JP2008291008A - 2,5-dimethylacetophenone derivative, 2,5-dimethylphenylacetic acid obtained from 2,5-dimethylacetophenone derivative and method for producing the same - Google Patents

Abstract

The present invention provides a high-purity 2.5-dimethylacetophenone derivative, 2,5-dimethylphenylacetic acid obtained from a 2.5-dimethylacetophenone derivative and a derivative thereof in a high yield.
2,5-dimethylacetophenone, sulfur, and morpholine are reacted at a temperature of 100 ° C. or higher and lower than the boiling point of the reaction system to produce 2,5-dimethylphenylthioacetomorpholine. The temperature may be about 100 to 125 ° C. The manufacturing method may include a step of isolating 2,5-dimethylphenylthioacetomorpholine by crystallization. Moreover, in the said manufacturing method, the ratio of sulfur may be about 1-2 mol with respect to 1 mol of 2, 5- dimethyl acetophenone, and the ratio of morpholine may be excess mol.
[Selection figure] None

Description

  The present invention relates to a method for producing a highly pure 2,5-dimethylacetophenone derivative, and 2,5-dimethylphenylacetic acid useful as an intermediate for fine chemicals such as pharmaceuticals and agricultural chemicals obtained from the 2,5-dimethylacetophenone derivative, and The present invention relates to a method for producing the derivative.

  Several methods are known as a method for synthesizing 2,5-dimethylphenylacetic acid or a derivative thereof.

  For example, in International Publication WO2005 / 075041 (Patent Document 1), 2-chloro- (2,5-dimethylphenyl) ethanone is used as a starting material, and this is reacted with a diol to form an acetal, followed by heat treatment and A method for obtaining 2,5-dimethylphenylacetic acid by hydrolysis is disclosed. However, this method requires a high temperature of 180 to 185 ° C. when rearranging the acetal and inducing it to 2,5-dimethylphenylacetic acid.

  Japanese Patent Application Laid-Open No. 59-27848 (Patent Document 2) discloses a process for obtaining 2,5-dimethylphenylacetic acid by reacting 1-halomethyl-2,5-dimethylbenzene with carbon monoxide in the presence of a catalyst. Has been. In addition, US Pat. No. 3,839,428 (Patent Document 3) discloses that 1-hydroxymethyl-2,5-dimethylbenzene formate is reacted with carbon monoxide in the presence of a catalyst. A method for obtaining 5-dimethylphenylacetic acid is disclosed. However, in these methods, since carbon monoxide which is a toxic gas is used, there is a problem that it is difficult to implement industrially.

  On the other hand, the Wilgeroth-Kindler reaction is well known as a method for synthesizing aryl acetic acid. This reaction is a method in which arylmethyl ketone, sulfur and amine are reacted to synthesize arylthioacetamide corresponding to arylmethylketone and hydrolyze it to obtain arylacetic acid. A general example of this reaction is described in, for example, Journal of American Chemical Society, 1942, 64, 3051-3052 (Non-patent Document 1). Such reaction is usually carried out at a temperature higher than the boiling point of the solvent, such as 140 to 180 ° C., when ammonium sulfide, alkylamine or the like is used as the amine source. On the other hand, when morpholine is used as the amine source, it is usually carried out at a heating reflux temperature.

In Journal of American Chemical Society, 1948, 70, 3224-3228 (Non-patent Document 2), in a conventional method, 2,5-dimethylphenylthioacetomorpholine is obtained in a yield of 63%. It is described that it can be obtained and is difficult to obtain in a sufficient yield.
International Publication WO2005 / 075041 (Summary) JP 59-27848 (Claim (1)) US Pat. No. 3,839,428 (Claim 1) Journal of American Chemical Society, 1942, 64, 3051-3052 Journal of American Chemical Society, 1948, 70, 3224-3228

  Therefore, an object of the present invention is to provide a method for producing a high-purity 2,5-dimethylacetophenone derivative, 2,5-dimethylphenylacetic acid obtained from a 2,5-dimethylacetophenone derivative, and derivatives thereof. There is to do.

  Another object of the present invention is 2,5-dimethylphenylacetic acid and its derivatives obtained from 2,5-dimethylacetophenone derivatives, 2,5-dimethylacetophenone derivatives easily and efficiently even on an industrial scale. It is in providing the method of manufacturing.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that when 2,5-dimethylacetophenone, sulfur, and morpholine are reacted in a liquid phase reaction system at a specific temperature, high-purity 2,5-dimethylacetophenone. The inventors have found that a derivative can be obtained in a high yield and that 2,5-dimethylphenylacetic acid and its derivative can be efficiently produced from a 2,5-dimethylacetophenone derivative, thereby completing the present invention.

  That is, in the present invention, 2,5-dimethylacetophenone, sulfur, and morpholine are reacted in a liquid phase reaction system at a temperature of 100 ° C. or higher to produce 2,5-dimethylphenylthioacetomorpholine. The temperature may be about 100 to 125 ° C. The manufacturing method may include a step of isolating 2,5-dimethylphenylthioacetomorpholine by crystallization. When isolated by crystallization, most of the unreacted sulfur can be easily removed. Moreover, in the said manufacturing method, the ratio of sulfur may be about 1-2 mol with respect to 1 mol of 2, 5- dimethyl acetophenone, and the ratio of morpholine may be excess mol.

  The present invention also includes a method for producing 2,5-dimethylphenylacetic acid, in which the 2,5-dimethylphenylthioacetomorpholide is subjected to hydrolysis treatment and oxidation treatment with an oxidizing agent. In the production method, 2,5-dimethylphenylthioacetomorpholine may be hydrolyzed with an alkali metal hydroxide and then oxidized with hydrogen peroxide.

  Further, the present invention includes a step of chlorinating the 2,5-dimethylphenylacetic acid to produce 2,5-dimethylphenylacetic acid chloride, a degassing treatment step of removing low boiling components from the reaction system, and 2 And a process for producing 2,5-dimethylphenylacetic acid chloride comprising a step of distilling 5-dimethylphenylacetic acid chloride under reduced pressure. In the production method, 2,5-dimethylphenylacetic acid chloride may be produced by chlorinating 2,5-dimethylphenylacetic acid using thionyl chloride.

  In the present invention, 2,5-dimethylacetophenone, sulfur, and morpholine are reacted in a liquid phase reaction system at a specific temperature, so that the conversion and selectivity can be improved, and a highly pure 2,5-dimethylacetophenone derivative is increased. It can be produced in a yield. In addition, 2,5-dimethylphenylacetic acid and its derivatives can be efficiently produced from 2,5-dimethylacetophenone derivatives. Furthermore, even on an industrial scale, 2,5-dimethylacetophenone derivatives, 2,5-dimethylphenylacetic acid and derivatives thereof can be easily and efficiently produced.

(Method for producing 2,5-dimethylphenylthioacetomorpholide)
In the present invention, 2,5-dimethylphenylthioacetomorpholine is produced by reacting 2,5-dimethylacetophenone, sulfur and morpholine at a specific temperature in a liquid phase reaction system.

  The proportion of sulfur is 1 to 3 mol, preferably 1 to 2 mol, more preferably 1.1 to 1.8 mol (particularly 1.2 to 1.6 mol) per mol of 2,5-dimethylacetophenone. Mol) degree. Furthermore, considering the point of removal of unreacted sulfur in the isolation step described later, the ratio of sulfur is 1 to 1.5 mol, particularly 1.1 to 1.1, based on 1 mol of 2,5-dimethylacetophenone. About 3 mol may be sufficient. If the ratio of sulfur increases, the conversion rate can be improved, but if the ratio of sulfur is too large, efficient removal of unreacted sulfur may be difficult.

  The proportion of morpholine is an excess mole, for example, 1.5 to 7.5 moles, preferably 1.8 to 7 moles, more preferably 2 to 6.5 moles per mole of 2,5-dimethylacetophenone. In particular, it may be about 2 to 6 mol). The morpholine may be used alone as a solvent.

  In the liquid phase reaction system, the reaction is usually performed in the presence of a solvent, and morpholine may be used as a solvent as described above.

  Solvents that can be used in addition to morpholine are usually solvents having a boiling point of 100 ° C. or higher, such as hydrocarbons [aliphatic hydrocarbons (such as octane), alicyclic hydrocarbons (such as cyclooctane), aromatic hydrocarbons (such as Toluene, xylene, etc.)] and the like. These solvents may be used alone or in combination of two or more with morpholine.

  The ratio (weight ratio) between the morpholine and a solvent other than morpholine is the former / the latter = 20/80 to 100/0, preferably 30/70 to 100/0, more preferably 50/50 to 100 /. It may be about zero.

  The reaction is usually carried out by stirring in a liquid phase reaction system at a predetermined temperature. In the liquid phase reaction system, the reaction is carried out without reflux (without boiling the reaction system). The reaction temperature can be selected from 100 ° C. or higher (for example, 100 to 130 ° C.), preferably 100 to 125 ° C., more preferably about 105 to 120 ° C. The selectivity in the reaction depends on the temperature, and the selectivity can be improved by precisely controlling the temperature. Note that when the reaction system is refluxed (the reaction system is boiled), the selectivity decreases, and when the temperature is lower than 100 ° C., the conversion rate may decrease. The reaction time is not particularly limited, and may be, for example, 1 to 20 hours, preferably 3 to 15 hours, and more preferably about 5 to 10 hours.

  The reaction may be performed under pressure, but is usually performed at normal pressure in many cases.

  After completion of the reaction, if necessary, the solvent can be removed by a conventional method to isolate (or separate) 2,5-dimethylphenylthioacetomorpholine. As an isolation method, a conventional isolation method such as crystallization, filtration, concentration, extraction, recrystallization, column chromatography and the like can be used. In particular, it is preferable to isolate by crystallization because most of the unreacted sulfur can be easily removed.

  Examples of the crystallization solvent used for crystallization include water, alcohols (alkyl alcohols such as methanol, ethanol, n-propanol, isopropanol, and cyclohexanol), hydrocarbons [aliphatic hydrocarbons (hexane, heptane, etc.), and the like. , Alicyclic hydrocarbons (such as cyclohexane), aromatic hydrocarbons (such as toluene and xylene), halogenated hydrocarbons (such as dichloromethane)], ketones (alkyl ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone), cyclohexanone, etc. ), Ethers (dialkyl ethers such as diethyl ether and diisopropyl ether) and the like. These crystallization solvents may be used alone or in combination of two or more. Of these crystallization solvents, alcohols such as ethanol are preferred.

  In addition, the usage-amount of a crystallization solvent is not specifically limited, 0.5-50 weight part with respect to 1 weight part of total amounts of 2, 5- dimethylacetophenone, sulfur, and morpholine, Preferably it is 1-40 weight part More preferably, it may be about 5 to 30 parts by weight.

  By such a method, high-purity 2,5-dimethylphenylthioacetomorpholide can be obtained in a high yield. The resulting 2,5-dimethylphenylthioacetomorpholine is suitable for producing 2,5-dimethylphenylacetic acid.

(Method for producing 2,5-dimethylphenylacetic acid)
The 2,5-dimethylphenylthioacetomorpholine thus obtained can be subjected to hydrolysis treatment and oxidation treatment with an oxidizing agent to produce 2,5-dimethylphenylacetic acid.

  For the hydrolysis treatment, a conventional method can be used. For example, hydrolysis may be performed using a hydrolysis catalyst such as acid (hydrochloric acid, sulfuric acid, etc.), alkali, etc., usually by alkaline hydrolysis using an alkaline aqueous solution. There are many cases. The alkali of the alkaline aqueous solution is not particularly limited, and an alkali metal compound (an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, or potassium hydroxide; an alkali metal carbonate such as lithium carbonate, sodium carbonate, or potassium carbonate). Etc. can be exemplified. Of these alkali metal compounds, alkali metal hydroxides such as sodium hydroxide are particularly preferable.

  The ratio of the hydrolysis catalyst is, for example, 0.8 to 5 mol, preferably 1 to 4.5 mol, more preferably 1.5 to 4 mol, with respect to 1 mol of 2,5-dimethylphenylthioacetomorpholine. It may be about a mole (particularly 2 to 3.8 moles).

  Moreover, you may use a solvent for a hydrolysis process as needed. The solvent is not particularly limited as long as it is miscible with an aqueous alkali solution. Water-soluble organic solvents such as alcohols [monohydric alcohols such as methanol, ethanol, n-propanol and isopropanol, polyhydric alcohols (ethylene glycol, diethylene glycol) Etc.), cellosolves, carbitols and the like. These solvents may be used alone or in combination of two or more. Of these solvents, high boiling point solvents (polyhydric alcohols such as ethylene glycol) are often used.

  In addition, the ratio of the solvent is 0.1 to 30 parts by weight, preferably 1 to 20 parts by weight, more preferably 1.5 to 10 parts by weight with respect to 1 part by weight of 2,5-dimethylphenylthioacetomorpholide. It may be about parts by weight.

  The temperature in the hydrolysis treatment is not particularly limited, and may be about 50 to 200 ° C, preferably 70 to 150 ° C, more preferably about 100 to 130 ° C (particularly 110 to 120 ° C). The reaction time in the hydrolysis treatment may be, for example, 1 to 20 hours, preferably 3 to 15 hours, and more preferably about 5 to 10 hours.

  By such hydrolysis, the thiocarbonyl group (═C═S) of 2,5-dimethylphenylthioacetomorpholide can be efficiently substituted with the carbonyl group (═C═O).

Examples of the oxidizing agent in the oxidation treatment include hypochlorite metal salts such as NaClO; peracids (peracetic acid, performic acid, perbenzoic acid, etc.), hydrogen peroxide (H ₂ O ₂ ), metal peroxides (peroxides). And peroxides such as alkali metal peroxides such as sodium oxide). These oxidizing agents may be used alone or in combination of two or more. Of these oxidizing agents, hydrogen peroxide that does not generate by-products due to oxidation is preferable.

  The ratio of the oxidizing agent is, for example, about 0.8 to 10 mol, preferably 0.9 to 8 mol, more preferably about 1 to 6 mol, relative to 1 mol of 2,5-dimethylphenylthioacetomorpholine. There may be. For example, when a hydrogen peroxide solution having a concentration of 35% by weight is used as the oxidizing agent, the proportion of the hydrogen peroxide solution having a concentration of 35% by weight is 60 parts by weight with respect to 100 parts by weight of 2,5-dimethylphenylthioacetomorpholine. It may be about ~ 65 parts by weight.

  The temperature in the oxidation treatment may be, for example, about 60 to 150 ° C, preferably 70 to 120 ° C, and more preferably about 80 to 100 ° C. The reaction time in the oxidation treatment may be, for example, about 1 minute to 5 hours, preferably about 20 minutes to 3 hours, and more preferably about 30 minutes to 1 hour.

  By such oxidation treatment, the sulfur component of impurities [sulfur from thiocarbonyl group (sulfur derived from thiocarbonyl group), unreacted sulfur remaining in the reaction system, etc.] is oxidized and removed out of the system. Can do.

  In addition, the order of the said hydrolysis process and an oxidation process usually performs an oxidation process after a hydrolysis process in many cases.

  After completion of the reaction, 2,5-dimethylphenylacetic acid can be isolated using the conventional isolation method exemplified above. Isolation is usually carried out by extraction in many cases. Specifically, separation is performed using water and an organic solvent that can be separated from water, and the aqueous phase is acidified to give 2,5- Dimethylphenylacetic acid may be precipitated and isolated.

  Separable organic solvents include hydrocarbons [aliphatic hydrocarbons (hexane, heptane, etc.), alicyclic hydrocarbons (cyclohexane, etc.), aromatic hydrocarbons (toluene, xylene, etc.), halogenated hydrocarbons ( Examples thereof include ketones (alkyl ketones such as methyl ethyl ketone and methyl isobutyl ketone), esters (such as ethyl acetate), ethers (dialkyl ethers such as diethyl ether and diisopropyl ether), and the like. These organic solvents may be used alone or in combination of two or more. Of these organic solvents, halogenated hydrocarbons such as methylene chloride are often used.

  For acidification of the aqueous phase, it is only necessary to liberate 2,5-dimethylphenylacetate (such as sodium 2,5-dimethylphenylacetate). In addition to inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids ( Acids such as acetic acid) may be used. Acidification can be performed by adding an acid until pH becomes 7 or less. The precipitated 2,5-dimethylphenylacetic acid can be separated by a conventional liquid separation method such as filtration.

  By such a method, 2,5-dimethylphenylacetic acid can be obtained with high purity and high yield.

(Method for producing 2,5-dimethylphenylacetic acid chloride)
Chlorinating the 2,5-dimethylphenylacetic acid to produce 2,5-dimethylphenylacetic acid chloride; a degassing treatment step for removing low-boiling components out of the reaction system; and 2,5-dimethylphenylacetic acid chloride. A process for producing 2,5-dimethylphenylacetic acid chloride comprising a step of distillation under reduced pressure is also included in the present invention.

  For chlorination, chlorinating agents such as thionyl chloride and phosgene can be used.

  The ratio of the chlorinating agent (particularly thionyl chloride) is 0.5 to 2 mol, preferably 0.8 to 1.8 mol, more preferably 1 to 1. mol per mol of 2,5-dimethylphenylacetic acid. About 5 mol (especially 1.04-1.4 mol) may be sufficient. If the ratio of the chlorinating agent is too large, it may contribute to the formation of by-products.

  A solvent may be used for chlorination. As a solvent, it can select suitably in the range which does not impair reaction, for example, hydrocarbons [aliphatic hydrocarbons (hexane, heptane, etc.), alicyclic hydrocarbons (cyclohexane, etc.), aromatic hydrocarbons (toluene, xylene, etc.) Etc.], ketones (alkyl ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, cyclohexanone etc.), esters (such as ethyl acetate), ethers (dialkyl ethers such as diethyl ether and diisopropyl ether) and the like. These solvents may be used alone or in combination of two or more. Of these solvents, aromatic hydrocarbons such as toluene are preferred.

  The ratio of the solvent is not particularly limited, and is 0.1 to 30 parts by weight, preferably 1 to 20 parts by weight, more preferably 1 part by weight of the total amount of the 2,5-dimethylphenylacetic acid and the chlorinating agent. It may be about 1.5 to 10 parts by weight.

  The chlorination temperature can be appropriately selected according to the type of chlorinating agent (for example, unreacted thionyl chloride comes out of the system together with the boiling point of thionyl chloride and hydrogen chloride gas generated by the reaction of thionyl chloride). 20 to 80 ° C., preferably 30 to 75 ° C., more preferably 50 to 70 ° C. (especially 60 to 70 ° C.). At such a temperature, the reaction proceeds efficiently. The reaction time in chlorination may be, for example, 1 to 10 hours, preferably 2 to 8 hours, more preferably about 3 to 6 hours.

  Further, chlorination is usually often performed in an atmosphere or flow of an inert gas (such as helium gas, nitrogen gas, or argon gas).

  In the degassing treatment step, it is sufficient that low-boiling components (for example, excess thionyl chloride, dissolved hydrogen chloride, etc.) can be removed from the reaction system, and degassing treatment may be performed under reduced pressure. The degree of decompression may be small, and may be 150 to 250 hPa, preferably 170 to 220 hPa, and more preferably about 190 to 200 hPa.

  The temperature in the deaeration treatment step may be 10 to 50 ° C., preferably 12 to 40 ° C., more preferably about 15 to 35 ° C., particularly around 25 ° C. (for example, about 20 to 30 ° C.). Further, the reaction time in the degassing treatment step may be 1 to 10 hours, preferably 2 to 6 hours, and more preferably about 3 to 5 hours.

  In addition, the deaeration treatment may be performed in the air, but usually it is often performed in the atmosphere or circulation of the above-described inert gas.

  The reduced pressure in the vacuum distillation may be 1 to 300 hPa, preferably 10 to 250 hPa, more preferably 15 to 200 hPa (particularly 20 to 40 hPa). Moreover, the temperature in vacuum distillation may be 30-130 degreeC, Preferably it is 50-120 degreeC, More preferably, about 70-110 degreeC may be sufficient.

  By such a method, 2,5-dimethylphenylacetic acid chloride with high purity can be obtained in high yield.

  In the present invention, a reaction process for obtaining 2,5-dimethylphenylacetic chloride using 2,5-dimethylacetophenone as a starting material is shown below.

  In the present invention, a highly pure 2,5-dimethylacetophenone derivative can be produced in a high yield, and 2,5-dimethylphenylacetic acid and its derivative obtained from the 2,5-dimethylacetophenone derivative are used as fine chemicals such as pharmaceuticals and agricultural chemicals. It can be used as an intermediate in the field.

  Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited to these examples.

  The properties of the products obtained in the examples were measured by the following method.

⁽¹ H-NMR spectrum)
^{The 1} H-NMR spectrum was measured using tetramethylsilane as an internal standard, using CDCl ₃ as a solvent in Examples 1 and 3, and using heavy acetone in Example 2.

Example 1
(Synthesis of 2,5-dimethylphenylthioacetomorpholine)
2,5-Dimethylacetophenone (125 g, 0.84 mol), sulfur (35 g, 1.1 mol), and morpholine (147 g, 1.64 mol) were added to the reactor and stirred at 110 ± 5 ° C. for 7 hours. Reaction tracking was performed by gas chromatography (GC) (GC-14A, column DB-1 manufactured by Shimadzu Corporation), and heating was stopped after no increase in conversion was observed. The reaction yield by GC was 81%. After cooling to room temperature (25 ° C.), morpholine was distilled off under reduced pressure of 50 hPa. Ethanol (1400 ml) was added to the crude product, and crystallization was performed to obtain 2,5-dimethylphenylthioacetomorpholine in a yield of 66%.
The ¹ H-NMR spectrum data of the obtained 2,5-dimethylphenylthioacetomorpholide is shown below.
¹ H-NMR (CDCl ₃ ): 2.20 (s, 3H), 2.29 (s, 3H), 3.47 (s, 4H), 3.79 (t, 2H, j = 4.9 Hz) , 4.20 (s, 2H), 4.41 (t, 2H, J = 4.9 Hz), 6.79 (d, 1H, j = 7.5 Hz), 6.98 (s, 1H), 7 .05 (d, 1H, j = 7.5Hz)

Example 2
(Synthesis of 2,5-dimethylphenylacetic acid)
In a reactor, 2,5-dimethylphenylthioacetomorpholine (135 g, 0.54 mol) obtained in Example 1, an aqueous solution of sodium hydroxide (252 ml, 1.89 mol) having a concentration of 30% by weight, and ethylene glycol ( 302 g, 4.86 mol) was added and the mixture was stirred at 120 ° C. for 7 hours. The reaction was monitored by GC, and after confirming the disappearance of 2,5-dimethylphenylthioacetomorpholide, the heating was stopped and the mixture was allowed to cool to 65 ° C. To this reaction solution, 35% by weight of hydrogen peroxide solution (293 g) was added dropwise, followed by stirring at 100 ° C. for 2 hours. Then, methylene chloride (408 ml, 6.37 mol) and water (408 ml, 22.6 mol) were added, and the mixture was stirred for 30 minutes to carry out a liquid separation treatment. Subsequently, sulfuric acid (70 ml, 0.32 mol) having a concentration of 45% by weight was added dropwise to the aqueous phase obtained by the liquid separation treatment for neutralization, and further acidification was performed. The precipitated solid was isolated by filtration to obtain 2,5-dimethylphenylacetic acid in a yield of 98%.
The ¹ H-NMR spectrum data of the obtained 2,5-dimethylphenylacetic acid is shown below.
¹ H-NMR (heavy acetone): 2.25 (s, 6H), 3.60 (s, 2H), 6.96 (d, 1H, j = 7.5 Hz), 7.03 (s, 1H) 7.04 (d, 1H, j = 7.5 Hz)

Example 3
(Synthesis of 2,5-dimethylphenylacetic acid chloride)
To the reactor, 2,5-dimethylphenylacetic acid (81.5 g, 0.50 mol) obtained in Example 2 and toluene (287 ml, 3.1 mol) were added and heated at 50 ° C. To this was added dropwise thionyl chloride (65.3 g, 0.52 mol) over 3 hours, followed by stirring at 65 ° C. for 3 hours. The reaction was traced by GC and after confirming the disappearance of 2,5-dimethylphenylacetic acid, the heating was stopped and the mixture was allowed to cool to room temperature (25 ° C.). Thereafter, the mixture was stirred for 4 hours while flowing (venting) nitrogen under a reduced pressure of 190 hPa, and dissolved hydrogen chloride and excess thionyl chloride were distilled out of the reaction system. After confirming disappearance of thionyl chloride by GC, distillation was performed under reduced pressure at 110 ° C. and 20 hPa to obtain 2,5-dimethylphenylacetic chloride in a yield of 70%.
The ¹ H-NMR spectrum data of the obtained 2,5-dimethylphenylacetic chloride is shown below.
¹ H-NMR (CDCl ₃ ): 2.26 (s, 3H), 2.31 (s, 3H), 4.10 (s, 2H), 6.99 (s, 1H), 7.05 (d , 1H, j = 7.6 Hz), 7.09 (d, 1H, j = 7.6 Hz)

Comparative Example 1
(Synthesis of 2,5-dimethylphenylthioacetomorpholine)
Add 2,5-dimethylacetophenone (5.0 g, 33.7 mmol), sulfur (1.6 g, 50.6 mmol), and morpholine (8.8 g, 0.10 mol) to the reactor and heat to reflux at 125 ° C. And stirred for 4 hours. The reaction was monitored by GC, and heating was stopped after no increase in the conversion rate was observed. The reaction yield by GC was 62%.

Comparative Example 2
(Synthesis of 2,5-dimethylphenylthioacetomorpholine)
2,5-dimethylacetophenone (355 g, 2.4 mol), sulfur (154 g, 4.8 mol), and morpholine (626 g, 7.2 mol) were added to the reactor, and the mixture was stirred at 110 ± 5 ° C. for 7 hours. The reaction was monitored by GC, and heating was stopped after no increase in the conversion rate was observed. The reaction yield by GC was 75%. After allowing to cool to room temperature (25 ° C.), morpholine was distilled off under reduced pressure of 50 hPa, and crystallization was not performed to obtain crude 2,5-dimethylphenylthioacetomorpholine in a yield of 75%.

Comparative Example 3
(Synthesis of 2,5-dimethylphenylacetic acid)
In a reactor, 2,5-dimethylphenylthioacetomorpholine (448 g, 1.79 mol) obtained in Comparative Example 2, a 30% strength by weight aqueous sodium hydroxide solution (958 ml, 7.2 mol), and ethylene glycol (780 g, 12.9 mol) was added and stirred at 120 ° C. for 8 hours. The reaction was monitored by GC, and after confirming the disappearance of 2,5-dimethylphenylthioacetomorpholine, the heating was stopped and the mixture was allowed to cool to 25 ° C. Then, methylene chloride (700 ml, 10.9 mol) was added without performing oxidation treatment, and the mixture was stirred for 30 minutes to carry out a liquid separation treatment. Subsequently, sulfuric acid (470 ml, 2.2 mol) having a concentration of 45% by weight was added dropwise to the aqueous phase obtained by the liquid separation treatment for neutralization, and further acidification was performed. Thereafter, extraction was performed once with 1000 ml of methylene chloride and once with 500 ml of methylene chloride, followed by concentration to obtain 2,5-dimethylphenylacetic acid in a yield of 95%.

Comparative Example 4
(Synthesis of 2,5-dimethylphenylacetic acid chloride)
To the reactor, 2,5-dimethylphenylacetic acid (278.9 g, 1.70 mol) obtained in Comparative Example 3 and toluene (736 ml, 7.9 mol) were added and heated at 50 ° C. To this was added dropwise thionyl chloride (303.2 g, 2.55 mol) over 1 hour, followed by stirring at 65 ° C. for 1.5 hours. The reaction was traced by GC and after confirming the disappearance of 2,5-dimethylphenylacetic acid, the heating was stopped and the mixture was allowed to cool to room temperature (25 ° C.). Then, degassing was not performed, and distillation was performed under reduced pressure at 110 ° C. and 20 hPa to obtain 2,5-dimethylphenylacetic acid chloride in a yield of 40%.

Claims (8)

  A method for producing 2,5-dimethylphenylthioacetomorpholine by reacting 2,5-dimethylacetophenone, sulfur and morpholine at a temperature of 100 ° C. or higher in a liquid phase reaction system.   The manufacturing method according to claim 1, wherein the temperature is 100 to 125 ° C.   The production method according to claim 1, comprising a step of isolating 2,5-dimethylphenylthioacetomorpholide by crystallization.   The production method according to claim 1, wherein the ratio of sulfur is 1 to 2 moles and the ratio of morpholine is an excess mole relative to 1 mole of 2,5-dimethylacetophenone.   A method for producing 2,5-dimethylphenylacetic acid, which comprises subjecting 2,5-dimethylphenylthioacetomorpholine obtained by the production method according to claim 1 to hydrolysis treatment and oxidation treatment with an oxidizing agent.   The production method according to claim 5, wherein 2,5-dimethylphenylthioacetomorpholine is hydrolyzed with an alkali metal hydroxide and then oxidized with hydrogen peroxide.   A step of chlorinating 2,5-dimethylphenylacetic acid obtained by the production method according to claim 5 to produce 2,5-dimethylphenylacetic acid chloride, and a deaeration treatment step of removing low-boiling components out of the reaction system And a method for producing 2,5-dimethylphenylacetic acid chloride, comprising a step of distilling 2,5-dimethylphenylacetic acid chloride under reduced pressure. The production method according to claim 7, wherein 2,5-dimethylphenylacetic acid chloride is chlorinated using thionyl chloride to produce 2,5-dimethylphenylacetic acid chloride.