Method for producing 3-hydroxy-γ-butyrolactone

Abstract

To provide a method for producing 3-hydroxy-γ-butyrolactone that suppresses the formation of impurities and allows improved yield .SOLUTION: The present invention discloses a method for producing 3-hydroxy-γ-butyrolactone represented by formula (2) by subjecting 4-halogeno-3-hydroxybutyric acid ester represented by formula (1) to a cyclization reaction in a medium containing water, the method including a pH adjustment step for adjusting the pH of a reaction liquid after the start of and before the finish of the cyclization reaction. In the formula, X is a halogen atom, and R is an ester-based protecting group.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing 3-hydroxy-γ-butyrolactone. [Background technology]

[0002] 3-Hydroxy-γ-butyrolactone is useful, for example, as a raw material for monomers of resist polymers used in the semiconductor manufacturing field. In addition, optically active 3-hydroxy-γ-butyrolactone is useful as an intermediate for pharmaceuticals, agricultural chemicals, etc.

[0003] Patent Document 1 describes a method for producing 3-hydroxy-γ-butyrolactone by subjecting ethyl 4-chloro-3-hydroxybutyrate to a cyclization reaction. The examples in Patent Document 1 describe a process in which an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution is added to ethyl 4-chloro-3-hydroxybutyrate, the mixture is heated to reflux, neutralized with caustic soda solution, water is distilled off under reduced pressure, ethyl acetate is added to the mixture of remaining crystals and oil and the mixture is stirred, the crystals are separated by filtration, and the filtrate is concentrated under reduced pressure to produce 3-hydroxy-γ-butyrolactone. Patent Document 2 describes an example in which ethyl 4-chloro-3-hydroxybutyrate is subjected to a cyclization reaction in an aqueous solvent without adding an acid to produce 3-hydroxy-γ-butyrolactone. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 3855033 [Patent Document 2] International Publication No. 2002 / 26725 Summary of the Invention [Problem to be solved by the invention]

[0005] In the production of 3-hydroxy-γ-butyrolactone, it is desirable to have a high yield and to produce a small amount of impurities. The present invention provides a method for producing 3-hydroxy-γ-butyrolactone, which can suppress the formation of impurities and improve the yield. [Means for solving the problem]

[0006] The present invention has the following aspects. [1] A method for producing 3-hydroxy-γ-butyrolactone represented by the following formula (2) by subjecting a 4-halogeno-3-hydroxybutyric acid ester represented by the following formula (1) to a cyclization reaction in a medium containing water, the method comprising the step of adjusting the pH of the reaction solution after the initiation and before the completion of the cyclization reaction. In formula (1), X represents a halogen atom, and R represents an ester-type protecting group.

[0007] [ka] [2] The method according to [1], further comprising an alcohol removing step of removing an alcohol by-produced in the cyclization reaction after the initiation of the cyclization reaction and before the pH adjustment step. [3] The method according to [1] or [2], wherein in the pH adjustment step, the pH of the reaction solution is adjusted to 0.5 to 5.5. [4] The method according to any one of [1] to [3], wherein an alkaline compound is added to the reaction solution in the pH adjustment step. Effect of the Invention

[0008] According to the method for producing 3-hydroxy-γ-butyrolactone of the present invention, the production of impurities can be suppressed and the yield can be improved. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The production method of this embodiment (hereinafter also simply referred to as "this production method") is a method for producing 3-hydroxy-γ-butyrolactone (hereinafter also referred to as "target compound") represented by the following formula (2) by cyclizing a 4-halogeno-3-hydroxybutyric acid ester (hereinafter also referred to as "starting compound") represented by the following formula (1).

[0010] [ka]

[0011] In formula (1), X represents a halogen atom. Examples of the halogen atom include a chlorine atom, a bromine atom, and an iodine atom. A chlorine atom is preferred. In formula (1), R represents an ester-type protecting group. In this specification, the term "ester-type protecting group" refers to a group capable of protecting a carboxylic acid as an ester. Examples of ester-type protecting groups include alkyl groups having 1 to 10 carbon atoms, aryl groups having 6 to 20 carbon atoms, aralkyl groups having 7 to 20 carbon atoms, and silyl-based protecting groups. Specific examples include methyl groups, ethyl groups, n-propyl groups, isopropyl groups, n-butyl groups, isobutyl groups, tert-butyl groups, phenyl groups, benzyl groups, α-methylbenzyl groups, phenylpropyl groups, trimethylsilyl groups, tert-butyldimethylsilyl groups, and groups in which these groups are partially substituted with a substituent. Examples of the substituent include halogen atoms, nitro groups, hydroxyl groups, ether groups, and amide groups. R is preferably a hydrocarbon group, more preferably an alkyl group, and is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, or a tert-butyl group, more preferably an ethyl group. The 4-halogeno-3-hydroxybutyric acid ester used in this production method may be either the (R)- or (S)-optical isomer, and these may be used in combination.

[0012] In this production method, the cyclization reaction of the 4-halogeno-3-hydroxybutyric acid ester is carried out in a medium containing water. Specifically, raw material compounds are added to the medium to prepare a raw material composition, and the raw material composition is heated to initiate the cyclization reaction. After the initiation of the cyclization reaction and before its completion, the pH of the reaction solution is adjusted (pH adjustment step). When an alcohol is produced as a by-product in the cyclization reaction, it is preferable to remove the by-product alcohol before the pH adjustment step (alcohol removal step). When the alcohol removing step is carried out, the period from the start of the cyclization reaction to before the alcohol removing step is defined as the first reaction step, and the period from after the pH adjustment step to before the end of the cyclization reaction is defined as the second reaction step. When the alcohol removal step is not performed, the first reaction step is from the start of the cyclization reaction to before the pH adjustment step, and the second reaction step is from after the pH adjustment step to before the end of the cyclization reaction.

[0013] The medium may contain a water-soluble organic solvent in addition to water. Examples of water-soluble organic solvents include ketone solvents such as acetone and methyl ethyl ketone, ether solvents such as dioxane and tetrahydrofuran, alcohol solvents such as methanol, ethanol and isopropanol, and nitrile solvents such as acetonitrile. The ratio of water to the medium is preferably 30% by mass or more, more preferably 60% by mass or more, and particularly preferably 100% by mass. The content of the medium in the raw material composition is preferably 1 to 10 times by weight, and more preferably 2 to 6 times by weight, the amount of the 4-halogeno-3-hydroxybutyric acid ester.

[0014] It is preferable to add the acidic compound to the raw material composition before the initiation of the cyclization reaction. For example, it is preferable to prepare a raw material composition by adding the raw material compound to an aqueous solution of an acidic compound in which the acidic compound is dissolved in a medium containing water, and to heat the raw material composition to initiate the cyclization reaction. In this specification, an acidic compound refers to a compound whose 0.5 M aqueous solution has a pH of 6.0 or less at 20° C. Specific examples include hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, perchloric acid, phosphoric acid, acetic acid, propionic acid, butyric acid, isobutyric acid, crotonic acid, acrylic acid, methacrylic acid, oxalic acid, succinic acid, phthalic acid, benzoic acid, tartaric acid, lactic acid, glycolic acid, potassium hydrogen oxalate, potassium hydrogen tartrate, potassium hydrogen phthalate, ammonium chloride, trimethylamine hydrochloride, and the like. From the viewpoint of easiness in shortening the reaction time, compounds having a pH of 2.0 or less are preferred, and examples of suitable compounds include hydrochloric acid and sulfuric acid. From the viewpoint of ease of suppressing impurities, compounds having a pH of more than 2.0 and not more than 5.0 are preferred, and examples of suitable compounds include acetic acid and ammonium chloride. The content of the acidic compound in the raw material composition is preferably 0.05 to 2.0 molar equivalents, and more preferably 0.1 to 1.0 molar equivalents, relative to the 4-halogeno-3-hydroxybutyric acid ester. The pH of the aqueous acidic compound solution at 20° C. (hereinafter also referred to as “initial pH”) is preferably from 0 to 6.0, more preferably from 0 to 5.0.

[0015] (First reaction step) The reaction temperature in the first reaction step is preferably 40 to 150° C., more preferably 70 to 120° C. The cyclization reaction may be carried out while heating up to the boiling point of the medium and refluxing. In the first reaction step, the target compound is produced, and an acid component (HX) is also produced as a by-product, and further, when R is a hydrocarbon group, an alcohol (ROH) is produced as a by-product. In addition, the reaction solution after the start of the cyclization reaction may contain, in addition to the target compound, one or more selected from the group consisting of impurities, unreacted raw material compounds, and intermediates. In the cyclization reaction of 4-halogeno-3-hydroxybutyric acid ester, γ-crotonolactone represented by the following formula (3) may be generated as an impurity.

[0016] [ka]

[0017] In the first reaction step, it is preferable to carry out the cyclization reaction until the yield (intermediate yield) of the target compound obtained by the measurement method described below is 10% or more. Specifically, the yield (intermediate yield) at the end of the first reaction step is preferably 10 to 60%, more preferably 20 to 50%. If the intermediate yield is equal to or greater than the lower limit of the above range, it is easy to shorten the reaction time in the second reaction step, and if it is equal to or less than the upper limit, it is easy to suppress the generation of impurities.

[0018] (Alcohol removal process) When the ester-type protecting group R in the starting compound is a hydrocarbon group, it is preferable to remove the alcohol (ROH) by-produced in the cyclization step during the cyclization step. In the alcohol removal step, at least a portion of the alcohol contained in the reaction solution is removed. It is preferable to remove a larger amount of alcohol, and it is also possible to remove all of the alcohol in the reaction solution. For example, the alcohol in the reaction solution is removed by concentrating the reaction solution under reduced pressure to remove a portion of the reaction solution. The amount of the reaction solution removed by concentrating the reaction solution under reduced pressure is, for example, preferably 1 to 10 times by weight, more preferably 2 to 8 times by weight, the amount of the alcohol in the reaction solution. In this process, the reaction time can be shortened by removing the alcohol during the cyclization step. In particular, by carrying out the alcohol removal step before the pH adjustment step, the production of the intermediate is promoted and the yield is improved.

[0019] (pH adjustment process) The pH adjustment step is a step for varying the pH of the reaction solution in addition to the change in pH that accompanies an increase in the acid components produced as by-products in the cyclization reaction. The pH is preferably adjusted by adding an alkaline compound to the reaction solution. In this specification, an alkaline compound refers to a compound whose 5% by mass aqueous solution has a pH of 8.0 or higher at 20° C. Specific examples include alkali metal hydroxides (sodium hydroxide, etc.), carbonates (sodium carbonate, potassium carbonate, etc.), and bicarbonates (sodium bicarbonate, etc.).

[0020] In the pH adjustment step, the pH of the reaction solution at 20°C is preferably adjusted to 0.5 to 5.5. The pH is more preferably 1.0 to 4.5, and even more preferably 1.5 to 4.5. When the pH is equal to or higher than the lower limit of the above range, the yield is improved and the impurity formation is inhibited. When the pH is equal to or lower than the upper limit, the impurity formation is inhibited. In particular, when the pH is 4.5 or less, the yield is improved. The temperature of the reaction solution in the pH adjustment step is not particularly limited, and may be the temperature at the end of the immediately preceding step.

[0021] (Second reaction step) In the second reaction step, the reaction solution whose pH has been adjusted in the pH adjustment step is heated to carry out a cyclization reaction. The reaction temperature in the second reaction step is preferably 40 to 150° C., more preferably 70 to 120° C. The cyclization reaction may be carried out while heating to the boiling point of the medium and refluxing. The reaction time in the second reaction step is not particularly limited, and is preferably 0.5 to 24 hours, more preferably 1 to 10 hours. When the desired yield is reached, the reaction is terminated by lowering the temperature of the reaction solution, for example by allowing the reaction solution to cool to room temperature.

[0022] The target compound can be isolated and purified from the reaction mixture after the cyclization reaction by a known method. For example, an alkali such as sodium hydroxide or sodium carbonate is added to the reaction solution to neutralize it, and the medium is then distilled off under reduced pressure to obtain a neutralized solution containing the target compound and a salt. To this neutralized solution, one or more organic solvents capable of dissolving the target compound are added to precipitate the salt, the precipitate is filtered off, and the filtrate is concentrated under reduced pressure to obtain the crude target compound. This procedure can be repeated several times for purification to obtain a purified product of the target compound. EXAMPLES

[0023] The present invention will be described in more detail below using examples, but the present invention is not limited to these examples. The reaction was monitored by gas chromatography, and the yield and impurity formation ratio were calculated from the peak area ratio according to the following formula. Yield (%) = target compound / (unreacted raw material compound + intermediate + target compound + impurities) x 100 Impurity generation ratio (%) = impurity / target compound x 100

[0024] In the following Examples 1 to 12, ethyl (S)-4-chloro-3-hydroxybutyrate (X in formula (1) is a chlorine atom, and R is an ethyl group) was used as the raw material compound. In Examples 1 to 12, the yield and impurity formation ratio were calculated from the following peak areas. Raw material compound: Peak area of ​​(S)-ethyl 4-chloro-3-hydroxybutyrate Target compound: (S)-3-hydroxy-γ-butyrolactone peak area Impurity: γ-crotonolactone peak area Intermediate: (S)-4-chloro-3-hydroxybutyric acid peak area

[0025] Example 1 is a comparative example in which the pH adjustment step was not performed, and Example 2 , 3 is a reference example, and Example 4 ~12 are examples. Examples 1 to 8 are examples in which hydrochloric acid was added as an acidic compound to the raw material composition, and Examples 9 to 12 are examples in which acetic acid was added.

[0026] <Example 1> A raw material composition was prepared by adding 15.59 g (150 mmol) of 35% hydrochloric acid, 131 mL of water, and 30.0 g (180 mmol) of ethyl (S)-4-chloro-3-hydroxybutyrate to a glass flask equipped with a thermometer, a condenser, and a stirrer. The raw material composition was stirred at 90° C. for 20 minutes (first reaction step). The resulting reaction solution was analyzed by gas chromatography, and the intermediate yield was determined by the above-mentioned method. The results are shown in Table 1 (the same applies below). After the first reaction step, 40 g of the reaction solution was distilled off under reduced pressure (alcohol removal step), and then the mixture was heated under reflux for 3 hours (second reaction step), and cooled to room temperature to terminate the reaction. The pH of the reaction solution at 20°C after the alcohol removal step and before the start of the second reaction step was 0. The reaction solution thus obtained was analyzed by gas chromatography, and the yield and the impurity formation ratio were determined by the above-mentioned method. The results are shown in Table 1 (hereinafter the same).

[0027] <Example 2> The steps up to the alcohol removal step were carried out in the same manner as in Example 1. A 40% aqueous solution of sodium hydroxide was added to the remaining reaction liquid to adjust the pH to 0.5 at 20° C. (pH adjustment step). Thereafter, the second reaction step was carried out in the same manner as in Example 1, and the reaction was terminated by allowing the mixture to cool to room temperature.

[0028] <Examples 3 to 8> In Example 2, the amount of sodium hydroxide aqueous solution added in the pH adjustment step was changed, and the adjusted pH was changed as shown in Table 1. The rest was the same as in Example 2.

[0029] <Example 9> A raw material composition was prepared by adding 9.0 g (150 mmol) of acetic acid, 131 mL of water, and 30.0 g (180 mmol) of ethyl (S)-4-chloro-3-hydroxybutyrate to a glass flask equipped with a thermometer, a condenser, and a stirrer. The raw material composition was stirred at 90° C. for 20 minutes, and then heated under reflux for 1.5 hours (first reaction step). The intermediate yield of the resulting reaction solution was determined. After the first reaction step, 42 g of the reaction liquid was distilled off under reduced pressure (alcohol removal step). A 40% aqueous solution of sodium hydroxide was added to the remaining reaction liquid to adjust the pH to 1.5 at 20° C. (pH adjustment step). The mixture was then heated under reflux for 4 hours (second reaction step), and allowed to cool to room temperature to terminate the reaction. The yield and impurity generation ratio of the resulting reaction solution were determined.

[0030] <Examples 10-12> In Example 9, the amount of sodium hydroxide aqueous solution added in the pH adjustment step was changed, and the adjusted pH was changed as shown in Table 1. The rest was the same as in Example 9.

[0031] [Table 1]

[0032] As shown in the results in Table 1, compared with Example 1 in which the pH adjustment step was not performed during the cyclization reaction, Examples 2 to 12 in which the pH adjustment step was performed provided good yields and also suppressed the production of impurities. In Examples 2 to 12, the yield improved as the adjusted pH increased, and the yield was highest when the pH was 4.5.

Claims

1. A method for producing 3-hydroxy-γ-butyrolactone represented by the following formula (2) by subjecting a 4-halogeno-3-hydroxybutyric acid ester represented by the following formula (1) to a cyclization reaction in a medium containing water, the method comprising the steps of: The method for producing 3-hydroxy-γ-butyrolactone comprises a pH adjustment step of adjusting the pH of the reaction solution at 20° C. to 1.5 or more by adding an alkaline compound at a point in time when the intermediate yield is 10 to 60% after the initiation and before the completion of the cyclization reaction. 【Chemistry 1】 (In the formula, X represents a halogen atom, and R represents an ester-type protecting group.) 【Chemistry 2】

2. The method according to claim 1 , further comprising an alcohol removing step of removing an alcohol by-produced by the cyclization reaction after the initiation of the cyclization reaction and before the pH adjustment step.

3. The method according to claim 1 or 2, wherein the pH of the reaction solution is adjusted to 1.5 to 5.5 in the pH adjustment step.

Images