JP2018095581A - Method for producing hexyl 4-hydroxybenzoate - Google Patents

Abstract

【選択図】なしAn object of the present invention is to provide a production method capable of obtaining hexyl 4-hydroxybenzoate in a high yield while suppressing production of by-products while being excellent in productivity, and to obtain hexyl 4-hydroxybenzoate having high purity. Providing a manufacturing method.
The 4-hydroxybenzoate represented by the formula (1) includes a step of reacting 1 molar equivalent of 4-hydroxybenzoic acid with 0.8 to 3.0 molar equivalents of 1-hexanol in the presence of an acid catalyst. A method for producing hexyl benzoate.

[Selection figure] None

Description

  The present invention relates to a method for producing hexyl 4-hydroxybenzoate.

  Paraben is a generic name for esters of 4-hydroxybenzoic acid, and is widely used as a preservative or antibacterial agent for cosmetics, pharmaceuticals, foods and the like.

  As parabens, methyl 4-hydroxybenzoate (methylparaben), ethyl 4-hydroxybenzoate (ethylparaben), propyl 4-hydroxybenzoate (propylparaben), hexyl 4-hydroxybenzoate (hexylparaben), etc. are known. Among them, hexyl 4-hydroxybenzoate has strong antibacterial activity and is expected to be developed for further antibacterial applications.

  These parabens are usually produced by reacting hydroxybenzoic acid and an aliphatic alcohol in the presence of an acid catalyst. However, since this reaction is an equilibrium reaction, either one of the raw materials becomes excessive. Thus, it is known to improve the production rate of the target product by subjecting it to the reaction. For example, a method has been proposed in which 20 to 60 molar equivalents of an aliphatic alcohol are used for the reaction with respect to 1 mol of carboxylic acid of hydroxybenzoic acid to obtain the target product at a high production rate (Patent Document 1).

  However, when an excessive amount of aliphatic alcohol is used for the reaction, a large-volume reaction apparatus is required, and there is a problem in that production efficiency is reduced and a long time is required for the removal process of the aliphatic alcohol in the post-treatment. .

  Further, in the production of hexyl 4-hydroxybenzoate, hexyl 4-hydroxybenzoate, which is the target product, and 1-hexanol used in the reaction are similar in properties such as solubility. There was a problem that it was difficult.

  Furthermore, hexyl 4-hydroxybenzoate obtained by the method of Patent Document 1 has a low purity because impurities such as catalyst and raw material remain in addition to 1-hexanol. Therefore, there has been a demand for a production method that is excellent in productivity, and that provides hexyl 4-hydroxybenzoate with high yield and high purity.

JP 2014-108929 A

  The objective of this invention is providing the manufacturing method which is excellent in productivity, suppresses the production | generation of a by-product, and can obtain hexyl 4-hydroxybenzoate with a high yield. Another object of the present invention is to provide a production method for obtaining high-purity hexyl 4-hydroxybenzoate.

  As a result of intensive studies on a method for producing hexyl 4-hydroxybenzoate, the present inventors have reacted 4-hydroxybenzoic acid with a predetermined amount of 1-hexanol in the presence of an acid catalyst, thereby producing 4-hydroxybenzoic acid. The inventors have found that hexyl can be obtained with high yield and high production efficiency, and have completed the present invention.

  The inventors also added a basic aqueous solution to a crude composition containing hexyl 4-hydroxybenzoate obtained by reacting 4-hydroxybenzoic acid with 1-hexanol in the presence of an acid catalyst. After neutralizing the crude composition, the organic layer and the aqueous layer are separated, and the organic layer is extracted to find that unreacted carboxylic acid, acid catalyst, etc. can be removed and to complete the present invention. It came.

That is, the present invention includes a step of reacting 1 molar equivalent of 4-hydroxybenzoic acid with 0.8 to 3.0 molar equivalents of 1-hexanol in the presence of an acid catalyst. A process for producing hexyl hydroxybenzoate is provided.

The present invention also provides a step of obtaining a crude composition containing hexyl 4-hydroxybenzoate represented by formula (1) by reacting 4-hydroxybenzoic acid with 1-hexanol in the presence of an acid catalyst. Next, the step represented by the formula (1) includes the step of neutralizing the crude composition by adding a basic aqueous solution to the crude composition, and then separating the organic layer and the aqueous layer and extracting the organic layer. A method for producing hexyl hydroxybenzoate is provided.

  According to this invention, while being excellent in productivity, the production | generation of a by-product can be suppressed and 4-hydroxybenzoic acid hexyl can be obtained with a high yield.

  Further, according to the present invention, hexyl 4-hydroxybenzoate having higher purity can be obtained by a simple method.

  In the present invention, commercially available 4-hydroxybenzoic acid and 1-hexanol used as reaction raw materials may be used, or those produced by methods known to those skilled in the art may be used.

  1-hexanol used in the present invention is 0.8 to 3.0 molar equivalents, preferably 0.9 to 2.5 molar equivalents, more preferably 1.0 to 1 molar equivalent of 4-hydroxybenzoic acid. It is good to make it react -2.0 molar equivalent, More preferably, 1.1-1.8 molar equivalent.

  When the amount of 1-hexanol is less than 0.8 molar equivalents relative to 1 molar equivalent of 4-hydroxybenzoic acid, the yield of the resulting hexyl 4-hydroxybenzoic acid decreases. Moreover, when the amount of 1-hexanol exceeds 3.0 molar equivalents, an excessive amount of 1-hexanol remains, production efficiency is lowered, and in the post-treatment process, it takes a long time to remove 1-hexanol.

  In the present invention, for example, reacting 1 molar equivalent of 4-hydroxybenzoic acid with 1.5 molar equivalent of 1-hexanol means that 1 molar ratio of 1-hexanol is 1.5 molar equivalents with respect to 1 molar equivalent of 4-hydroxybenzoic acid. It is made to react by making it exist in such quantity.

  Examples of the acid catalyst used in the present invention include one or more selected from the group consisting of p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid and nitric acid, and are excellent in availability and reactivity. Sulfuric acid or p-toluenesulfonic acid is preferable, and p-toluenesulfonic acid is particularly preferable in terms of excellent reactivity and by-product suppression effect. Hydrate may be sufficient as p-toluenesulfonic acid.

  These catalysts may be used alone or in combination of two or more.

  The amount of the acid catalyst used in the present invention is not particularly limited, but is preferably 0.1 to 10 parts by weight, more preferably 0.3 to 6 parts by weight, and still more preferably 100 parts by weight of 4-hydroxybenzoic acid. Is 0.5 to 3 parts by weight.

  When the amount of the acid catalyst is less than 0.1 parts by weight with respect to 100 parts by weight of 4-hydroxybenzoic acid, the reaction tends not to proceed sufficiently. When the amount of the acid catalyst exceeds 10 parts by weight, by-products such as a dimerized ether form of 1-hexanol tend to be generated, and this is economically disadvantageous.

  The reaction temperature in the reaction of 4-hydroxybenzoic acid and 1-hexanol is not particularly limited, but is preferably 100 ° C. or higher, and more preferably 135 ° C. or higher. When reaction temperature is less than 100 degreeC, there exists a tendency for reaction not to fully advance.

  The reaction time is not particularly limited because it varies depending on conditions such as the reaction temperature, but is appropriately selected between 1 to 20 hours, preferably 2 to 14 hours, and more preferably 4 to 8 hours.

  In the present invention, the reaction between 4-hydroxybenzoic acid and 1-hexanol is preferably carried out under an inert gas stream or bubbling, or under reduced pressure conditions. By reacting under such conditions, reaction inhibition and catalyst deactivation due to oxygen and moisture can be avoided and the reaction can proceed smoothly.

  The inert gas may be any gas that does not inhibit the reaction between 4-hydroxybenzoic acid and 1-hexanol. Specifically, the inert gas is selected from the group consisting of nitrogen, carbon dioxide, argon, helium, neon, xenon, and krypton. One or more selected may be mentioned. Among these, nitrogen is preferable because it is easily available and economical.

  The inert gas may be blown into the space above the reaction solution in the reaction vessel containing 4-hydroxybenzoic acid and 1-hexanol as raw materials, or may be blown directly into the reaction solution.

  The crude composition containing hexyl 4-hydroxybenzoate represented by the formula (1) obtained by the step of reacting 4-hydroxybenzoic acid and 1-hexanol in the presence of an acid catalyst is purified by purification. Can be increased.

  The purification includes the step of neutralizing the crude composition by adding a basic aqueous solution to the crude composition, and then separating the organic layer and the aqueous layer and extracting the organic layer. This is preferable because it can be efficiently increased. The crude composition after the reaction is preferably cooled to 40 to 100 ° C. from the reaction temperature and then subjected to the subsequent purification method.

  The crude composition containing hexyl 4-hydroxybenzoate represented by the formula (1) is a composition containing impurities such as a reaction raw material, a catalyst, and a reaction byproduct in addition to hexyl 4-hydroxybenzoate which is the target product. Means.

  Examples of impurities contained in the crude composition include 4-hydroxybenzoic acid, 1-hexanol, and a catalyst as raw materials. Further, the impurities include reaction by-products such as dimerized ether of 1-hexanol and sulfate ester by reaction of 1-hexanol with an acid catalyst.

  A step of neutralizing the crude composition by adding a basic aqueous solution into the crude composition (hereinafter referred to as neutralization step), and a step of separating the organic layer and the aqueous layer and extracting the organic layer (hereinafter referred to as extraction step) Specifically, after cooling the crude composition after the reaction, a basic aqueous solution is added to the crude composition in the neutralization step, and the acid catalyst is deactivated by continuing stirring. Thereafter, in the extraction step, the reaction system is allowed to stand to separate into an organic layer and an aqueous layer, and the organic layer is recovered.

  Basic compounds contained in the basic aqueous solution include triethylamine, monoethylamine, diethylamine, trimethylamine, monomethylamine, dimethylamine, ethylenediamine, triethanolamine, tetramethylethylenediamine, pyrrolidine, piperidine, pyridine, sodium hydroxide, sodium bicarbonate. And at least one selected from the group consisting of sodium carbonate, potassium hydroxide, potassium carbonate and potassium hydrogen carbonate. Among these, sodium hydrogencarbonate is preferable because it is excellent in separability between the organic layer and the aqueous layer and availability.

  The addition amount of the basic compound may be more than the amount capable of neutralizing the acid catalyst, and is usually 1 to 10% by weight based on the total amount of the basic aqueous solution.

  When the addition amount of the basic compound is less than 1% by weight based on the total amount of the basic aqueous solution, neutralization tends to be incomplete. When the addition amount of the basic compound exceeds 10% by weight, an excessive basic substance tends to remain in the target product as an impurity, and it is economically disadvantageous.

  The amount of water in the extraction step is preferably 100 parts by weight or more with respect to 100 parts by weight of 4-hydroxybenzoic acid as a raw material. When the amount of water is less than 100 parts by weight with respect to 100 parts by weight of 4-hydroxybenzoic acid, the raw material 4-hydroxybenzoic acid, catalyst, and metal remain in the target product and the quality is lowered. In order to adjust the amount of water in the extraction process, water may be further added in the extraction process.

  The neutralization step and the extraction step may be repeated to further enhance the purification effect, and water washing may be performed to remove the metal.

  The organic layer recovered in the extraction step is preferably subjected to the following purification step A or B. The purification steps A and B are appropriately selected depending on the quality of hexyl 4-hydroxybenzoate required after purification. In addition, these purification steps can be performed alone or in combination.

[Purification Step A]
The purification step A includes a step of distilling out impurities in the extracted organic layer (hereinafter referred to as an impurity distilling step), and then a step of adding a solvent to the organic layer for crystallization (hereinafter referred to as a crystallization step). .

  In the impurity distillation step, the impurities to be distilled off include, in addition to 1-hexanol as a raw material, low boiling point compounds such as dimerized ether of 1-hexanol produced as a by-product in the reaction.

  The impurities are distilled off by heating and / or depressurizing the organic layer. The temperature and pressure in heating and decompression are preferably 60 to 160 ° C. and 40 to 80 Torr, more preferably 80 to 140 ° C. and 50 to 70 Torr, when carried out simultaneously. When distilling off by heating alone, it is preferable to add water and azeotrope at 90 to 130 ° C.

  The heating and / or decompression time is not particularly limited, but it is preferable to carry out until the impurities are not distilled off from the organic layer under the above conditions.

  Next, in the crystallization step, hexyl 4-hydroxybenzoate can be crystallized by adding a solvent to the organic layer, heating and dissolving it, and then cooling. The precipitated crystals are separated into solid and liquid by filtration or the like, washed and dried to obtain hexyl 4-hydroxybenzoate having high purity.

  Examples of the solvent used in the crystallization step include an aqueous alcohol solution containing one or more alcohols selected from the group consisting of methanol, ethanol, 1-propanol, 2-propanol, ethylene glycol, and the like. Purification efficiency and availability A methanol aqueous solution is preferable from the viewpoint of ease.

  The concentration of the aqueous alcohol solution is preferably 10 to 50% by weight, more preferably 20 to 40% by weight. When the concentration of the aqueous alcohol solution is less than 10% by weight, the purity of the resulting hexyl 4-hydroxybenzoate crystal tends to decrease, and when the concentration of the aqueous alcohol solution exceeds 50% by weight, the resulting 4-hydroxybenzoic acid is obtained. There is a tendency for the yield of hexyl to decrease.

  The amount of the solvent used in the crystallization step is not particularly limited because it varies depending on the type of the solvent used, but it is 1 to 20 times by weight, preferably 2 to 15 times by weight, more preferably the raw material 4-hydroxybenzoic acid. Is 3 to 10 times the weight.

  When the amount of the solvent is less than 1 times the weight, stirring failure tends to occur at the time of crystallization, and when it exceeds 20 times the weight, the yield tends to decrease and it is economically disadvantageous.

  The crystallization step is performed by adding a solvent, heating to completely dissolve the organic matter in the organic layer, and then slowly cooling and crystallization while continuing stirring.

  When a supersaturation phenomenon occurs during crystallization, a seed crystal may be added as appropriate to promote crystallization.

  Crystals precipitated in the crystallization step are subjected to solid-liquid separation by conventional means such as filtration, and the target hexyl 4-hydroxybenzoate is recovered. In solid-liquid separation, it is preferable to wash the crystals by pouring a solvent as appropriate. As the solvent used in the solid-liquid separation, the same solvent as that used in the crystallization step is used.

  Crystals recovered by solid-liquid separation can be heated and / or decompressed to distill off the solvent to obtain high purity hexyl 4-hydroxybenzoate.

  The heating temperature is not particularly limited as long as hexyl 4-hydroxybenzoate does not melt and the solvent can be distilled off, but it is usually 40 to 50 ° C.

  The pressure at the time of depressurization is not particularly limited because it varies depending on the type and amount of the remaining solvent, but it is usually preferable to carry out at 10 Torr or less.

[Purification Step B]
The purification step B includes a step of distilling the extracted organic layer.

  Examples of the distillation include atmospheric distillation, reduced pressure distillation, steam distillation and the like, and distillation including heating and reduced pressure is particularly preferable. The temperature and pressure during heating and decompression are preferably 130 to 180 ° C. and 0.1 to 10 Torr, and more preferably 140 to 170 ° C. and 0.1 to 3 Torr. By performing heating and decompression within the above range, decomposition of hexyl 4-hydroxybenzoate is suppressed. Moreover, the side reaction during distillation can be suppressed by using the neutralized organic layer.

  The heating and decompression time is not particularly limited, but it is preferable to carry out until hexyl 4-hydroxybenzoate is no longer extracted from the organic layer under the above distillation conditions.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited to this.

  The composition of the crude composition and the composition of the obtained crystal were determined by quantitative analysis by high performance liquid chromatography (HPLC) and gas chromatography (GC) under the following conditions.

[High-performance liquid chromatography (HPLC)]
Equipment: Waters Alliance 2690/2996
Column model number: L-Column
Liquid volume: 1.0 mL / min
Solvent ratio: H ₂ O (pH 2.3) / CH ₃ OH = 80/20 (8 min) → 30/70 (21 min) → 10/90 (14 min), gradient analysis Wavelength: 254 nm
Column temperature: 40 ° C

[Gas chromatography (GC)]
Equipment: GC-2014 / GC-14A manufactured by Shimadzu Corporation
Column model number: G-950
Injection volume: 1.0 μL
Oven temperature: 225 ° C
Carrier gas: Helium Detector: FID

Example 1
A 300 mL scale four-necked flask (reaction vessel) equipped with a stirrer, temperature sensor and Dean-Stark apparatus was charged with 91.2 g (0.66 mol) of 4-hydroxybenzoic acid (POB) and 1-hexanol (HexOH) 101. 0.1 g (0.99 mol) and 1.8 g of p-toluenesulfonic acid monohydrate (PTS · H ₂ O) as a catalyst were added, and the temperature was raised to 145 ° C. in a nitrogen stream of 38 mL / min. For 6 hours to obtain a crude composition. The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.

Example 2
A crude composition was obtained in the same manner as in Example 1 except that 60.7 g (0.59 mol) of 1-hexanol was used. The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.

Example 3
A crude composition was obtained in the same manner as in Example 1 except that 1-hexanol was changed to 80.9 g (0.79 mol). The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.

Example 4
A crude composition was obtained in the same manner as in Example 1 except that 134.8 g (1.32 mol) of 1-hexanol was used. The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.

Example 5
A crude composition was obtained in the same manner as in Example 1 except that p-toluenesulfonic acid monohydrate was concentrated sulfuric acid. The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.

Comparative Example 1
A crude composition was obtained in the same manner as in Example 1 except that 337.2 g (3.30 mol) of 1-hexanol was used and the reaction vessel was a 1 L four-necked flask. The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.

Comparative Example 2
A crude composition was obtained in the same manner as in Example 2 except that 1.8 g of p-toluenesulfonic acid monohydrate was changed to 7.4 g of tetraisopropoxytitanium. The obtained crude composition was quantitatively analyzed by HPLC and GC. The results are shown in Table 1.

Comparative Example 3
A crude composition was obtained in the same manner as in Example 1 except that 1-hexanol was changed to 33.7 g (0.33 mol), but the reaction was interrupted because POB did not dissolve and the stirring was poor. .

Example 6
Into a 1 L scale bottomed four-necked flask equipped with a stirrer, temperature sensor and cooling pipe and provided with a discharge port with a cock at the bottom, 179.9 g of the crude composition obtained in Example 1 was cooled to 80 ° C. Added after. To this was added 127.7 g of 5 wt% aqueous sodium hydrogen carbonate solution, and the mixture was neutralized by stirring at 80 ° C. for 1 hour. Thereafter, the stirring was stopped and the mixture was allowed to stand at the same temperature for 30 minutes to separate into an organic layer and an aqueous layer. The lower aqueous layer was discarded from the bottom outlet, and the organic layer was extracted. This extraction step was further performed 3 times to obtain 175.7 g of an organic layer. The obtained organic layer was quantitatively analyzed by HPLC and GC. The results are shown in Table 2.

Example 7
175.7 g of the organic layer obtained in Example 6 was added to a 1 L-scale vacuum distillation apparatus equipped with a stirrer, a temperature sensor, a Liebig condenser, and a flask for storing an adapter and a distillate at the tip, and a reduced pressure of 60 Torr. The solvent was distilled off for 2 hours while raising the temperature from 80 ° C to 145 ° C. The amount of solvent distilled off was 23.5 g.

  After the solvent was distilled off, the residual liquid was cooled to 50 ° C., 127.7 g of 30 wt% aqueous methanol solution was added, kept at 50 ° C. for 30 minutes, dissolved, cooled to 25 ° C., and purified with a purity of 99.5 wt%. 1.8 g of NHPB was added, and the mixture was cooled to 15 ° C. for crystallization. The solid matter obtained by crystallization was taken out by filtration, washed with 91.2 g of a 30 wt% aqueous methanol solution, and then dried under conditions of 40 ° C. and 4.5 Torr to obtain 84.5 g of crystals (yield) 57.1 mol%).

  The obtained crystals were quantitatively analyzed by HPLC and GC. The results are shown in Table 2.

Example 8
Into a 1 L-scale vacuum distillation apparatus equipped with a stirrer, a temperature sensor, a Liebig condenser, and a flask for storing an adapter and a distillate at the tip, 175.7 g of the organic layer obtained in Example 6 and 273.6 g of water were added. In addition, the solvent was distilled off at 110 ° C. for 3 hours. The amount of solvent distilled off was 291.3 g.

  After the solvent was distilled off, the residual liquid was cooled to 50 ° C., 127.7 g of 30 wt% aqueous methanol solution was added, kept at 50 ° C. for 30 minutes, dissolved, cooled to 25 ° C., and purified with a purity of 99.5 wt%. 1.8 g of NHPB was added, and the mixture was cooled to 15 ° C. for crystallization. The solid matter obtained by crystallization was taken out by filtration, washed with 91.2 g of a 30 wt% aqueous methanol solution, and then dried at 40 ° C. and 4.5 Torr to obtain 115.8 g of crystals (yield 78 .9 mol%).

  The obtained crystals were quantitatively analyzed by HPLC and GC. The results are shown in Table 2.

Example 9
175.7 g of the organic layer obtained in Example 6 was added to a 1 L scale vacuum distillation apparatus equipped with a stirrer, a temperature sensor, a Liebig condenser, and a flask for storing an adapter and a distillate at the end. 138.9 g of crystals distilled at 1.5 Torr were obtained (yield 94.7 mol%). The obtained crystals were quantitatively analyzed by HPLC and GC. The results are shown in Table 2.

  Thus, as can be seen from Table 1, according to the present invention, by-products and excess residual alcohol can be reduced, so that hexyl 4-hydroxybenzoate can be obtained with high yield and high production efficiency.

  Furthermore, as can be seen from Table 2, according to the present invention, by purifying a crude composition containing hexyl 4-hydroxybenzoate, reaction raw materials and by-products are removed, and high-purity hexyl 4-hydroxybenzoate is obtained. Is obtained.

Claims (13)

Of hexyl 4-hydroxybenzoate represented by formula (1), which comprises reacting 1 molar equivalent of 4-hydroxybenzoic acid with 0.8 molar equivalent of 1-hexanol in the presence of an acid catalyst. Production method.

  The manufacturing method of Claim 1 whose quantity of an acid catalyst is 0.1-10 weight part with respect to 100 weight part of 4-hydroxybenzoic acid.   The production method according to claim 1 or 2, wherein the acid catalyst is at least one selected from the group consisting of p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid and nitric acid.   The manufacturing method in any one of Claims 1-3 whose acid catalyst is p-toluenesulfonic acid.   The manufacturing method according to any one of claims 1 to 4, wherein the step is a step of obtaining a crude composition containing hexyl 4-hydroxybenzoate represented by the formula (1).   The production method according to claim 5, further comprising a step of neutralizing the crude composition by adding a basic aqueous solution to the crude composition, and then a step of separating the organic layer and the aqueous layer and extracting the organic layer.   The manufacturing method of Claim 6 which further includes the process of distilling off the impurity of the extracted organic layer, and the process of adding and then crystallizing a solvent to the organic layer.   The production method according to claim 7, wherein the distillation is performed at a temperature of 60 to 160 ° C. and a pressure of 40 to 80 Torr.   The manufacturing method of Claim 7 whose solvent is alcohol aqueous solution.   The manufacturing method of Claim 9 whose alcohol aqueous solution is 10-50% methanol aqueous solution.   The manufacturing method of Claim 6 which further includes the process of distilling the extracted organic layer.   The production method according to claim 11, wherein the distillation is performed at a temperature of 130 to 180 ° C and a pressure of 0.1 to 10 Torr. A step of obtaining a crude composition containing hexyl 4-hydroxybenzoate represented by formula (1) by reacting 4-hydroxybenzoic acid with 1-hexanol in the presence of an acid catalyst;
Next, adding a basic aqueous solution to the crude composition to neutralize the crude composition,
Next, a method for producing hexyl 4-hydroxybenzoate represented by the formula (1), which comprises a step of separating the organic layer and the aqueous layer and extracting the organic layer.