Method for producing aromatic nitrile compound

Abstract

Provided is a method for producing high-purity aromatic nitrile compounds and aromatic carboxylic acid compounds industrially safely, inexpensively and efficiently. The compound (2) is subjected to a Vilgel reaction as necessary in the presence of an additive, and the obtained amide compound (3) is hydrolyzed and then neutralized to obtain a carboxylic acid compound (4). The nitrile compound (1) is obtained by reacting a carboxylic acid compound (4), if necessary, with a halogenating agent in an organic solvent in the presence of a catalyst and further with an amidating agent, and reacting the obtained amide compound (5) or (6) with a dehydrating agent. Alternatively, if necessary, the carboxylic acid compound (4) is reacted with a halogenating agent and a compound represented by formula R6SO2R7 in an organic solvent in the presence of a catalyst to obtain the nitrile compound (1). Np represents a naphthyl group which may have a substituent, R5 represents an alkylene group having 1-3 carbon atoms, and the other symbols are as described in the specification. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 201980028082.1 (international application number PCT / JP2019 / 018065), Chinese national phase entry date of October 23, 2020 (international application date of April 26, 2019), and invention name “Method for producing aromatic nitrile compounds”. Technical Field

[0002] The present invention relates to a method for producing an aromatic nitrile compound, preferably 2-naphthylacetonitrile, which is useful as a synthetic raw material or synthetic intermediate for various pharmaceuticals, pesticides, and chemicals.

[0003] Furthermore, the present invention relates to a method for producing an aromatic carboxylic acid compound, preferably 2-naphthaleneacetic acid, which is useful as a raw material or synthetic intermediate for the aromatic nitrile compound of the present invention and as a raw material or synthetic intermediate for various pharmaceuticals, pesticides, and chemical products. Background Art

[0004] 2-Naphthylacetonitrile is useful as a raw material or intermediate for the synthesis of various pharmaceuticals, pesticides, and chemicals. Furthermore, aromatic nitrile compounds having a chemical structure similar to 2-naphthylacetonitrile are also expected to be used as raw materials or intermediates for the synthesis of various pharmaceuticals, pesticides, and chemicals.

[0005] For example, 2-naphthylacetonitrile is useful as a raw material or synthetic intermediate for drugs used in the prevention and treatment of CNS diseases such as depression (e.g., major depressive disorder, manic depression), fibromyalgia, pain (e.g., neuropathic pain), sleep disorders, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), restless legs syndrome, schizophrenia, anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, seasonal affective disorder (SAD), premenstrual syndrome, neurodegenerative diseases (e.g., Parkinson's disease, Alzheimer's disease), urinary incontinence and irritable bowel syndrome (IBS)-related diseases, diabetes, etc., erythropoietin (EPO) derivatives, calcium antagonists, histamine receptor antagonists, tachykinin receptor antagonists, 12-lipoxygenase inhibitors, protein kinase C (PKC) inhibitors, and PDEIV inhibitors.

[0006] 2-Naphthylacetonitrile can be particularly preferably used as a raw material and intermediate for producing (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane described in Patent Documents 1, 2, and 3.

[0007] Known methods for producing 2-naphthylacetonitrile include, for example, a method in which 2-methylnaphthalene is brominated to obtain 2-(bromomethyl)naphthalene and the resulting product is reacted with sodium cyanide (Patent Document 4), and a method in which 2'-naphthylacetonitrile is reacted with iodic acid or titanium tetranitrate and trimethoxymethane to obtain 2-naphthylacetonitrile (Non-Patent Document 1). However, these methods are not preferred as industrial production methods due to low yields, the formation of large amounts of by-products, insufficient reaction progress, heat generation during the reaction, and the use of highly toxic compounds.

[0008] In addition, a method is known in which 2-(hydroxymethyl)naphthalene is obtained from 2-methylnaphthalene by a biochemical reaction using an enzyme or the like, and the obtained product is reacted with methanesulfonyl chloride and sodium cyanide to obtain 2-naphthylacetonitrile (Non-Patent Document 2). However, this method is not preferred as an industrial production method due to the low yield, the high production of by-products, and the use of highly toxic compounds.

[0009] Further, several methods for synthesizing nitrile compounds from aromatic carboxylic acids, aromatic carboxylic acid derivatives, etc. have also been reported (Patent Document 5, Non-Patent Document 3, Non-Patent Document 4, etc.). However, these methods are also due to low yields, many by-products, and the inability to fully proceed with the reaction, and therefore require further improvement as industrial manufacturing methods.

[0010] Several methods for synthesizing aromatic carboxylic acids and aromatic thioamides from aromatic ketones via the Willgerodt reaction have been reported (Non-Patent Documents 5, 6, 7, and 8, etc.). However, these methods have insufficient yields, and since sulfur is used in the Willgerodt reaction, the resulting aromatic carboxylic acids and the like are believed to contain a high amount of sulfur. Therefore, further improvements are required as industrial production methods.

[0011] Prior art literature

[0012] Patent Literature

[0013] Patent Document 1: WO2007 / 016155

[0014] Patent Document 2: WO2015 / 089111

[0015] Patent Document 3: WO2015 / 102826

[0016] Patent Document 4: Japanese Patent Application Laid-Open No. 2001-39904

[0017] Patent Document 5: WO2014 / 001939

[0018] Non-patent literature

[0019] Non-patent document 1: ARKIVOC 2011 (V) pp. 67-75

[0020] Non-patent document 2: Journal of Molecular Catalysis B: Enzymatic, 6(1-2) 234-240, 2010

[0021] Non-patent document 3: Tetrahedron Letters, Vol. 23, No. 14, pp. 1505-1508, 1982

[0022] Non-patent document 4: Organic Process Research & Development 2003, 7, 74-81

[0023] Non-patent document 5: Green Chemistry Letters and Reviews, 2010, 315-318

[0024] Non-Patent Literature 6: Synthetic Communications, Vol. 33, No. 1, pp. 59-63, 2003

[0025] Non-patent document 7: Chem. Soc. Rev., 2013, 42, 7870-7880

[0026] Non-patent document 8: J. Soc. Ouest-Afr. Chim. (2010) 029, 89-94 Summary of the Invention

[0027] Problems to be solved by the invention

[0028] The present invention provides a method for producing high-purity aromatic nitrile compounds and aromatic carboxylic acid compounds industrially safely, inexpensively, and with high efficiency.

[0029] Methods used to solve problems

[0030] To solve the above-mentioned problems, the present inventors conducted intensive research on the steps of producing aromatic carboxylic acid compounds by Willgerodt rearrangement of relatively inexpensive and commonly used aromatic ketone compounds such as 2'-acetonapthone, and on the steps of producing high-purity aromatic nitrile compounds from aromatic carboxylic acid compounds in high yield while suppressing the formation of by-products, resulting in the completion of the present invention.

[0031] That is, the gist of the present invention is as follows.

[0032] [1] A method for producing a nitrile compound represented by the general formula (1), characterized by comprising the following steps 1 and 2.

[0033] Np-R 5 -CN (1)

[0034] (In the general formula (1), Np represents a naphthyl group which may have a substituent, R 5 represents an alkylene group having 1 to 3 carbon atoms.)

[0035] Step 1:

[0036] The step of obtaining the carboxylic acid compound represented by the general formula (4) is characterized in that the compound represented by the general formula (2) is subjected to a Wilgenre reaction in the presence of an additive as needed to obtain the compound represented by the general formula (3), and the obtained compound represented by the general formula (3) is hydrolyzed and then neutralized;

[0037] Np-CO-R 1 (2)

[0038] (In the general formula (2), Np has the same meaning as above, R 1 represents an alkyl group having 1 to 3 carbon atoms.)

[0039] Np-R 5 -C(=X)-NR 3 R 4 (3)

[0040] (In general formula (3), Np and R 5 Same as above, X represents oxygen atom or sulfur atom, R 3 and R 4 Each independently represents an alkyl group having 1 to 3 carbon atoms or a hydrogen atom which may have a nitrogen atom, an oxygen atom or a sulfur atom, and R 3 and R 4 May bond to form a ring.)

[0041] Np-R 5 -COOH (4)

[0042] (In general formula (4), Np and R 5 Same meaning as above.)

[0043] Step 2: Either Step 2A or Step 2B,

[0044] Step 2A:

[0045] A step of reacting the carboxylic acid compound represented by the general formula (4) obtained in the above step 1 with a halogenating agent in an organic solvent in the presence of a catalyst as needed and further reacting it with an amidating agent to obtain a compound represented by the general formula (5) or the general formula (6), and reacting the obtained compound represented by the general formula (5) or the general formula (6) with a dehydrating agent to obtain a nitrile compound represented by the above general formula (1);

[0046] Np-R 5 -CONH2 (5)

[0047] (In general formula (5), Np and R 5 Same meaning as above.)

[0048] Np-R 5 -CONHOH (6)

[0049] (In general formula (6), Np and R 5 Same meaning as above.)

[0050] Step 2B:

[0051] A step of reacting the carboxylic acid compound represented by the general formula (4) obtained in the above step 1 with a halogenating agent and a compound represented by the general formula (7) in an organic solvent in the presence of a catalyst as needed to obtain a nitrile compound represented by the general formula (1).

[0052] R 6 SO2R 7 (7)

[0053] (In general formula (7), R 6 and R 7 Each independently represents a chlorine atom, a hydroxyl group, an amino group, an isocyanate group or a p-tolyl group.)

[0054] [2] The method for producing a nitrile compound according to [1], wherein the step 2B is the following step 2B-1 or step 2B-2.

[0055] Step 2B-1:

[0056] A step of reacting the carboxylic acid compound represented by the general formula (4) with a halogenating agent and the compound represented by the general formula (7) in an organic solvent at 80° C. to 180° C. in the presence of a catalyst as needed to obtain the nitrile compound represented by the general formula (1);

[0057] Step 2B-2:

[0058] A step of reacting a reaction material 1 obtained by mixing a carboxylic acid compound represented by the above general formula (4), a halogenating agent, a first organic solvent and, if necessary, a catalyst, with a reaction material 2 obtained by mixing a compound represented by the above general formula (7) and a second organic solvent at 80° C. to 180° C. to obtain a nitrile compound represented by the above general formula (1).

[0059] [3] A method for producing a nitrile compound represented by the general formula (1), comprising any one of the following steps 2A and 2B.

[0060] Np-R 5 -CN (1)

[0061] (In the general formula (1), Np represents a naphthyl group which may have a substituent, R 5 represents an alkylene group having 1 to 3 carbon atoms.)

[0062] Step 2A:

[0063] A step of reacting a carboxylic acid compound represented by the general formula (4) with a halogenating agent in an organic solvent in the presence of a catalyst as needed and further reacting it with an amidating agent to obtain a compound represented by the general formula (5) or the general formula (6), and reacting the obtained compound represented by the general formula (5) or the general formula (6) with a dehydrating agent to obtain the nitrile compound represented by the general formula (1);

[0064] Np-R 5 -COOH (4)

[0065] (In general formula (4), Np and R 5 Same meaning as above.)

[0066] Np-R 5 -CONH2 (5)

[0067] (In general formula (5), Np and R 5 Same meaning as above.)

[0068] Np-R 5 -CONHOH (6)

[0069] (In general formula (6), Np and R 5 Same meaning as above.)

[0070] Step 2B:

[0071] A step of reacting a carboxylic acid compound represented by the general formula (4) with a halogenating agent and a compound represented by the general formula (7) in an organic solvent in the presence of a catalyst as needed to obtain a nitrile compound represented by the general formula (1).

[0072] Np-R 5-COOH (4)

[0073] (In general formula (4), Np and R 5 Same meaning as above.)

[0074] R 6 SO2R 7 (7)

[0075] (In general formula (7), R 6 and R 7 Each independently represents a chlorine atom, a hydroxyl group, an amino group, an isocyanate group or a p-tolyl group.)

[0076] [4] The method for producing a nitrile compound according to [3], wherein step 2B is the following step 2B-1 or step 2B-2.

[0077] Step 2B-1:

[0078] A step of reacting the carboxylic acid compound represented by the general formula (4) with a halogenating agent and the compound represented by the general formula (7) in an organic solvent at 80° C. to 180° C. in the presence of a catalyst as needed to obtain the nitrile compound represented by the general formula (1);

[0079] Step 2B-2:

[0080] A step of reacting a reaction material 1 obtained by mixing a carboxylic acid compound represented by the above general formula (4), a halogenating agent, a first organic solvent and, if necessary, a catalyst, with a reaction material 2 obtained by mixing a compound represented by the above general formula (7) and a second organic solvent at 80° C. to 180° C. to obtain a nitrile compound represented by the above general formula (1).

[0081] [5] A method for producing a carboxylic acid compound represented by the general formula (4), characterized in that the compound represented by the general formula (2) is subjected to a Wilgenhall reaction in the presence of an additive as needed to obtain a compound represented by the general formula (3), and the obtained compound represented by the general formula (3) is hydrolyzed and then neutralized.

[0082] Np-CO-R 1 (2)

[0083] (In the general formula (2), Np represents a naphthyl group which may have a substituent, R 1 represents an alkyl group having 1 to 3 carbon atoms.)

[0084] Np-R 5 -C(=X)-NR 3 R 4 (3)

[0085] (In the general formula (3), Np has the same meaning as above, X represents an oxygen atom or a sulfur atom, R 5 represents an alkylene group having 1 to 3 carbon atoms, R 3 and R 4 Each independently represents an alkyl group having 1 to 3 carbon atoms or a hydrogen atom which may have a nitrogen atom, an oxygen atom or a sulfur atom, and R 3 and R 4 May bond to form a ring.)

[0086] Np-R 5 -COOH (4)

[0087] (In general formula (4), Np and R 5 Same meaning as above.)

[0088] [6] The method for producing a carboxylic acid compound according to [5], characterized in that the reaction product obtained by hydrolysis is contacted with a hydrocarbon solvent after the hydrolysis, a hydrocarbon solvent is present during the neutralization, or the reaction product obtained by the neutralization is contacted with a hydrocarbon solvent.

[0089] [7] A carboxylic acid compound represented by the general formula (4), characterized in that the sulfur content is 0.001 mol% to 1 mol% and the purity is 98 mol% or more.

[0090] Np-R 5 -COOH (4)

[0091] (In general formula (4), R 5 represents an alkylene group having 1 to 3 carbon atoms, and Np represents a naphthyl group which may have a substituent.

[0092] Effects of the Invention

[0093] The present invention provides a novel method for industrially safely and inexpensively producing aromatic nitrile compounds such as 2-naphthylacetonitrile and aromatic carboxylic acid compounds such as 2-naphthylacetic acid, which are useful as synthetic raw materials and synthetic intermediates for various pharmaceuticals, pesticides, and chemicals, with high efficiency and high purity. Furthermore, by using the aromatic nitrile compounds such as 2-naphthylacetonitrile obtained in this manner, pharmaceuticals such as (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane can be safely and inexpensively produced. BRIEF DESCRIPTION OF THE DRAWINGS

[0094] Figure 1 This is a graph showing the results of HPLC analysis of the crude crystals of the carboxylic acid compound obtained in Example 1.

[0095] Figure 2 This is a graph showing the results of HPLC analysis of the purified crystals of the carboxylic acid compound obtained in Example 1.

[0096] Figure 3 To show the purified crystals of the carboxylic acid compound obtained in Example 1 1 Graph showing H-NMR measurement results.

[0097] Figure 4 This is a graph showing the results of HPLC analysis of the carboxylic acid compound obtained in Example 2.

[0098] Figure 5 To show the carboxylic acid compound obtained in Example 2 1 Graph showing H-NMR measurement results.

[0099] Figure 6 This is a graph showing the results of HPLC analysis of the amide compound obtained in Example 4.

[0100] Figure 7 This is a graph showing the results of HPLC analysis of the nitrile compound obtained in Example 4.

[0101] Figure 8 This is a graph showing the results of HPLC analysis of the nitrile compound obtained in Example 5.

[0102] Figure 9 To show the nitrile compound obtained in Example 5 1 Graph showing H-NMR measurement results. DETAILED DESCRIPTION

[0103] The following describes the terms used in this specification.

[0104] In this specification, Np represents a naphthyl group which may have a substituent. Examples of the naphthyl group include 1-naphthyl and 2-naphthyl, with 2-naphthyl being preferred. Examples of substituents that Np may have include halogen atoms (e.g., chlorine atoms, bromine atoms), linear or branched alkyl groups having 1 to 6 carbon atoms (e.g., methyl groups, ethyl groups), and linear or branched alkoxy groups having 1 to 6 carbon atoms (e.g., methoxy groups, ethoxy groups). Np is particularly preferably 2-naphthyl.

[0105] In this manual, R 1 represents a linear or branched alkyl group having 1 to 3 carbon atoms. 1 It is an alkyl group having 1 to 2 carbon atoms, and a methyl group is particularly preferred.

[0106] In this manual, R 3 and R 4 Each independently represents a linear or branched alkyl group having 1 to 3 carbon atoms which may have a nitrogen atom, an oxygen atom or a sulfur atom, or a hydrogen atom. 3 With R 4 Can be bonded to form a ring. 3 and R4 Each independently represents an alkyl group having 1 to 2 carbon atoms which may have an oxygen atom, preferably R 3 With R 4 Bonded to form a ring. Particularly preferred is -NR 3 R 4 It is a morpholinyl group.

[0107] In this specification, X represents an oxygen atom or a sulfur atom.

[0108] In this manual, R 5 represents an alkylene group having 1 to 3 carbon atoms. 5 It is an alkylene group having 1 to 2 carbon atoms, and a methylene group is particularly preferred.

[0109] In this manual, R 6 and R 7 Each independently represents a chlorine atom, a hydroxyl group, an amino group, an isocyanate group or a p-tolyl group. 6 is an amino group or an isocyanate group, R 7 is a hydroxyl group, an amino group or a chlorine atom. In particular, R 6 and R 7 is amino, R 6 is amino and R 7 is hydroxyl, or R 6 is an isocyanate group and R 7 A chlorine atom.

[0110] In the present specification, Z represents a halogen atom, preferably a bromine atom or a chlorine atom, and particularly preferably a chlorine atom.

[0111] The present invention is described in detail below.

[0112] 1. Step 1

[0113]

[0114] Step 1 is a step of subjecting the compound represented by general formula (2) to a Wilgenre reaction in the presence of an additive as needed to obtain an amide compound represented by general formula (3), and then hydrolyzing the obtained amide compound represented by general formula (3) and neutralizing it to obtain a carboxylic acid compound represented by general formula (4).

[0115] In this specification, the Willgerodt reaction refers to the Willgerodt reaction and the Willgerodt-Kindler reaction.

[0116] As the compound represented by the general formula (2), 2'-acetonapthone is particularly preferred.

[0117] The Wilgenhall reaction can be carried out by allowing a sulfur compound such as sodium sulfide (Na2S·9H2O) or ammonium sulfide ((NH4)2S) to react with the compound represented by general formula (2) under heating. The sulfur compound may be used alone or in any combination and ratio. The reaction can be carried out in the presence of an aqueous solvent such as water.

[0118] The amount of the sulfur compound used is not particularly limited as long as it is an amount effective for causing the compound represented by general formula (2) to undergo a Wilgenhall reaction. The amount of the sulfur compound used is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of the compound represented by general formula (2).

[0119] The reaction temperature is usually 90° C. to 150° C., preferably 100° C. to 140° C., particularly preferably 110° C. to 130° C. The reaction is usually carried out under normal pressure.

[0120] The reaction time can be appropriately selected depending on the progress of the reaction and is usually 1 to 12 hours, preferably 2 to 10 hours.

[0121] The Wilgerrot reaction of the present invention can be carried out by allowing sulfur and a secondary amine such as a dialkylamine or morpholine to act on the compound represented by the general formula (2) under heating (Wilgerrot-Kindler reaction).

[0122] The amount of sulfur used is not particularly limited as long as it is an amount effective for causing the compound represented by formula (2) to undergo a Wilgerot-Kindler reaction. The amount of sulfur used is usually 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of the compound represented by formula (2).

[0123] As the secondary amine, morpholine is preferred in industrial production because the reaction can be efficiently carried out in the absence of a solvent.

[0124] The amount of the secondary amine used is not particularly limited as long as it is an amount effective for causing the compound represented by general formula (2) to undergo a Wilgerot-Kindler reaction. The amount of the secondary amine used is usually 2 to 6 mol, preferably 2 to 4 mol, per 1 mol of the compound represented by general formula (2).

[0125] The reaction can be carried out in the absence of a solvent or in an organic solvent that is inert to the reaction. Examples of such organic solvents include dioxane, water, and dimethylformamide. These organic solvents can be used alone or in any combination and ratio.

[0126] The reaction temperature is usually 90° C. to 150° C., preferably 100° C. to 140° C., particularly preferably 110° C. to 130° C. The reaction is usually carried out under normal pressure.

[0127] The reaction time can be appropriately selected depending on the progress of the reaction, and is usually 1 to 12 hours or longer, preferably 2 to 10 hours.

[0128] When performing the Wilgrove reaction, additives can be used as needed. As additives, dehydrating agents such as zeolite, molecular sieves, magnesium sulfate or sodium sulfate can be listed. The dehydrating agent can be used alone or in any combination and ratio. By using a dehydrating agent to control the amount of water in the reaction system, the reaction can be carried out efficiently. The amount of the dehydrating agent used is generally 1 mol to 5 mol, preferably 1.5 mol to 4 mol, relative to 1 mol of the compound represented by the general formula (2).

[0129] In addition, examples of additives include organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, and trifluoroacetic acid. One organic acid may be used alone, or two or more may be used in any combination and ratio. P-toluenesulfonic acid and methanesulfonic acid are particularly preferred as organic acids. Using these organic acids as additives can suppress the generation of byproducts, particularly the ketothioamide compound shown in the following formula, and allow the reaction to proceed efficiently.

[0130]

[0131] The amount of the organic acid used is usually 0.01 to 5 mol, preferably 0.05 to 3 mol, based on 1 mol of the compound represented by the general formula (2).

[0132] In order to control the reaction system so as to reduce the amount of water, the reaction may be carried out while dehydrating the reaction system by distillation.

[0133] The amide compound represented by the general formula (3) obtained by the Wilgerot reaction may be subjected to hydrolysis after being isolated from the reaction system, or may be directly subjected to the subsequent hydrolysis without isolation.

[0134] In the present invention, the amide compound represented by the general formula (3) is hydrolyzed using a base. Examples of the base include: alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkaline earth metal carbonates such as calcium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkaline earth metal bicarbonates such as calcium bicarbonate; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, and potassium ethoxide. In terms of cost and ease of acquisition, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are preferably used industrially. The base may be used alone or in any combination and ratio.

[0135] The amount of the base used is not particularly limited as long as it is an amount effective for hydrolyzing the amide compound represented by general formula (3). The amount of the base used is preferably 1 to 10 mol, more preferably 1 to 5 mol, per 1 mol of the amide compound represented by general formula (3).

[0136] The hydrolysis may be carried out without a solvent or in a solvent such as water. However, it is preferably carried out in a solvent from the viewpoint of excellent stirring properties and uniformity.

[0137] The temperature of the hydrolysis is not particularly limited as long as it is a temperature at which the hydrolysis proceeds. The temperature of the hydrolysis is usually 80°C to 115°C, preferably 85°C to 110°C.

[0138] The hydrolysis is usually carried out under normal pressure.

[0139] The reaction product obtained by hydrolysis (e.g., sodium 2-naphthylacetate) is neutralized to obtain a carboxylic acid compound represented by the general formula (4). For neutralization, an acid such as hydrochloric acid, sulfuric acid, or hydrobromic acid can be used. One acid can be used alone, or two or more acids can be used in any combination and ratio. From the perspectives of reaction efficiency and cost, hydrochloric acid is industrially preferred.

[0140] The amount of the acid used is not particularly limited as long as it is an amount effective for neutralization. The amount of the acid used is preferably 1 to 20 mol, more preferably 3 to 10 mol, per 1 mol of the reaction product obtained by hydrolysis.

[0141] The pH at the end point of neutralization is usually between 0 and 5.

[0142] The neutralization temperature is not particularly limited as long as it is a temperature at which neutralization proceeds. The neutralization temperature is usually 10°C to 80°C, and preferably 20°C to 50°C.

[0143] The reaction product obtained by neutralization may be washed once or multiple times with an appropriate washing liquid such as water or an aqueous solution.

[0144] An organic solvent can be used to extract and recover the carboxylic acid compound represented by the general formula (4) from the reaction product obtained by neutralization. As the organic solvent, hydrocarbon solvents that can dissolve the carboxylic acid compound represented by the general formula (4) can be cited. As hydrocarbon solvents, preferred examples include: alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; aromatic hydrocarbon solvents such as benzene, toluene, xylene, mesitylene, ethylbenzene, tert-butylbenzene, trifluoromethylbenzene, nitrobenzene, chlorobenzene, chlorotoluene, and bromobenzene. The hydrocarbon solvent can be used alone or in combination of two or more in any proportion. As hydrocarbon solvents, cyclohexane, toluene, xylene, and chlorobenzene are particularly preferred.

[0145] For example, an organic solvent (e.g., toluene, xylene, cyclohexane, chlorobenzene, etc.) capable of dissolving the carboxylic acid compound represented by the general formula (4) is added to the reaction product obtained by neutralization, and the mixture is stirred under acidic conditions (e.g., pH 3 or less) and heated (e.g., 50°C to 90°C). Washing, separation of the aqueous layer, concentration, etc. are performed as needed, and then cooling is performed. In this way, the carboxylic acid compound represented by the general formula (4) can be precipitated as a solid and recovered.

[0146] Since sulfur and sulfur compounds are used in the Wilgenhall reaction, the resulting reaction product generally contains several mol% or more of sulfur. Sulfur is an impurity in the target product of step 1, the carboxylic acid compound represented by general formula (4). Furthermore, when a chemical reaction is carried out using the carboxylic acid compound represented by general formula (4) as a raw material, it may reduce the reaction efficiency. Therefore, it is preferably removed as much as possible.

[0147] In the present invention, the sulfur content of the carboxylic acid compound represented by the general formula (4) obtained in step 1 can be reduced by contacting the compound with a hydrocarbon solvent after the hydrolysis, by containing a hydrocarbon solvent during the neutralization, or by contacting the reaction product obtained by the neutralization with a hydrocarbon solvent. When contacting the compound with a hydrocarbon solvent, water, an aqueous solution, or the like may be present as needed.

[0148] Preferred hydrocarbon solvents include, for example, alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; and aromatic hydrocarbon solvents such as benzene, toluene, xylene, mesitylene, ethylbenzene, tert-butylbenzene, trifluorotoluene, nitrobenzene, chlorobenzene, chlorotoluene, and bromobenzene. Toluene, xylene, and chlorobenzene are more preferred, and toluene is particularly preferred.

[0149] When the product is contacted with a hydrocarbon solvent after the hydrolysis, the hydrocarbon solvent may be added to the reaction product obtained by the hydrolysis reaction, or the reaction product obtained by the hydrolysis reaction may be added to the hydrocarbon solvent. In this case, water, an aqueous solution, or the like may be added as needed.

[0150] The hydrocarbon solvent is usually used in an amount of 1 to 20 times by volume, preferably 1.5 to 10 times by volume, and particularly preferably 3 to 5 times by volume, based on the carboxylic acid compound represented by the general formula (4).

[0151] The contact temperature is usually 50° C. to 90° C., preferably 60° C. to 80° C. The contact time is usually 10 minutes to 5 hours, preferably 30 minutes to 2 hours.

[0152] Then, the hydrocarbon solvent layer is removed by liquid separation or the like, and the aqueous layer containing the reaction product obtained by the hydrolysis reaction is subjected to a neutralization reaction.

[0153] When a hydrocarbon solvent is present during the neutralization, the neutralization reaction is carried out by adding an acid and a hydrocarbon solvent to the reaction product obtained by the hydrolysis reaction, or by adding the reaction product obtained by the hydrolysis reaction to a mixture of an acid and a hydrocarbon solvent. In this case, water, an aqueous solution, etc. may be added as needed.

[0154] The hydrocarbon solvent is usually used in an amount of 1 to 30 times by volume, preferably 3 to 20 times by volume, and particularly preferably 5 to 15 times by volume, based on the carboxylic acid compound represented by the general formula (4).

[0155] After the neutralization reaction, the aqueous layer is removed by separation or the like to obtain an organic layer containing the carboxylic acid compound represented by the general formula (4). The obtained organic layer can be washed once or multiple times with an appropriate washing liquid such as water or an aqueous solution.

[0156] When the reaction product obtained by the above neutralization is contacted with a hydrocarbon solvent, the hydrocarbon solvent is added to the reaction product obtained by the neutralization, or the reaction product obtained by the neutralization is added to the hydrocarbon solvent. In this case, water, an aqueous solution, etc. may be added as needed.

[0157] The hydrocarbon solvent is usually used in an amount of 1 to 20 times by volume, preferably 1.5 to 10 times by volume, and particularly preferably 3 to 5 times by volume, based on the carboxylic acid compound represented by the general formula (4).

[0158] The contact temperature is usually 50° C. to 90° C., preferably 60° C. to 80° C. The contact time is usually 10 minutes to 5 hours, preferably 30 minutes to 2 hours. Furthermore, the contact is preferably carried out under acidic conditions of pH 3 or less, preferably pH 2 or less.

[0159] Then, the aqueous layer is removed by separation or the like to obtain an organic layer containing the carboxylic acid compound represented by the general formula (4). The obtained organic layer can be washed once or multiple times with a suitable washing liquid such as water or an aqueous solution. The obtained organic layer is concentrated and cooled as needed to precipitate and recover the carboxylic acid compound represented by the general formula (4) in a solid form.

[0160] In the present invention, sulfur removal and extraction of the carboxylic acid compound represented by the general formula (4) can be performed using a single solvent. Therefore, toluene is particularly preferred as the hydrocarbon solvent.

[0161] Thus, the carboxylic acid compound represented by the general formula (4) obtained by contacting with a hydrocarbon solvent in step 1 of the present invention is a high-quality carboxylic acid compound having a sulfur content of 0.001 mol% to 1 mol%, preferably 0.001 mol% to 0.5 mol% and a purity of 98 mol% or more, preferably 99 mol% or more.

[0162] The carboxylic acid compound represented by the general formula (4) obtained in step 1 is useful as a synthetic raw material or synthetic intermediate for various industrial products, pharmaceuticals, etc., and can also be used in step 2 of the present invention.

[0163] 2. Step 2

[0164] Step 2 is a step of obtaining the nitrile compound represented by the above general formula (1) from the carboxylic acid compound represented by the above general formula (4).

[0165] Step 2 can be any of the following steps 2A or 2B.

[0166] The carboxylic acid compound represented by the general formula (4) may be a commercially available carboxylic acid compound or the carboxylic acid compound obtained in the above step 1. As the carboxylic acid compound represented by the general formula (4), 2-naphthylacetic acid is particularly preferred.

[0167] (1) Step 2A

[0168]

[0169] Step 2A is a step of reacting the carboxylic acid compound represented by the general formula (4) with a halogenating agent in an organic solvent in the presence of a catalyst as needed and further reacting it with an amidating agent to obtain an amide compound represented by the general formula (5) or the general formula (6), and reacting the obtained amide compound represented by the general formula (5) or the general formula (6) with a dehydrating agent to obtain the nitrile compound represented by the above-mentioned general formula (1).

[0170] First, the carboxylic acid compound represented by the general formula (4) is reacted with a halogenating agent in the presence of a catalyst as needed (acid halogenation).

[0171] As a halogenating agent, there is no particular limitation as long as the carboxylic acid compound shown in the general formula (4) can be halogenated. As a halogenating agent, preferably a chlorinating agent and a brominating agent, more preferably a chlorinating agent. As a chlorinating agent, thionyl chloride, oxalyl chloride, sulfuryl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride etc. can be listed, and as a brominating agent, thionyl bromide, phosphorus tribromide etc. can be listed. These halogenating agents can be used alone or in any combination and ratio. Among these, from the viewpoints of cost, versatility, reactivity, preferably thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, thionyl bromide, phosphorus tribromide, particularly preferably thionyl chloride.

[0172] The amount of the halogenating agent used is not particularly limited as long as it is an amount effective for acid halogenation, but is preferably 1 to 5 mol, more preferably 1 to 3 mol, and particularly preferably 1 to 2 mol per mol of the carboxylic acid compound represented by the general formula (4).

[0173] The organic solvent is not particularly limited as long as the reaction proceeds, and examples thereof include ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents, sulfoxide solvents, hydrocarbon solvents, and alkaline organic solvents. The organic solvents may be used alone or in any combination and ratio.

[0174] As the organic solvent, hydrocarbon solvents are preferred, for example, alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; and aromatic hydrocarbon solvents such as benzene, toluene, xylene, mesitylene, ethylbenzene, tert-butylbenzene, trifluoromethylbenzene, nitrobenzene, chlorobenzene, chlorotoluene, and bromobenzene. In particular, toluene, xylene, and chlorobenzene are preferred from the viewpoints of cost, versatility, and reactivity.

[0175] During the acyl halide reaction, a catalyst may be present to promote the reaction. The catalyst is not particularly limited as long as it promotes the reaction between the carboxylic acid compound represented by the general formula (4) and the halogenating agent. Examples of the catalyst include N,N-dimethylformamide, N-methylpyrrolidone, and N,N-dimethylacetamide, with N,N-dimethylformamide being particularly preferred.

[0176] The amount of the catalyst used is not particularly limited as long as it is an amount that functions as a catalyst. The amount of the catalyst used is preferably 0.0001 to 1 mol, particularly preferably 0.001 to 0.1 mol, per 1 mol of the carboxylic acid compound represented by the general formula (4).

[0177] The temperature of the acid halogenation reaction is generally 20°C to 60°C, preferably 30°C to 50°C, from the viewpoint of productivity. The reaction time can be appropriately selected depending on the progress of the reaction and is generally 0.5 to 10 hours, preferably 1 to 5 hours. The reaction is generally carried out under normal pressure.

[0178] The obtained acid halide reaction solution can be directly used in the subsequent amidation step.

[0179] The acid halide reaction solution obtained above is reacted with an amidating agent to obtain an amide compound represented by the general formula (5) or (6).

[0180] Examples of the amidating agent include ammonia (gas, aqueous solution) and hydroxylamine. As the amidating agent, ammonia (gas, aqueous solution) is preferred from the viewpoints of cost, versatility, reactivity, and the like.

[0181] When ammonia (gas or aqueous solution) is used as the amidating agent, an amide compound represented by the general formula (5) is obtained. When hydroxylamine is used as the amidating agent, an amide compound represented by the general formula (6) is obtained.

[0182] The amount of the amidating agent used is not particularly limited as long as it is an amount capable of amidation. From the viewpoints of cost, reactivity, etc., it is preferably 1 to 20 mol, more preferably 2 to 10 mol, per 1 mol of the carboxylic acid compound represented by general formula (4).

[0183] In the amidation reaction, the amidating agent may be added to the acid halide reaction solution, or the acid halide reaction solution may be added to the amidating agent. If necessary, a solvent such as water or an organic solvent may be present which does not inhibit the amidation reaction.

[0184] From the perspective of productivity, the amidation reaction temperature is generally 20°C to 60°C, preferably 30°C to 50°C. The reaction time can be appropriately selected depending on the progress of the reaction and is generally 0.5 to 10 hours, preferably 1 to 5 hours. The reaction is generally carried out under normal pressure.

[0185] When ammonia gas is used as the amidating agent, it can be supplied by purging the gas phase of the reaction vessel with ammonia gas, by reducing the pressure in the reaction vessel and then restoring the pressure with ammonia gas, or by bubbling ammonia gas into the reaction solution. From the perspective of productivity, the temperature in this case is generally 10°C to 80°C, preferably 20°C to 70°C.

[0186] Furthermore, when using ammonia as the amidating agent, it is preferable to reduce the amount of ammonia contained in the amidation reaction liquid obtained during the amidation prior to the reaction with the dehydrating agent. This can reduce the amount of dehydrating agent used later, improve operability, suppress the formation of by-products, and reduce costs.

[0187] Examples of methods for reducing ammonia gas contained in the reaction liquid include heating the reaction liquid, purging the gas phase in the reaction container with nitrogen, and reducing the pressure in the reaction container.

[0188] The amide compound represented by the general formula (5) or (6) obtained above is reacted with a dehydrating agent (dehydration cyanation) to obtain the nitrile compound represented by the general formula (1).

[0189] The amide compound represented by the general formula (5) or (6) may be directly subjected to the reaction with the dehydrating agent, or may be subjected to the reaction with the dehydrating agent after being separated, purified, or the like.

[0190] Examples of dehydrating agents include phosphorus-based dehydrating agents, chlorine-based dehydrating agents, and nitrogen-based dehydrating agents. Specifically, examples include phosphorus pentoxide, polyphosphoric acid, phosphorus pentachloride, thionyl chloride, phosphorus oxychloride, acetyl chloride, tosyl chloride-pyridine, cyanuric chloride, benzenesulfonyl chloride, oxalyl chloride, and phosphorus tribromide. The dehydrating agents may be used alone or in any combination and ratio.

[0191] As the dehydrating agent, phosphorus pentoxide, phosphorus oxychloride, cyanuric chloride, and phosphorus tribromide are preferred from the viewpoints of cost, reactivity, and the like.

[0192] The amount of the dehydrating agent used is not particularly limited as long as it is an amount capable of dehydration cyanation. From the viewpoints of cost and reactivity, it is preferably 0.1 to 10 mol, more preferably 0.5 to 10 mol, per 1 mol of the amide compound.

[0193] In the reaction of the amide compound with the dehydrating agent, the dehydrating agent may be added to the amidation reaction solution, or the amidation reaction solution may be added to the dehydrating agent. If necessary, a solvent such as water or an organic solvent may be present which does not inhibit the dehydration cyanation reaction.

[0194] From the perspective of productivity, the reaction temperature is usually 20°C to 120°C, preferably 50°C to 110°C, and particularly preferably 70°C to 100°C. The reaction time can be appropriately selected depending on the progress of the reaction and is usually 0.5 to 10 hours, preferably 1 to 8 hours. The reaction is usually carried out under normal pressure.

[0195] The nitrile compound represented by the general formula (1) thus obtained can be extracted and recovered from the dehydration cyanation reaction product using an organic solvent. For example, the dehydration cyanation reaction product can be mixed with an organic solvent capable of dissolving the nitrile compound represented by the general formula (1) (e.g., toluene, ethyl acetate, tert-butyl methyl ether, etc.), washed as needed, and the aqueous layer separated and concentrated, and then cooled, thereby precipitating the nitrile compound represented by the general formula (1) as a solid and recovering it.

[0196] In this step 2A, the amide compound represented by the general formula (5) or (6) has high crystallinity, and therefore, the high-purity amide compound can be easily separated and recovered. In addition, by using this high-purity amide compound, the nitrile compound represented by the general formula (1) can be obtained with high purity and high quality.

[0197] (2) Step 2B

[0198]

[0199] Step 2B is a step of reacting the carboxylic acid compound represented by the above general formula (4) with a halogenating agent and a compound represented by the following general formula (7) in an organic solvent in the presence of a catalyst as needed to obtain the nitrile compound represented by the above general formula (1).

[0200] R 6 SO2R 7 (7)

[0201] As the compound represented by the general formula (7), sulfonamide, aminosulfonic acid and chlorosulfonyl isocyanate are particularly preferred.

[0202] The target nitrile compound represented by the general formula (1) can be purified by crystallization using an organic solvent such as toluene or heptane.

[0203] Alternatively, water can be added to a reaction solution containing the target nitrile compound represented by the general formula (1), thereby precipitating the nitrile compound as crystals.

[0204] Step 2B can be carried out in one reactor and is therefore industrially preferred.

[0205] In step 2B, a high-quality nitrile compound represented by the general formula (1) can be obtained with a purity (HPLC) of preferably 98 area % or higher, particularly preferably 99 area % or higher.

[0206] Specifically, step 2B may be any one of the following steps 2B-1 and 2B-2.

[0207] Step 2B-1:

[0208]

[0209] Step 2B-1 is a step of reacting the carboxylic acid compound represented by the above general formula (4) with a halogenating agent and a compound represented by the general formula (7) in an organic solvent at 80°C to 180°C in the presence of a catalyst as needed to obtain the nitrile compound represented by the above general formula (1).

[0210] As a halogenating agent, there is no particular limitation as long as the carboxylic acid compound shown in the general formula (4) can be halogenated. As a halogenating agent, preferably a chlorinating agent and a brominating agent, more preferably a chlorinating agent. As a chlorinating agent, thionyl chloride, oxalyl chloride, sulfuryl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride etc. can be listed, and as a brominating agent, thionyl bromide, phosphorus tribromide etc. can be listed. These halogenating agents can be used alone or in any combination and ratio. Among these, from the viewpoints of cost, versatility, reactivity, preferably thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, thionyl bromide, phosphorus tribromide, particularly preferably thionyl chloride.

[0211] The amount of the halogenating agent used is not particularly limited as long as it is an amount capable of halogenating the carboxylic acid compound represented by the general formula (4). However, in order to sufficiently halogenate the carboxylic acid compound, it is preferably used in an amount of 1 mol or more per 1 mol of the carboxylic acid compound.

[0212] The upper limit of the amount used is not particularly limited, but from the perspectives of cost and productivity, it is preferably 3 mol or less per mol of the carboxylic acid compound. That is, the amount of the halogenating agent used is 1 to 3 mol, more preferably 1.02 to 2 mol, and particularly preferably 1.05 to 1.5 mol, per mol of the carboxylic acid compound. In order to complete the reaction, it is preferred to use a slightly larger amount of the halogenating agent than the theoretical amount.

[0213] The amount of the compound represented by the general formula (7) used is not particularly limited as long as it is an amount capable of cyanating the acid halide compound represented by the general formula (8) produced by the reaction of the carboxylic acid compound represented by the general formula (4) with the halogenating agent.

[0214] Np-R 5 -COZ (8)

[0215] (In general formula (8), Z represents a halogen atom, Np and R 5 Has the same meaning as defined above.)

[0216] The amount of the compound represented by the general formula (7) is 1 to 3 mol, more preferably 1.02 to 2 mol, and particularly preferably 1.05 to 1.5 mol, per mol of the carboxylic acid compound.

[0217] In step 2B-1, it is preferred that the amount of the compound represented by the general formula (7) is greater than the amount of the halogenating agent. From the viewpoints of effect and cost, it is preferred that the amount of the compound represented by the general formula (7) is 2% to 20%, preferably 5% to 15%, more than the amount of the halogenating agent. Thus, the nitrile compound represented by the general formula (1) as the target can be obtained in high yield. When the amount of the compound represented by the general formula (7) is less than the amount of the halogenating agent, it is possible to generate more by-products and reduce the yield of the target nitrile compound. In addition, when the amount of the compound represented by the general formula (7) is the same as the amount of the halogenating agent, it is possible that the reaction cannot be fully carried out.

[0218] It should be noted that a catalyst may be present to promote the reaction. The catalyst is not particularly limited as long as it promotes the reaction in step 2B-1. Examples of the catalyst include N,N-dimethylformamide, N-methylpyrrolidone, and N,N-dimethylacetamide, with N,N-dimethylformamide being particularly preferred.

[0219] The amount of the catalyst used is not particularly limited as long as it is an effective amount for catalytic function. The amount of the catalyst used is preferably 0.0001 to 1 mol, more preferably 0.001 to 0.1 mol, per 1 mol of the carboxylic acid compound represented by general formula (4).

[0220] The organic solvent is not particularly limited as long as the reaction of Step 2B-1 can proceed. Examples of the organic solvent include ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents, sulfoxide solvents, sulfone solvents, hydrocarbon solvents, and alkaline organic solvents. These organic solvents may be used alone or in any combination and ratio.

[0221] As the ester solvent, for example, acetic acid esters such as ethyl acetate, propyl acetate, and butyl acetate can be used.

[0222] As the ether solvent, for example, chain ethers such as diethyl ether, di-n-butyl ether, diisopropyl ether, and tert-butyl methyl ether; and cyclic ethers such as cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane can be used.

[0223] As the ketone solvent, for example, aliphatic ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone can be used.

[0224] As the nitrile solvent, for example, aliphatic nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, and isovaleronitrile; and aromatic nitriles such as benzonitrile can be used.

[0225] As the amide solvent, for example, aprotic amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone can be used.

[0226] As the sulfoxide solvent, for example, an aprotic sulfoxide such as dimethyl sulfoxide can be used.

[0227] As the sulfone solvent, for example, aprotic sulfones such as ethyl methyl sulfone, ethyl isopropyl sulfone, 3-methyl sulfolane, and sulfolane can be used.

[0228] As the hydrocarbon solvent, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, and cycloheptane; and aromatic hydrocarbons such as toluene and xylene can be used.

[0229] As the basic organic solvent, for example, a pyridine-based solvent such as pyridine, 2-picoline, 3-picoline, 4-picoline, or 2,6-lutidine can be used.

[0230] The amount of the organic solvent used is usually 1 L or more relative to 1 kg of the carboxylic acid compound represented by the general formula (4). From the viewpoint of operability, etc., it is preferably 2 L or more, and more preferably 3 L or more. As the upper limit, from the viewpoint of operability, productivity and cost, it is usually 50 L or less, preferably 20 L or less, more preferably 10 L or less, further preferably 4.5 L or less, and particularly preferably 4 L or less.

[0231] In this step, from the viewpoints of reactivity, productivity, etc., it is preferred to use a sulfone solvent as the organic solvent. In particular, from the viewpoint of increasing the yield of the target nitrile compound, it is preferred to use sulfolane. The sulfone solvent is preferably used alone, but it can also be used in combination with other organic solvents in any ratio.

[0232] The reaction temperature with the halogenating agent may vary depending on the organic solvent, catalyst, etc. used. As a lower limit, from the viewpoints of quality and reactivity, it is usually 80°C or higher, preferably 85°C or higher, and particularly preferably 90°C or higher. As an upper limit, from the viewpoints of quality, reactivity, cost, etc., it is usually 180°C or lower, preferably 150°C or lower, and particularly preferably 120°C or lower.

[0233] If the reaction temperature is too low, the reaction may proceed slowly and productivity may decrease. If it is too high, by-products may be generated and the quality of the target nitrile compound may decrease.

[0234] The reaction temperature with the compound represented by the above general formula (7) is not particularly limited as long as the reaction can proceed. As a lower limit, from the viewpoint of productivity, it is usually 0°C or above, preferably 10°C or above, more preferably 15°C or above. As an upper limit, from the viewpoint of quality and cost, it is usually 180°C or below, preferably 150°C or below, more preferably 120°C or below, and particularly preferably 20°C to 110°C.

[0235] If the reaction temperature is too low, the reaction may proceed slowly and productivity may decrease. If it is too high, by-products may be generated and the quality of the target nitrile compound may decrease.

[0236] The reaction time may vary depending on the organic solvent, catalyst, etc. used, and can be appropriately selected according to the progress of the reaction, but is generally 0.5 to 30 hours, preferably 1 to 15 hours. The pressure during the reaction is generally normal pressure.

[0237] One embodiment of this step includes mixing the carboxylic acid compound represented by the general formula (4), a halogenating agent, a compound represented by the general formula (7), an organic solvent, and, if necessary, a catalyst at 20°C to 70°C, and then heating the mixture to 80°C to 180°C.

[0238] Another embodiment of this step includes mixing the carboxylic acid compound represented by the general formula (4), the halogenating agent, the compound represented by the general formula (7), an organic solvent, and, if necessary, a catalyst at 80°C to 180°C.

[0239] Another embodiment of this step is to mix the carboxylic acid compound represented by the general formula (4), the compound represented by the general formula (7), an organic solvent, and, if necessary, a catalyst at 20°C to 70°C, then raise the temperature to 80°C to 180°C and add a halogenating agent. This embodiment is preferred because it can easily suppress the precipitation of the sulfonamide compound as a reaction intermediate.

[0240] Step 2B-2:

[0241]

[0242] Step 2B-2 is a step of reacting a reaction raw material 1 obtained by mixing a carboxylic acid compound represented by the above general formula (4), a halogenating agent, a first organic solvent and, if necessary, a catalyst, with a reaction raw material 2 obtained by mixing a compound represented by the above general formula (7) and a second organic solvent at 80°C to 180°C to obtain a nitrile compound represented by the above general formula (1).

[0243] Examples of the halogenating agent and the compound represented by the above general formula (7) include the same ones as in step 2B-1.

[0244] The amount of the halogenating agent used is preferably 1 mol or more relative to 1 mol of the carboxylic acid compound represented by the general formula (4). In addition, from the viewpoints of cost, productivity, etc., it is preferably set to 3 mol or less relative to 1 mol of the carboxylic acid compound. The amount of the halogenating agent used is preferably 1.02 mol to 2 mol, particularly preferably 1.05 mol to 1.5 mol relative to 1 mol of the carboxylic acid compound. In order to complete the reaction, it is preferred to use a slightly larger amount of the halogenating agent than the theoretical amount.

[0245] The amount of the compound represented by the general formula (7) is preferably 1 mol or more per mol of the carboxylic acid compound represented by the general formula (4). The amount of the compound represented by the general formula (7) is preferably 1 to 5 mol, more preferably 1.02 to 3 mol, and particularly preferably 1.05 to 2 mol, per mol of the carboxylic acid compound.

[0246] In step 2B-2, it is preferred that the amount of the compound represented by the general formula (7) is greater than the amount of the halogenating agent. From the viewpoints of effect and cost, it is preferred that the amount of the compound represented by the general formula (7) is 2% to 20%, preferably 5% to 15%, more than the amount of the halogenating agent. Thus, the nitrile compound represented by the general formula (1) as the target can be obtained in high yield. When the amount of the compound represented by the general formula (7) is less than the amount of the halogenating agent, it is possible to generate more by-products and reduce the yield of the target nitrile compound. In addition, when the amount of the compound represented by the general formula (7) is the same as the amount of the halogenating agent, it is possible that the reaction cannot be fully carried out.

[0247] The first organic solvent is not particularly limited as long as the reaction in Step 2B-2 can proceed. Examples of the organic solvent include ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents, sulfoxide solvents, sulfone solvents, hydrocarbon solvents, and alkaline organic solvents. These organic solvents may be used alone or in any combination and ratio.

[0248] As the ester solvent, for example, acetic acid esters such as ethyl acetate, propyl acetate, and butyl acetate can be used.

[0249] As the ether solvent, for example, chain ethers such as diethyl ether, di-n-butyl ether, diisopropyl ether, and tert-butyl methyl ether; and cyclic ethers such as cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and dioxane can be used.

[0250] As the ketone solvent, for example, aliphatic ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone can be used.

[0251] As the nitrile solvent, for example, aliphatic nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, and isovaleronitrile; and aromatic nitriles such as benzonitrile can be used.

[0252] As the amide solvent, for example, aprotic amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone can be used.

[0253] As the sulfoxide solvent, for example, an aprotic sulfoxide such as dimethyl sulfoxide can be used.

[0254] As the sulfone solvent, for example, aprotic sulfones such as ethyl methyl sulfone, ethyl isopropyl sulfone, 3-methyl sulfolane, and sulfolane can be used.

[0255] As the hydrocarbon solvent, alicyclic hydrocarbons such as cyclohexane and methylcyclohexane; and aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, ethylbenzene, tert-butylbenzene, trifluoromethylbenzene, nitrobenzene, chlorobenzene, chlorotoluene, and bromobenzene can be used.

[0256] As the basic organic solvent, for example, a pyridine-based solvent such as pyridine, 2-picoline, 3-picoline, 4-picoline, or 2,6-lutidine can be used.

[0257] As the first organic solvent, a hydrocarbon solvent is preferred. From the viewpoints of operability, productivity, and cost, toluene, xylene, and chlorobenzene are more preferred, and toluene is particularly preferred.

[0258] Furthermore, as the first organic solvent, a sulfone solvent is also preferred, and sulfolane is preferred from the viewpoints of reactivity, productivity, and the like.

[0259] Furthermore, as the first organic solvent, a mixture of a hydrocarbon solvent and a sulfone solvent is also preferably used, and a mixture of toluene and sulfolane is particularly preferred. The mixing ratio (volume ratio) of the hydrocarbon solvent to the sulfone solvent can be appropriately selected within the range of 1:99 to 99:1.

[0260] The amount of the first organic solvent used is usually 1 L or more relative to 1 kg of the carboxylic acid compound represented by the general formula (4). From the viewpoint of operability, etc., it is preferably 2 L or more, and more preferably 3 L or more. As the upper limit, from the viewpoint of operability, productivity and cost, it is usually 50 L or less, preferably 30 L or less, more preferably 20 L or less, further preferably 4.5 L or less, and particularly preferably 4 L or less.

[0261] As the second organic solvent, a sulfone solvent is preferably used from the viewpoint of reactivity, productivity, etc. Examples of the sulfone solvent include aprotic sulfones such as ethyl methyl sulfone, ethyl isopropyl sulfone, 3-methylsulfolane, and sulfolane.

[0262] In particular, sulfolane is preferably used from the viewpoint of increasing the yield of the target nitrile compound. The sulfone solvent is preferably used alone, but may also be used in admixture with other organic solvents (eg, hydrocarbon solvents) in any proportion.

[0263] The amount of the second organic solvent used is usually 1 L or more relative to 1 kg of the carboxylic acid compound represented by the general formula (4). From the viewpoint of operability, etc., it is preferably 2 L or more, and more preferably 3 L or more. As the upper limit, from the viewpoint of operability, productivity and cost, it is usually 50 L or less, preferably 30 L or less, more preferably 20 L or less, further preferably 4.5 L or less, and particularly preferably 4 L or less.

[0264] The type and amount of catalyst used are the same as those in step 2B-1.

[0265] The reaction raw material 1 is prepared by mixing a carboxylic acid compound represented by the general formula (4), a halogenating agent, a first organic solvent, and, if necessary, a catalyst. The preparation temperature is generally 15°C to 65°C, preferably 20°C to 60°C, and particularly preferably 30°C to 50°C. If the preparation temperature is too low, the reaction proceeds slowly and productivity decreases. If it is too high, by-products are generated, which may reduce the quality of the target nitrile compound.

[0266] The reaction raw material 1 may be concentrated, purified, etc.

[0267] The reaction material 2 is prepared by mixing the compound represented by the above general formula (7) with a second organic solvent. The preparation temperature is not particularly limited, but is usually 10°C to 180°C, preferably 20°C to 150°C.

[0268] In addition, inorganic additives (such as diatomaceous earth, anhydrous silicic acid, silicon dioxide, sodium sulfate, magnesium sulfate, sodium chloride, magnesium chloride, calcium carbonate, magnesium carbonate, etc.) can be added to the reaction raw materials 1 or 2 as needed. By using inorganic additives, the reaction can proceed more smoothly.

[0269] In this step, the reaction raw materials 1 and 2 may be mixed and then heated to react at 80°C to 180°C, or the reaction raw materials 1 at 80°C to 180°C and the reaction raw materials 2 at 80°C to 180°C may be mixed and reacted. Furthermore, the reaction raw material 2 may be added to the reaction raw material 1 and mixed, or the reaction raw material 1 may be added to the reaction raw material 2 and mixed.

[0270] The reaction time of reaction raw material 1 and reaction raw material 2 may vary according to the halogenating agent, organic solvent, catalyst, etc. used and can be appropriately selected according to the progress of the reaction, usually 0.5 hour to 30 hours, preferably 1 hour to 15 hours, and particularly preferably 2 hours to 10 hours. The pressure during the reaction is usually normal pressure.

[0271] (3) Post-steps

[0272] The reaction solution containing the nitrile compound represented by the general formula (1) obtained in the above step 2A or 2B may be subjected to treatments such as neutralization, separation, filtration, etc., or the target nitrile compound represented by the general formula (1) may be isolated by separation means such as concentration and crystallization.

[0273] The nitrile compound represented by the general formula (1) obtained in the present invention is of high quality with a purity (HPLC) of preferably 98% or more, particularly preferably 99% or more, but can be further purified by known purification means such as recrystallization and column chromatography as needed.

[0274] The production method of the present invention may be a batch method or a continuous method.

[0275] Furthermore, each compound in the present invention may form a solvate such as a hydrate or an organic solvate, and the form thereof is not particularly limited as long as it does not inhibit the reaction.

[0276] In the present invention, the following steps are particularly preferred.

[0277] Step 1: A step of reacting 2'-acetonapthone, sulfur, and morpholine and then hydrolyzing to obtain 2-naphthylacetic acid

[0278]

[0279] Step 2A: reacting 2-naphthylacetic acid with thionyl chloride and ammonia (gas or aqueous solution) to obtain 2-naphthylacetamide, and further reacting it with phosphorus oxychloride to obtain 2-naphthylacetonitrile

[0280]

[0281] Step 2B-1: a step of reacting 2-naphthylacetic acid, sulfolane, thionyl chloride, sulfonamide, and a catalyst as needed at 80°C to 180°C to obtain 2-naphthylacetonitrile

[0282]

[0283] Step 2B-2: a step of reacting a reaction material 1 obtained by mixing 2-naphthylacetic acid, thionyl chloride, toluene and a catalyst as needed with a reaction material 2 obtained by mixing sulfonamide and sulfolane at 80°C to 180°C to obtain 2-naphthylacetonitrile

[0284]

[0285] Example

[0286] The present invention will be further described in detail with reference to the following examples, but the present invention is not limited to these examples.

[0287] In the following examples and comparative examples, commercially available 2'-acetonapthone was used. The purity of the obtained compound was measured by HPLC under the following analytical conditions.

[0288] (HPLC analysis conditions-1)

[0289] Analytical equipment: HPLC (1200 series) manufactured by Agilent

[0290] Column: Cadenza CD-C18, 3 μm, 150 mm × 4.6 mm

[0291] Mobile phase A: 0.1% trifluoroacetic acid in water

[0292] Mobile phase B: acetonitrile

[0293] Gradient: 0 min (B: 15%) - 15 min (B: 90%) - 20 min (B: 90%)

[0294] Flow rate: 1.0 mL / min

[0295] Injection volume: 5 μL

[0296] Detection wavelength: 215 nm

[0297] Column temperature: 40°C

[0298] (HPLC analysis conditions-2)

[0299] Analytical equipment: HPLC (1200 series) manufactured by Agilent

[0300] Column: Cadenza CD-C18, 3 μm, 150 mm × 4.6 mm

[0301] Mobile phase A: 0.1% trifluoroacetic acid in water

[0302] Mobile phase B: acetonitrile

[0303] Gradient: 0 min (B: 15%) - 20 min (B: 90%) - 25 min (B: 90%)

[0304] Flow rate: 1.0 mL / min

[0305] Injection volume: 5 μL

[0306] Detection wavelength: 280 nm

[0307] Column temperature: 40°C

[0308] (HPLC analysis conditions-3)

[0309] Analytical equipment: HPLC (1200 series) manufactured by Agilent

[0310] Column: Zorbax Eclipse Plus Phenyl-Hexyl, 5 μm, 250 mm × 4.6 mm

[0311] Mobile phase A: 0.1% trifluoroacetic acid in water

[0312] Mobile phase B: acetonitrile

[0313] Gradient: 0 min (B: 30%) - 15 min (B: 60%) - 20 min (B: 95%) - 30 min (B: 95%)

[0314] Flow rate: 1.0 mL / min

[0315] Injection volume: 5 μL

[0316] Detection wavelength: 280 nm

[0317] Column temperature: 40°C

[0318] Example 1: Synthesis of carboxylic acid compounds

[0319]

[0320] To a reaction vessel purged with nitrogen, 3.00 g of 2'-acetonapthone and 0.85 g of sulfur (1.5 molar times relative to 2'-acetonapthone) were added, and further 4.61 g of morpholine (3 molar times relative to 2'-acetonapthone) was added. After stirring, the mixture was reacted at 115° C. to 125° C. for 4 hours (to produce a thioamide compound).

[0321] After the reaction solution is cooled to 70°C to 80°C, a sodium hydroxide aqueous solution with a concentration of 20% by weight (a solution obtained by mixing 3.53g of sodium hydroxide with 14.1g of water. The amount of sodium hydroxide is 5 moles of 2'-naphthone) is added, and the mixture is reacted at 90°C to 105°C for 8 hours (hydrolysis). The reaction solution is cooled to 50°C to 60°C, 0.15g of activated carbon (refined egret) is added, and the mixture is stirred and filtered. To the obtained filtrate, hydrochloric acid with a concentration of 35% (a solution obtained by mixing 14.69g of hydrochloric acid with 12.4mL of water) is added, stirred and cooled, and 2-naphthylacetic acid is recovered as crude crystals.

[0322] 2.0 g of the resulting crude crystals of 2-naphthylacetic acid (purity (HPLC analysis conditions - 1) 92.6%) were dissolved in 20 mL of toluene at 115°C and then cooled to below 10°C to precipitate the carboxylic acid compound. 1.3 g of the resulting 2-naphthylacetic acid had a purity of 98.2 area % as measured by HPLC (HPLC analysis conditions - 1).

[0323] 1 H-NMR(400MHz, CDCl3) δ3.80 (2H, s), 7.40 (1H, dd, J=8.4, 3.0Hz),7.43-7.49 (2H, m), 7.73 (1H, s), 7.78-7.82 (3H, m)

[0324] The results of HPLC analysis of the obtained crude crystals of the carboxylic acid compound (2-naphthylacetic acid) are shown in FIG. Figure 1In addition, the HPLC analysis results of the purified crystals of the obtained carboxylic acid compound (2-naphthylacetic acid) are shown in Figure 2 ,Will 1 The results of H-NMR measurements are shown in Figure 3 .

[0325] Example 2: Synthesis of carboxylic acid compounds

[0326]

[0327] To a nitrogen-purged reaction vessel were added 120.00 g of 2'-acetonapthone, 28.26 g of sulfur (1.25 molar times relative to 2'-acetonapthone), 13.41 g of p-toluenesulfonic acid monohydrate (0.10 molar times relative to 2'-acetonapthone), and 184.26 g of morpholine (3 molar times relative to 2'-acetonapthone). After stirring, the mixture was reacted at 115°C to 125°C for 9 hours (to produce a thioamide compound).

[0328] After cooling the reaction mixture to 70°C to 80°C, a 20% by weight aqueous sodium hydroxide solution (a solution obtained by mixing 141.00 g of sodium hydroxide with 564.01 g of water, representing 5 molar ratios of sodium hydroxide relative to 2'-acetonapthone) was added, and the mixture was reacted at 90°C to 105°C for 4 hours (hydrolysis). The reaction mixture was cooled to 60°C to 70°C, 120.00 g of water and 240.00 mL of toluene were added, and the mixture was stirred at 65°C to 75°C. After standing, the upper layer was discarded (to remove unreacted sulfur).

[0329] The obtained lower layer is added to a mixed solution of 1200 mL of toluene and 35% hydrochloric acid (a solution obtained by mixing 205.64 g of hydrochloric acid with 281.90 mL of water. The amount of hydrochloric acid is 8 times the molar amount of 2'-acetonapthone). 12.00 g of water is further added to the reaction vessel to which the lower layer has been added for washing, and the obtained liquid is also added to the mixed solution. The mixed solution to which the above-mentioned lower layer has been added is stirred at 65°C to 75°C and then allowed to stand (to extract the carboxylic acid compound), and the obtained lower layer is discarded. 600.00 g of water is added to the remaining upper layer, and the mixture is stirred at 65°C to 75°C and then allowed to stand, and the lower layer is discarded. 600.00 g of water is further added to the remaining upper layer, and the mixture is stirred at 65°C to 75°C and then allowed to stand, and the lower layer is discarded.

[0330] The upper layer was concentrated and cooled to below 10°C, and the precipitated carboxylic acid compound (2-naphthylacetic acid) crystals were recovered. The resulting carboxylic acid compound (2-naphthylacetic acid) was 104.14 g, and its purity as measured by HPLC (HPLC analysis condition - 3) was 99.6 area %.

[0331] 1 H-NMR(400MHz, CDCl3) δ3.80 (2H, s), 7.40 (1H, dd, J=8.4, 3.0Hz),7.43-7.49 (2H, m), 7.73 (1H, s), 7.78-7.82 (3H,m)

[0332] The HPLC analysis results of the obtained carboxylic acid compound (2-naphthylacetic acid) are shown in Figure 4 ,Will 1 The results of H-NMR measurements are shown in Figure 5 .

[0333] Example 3: Synthesis of carboxylic acid compounds

[0334]

[0335] To a nitrogen-purged reaction vessel were added 120.00 g of 2'-acetonapthone, 120 mL of toluene (1.0 volume times relative to 2'-acetonapthone), and 0.34 g of methanesulfonic acid (0.005 molar times relative to 2'-acetonapthone). Furthermore, 184.26 g of morpholine (3 molar times relative to 2'-acetonapthone) was added, and the mixture was stirred and distilled for 15 hours.

[0336] The mixture was then concentrated, and 28.26 g of sulfur (1.25 times by mole relative to 2'-acetonapthone) was added, followed by reaction at 95° C. to 105° C. for 7 hours (to produce a thioamide compound).

[0337] After the reaction solution was cooled to 70°C to 80°C, a 20% by weight aqueous sodium hydroxide solution (a solution obtained by mixing 141.00 g of sodium hydroxide with 564.01 g of water, 5 times the molar amount of sodium hydroxide relative to 2'-acetonapthone) was added, and the reaction was carried out at 90°C to 105°C for 7 hours (hydrolysis). The reaction solution was cooled to 60°C to 70°C, 120.00 g of water and 240.00 mL of toluene were added, and the mixture was stirred at 65°C to 75°C. After standing, the upper layer was separated and discarded.

[0338] The obtained lower layer is added to a mixed solution of 1200 mL of toluene and 35% hydrochloric acid (a solution obtained by mixing 205.64 g of hydrochloric acid with 281.90 mL of water. The amount of hydrochloric acid is 8 times the molar amount of 2'-acetonapthone). After stirring at 65°C to 75°C, the lower layer is discarded. 600.00 g of water is added to the upper layer, the mixture is stirred at 65°C to 75°C, the mixture is allowed to stand, and the lower layer is discarded. 600.00 g of water is further added to the upper layer, the mixture is stirred at 65°C to 75°C, the mixture is allowed to stand, and the lower layer is discarded.

[0339] The obtained upper layer was concentrated and then cooled to below 10° C. to obtain 2-naphthylacetic acid crystals. The obtained 2-naphthylacetic acid amounted to 104.83 g and had a purity of 99.8 area % as measured by HPLC (HPLC analysis condition-3).

[0340] Comparative Example 1: Synthesis of Carboxylic Acid Compounds

[0341]

[0342] To a nitrogen-purged reaction vessel, 1.00 g of 2'-acetonapthone and 0.24 g of sulfur (1.25 molar times relative to 2'-acetonapthone) were added, and further 1.50 g of piperidine (3.0 molar times relative to 2'-acetonapthone) was added. After stirring, the mixture was reacted at 115° C. to 125° C. for 5 hours (to produce a thioamide compound).

[0343] After the reaction solution was cooled to 70°C to 80°C, a 20% by weight aqueous sodium hydroxide solution (a solution obtained by mixing 0.70 g of sodium hydroxide and 2.82 g of water. The amount of sodium hydroxide is 3 times by mole relative to 2'-acetonapthone) was added, and the mixture was reacted at 90°C to 105°C for 6 hours. Then, a 48% by weight aqueous sodium hydroxide solution (a solution obtained by mixing 0.70 g of sodium hydroxide and 0.76 g of water. The amount of sodium hydroxide is 3 times by mole relative to 2'-acetonapthone) was further added, and the mixture was reacted at 90°C to 105°C for 3 hours (hydrolysis).

[0344] As a result of HPLC analysis (HPLC analysis condition-3), a carboxylic acid compound (2-naphthylacetic acid) was produced at a purity of 7 area %.

[0345] Since the yield of the carboxylic acid compound was small, it is considered that the reaction did not proceed sufficiently when piperidine was used instead of morpholine.

[0346] Reference Example 1: Synthesis of thioamide compounds

[0347]

[0348] To a nitrogen-purged reaction vessel, 1.00 g of 2'-acetonapthone and 0.20 to 0.28 g of sulfur (1.05 to 1.50 molar times relative to 2'-acetonapthone) were added, followed by 1.53 g of morpholine (3.0 molar times relative to 2'-acetonapthone). After stirring, the mixture was reacted at 80°C to 120°C for 6 to 22 hours to synthesize a thioamide compound.

[0349] As a result of HPLC analysis (HPLC analysis condition-3), a thioamide compound was produced at a purity of 77 area % to 85 area %. The results are shown in Table 1.

[0350] Reference Example 2: Synthesis of thioamide compounds

[0351]

[0352] To a nitrogen-purged reaction vessel, 1.00 g of 2'-acetonapthone, 0.23 g of sulfur (1.25 molar times relative to 2'-acetonapthone), and additives (see Table 1) were added. 1.54 g of morpholine (3.0 molar times relative to 2'-acetonapthone) was further added. After stirring, the mixture was reacted at 115°C to 125°C for 3 to 25 hours to synthesize a thioamide compound.

[0353] As a result of HPLC analysis (HPLC analysis condition-3), a thioamide compound was produced at a purity of 84 area % to 88 area %. The results are shown in Table 1.

[0354] In Table 1, Na2SO4 represents sodium sulfate, MgSO4 represents magnesium sulfate, pTsOH·H2O represents p-toluenesulfonic acid monohydrate, and MsOH represents methanesulfonic acid.

[0355] As can be seen from Table 1, the amount of thioamide compound produced increases by using appropriate additives.

[0356] [Table 1]

[0357]

[0358] Reference Example 3: Synthesis of thioamide compounds

[0359] Thioamide compounds were synthesized based on the method described in Non-Patent Document 5 (Green Chemistry Letters and Reviews, 2010, 315-318).

[0360] To a nitrogen-purged reaction vessel, 1.00 g of 2'-acetonapthone and 0.21 g of sulfur (1.10 molar times relative to 2'-acetonapthone) were added, followed by 0.56 g of morpholine (1.10 molar times relative to 2'-acetonapthone) and 3.0 mL of polyethylene glycol (PEG-600) (3.0 volume times relative to 2'-acetonapthone). The mixture was stirred and reacted at 100°C for 7 hours to synthesize a thioamide compound.

[0361] As a result of HPLC analysis (HPLC analysis condition-3), a thioamide compound was produced at a purity of 34 area %.

[0362] When polyethylene glycol was used, the yield of the thioamide compound was low, and improvement in reactivity due to the use of polyethylene glycol was not observed.

[0363] Example 4: Synthesis of Nitrile Compounds

[0364]

[0365] Into a nitrogen-purged reaction vessel, 0.50 g of 2-naphthylacetic acid obtained in Example 1, 0.38 g of thionyl chloride (1.2 times by mole relative to the carboxylic acid compound), and 2.5 mL of toluene (5 times by volume relative to the carboxylic acid compound) were mixed. One drop of N,N-dimethylformamide was added as a catalyst, and the mixture was reacted at 40° C. for 3 hours (acid chlorination).

[0366] The chlorination reaction solution was further added dropwise to 0.82 g of a 28% aqueous ammonia solution (5 molar times of ammonia relative to the carboxylic acid compound) and reacted at 50° C. for 1 hour. After cooling to room temperature, the precipitated amide compound was recovered by filtration (yield 77%).

[0367] 0.40 g of the amide compound obtained above and 0.36 g of phosphoryl chloride (1.1 molar times relative to the amide compound) were reacted at 85° C. for 4 hours. The resulting reaction solution was separated, and the resulting organic layer was concentrated under reduced pressure. To the resulting concentrated residue was added 0.8 mL of a mixed solution of toluene and 3.2 mL of heptane (2 volumes and 8 volumes, respectively, relative to the amide compound) and stirred. The precipitated 2-naphthylacetonitrile was recovered. The resulting 2-naphthylacetonitrile weighed 0.26 g and had a purity of 97.2 area % as measured by HPLC (HPLC analysis condition -2).

[0368] The HPLC analysis results of the obtained amide compound (HPLC analysis condition-2) are shown in Figure 6 The HPLC analysis results of 2-naphthylacetonitrile are shown in Figure 7 .

[0369] Example 5: Synthesis of Nitrile Compounds

[0370]

[0371] 90.0 g of 2-naphthylacetic acid obtained in Example 2, 51.1 g of sulfamide (1.1 molar times relative to the carboxylic acid compound), and 315 mL of sulfolane (3.5 volume times relative to the carboxylic acid compound) were added to the reaction vessel after nitrogen substitution, and the temperature was raised after stirring. 69.0 g of thionyl chloride (1.2 molar times relative to the carboxylic acid compound) was added at 95° C. to 105° C. After reacting for 7 hours at 95° C. to 105° C., the reaction solution was cooled, 1.8 g of activated carbon (Strong Egret) (0.02 weight times relative to the carboxylic acid compound) and 180 mL of methanol (2 volume times relative to the carboxylic acid compound) were added at 50° C. to 60° C., and the mixture was filtered after stirring. The filtered residue was washed with 90 mL of methanol (1 volume times relative to the carboxylic acid compound). After mixing the filtrate with the washed liquid, 540 mL of water (6 times the volume of the carboxylic acid compound) was added at 35°C to 45°C, stirred, and then cooled to 0°C to 10°C to recover the precipitated 2-naphthylacetonitrile. The resulting 2-naphthylacetonitrile was 63.2 g, and the purity measured by HPLC (HPLC analysis condition -3) was 99.5 area %.

[0372] The HPLC analysis results of the obtained 2-naphthylacetonitrile are shown in Figure 8 ,Will 1 The results of H-NMR measurements are shown in Figure 9 .

[0373] Example 6: Synthesis of Nitrile Compounds

[0374] Into a nitrogen-purged reaction vessel, 1 g of 2-naphthylacetic acid synthesized in the same manner as in Example 2, 10 mL of toluene (10 times by volume relative to 2-naphthylacetic acid), 10 μL of N,N-dimethylformamide, and 0.672 g of thionyl chloride (1.05 times by mole relative to 2-naphthylacetic acid) were mixed and reacted at 40° C. for 3 hours, followed by distillation to remove the solvent. The residue was mixed with 10 mL of sulfolane (10 times by volume relative to 2-naphthylacetic acid) and 0.620 g of sulfonamide (1.2 times by mole relative to 2-naphthylacetic acid), and reacted at 120° C. for 3 hours. Analysis of the reaction product by HPLC (HPLC analysis condition-3) revealed that 2-naphthylacetonitrile was produced at 94.1 area %.

[0375] Example 7: Synthesis of Nitrile Compounds

[0376] 1.00 g of 2-naphthylacetic acid synthesized in the same manner as in Example 2, 5 mL of sulfolane (5 times by volume relative to 2-naphthylacetic acid), and 0.620 g of sulfonamide (1.2 times by mole relative to 2-naphthylacetic acid) were added to the reaction vessel after nitrogen substitution and mixed. 0.672 g of thionyl chloride (1.05 times by mole relative to 2-naphthylacetic acid) was added dropwise at 100° C., and the mixture was stirred for 8 hours at 100° C. The reaction product was analyzed by HPLC (HPLC analysis condition-3) to obtain 2-naphthylacetonitrile with a purity of 96.8 area %.

[0377] Comparative Example 2: Synthesis of Nitrile Compounds

[0378] To a nitrogen-purged reaction vessel, 1.00 g of 2-naphthylacetic acid synthesized in the same manner as in Example 2, 10 mL of toluene (10 times the volume relative to the 2-naphthylacetic acid), 0.672 g of thionyl chloride (1.05 times the molar ratio relative to the 2-naphthylacetic acid), and 10 μL of N,N-dimethylformamide were added, mixed, and stirred at 40°C for 1 hour. To the resulting reaction solution, 0.620 g of sulfonamide (1.2 times the molar ratio relative to the 2-naphthylacetic acid) was added, and the mixture was reacted at 120°C for 3 hours. Analysis of the reaction product by HPLC (HPLC analysis condition - 3) revealed 2-naphthylacetonitrile with a purity of 18.6 area %.

[0379] Comparative Example 3: Synthesis of Nitrile Compounds

[0380] To a nitrogen-purged reaction vessel, 1.00 g of 2-naphthylacetic acid synthesized in the same manner as in Example 2, 10 mL of toluene (10 times by volume relative to 2-naphthylacetic acid), 0.672 g of thionyl chloride (1.05 times by mole relative to 2-naphthylacetic acid), and 10 μL of N,N-dimethylformamide were added and mixed. After stirring at 40°C for 1 hour, the reaction solution was concentrated. Separately, the concentrated residue prepared previously was added dropwise to a solution obtained by mixing 0.620 g of sulfonamide (1.2 times by mole relative to 2-naphthylacetic acid) and 5 mL of N-methylpyrrolidone (5 times by volume relative to 2-naphthylacetic acid), and the mixture was stirred at 100°C for 7 hours to react. Analysis of the reaction product by HPLC (HPLC analysis condition - 3) revealed that 2-naphthylacetonitrile was produced with a purity of 63.4 area %.

[0381] Comparative Example 4: Synthesis of Nitrile Compounds

[0382] To a nitrogen-purged reaction vessel, 1.00 g of 2-naphthylacetic acid synthesized in the same manner as in Example 2, 0.620 g of sulfonamide (1.2 times by mole relative to 2-naphthylacetic acid), 10 μL of N,N-dimethylformamide, and 10 mL of acetonitrile (10 times by volume relative to 2-naphthylacetic acid) were added and mixed. 0.672 g of thionyl chloride (1.05 times by mole relative to 2-naphthylacetic acid) was added under reflux, and the mixture was reacted for 1 hour. Analysis of the reaction product by HPLC (HPLC analysis condition -3) revealed that 2-naphthylacetonitrile was produced with a purity of 0.3 area %.

[0383] Comparative Example 5: Synthesis of Nitrile Compounds

[0384] 2-naphthylacetic acid 1g, sulfolane 5mL (being 5 volume times with respect to 2-naphthylacetic acid), sulfonamide 0.620g (being 1.2 mole times with respect to 2-naphthylacetic acid) synthesized in the same manner as Example 2 are added to the reaction vessel after nitrogen replacement and mixed, thionyl chloride 0.672g (being 1.05 mole times with respect to 2-naphthylacetic acid) is added dropwise at 60 ℃, stirred at 60 ℃ for 2 hours.After stirring, the crystalline component of precipitation solidifies the reaction solution, is therefore warmed up to 80 ℃ and is stirred.Become solution state by stirring at 80 ℃, therefore stir in this state for 5 hours and make its reaction.The result of utilizing HPLC (HPLC analysis condition-3) to analyze reaction product is, 2-naphthylacetonitrile is not detected.

[0385] Example 8: Synthesis of Nitrile Compounds

[0386] To a nitrogen-purged reaction vessel, 0.4 g of 2-naphthylacetamide synthesized in the same manner as in Example 4, 2.8 mL of toluene (7 volumes relative to 2-naphthylacetamide), and 0.364 g of phosphorus oxychloride (1.1 molar ratio relative to 2-naphthylacetamide) were added, and the mixture was stirred at 80° C. for 2 hours to allow the reaction to proceed. Analysis of the reaction product by HPLC (HPLC analysis condition - 3) revealed that 2-naphthylacetonitrile was produced with a purity of 95.2 area %.

[0387] Example 9: Synthesis of Nitrile Compounds

[0388] To a nitrogen-purged reaction vessel, 0.3 g of 2-naphthylacetamide synthesized in the same manner as in Example 4, 4 mL of toluene (13.3 times by volume relative to 2-naphthylacetamide), and 0.328 g of cyanuric chloride (1.1 times by mole relative to 2-naphthylacetamide) were added, and the mixture was stirred at 120° C. for 6 hours to allow the reaction to proceed. Analysis of the reaction product by HPLC (HPLC analysis condition -3) revealed that 2-naphthylacetonitrile was produced with a purity of 73.8 area %.

[0389] Example 10: Synthesis of Nitrile Compounds

[0390] To a nitrogen-purged reaction vessel, 0.3 g of 2-naphthylacetamide synthesized in the same manner as in Example 4, 4.0 mL of toluene (13.3 times by volume relative to 2-naphthylacetamide), and 0.253 g of phosphorus pentoxide (1.1 times by mole relative to 2-naphthylacetamide) were added, and the mixture was stirred at 80° C. for 5 hours to allow the reaction to proceed. Analysis of the reaction product by HPLC (HPLC analysis condition - 3) revealed that 2-naphthylacetonitrile was produced with a purity of 94.1 area %.

[0391] Example 11: Synthesis of Nitrile Compounds

[0392] To a nitrogen-purged reaction vessel, 0.3 g of an amide compound (2-naphthylacetamide) synthesized in the same manner as in Example 4, 4.0 mL of toluene (13.3 times by volume relative to 2-naphthylacetamide), 0.341 g of p-toluenesulfonyl chloride (1.1 times by mole relative to 2-naphthylacetamide), and 0.327 μL of pyridine (2.5 times by mole relative to 2-naphthylacetamide) were added, and the mixture was stirred at 120° C. for 1.5 hours to allow the reaction to proceed. Analysis of the reaction product by HPLC (HPLC analysis condition -3) revealed that 2-naphthylacetonitrile was produced with a purity of 84.8 area %.

[0393] Comparative Example 6: Synthesis of Nitrile Compounds

[0394] To a nitrogen-purged reaction vessel, 0.3 g of an amide compound (2-naphthylacetamide) synthesized in the same manner as in Example 4, 3 mL of toluene (10 times the volume relative to 2-naphthylacetamide), and 0.251 g of thionyl chloride (1.3 times the molar ratio relative to 2-naphthylacetamide) were added, and the mixture was stirred at 90° C. for 15 hours to allow the reaction to proceed. Analysis of the reaction product by HPLC (HPLC analysis condition - 3) revealed that 2-naphthylacetonitrile was produced with a purity of 34.4 area %.

[0395] Comparative Example 7: Synthesis of Nitrile Compounds

[0396] To a nitrogen-purged reaction vessel, 0.3 g of an amide compound (2-naphthylacetamide) synthesized in the same manner as in Example 4, 4.0 mL of toluene (13.3 times by volume relative to 2-naphthylacetamide), 0.341 g of p-toluenesulfonyl chloride (1.1 times by mole relative to 2-naphthylacetamide), and 0.563 μL of triethylamine (2.5 times by mole relative to 2-naphthylacetamide) were added, and the mixture was stirred at 120° C. for 9.5 hours to allow the reaction to proceed. Analysis of the reaction product by HPLC (HPLC analysis condition -3) revealed that 2-naphthylacetonitrile was produced with a purity of 51.6 area %.

[0397] Comparative Example 8: Synthesis of Nitrile Compounds

[0398] To a nitrogen-purged reaction vessel were added 0.3 g of an amide compound (2-naphthylacetamide) synthesized in the same manner as in Example 4, 3.0 mL of toluene (10.0 volume times relative to 2-naphthylacetamide), 0.409 g of triethylamine (2.5 molar times relative to 2-naphthylacetamide), 1.2 μL of dimethyl sulfoxide (0.01 molar times relative to 2-naphthylacetamide), and 0.247 g of oxalyl chloride (1.2 molar times relative to 2-naphthylacetamide), and the mixture was stirred at 25° C. for 1 hour to allow the reaction to proceed. Analysis of the reaction product by HPLC (HPLC analysis condition -3) revealed that 2-naphthylacetonitrile was produced with a purity of 28.2 area %.

[0399] Example 12: Synthesis of 2-naphthylacetonitrile

[0400] To the reaction vessel after nitrogen substitution, 1.00 g of 2-naphthylacetic acid obtained in the same manner as in Example 2, 3.5 mL of sulfolane (3.5 times by volume relative to 2-naphthylacetic acid), and 0.620 g of sulfonamide (1.2 times by mole relative to 2-naphthylacetic acid) were added and mixed, 0.704 g of thionyl chloride (1.1 times by mole relative to 2-naphthylacetic acid) was added dropwise at 100° C., and the mixture was stirred for 7.5 hours at 100° C. The reaction product was analyzed by HPLC (HPLC analysis condition-3), and 2-naphthylacetonitrile was produced with a purity of 96.2 area %.

[0401] Comparative Example 9: Synthesis of 2-naphthylacetonitrile

[0402] To the reaction vessel after nitrogen substitution, 1.00 g of 2-naphthylacetic acid obtained in the same manner as in Example 2, 3.5 mL of sulfolane (3.5 times by volume relative to 2-naphthylacetic acid), and 0.568 g of sulfonamide (1.1 times by mole relative to 2-naphthylacetic acid) were added and mixed, and 0.768 g of thionyl chloride (1.2 times by mole relative to 2-naphthylacetic acid) was added dropwise at 100° C., and the mixture was stirred for 4.5 hours at 100° C. The reaction product was analyzed by HPLC (HPLC analysis condition-3), and 2-naphthylacetonitrile was produced with a purity of 84.1 area %.

[0403] Comparative Example 10: Synthesis of 2-naphthylacetonitrile

[0404] In the reaction vessel after nitrogen replacement, add carboxylic acid compound (2-naphthylacetic acid) 0.5g, sulfolane 1.5mL (being 3 volumes times with respect to 2-naphthylacetic acid), sulfonamide 0.284g (being 1.1 mole times with respect to 2-naphthylacetic acid) obtained in embodiment 2 and mix, at 100 DEG C, drip thionyl chloride 0215 μ L (being 1.1 mole times with respect to 2-naphthylacetic acid).Further add sulfolane 0.25mL (being 0.5 volume times with respect to 2-naphthylacetic acid), at 100 DEG C, stir and make its reaction within 7.5 hours.The result of utilizing HPLC (HPLC analysis condition-3) analytical reaction product is, has generated 2-naphthylacetonitrile with the purity of 79.2 area %.

[0405] [Table 2]

[0406]

[0407] As shown in Table 2, when the amount of sulfonamide is more than the amount of thionyl chloride, highly purified 2-naphthylacetonitrile (Example 12) can be obtained. On the other hand, when the amount of sulfonamide is less than the amount of thionyl chloride, more high polar impurities as by product are generated, and the purity of the 2-naphthylacetonitrile obtained is also low (Comparative Example 9). In addition, when the amount of sulfonamide is identical with the amount of thionyl chloride, the amount of high polar impurities as by product is less, but the purity of 2-naphthylacetonitrile is low, and it is thought that the reaction is not fully carried out.

[0408] Comparative Example 11: Bromination method

[0409] The method for synthesizing 2-(bromomethyl)naphthalene from 2-methylnaphthalene was studied.

[0410] (1) Synthesis of 2-(bromomethyl)naphthalene

[0411] To a reaction vessel purged with nitrogen, 1.0 g of commercially available 2-methylnaphthalene (2-Methylnaphthalene), 4.0 mL of cyclohexane (4.0 times by volume relative to 2-methylnaphthalene), 1.00 g to 1.46 g of N-bromosuccinimide (NBS) (0.80 to 1.17 times by mole relative to 2-methylnaphthalene), and 3.5 mg of azobisisobutyronitrile (AIBN) (0.003 times by mole relative to 2-methylnaphthalene) were added and reacted at 40° C., 60° C., and 80° C. (reflux) for 2 hours. After the reaction, the mixture was cooled to room temperature and 2.0 mL of a 20% by weight aqueous sodium hydroxide solution was added to stop the reaction. The upper layer was then analyzed by HPLC (HPLC analysis condition -1) to analyze the reaction composition. The results are shown in Table 3.

[0412] It should be noted that in the following Tables 3 to 5, MR represents the molar ratio relative to 2-methylnaphthalene, VR represents the volume ratio relative to 2-methylnaphthalene, c-Hex represents cyclohexane, Product represents 2-(bromomethyl)naphthalene, SM represents 2-methylnaphthalene, DiBr represents dibromoform, A% represents the area % (Area %) obtained by HPLC analysis, and ND represents not detected.

[0413] [Table 3]

[0414]

[0415] (2) Synthesis of 2-(bromomethyl)naphthalene

[0416] To a nitrogen-purged reaction vessel, 1.0 g of commercially available 2-methylnaphthalene, 4.0 mL of cyclohexane (4.0 times the volume of 2-methylnaphthalene), 0.91-1.21 g of 1,3-dibromo-5,5-dimethylhydantoin (DBMH) (0.45-0.60 times the molar ratio of 2-methylnaphthalene), and 3.5 mg of azobisisobutyronitrile (AIBN) (0.003 times the molar ratio of 2-methylnaphthalene) were added. The mixture was reacted at 80°C (reflux) for 2 hours. After the reaction, the mixture was cooled to room temperature and 2.0 mL of a 20% by weight aqueous sodium hydroxide solution was added to terminate the reaction. The upper layer was then analyzed by HPLC (HPLC analysis conditions - 1) to analyze the reaction composition. The results are shown in Table 4.

[0417] [Table 4]

[0418]

[0419] (3) Synthesis of 2-(bromomethyl)naphthalene

[0420] To a nitrogen-purged reaction vessel, 1.0 g of commercially available 2-methylnaphthalene, 4.0 mL of solvent (4.0 times the volume of 2-methylnaphthalene), 1.21 g of 1,3-dibromo-5,5-dimethylhydantoin (DBMH) (0.60 times the molar ratio of 2-methylnaphthalene), and 3.5 mg of azobisisobutyronitrile (AIBN) (0.003 times the molar ratio of 2-methylnaphthalene) were added and reacted at 80°C for 2 hours. After the reaction, the mixture was cooled to room temperature and 2.0 mL of a 20% by weight aqueous sodium hydroxide solution was added to terminate the reaction. The upper layer was then analyzed by HPLC (HPLC analysis conditions - 1) to analyze the reaction composition. The results are shown in Table 5.

[0421] [Table 5]

[0422]

[0423] The above research results confirm that increasing the yield of the target product (2-(bromomethyl)naphthalene) increases the dibromo form as a by-product, and that the yield of the target product must be reduced to suppress the formation of the dibromo form. Subsequent research has also revealed that it is difficult to improve this relationship, and it is difficult to increase the yield when synthesizing 2-(bromomethyl)naphthalene by bromination of 2-methylnaphthalene.

[0424] (4) Synthesis of 2-naphthylacetonitrile from 2-(bromomethyl)naphthalene

[0425] 2.0 g of 2-(bromomethyl)naphthalene (containing 17 area % of the dibromo compound) synthesized using the same method as in Run 6 above, 10.0 mL of dimethyl sulfoxide (5.0 volume times relative to 2-(bromomethyl)naphthalene), and 0.89 g of sodium cyanide (2.0 mole times relative to 2-(bromomethyl)naphthalene) were added, and the mixture was reacted at 40°C for 3.5 hours. After the reaction, 10.0 mL of water (5.0 volume times relative to 2-(bromomethyl)naphthalene) was added dropwise to precipitate crystals. The mixture was cooled and stirred at 13°C for 2.5 hours, and then the crystals were recovered by filtration. Analysis of the resulting crystals using HPLC (HPLC analysis condition - 1) revealed that 2-naphthylacetonitrile was produced with a purity of 60.2 area % and contained 5.4 area % of the dibromo compound.

[0426] Industrial applicability

[0427] The present invention provides a novel method for industrially safely and inexpensively producing aromatic nitrile compounds such as 2-naphthylacetonitrile and aromatic carboxylic acid compounds such as 2-naphthylacetic acid, which are useful as synthetic raw materials and synthetic intermediates for various pharmaceuticals, pesticides, and chemicals, with high efficiency and high purity. Furthermore, by using the aromatic nitrile compounds such as 2-naphthylacetonitrile obtained in this manner, pharmaceuticals such as (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane can be safely and inexpensively produced.

[0428] This application is based on U.S. Provisional Patent Application No. 62 / 663,014 (filing date: April 26, 2018) and U.S. Provisional Patent Application No. 62 / 780,445 (filing date: December 17, 2018), the contents of which are incorporated herein by reference in their entirety.

Claims

1. A method for producing a nitrile compound represented by general formula (1), characterized in that: The method comprises the following steps 1 and 2B, Np-R 5 -CN (1) In the general formula (1), Np represents a naphthyl group which may have a substituent, and R 5 represents an alkylene group having 1 to 3 carbon atoms, Step 1: The step of obtaining a carboxylic acid compound represented by the general formula (4) is characterized by subjecting the compound represented by the general formula (2) to a Wilgenhall reaction in the presence of an additive as needed to obtain a compound represented by the general formula (3), and then hydrolyzing the obtained compound represented by the general formula (3) and neutralizing it. Np-CO-R 1 (2) In the general formula (2), Np has the same meaning as above, R 1 represents an alkyl group having 1 to 3 carbon atoms, Np-R 5 -C(=X)-NR 3 R 4 (3) In the general formula (3), Np and R 5 Same as above, X represents oxygen atom or sulfur atom, R 3 and R 4 Each independently represents an alkyl group having 1 to 3 carbon atoms or a hydrogen atom which may have a nitrogen atom, an oxygen atom or a sulfur atom, and R 3 and R 4 Can bond to form a ring, Np-R 5 -COOH (4) In general formula (4), Np and R 5 Has the same meaning as above; Step 2B: a step of reacting the carboxylic acid compound represented by the general formula (4) obtained in the step 1 with a halogenating agent and a compound represented by the general formula (7) in an organic solvent in the presence of a catalyst as needed to obtain the nitrile compound represented by the general formula (1); R 6 SO2R 7 (7) In the general formula (7), R 6 and R 7 Each independently represents a chlorine atom, a hydroxyl group, an amino group, an isocyanate group or a p-tolyl group.

2. The method for producing a nitrile compound according to claim 1, wherein The step 2B is the following step 2B-1 or step 2B-2, Step 2B-1: A step of reacting the carboxylic acid compound represented by the general formula (4) with a halogenating agent and the compound represented by the general formula (7) in an organic solvent in the presence of a catalyst as needed at 80° C. to 180° C. to obtain the nitrile compound represented by the general formula (1); Step 2B-2: A step of reacting a reaction material 1 obtained by mixing a carboxylic acid compound represented by the general formula (4), a halogenating agent, a first organic solvent and, if necessary, a catalyst, with a reaction material 2 obtained by mixing a compound represented by the general formula (7) and a second organic solvent at 80° C. to 180° C. to obtain a nitrile compound represented by the general formula (1).

3. A method for producing a nitrile compound represented by general formula (1), comprising the following step 2B, Np-R 5 -CN (1) In the general formula (1), Np represents a naphthyl group which may have a substituent, and R 5 represents an alkylene group having 1 to 3 carbon atoms, Step 2B: A step of reacting a carboxylic acid compound represented by the general formula (4) with a halogenating agent and a compound represented by the general formula (7) in an organic solvent in the presence of a catalyst as needed to obtain the nitrile compound represented by the general formula (1), Np-R 5 -COOH (4) In general formula (4), Np and R 5 Same meaning as above, R 6 SO2R 7 (7) In the general formula (7), R 6 and R 7 Each independently represents a chlorine atom, a hydroxyl group, an amino group, an isocyanate group or a p-tolyl group.

4. The method for producing a nitrile compound according to claim 3, wherein Step 2B is the following step 2B-1 or step 2B-2, Step 2B-1: A step of reacting the carboxylic acid compound represented by the general formula (4) with a halogenating agent and the compound represented by the general formula (7) in an organic solvent in the presence of a catalyst as needed at 80° C. to 180° C. to obtain the nitrile compound represented by the general formula (1); Step 2B-2: A step of reacting a reaction material 1 obtained by mixing a carboxylic acid compound represented by the general formula (4), a halogenating agent, a first organic solvent and, if necessary, a catalyst, with a reaction material 2 obtained by mixing a compound represented by the general formula (7) and a second organic solvent at 80° C. to 180° C. to obtain a nitrile compound represented by the general formula (1).

5. A method for producing a carboxylic acid compound represented by general formula (4), characterized in that: The compound represented by the general formula (2) is subjected to a Wilgenhall reaction in the presence of an additive as needed to obtain a compound represented by the general formula (3), and the obtained compound represented by the general formula (3) is hydrolyzed and then neutralized. Np-CO-R 1 (2) In the general formula (2), Np represents a naphthyl group which may have a substituent, and R 1 represents an alkyl group having 1 to 3 carbon atoms, Np-R 5 -C(=X)-NR 3 R 4 (3) In the general formula (3), Np has the same meaning as above, X represents an oxygen atom or a sulfur atom, and R 5 represents an alkylene group having 1 to 3 carbon atoms, R 3 and R 4 Each independently represents an alkyl group having 1 to 3 carbon atoms or a hydrogen atom which may have a nitrogen atom, an oxygen atom or a sulfur atom, and R 3 and R 4 can bond to form a ring, Np-R 5 -COOH (4) In general formula (4), Np and R 5 Same meaning as above.

6. The method for producing a carboxylic acid compound according to claim 5, wherein The reaction product obtained by the hydrolysis is brought into contact with a hydrocarbon solvent after the hydrolysis, a hydrocarbon solvent is present during the neutralization, or the reaction product obtained by the neutralization is brought into contact with a hydrocarbon solvent.

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