JP2010100651A - Process for production of 3-hydroxytetrahydrofuran - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide high-purity 3-hydroxytetrahydrofuran in a high yield easily and simply by an industrially advantageous process. <P>SOLUTION: The process includes: reducing a 4-halo-3-hydroxybutyric acid ester with a boron hydride compound and/or an aluminum hydride compound in an organic solvent immiscible with water; treating the reaction mixture with an acid and water to convert it into the corresponding 4-halo-1, 3-butanediol and at the same time obtaining an aqueous solution containing the compound; carrying out the cyclization reaction in the aqueous solution; extracting the resulting 3-hydroxytetrahydrofuran from the aqueous solution using an organic solvent immiscible with water; and isolating the 3-hydroxytetrahydrofuran by concentration and/or distillation of the solution obtained. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

The present invention relates to a method for producing 3-hydroxytetrahydrofuran, particularly optically active high-quality 3- (S) -hydroxytetrahydrofuran, in a high yield, in a simple and industrially advantageous manner.

3-Hydroxytetrahydrofuran is an extremely useful compound as a synthetic intermediate for pharmaceuticals and agricultural chemicals. As a production method thereof, a method is known in which an easily available 4-halo-3-hydroxybutyric acid ester is reduced and the obtained 4-halo-1,3-butanediol is cyclized to synthesize. Specifically, 4-halo-3-hydroxybutyric acid ester was reduced using sodium borohydride in an organic solvent compatible with water such as tetrahydrofuran (hereinafter also referred to as THF), and obtained 4 A method of producing 3-hydroxytetrahydrofuran by cyclizing halo-1,3-butanediol in an aqueous hydrochloric acid solution [see Patent Document 1, Non-Patent Document 1] and the like is known.

Among these, as a typical production method, for example,
First step: ethyl 4-chloro-3-hydroxybutyrate is reduced with sodium borohydride in THF,
Step 2: Concentrate the reaction mixture, add aqueous hydrochloric acid to the residue, extract with ethyl acetate, dehydrate the extract with a solid desiccant, filter off the desiccant, and concentrate the extraction solvent. After removal, 4-chloro-1,3-butanediol is obtained as an oil,
Third step: This is dissolved in an aqueous hydrochloric acid solution and heated to perform a cyclization reaction.
Fourth step: neutralize the reaction mixture, add methanol to the residue obtained by concentrating and removing water, and filter off the precipitated inorganic salt;
Fifth step: A method consisting of concentrating and distilling the filtrate to obtain 3-hydroxytetrahydrofuran is described.

However, such a method requires complicated steps such as a plurality of concentration operations and solid-liquid separation operations. If the concentration operation is omitted and water is added directly to the reaction mixture, the solvent is compatible with water, resulting in a mixed solvent in which the solvent and water are mixed. As a result of studies by the present inventors, it was found that the following cyclization reaction in such a solvent is not preferable because the reaction rate decreases and impurities increase. Therefore, when the reduction reaction is performed using an organic solvent compatible with water, a step of removing the organic solvent is indispensable before adding water to the reaction mixture. Therefore, the conventional method is low in productivity, and cannot be said to be an advantageous production method in practice on an industrial scale.

Further, in the conventional method, the yield of the target product is not necessarily a satisfactory number, such as 86% in the reduction step, 68 to 79% in the cyclization step, and 58 to 68% when both steps are combined. Furthermore, 3,4-epoxy-1-butanol is by-produced during the reduction reaction (about 16 to 21% by-product, JP-A-2-174733), and 2,5-dihydrofuran is by-produced during the cyclization reaction. [About 15% by-product, see Non-Patent Document 1], and the conventional method has a problem with respect to the quality of the target product.

As described above, conventionally, 4-halo-3-hydroxybutyric acid ester is reduced, and the produced 4-halo-1,3-butanediol is cyclized to produce high-quality 3-hydroxytetrahydrofuran in high yield. A simple and efficient production method to be obtained, particularly a production method advantageous for implementation on an industrial scale, has not been known.

JP-A-9-77759

Liebigs Ann./Recl. 1877 (1997)

In view of the above situation, the present invention reduces 4-halo-3-hydroxybutyric acid ester (1) and cyclizes the resulting 4-halo-1,3-butanediol (2) to produce a high-quality product. The object is to provide a simple and industrially advantageous method for producing 3-hydroxytetrahydrofuran (3) in high yield.

That is, the present invention relates to the general formula (1):

(Wherein R represents an ester-type protecting group, X represents a halogen atom), a general formula (2) obtained by reducing a 4-halo-3-hydroxybutyric acid ester represented by:

(Wherein X represents a halogen atom) by cyclization of 4-halo-1,3-butanediol represented by formula (3):

A process for producing 3-hydroxytetrahydrofuran represented by:
First step: 4-halo-3-hydroxybutyric acid ester (1) is reduced using a borohydride compound and / or an aluminum hydride compound as a reducing agent in an organic solvent incompatible with water,
Second step: The obtained reaction mixture is treated with acid and water to convert it into 4-halo-1,3-butanediol (2), and an aqueous solution containing the compound is obtained.
Third step: In the above aqueous solution, cyclization reaction of 4-halo-1,3-butanediol (2) is performed,
Fourth step: Extracting 3-hydroxytetrahydrofuran (3) from the resulting aqueous solution containing 3-hydroxytetrahydrofuran (3) using an organic solvent incompatible with water,
Fifth step: a method for producing 3-hydroxytetrahydrofuran, comprising concentrating and / or distilling the obtained solution to isolate 3-hydroxytetrahydrofuran (3).

The present invention also reduces 4-halo-3-hydroxybutyric acid ester (1) using a borohydride compound and / or an aluminum hydride compound as a reducing agent in an organic solvent incompatible with water, The resulting mixture is treated with acid and water to convert it into 4-halo-1,3-butanediol (2) and obtaining an aqueous solution containing the compound, 4-halo-1 , 3-butanediol production method.

The present invention further relates to a method for producing 3-hydroxytetrahydrofuran (3) by cyclizing 4-halo-1,3-butanediol (2) in an aqueous solution, wherein the cyclization reaction is weakly acidic to It is also a production method carried out under neutral conditions.

The present invention is also a method for obtaining 3-hydroxytetrahydrofuran, wherein 3-hydroxytetrahydrofuran is extracted from an aqueous solution containing 3-hydroxytetrahydrofuran at a temperature of 40 ° C. or higher using an organic solvent incompatible with water. .

The present invention is also a method for obtaining 3-hydroxytetrahydrofuran, wherein 3-hydroxytetrahydrofuran is extracted from an aqueous solution containing 3-hydroxytetrahydrofuran using monohydric alcohols having 4 to 8 carbon atoms.

The present invention is also a method for obtaining 3-hydroxytetrahydrofuran by distilling 3-hydroxytetrahydrofuran mixed with a boron compound and / or an aluminum compound,
In the distillation method, the 3-hydroxytetrahydrofuran mixed with the boron compound and / or the aluminum compound is treated with monohydric alcohols having 1 to 3 carbon atoms or polyhydric alcohols having 6 or more carbon atoms. is there.

Finally, the present invention is also a method for obtaining 3-hydroxytetrahydrofuran, in which distillation (including rectification) of 3-hydroxytetrahydrofuran is carried out in the presence of a base.
The present invention is described in detail below.

Since the present invention has the above-described configuration, a complicated operation such as concentration and solid-liquid separation is omitted by using easily available 4-halo-3-hydroxybutyric acid ester as a raw material, and high-purity 3-hydroxytetrahydrofuran. Can be produced in a high yield, in a convenient and industrially advantageous manner. It is also possible to obtain 3-hydroxytetrahydrofuran with high optical purity.

Below, the manufacturing method of 3-hydroxytetrahydrofuran which consists of five processes is demonstrated. Other production methods of the present invention can be carried out in the same manner as described below.

In the first step of this production method, 4-halo-3-hydroxybutyric acid ester represented by the above general formula (1) [also referred to as 4-halo-3-hydroxybutyric acid ester (1) in this specification] is prepared. 4-halo-1,3-represented by the general formula (2) by reduction using a borohydride compound and / or an aluminum hydride compound as a reducing agent in an organic solvent incompatible with water. Butanediol [also referred to herein as 4-halo-1,3-butanediol (2)] is formed.

R in the general formula (1) represents an ester-type protecting group. Here, the ester-type protecting group refers to a group capable of protecting a carboxylic acid as an ester. The ester-type protecting group is not particularly limited, and a general ester-type protecting group can be used, but an alkyl group is preferable. More preferred is an alkyl group having 1 to 4 carbon atoms, and particularly preferred is an ethyl group.

X in the general formulas (1) and (2) is a leaving group that is eliminated when an ether bond is formed between the hydroxyl group at the 1-position and the carbon atom at the 4-position in the general formula (2). Represents a halogen atom. Preferably, it represents chlorine, bromine or iodine, more preferably chlorine.

The 4-halo-3-hydroxybutyric acid ester (1) as a reaction substrate is generally obtained by reducing an easily available 4-haloacetoacetic acid ester. In order to obtain an optically active substance particularly useful as a synthetic raw material in the field of pharmaceuticals and agrochemicals, a reduction method using an asymmetric reducing agent or a microorganism or an enzyme is known. -Of American Chemical Society (J. Am. Chem. Soc.), Vol. 105, page 5925 (1983), Japanese Patent Publication No. 4-7195, etc. . In the production method of the present invention, even if this compound is optically active, 4-halo-1,3-butanediol (2) and 3-hydroxytetrahydrofuran (3) are obtained while maintaining the optical activity. Can do. For example, when this production method is carried out using 4-halo-3- (S) -hydroxybutyric acid ester, 3- (S) -hydroxytetrahydrofuran can be obtained with high purity and high yield.

The reducing agent used is a borohydride compound and / or an aluminum hydride compound. Specific examples include alkali metal borohydride, alkaline earth metal borohydride, aluminum hydride alkali metal, dialkylaluminum hydride, diborane and the like, but are not limited thereto. Absent. These may be used alone or in combination of two or more. The alkali metal from which the reducing agent forms a salt is, for example, lithium, sodium or potassium, and the alkaline earth metal is calcium or magnesium. Of these, alkali metal borohydride is preferable and sodium borohydride is more preferable in terms of ease of handling and the like. Together with these reducing agents, commonly known activators can be used in combination to improve the reducing agent's reducing power.

The amount of the reducing agent to be used is not particularly limited, but an amount such that the hydrogen donation amount is more than the stoichiometric amount with respect to the 4-halo-3-hydroxybutyric acid ester (1) is preferable. For example, although sodium borohydride can also be implemented with 0.5 mol or more with respect to 1 mol of 4-halo-3-hydroxybutyric acid ester (1), Preferably it is 0.75 mol or more. In view of economy, the use of 10.0 mol or less is preferable, more preferably 5.0 mol or less, and still more preferably 2.0 mol or less.

The concentration of 4-halo-3-hydroxybutyric acid ester (1) in the reaction solution varies depending on the type of reaction solvent, and thus cannot be defined unconditionally. For example, it is generally 1 to 50% by weight, preferably 5 -40% by weight, more preferably 10-30% by weight.

The reaction temperature varies depending on the type of reducing agent and reaction solvent used, and thus cannot be defined unconditionally, but is usually a temperature in the range from the freezing point to the boiling point of the reaction solvent used. The reaction temperature is preferably 20 to 80 ° C., but is preferably 40 ° C. or more in order to allow the reaction to proceed efficiently and in particular to have a reaction time suitable for production on an industrial scale. On the other hand, in order to suppress side reactions and decomposition, it is important not to raise the reaction temperature too much. For example, it is preferable to perform the reaction at 80 ° C. or lower, preferably 60 ° C. or lower. The reaction time is usually up to about 24 hours.

The reduction reaction in the present invention is an exothermic reaction, and particularly involves an abrupt exotherm at the beginning of the reaction. Therefore, it is important to appropriately control the reaction so that it proceeds smoothly. From such a viewpoint, it is preferable to perform the reaction by sequentially adding 4-halo-3-hydroxybutyric acid ester (1) and / or the reducing agent or by adding them in portions. Specifically, the reaction may be carried out while adding either one of 4-halo-3-hydroxybutyric acid ester (1) and the reducing agent, or the reduction reaction may be carried out while simultaneously adding both compounds. it can. Generally, in order to carry out the reduction reaction simply and safely on an industrial scale, it is preferable to add a reducing agent to the solution of 4-halo-3-hydroxybutyric acid ester (1) sequentially. The time required for this addition is preferably 1 hour or more, more preferably 2 hours or more, and further preferably 5 hours or more.

The organic solvent that is incompatible with water used as a solvent in this reduction reaction is generally a mixture of pure water of the same volume at 20 ° C. under 1 atm even after the flow has stopped. An organic solvent having physical properties that give a non-uniform appearance. Although the solubility in water is not particularly limited, for example, an organic solvent that is generally 30% by weight or less, particularly 10% by weight or less is preferable, more preferably 5% by weight or less, and still more preferably 1% by weight or less. It is a solvent.

The organic solvent incompatible with the above water preferably has a boiling point of 40 ° C. or higher, more preferably 50 ° C. or higher. When a solvent having a boiling point of less than 40 ° C. is used, the reduction reaction temperature cannot be increased, resulting in a delay in the reaction time, and the reduction reaction is accompanied by a sudden exotherm, which easily causes bumping. It has been found that there are problems such as making it difficult to properly control the reaction. This is disadvantageous in terms of securing productivity and safety, which are particularly important in production on an industrial scale.

Specific examples of organic solvents that are preferably incompatible with water from such a viewpoint include aromatic hydrocarbons such as benzene, toluene, xylene, and ethylbenzene; methyl acetate, ethyl acetate, n-propyl acetate, and isopropyl acetate. Acetates such as n-butyl acetate, isobutyl acetate and tert-butyl acetate; aliphatic hydrocarbons such as hexane, cyclohexane and methylcyclohexane; halogenated hydrocarbons such as methylene chloride and chloroform; diisopropyl ether, methyl tert -Ethers such as butyl ether and ethylene glycol dibutyl ether can be mentioned. Of these, hydrocarbons (especially aromatic hydrocarbons) and acetate esters are preferable, and toluene and alkyl esters of 1 to 4 carbon atoms of acetic acid are more preferable. These organic solvents may be used alone or in combination of two or more. It is also preferable that the organic solvent incompatible with water is an aprotic organic solvent incompatible with water.

When the reduction reaction is carried out using the above-mentioned solvent, the by-product of impurities such as 3,4-epoxy-1-butanol (Japanese Patent Laid-Open No. 2-174733) known in the art is suppressed, and a high yield is achieved. 4-halo-1,3-butanediol (2) can be produced.

In the second step of the production method of the present invention, the reaction mixture obtained in the first step is treated with an acid and water to produce 4-halo-1,3-butanediol (2), It transfers to an aqueous phase and the aqueous solution containing this is acquired.
Although it does not specifically limit as an acid used here, From a practical point, a mineral acid is preferable and hydrochloric acid and a sulfuric acid are preferable especially. These may be used alone or in combination of two or more. In addition, as an acid and water, the aqueous solution obtained by diluting concentrated hydrochloric acid, concentrated sulfuric acid, etc. with water may be sufficient.

The amount of the acid used is an amount that can neutralize the basic component derived from the reducing agent used in the first step to form a neutral inorganic salt, and usually the same molar equivalent or more as the reducing agent. It is. It is preferable to adjust the reaction mixture to neutral to acidic conditions by using an acid having the same molar equivalent or more as the reducing agent.
The amount of water used is preferably such an amount that the obtained 4-halo-1,3-butanediol (2) can be sufficiently transferred to the aqueous phase.

The treatment of the reaction mixture obtained in the first step with acid and water is generally carried out by mixing the acid and water into the reaction mixture at the same time, but first by mixing with acid and then by mixing water. It can also be done. These mixing methods are not particularly limited, and an acid can be added to the reaction mixture, but it is also preferable to add the reaction mixture to the acid. These operations are preferably carried out at a low temperature, and it is desirable to carry out at a temperature from room temperature to freezing of the solvent.

In the production method of the present invention, an organic solvent that is not compatible with water is used in the first step. Therefore, when mixed with an acid and water, it is separated into two phases, and this aqueous solution can be used in the third step as it is. Moreover, the aqueous solution containing 4-halo-1,3-butanediol (2) can also be easily obtained by separating and removing the organic phase from here. Further, the yield can be further increased by extracting the separated organic phase with water.

In order to increase the yield, it is preferable to carry out the separation removal of the organic phase at a low temperature. Thereby, the transfer of 4-halo-1,3-butanediol (2) into the organic phase can be suppressed, and a decrease in yield can be prevented. The specific operation temperature is preferably 30 ° C. to a temperature until the solvent freezes, more preferably 20 ° C. or less, and still more preferably 10 ° C. or less.

It is preferable to separate and remove the organic phase in this way from the viewpoint of reducing impurities and by-products slightly present in the reaction mixture obtained in the first step. However, the organic phase may be removed by concentrating the organic phase to obtain an aqueous solution. In the aqueous solution obtained in this step, an organic phase may coexist in a range that does not adversely affect the cyclization reaction in the third step, and at this time, the organic phase and the aqueous phase may form two phases.

Next, in the third step, a cyclization reaction of 4-halo-1,3-butanediol (2) is performed in the aqueous solution obtained in the second step. The aqueous solution obtained in the second step coexists with the boron compound, aluminum compound and other inorganic salts produced by the decomposition of the reducing agent used in the first step. In this cyclization reaction, 3-hydroxytetrahydrofuran is present. (3) can be obtained in high yield.

Even if the cyclization reaction is carried out in a two-phase system in which the organic solvent coexists as it is without removing the organic solvent that is not compatible with water in the second step, the cyclization reaction proceeds smoothly and at a high yield. 3-hydroxytetrahydrofuran (3) can be obtained. This also has the effect of transferring impurities to the organic phase, reducing the concentration of impurities in the aqueous phase where the cyclization reaction proceeds substantially preferentially, suppressing side reactions, and reducing the amount of impurity by-products. . Furthermore, the cyclized product 3-hydroxytetrahydrofuran (3) is distributed into an organic solvent phase that is incompatible with water compared to the compound 4-halo-1,3-butanediol (2) before cyclization. Since the rate is generally low, even if the organic phase is separated and removed after the cyclization reaction, there is little loss of the target product to the organic phase, which is advantageous in that a higher yield can be obtained.

The operation temperature during the cyclization reaction is not particularly limited. The cyclization reaction proceeds even near room temperature. However, in order to increase the reaction rate and complete the reaction in a short time, it is desirable to perform the reaction by heating to room temperature or higher. That is, the cyclization reaction is preferably performed at 40 ° C. or higher, more preferably 50 ° C. or higher, and further preferably 70 ° C. or higher. In general, it is advantageous to increase the temperature to the vicinity of the boiling point of the reaction system to be used.

This cyclization reaction is preferably carried out under acidic to neutral conditions. Although the cyclization reaction proceeds even under basic conditions, it is generally not preferable because impurities are easily produced as a by-product. Therefore, in general, it is preferable to start the reaction from neutral to acidic conditions. However, the reaction solution is gradually acidified by an acid component (for example, hydrogen halide) generated as the cyclization reaction proceeds. If the acidity is too strong, impurities are easily produced as a by-product, and therefore, for example, it is more preferable to start the cyclization reaction from neutral conditions in order to reduce the adverse effect of the acid component. In this case, the by-product of 2,5-dihydrofuran [Liebigs-Analen / Requigs (Liebigs), which is an impurity easily generated as a by-product when the cyclization reaction is started under the strong acid conditions known in the past. Ann./Recl.) 1877 (1997)], and 3-hydroxytetrahydrofuran (3) can be obtained in a higher yield.

More preferably, from the viewpoint of minimizing the adverse effects of the acid during the cyclization reaction, the acid component (for example, hydrogen halide) generated with the progress of the reaction is neutralized with a base while maintaining an appropriate acidity. However, 3-hydroxytetrahydrofuran (3) can be produced with the highest yield and quality by carrying out the cyclization reaction under mildly acidic to neutral conditions. The appropriate acidity in this case varies depending on the operating temperature and concentration of the cyclization reaction, and the type and amount of the coexisting inorganic salt and the like, but cannot be defined unconditionally, but is preferably pH 2-7, more preferably It is preferable to carry out the reaction while neutralizing the acid component in the range of pH 2-6.

Although it does not specifically limit as a base used in order to neutralize the said acid component, For example, inorganic bases, such as a hydroxide of an alkali metal or an alkaline-earth metal, carbonate, and hydrogencarbonate; Secondary amine, 3 Mention may be made of organic bases such as quaternary amines and quaternary ammonium hydroxides. Specifically, for example, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, and lithium carbonate; sodium bicarbonate, potassium bicarbonate, etc. Alkaline metal hydrogen carbonates; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; alkaline earth metal carbonates such as calcium carbonate and barium carbonate; 2 such as dimethylamine, diethylamine, diisopropylamine and dicyclohexylamine Tertiary amines; tertiary amines such as triethylamine, tripropylamine, tributylamine, triallylamine, pyridine, N-methylmorpholine; tetramethyl, tetraethyl, tetrapropyl, tetrabutyl, tetraamyl, tetrahexyl, benzyltrimethyl Re respectively include quaternary ammonium hydroxides or the like of, but not limited thereto. Of these bases, from the viewpoints of being inexpensive, easy handling, wastewater treatment, etc., inorganic bases, particularly alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide are preferred, In particular, sodium hydroxide and potassium hydroxide are preferable.

The inorganic base is preferably used as an aqueous solution from the viewpoint of operability. For example, it is advantageous to use it as an aqueous solution of 2-20N, preferably 5-20N alkali metal hydroxide. In addition, the said base may be used independently and may be used together 2 or more types. These bases can be reacted while being sequentially added at a rate that maintains the reaction solution at an appropriate pH, but they can also be added by adding sodium carbonate, barium carbonate, calcium carbonate, disodium hydrogen phosphate, or the like. It is also possible to utilize the pH buffering property of

The concentration in the 4-halo-1,3-butanediol (2) aqueous solution at the time of carrying out the cyclization reaction is not particularly limited. However, if the concentration is too high, the reaction rate decreases, which is not preferable. Generally, it is 1 to 50% by weight, preferably 1 to 35% by weight, and more preferably 1 to 20% by weight. Further, as described above, by performing the cyclization reaction while maintaining an appropriate acidity, the reaction concentration can be further increased without reducing the reaction rate, for example, 1 to 30% by weight, preferably 5%. The cyclization reaction can be suitably performed at a concentration of ˜30% by weight.

When 3-hydroxytetrahydrofuran (3) is used in a field where it is desired to improve the quality by reducing a few impurities, such as pharmaceutical production, the aqueous solution obtained from the third step is compatible with water. It is also preferred to wash with no organic solvent. This has the effect of reducing the impurities slightly contained in the aqueous phase and improving the quality of the resulting 3-hydroxytetrahydrofuran (3).

When the cyclization reaction is carried out in a two-phase system in which an organic solvent incompatible with water coexists, the organic phase is separated and removed after the cyclization reaction to separate an aqueous solution of 3-hydroxytetrahydrofuran (3). By simply doing this, it is possible to improve the quality by reducing impurities from the aqueous phase.

These operations (washing and removal of the organic phase separation) are preferably carried out at a low temperature. Thereby, the distribution rate to the organic phase of 3-hydroxytetrahydrofuran (3) can be reduced, the loss to an organic phase can be reduced, and a yield can be raised. Specifically, the operation is preferably performed at a temperature of 30 ° C. or lower, more preferably 20 ° C. or lower, and even more preferably 10 ° C. or lower, until the solvent freezes.

In the fourth step, 3-hydroxytetrahydrofuran (3) is extracted from the aqueous solution containing 3-hydroxytetrahydrofuran (3) obtained in the third step using an organic solvent incompatible with water. By this extraction operation, the inorganic salt coexisting in the aqueous solution, the boron compound and the aluminum compound derived from the reducing agent are separated from the target product, and an organic solution of 3-hydroxytetrahydrofuran (3) can be obtained.

The organic solvent incompatible with water used here is not particularly limited. For example, it can be selected from organic solvents incompatible with water used in the above-described reduction reaction, but in addition to these, Monohydric alcohols having 4 to 8 carbon atoms such as butanols such as 1-butanol, 2-butanol and isobutanol can be used. Preferably, they are aromatic hydrocarbons, acetate esters, or monohydric alcohols having 4 to 8 carbon atoms, more preferably acetate esters. Among them, alkyl esters of acetic acid having 1 to 4 carbon atoms. Is more preferable, and ethyl acetate is particularly preferable. These organic solvents may be used alone or in combination of two or more.

The aqueous solution obtained in the third step is generally acidified, but may be extracted while maintaining the acidic condition, or may be extracted after neutralization with a base. In general, the extraction operation is preferably carried out under neutral conditions. The base used in the neutralization is not particularly limited. For example, alkali hydroxide metal salts such as sodium hydroxide and potassium hydroxide; alkaline earth metal salts such as calcium hydroxide and magnesium hydroxide; Examples thereof include alkali metal hydrogen carbonates such as sodium hydrogen and potassium hydrogen carbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate. In addition, organic bases such as ammonia water, amines such as triethylamine and pyridine may be used. These may be used alone or in combination of two or more.

It is also preferable that the aqueous solution obtained in the third step is once basified with a base and then neutralized with an acid and extracted. This can improve the purity of the extracted target product by converting impurities contained therein into impurities that are easily transferred to the aqueous phase, and making the impurities easily remain in the aqueous phase after extraction after neutralization. . This basification can be performed using, for example, the above base. In order to enhance the treatment effect, the pH is preferably 10 or more, more preferably pH 12 or more, but is not limited thereto. These operations can be carried out at a temperature higher than the temperature at which the solvent freezes, but the temperature can be raised in the range of room temperature to the boiling point of the solvent to shorten the treatment time. The treatment time depends on pH and temperature, but is generally about 0.1 to 24 hours. After the base treatment, the aqueous phase is preferably neutralized and extracted.

Although the operation temperature of extraction in the fourth step varies depending on the type of organic solvent used, it cannot be defined unconditionally, but it can be carried out below the boiling point from the freezing point of the solvent used. Generally, the temperature is 20 to 100 ° C., but extraction at a high temperature is particularly preferable. That is, an extraction operation at 40 ° C. or higher is preferable, more preferably 50 ° C. or higher, and further preferably 60 ° C. or higher. In particular, for example, when hydrocarbons or acetates are used as the solvent, extraction at a high temperature is desirable to increase extraction efficiency.

When the above-mentioned monohydric alcohol having 4 to 8 carbon atoms is used as a solvent, a high extraction effect can be obtained even near room temperature. However, it is also possible to increase the extraction temperature by increasing the liquid temperature. Specifically, extraction can be performed using monohydric alcohols having 4 to 8 carbon atoms at a temperature of 40 ° C. or higher.

In the fifth step, 3-hydroxytetrahydrofuran (3) is isolated by concentrating and / or distilling the extracted solution obtained in the fourth step. That is, the 3-hydroxytetrahydrofuran (3) is isolated by concentrating the extract to remove the organic solvent or by distilling the extract (including rectification). Further, after the extract is concentrated to remove the solvent, 3-hydroxytetrahydrofuran (3) may be isolated by further distillation (including rectification). In this case, the residue after concentration can be distilled as it is under reduced pressure.

When purifying and isolating 3-hydroxytetrahydrofuran (3) by distillation (including rectification), boron compounds such as reducing agent-derived substances slightly mixed in the extract obtained in the fourth step And the distillation yield may decrease due to aluminum compounds. Therefore, in order to increase the final distillation yield to the limit, in performing the distillation in the fifth step, the solution and / or concentrate of 3-hydroxytetrahydrofuran (3) is treated with alcohols. These are preferably removed beforehand. For example, when a monohydric alcohol having 1 to 3 carbon atoms such as methanol or ethanol is added, a compound having a lower boiling point than 3-hydroxytetrahydrofuran (3) can be formed and distilled off first. On the other hand, when a polyhydric alcohol having 6 or more carbon atoms such as polyethylene glycol or sorbitol is added, a compound having a boiling point higher than that of 3-hydroxytetrahydrofuran (3) can be formed and left. This step can be suitably used when 3-hydroxytetrahydrofuran in which the above boron compound or aluminum compound is mixed is purified and isolated.

The amount of these alcohols to be used varies depending on the type of alcohol used and the type and amount of the reducing agent-derived substance mixed in, but it is not unconditionally specified. Use at least the same molar equivalent as the amount of contamination. In addition, it may be used in excess relative to the amount of the reducing agent-derived substance mixed. Especially when monohydric alcohols having 1 to 3 carbon atoms are used, the treatment effect is considered in consideration of the influence of coexisting moisture. It is preferable to use it excessively to enhance it. Specifically, for example, in monohydric alcohols having 1 to 3 carbon atoms, the content is 50% by weight or more, more preferably the same weight or more with respect to 3-hydroxytetrahydrofuran (3). In the case of polyhydric alcohols having 6 or more carbon atoms, the treatment is performed using 20% by weight or more, more preferably 30% by weight or more. By the above, the coexisting boron compound and / or aluminum compound can be effectively reduced and removed, but the residual amount of the boron compound and / or aluminum compound after treatment is 10 mol% or less of 3-hydroxytetrahydrofuran. More preferably, it is 5 mol% or less. Thereby, distillation can be favorably implemented by increasing the distillation yield to the limit.

When purifying 3-hydroxytetrahydrofuran (3) by distillation (including rectification) on an industrial scale, since a long heating operation is required, for example, 4-halo- which is slightly contained as an impurity The 3-hydroxyacetic acid ester (1), 4-halo-1,3-butanediol (2) and their related impurities are gradually subjected to thermal decomposition, and the resulting decomposition product contains the desired product during distillation. It tends to cause problems such as mixing in the fraction and lowering the quality. It was also found that these thermal decompositions accompanied by the release of acid components showed a tendency of acidification to proceed and thermal decomposition to be promoted. From such a viewpoint, for example, it is also preferable to use an apparatus capable of performing distillation while suppressing thermal decomposition by reducing thermal history, such as a thin film distillation apparatus.

However, in the case of performing distillation using a general-purpose general distillation apparatus, for example, when performing distillation, an acid is added to the solution and / or concentrate of 3-hydroxytetrahydrofuran (3) to perform the treatment. It is also preferable to heat treatment after the acid addition to promote thermal decomposition in advance before distillation. This contributes to the stable enhancement of the distillation purification effect by suppressing the by-product of new impurities during the distillation operation. It is also preferable to use a solvent for this acid treatment. For example, it is also preferable to carry out distillation after acid treatment as a solution of monohydric alcohols having 1 to 3 carbon atoms.

The type of acid to be added is not particularly limited, and inorganic acids and organic acids can be used. From the viewpoint of practicality, inorganic acids are preferable, and hydrochloric acid and sulfuric acid are particularly preferable. These may be used alone or in combination of two or more. The amount of acid used is not particularly limited, but is preferably 0.1% by weight or more of 3-hydroxytetrahydrofuran (3), more preferably 0.2% by weight or more, and further preferably 0.5% by weight or more. is there. Although the operating temperature in the case of heat-processing by adding an acid is not specifically limited, For example, it is below the boiling point of the system used from room temperature. The acid treatment time is usually 0.1 hour or longer, preferably 0.5 hour or longer.

It is also preferable to carry out the purification (including rectification) of 3-hydroxytetrahydrofuran (3) in the presence of a base. This has the effect of neutralizing the acid component released by thermal decomposition of the coexisting impurities as described above and enhancing the distillation purification effect while suppressing the influence of the acid component. Furthermore, it contributes to increasing the thermal stability of 3-hydroxytetrahydrofuran (3). By performing distillation (including rectification) purification in this manner, the quality and yield of the target product can be increased.

Although the base used in this case is not particularly limited, a base having a boiling point higher than that of 3-hydroxytetrahydrofuran (3) is preferable, and an inorganic base is more preferable. Specifically, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide and magnesium hydroxide; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate Examples thereof include salts; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as magnesium carbonate and calcium carbonate. Alkali metal hydrogen carbonates and alkali metal carbonates are preferable, and alkali metal hydrogen carbonates, particularly sodium hydrogen carbonate, are particularly preferable. These may be used alone or in combination of two or more. The amount of these bases used is not particularly limited, and is generally 0.1 to 30% by weight of the distillate, but is preferably 10% by weight or less, more preferably from the viewpoint of economy and operability. Is 5% by weight or less, more preferably 2% by weight or less.

Here, a preferred embodiment of the present invention will be described when ethyl 4-chloro-3- (S) -hydroxybutyrate is used as the reaction substrate.
Ethyl 4-chloro-3- (S) -hydroxybutyrate is reduced in toluene using sodium borohydride and mixed with aqueous hydrochloric acid to form an aqueous solution of 4-chloro-1,3- (S) -butanediol. To get. The aqueous solution is heated as it is to carry out the cyclization reaction. Preferably, the cyclization reaction is carried out while appropriately neutralizing the acid component generated in the reaction, and this is extracted with ethyl acetate under heating. Concentrate and / or distill to obtain 3- (S) -hydroxytetrahydrofuran.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited to these examples. The analysis was performed by liquid chromatography (column: ALLTIMA C8 5 μm, φ4.6 mm × 250 mm, column temperature: 30 ° C., mobile phase: acetonitrile / distilled water [3/97], detection: RI), and gas chromatography. (Column: PEG20M 10% Chromosorb WAW, φ3.2 mm × 3.1 m, column temperature: 130 ° C., detection: FID).

Example 1
104.1 g of sodium borohydride was suspended in 2300 mL of toluene, and 458.5 g of ethyl 4-chloro-3- (S) -hydroxybutyrate (optical purity 99.4% ee) was stirred for 1 hour while stirring at 40 ° C. The mixture was further stirred and allowed to react for about 20 hours. The reaction mixture was cooled to 10 ° C. or lower, and 286.7 g of concentrated hydrochloric acid and 940 ml of water were added and stirred. The pH was adjusted to 7.0 ± 0.2 using 88.6 g of 30% aqueous sodium hydroxide, and after standing, the toluene phase was removed by separation to give 4-chloro-1,3- (S) -butanediol. An aqueous phase containing 321.8 g (94% yield) was obtained.

When this aqueous phase was heated to 74 ° C., the pH became 2 or less in about 2 hours, and then further reacted at 74 to 90 ° C. for 20 hours. The mixture was cooled to 10 ° C. or lower, adjusted to pH 7.0 ± 0.2 using 327 g of 30% aqueous sodium hydroxide solution, heated to 70 ° C., continuously extracted at 70 ° C. with 2 L of ethyl acetate, and A vacuum concentration operation was performed. 460 g of methanol was added to the obtained residue, and after concentration, the residue was distilled under reduced pressure to obtain 198.8 g of colorless 3- (S) -hydroxytetrahydrofuran (yield 87%, overall yield 82%). Purity 99% or more, optical purity 99% or more.

Example 2
22.0 g of sodium borohydride was suspended in 528 ml of ethyl acetate, 96.8 g of ethyl 4-chloro-3-hydroxybutyrate was added over 1 hour with stirring at 50-60 ° C., and stirring was continued for about 2 Reacted for hours. The reaction mixture was cooled to 10 ° C. or lower, and 60.5 g of concentrated hydrochloric acid and 100 ml of water were added and stirred well. The pH was adjusted to 7.0 ± 0.2 using 26.1 g of a 30% aqueous sodium hydroxide solution, and after standing, the ethyl acetate phase was separated. The ethyl acetate phase was extracted with 50 ml of water and mixed with the aqueous phase to obtain an aqueous phase containing 66.6 g of 4-chloro-1,3-butanediol (yield 92%).

Example 3
When 192.5 g (concentration 20.0 wt%) of an aqueous phase containing 38.5 g of 4-chloro-1,3- (S) -butanediol obtained according to Example 1 was heated to 70 ° C., it took about 1 hour. The pH became 4, and thereafter, the pH of the reaction mixture was maintained at 4 while successively dropping a 30% aqueous sodium hydroxide solution and reacted at 70 to 90 ° C. for 20 hours. The obtained reaction mixture was cooled to 10 ° C. or lower and adjusted to pH 7.0 ± 0.2 using a 30% aqueous sodium hydroxide solution to obtain 222.5 g of an aqueous solution. This aqueous solution contained 11.5% by weight (25.7 g, yield 95%) of 3- (S) -hydroxytetrahydrofuran.

Example 4
In the same manner as in Example 3, the reaction was carried out while adjusting the pH of the reaction mixture to the pH shown in Table 1, and the yield of 3- (S) -hydroxytetrahydrofuran (3) produced and the remaining 4-chloro- The residual ratio of 1,3-butanediol (2) was determined, and the influence of pH in the cyclization reaction was examined. The results are shown in Table 1.

Example 5
144.7 g of ethyl 4-chloro-3- (S) -hydroxybutyrate (optical purity 99.4% ee) was dissolved in 720 mL of toluene, and 32.9 g of sodium borohydride was stirred for 10 hours at 45 ° C. The mixture was further added and stirred for about 5 hours. The reaction mixture was cooled to 20 ° C. or lower, added to a mixture of 90.5 g of concentrated hydrochloric acid and 215 ml of water cooled to 5 ° C. or lower, and stirred. Water and toluene containing 104.0 g of 4-chloro-1,3- (S) -butanediol (yield 96%) adjusted to pH 7.0 ± 0.2 using 38 g of 30% aqueous sodium hydroxide solution A liquid mixture was obtained.

When this mixture is heated to 85 ° C., the pH becomes 4 in about 1 hour, and then the pH of the reaction mixture is maintained at 4 ± 0.5 while successively dropping a 30% aqueous sodium hydroxide solution, and at the same temperature, 20 ° C. When reacted for a period of time, the residual ratio of 4-chloro-1,3- (S) -butanediol was 0.8%. The mixed solution cooled to 10 ° C. or lower was adjusted to pH 7.0 ± 0.2 using 100 g of 30% aqueous sodium hydroxide solution, and allowed to stand, and then the toluene phase was separated and removed. The obtained aqueous phase was heated to about 68 ° C., extracted continuously at 68 ° C. using 1 L of ethyl acetate, and concentrated under reduced pressure. To the residue, 80 g of methanol was added and concentrated under reduced pressure. 80 g of methanol and 0.8 g of concentrated hydrochloric acid were added to the residue, and the mixture was heated to reflux for about 2 hours. The solvent was concentrated under reduced pressure, 1.2 g of sodium bicarbonate was added to the resulting residue, and rectified under reduced pressure to give 60.9 g of colorless 3- (S) -hydroxytetrahydrofuran (yield 83%, total yield). 80%). Purity 99% or more, optical purity 99% or more.

Example 6
According to Example 1, a 3-hydroxytetrahydrofuran aqueous solution after completion of the cyclization reaction was obtained. 10 ml of each solvent shown in Table 2 was added to 10 g of this aqueous solution, stirred for 10 minutes at each temperature, allowed to stand for 10 minutes, and then separated to obtain an extraction rate, and the relationship between the extraction temperature and the extraction rate was examined. The results are shown in Table 2.

Example 7
According to Example 1, the ethyl acetate extract of 3-hydroxytetrahydrofuran was concentrated to obtain a residue. A predetermined amount of alcohol shown in Table 3 was added to 10 g of the residue and distilled, and the amount of boric acid remaining after the added methanol was evaporated and further distilled to determine the distillation recovery rate. The effect of alcohol was investigated. The results are shown in Table 3. In the table, PEG 300 represents polyethylene glycol having an average molecular weight of 300. The amount of boric acid present was measured by a neutralization titration method as a monobasic acid in the presence of sorbitol. (New Experimental Chemistry Course 9 Analytical Chemistry I published by Maruzen Co., Ltd.)
(Method) A precisely weighed sample was dissolved in 25 ml of distilled water to adjust the pH to 7, and a solution obtained by adding several drops of phenolphthalein indicator and about 5 g of sorbitol was dissolved in a 0.1N sodium hydroxide aqueous solution. Titration was carried out until a slight red color was observed, and the amount of boric acid was quantified from a calibration curve prepared in advance using a predetermined amount of boric acid.

Example 8
10 g of methanol concentrate of 3- (S) -hydroxytetrahydrofuran obtained according to Example 5 was heated to 120 ° C. and residual 3- (S) -hydroxytetrahydrofuran with and without addition of 0.2 g of sodium bicarbonate. The rate was determined over time to examine the effect of base addition. The results are shown in Table 4.

Claims (9)

General formula (2):

Formula (3) is obtained by cyclizing 4-halo-1,3-butanediol represented by the formula (wherein X represents a halogen atom) in an aqueous solution:

A process for producing 3-hydroxytetrahydrofuran represented by:
The manufacturing method characterized by implementing cyclization reaction on weakly acidic-neutral conditions. The method according to claim 1, wherein the cyclization reaction is performed at a temperature of 40 ° C or higher. The production method according to claim 2, wherein the cyclization reaction is carried out by raising the temperature to near the boiling point of the reaction system. The production method according to claim 1, 2 or 3, wherein the cyclization reaction is carried out while maintaining the pH at 2 to 7 while neutralizing the generated acid component. The production method according to any one of claims 1 to 4, wherein the cyclization reaction is carried out in a two-phase system in which an organic solvent incompatible with water coexists. The method according to claim 5, wherein the organic phase is separated and removed after the cyclization reaction to separate an aqueous solution of 3-hydroxytetrahydrofuran (3). The method according to claim 6, wherein the separation of the organic phase is performed at 30 ° C or lower. The manufacturing method of any one of Claims 1-7 which wash | cleans the aqueous solution of 3-hydroxy tetrahydrofuran (3) obtained after cyclization reaction with the organic solvent incompatible with water. The manufacturing method according to claim 8, wherein the cleaning is performed at 30 ° C. or lower.