained by treating hydrochloric acid, sulfuric acid, and sulfonic acid with an organic base such as triethylamine and pyridine; Mineral acids and sulfonic acids are preferable from the viewpoint of having sufficient acidity and solubility in a reaction solvent, and hydrochloric acid and sulfuric acid are preferable as inorganic acids because they are inexpensive and easily available. Preferred are methanesulfonic acid, p-toluenesulfonic acid, and 10-campersulfonic acid. More preferably, sulfuric acid, p-toluenesulfonic acid and 10-camphorsulfonic acid, which have low volatility and do not generate acid gas.

The amount of the acid catalyst used varies depending on the type of catalyst, but is usually 0.001 times mol to 10 times mol with respect to the raw material inositol derivative. If it is too small, the reaction will be slow, and if it is too large, the post-treatment load will increase. Therefore, 0.005 times to 1-fold mol is preferable, because the reaction proceeds sufficiently and the post-treatment load can be reduced. , 0.007-fold to 0.5-fold, more preferably 0.01-fold to 0.2-fold.

The solvent used in the production method of the first aspect of the present invention allows the reaction to proceed at a sufficient reaction rate and crystallizes the target compound, a 1,2; 4,5-inositol derivative represented by the above formula (2). Any material can be used, and specific examples thereof include hydrocarbon solvents such as toluene, xylene, trimethylbenzene, n-pentane, n-hexane, n-heptane, and cyclohexane; methyl acetate, ethyl acetate, and acetate. Ester solvents such as isopropyl and butyl acetate; ether solvents such as diethyl ether, diisopropyl ether, dinormal butyl ether, methyl-t-butyl ether, cyclopentyl methyl ether and tetrahydrofuran; halogenation of dichloromethane, chloroform, carbon tetrachloride, chlorobenzene and the like. Hydrocarbons can be mentioned. Further, by using a carbonyl compound and / or an acetal compound as a solvent, the reaction may be carried out without adding another solvent. Among them, since the 1,2; 4,5-inositol derivative represented by the above formula (2), which is the target compound, can be easily selectively crystallized, a hydrocarbon solvent, an ester solvent, an ether solvent or these Is preferably a mixture of. More preferably, the solubility of the 1,2; 4,5-inositol derivative represented by the above formula (2), which is the target compound, is low, and 1,2; 4, such as 1,2; 3,4-inositol derivative, etc. Toluene, xylene, n-pentane, n-hexane and n-heptane are more preferable as hydrocarbon solvents, and acetic acid is used as ester solvents because it can dissolve inositol derivatives other than 5-inositol derivatives. Ethyl and isopropyl acetate, and the ether solvent is diethyl ether, diisopropyl ether, methyl-t-butyl ether, cyclopentyl methyl ether, and a mixed solvent thereof, and particularly preferably, toluene, xylene, n-pentane, and n-hexane. , N-heptane, and a mixed solvent of toluene / n-heptane and xylene / n-heptane.

The solvent may be a single solvent or a mixture of two or more kinds of solvents. When two or more kinds of mixed solvents are used, the mixed solvent may be used from the initial stage of the reaction, or the solvent used at the beginning after the isomerization crystallization proceeds and the crystals are precipitated by using one kind of solvent. May add different solvents. As long as the reaction proceeds and the desired 1,2; 4,5-inositol derivative can be sufficiently precipitated.
There is no limitation on the method of mixing the solvent.

Under the reaction conditions of the present invention, the target compound 1,2; 4,5-inositol derivative needs to be precipitated without being dissolved. Therefore, it is preferable that the solvent used has a physical property value of 0 to 20% by weight in solubility of the target compound 1,2; 4,5-inositol derivative in the range of 0 to 10 ° C. A solvent having a solubility of 0 to 10% by weight is more preferable, and a solvent having a solubility of 0 to 5 is more preferable, because the lower the solubility of the 1,2; 4,5-inositol derivative, the larger the precipitation amount and the higher the yield. A solvent of% by weight is more preferable, and a solubility of 0 to 2% by weight is particularly preferable.

Since the solubility of the target 1,2; 4,5-inositol derivative becomes low when the solvent has a lower polarity, the relative permittivity of the solvent is preferably 8 or less, and the lower the solubility, the lower the target 1,2. It is more preferably 6 or less, still more preferably 4 or less, and particularly preferably 3 or less, because the 4,5-inositol derivative is precipitated and the yield is increased.
On the other hand, in order to proceed the reaction, at least a part of the inositol derivative other than the target substance such as 1,2; 3,4-inositol derivative needs to be dissolved. Since a solvent having a higher polarity increases the solubility of inositol derivatives other than the target substance, the relative permittivity of the solvent is preferably 1 or more, more preferably 2 or more, and further preferably 3 or more.

In particular, a solvent capable of carrying out the reaction while crystallizing the desired 1,2; 4,5-inositol derivative is preferable in order to simplify the step (C) described later.
The amount of the solvent used can be arbitrarily selected as long as the object of the present invention can be achieved, but usually, the ratio of the weight (g) of the solvent to the weight (g) of the inositol derivative used as the raw material for the reaction is 0.1 to 1. The amount of solvent to be 10 g / g is preferable. If the amount of the solvent used is too small, stirring becomes impossible when crystals are precipitated and the acid catalyst does not function sufficiently. Therefore, 0.1 or more is preferable, 0.2 or more is more preferable, and 0.3 or more is particularly preferable. It is preferably 0.6 or more. On the other hand, if the amount used is too large, the amount of dissolved components increases and the yield decreases, and the amount of the target 1,2; 4,5-inositol derivative dissolved increases, resulting in a decrease in yield. It is preferably 8 or less, more preferably 6 or less, and particularly preferably 4 or less.

The reaction temperature varies depending on the solvent used, but is usually −78 ° C. to 100 ° C. If the reaction temperature is too low, the reaction is slow and it takes a long time to complete the reaction. Therefore, −78 ° C. or higher is preferable, more preferably −50 ° C. or higher, still more preferably −20 ° C. or higher, and particularly preferably. It is -5 ° C or higher. On the other hand, if the reaction temperature is too high, side reactions will occur, and the solubility of the target 1,2; 4,5-inositol derivative in the solvent will increase, leading to a decrease in yield. Therefore, 100 ° C. or lower is preferable, and more preferably. It is 50 ° C. or lower, more preferably 25 ° C. or lower, and particularly preferably 10 ° C. or lower.

The reaction temperature may be kept constant, but if the reaction is continued at a low temperature, the isomerization reaction is slow and it takes a long time to reach an equilibrium state. Therefore, after the reaction is carried out at 20 to 80 ° C., −78 It is preferable to lower the temperature to about 20 ° C. to precipitate the desired 1,2; 4,5-inositol derivative outside the system. Further, for the purpose of suppressing side reactions, the reaction is carried out at 20 to 50 ° C., the target 1,2; 4,5-inositol derivative is increased by isomerization, and then cooled to -50 to 20 ° C. for the desired purpose. It is more preferable to lower the solubility of the 1,2; 4,5-inositol derivative for precipitation, and the reaction was carried out at 20 to 30 ° C. to increase the target 1,2; 4,5-inositol derivative by isomerization. After that, it is more preferable to cool the temperature to −5 to 10 ° C. to lower the solubility of the desired 1,2; 4,5-inositol derivative and precipitate it.

The reaction time is not particularly limited, and the reaction is preferably performed for several minutes to 10 days. If the time is too short, the reaction will be incomplete and the yield will decrease. Therefore, more preferably 10 minutes or more, further preferably 30 minutes or more, particularly preferably 1 hour or more, and if the time is too long, side reactions will occur together. It is more preferably 5 days or less, further preferably 3 days or less, and particularly preferably 1 day or less, because it causes an occurrence or becomes an economic burden.

The reaction may be carried out under stirring conditions using a stirrer or a stirring blade, or the container containing the reaction solution may be allowed to stand at room temperature or in a refrigerator. As long as the reaction proceeds, the presence or absence of stirring is not limited, but it is preferable to carry out under stirring conditions because the solution is uniformly mixed in the reaction vessel to eliminate concentration unevenness and efficiently precipitate crystals. ..
The reaction termination is usually carried out with a base, but is not particularly limited, and if the reaction is terminated, either an organic base or an inorganic base can be used. Examples of the organic base include pyridine, 2-methylpyridine, 2-methyl-5-ethylpyridine, 4-dimethylaminopyridine, 2,6-dimethylpyridine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, diethylamine and di. Amine compounds such as propylamine, dibutylamine, piperazin, triethylenetetramine, triethanolamine, diazabicyclo [2.2.2] octane; tetramethylammonium hydroxide, tetrabutylammonium hydroxide, trimethylbenzylammonium hydroxide and the like 4 Examples thereof include tertiary ammonium hydroxide, and examples of the inorganic base include carbonates such as lithium carbonate, sodium hydrogencarbonate, sodium carbonate, potassium hydrogencarbonate, potassium carbonate, calcium carbonate, barium carbonate, sodium hydroxide, potassium hydroxide, and hydroxide. Hydroxides such as lithium, hydrides such as potassium hydride and sodium hydride; may be mentioned. The organic base is preferably an amine compound because it is a liquid at room temperature and easy to handle, and the reaction can be stopped efficiently by addition. Therefore, pyridine, triethylamine, etc. are industrially inexpensive and easily available. Diisopropylethylamine and piperazine are more preferable, and as an inorganic base, heat generation control by neutralization is easy, and the reaction can be stopped under milder conditions. Therefore, it is a carbonate and is industrially inexpensive and easily available. Therefore, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, and potassium carbonate are more preferable.

In the production method of the first aspect of the present invention, 1,2; 4,5-inositol represented by the formula (2), which is the target compound, is obtained by appropriately setting the above conditions, particularly solvent selection and reaction temperature. The reaction of introducing and / or eliminating the cyclic protecting group can proceed while crystallizing the derivative, and isomerization crystallization can be carried out. Here, since the inositol derivatives represented by the above formulas (3) to (5) are often solid, only the 1,2: 4,5-inositol derivatives intended for isomerization crystallization are used. There was a problem in selecting the conditions for selectively precipitating. According to the studies by the present inventors, effective isomerization by comparing the solubilities of the respective isomers and protective compounds for a plurality of target compounds and then appropriately setting the above-mentioned conditions, particularly solvent selection and reaction temperature. It has been found that crystallization can be performed, and it has become possible to improve the yield of the desired inositol derivative by a simple method.

Under the reaction conditions of the present invention, seed crystals may be added for the purpose of promoting crystal precipitation and facilitating isomerization crystallization. The seed crystal added here is usually a racemate of 1,2; 4,5-inositol derivative represented by the above formula (2), but 1,2; 4, represented by the above formula (2). It may be an optically active substance of a 5-inositol derivative. Further, when R ^{7 to} R ¹⁰ are not all the same in the 1,2; 4,5-inositol derivatives represented by the above formula (2), a plurality of isomers are present, but the seed crystal to be added is one of them. It may be a species isomer (racemic or optically active) or a mixture of two or more isomers.

Seed crystals are usually added before crystal precipitation begins. It is preferable to add the seed crystal after adding the solvent or immediately after adding the acid catalyst.
The amount to be added can be any amount as long as it promotes crystal precipitation, but is usually 0.00001 times to 0.5 times mol with respect to the raw material inositol derivative. If the amount is too small, the crystal precipitation rate becomes slow, so 0.0001 times mol or more is preferable, and 0.001 times mol or more is particularly preferable. On the other hand, if the amount is too large, a large amount of seed crystals must be prepared, so 0.1 times the molar amount or less is preferable, and 0.01 times the molar amount or less is particularly preferable.

When the seed crystal to be added is an optically active substance, the crystal obtained by isomerization crystallization may also become optically active. When the solubility of the racemate is higher than that of the optically active substance under the reaction conditions, it is relatively easy to obtain optically active crystals. On the other hand, when the solubility of the racemate is lower than that of the optically active substance under the reaction conditions, it is difficult to obtain an optically active crystal, and a seed crystal having a higher optical purity is required. The optical purity of the seed crystal used at this time is usually 20% ee or more, preferably 50% ee or more, more preferably 90% ee or more, still more preferably 95% ee or more, particularly preferably 99% ee or more, most preferably. Is 99.9% ee or more. Here, "% ee" indicates an enantiomeric excess, and if the mole fraction of the target optically active substance is x and the mole fraction of the enantiomer is y, then (xy) / (x + y) x 100. expressed.

In the production method of the first aspect of the present invention, inositol and inositol derivatives represented by the above formulas (3) to (5) are represented by the above formula (2) under an acid catalyst by isomerization crystallization 1. , 2; Convert to 4,5-inositol derivative. In this step, if the desired 1,2; 4,5-inositol derivative is produced, isomerization from the other 2 protectors, elimination of the cyclic protecting group from the 3 protectors, to inositol or 1 protector. Any reaction such as introduction of a cyclic protecting group may be used. Specifically, it is preferable to include any one or more of the following reactions (b-1) to (b-4) in the presence of a catalyst.

(B-1) An isomerization reaction for converting the 1,2; 3,4-inositol derivative represented by the above formula (3) into the 1,2; 4,5-inositol derivative represented by the above formula (2). (B-2) 1,2; 3,4; 5,6-inositol derivative represented by the above formula (5) is reacted with water, alcohol or the like, and 1, represented by the above formula (2) 2; Desorption reaction of cyclic protective group to convert to 4,5-inositol derivative (b-3) Raw material inositol and / or 1,2-inositol derivative represented by the above formula (4) is a carbonyl compound and / or acetal. Reaction of introducing a cyclic protective group to convert into a 1,2; 4,5-inositol derivative represented by the above formula (2) by reacting with a compound (b-4) 1, represented by the above formula (5) Desorption and introduction of cyclic protective groups that move cyclic protective groups from the raw material inositol and / or the 1,2-inositol derivative represented by the above formula (4) from 2; 3,4; 5,6-inositol derivatives. Reaction In particular, the reaction of (b-1) is preferably the main reaction, and the inositol represented by the above formula (3) can be obtained in a high yield because the desired 1,2; 4,5-inositol derivatives can be obtained. It is preferable to convert 10% or more, more preferably 25% or more, still more preferably 40% or more, particularly preferably 50% or more of the total amount of the derivative into 1,2; 4,5-inositol derivatives.

1,2; 4,5 represented by the above formula (2) by removing the cyclic protecting group from the 1,2; 3,4; 5,6-inositol derivative represented by the above formula (5). -In the step of converting to an inositol derivative, water and / or alcohol can be added. The cyclic protecting group is hydrolyzed by the coexisting acid catalyst and water or alcohol, or one of the cyclic protecting groups is eliminated from the inositol 3 protecting group by solvolysis, so that the inositol 2 protecting group can be efficiently obtained. The type of water or alcohol to be added is not limited as long as the desorption reaction proceeds, and water; primary alcohols such as methanol, ethanol, 1-propanol and 1-butanol; 2-propanol, isobutanol, cyclohexanol and the like. Secondary alcohol; Of these, water and primary alcohols are preferable because of their high reactivity, and methanol and ethanol are more preferable because they can be easily removed by concentration after the reaction. In addition, water is preferable because it can be converted irreversibly.

The amount of water or alcohol to be added varies depending on the amount of the inositol 3 protector contained in the raw material inositol derivative, but is usually 0.0001 to 0.1 times the amount of the raw material inositol derivative. .. If it is too small, the reaction will be slow, and if it is too large, the elimination of the cyclic protecting group will proceed too much. Therefore, 0.0005 times to 0.05 times mol is more preferable, and 0.001 times to 0.01 times mol is more preferable. It is a mol. The same effect can be obtained by using a raw material, a reagent, or a solvent containing a predetermined amount of water in the reaction.

The order in which water and / or alcohol is added is not limited as long as the reaction proceeds, and may be added in the early stage of the reaction or in the late stage when the reaction has sufficiently progressed.
By introducing a cyclic protecting group into inositol and / or the 1,2-inositol derivative represented by the above formula (5), the 1,2; 4,5-inositol derivative represented by the above formula (2) can be obtained. In the step of conversion, a carbonyl compound and / or an acetal compound can be added. By introducing a cyclic protecting group with a coexisting acid catalyst and a carbonyl compound and / or an acetal compound, an inositol 2-protected substance can be efficiently obtained.

The amount of the carbonyl compound and / or the acetal compound to be added varies depending on the amount of inositol contained in the raw material inositol derivative and / or the 1,2-inositol derivative represented by the above formula (5), but is usually a raw material. It is 0.01 times to 1 times mol with respect to the inositol derivative of. If the amount is too small, the reaction is slow, and if the amount is too large, the target 1,2; 4,5-inositol derivative is dissolved. Therefore, 0.05-fold to 0.8-fold mol is more preferable, and 0. It is 1 to 0.5 times the molar amount.

Since the elimination of the cyclic protecting group proceeds too much, 0.0005 times to 0.05 times mol is more preferable, and 0.001 times to 0.01 times mol is more preferable.
When a mixture of inositol and inositol derivatives represented by the above formulas (3) to (5) is used as a raw material, the excess or deficiency of the carbonyl compound and / or the acetal compound as the cyclic protecting group is calculated, and the carbonyl compound and / Alternatively, it is preferable to add an acetal compound or water and / or alcohol because the yield of the 1,2; 4,5-inositol derivative represented by the above formula (2) can be maximized. For example, the value obtained by subtracting the number of moles of the inositol derivative represented by the above formula (5) from the sum of twice the number of moles of inositol and the number of moles of the inositol derivative represented by the above formula (4) is positive. In the case of a value, a corresponding amount of the carbonyl compound and / or the acetal compound may be added, and in the case of a negative value, water and / or alcohol may be added.

2. 2. The second aspect of the present invention The method for producing the 1,2; 4,5-inositol derivative of the second aspect of the present invention is (A) condensation reaction step, (B) 1,2; 4,5-inositol derivative. It has three steps, a reaction step of converting to (C) and a separation step (C). Hereinafter, each step will be described in detail.
Here, the production method of the second aspect of the present invention can be mentioned as one form of the production method of 1,2; 4,5-inositol derivatives including the isomerization crystallization reaction of the first aspect of the present invention. That is, the production method of the second aspect of the present invention is a method for producing a 1,2; 4,5-inositol derivative such that the step (B) includes the isomerization crystallization reaction of the first aspect of the present invention. is there. Therefore, the step (B) can be considered in the same manner as the preferable range of the first aspect of the present invention described above.

(A) Condensation reaction step The condensation reaction step (step (A)) in the production method of the second aspect of the present invention is a step of subjecting inositol and a carbonyl compound and / or an acetal compound to a condensation reaction in the presence of an acid catalyst. Is. Preferably, it is a step of subjecting inositol and a carbonyl compound or an acetal compound to a condensation reaction in the presence of an acid catalyst. At this time, a solvent may be used.

As the inositol used in the present invention, those having arbitrary steric chemistry can be used, and cis-inositol, epi-inositol, allo-inositol, muco-inositol, neo-inositol, sillo-inositol, D-chiro can be used. -Inositol, L-chiro-inositol can be mentioned. Any two or more of the above inositols may be used in combination, but since the stereochemistry of inositol causes the solubility of the target 1,2; 4,5-inositol derivatives to differ, which makes control difficult, a single solid. It is preferable to use inositol having chemistry. Of these, myo-inositol, which is available at a relatively low cost, is preferable.

The carbonyl compound and / or acetal compound used as a raw material becomes a substituent constituting R ^{7 to} R ²² of the formulas (2) to (5) described later after the condensation reaction. The type is not particularly limited, but the preferred carbon number is 3 to 20, the more preferable carbon number is 3 to 15, and the more preferable carbon number is 3 to 10. Further, it is preferable to use an acetal compound because the inositol derivative represented by the formula (2) can be directly synthesized and has high reactivity with inositol.

For example, examples of carbonyl compounds include cyclopropanone, cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone, cyclooctanone, cyclononanone, cyclodecanone, cycloundecanone, cyclododecanone, isophorone, 3,3,5-trimethylcyclohexanone, 2 -Cyclic ketones such as norbornanone, 1-indanone, 2-adamantanone, camphor; acetone, 4-methyl-2-pentanone, dicyclohexyl ketone, methyl ethyl ketone, diethyl ketone, methyl isoamyl ketone, methyl isobutyl ketone, methyl propyl ketone, methyl butyl Chain ketones such as ketones, methylpentyl ketones, ethylpropyl ketones, ethylbutyl ketones, dipropyl ketones, diisopropyl ketones, t-butyl methyl ketones, methyl isopropyl ketones, 2,6-dimethyl-4-heptanone; 9-fluorenone, Benzophenone, acetphenone, 4-acetylbiphenyl, 2-acetylbiphenyl, 4'-ethyl-4-acetylbiphenyl, 1-acetylnaphthalene, 2-acetylnaphthalene, 1-hydroxy-2-acetylnaphthalene, 2-hydroxy-1-acetyl Aromatic ketones such as naphthalene, 3-hydroxy-2-acetylnaphthalene, 6-methyl-2-acetylnaphthalene; formaldehyde, acetaldehyde, propanal, butanal, pentanal, hexanal, heptanal, octanal, nonal, decanal, undecanal, dodecanal , Cyclohexanecarboxyaldehyde, 5-norbornen-2-carboxyaldehyde, crotonaldehyde and other aliphatic aldehydes; phenylacetaldehyde, 3-phenylpropionaldehyde, biphenyl-4-carboxyaldehyde, 2-thiophenecarboxyaldehyde, 1-naphthaldehyde, benzaldehyde , Anisaldehyde, p-chlorobenzaldehyde, p-methylbenzaldehyde, vanillin, 2-naphthalene aldehyde and other aromatic aldehydes; furfuryl aldehyde, pyridine aldehyde, nicotine aldehyde, 2-formylthiophene, 5-formylindole, 3-formylthiazolidine , 5-Formylpyrimidine, 2-formylpyrazine and other heterocyclic aldehydes; Of these, cyclic ketones and chain ketones are preferable, and cyclohexanone, 2-adamantanone, and 2,6-dimethyl-4-heptanone are more preferable because of the weather resistance and light resistance of the resin.

Further, examples of the acetal compound include a compound obtained by reacting the above-mentioned ketone compound with two molecules of alcohol. Specifically, acetals of cyclic ketones such as 1,1-dimethoxycyclohexane, 1,1-diethoxycyclohexane, 2,2-dimethoxyadamantane, 2,2-dimethoxypropane, 2,2-diethoxypropane, 4 , 4-Dimethoxy-2,6-dimethylheptane and the like are acetals of chain ketones. As these acetals, a commercially available product or an isolated compound may be used, or an unpurified mixture prepared from a ketone compound and an orthoester compound and / or an alcohol may be used. The acetal compound prepared from the ketone compound, the orthoester compound, and / or the alcohol may contain an enol ether from which one molecule of alcohol has been eliminated. Examples of the alcohol to be reacted with the ketone compound include primary alcohols such as methanol, ethanol, 1-propanol and 1-butanol, and secondary alcohols such as 2-propanol and 2-butanol. Among them, primary alcohols are preferable because of the high reactivity of the produced acetal compound and the inositol derivative, and methanol and ethanol are more preferable, and methanol is more preferable because they are available at low cost.

Examples of the orthoester compound to be reacted with the carbonyl compound include orthoesters such as trimethyl orthoformate, triethyl orthoformate, trimethyl orthoformate, triethyl orthoformate, trimethyl orthopropionate, and triethyl orthopropionate, and more preferably reactivity. It is an orthoester such as trimethyl orthoformate and triethyl orthoformate, which is highly available and easily available.

The acid catalyst is not particularly limited as long as the reaction proceeds, and either an inorganic acid or an organic acid can be used. Examples of the inorganic acid include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid; heteropolyacids such as phosphomolybdic acid, silicate molybdic acid, phosphotungstic acid and silicate tungstic acid; zeolite, cation exchange resin and the like. Solid catalyst; Examples of the organic acid include carboxylic acids such as formic acid, acetic acid and trifluoroacetic acid; methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and 10-campersulfonic acid and the like. Acids; onium salts obtained by treating hydrochloric acid, sulfuric acid, and sulfonic acid with an organic base such as triethylamine and pyridine; Hydrochloric acid and sulfuric acid are preferable as the inorganic acid, and methanesulfonic acid, p-toluenesulfonic acid and 10-camphorsulfonic acid are preferable as the organic acid because they are inexpensive and easily available. More preferably, sulfuric acid, p-toluenesulfonic acid, or 10-camphorsulfonic acid, which has a sufficiently strong acidity to allow the reaction to proceed and is industrially inexpensive.

The amount of the acid catalyst used varies depending on the type of catalyst, but is usually about 0.001 to 0.1 equivalent with respect to inositol, and 0.01 equivalent or more is preferable because the reaction is completed in a shorter time. , More preferably 0.02 equivalents or more, preferably 0.1 equivalents or less, more preferably 0.03 equivalents or less, for the reason of suppressing side reactions and reducing the load of post-treatment.

The solvent used in the condensation reaction step is arbitrary as long as the condensation reaction proceeds at a sufficient reaction rate, but usually N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like are used. Amide solvent; dimethyl sulfoxide; tetrahydrofuran,
And ether solvents such as dioxane; ketone solvents such as methyl isobutyl ketone, methyl ethyl ketone, and cyclohexanone; ester solvents such as methyl acetate, ethyl acetate, and butyl acetate; hydrocarbon solvents such as xylene, toluene, and benzene are preferred. The reaction solvent may be used alone or as a mixture. Amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone because inositol is easily dissolved; dimethyl sulfoxide is more preferable, and more preferably, it is highly reactive. It is N, N-dimethylformamide.

The condensation reaction step may be carried out without using a solvent and without using a solvent.
The amount of the solvent used is arbitrary as long as the desired reaction proceeds at a sufficient reaction rate, but usually, the ratio of the weight (g) of the solvent to the mass (g) of inositol used in the reaction is 1. The amount of solvent to be ~ 100 g / g is preferable, and if it is too small, the stirring efficiency is lowered and the reaction is slowed down. Therefore, it is preferably 1 g / g or more, more preferably 2 g / g or more, and if it is too large, the acid concentration is lowered. It is preferably 50 g / g or less because the reaction is slowed down, and more preferably 10 g / g or less for economic reasons.

The carbonyl compound and / or acetal compound used in the reaction is stoichiometrically reacted with inositol above the equivalent equivalent. The molar ratio of the total amount of the carbonyl compound and the acetal compound to inositol is usually preferably 2.0 to 30 for the carbonyl compound and the acetal compound / inositol, and 2.0 or more is preferable because the reaction is slow if the amount is too small. It is more preferably 2.5 or more for the reason of obtaining a yield, preferably 10 or less for the reason that the acid concentration is lowered and the reaction is delayed if it is too much, and more preferably 5 or less for economic reasons. ..

The reaction temperature is usually preferably 0 ° C. to 200 ° C., more preferably 80 ° C. to 160 ° C. The reaction time is several minutes to several tens of hours, preferably 30 minutes to 24 hours.
Further, in order to promote the condensation reaction, it is preferable to carry out the reaction while removing water or alcohol produced as a by-product of the condensation reaction from the system.

The condensation reaction is usually stopped with a base. The reaction termination is usually carried out with a base, but is not particularly limited, and if the reaction is terminated, either an organic base or an inorganic base can be used. Examples of the organic base include nitrogen-containing heterocyclic aromatic compounds such as pyridine, 2-methylpyridine, 2-methyl-5-ethylpyridine, 4-dimethylaminopyridine, and 2,6-dimethylpyridine; triethylamine and triethylenetetramine. , Amines such as triethanolamine, piperazine, diazabicyclo [2.2.2] octane; quaternary ammonium hydroxides such as tetramethylammonium hydroxide, tetrabutylammonium hydroxide, trimethylbenzylammonium hydroxide and the like, and inorganic bases. Examples include carbonates such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate and potassium carbonate, hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide, and hydrides such as potassium hydride and sodium hydride; Can be mentioned. Among them, industrially inexpensive and available inorganic bases are preferable, heat generation control by neutralization is easy, and the reaction can be stopped under milder conditions. Therefore, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate. Is more preferable.
However, in this step, it is not always necessary to stop the reaction using a base.

(B) Inositol crystallization reaction step The reaction step (step (B)) in the production method of the present invention is 1, 2, 4 of the following formula (1) contained in the solution obtained in the step (A). This is a step of converting a reaction product other than the 5-inositol derivative into a 1,2; 4,5-inositol derivative represented by the following formula (2) under an acid catalyst.

(R ^{7 to} R ¹⁰ in the above formula (2) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups may have an arbitrary substituent. Further, R ⁷ and R ⁸ and R ⁹ and R ¹⁰ may be coupled to each other to form a ring.)
In addition to the inositol, carbonyl compound and / or acetal compound used as raw materials, the solution obtained in the step (A) usually contains 1, 2, 4, 5 of the above formula (2) as a reaction product thereof. -Inositol derivative, inositol 2 protector such as 1,2; 3,4-inositol derivative represented by the following formula (3), inositol 1 protection such as 1,2-inositol derivative represented by the following formula (4) Includes the body and one or more compounds selected from the group consisting of inositol triprotectors such as 1,2; 3,4; 5,6-inositol derivatives represented by the following formula (5). In particular, even when the purpose is to produce 1,2; 4,5-inositol derivatives, unreacted inositol, 1,2; 3,4-inositol derivatives, 1,2; 3,4; 5, It often contains one or more compounds selected from the group consisting of 6-inositol derivatives and 1,2-inositol derivatives. Hereinafter, inositol derivatives other than these purposes are collectively referred to as by-products.

(In the above formulas (3) to (5), R ^{11 to} R ²² each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups have arbitrary substituents. R ¹¹ and R ¹² , R ¹³ and R ¹⁴ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , and R ²¹ and R ²² are coupled to each other and ring. May be formed.)
In the above formulas (2) to (5), examples of the organic group having 1 to 30 carbon atoms represented by R ^{7 to} R ²² include a methyl group, an ethyl group, a normal propyl group, a normal butyl group and a normal group. Substituentally substituted or unsubstituted linear alkyl group having 1 to 30 carbon atoms such as pentyl group, normal hexyl group, normal heptyl group, normal octyl group, trifluoromethyl group and benzyl group; isopropyl group, isobutyl group, sec- Substituent or unsubstituted branched or cyclic alkyl group having 1 to 30 carbon atoms such as butyl group, tert-butyl group and cyclohexyl group; phenyl group, naphthyl group, 4-methylphenyl group, frill group, thienyl group and the like. Substituted or unsubstituted aryl groups having 4 to 30 carbon atoms which may be substituted; and the like can be mentioned. A branched or cyclic alkyl group or aryl group that can impart high heat resistance to the resin when used as a resin raw material is preferable, while a linear alkyl group or branched group can be imparted from the viewpoint of imparting high weather resistance. Alternatively, a cyclic alkyl group is preferable. Methyl group, ethyl group, isopropyl group, normal propyl group, normal butyl group, isobutyl group, sec-butyl group, tert-butyl group, normal pentyl group, because the raw materials are easily available and synthesized. A linear or branched alkyl group having 1 to 8 carbon atoms such as a normal hexyl group, a normal heptyl group, and a normal octyl group is preferable, and an isopropyl group, an isobutyl group, and sec-butyl that can impart heat resistance and weather resistance in a well-balanced manner are preferable. A branched alkyl group having 3 to 4 carbon atoms such as a group is more preferable.

Here, R ^{7 to} R ²² may be independently different organic groups or a combination of a hydrogen atom and an organic group, but are groups derived from a single carbonyl compound and / or an acetal compound. This is preferable from the viewpoint of synthesis, and the fact that R ^{7 to} R ²² are the same reduces the number of isomers and increases the yield of the desired 1,2; 4,5-inositol derivative. More preferred.

R ⁷ and R ⁸ , R ⁹ and R ¹⁰ , R ¹¹ and R ¹² , R ¹³ and R ¹⁴ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , R ²¹ and R ²² are mutual. When a ring is formed by being bonded to, examples of the ring formed by the acetal carbon and each R include a substituted or unsubstituted cycloalkyl group having 3 to 30 carbon atoms, and even a monocyclic type is often used. It may be ring-shaped. Specifically, monocyclic cycloalkylidene groups such as cyclopropylidene group, cyclobutylidene group, cyclopentylidene group, cyclohexylidene group, cycloheptilidene group, cyclooctylidene group, 9,9-fluorenylidene; Polycyclic cycloalkylidene groups such as an adamantylidene group, a norbornylidene group, and a camphanilidene group; can be mentioned. Of these, a monocyclic cycloalkylidene group is preferable from the viewpoint of reducing the number of isomers and increasing the yield of the desired 1,2; 4,5-inositol derivative. Further, the cyclopentylidene group, the cyclohexylidene group, the cycloheptylidene group, the cyclooctylidene group, the adamantylidene group, and the norbornylidene group are preferable because the raw materials are easily available and the synthesis is easy. Preferably, when the target 1,2; 4,5-inositol derivative is used as a resin raw material, a cyclopentylidene group, a cyclohexylidene group, and an adamantylidene group that can impart heat resistance and weather resistance to the resin in a well-balanced manner can be imparted. Can be mentioned.

Here, R ^{7 to} R ²² may be independently different organic groups, but it is preferable from a synthetic point of view that they are groups derived from a single carbonyl compound and / or an acetal compound.
The amount of unreacted inositol contained in the solution obtained in step (A) and the 1,2-inositol derivative represented by the above formula (4) is particularly limited because it can be removed by the subsequent extraction step. However, in order to obtain the 1,2; 4,5-inositol derivative represented by the above formula (2) in a high yield, preferably 10 mol% or less, more preferably 5 mol, of the inositol used. % Or less, more preferably 3 mol% or less.

The amount of the 1,2; 3,4-inositol derivative represented by the above formula (3) contained in the solution obtained in the step (A) is represented by the above formula (2) according to the subsequent step (B). Since it is converted into the 1,2; 4,5-inositol derivative, the amount is not particularly limited, but the smaller the amount, the more the side reaction is suppressed and the yield is improved. Therefore, 90 of the inositol used is preferable. It is mol% or less, more preferably 70 mol% or less, still more preferably 50 mol% or less.

The amount of the 1,2; 3,4; 5,6-inositol derivative represented by the above formula (5) contained in the solution obtained in the step (A) is determined by the above formula (B) according to the following step (B). Since it is converted into the 1,2; 4,5-inositol derivative represented by 2), it is not particularly limited, but the 1,2; 3,4-inositol derivative represented by the above formula (3). Compared with the above, the conversion to the target 1,2; 4,5-inositol derivative represented by the above formula (2) is slow, and the yield is low because it remains after the reaction. Is 50 mol% or less, more preferably 30 mol% or less, still more preferably 10 mol% or less of the inositol used.

The amount of by-products other than the above-mentioned by-products is not limited as long as the reaction is not inhibited, but the yield of the 1,2; 4,5-inositol derivative represented by the above formula (2) is not limited. In order to reduce the purity, the amount is preferably less, preferably 10% by weight or less, more preferably 5% by weight or less, still more preferably 1% by weight or less, based on the raw material inositol derivative. The by-product described here means a compound having no inositol skeleton such as an aldol condensate of a carbonyl compound and / or an acetal compound or a dehydrated product thereof, and the carbonyl compound and / or the acetal compound added as a reaction raw material or the like. It does not contain the resulting water, alcohol or reaction compounds.

In this step (B), unreacted inositol and inositol derivatives represented by the above formulas (3) to (5) are represented by the above formula (2) in the presence of an acid catalyst 1, 2, 4, 4. Convert to 5-inositol derivative. In this step, if the desired 1,2; 4,5-inositol derivative is produced, isomerization from the other 2 protectors, elimination of the cyclic protecting group from the 3 protectors, to inositol or 1 protector. Any reaction such as introduction of a cyclic protecting group may be used.

Specifically, it is preferable to include any one or more of the reactions (b-1) to (b-4) described in the first aspect of the present invention in the presence of an acid catalyst, such as conversion efficiency. The same applies to the preferred range.
The entire amount of the solution obtained in the step (A) may be supplied to the reaction step, or after any one or more operations of neutralization, concentration, crystallization, solvent substitution, recrystallization and column chromatography. A reaction solution may be used. Preferably, after the step (A), the reaction solution is neutralized and concentrated, and then the filtrate after isolating the target inositol derivative by crystallization is concentrated, or after the step (A), the reaction solution is medium. The solution is a mixture and concentrated solution, or a solution in which the solvent is distilled off after the step (A), or a solution in which the reaction solution is neutralized and concentrated after the step (A), washed with water, and extracted. More preferably, after the step (A), the reaction solution is neutralized, concentrated, washed with water, and extracted because it can remove unnecessary inorganic substances.

As the acid catalyst to be used, the same catalyst as the acid catalyst used in the reaction for introducing and / or removing the cyclic protecting group in the production method of the first aspect described above can be preferably used in the same amount.
As the solvent to be used, the solvent contained in the solution obtained in the step (A) may be used as it is, and is preferably used for the reaction for introducing and / or eliminating the cyclic protecting group by the production method of the first aspect described above. The same solvent as the solvent can be used.
Further, the amount of the solvent used, the reaction temperature, and the preferable range of the reaction termination are the same as in the reaction of introducing and / or removing the cyclic protecting group in the production method of the first aspect described above.

In this step (B), seed crystals may be added for the purpose of promoting crystal precipitation and facilitating isomerization crystallization. Examples of the seed crystal to be used include the seed crystal used in the production method of the first aspect described above, and the seed crystal can be preferably used in the same amount as the amount used in the first aspect.

(C) Separation Step The reaction solution after the step (B) usually contains the catalyst, inositol, carbonyl compound and / or acetal compound, inositol 1 protector, inositol 2 protector, inositol 3 protector and the like. The 1,2; 4,5-inositol derivative represented by the above formula (2), which is the target compound, is isolated from the reaction solution by a conventional method. For example, the reaction solvent may be distilled off, water-soluble impurities may be removed by an extraction liquid separation operation using an organic solvent and water, the organic solvent may be distilled off, and crystallization may be carried out with a mixed solvent. If the desired inositol derivative is precipitated in B), it may be filtered as it is. The organic solvent used in the extraction liquid separation operation is not particularly limited as long as it is a solvent that dissolves the 1,2,4,5-inositol derivative represented by the above formula (2), which is the target compound, but as a specific example. Is a hydrocarbon solvent such as toluene, xylene, trimethylbenzene; an ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate; an ether solvent such as diethyl ether, diisopropyl ether, methyl-t-butyl ether, cyclopentyl methyl ether, etc. Can be mentioned. Toluene, xylene, ethyl acetate, isopropyl acetate, diisopropyl ether, and methyl-t-butyl ether, which are industrially inexpensive and easily available in large quantities, are preferable, and toluene, ethyl acetate, and diisopropyl, which can be easily distilled off in the concentration operation after liquid separation, are preferable. More preferably, ether and methyl-t-butyl ether.

The solid containing the 1,2; 4,5-inositol derivative represented by the above formula (2), which is the target compound extracted by filtration, is washed by sprinkling a solvent in order to remove and / or reduce impurities. Alternatively, a solid may be added to a solvent and washed as a slurry (suspension washing), and if necessary, purification may be performed by a method such as recrystallization, high-speed liquid chromatography, or column chromatography.

The method for increasing the purity of the 1,2; 4,5-inositol derivative represented by the above formula (2), which is the target compound, is not particularly limited, but the purity can be efficiently increased. For this reason, recrystallization is preferable, and when the impurities contained are organic compounds such as carbonyl compounds and / or acetal compounds and inositol derivatives other than 1,2; 4,5-inositol derivatives, hydrocarbon solvents and ester-based ones. Recrystallization using a solvent or an ether solvent is preferable, and more preferably toluene, xylene, n-hexane, n-heptane for a hydrocarbon solvent; ethyl acetate, isopropyl acetate for an ester solvent; Diisopropyl ether, methyl-t-butyl ether; and a mixed solvent thereof, more preferably toluene, xylene, ethyl acetate, toluene / n-heptane.

When the impurities contained are highly polar substances such as salts, it is preferable to carry out recrystallization using an alcohol solvent, a sulfonyl solvent, an amide solvent, a water-soluble ether solvent, and water, and more preferably an alcohol solvent. In, methanol, ethanol, 1-propanol, 2-propanol; 1,4-dioxane, tetrahydrofuran; water as a water-soluble ether solvent, and a mixed solvent thereof. The solvent used for crystallization is not limited to these solvents.
The mother liquor obtained after crystallization separation usually contains 2 protectors and 3 protectors, but may contain inositol and 1 protector, and may be recycled again in step (B). ..

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to the following examples.
The compounds used in the following examples and comparative examples are as follows.
DMF: N, N-dimethylformamide The inositol derivatives produced in the following Examples and Comparative Examples are referred to as abbreviations.

DCMI: DL-1,2:4,5-di-O-cyclohexylidene-myo-inositol DHMI: DL-1,2:4,5-bis-O- (2,6-dimethyl-4-heptylidene) -Myo-inositol DAMI: DL-1,2:4,5-di-O- (2-adamantilidene) -myo-inositol The structural formulas of each product compound are shown below.

(Comparative Example 1)
The production of DCMI from myo-inositol was carried out by a known method.
After nitrogen substitution of a 500 mL reaction vessel equipped with a Dimroth condenser, 30 g (167 mmol) of myo-inositol, 200 mL of DMF, 863 mg of p-toluenesulfonic acid monohydrate, and 75 mL of 1,1-dimethoxycyclohexane were added, and 3 at 100 ° C. Stirred for hours. After cooling to 40 ° C., 2.5 mL of triethylamine was added, and DMF as a reaction solvent was distilled off under reduced pressure.

Then, 250 mL of ethyl acetate was added, the solution was separated with 300 mL of a 5 wt% sodium carbonate aqueous solution, and then washed once with 300 mL of ion-exchanged water. The obtained organic layer was distilled off under reduced pressure, crystallization was carried out with 50 mL of ethyl acetate / 70 mL of n-hexane, and the obtained white precipitate was filtered. Then, crystallization was carried out again with 50 mL of ethyl acetate / 70 mL of n-hexane.
The obtained solid was vacuum dried at 60 ° C. for 5 hours to obtain 9.8 g (yield 17.2%) of DCMI, which is the target compound. ¹ H-NMR analysis of this compound was performed, and it was confirmed that it was the target compound DCMI.

(Example 1)
DCMI was synthesized from myo-inositol by the method of the present invention.
To a 500 mL 4-neck flask equipped with a Dean-Stark reflux tube, 95.5 g (973 mmol) of cyclohexanone, 70.5 g of methanol, and 1.18 g (11.8 mmol) of 98 wt% sulfuric acid were added, and trimethyl orthoformate was stirred with stirring. 95.7 g (2.32 mmol) was added dropwise to prepare a reaction solution. The reaction mixture was stirred in the range of 20-40 ° C. for 3 hours. To this reaction solution, 70.0 g (389 mmol) of myo-inositol and 148 g of DMF were added, and the mixture was heated at an internal temperature of 100 to 145 ° C. for 4 hours. After cooling to room temperature, 41.3 g of a 5.1 wt% sodium hydrogen carbonate aqueous solution was added, and the mixture was stirred for 30 minutes. After distilling off DMF under reduced pressure, toluene was added. The obtained toluene solution was divided into two and an extraction step was carried out.

To half the amount of the toluene solution, 125 g of toluene was added, 145 g of water at 90 ° C. was added, and the mixture was stirred at an internal temperature of 70 to 80 ° C. for 10 minutes. After allowing to stand for 10 minutes, the aqueous layer was separated, 180 g of water at 90 ° C. was added to the obtained organic layer, and the mixture was stirred at an internal temperature of 70 to 80 ° C. for 10 minutes. After allowing to stand for 10 minutes, the aqueous layer was separated, 160 g of water at 90 ° C. was added to the obtained organic layer, and the mixture was stirred at an internal temperature of 70 to 80 ° C. for 10 minutes. After allowing to stand for 10 minutes, the aqueous layer was separated to obtain 240 g of an organic layer. The remaining toluene solution previously divided into two was also washed with water in the same manner to obtain 240 g of an organic layer.

After combining the obtained organic layers, toluene was added to obtain 494 g of a pale yellow solution. As a result of GC analysis, the oily substance was 12.4 g of DL-1,2; 3,4; 5,6-tri-O-cyclohexylidene-myo-inositol (hereinafter abbreviated as DCMI-3 protectant). (29.4 mmol), DL-1,2: 3,4-di-O-cyclohexylidene-myo-inositol and DCMI and DL-1,2: 5,6-di-O-cyclohexylidene-myo- It contained 91.8 g (270 mmol) of a mixture of inositol (hereinafter abbreviated as DCMI-2 protector mixture), and of the two protector mixture, DCMI was 27.4 g (80.4 mmol).

Toluene was distilled off under reduced pressure to obtain 376 g of an oily substance, and then the water content was measured with a Karl Fischer titer and found to be 104 ppm. To a 1 L 4-neck flask, 76.0 g of toluene, 0.70 g (3.01 mmol) of 10-camphorsulfonic acid was added, and the mixture was stirred at room temperature for 1 hour. Then, the reaction was carried out at an internal temperature of 5 to 10 ° C., and as a result of GC analysis of a part of the slurry obtained 21 hours later, 15.0 g (35.7 mmol) of DCMI-3 protected product and DCMI-2 protected product were obtained. 86.0 g (253 mmol) of the mixture, 1.43 g (5.50 mmol) of DL-1,2-O-cyclohexylidene-myo-inositol (hereinafter abbreviated as DCMI-1 protector), myo-inositol. It contained 1.01 g (5.61 mmol). Of the DCMI-2 protecting mixture, DCMI is 75.8 g (223 mmol), which is 75.8 g / 27.4 g = 2.75 times that of DCMI contained in the oily substance before isomerization crystallization. It turned out that it increased to. Further, the reaction was carried out at an internal temperature of 5 to 10 ° C. for 15 hours, 2.43 g of a 13.6 wt% potassium hydrogen carbonate aqueous solution was added, and the mixture was stirred at an internal temperature of 5 to 10 ° C. for 1 hour.

The precipitated solid was filtered through a Kiriyama funnel, sprinkled with 86.7 g of toluene at 5 ° C. for washing, and then the obtained white solid was vacuum dried at room temperature to obtain 90.9 g of a white solid. ¹ As a result of ¹ H-NMR analysis, it was confirmed that the obtained white solid was DCMI. As a result of GC analysis, the purity of DCMI of the obtained white solid was 87.5% by weight and 94.4 area%. The DCMI obtained by isomerization crystallization was 79.5 g (234 mmol), and the yield based on myo-inositol used was 60.2%. Moreover, since the total amount of the DCMI-2 protected substance contained in the oily substance before the isomerization crystallization was 91.8 g (270 mmol), the yield based on this was 86.7%.

Since the DCMI in the raw material used was 80.4 mmol, the DCMI increased by isomerization crystallization was 234-80.4 = 153.6 mmol, other than the DCMI (80.4 mmol) in the raw material used. Of the total amount of DCMI-2 protecting (189.6 mmol), 81% was converted to DCMI. Moreover, since DCMI was 27.4 g (80.4 mmol) in the total amount of DCMI-2 protecting group contained in the oily substance before isomerization crystallization, DCMI was 234/80 by isomerization crystallization. It was found that .4 = 2.91 times.
¹ H-NMR analysis of the obtained compound was performed, and it was confirmed that it was the target compound DCMI. An NMR chart of DCMI is shown in FIG.

(Example 2)
DCMI was synthesized from myo-inositol, and the DCMI was prepared by the method of the present invention using the filtrate obtained by removing the DCMI by filtration.
45.0 g (250 mmol) of myo-inositol, 100 g of DMF, 0.735 g (7.49 mmol) of 98 wt% sulfuric acid, 90.1 g of 1,1-dimethoxycyclohexane in a 300 mL four-necked flask equipped with a Dean-Stark reflux tube. 625 mmol) was added, and the mixture was stirred at an internal temperature of 85 to 125 ° C. for 3 hours and 20 minutes. After cooling to room temperature, 8.6 g of a 12.0 wt% potassium hydrogen carbonate aqueous solution was added to 131 g (65.8% of the total amount charged) out of 199 g of the obtained reaction solution. After distilling off DMF under reduced pressure, 200 mL of toluene and 180 g of water at 90 ° C. were added, and the organic layer was washed with water. Further, the organic layer was washed twice with 300 g of water at 90 ° C. The organic layer obtained by liquid separation was concentrated to obtain 82.7 g of a pale yellow oily substance. As a result of GC analysis, the oily substance contained 6.06 g (14.4 mmol) of the DCMI-3 protectant, 39.5 g (116 mmol) of the DCMI-2 protector mixture, and 11 of the DCMI-2 protector mixture was DCMI. It was .4 g (33.4 mmol).

To this oily substance, 43.4 g of toluene and 47.9 g of heptane were added for crystallization, and the obtained white crystals were filtered and sprinkled with 6.8 g of heptane for washing. The obtained white crystals were vacuum dried at 50 ° C. to obtain 10.0 g of white crystals.
On the other hand, the filtrate obtained in the above-mentioned filtration step was concentrated under reduced pressure to obtain 46.4 g of a yellow oily substance. As a result of GC analysis, it contained 5.89 g (14.0 mmol) of the DCMI-3 protectant, 27.1 g (79.6 mmol) of the DCMI-2 protector mixture, and 1.26 g (12.6 mmol) of the two protector mixture. It was 3.7 mmol).

Toluene (60.4 g) was added to 46.4 g of a yellow oily substance to prepare a 107 g toluene solution, and then isomerization crystallization was performed using 58.0 g of this solution. To a 200 mL 4-neck flask, 58.0 g of a toluene solution was added, 0.29 g (1.26 mmol) of 10-camphorsulfonic acid was added, and the reaction was carried out at an internal temperature of 5-10 ° C. for 24 hours.
After stopping the reaction by adding 0.253 g (2.53 mmol) of triethylamine, the precipitated solid was filtered through a Kiriyama funnel, sprinkled with 17.3 g of toluene at 5 ° C. and washed, and then the obtained white solid was obtained. Was vacuum dried at 50 ° C. to obtain 11.2 g of a white solid. As a result of GC analysis, the purity of DCMI of the obtained white solid was 90.3% by weight and 95.3 area%. The DCMI obtained by isomerization crystallization was 10.1 g (29.7 mmol), and the yield based on myo-inositol (250 mmol × 65.8% / 107 g × 58.0 g = 89.2 mmol) was 33. It was 3%. Moreover, since the total amount of the DCMI-2 protecting mixture mixture contained in the oily substance before isomerization crystallization was 14.7 g (43.2 mmol), the yield based on this was 68.8%. ..

Since the DCMI in the raw material used for the isomerization crystallization was 2.01 mmol, the DCMI increased by the isomerization crystallization was 29.7-2.0 = 27.7 mmol, and the DCMI in the raw material used was Of the total amount of DCMI-2 protecting (41.2 mmol) other than (2.01 mmol), 67% was converted to DCMI.
Moreover, since DCMI was 0.683 g (2.01 mmol) in the total amount of DCMI-2 protected substance contained in the oily substance before isomerization crystallization, DCMI was 29. It was found that 7 / 2.01 = 14.8 times increased.

In Comparative Example 1, the yield of DCMI obtained through one crystallization was as low as 17.2% with respect to the raw material myo-inositol used, whereas in Example 1, DCMI was crystallized. However, the yield of DCMI obtained through one crystallization was used by advancing the reaction to produce DCMI from the DCMI-2 protector mixture or the DCMI-3 protector to carry out isomerization crystallization. It was possible to improve up to 60.2% with respect to the raw material myo-inositol. Further, in Example 1, 81% of the total amount of DCMI-2 protecting group (189.60 mmol) other than DCMI (80.4 mmol) in the raw material used was converted to DCMI, and in Example 2, Since 67% of the total amount of DCMI-2 protecting group (41.2 mmol) other than DCMI (2.01 mmol) in the raw material used for isomerization crystallization is converted to DCMI, isomerization crystallization is performed. In the process, it is presumed that DCMI was produced mainly by changing the position of the cyclic protecting group of the DCMI-2 protector other than DCMI.

(Comparative Example 2)
DHMI was produced from myo-inositol without using the method of the present invention.
After nitrogen substitution of a 500 mL reaction vessel equipped with Dimroth, 72 g (500 mmol) of 2,6-dimethyl-4-heptanone, 54 mL (500 mmol) of trimethyl orthoformate, methanol (150 mL), p-toluenesulfonic acid monohydrate After adding 863 mg (4.5 mmol) and stirring at room temperature for 5 minutes, 30 g (167 mmol) of myo-inositol and DMF (210 mL) were added, and the mixture was stirred at 125 ° C. for 3 hours. During that time, the liquid distilled off in the Dean-Stark tube was removed.

After cooling to room temperature, 9.5 g of a 6 wt% sodium hydrogen carbonate aqueous solution was added, and DMF was distilled off under reduced pressure. After adding 100 mL of ethyl acetate, the obtained solid was filtered. It was recrystallized from 50 mL of methanol to obtain 3.2 g (yield 4.4%) of the target compound, DHMI.
¹ H-NMR analysis of this compound was performed, and it was confirmed that it was the target compound. The NMR chart of DHMI is shown in FIG.

(Example 3)
DHMI was synthesized from myo-inositol, and DHMI was produced by the method of the present invention using the filtrate obtained by removing DHMI by filtration.
According to the method according to Comparative Example 3, ethyl acetate was distilled off under reduced pressure from the filtrate after filtering the solid of DHMI, and then toluene was added and the distillation under reduced pressure was repeated to distill off ethyl acetate and water. A crude DHMI oily substance was obtained.

A 100 mL 4-neck flask was charged with 30.1 g of a toluene solution of a crude DHMI oily substance. This toluene solution contains 0.06 g (0.33 mmol) of myo-inositol, DL-1,2-O- (2,6-dimethyl-4-heptylidene) -myo-inositol (hereinafter referred to as DHMI-1 protectant). 0.81 g (2.66 mmol), DL-1,2: 3,4: 5,6-tris-O- (2,6-dimethyl-4-heptylidene) -myo-inositol (hereinafter, DHMI) 0.12 g (0.22 mmol) (abbreviated as -3 protector), DL-1,2: 3,4-bis-O- (2,6-dimethyl-4-heptylidene) -myo-inositol, DHMI, 5.64 g (13) of a mixture of DL-1,2: 5,6-bis-O- (2,6-dimethyl-4-heptylidene) -myo-inositol (hereinafter abbreviated as DHMI-2 protector mixture). .2 mmol), of which 1.47 g (3.43 mmol) of DHMI is contained.

When 0.100 g (0.430 mmol) of 10-camphorsulfonic acid was added to the toluene solution and the mixture was stirred at an internal temperature of 5 to 10 ° C. for 1 hour, white crystals were precipitated and the reaction system became a slurry. 0.086 g (0.86 mmol) of triethylamine was added, and the mixture was stirred at an internal temperature of 5 to 10 ° C. for 30 minutes. 13.7 g of heptane is added to this slurry to dilute it, the precipitated solid is filtered through a Kiriyama funnel, sprinkled with 17.3 g of toluene at 5 ° C. and washed, and then the obtained white solid is vacuumed at 50 ° C. It was dried to obtain 6.14 g of a white solid.

As a result of GC analysis, the purity of DHMI of the obtained white solid was 67.1% by weight and 87.0 area%. From this result, the DHMI obtained by isomerization crystallization is 4.12 g (9.61 mmol), and the total amount of the DHMI-2 protecting mixture mixture contained in the toluene solution before isomerization crystallization is 5.64 g. Since it was (13.2 mmol), the yield with respect to this was 72.8%.

Since the DHMI in the raw material used for the isomerization crystallization was 3.43 mmol, the DHMI increased by the isomerization crystallization was 9.61-3.43 = 6.18 mmol, and the DHMI in the raw material used. Of the total amount of DHMI-2 protecting group (9.77 mmol) other than (3.43 mmol), 63% was converted to DHMI.
Further, since the DHMI was 1.47 g (3.43 mmol) in the DHMI-2 protected mixture contained in the toluene solution before the isomerization crystallization, the DHMI was 4.12 by the isomerization crystallization. It was found that /1.47 = 2.8-fold increase.

In Comparative Example 2, the yield of DHMI obtained through one crystallization was as low as 4.4% with respect to the raw material myo-inositol used, whereas in Example 3, DHMI was crystallized. However, it is obtained through one crystallization by advancing the reaction to generate DHMI from myo-inositol, DHMI-1 protected group, DHMI-2 protected mixture, and DHMI-3 protected body to perform isomerization crystallization. The resulting DHMI increased 2.8-fold with respect to the DHMI contained in the raw material inositol derivative used. Further, in Example 3, since 63% of the total amount of DHMI-2 protecting group (9.77 mmol) other than DHMI (3.43 mmol) in the raw material used was converted to DHMI, isomerization crystallization was performed. It is presumed that DHMI was generated mainly by changing the position of the cyclic protecting group of the DHMI-2 protector other than DHMI in the step.

(Comparative Example 3)
DAMI was produced from myo-inositol without using the method of the present invention.
After nitrogen substitution of a 500 mL reaction vessel equipped with a Dimroth condenser, 50 g (334 mmol) of 2-adamantanone, 37 mL (334 mmol) of trimethyl orthoformate, methanol (100 mL), and 575 mg (3 mmol) of p-toluenesulfonic acid monohydrate were added. In addition, after stirring at room temperature for 5 minutes, 20 g (111 mmol) of myo-inositol and DMF (140 mL) were added, and the mixture was stirred at 130 ° C. for 3 hours. During that time, the liquid distilled off in the Dean-Stark tube was removed. After cooling to room temperature, 6.5 g of a 6 wt% sodium hydrogen carbonate aqueous solution was added, and DMF was distilled off under reduced pressure. After adding 250 mL of ethyl acetate, the obtained solid was filtered. Wash with 50 mL of water / 50 mL of methanol and use DAMI as the target compound.
Was obtained in an amount of 7.2 g (yield 15%). ¹ H-NMR analysis of this compound was performed, and it was confirmed that it was the target compound. The NMR chart of DAMI is shown in FIG.

(Example 4)
DAMI was synthesized from myo-inositol, and DAMI was produced by the method of the present invention using the filtrate obtained by removing DAMI by filtration. According to the method according to Comparative Example 3, ethyl acetate was distilled off under reduced pressure from the filtrate after filtering the solid of DAMI, and then toluene was added and the distillation under reduced pressure was repeated to distill off ethyl acetate and water. , A crude DAMI oily substance was obtained.

A 500 mL 4-neck flask was charged with 90.5 g of a toluene solution in which a crude DAMI oily substance was dissolved in toluene. The toluene solution contains 0.36 g (1.15 mmol) of DL-1,2-O- (2-adamantilidene) -myo-inositol (hereinafter abbreviated as DAMI-1 protectant), DL-1,2. : 3,4-di-O- (2-adamanchiliden) -myo-inositol, DAMI, DL-1,2: 5,6-di-O- (2-adamanchiliden) -myo-inositol (hereinafter , Abbreviated as DAMI-2 protector mixture), containing 20.9 g (47.0 mmol), of which DAMI contains 0.28 g (0.630 mmol).

0.459 g (1.98 mmol) of 10-camphorsulfonic acid was added to the toluene solution, and the mixture was stirred at room temperature for 30 minutes and then reacted at an internal temperature of 5-10 ° C. for 3 days. After diluting with 20.5 g of heptane, 0.300 g (2.97 mmol) of triethylamine was added. The precipitated solid was filtered through a Kiriyama funnel, sprinkled with 34.2 g of heptane at 5 ° C. and washed, and then the obtained white solid was vacuum dried at 50 ° C. to obtain 15.3 g of a white solid.

As a result of GC analysis, the purity of the obtained white solid DAMI was 93.5% by weight and 93.5 area%. The DAMI obtained by isomerization crystallization is 14.3 g (32.2 mmol), and the total amount of the DAMI-2 protecting mixture mixture contained in the toluene solution before isomerization crystallization is 20.9 g (47. Since it was 0 mol), the yield with respect to this was 68.4%. Further, since the DAMI was 0.28 g (0.630 mmol) in the DAMI-2 protecting mixture mixture contained in the toluene solution before the isomerization crystallization, the DAMI was 14.3 / by the isomerization crystallization. It was found that 0.28 = 51 times increased.

Since the DAMI in the raw material used for the isomerization crystallization was 0.63 mmol, the DAMI increased by the isomerization crystallization was 32.2-0.63 = 31.6 mmol, and the DAMI in the raw material used was Of the total amount of DAMI-2 protecting group (46.4 mmol) other than (0.63 mmol), 68% was converted to DAMI.
This white solid was suspended and washed with 80.7 g of ethyl acetate, filtered through a Kiriyama funnel, and sprinkled with 8.97 g of ethyl acetate for washing. The obtained white solid was vacuum dried at room temperature to obtain 12.3 g of a white solid. As a result of GC analysis, the purity of the obtained white solid DAMI was 79.1% by weight and 94.5 area%.

In Comparative Example 3, the yield of DAMI obtained through one crystallization was as low as 15% with respect to the raw material myo-inositol used, whereas in Example 4, DAMI was crystallized while DAMI was crystallized. By advancing the reaction to generate DAMI from a mixture of -1 protector and DAMI-2 protector and performing isomerization crystallization, DAMI obtained through one crystallization can be used as the raw material inositol derivative. It increased 51-fold with respect to the included DAMI. Further, in Example 4, since 68% of the total amount of DAMI-2 protecting group (46.37 mmol) other than DAMI (0.63 mmol) in the raw material used was converted to DAMI, isomerization crystallization was performed. It is presumed that DAMI was generated mainly by changing the position of the cyclic protecting group of the DHMI-2 protector other than DAMI in the step.

According to the method for producing an inositol derivative of the present invention, the by-products produced when the 1,2; 4,5-inositol derivative is synthesized can be used by a simple method, and the yield of the desired inositol derivative can be obtained. The rate can be expected to improve. Further, the obtained 1,2; 4,5-inositol derivatives are useful as raw materials for highly heat-resistant resins.

Claims (14)

A method for producing an inositol derivative represented by the following formula (2) by a reaction of introducing and / or removing a cyclic protecting group into the inositol derivative represented by the following formula (1) in the presence of a catalyst. A method for producing an inositol derivative, which comprises advancing a reaction for introducing and / or removing the cyclic protecting group while crystallizing the 1,2; 4,5-inositol derivative represented by the formula (2). ..

(R ^{1 to} R ⁶ in the above formula (1) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups may have an arbitrary substituent. Further, any two of R ^{1 to} R ⁶ may be bonded to each other to form a ring.)

(R ^{7 to} R ¹⁰ in the above formula (2) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups may have an arbitrary substituent. Further, R ⁷ and R ⁸ and R ⁹ and R ¹⁰ may be coupled to each other to form a ring.) The inositol derivative represented by the formula (1) is myo-inositol or myo-.
The method for producing a 1,2; 4,5-inositol derivative according to claim 1, which comprises a derivative of inositol. The 1,2; 4,5 according to claim 1 or 2, wherein the inositol derivative represented by the formula (1) contains the 1,2; 3,4-inositol derivative represented by the following formula (3). -A method for producing an inositol derivative.

(R ^{11 to} R ¹⁴ in the above formula (3) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups may have an arbitrary substituent. In addition, R ¹¹ and R ¹² , and R ¹³ and R ¹⁴ may be coupled to each other to form a ring.) The 1,2,4,5-inositol derivative according to claim 3, which converts 10% or more of the total amount of the inositol derivative represented by the formula (3) into 1,2; 4,5-inositol derivative. Production method. The inositol derivative represented by the formula (1) is a 1,2-inositol derivative represented by the following formula (4) and / or 1,2; 3,4; 5 represented by the following formula (5). , The method for producing a 1,2; 4,5-inositol derivative according to any one of claims 1 to 4, which comprises a 6-inositol derivative.

(Rs ^{15 to} R ²² in the above formulas (4) and (5) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups have an arbitrary substituent. R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , and R ²¹ and R ²² may be coupled to each other to form a ring.) In the reaction of introducing and / or eliminating the cyclic protecting group, a solvent having a solubility of 1,2; 4,5-inositol derivative represented by the above formula (2) at 0 to 10 ° C. of 0 to 20% by weight or less. The method for producing a 1,2; 4,5-inositol derivative according to any one of claims 1 to 5, wherein the reaction is carried out using the above. The reaction according to any one of claims 1 to 6, wherein the reaction is carried out using a hydrocarbon solvent, an ester solvent and / or an ether solvent in the reaction for introducing and / or removing the cyclic protecting group. 1,2; 4,5-A method for producing an inositol derivative. The method for producing a 1,2; 4,5-inositol derivative according to any one of claims 1 to 7, wherein the reaction proceeds at 50 ° C. or lower in the reaction for introducing and / or eliminating the cyclic protecting group. .. (A) Condensation reaction step in which inositol and a carbonyl compound and / or an acetal compound are condensed in the presence of an acid catalyst.
(B) Reaction products other than the 1,2,4,5-inositol derivatives of the following formula (2) contained in the solution obtained in the condensation reaction step are represented by the following formula (2) under an acid catalyst. 1,2; 4,5-Reaction step to convert to inositol derivative,
(C) A separation step of separating 1,2,4,5-inositol derivatives of the following formula (2) from the reaction solution after the reaction step.
A method for producing a 1,2; 4,5-inositol derivative having the above, in which the 1,2; 4,5-inositol derivative represented by the following formula (2) is crystallized in the reaction step (B). A method for producing a 1,2; 4,5-inositol derivative, which comprises allowing the reaction to proceed while allowing the reaction to proceed.

(R ^{7 to} R ¹⁰ in the above formula (2) each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups may have an arbitrary substituent. Further, R ⁷ and R ⁸ and R ⁹ and R ¹⁰ may be coupled to each other to form a ring.) The solution obtained in the step (A) is inositol, a 1,2; 3,4-inositol derivative represented by the following formula (3), a 1,2-inositol derivative represented by the following formula (4). The 1,2; 4,5- according to claim 9, which comprises one or more compounds selected from the group consisting of 1,2; 3,4; 5,6-inositol derivatives represented by the following formula (5). A method for producing an inositol derivative.

(In the above formulas (3) to (5), R ^{11 to} R ²² each independently represent a hydrogen atom or an organic group having 1 to 30 carbon atoms. These organic groups have arbitrary substituents. R ¹¹ and R ¹² , R ¹³ and R ¹⁴ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , and R ²¹ and R ²² are coupled to each other and ring. May be formed.) In the step (B), the reaction is carried out using a solvent having a solubility of the 1,2; 4,5-inositol derivative represented by the formula (2) at 0 to 10 ° C. of 0 to 20% by weight or less. The method for producing a 1,2; 4,5-inositol derivative according to claim 9 or 10. 1, 2, 4, 5- according to any one of claims 9 to 11, wherein in the step (B), the reaction is allowed to proceed using a hydrocarbon solvent, an ester solvent and / or an ether solvent. A method for producing an inositol derivative. The method for producing a 1,2; 4,5-inositol derivative according to any one of claims 9 to 12, wherein the reaction proceeds at 50 ° C. or lower in the step (B). Any one of claims 9 to 13, wherein after the step (A), the 1,2; 4,5-inositol derivatives of the formula (2) are separated and the remaining solution is subjected to the step (B). The method for producing a 1,2; 4,5-inositol derivative according to the above item.

Images