Title of invention: Method for producing aromatic nitrile compound
Technical field
[0001]
　The present invention relates to a method for producing a synthetic raw material for various pharmaceuticals, pesticides and chemical products, an aromatic nitrile compound useful as a synthetic intermediate, preferably 2-naphthylacetonitrile.
[0002]
　Furthermore, the present invention is useful as a synthetic raw material or a synthetic intermediate for the aromatic nitrile compound of the present invention, and is also a useful aromatic as a synthetic raw material or a synthetic intermediate for various pharmaceuticals, pesticides and chemical products. It relates to a method for producing a carboxylic acid compound, preferably 2-Naphthaleneacetic Acid.
Background technology
[0003]
　2-naphthylacetonitrile is useful as a synthetic raw material and a synthetic intermediate for various pharmaceuticals, pesticides and chemical products. Aromatic nitrile compounds having a chemical structure similar to 2-naphthylacetonitrile are also expected to be used as synthetic raw materials and intermediates for various pharmaceuticals, pesticides, and chemical products.
[0004]
　For example, 2-naphthyl acetonitrile can be used for depression (eg, major depressive disorder, bipolar disease), fibromuscular pain, pain (eg, neuropathic pain), sleep disorders, attention deficit disorder (ADD), attention deficit activity. Disorders (ADHD), lower limb immobility syndrome, schizophrenia, anxiety, compulsive disorders, post-traumatic stress disorders, seasonal emotional disorders (SAD), premenstrual disorders, neurodegenerative disorders (eg Parkinson's disease, Alzheimer's disease) CNS diseases such as (disease), diseases related to urinary incontinence and hypersensitivity intestinal syndrome (IBS), drugs used for prevention and treatment of diabetes, etc., erythropoetin (EPO) inducer, calcium antagonist, histamine receptor antagonist, takinin receptor antagonist It is useful as a raw material for synthesis and an intermediate for synthesis of pharmaceuticals such as agents, 12-lipoxygenase inhibitors, protein kinase C (PKC) inhibitors, and PDEIV inhibitors.
[0005]
　2-naphthylacetonitrile is described in particular in Patent Document 1, Patent Document 2, Patent Document 3 and the like (1R, 5S) -1- (naphthalene-2-yl) -3-azabicyclo [3.1.0. ] It can be suitably used as a raw material / intermediate for the production of hexane.
[0006]
　Examples of the method for producing 2-naphthylacetonitrile include a method of brominating 2-methylnaphthalene to obtain 2- (bromomethyl) naphthalene and reacting it with sodium cyanide (Patent Document 4) and 2'-. A method of reacting acetonafton with iodic acid or titanium tetranitrate with trimethoxymethane to obtain 2-naphthylacetonitrile is known (Non-Patent Document 1). However, these methods are not preferable as industrial production methods because of low yield, large production of by-products, insufficient progress of reaction, heat generation during reaction, use of highly toxic compounds, and the like. ..
[0007]
　Further, a method of obtaining 2- (hydroxymethyl) naphthalene from 2-methylnaphthalene by a biochemical reaction using an enzyme or the like and reacting it with methanesulfonyl chloride and sodium cyanide to obtain 2-naphthyl acetonitrile (non-patent). Although Document 2) is known, it is not preferable as an industrial production method because of its low yield, high production of by-products, and the use of highly toxic compounds.
[0008]
　Further, some methods for synthesizing a nitrile compound from an aromatic carboxylic acid, an aromatic carboxylic acid derivative, etc. have been reported (Patent Document 5, Non-Patent Document 3, Non-Patent Document 4, etc.). However, these methods are also required to be further improved as industrial production methods in terms of low yield, large production of by-products, insufficient reaction, and the like.
[0009]
　In addition, several methods for synthesizing aromatic carboxylic acids and aromatic thioamides from aromatic ketones by the Wilgerot reaction have been reported (Non-Patent Document 5, Non-Patent Document 6, Non-Patent Document 7, Non-Patent Document 8, etc.). .. However, these methods do not have sufficient yields, and since sulfur is used in the Wilgerot reaction, it is considered that the produced aromatic carboxylic acid and the like contain a large amount of sulfur, so that this method is an industrial production method. , Further improvement is required.
Prior art literature
Patent documents
[0010]
Patent Document 1: WO2007 / 016155
Patent Document 2: WO2015 / 089111
Patent Document 3: WO2015 / 102826
Patent Document 4: Japanese Patent Application Laid-Open No. 2001-39904
Patent Document 5: WO2014 / 001939
Non-patent literature
[0011]
Non-Patent Document 1: ARKIVOC 2011 (V) pp.67-75
Non-Patent Document 2: Journal of Molecular Catalysis B: Enzymatic, 6 (1-2) 234-240, 2010
Non-Patent Document 3: Tetrahedron Letters, Vol.23 , No.14, pp1505-1508, 1982
Non-Patent Document 4: Organic Process Research & Development 2003,7, 74-81
Non-Patent Document 5: Green Chemistry Letters and Reviews, 2010, 315-318
Non-Patent Document 6: Synthetic Communications , Vol.33, No.1, pp.59-63, 2003
Non-Patent Document 7: Chem. Soc. Rev., 2013, 42, 7870-7880
Non-Patent Document 8: J. Soc. Ouest-Afr. Chim. (2010) 029, 89-94
Outline of the invention
Problems to be solved by the invention
[0012]
　The present invention provides a method for industrially, safely, inexpensively, and highly efficiently producing high-purity aromatic nitrile compounds and aromatic carboxylic acid compounds.
Means to solve problems
[0013]
　In order to solve the above problems, the present inventors have used a relatively inexpensive and general-purpose aromatic ketone compound such as 2'-Acetonaphthone with an aromatic carboxylic acid by utilizing Willgerodt rearrangement. The present invention has been reached as a result of diligent studies on the production of an acid compound and the production of a high-purity aromatic nitrile compound in a high yield by suppressing the formation of by-products from the aromatic carboxylic acid compound.
[0014]
　That is, the gist of the present invention is as follows.
[1] General formula (1)
Np-R 5- CN (1), which comprises the following steps 1 and 2
, Np may have a substituent in the general formula (1). indicates naphthyl group, R 5 represents.) an alkylene group having 1 to 3 carbon atoms
manufacturing method of a nitrile compound represented by the.
Step 1:
　General formula
(2) Np-CO-R　　1 (2)
(In the general formula (2), Np is the same as defined above, R 1 represents an alkyl group having 1 to 3 carbon atoms.)
Table with General formula (3)
Np-R 5- C (= X) -NR 3 R 4　　(3)
(general formula (1 ) ), Np and R 5 are synonymous with the above, X indicates an oxygen atom or a sulfur atom, and R 3 and R 4 are each independently a nitrogen atom, an oxygen atom or an alkyl group or a hydrogen atom of having 1 carbon atoms which may 3 have a sulfur atom, R 3 and R 4 combine to form a ring You may be. ) Is
hydrolyzed and then neutralized. General formula (4)
Np-R 5- COOH (4)
(In the general formula (4), Np and R 5 are described above. . synonymous)
obtaining a carboxylic acid compound represented by;
step 2: any of the steps of step 2A or step 2B
step 2A:
　represented by the general formula obtained in the step 1 (4) The general formula (5)
Np-R 5- CONH 2　　(5 ) obtained by reacting a carboxylic acid compound with a halogenating agent in an organic solvent in the presence of a catalyst, if necessary, and further reacting with an amidating agent. )
in (formula (5), Np and R 5 are as defined above.)
or general formula
(6) Np-R 5-CONHOH (6)
(In the general formula (6), Np and R 5 are as defined above.)
The compound represented by is reacted with a dehydrating agent, nitrile represented by the general formula (1) obtaining a compound;
step 2B:
　the step 1 obtained in the above general formula (4) a carboxylic acid compound represented by the presence of a catalyst if necessary, in an organic solvent, the halogenating agent and the general formula (
7) R 6 SO 2 R　　7 (7)
in (formula (7), R 6 and R 7 are each independently a chlorine atom, a hydroxyl group, an amino group, an isocyanate group or p- tolyl group.)
in A step of reacting with a compound represented by the compound to obtain a nitrile compound represented by the general formula (1).
[0015]
[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.
Step 2B-1: The
　carboxylic acid compound represented by the general formula (4) is subjected to a halogenating agent and the general formula (7) at 80 ° C. to 180 ° C. in an organic solvent in the presence of a catalyst, if necessary. in reacted with a compound represented by, obtaining a nitrile compound represented by the general formula (1);
step 2B-2:
　carboxylic acid compound represented by the general formula (4), halogenating agents, the The reaction raw material 1 in which one organic solvent and, if necessary, a catalyst are mixed, and the reaction raw material 2 in which the compound represented by the general formula (7) and the second organic solvent are mixed are reacted at 80 ° C. to 180 ° C. A step of obtaining a nitrile compound represented by the general formula (1).
[0016]
[3] General formula (1)
Np-R 5- CN (1) including any of the following steps 2A or 2B
(In the general formula (1), Np may have a substituent naphthyl. represents a group, R 5 represents.) an alkylene group having 1 to 3 carbon atoms
manufacturing method of a nitrile compound represented by the.
Step 2A: A carboxylic acid compound represented by the
　general formula (4)
Np-R 5- COOH (4)
(in the general formula (4), Np and R 5 have the same meanings as described above)
, if necessary. General formula (5)
Np-R 5- CONH 2　　(5) obtained by reacting with a halogenating agent and further reacting with an amidating agent in an organic solvent in the presence of a catalyst
(in the general formula (5), Np and R 5 are synonymous with the above.)
Or general formula (6)
Np-R 5- CONHOH (6)
(In the general formula (6), Np and R 5 has the same meaning as defined above.)
Step a compound represented by is reacted with a dehydrating agent to obtain a represented by a nitrile compound by the general formula (1);
Step 2B: A carboxylic acid compound represented by the
　general formula (4)
Np-R 5- COOH (4)
(in the general formula (4), Np and R 5 are synonymous with the above)
, if necessary. In the presence of a catalyst, in an organic solvent, a halogenating agent and the general formula (7)
R 6 SO 2 R 7　(7)
(In the general formula (7), R 6 and R 7 are independently chlorine atoms and hydroxyl groups, respectively. , Amino group, isocyanate group or p-tolyl group
) to obtain a nitrile compound represented by the general formula (1).
[0017]
[4] The method for producing a nitrile compound according to [3], wherein the step 2B is the following step 2B-1 or step 2B-2.
Step 2B-1: The
　carboxylic acid compound represented by the general formula (4) is subjected to a halogenating agent and the general formula (7) at 80 ° C. to 180 ° C. in an organic solvent in the presence of a catalyst, if necessary. in reacted with a compound represented by, obtaining a nitrile compound represented by the general formula (1);
step 2B-2:
　carboxylic acid compound represented by the general formula (4), halogenating agents, the The reaction raw material 1 in which one organic solvent and, if necessary, a catalyst are mixed, and the reaction raw material 2 in which the compound represented by the general formula (7) and the second organic solvent are mixed are reacted at 80 ° C. to 180 ° C. A step of obtaining a nitrile compound represented by the general formula (1).
[0018]
[5] General formula (2)
Np-CO-R 1　　(2)
(In the general formula (2), Np represents a naphthyl group which may have a substituent, and R 1 has 1 to 3 carbon atoms.
General formula (3)
Np-R 5- C (= X) -NR 3 R 4 obtained by reacting the compound represented by (indicating an alkyl group) with Wilgerot reaction in the presence of an additive, if necessary . 　　(3)
(In the general formula (1), Np is synonymous with the above, X represents an oxygen atom or a sulfur atom, R 5 represents an alkylene group having 1 to 3 carbon atoms, and R 3 and R 4 are. Each independently represents an alkyl group or hydrogen atom having 1 to 3 carbon atoms which may have a nitrogen atom, an oxygen atom or a sulfur atom, and even if R 3 and R 4 are bonded to form a ring. The
compound represented by ( good) is hydrolyzed and then neutralized. General formula (4)
Np-R 5- COOH (4)
(In the general formula (4), Np and R 5 has the same meaning as defined above.)
Method for producing a carboxylic acid compound represented by.
[0019]
[6] After the hydrolysis, the reaction product obtained by the hydrolysis is brought into contact with a hydrocarbon solvent, the hydrocarbon solvent is present at the time of the neutralization, or the reaction product obtained by the neutralization is generated. The method for producing a carboxylic acid compound according to [5], which comprises contacting the substance with a hydrocarbon solvent.
[0020]
[7] General formula (4)
Np-R 5- COOH (4)
(general formula (4) ] characterized in that the sulfur content is 0.001 mol% to 1 mol% and the purity is 98 mol% or more. Among them, R 5 represents an alkylene group having 1 to 3 carbon atoms, and Np
represents a naphthyl group which may have a substituent.) A carboxylic acid compound represented by.
Effect of the invention
[0021]
　According to the present invention, aromatic nitrile compounds such as 2-naphthylacetonitrile and aromatic carboxylic acid compounds such as 2-naphthylacetic acid, which are useful as raw materials for synthesis of various pharmaceuticals, pesticides and chemical products, and intermediates for synthesis, are industrialized. Therefore, it is possible to provide a novel method for producing with high purity, safely and inexpensively, with high efficiency. Furthermore, by using the aromatic nitrile compound such as 2-naphthylacetonitrile thus obtained, it is safe and inexpensive (1R, 5S) -1- (naphthalene-2-yl) -3-azabicyclo [3]. .1.0] Pharmaceuticals such as hexane can be produced.
A brief description of the drawing
[0022]
FIG. 1 is a diagram showing the results of HPLC analysis of crude crystals of the carboxylic acid compound obtained in Example 1.
FIG. 2 is a diagram showing the results of HPLC analysis of the refined crystals of the carboxylic acid compound obtained in Example 1.
FIG. 3 is a diagram showing 1 H-NMR measurement results of the purified crystals of the carboxylic acid compound obtained in Example 1 .
FIG. 4 is a diagram showing the results of HPLC analysis of the carboxylic acid compound obtained in Example 2.
FIG. 5 is a diagram showing 1 H-NMR measurement results of the carboxylic acid compound obtained in Example 2 .
FIG. 6 is a diagram showing the results of HPLC analysis of the amide compound obtained in Example 4.
FIG. 7 is a diagram showing the results of HPLC analysis of the nitrile compound obtained in Example 4.
FIG. 8 is a diagram showing the results of HPLC analysis of the nitrile compound obtained in Example 5.
FIG. 9 is a diagram showing 1 H-NMR measurement results of the nitrile compound obtained in Example 5 .
Mode for carrying out the invention
[0023]
　Hereinafter, terms used in the present specification will be described.
　In the present specification, Np indicates a naphthyl group which may have a substituent. Examples of the naphthyl group include a 1-naphthyl group and a 2-naphthyl group, and a 2-naphthyl group is preferable. Substituents that Np may have include halogen atoms (eg, chlorine atoms, bromine atoms), linear or branched alkyl groups with 1 to 6 carbon atoms (eg, methyl groups, ethyl groups), carbons. Examples thereof include linear or branched alkoxy groups (eg, methoxy group, ethoxy group) of Nos. 1 to 6. Np is particularly preferably a 2-naphthyl group.
　In the present specification, R 1 represents a linear or branched alkyl group having 1 to 3 carbon atoms. Preferably, R 1 is an alkyl group having 1 to 2 carbon atoms, and particularly preferably a methyl group.
　In the present specification, R 3 and R 4 each independently have a linear or branched alkyl group or hydrogen atom having 1 to 3 carbon atoms which may have a nitrogen atom, an oxygen atom or a sulfur atom. Shown. Further, R 3 and R 4 may be combined to form a ring. R 3 and R 4 are alkyl having 1 to 2 carbon atoms which may independently have an oxygen atom, respectively, and R 3 and R 4 are R 3 and R. It is preferable that 4 are bonded to form a ring. In particular, it is preferable that -NR 3 R 4 is a morpholino group.
　In the present specification, X represents an oxygen atom or a sulfur atom.
　In the present specification, R 5 represents an alkylene group having 1 to 3 carbon atoms. Preferably, R 5 is an alkylene group having 1 or 2 carbon atoms, particularly preferably a methylene group.
　In the present specification, R 6 and R 7 each independently represent a chlorine atom, a hydroxyl group, an amino group, an isocyanate group or a p-tolyl group. Preferably, R 6 is an amino group or an isocyanate group and R 7 is a hydroxyl group, an amino group or a chlorine atom. In particular, it is particularly preferable that R 6 and R 7 are amino groups, R 6 is an amino group and R 7 is a hydroxyl group, or R 6 is an isocyanate group and R 7 is a chlorine atom.
　In the present specification, Z represents a halogen atom. It is preferably a bromine atom or a chlorine atom, and particularly preferably a chlorine atom.
[0024]
　Hereinafter, the present invention will be described in detail.
1. 1. Process 1
[0025]
[Chemical 1]

[0026]
　In step 1, the compound represented by the general formula (2) is hydrolyzed by the Wilgerot reaction in the presence of an additive, if necessary, and then the amide compound represented by the general formula (3) is hydrolyzed. This is a step of neutralizing to obtain a carboxylic acid compound represented by the general formula (4).
　As used herein, the Wilgerot reaction means the Wilgerott reaction and the Wilgerot-Kindler reaction.
　As the compound represented by the general formula (2), 2'-acetonafton is particularly preferable.
[0027]
　In the Wilgerot reaction, a sulfur compound such as sodium sulfide (Na 2 S / 9H 2 O) or ammonium sulfide ((NH 4 ) 2 S) is allowed to act on the compound represented by the general formula (2) under heating. Can be done. As the sulfur compound, one type may be used alone, or two or more types may be used in any combination and ratio. The reaction can be carried out in the presence of an aqueous solvent such as water.
　The amount of the sulfur compound used is not particularly limited as long as it is an amount effective for the Wilgerot reaction of the compound represented by the general formula (2). The amount of the sulfur compound used is usually 1 mol to 5 mol, preferably 1 mol to 3 mol, relative to 1 mol of the compound represented by the general formula (2).
　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.
　The reaction time can be appropriately selected depending on the progress of the reaction, and is usually 1 hour to 12 hours, preferably 2 hours to 10 hours.
[0028]
　Further, the Wilgerott reaction of the present invention can be carried out by allowing sulfur and a secondary amine such as dialkylamine or morpholine to act on the compound represented by the general formula (2) under heating (Wirgelot).・ Kindler reaction).
　The amount of sulfur used is not particularly limited as long as it is an amount effective for the Wilgerot-Kindler reaction of the compound represented by the general formula (2). The amount of sulfur used is usually 1 mol to 5 mol, preferably 1 mol to 3 mol, relative to 1 mol of the compound represented by the general formula (2).
　As the secondary amine, morpholine is preferable for industrial production because the reaction can be efficiently performed without a solvent.
　The amount of the secondary amine used is not particularly limited as long as it is an amount effective for the Wilgerot-Kindler reaction of the compound represented by the general formula (2). The amount of the secondary amine used is usually 2 mol to 6 mol, preferably 2 mol to 4 mol, based on 1 mol of the compound represented by the general formula (2).
　The reaction can be carried out in a solvent-free or organic solvent that is inert to the reaction. Examples of such an organic solvent include dioxane, water, dimethylformamide and the like. One of these organic solvents may be used alone, or two or more of these organic solvents may be used in any combination and ratio.
　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.
　The reaction time can be appropriately selected depending on the progress of the reaction, and is usually 1 hour to 12 hours or more, preferably 2 hours to 10 hours.
[0029]
　When carrying out the Wilgerot reaction, additives may be used if necessary. Examples of the additive include dehydrating agents such as zeolite, molecular sieves, magnesium sulfate and sodium sulfate. As the dehydrating agent, one type may be used alone, or two or more types may be used in any combination and ratio. The reaction can proceed efficiently by controlling the amount of water in the reaction system to be small by using a dehydrating agent. The amount of the dehydrating agent used is usually 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).
　In addition, examples of the additive include organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, and trifluoroacetic acid. As the organic acid, one kind may be used alone, or two or more kinds may be used in any combination and ratio. As the organic acid, p-toluenesulfonic acid and methanesulfonic acid are particularly preferable. By using these organic acids as additives, by-products, especially the following formula
[0030]
[Chemical 2]

[0031]
The production of the thiocarbamate compound represented by is suppressed, and the reaction can proceed efficiently.
　The amount of the organic acid used is usually 0.01 mol to 5 mol, preferably 0.05 mol to 3 mol, based on 1 mol of the compound represented by the general formula (2).
　In addition, in order to control the amount of water in the reaction system to be small, the reaction may be carried out while dehydrating by distillation.
　The amide compound represented by the general formula (3) obtained by the Wilgerot reaction may be subjected to hydrolysis after being separated from the reaction system, or may be subjected to the next hydrolysis without separation.
[0032]
　In the present invention, the amide compound represented by the general formula (3) is hydrolyzed with 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; calcium carbonate and the like. Alkali earth metal carbonates; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate; Alkali earth metal hydrogen carbonates such as calcium hydrogen carbonate; Alkali metal alkoxides such as. Industrially, it is preferable to use alkali metal hydroxides such as sodium hydroxide and potassium hydroxide from the viewpoint of cost and availability. One type of base may be used alone, or two or more types may be used in any combination and ratio.
　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 the general formula (3). The amount of the base used is preferably 1 mol to 10 mol, preferably 1 mol to 5 mol, based on 1 mol of the amide compound represented by the general formula (3).
　Hydrolysis may be carried out without a solvent or in a solvent such as water, but it is preferably carried out in a solvent from the viewpoint of excellent agitation and uniformity.
　The temperature of hydrolysis is not particularly limited as long as the temperature at which hydrolysis proceeds. The hydrolysis temperature is usually 80 ° C. to 115 ° C., preferably 85 ° C. to 110 ° C.
　Hydrolysis is usually carried out at normal pressure.
[0033]
　The reaction product obtained by hydrolysis (for example, sodium 2-naphthyl acetate) is neutralized to obtain a carboxylic acid compound represented by the general formula (4). Acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid can be used for neutralization. One type of acid may be used alone, or two or more types may be used in any combination and ratio. From the viewpoint of reaction efficiency and cost, hydrochloric acid is industrially preferable.
　The amount of acid used is not particularly limited as long as it is an effective amount for neutralization. The amount of the acid used is preferably 1 mol to 20 mol, preferably 3 mol to 10 mol, based on 1 mol of the reaction product obtained by hydrolysis.
　The pH at the end of neutralization is usually between 0 and 5.
　The temperature of neutralization is not particularly limited as long as the temperature at which neutralization proceeds. The neutralization temperature is usually 10 ° C to 80 ° C, preferably 20 ° C to 50 ° C.
　The reaction product obtained by neutralization may be washed once or multiple times with an appropriate washing solution such as water or an aqueous solution.
[0034]
　The carboxylic acid compound represented by the general formula (4) can be extracted and recovered from the reaction product obtained by neutralization using an organic solvent. Examples of the organic solvent include a hydrocarbon solvent capable of dissolving the carboxylic acid compound represented by the general formula (4). Examples of the hydrocarbon solvent include alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; benzene, toluene, xylene, mesityrene, ethylbenzene, tert-butylbenzene, trifluoromethylbenzene, nitrobenzene, chlorobenzene, chlorotoluene and bromobenzene. Aromatic hydrocarbon solvents such as are preferred. The hydrocarbon solvent can be used alone or in combination of two or more at any ratio. As the hydrocarbon solvent, cyclohexane, toluene, xylene and chlorobenzene are particularly preferable.
　For example, an organic solvent (for example, 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 to make it acidic. The general formula (for example, pH 3 or less) and heating (for example, 50 ° C. to 90 ° C.) are performed by stirring, washing, separating the aqueous layer, concentrating, etc. as necessary, and then cooling. The carboxylic acid compound represented by 4) can be precipitated and recovered as a solid.
[0035]
　Since sulfur and sulfur compounds are used in the Wilgerot reaction, the obtained reaction product usually contains several mol% or more of sulfur. Sulfur is an impurity for the carboxylic acid compound represented by the general formula (4), which is the object of step 1, and when a chemical reaction or the like is carried out using the carboxylic acid compound represented by the general formula (4) as a raw material. It is preferable to remove as much as possible because the reaction efficiency may be lowered.
　In the present invention, the hydrocarbon solvent is contacted after the hydrolysis, the hydrocarbon solvent is present at the time of the neutralization, or the hydrocarbon solvent is contacted with the reaction product obtained by the neutralization. Therefore, the sulfur content of the carboxylic acid compound represented by the general formula (4) obtained in step 1 can be reduced. When contacting with a hydrocarbon solvent, water, an aqueous solution, or the like may be present, if necessary.
　Examples of the hydrocarbon solvent include alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; benzene, toluene, xylene, mesityrene, ethylbenzene, tert-butylbenzene, trifluoromethylbenzene, nitrobenzene, chlorobenzene, chlorotoluene and bromobenzene. Aromatic hydrocarbon solvents such as, etc. are preferable, toluene, xylene and chlorobenzene are more preferable, and toluene is particularly preferable.
[0036]
　When contacting with a hydrocarbon solvent after the hydrolysis, the hydrocarbon solvent is added to the reaction product obtained by the hydrolysis reaction, or the reaction product obtained by the hydrolysis reaction is added to the hydrocarbon solvent. To do. In this case, water, an aqueous solution, or the like may be added as needed.
　The hydrocarbon solvent is usually 1 volume to 20 volume, preferably 1.5 volume to 10 volume, and particularly preferably 3 volume to 5 times the carboxylic acid compound represented by the general formula (4). Use twice the capacity.
　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.
　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.
[0037]
　When a hydrocarbon solvent is present at the time of the neutralization, an acid and a hydrocarbon solvent are added to the reaction product obtained by the hydrolysis reaction, or a mixture of the acid and the hydrocarbon solvent is obtained by the hydrolysis reaction. The reaction product is added to carry out a neutralization reaction. In this case, water, an aqueous solution, or the like may be added as needed.
　The hydrocarbon solvent is usually 1 volume to 30 volume, preferably 3 volume to 20 volume, and particularly preferably 5 volume to 15 volume, the carboxylic acid compound represented by the general formula (4). use.
　After the neutralization reaction, the aqueous layer is removed by liquid separation or the like to obtain an organic layer containing the carboxylic acid compound represented by the general formula (4). The obtained organic layer may be washed once or multiple times with an appropriate washing solution such as water or an aqueous solution.
[0038]
　When the hydrocarbon solvent is brought into contact with the reaction product obtained by the neutralization, the hydrocarbon solvent is added to the reaction product obtained by the neutralization, or the reaction obtained by neutralizing the hydrocarbon solvent. Add the product. In this case, water, an aqueous solution, or the like may be added as needed.
　The hydrocarbon solvent is usually 1 volume to 20 volume, preferably 1.5 volume to 10 volume, and particularly preferably 3 volume to 5 times the carboxylic acid compound represented by the general formula (4). Use twice the capacity.
　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. Further, the contact is preferably performed under acidic conditions of pH 3 or less, preferably pH 2 or less.
　Then, the aqueous layer is removed by liquid separation or the like to obtain an organic layer containing the carboxylic acid compound represented by the general formula (4). The obtained organic layer may be washed once or multiple times with an appropriate washing solution such as water or an aqueous solution. By concentrating the obtained organic layer as necessary and cooling it, the carboxylic acid compound represented by the general formula (4) can be precipitated and recovered as a solid.
[0039]
　In the present invention, toluene is particularly preferable as the hydrocarbon solvent because sulfur can be removed and the carboxylic acid compound represented by the general formula (4) can be extracted with a single solvent.
　As described above, the carboxylic acid compound represented by the general formula (4) obtained by contacting with a hydrocarbon solvent in step 1 of the present invention has a sulfur content of 0.001 mol% to 1 mol%. It is preferably of high quality having a purity of 0.001 mol% to 0.5 mol% and a purity of 98 mol% or more, preferably 99 mol% or more.
　The carboxylic acid compound represented by the general formula (4) obtained in step 1 is useful as a synthetic raw material for various industrial products and pharmaceuticals, and as a synthetic intermediate, and is also used in step 2 of the present invention. Can be done.
[0040]
2. 2. Step 2
　Step 2 is a step of obtaining the nitrile compound represented by the general formula (1) from the carboxylic acid compound represented by the general formula (4).
　Step 2 may be any of the following steps 2A or 2B.
　As the carboxylic acid compound represented by the general formula (4), a commercially available compound or a compound obtained in the above step 1 can be used. As the carboxylic acid compound represented by the general formula (4), 2-naphthylacetic acid is particularly preferable.
[0041]
(1) Step 2A
[0042]
[Chemical 3]

[0043]
　Step 2A is a general obtained by 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, if necessary, and further reacting with an amidating agent. This is a step of reacting an amide compound represented by the formula (5) or the general formula (6) with a dehydrating agent to obtain a nitrile compound represented by the general formula (1).
[0044]
　First, the carboxylic acid compound represented by the general formula (4) is reacted with a halogenating agent in the presence of a catalyst, if necessary (acid halogenation).
　The halogenating agent is not particularly limited as long as it can halogenate the carboxylic acid compound represented by the general formula (4). As the halogenating agent, a chlorinating agent and a brominating agent are preferable, and a chlorinating agent is more preferable. Examples of the chlorinating agent include thionyl chloride, oxalyl chloride, sulfyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride and the like, and examples of the brominating agent include thionyl bromide and phosphorus tribromide. One of these halogenating agents may be used alone, or two or more of these halogenating agents may be used in any combination and ratio. Among these, thionyl chloride, phosphoryl chloride, phosphorus pentachloride, thionyl bromide, and phosphorus tribromide are preferable, and thionyl chloride is particularly preferable, from the viewpoint of cost, versatility, reactivity, and the like.
　The amount of the halogenating agent used is not particularly limited as long as it is an effective amount for acid halogenation, but is preferably 1 mol to 5 mol, more preferably 1 mol, with respect to 1 mol of the carboxylic acid compound represented by the general formula (4). It is 1 mol to 3 mol, particularly preferably 1 mol to 2 mol.
　The organic solvent is not particularly limited as long as the reaction proceeds, and examples thereof include an ester solvent, an ether solvent, a ketone solvent, a nitrile solvent, an amide solvent, a sulfoxide solvent, a hydrocarbon solvent, and a basic organic solvent. As the organic solvent, one type may be used alone, or two or more types may be used in any combination and ratio.
　Among these, hydrocarbon solvents are preferable as organic solvents, for example, alicyclic hydrocarbon solvents such as cyclohexane and methylcyclohexane; benzene, toluene, xylene, mesitylene, ethylbenzene, tert-butylbenzene, trifluoromethylbenzene, nitrobenzene, etc. Aromatic hydrocarbon solvents such as chlorobenzene, chlorotoluene and bromobenzene are preferred. In particular, toluene, xylene and chlorobenzene are preferable from the viewpoints of cost, versatility, reactivity and the like.
　A catalyst may be present to accelerate the reaction during acid halogenation. 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, N, N-dimethylacetamide and the like, and N, N-dimethylformamide is particularly preferable.
　The amount of the catalyst used is not particularly limited as long as it is an amount effective for functioning as a catalyst. The amount of the catalyst used is preferably 0.0001 mol to 1 mol, particularly preferably 0.001 mol to 0.1 mol, with respect to 1 mol of the carboxylic acid compound represented by the general formula (4).
　The temperature of the acid halide reaction is usually 20 ° C. to 60 ° C., preferably 30 ° C. to 50 ° C. from the viewpoint of productivity and the like. The reaction time can be appropriately selected depending on the progress of the reaction, and is usually 0.5 hours to 10 hours, preferably 1 hour to 5 hours. The reaction is usually carried out under normal pressure.
　The obtained acid halide reaction solution can be directly used for the next amidation step.
[0045]
　The acid halide reaction solution obtained as described above is reacted with an amidating agent to obtain an amide compound represented by the general formula (5) or the general formula (6).
　Examples of the amidating agent include ammonia (gas, aqueous solution) and hydroxyamine. As the amidating agent, ammonia (gas, aqueous solution) is preferable from the viewpoint of cost, versatility, reactivity and the like.
　When ammonia (gas, aqueous solution) is used as the amidating agent, an amide compound represented by the general formula (5) is obtained, and when hydroxyamine is used, an amide compound represented by the general formula (6) is obtained.
　The amount of the amidating agent used is not particularly limited as long as it can be amidated, but is preferably from 1 mol to 1 mol of the carboxylic acid compound represented by the general formula (4) from the viewpoint of cost, reactivity and the like. It is 20 mol, preferably 2 mol to 10 mol.
　In the amidation reaction, an 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 that does not inhibit the amidation reaction may be present.
　The temperature of the amidation reaction is usually 20 ° C. to 60 ° C., preferably 30 ° C. to 50 ° C. from the viewpoint of productivity and the like. The reaction time can be appropriately selected depending on the progress of the reaction, and is usually 0.5 hours to 10 hours, preferably 1 hour to 5 hours. The reaction is usually carried out under normal pressure.
　When ammonia gas is used as the amidating agent, the ammonia gas may be purged and supplied to the gas phase portion of the reaction vessel, or the reaction vessel may be depressurized and then repressurized with ammonia gas to be supplied. Then, ammonia gas may be bubbled and supplied to the reaction solution. In this case, the temperature is usually 10 ° C. to 80 ° C., preferably 20 ° C. to 70 ° C. from the viewpoint of productivity and the like.
　When ammonia gas is used as the amidating agent, it is preferable to reduce the ammonia gas contained in the amidation reaction solution obtained by amidation before the reaction with the dehydrating agent. As a result, the amount of the dehydrating agent used next can be reduced, the operability can be improved, the production of by-products can be suppressed, and the cost can be reduced.
　Examples of the method for reducing the ammonia gas contained in the reaction solution include heating the reaction solution, purging the gas phase portion in the reaction vessel with nitrogen, and setting the inside of the reaction vessel to a reduced pressure condition.
　The amide compound represented by the general formula (5) or the general formula (6) obtained as described above is reacted with a dehydrating agent (dehydration cyanation), and the nitrile compound represented by the general formula (1) is reacted. To get.
　The amide compound represented by the general formula (5) or the general formula (6) may be subjected to a reaction with a dehydrating agent as it is, or may be once isolated, purified, etc. and then subjected to a reaction with a dehydrating agent. You may.
　Examples of the dehydrating agent include a phosphorus-based dehydrating agent, a chlorine-based dehydrating agent, and a nitrogen-based dehydrating agent. Specific examples include diphosphorus pentoxide, polyphosphate, phosphorus pentachloride, thionyl chloride, phosphoryl chloride, acetyl chloride, tosyl pyridine chloride, cyanuric acid chloride, benzenesulfonic acid chloride, oxalyl chloride, and phosphorus tribromide. Be done. As the dehydrating agent, one type may be used alone, or two or more types may be used in any combination and ratio.
　As the dehydrating agent, diphosphorus pentoxide, phosphoryl chloride, cyanuric acid chloride, and phosphorus tribromide are preferable from the viewpoint of cost, reactivity, and the like.
　The amount of the dehydrating agent used is not particularly limited as long as it can be dehydrated and cyanated, but from the viewpoint of cost, reactivity and the like, preferably 0.1 mol to 10 mol, preferably 0.5 mol, based on 1 mol of the amide compound. It is ~ 10 mol.
　In the reaction between the amide compound and 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 that does not inhibit the dehydration cyanation reaction may be present.
　The reaction temperature is usually 20 ° C. to 120 ° C., preferably 50 ° C. to 110 ° C., and particularly preferably 70 ° C. to 100 ° C. from the viewpoint of productivity and the like. The reaction time can be appropriately selected depending on the progress of the reaction, and is usually 0.5 hours to 10 hours, preferably 1 hour to 8 hours. The reaction is usually carried out under normal pressure.
[0046]
　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 is mixed with an organic solvent capable of dissolving the nitrile compound represented by the general formula (1) (for example, toluene, ethyl acetate, tert-butyl methyl ether, etc.), and if necessary. The nitrile compound represented by the general formula (1) can be precipitated and recovered as a solid by cooling after performing washing, separating the aqueous layer, concentrating and the like accordingly.
　In this step 2A, since the amide compound represented by the general formula (5) or the general formula (6) has high crystallinity, a high-purity amide compound can be easily isolated and recovered. Further, by using the high-purity amide compound, a high-purity and high-quality nitrile compound represented by the general formula (1) can be obtained.
[0047]
(2) Step 2B
[0048]
[Chemical 4]

[0049]
　In step 2B, the carboxylic acid compound represented by the general formula (4) is subjected to a halogenating agent and the following general formula (7)
R 6 SO 2 R 7　(7 ) in an organic solvent in the presence of a catalyst, if necessary. )
Is reacted with the compound represented by the above general formula (1) to obtain the nitrile compound represented by the general formula (1).
　As the compound represented by the general formula (7), sulfamide, sulfamic acid and chlorosulfonyl isocyanate are particularly preferable.
　The target nitrile compound represented by the general formula (1) can be crystallized and purified with an organic solvent such as toluene or heptane.
　Further, by adding water to the target reaction solution containing the nitrile compound represented by the general formula (1), the nitrile compound can be precipitated as crystals.
　Step 2B is industrially preferred as it can be carried out in one reactor.
　In step 2B, a high-quality nitrile compound represented by the general formula (1) having a purity (HPLC) of preferably 98Area% or more, particularly preferably 99Area% or more can be obtained.
[0050]
　Specifically, the step 2B may be any of the following steps 2B-1 and 2B-2.
[0051]
Step 2B-1:
[0052]
[Chemical 5]

[0053]
　In step 2B-1, the carboxylic acid compound represented by the general formula (4) is subjected to a halogenating agent and the general formula (7) at 80 ° C. to 180 ° C. in an organic solvent, if necessary, in the presence of a catalyst. This is a step of reacting with the compound represented by the above formula (1) to obtain the nitrile compound represented by the general formula (1).
　The halogenating agent is not particularly limited as long as it can halogenate the carboxylic acid compound represented by the general formula (4). As the halogenating agent, a chlorinating agent and a brominating agent are preferable, and a chlorinating agent is more preferable. Examples of the chlorinating agent include thionyl chloride, oxalyl chloride, sulfyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride and the like, and examples of the brominating agent include thionyl bromide and phosphorus tribromide. One of these halogenating agents may be used alone, or two or more of these halogenating agents may be used in any combination and ratio. Among these, thionyl chloride, phosphoryl chloride, phosphorus pentachloride, thionyl bromide, and phosphorus tribromide are preferable, and thionyl chloride is particularly preferable, from the viewpoint of cost, versatility, reactivity, and the like.
　The amount of the halogenating agent used is not particularly limited as long as the carboxylic acid compound represented by the general formula (4) can be halogenated, but the carboxylic acid compound can be sufficiently halogenated in order to sufficiently halogenate the carboxylic acid compound. It is preferable to use 1 mol or more with respect to 1 mol of the acid compound.
　The upper limit of the amount used is not particularly limited, but is preferably 3 mol or less with respect to 1 mol of the carboxylic acid compound from the viewpoint of cost, productivity and the like. That is, the amount of the halogenating agent used is 1 mol to 3 mol, more preferably 1.02 mol to 2 mol, and particularly preferably 1.05 mol to 1.5 mol with respect to 1 mol of the carboxylic acid compound. The halogenating agent is preferably used in a slightly larger amount than the theoretical amount in order to complete the reaction.
　The amount of the compound represented by the general formula (7) used is the general formula (8)
Np-R 5- COZ ( 8) produced by the reaction of the carboxylic acid compound represented by the general formula (4) with the halogenating agent. 8)
in (formula (8), Z represents a halogen atom, Np and R 5 are defined the same meaning.)
it is not particularly limited as long as it is an amount capable cyanation acid halide compound represented by the. Usually, it is preferable to use 1 mol or more with respect to 1 mol of the acid halide compound. The amount of the compound represented by the general formula (7) used is 1 mol to 3 mol, more preferably 1.02 mol to 2 mol, and particularly preferably 1.05 mol to 1.5 mol with respect to 1 mol of the carboxylic acid compound. ..
　In step 2B-1, the amount of the compound represented by the general formula (7) is preferably larger than the amount of the halogenating agent used. From the viewpoint of effect, cost and the like, the amount of the compound represented by the general formula (7) is preferably 2% to 20%, preferably 5% to 15% more than the amount of the halogenating agent used. Thereby, the target nitrile compound represented by the general formula (1) can be obtained in a high yield. When the amount of the compound represented by the general formula (7) used is less than the amount of the halogenating agent used, many by-products may be produced and the yield of the target nitrile compound may decrease. Further, when the amount of the compound represented by the general formula (7) used is the same as the amount of the halogenating agent used, the reaction may not proceed sufficiently.
[0054]
　A catalyst may be present to promote the reaction. The catalyst is not particularly limited as long as it promotes the reaction of step 2B-1. Examples of the catalyst include N, N-dimethylformamide, N-methylpyrrolidone, N, N-dimethylacetamide and the like, and N, N-dimethylformamide is particularly preferable.
　The amount of the catalyst used is not particularly limited as long as it is an amount effective for functioning as a catalyst. The amount of the catalyst used is preferably 0.0001 mol to 1 mol, preferably 0.001 mol to 0.1 mol, based on 1 mol of the carboxylic acid compound represented by the general formula (4).
　The organic solvent is not particularly limited as long as the reaction of step 2B-1 proceeds. Examples of the organic solvent include an ester solvent, an ether solvent, a ketone solvent, a nitrile solvent, an amide solvent, a sulfoxide solvent, a sulfone solvent, a hydrocarbon solvent, and a basic organic solvent. One of these organic solvents may be used alone, or two or more of these organic solvents may be used in any combination and ratio.
　As the ester solvent, for example, acetic acid esters such as ethyl acetate, propyl acetate and butyl acetate can be used.
　As the ether solvent, for example, chain ethers such as diethyl ether, di-n-butyl ether, diisopropyl ether and tert-butyl methyl ether; cyclic ethers such as cyclopentyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran and dioxane can be used. it can.
　As the ketone solvent, for example, an aliphatic ketone such as acetone, methyl ethyl ketone, or methyl isobutyl ketone can be used.
　As the nitrile solvent, for example, aliphatic nitriles such as acetonitrile, propanonitrile, butyronitrile, isobutyronitrile, valeronitrile and isovaleronitrile; aromatic nitriles such as benzonitrile can be used.
　As the amide solvent, for example, aprotic amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidinone can be used.
　As the sulfoxide solvent, for example, an aprotic sulfoxide such as dimethyl sulfoxide can be used.
　As the sulfone solvent, for example, aprotic sulfones such as ethyl methyl sulfone, ethyl isopropyl sulfone, 3-methyl sulfolane, and sulfolane can be used.
　As the hydrocarbon solvent, aliphatic hydrocarbons such as hexane, cyclohexane, heptane and cycloheptane; and aromatic hydrocarbons such as toluene and xylene can be used.
　As the basic organic solvent, for example, a pyridine-based solvent such as pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, and 2,6-dimethylpyridine can be used.
　The amount of the organic solvent used is usually 1 L or more, preferably 2 L or more, more preferably 3 L or more from the viewpoint of operability, etc., with respect to 1 kg of the carboxylic acid compound represented by the general formula (4), and the upper limit is From the viewpoint of operability, productivity, cost and the like, it is usually 50 L or less, preferably 20 L or less, more preferably 10 L or less, still more preferably 4.5 L or less, and particularly preferably 4 L or less.
　In this step, it is preferable to use a sulfone solvent as the organic solvent from the viewpoint of reactivity, productivity and the like, and it is particularly preferable to use sulfolane because the yield of the target nitrile compound is improved. The sulfone solvent is preferably used alone, but may be used in combination with other organic solvents in any proportion.
　The reaction temperature with the halogenating agent may differ depending on the organic solvent used, the catalyst, etc., but the lower limit is usually 80 ° C. or higher, preferably 85 ° C. or higher, particularly preferably 90 ° C. or higher, from the viewpoint of quality, reactivity, etc. The upper limit is usually 180 ° C. or lower, preferably 150 ° C. or lower, particularly preferably 120 ° C. or lower, from the viewpoint of quality, reactivity, cost and the like.
　If the reaction temperature is too low, the progress of the reaction may be slowed and the productivity may be lowered, and if it is too high, by-products may be generated and the quality of the target nitrile compound may be lowered.
　The reaction temperature with the compound represented by the general formula (7) is not particularly limited as long as the reaction proceeds, but the lower limit is usually 0 ° C. or higher, preferably 10 ° C. or higher, from the viewpoint of productivity or the like. The temperature is preferably 15 ° C. or higher, and the upper limit is usually 180 ° C. or lower, preferably 150 ° C. or lower, more preferably 120 ° C. or lower, and particularly preferably 20 ° C. to 110 ° C. from the viewpoint of quality and cost. ..
　If the reaction temperature is too low, the progress of the reaction may be slowed and the productivity may be lowered, and if it is too high, by-products may be generated and the quality of the target nitrile compound may be lowered.
　The reaction time may vary depending on the organic solvent and catalyst used, but can be appropriately selected depending on the progress of the reaction, and is usually 0.5 hours to 30 hours, preferably 1 hour to 15 hours. The pressure during the reaction is usually normal pressure.
[0055]
　One aspect of this step is a 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, at 20 ° C to 70 ° C. The temperature may be raised to 80 ° C. to 180 ° C. after mixing the catalysts accordingly.
　Further, as another aspect of this step, a carboxylic acid compound represented by the general formula (4), a halogenating agent, a compound represented by the general formula (7), an organic solvent, and the like at 80 ° C. to 180 ° C. And, if necessary, mixing the catalyst.
　Further, as another aspect of this step, at 20 ° C. to 70 ° C., the carboxylic acid compound represented by the general formula (4), the compound represented by the general formula (7), an organic solvent, and if necessary After mixing the catalyst, the temperature is raised to 80 ° C. to 180 ° C., and a halogenating agent is added. This embodiment is preferable because the precipitation of the sulfonamide compound, which is a reaction intermediate, can be easily suppressed.
[0056]
Step 2B-2:
[0057]
[Chemical 6]

[0058]
　Step 2B-2 is the reaction raw material 1 in which the carboxylic acid compound represented by the general formula (4), the halogenating agent, the first organic solvent and, if necessary, the catalyst are mixed, and the general formula (7). This is a step of reacting the reaction raw material 2 in which the represented compound and the second organic solvent are mixed at 80 ° C. to 180 ° C. to obtain the nitrile compound represented by the general formula (1).
[0059]
　Examples of the halogenating agent and the compound represented by the general formula (7) include the same compounds as in Step 2B-1.
[0060]
　The amount of the halogenating agent used is usually preferably 1 mol or more with respect to 1 mol of the carboxylic acid compound represented by the general formula (4). Further, from the viewpoint of cost, productivity and the like, it is preferable that the amount is 3 mol or less with respect 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, based on 1 mol of the carboxylic acid compound. The halogenating agent is preferably used in a slightly larger amount than the theoretical amount in order to complete the reaction.
[0061]
　The amount of the compound represented by the general formula (7) is usually preferably 1 mol or more with respect to 1 mol of the carboxylic acid compound represented by the general formula (4). The amount of the compound represented by the general formula (7) used is 1 mol to 5 mol, more preferably 1.02 mol to 3 mol, and particularly preferably 1.05 mol to 2 mol with respect to 1 mol of the carboxylic acid compound.
[0062]
　In step 2B-2, it is preferable that the amount of the compound represented by the general formula (7) used is larger than the amount of the halogenating agent used. From the viewpoint of effect, cost and the like, the amount of the compound represented by the general formula (7) is preferably 2% to 20%, preferably 5% to 15% more than the amount of the halogenating agent used. As a result, the desired nitrile compound represented by the general formula (1) can be obtained in high yield. When the amount of the compound represented by the general formula (7) used is less than the amount of the halogenating agent used, many by-products may be produced and the yield of the target nitrile compound may decrease. Further, when the amount of the compound represented by the general formula (7) used is the same as the amount of the halogenating agent used, the reaction may not proceed sufficiently.
[0063]
　The first organic solvent is not particularly limited as long as the reaction of step 2B-2 proceeds. Examples of the organic solvent include an ester solvent, an ether solvent, a ketone solvent, a nitrile solvent, an amide solvent, a sulfoxide solvent, a sulfone solvent, a hydrocarbon solvent, and a basic organic solvent. One of these organic solvents may be used alone, or two or more of these organic solvents may be used in any combination and ratio.
　As the ester solvent, for example, acetic acid esters such as ethyl acetate, propyl acetate and butyl acetate can be used.
　As the ether solvent, for example, chain ethers such as diethyl ether, di-n-butyl ether, diisopropyl ether and tert-butyl methyl ether; cyclic ethers such as cyclopentyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran and dioxane can be used. it can.
　As the ketone solvent, for example, an aliphatic ketone such as acetone, methyl ethyl ketone, or methyl isobutyl ketone can be used.
　As the nitrile solvent, for example, aliphatic nitriles such as acetonitrile, propanonitrile, butyronitrile, isobutyronitrile, valeronitrile and isovaleronitrile; aromatic nitriles such as benzonitrile can be used.
　As the amide solvent, for example, aprotic amides such as N, N-dimethylformamide, N, N-dimethylacetamide, and N-methylpyrrolidinone can be used.
　As the sulfoxide solvent, for example, an aprotic sulfoxide such as dimethyl sulfoxide can be used.
　As the sulfone solvent, for example, aprotic sulfones such as ethyl methyl sulfone, ethyl isopropyl sulfone, 3-methyl sulfolane, and sulfolane can be used.
　Hydrocarbon solvents include alicyclic hydrocarbons such as cyclohexane and methylcyclohexane; aromatics such as benzene, toluene, xylene, mesityrene, ethylbenzene, tert-butylbenzene, trifluoromethylbenzene, nitrobenzene, chlorobenzene, chlorotoluene and bromobenzene. Group hydrocarbons can be used.
　As the basic organic solvent, for example, a pyridine-based solvent such as pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, and 2,6-dimethylpyridine can be used.
　As the first organic solvent, a hydrocarbon solvent is preferable, toluene, xylene and chlorobenzene are more preferable, and toluene is particularly preferable, from the viewpoint of operability, productivity, cost and the like.
　Further, as the first organic solvent, a sulfone solvent is also preferable, and sulfolane is preferable from the viewpoint of reactivity, productivity and the like.
　Further, it is also preferable to use a mixture of a hydrocarbon solvent and a sulfone solvent as the first organic solvent, and a mixture of toluene and sulfolane is particularly preferable. The mixing ratio (volume ratio) of the hydrocarbon solvent and the sulfone solvent can be appropriately selected in the range of 1:99 to 99: 1.
　The amount of the first organic solvent used is usually 1 L or more, preferably 2 L or more, and more preferably 3 L or more from the viewpoint of operability, etc., with respect to 1 kg of the carboxylic acid compound represented by the general formula (4). The upper limit is usually 50 L or less, preferably 30 L or less, more preferably 20 L or less, still more preferably 4.5 L or less, and particularly preferably 4 L or less, from the viewpoint of operability, productivity, cost and the like.
　As the second organic solvent, it is preferable to use a sulfone solvent from the viewpoint of reactivity, productivity and the like. As the sulfone solvent, for example, aprotic sulfones such as ethyl methyl sulfone, ethyl isopropyl sulfone, 3-methyl sulfolane, and sulfolane can be used.
In particular, it is preferable to use sulfolane because the yield of the target nitrile compound is improved. The sulfone solvent is preferably used alone, but may be mixed with another organic solvent (for example, a hydrocarbon solvent) in an arbitrary ratio.
　The amount of the second organic solvent used is usually 1 L or more, preferably 2 L or more, and more preferably 3 L or more from the viewpoint of operability, etc., with respect to 1 kg of the carboxylic acid compound represented by the general formula (4). The upper limit is usually 50 L or less, preferably 30 L or less, more preferably 20 L or less, still more preferably 4.5 L or less, and particularly preferably 4 L or less, from the viewpoint of operability, productivity, cost and the like.
　The type and amount of the catalyst used are the same as in Step 2B-1.
　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 a catalyst if necessary. The preparation temperature is usually 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 may slow down and productivity may decrease, and if it is too high, by-products may be produced and the quality of the target nitrile compound may decrease.
　The reaction raw material 1 may be concentrated, purified, or the like.
　The reaction raw material 2 is prepared by mixing the compound represented by the general formula (7) and the second organic solvent. The preparation temperature is not particularly limited, but is usually 10 ° C. to 180 ° C., preferably 20 ° C. to 150 ° C.
　Inorganic additives (for example, diatomaceous earth, silicic anhydride, silicon dioxide, sodium sulfate, magnesium sulfate, sodium chloride, magnesium chloride, calcium carbonate, magnesium carbonate, etc.) may be added to the reaction raw material 1 or 2, if necessary. May be added. By using an inorganic additive, the reaction can proceed smoothly.
　In this step, the reaction raw material 1 and the reaction raw material 2 may be mixed and then heated to react at 80 ° C. to 180 ° C., or the reaction raw material 1 at 80 ° C. to 180 ° C. and 80 ° C. to 180 ° C. The reaction raw material 2 may be mixed and reacted. Further, 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.
　The reaction time of the reaction raw material 1 and the reaction raw material 2 may differ depending on the halogenating agent, organic solvent, catalyst, etc. used, but can be appropriately selected depending on the progress of the reaction, and is usually 0.5 hours to 30 hours, preferably 0.5 hours to 30 hours. It is 1 hour to 15 hours, particularly preferably 2 hours to 10 hours. The pressure during the reaction is usually normal pressure.
[0064]
(3) Post-step The
　reaction solution containing the nitrile compound represented by the general formula (1) obtained by the step 2A or 2B may be subjected to treatments such as neutralization, liquid separation, filtration, etc., or concentrated. , The nitrile compound represented by the general formula (1) may be isolated by an isolation means such as crystallization.
　The nitrile compound represented by the general formula (1) obtained in the present invention has a high quality (HPLC) of preferably 98% or more, particularly preferably 99% or more, but can be recrystallized as necessary. Further purification may be performed by a known purification means such as crystal or column chromatography.
[0065]
　The production method of the present invention may be batch or continuous.
　In addition, each compound in the present invention may form a solvate such as a hydrate or an organic solvate, and its form is not particularly limited as long as it does not inhibit the reaction.
[0066]
　In the present invention, the following steps are particularly preferable.
Step 1: A step of reacting 2'-acetonafton, sulfur and morpholine and then hydrolyzing to obtain 2-naphthylacetic acid.
[0067]
[Chemical 7]

[0068]
Step 2A: A step of reacting 2-naphthylacetic acid with thionyl chloride and ammonia (gas or aqueous solution) to obtain 2-naphthylacetamide, and further reacting with phosphoryl chloride to obtain 2-naphthylacetonitrile.
[0069]
[Chemical 8]

[0070]
Step 2B-1: A step of reacting 2-naphthylacetic acid, sulfolane, thionyl chloride, sulfamide and, if necessary, a catalyst at 80 ° C. to 180 ° C. to obtain 2-naphthylacetonitrile.
[0071]
[Chemical 9]

[0072]
Step 2B-2: Reaction raw material 1 in which 2-naphthylacetic acid, thionyl chloride, toluene and, if necessary, a catalyst are mixed, and reaction raw material 2 in which sulfamide and sulfolane are mixed are reacted at 80 ° C. to 180 ° C. for 2-. Step to obtain naphthyl acetonitrile
[0073]
[Chemical 10]

Example
[0074]
　Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
　In the following Examples and Comparative Examples, commercially available 2'-acetonafton was used. The purity of the obtained compound was measured by HPLC under the following analytical conditions.
[0075]
(HPLC analysis condition -1)
　analytical instrument: Agilent Co. HPLC (1200 series)
　Column: Cadenza CD-C18, 3 μm , 150 mm × 4.6 mm
　Mobile phase A: 0.1% by volume trifluoroacetic acid in water
　Mobile phase B: Acetonitrile
　Grad Gentle: 0 min (B: 15%)-15 min (B: 90%)-20 min (B: 90%)
　Flow rate: 1.0 mL / min
　Injection volume: 5 μL
　Detection wavelength: 215 nm
　Column temperature: 40 ° C
[0076]
(HPLC analysis condition -2)
　analytical instrument: Agilent Co. HPLC (1200 series)
　Column: Cadenza CD-C18, 3 μm , 150 mm × 4.6 mm
　Mobile phase A: 0.1% by volume trifluoroacetic acid in water
　Mobile phase B: Acetonitrile
　Grad Gentle: 0 min (B: 15%)-20 min (B: 90%)-25 min (B: 90%)
　Flow rate: 1.0 mL / min
　Injection volume: 5 μL
　Detection wavelength: 280 nm
　Column temperature: 40 ° C
[0077]
(HPLC analysis condition-3)
　Analytical instrument: HPLC (1200 series)
　column manufactured by Agilent : Zorbax Eclipse Plus Phenyl-Hexyl, 5 μm, 250 mm × 4.6 mm
　Mobile phase A: 0.1 volume% Trifluoroacetic acid aqueous solution
　mobile phase B: Acetonitrile
　gradient: 0 minutes (B: 30%) -15 minutes (B: 60%) -20 minutes (B: 95%) -30 minutes (B: 95%)
　Flow rate: 1.0 mL / min
　Injection volume: 5 μL
　Detection wavelength: 280 nm
　Column temperature: 40 ° C
[0078]
Example 1: Synthesis of carboxylic acid compound
[0079]
[Chemical 11]

[0080]
　In a nitrogen-substituted reaction vessel, 3.00 g of 2'-acetonafton and 0.85 g of sulfur (1.5 mol times as much as 2'-acetonafton) were placed, and 4.61 g of morpholine (3 as opposed to 2'-acetonafton) was added. After adding (molar times) and stirring, the mixture was reacted at 115 ° C. to 125 ° C. for 4 hours (thioamide compound was produced).
　After cooling the reaction solution to 70 ° C to 80 ° C, a 20 wt% sodium hydroxide aqueous solution (a mixture of 3.53 g of sodium hydroxide and 14.1 g of water. 5 mol times as much water as 2'-acetonafton. Sodium oxide) was added and reacted at 90 ° C. to 105 ° C. for 8 hours (hydrolysis). The reaction mixture was cooled to 50 ° C. to 60 ° C., 0.15 g of activated carbon (purified Shirasagi) was added, the mixture was stirred, and then filtered. Hydrochloric acid (a mixture of 14.69 g of hydrochloric acid and 12.4 mL of water) having a concentration of 35% was added to the obtained filtrate, and the mixture was stirred and then cooled, and 2-naphthylacetic acid was recovered as crude crystals.
　2.0 g of the obtained crude crystal of 2-naphthylacetic acid (purity (HPLC analysis condition-1) 92.6%) was dissolved in 20 mL of toluene at 115 ° C. and then cooled to 10 ° C. or lower to obtain a carboxylic acid compound. Precipitated. The amount of 2-naphthylacetic acid obtained was 1.3 g, and the purity measured by HPLC (HPLC analysis condition-1) was 98.2 Area%.
1 1 H-NMR (400MHz, CDCl 3 ) 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)
　The results of HPLC analysis of the crude crystals of the obtained carboxylic acid compound (2-naphthylacetic acid) are shown in FIG. Further, the results of HPLC analysis of the obtained carboxylic acid compound (2-naphthylacetic acid) purified crystals are shown in FIG. 2, and the results of 1 H-NMR measurement are shown in FIG.
[0081]
Example 2: Synthesis of carboxylic acid compound
[0082]
[Chemical 12]

[0083]
　In a nitrogen-substituted reaction vessel, 120.00 g of 2'-acetonafton, 28.26 g of sulfur (1.25 mol times as much as 2'-acetonafton), and p-Toluenesulfonic acid monohydrate 13 .41 g (0.10 mol times relative to 2'-acetonafton) and 184.26 g morpholine (3 mol times relative to 2'-acetonafton) were added and stirred, followed by reaction at 115 ° C. to 125 ° C. for 9 hours. (A thioamide form is produced).
　After cooling the reaction solution to 70 ° C to 80 ° C, a 20 wt% sodium hydroxide aqueous solution (a mixture of 141.00 g of sodium hydroxide and 564.01 g of water. 5 mol times as much water as 2'-acetonafton. Sodium oxide) was added and 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, the mixture was stirred at 65 ° C. to 75 ° C., allowed to stand, and then the upper layer was discarded (removal of unreacted sulfur). ).
　The obtained lower layer was added to a mixed solution of 1200 mL of toluene and 35% hydrochloric acid (a mixture of 205.64 g of hydrochloric acid and 281.90 mL of water. 8 mol times hydrochloric acid with respect to 2'-acetonafton). Further, 12.00 g of water was added to the reaction vessel containing the lower layer for washing, and the obtained liquid was also added to the mixed solution. The mixed solution to which the lower layer and the like were added was stirred at 65 ° C. to 75 ° C. and then allowed to stand (extraction of the carboxylic acid compound), and the obtained lower layer was discarded. 600.00 g of water was added to the remaining upper layer, the mixture was stirred at 65 ° C. to 75 ° C., allowed to stand, and the lower layer was discarded. Further, 600.00 g of water was added to the remaining upper layer, the mixture was stirred at 65 ° C. to 75 ° C., allowed to stand, and the lower layer was discarded.
　After concentrating the obtained upper layer, it was cooled to 10 ° C. or lower, and the precipitated crystals of the carboxylic acid compound (2-naphthylacetic acid) were recovered. The obtained carboxylic acid compound (2-naphthylacetic acid) was 104.14 g, and the purity measured by HPLC (HPLC analysis condition-3) was 99.6 Area%.
1 1 H-NMR (400MHz, CDCl 3 ) 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) The
　results of HPLC analysis of the obtained carboxylic acid compound (2-naphthylacetic acid) are shown in FIG. 4, and the results of 1 H-NMR measurement are shown in FIG. 5, respectively.
[0084]
Example 3: Synthesis of carboxylic acid compound
[0085]
[Chemical 13]

[0086]
　In a nitrogen-substituted reaction vessel, 120.00 g of 2'-acetonafton, 120 mL of toluene (1.0 vol. ), And 184.26 g of morpholine (3 mol times as much as 2'-acetonafton) was added and stirred, and then distilled for 15 hours.
　Then, the mixture was concentrated, 28.26 g of sulfur (1.25 mol times with respect to 2'-acetonafton) was added, and then the reaction was carried out at 95 ° C. to 105 ° C. for 7 hours (thioamide compound was produced).
　After cooling the reaction solution to 70 ° C. to 80 ° C., a 20 wt% sodium hydroxide aqueous solution (a mixture of 141.00 g of sodium hydroxide and 564.01 g of water. Sodium oxide) was added and reacted at 90 ° C. to 105 ° C. for 7 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, stirred at 65 ° C. to 75 ° C., allowed to stand, and then the upper layer was separated and discarded.
　The obtained lower layer was added to a mixed solution of 1200 mL of toluene and 35% hydrochloric acid (a mixture of 205.64 g of hydrochloric acid and 281.90 mL of water. 8 mol times as hydrochloric acid with respect to 2'-acetonafton). After stirring at 65 ° C. to 75 ° C., the mixture was allowed to stand and the lower layer was discarded. 600.00 g of water was added to the upper layer, the mixture was stirred at 65 ° C. to 75 ° C., allowed to stand, and the lower layer was discarded. Further, 600.00 g of water was added to the upper layer, the mixture was stirred at 65 ° C. to 75 ° C., allowed to stand, and the lower layer was discarded.
　The obtained upper layer was concentrated and cooled to 10 ° C. or lower to obtain crystals of 2-naphthylacetic acid. The obtained 2-naphthylacetic acid weighed 104.83 g, and the purity measured by HPLC (HPLC analysis condition-3) was 99.8 Area%.
[0087]
Comparative Example 1: Synthesis of carboxylic acid compound
[0088]
[Chemical 14]

[0089]
　In a nitrogen-substituted reaction vessel, 1.00 g of 2'-acetonafton, 0.24 g of sulfur (1.25 mol times as much as 2'-acetonafton), and 1.50 g of piperidine (against 2'-acetonafton). (3.0 mol times) was added and stirred, and then reacted at 115 ° C. to 125 ° C. for 5 hours (thioamide compound was produced).
　After cooling the reaction solution to 70 ° C to 80 ° C, a 20 wt% sodium hydroxide aqueous solution (a mixture of 0.70 g of sodium hydroxide and 2.82 g of water. 3 mol times as much water as 2'-acetonafton. (Sodium oxide) was added and reacted at 90 ° C. to 105 ° C. for 6 hours, and then a 48 wt% sodium hydroxide aqueous solution (0.70 g of sodium hydroxide and 0.76 g of water were mixed. 2'-. (3 mol times sodium hydroxide) was added to acetonafton and reacted at 90 ° C. to 105 ° C. for 3 hours (hydrolysis).
　As a result of HPLC analysis (HPLC analysis condition-3), a carboxylic acid compound (2-naphthylacetic acid) was produced with a purity of 7Area%.
　Since the yield of the carboxylic acid compound was low, it is considered that the reaction does not proceed sufficiently when piperidine is used instead of morpholine.
[0090]
Reference example 1: Synthesis of thioamide
[0091]
[Chemical 15]

[0092]
　In a nitrogen-substituted reaction vessel, 1.00 g of 2'-acetonafton, 0.20 to 0.28 g of sulfur (1.05 to 1.50 mol times as much as 2'-acetonafton), and 1.53 g of morpholine (2'). -3.0 mol times with respect to acetnaphthone) was added and stirred, and then reacted at 80 ° C. to 120 ° C. for 6 to 22 hours to synthesize a thioamide compound.
　As a result of HPLC analysis (HPLC analysis condition-3), a thioamide compound was produced with a purity of 77Area% to 85Area%. The results are shown in Table 1.
[0093]
Reference example 2: Synthesis of thioamide
[0094]
[Chemical 16]

[0095]
　In a nitrogen-substituted reaction vessel, 1.00 g of 2'-acetonafton and 0.23 g of sulfur (1.25 mol times as much as 2'-acetonafton), additives (see Table 1), and 1.54 g of morpholine. (3.0 mol times as much as 2'-acetonafton) was added and stirred, and then reacted at 115 ° C. to 125 ° C. for 3 to 25 hours to synthesize a thioamide compound.
　As a result of HPLC analysis (HPLC analysis condition-3), a thioamide compound was produced with a purity of 84Area% to 88Area%. The results are shown in Table 1.
　In Table 1, Na 2 SO 4 means sodium sulfate , DDL 4 means magnesium sulfate, pTsOH / H 2 O means paratoluenesulfonic acid monohydrate, and MsOH means methanesulfonic acid.
　As is clear from Table 1, the amount of thioamide produced increases with the use of appropriate additives.
[0096]
[table 1]

[0097]
Reference Example 3: Synthesis of
　thioamide compound A thioamide compound was synthesized according to the method described in Non-Patent Document 5 (Green Chemistry Letters and Reviews, 2010, 315-318).
　In a nitrogen-substituted reaction vessel, 1.00 g of 2'-acetonafton, 0.21 g of sulfur (1.10 mol times as compared to 2'-acetonafton), and 0.56 g of morpholine (1.10 as compared to 2'-acetonafton). (Mole times) and 3.0 mL of polyethylene glycol (PEG-600) (3.0 volumes by volume with respect to 2'-acetonafton) were added and stirred, and then reacted at 100 ° C. for 7 hours to synthesize a thioamide compound.
　As a result of HPLC analysis (HPLC analysis condition-3), a thioamide compound was produced with a purity of 34 Area%.
　When polyethylene glycol was used, the yield of the thioamide compound was low, and improvement in reactivity by using polyethylene glycol could not be confirmed.
[0098]
Example 4: Synthesis of nitrile compounds
[0099]
[Chemical 17]

[0100]
　In a reaction vessel substituted with nitrogen, 0.50 g of 2-naphthylacetic acid obtained in Example 1, 0.38 g of thionyl chloride (1.2 mol times as much as that of a carboxylic acid compound) and 2.5 mL of toluene ( (5 volumes by volume with respect to the carboxylic acid compound) was mixed, 1 drop of N, N-dimethylformamide was added as a catalyst, and the mixture was reacted at 40 ° C. for 3 hours (acid chloride formation).
　Further, the acid chloride reaction solution was added dropwise to 0.82 g of an aqueous ammonia solution having a concentration of 28% (ammonia 5 mol times as large as that of the carboxylic acid compound), and the mixture was reacted at 50 ° C. for 1 hour. After cooling to room temperature, the precipitated amide compound was recovered by filtration (yield 77%).
　0.40 g of the amide compound obtained as described above and 0.36 g of phosphoryl chloride (1.1 mol times as large as that of the amide compound) were reacted at 85 ° C. for 4 hours. After separating the obtained reaction solution, the obtained organic layer was concentrated under reduced pressure, and 0.8 mL of toluene and 3.2 mL of heptane mixture (2 volumes each for the amide compound) were added to the obtained concentrated residue. 2 times and 8 times by volume) were added, and after stirring, the precipitated 2-naphthyl acetonitrile was recovered. The amount of 2-naphthylacetonitrile obtained was 0.26 g, and the purity measured by HPLC (HPLC analysis condition-2) was 97.2 Area%.
　The results of HPLC analysis of the obtained amide compound (HPLC analysis condition-2) are shown in FIG. 6, and the results of HPLC analysis of 2-naphthylacetonitrile are shown in FIG. 7, respectively.
[0101]
Example 5: Synthesis of nitrile compound
[0102]
[Chemical 18]

[0103]
　In a nitrogen-substituted reaction vessel, 90.0 g of 2-naphthylacetic acid obtained in Example 2, 51.1 g of sulfamide (1.1 mol times as much as that of a carboxylic acid compound), and 315 mL of sulfolane (carboxylic acid compound) were placed. After adding (3.5 volumes by volume with respect to the acid compound) and stirring, the temperature was raised, and 69.0 g of thionyl chloride (1.2 mol times with respect to the carboxylic acid compound) was added at 95 ° C. to 105 ° C. After reacting at 95 ° C. to 105 ° C. for 7 hours, the reaction solution was cooled, and at 50 ° C. to 60 ° C., 1.8 g of activated carbon (strong Shirasagi) (0.02 times by weight with respect to the carboxylic acid compound) and 180 mL of methanol (carboxylic acid compound) were added. (2 volumes by volume with respect to the acid compound) was added, stirred, and then filtered. The filtration residue was washed with 90 mL of methanol (1 volume times relative to the carboxylic acid compound). After mixing the filtrate and the washed liquid, 540 mL of water (6 volumes by volume with respect to the carboxylic acid compound) was added at 35 ° C to 45 ° C, and after stirring, the mixture was cooled to 0 ° C to 10 ° C and precipitated. 2-naphthylacetonitrile was recovered. The amount of 2-naphthylacetonitrile obtained was 63.2 g, and the purity measured by HPLC (HPLC analysis condition-3) was 99.5 Area%.
　The results of HPLC analysis of the obtained 2-naphthylacetonitrile are shown in FIG. 8, and the results of 1 H-NMR measurement are shown in FIG.
[0104]
Example 6: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 1 g of 2-naphthylacetic acid synthesized in the same manner as in Example 2, 10 mL of toluene (10 volumes by volume with respect to 2-naphthylacetic acid), N, N-dimethyl 10 μL of formamide and 0.672 g of thionyl chloride (1.05 mol times with respect to 2-naphthylacetic acid) were mixed, and the mixture was reacted at 40 ° C. for 3 hours, and then the solvent was distilled off. The residue was mixed with 10 mL of sulfolane (10 times by volume with respect to 2-naphthylacetic acid) and 0.620 g of sulfamide (1.2 mol times with respect to 2-naphthylacetic acid) and reacted at 120 ° C. for 3 hours. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 94.1Area% of 2-naphthylacetonitrile was produced.
[0105]
Example 7: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 1.00 g of 2-naphthylacetic acid synthesized in the same manner as in Example 2, 5 mL of sulfolane (5 volumes by volume with respect to 2-naphthylacetic acid), sulfamide 0. 620 g (1.2 mol times with respect to 2-naphthyl acetic acid) was added and mixed, and 0.672 g of thionyl chloride (1.05 mol times with respect to 2-naphthyl acetic acid) was added dropwise at 100 ° C. to 100 ° C. The mixture was stirred for 8 hours and reacted. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 96.8 Area%.
[0106]
Comparative Example 2: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 1.00 g of 2-naphthylacetic acid, 10 mL of toluene (10 volumes by volume with respect to 2-naphthylacetic acid), and 0 thionyl chloride synthesized in the same manner as in Example 2. .672 g (1.05 mol times with respect to 2-naphthylacetic acid) and 10 μL of N, N-dimethylformamide were added and mixed, and the mixture was stirred at 40 ° C. for 1 hour. To the obtained reaction solution, 0.620 g of sulfamide (1.2 mol times as much as 2-naphthylacetic acid) was added, and the mixture was reacted at 120 ° C. for 3 hours. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 18.6 Area%.
[0107]
Comparative Example 3: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 1.00 g of 2-naphthylacetic acid, 10 mL of toluene (10 volumes by volume with respect to 2-naphthylacetic acid), and 0 thionyl chloride synthesized in the same manner as in Example 2. .672 g (1.05 mol times with respect to 2-naphthylacetic acid) and 10 μL of N, N-dimethylformamide were added and mixed, and the mixture was stirred at 40 ° C. for 1 hour, and the reaction mixture was concentrated. Separately, the concentrated residue prepared in advance was added to a solution prepared by mixing 0.620 g of sulfamide (1.2 mol times with respect to 2-naphthyl acetic acid) and 5 mL of N-methylpyrrolidone (5 volumes with respect to 2-naphthyl acetic acid). Was added dropwise, and the mixture was stirred at 100 ° C. for 7 hours to react. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 63.4 Area%.
[0108]
Comparative Example 4: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 1.00 g of 2-naphthylacetic acid and 0.620 g of sulfamide synthesized in the same manner as in Example 2 (1.2 mol times as much as 2-naphthylacetic acid). , N, N-Dimethylformamide 10 μL, acetonitrile 10 mL (10 volumes by volume with respect to 2-naphthyl acetic acid), mixed, and thionyl chloride 0.672 g (1.05 mol times with respect to 2-naphthyl acetic acid) under reflux. ) Was added and reacted for 1 hour. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 0.3 Area%.
[0109]
Comparative Example 5: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 1 g of 2-naphthylacetic acid, 5 mL of sulfolane (5 volumes by volume with respect to 2-naphthylacetic acid), and 0.620 g of sulfamide synthesized in the same manner as in Example 2 ( Add (1.2 mol times to 2-naphthyl acetic acid) and mix, add 0.672 g thionyl chloride (1.05 mol times to 2-naphthyl acetic acid) at 60 ° C. Stirred for hours. After stirring, the reaction solution was solidified by the precipitated crystal components, so the temperature was raised to 80 ° C. and the mixture was stirred. Since the solution was obtained by stirring at 80 ° C., the mixture was stirred and reacted for 5 hours in that state. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was not detected.
[0110]
Example 8: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 0.4 g of 2-naphthylacetic acid amide synthesized in the same manner as in Example 4, 2.8 mL of toluene (7 volumes by volume based on 2-naphthylacetic acid amide), 0.364 g of phosphorus oxychloride (1.1 mol times based on 2-naphthylacetic acid amide) was added, and the mixture was reacted by stirring at 80 ° C. for 2 hours. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 95.2 Area%.
[0111]
Example 9: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 0.3 g of 2-naphthylacetic acid amide synthesized in the same manner as in Example 4, 4 mL of toluene (13.3 volumes by volume with respect to 2-naphthylacetic acid amide), 0.328 g of cyanuric acid chloride (1.1 mol times based on 2-naphthylacetic acid amide) was added, and the mixture was reacted by stirring at 120 ° C. for 6 hours. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 73.8 Area%.
[0112]
Example 10: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 0.3 g of 2-naphthylacetic acid amide synthesized in the same manner as in Example 4 and 4.0 mL of toluene (13.3 volumes by volume based on 2-naphthylacetic acid amide). ), 0.253 g of diphosphorus pentoxide (1.1 mol times with respect to 2-naphthylacetic acid amide) was added, and the mixture was reacted by stirring at 80 ° C. for 5 hours. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 94.1 Area%.
[0113]
Example 11: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 0.3 g of an amide compound (2-naphthylacetic acid amide) synthesized in the same manner as in Example 4 and 4.0 mL of toluene (13 with respect to 2-naphthylacetic acid amide). .3 volumes), 0.341 g of p-toluenesulfonyl chloride (1.1 mol times for 2-naphthylacetic acid amide), 0.327 μL of pyridine (2.5 mol times for 2-naphthylacetic acid amide) In addition, the reaction was carried out by stirring at 120 ° C. for 1.5 hours. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 84.8 Area%.
[0114]
Comparative Example 6: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 0.3 g of an amide compound (2-naphthylacetic acid amide) synthesized in the same manner as in Example 4 and 3 mL of toluene (10 volumes with respect to 2-naphthylacetic acid amide). , 0.251 g of thionyl chloride (1.3 mol times with respect to 2-naphthylacetic acid amide) was added, and the mixture was reacted by stirring at 90 ° C. for 15 hours. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 34.4 Area%.
[0115]
Comparative Example 7: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 0.3 g of an amide compound (2-naphthylacetic acid amide) synthesized in the same manner as in Example 4 and 4.0 mL of toluene (13 with respect to 2-naphthylacetic acid amide). .3 volumes), 0.341 g of p-toluenesulfonyl chloride (1.1 mol times for 2-naphthylacetic acid amide), 0.563 μL of triethylamine (2.5 mol times for 2-naphthylacetic acid amide) In addition, the reaction was carried out by stirring at 120 ° C. for 9.5 hours. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 51.6 Area%.
[0116]
Comparative Example 8: Synthesis of nitrile compound In a
　nitrogen-substituted reaction vessel, 0.3 g of an amide compound (2-naphthylacetic acid amide) synthesized in the same manner as in Example 4 and 3.0 mL of toluene (10 with respect to 2-naphthylacetic acid amide). .0 volume), 0.409 g of triethylamine (2.5 mol times with respect to 2-naphthylacetic acid amide), 1.2 μL of dimethylsulfoxide (0.01 mol times with respect to 2-naphthylacetic acid amide), oxalyl chloride 0 .247 g (1.2 mol times based on 2-naphthylacetic acid amide) was added, and the mixture was stirred at 25 ° C. for 1 hour for reaction. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 28.2 Area%.
[0117]
Example 12: Synthesis of 2-naphthylacetonitrile In a
　nitrogen-substituted reaction vessel, 1.00 g of 2-naphthylacetic acid and 3.5 mL of sulfolane obtained in the same manner as in Example 2 (3.5 with respect to 2-naphthylacetic acid). 0.620 g of sulfamide (1.2 mol times with respect to 2-naphthyl acetic acid) and mixed, and 0.704 g of thionyl chloride (1.1 mol times with respect to 2-naphthyl acetic acid) at 100 ° C. ) Was added dropwise, and the mixture was stirred at 100 ° C. for 7.5 hours to react. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 96.2 Area%.
[0118]
Comparative Example 9: Synthesis of 2-naphthylacetonitrile In a
　nitrogen-substituted reaction vessel, 1.00 g of 2-naphthylacetic acid and 3.5 mL of sulfolane (3.5 with respect to 2-naphthylacetic acid) obtained in the same manner as in Example 2 were placed. 0.568 g of sulfamide (1.1 mol times with respect to 2-naphthyl acetic acid) and mixed, and 0.768 g of thionyl chloride (1.2 mol times with respect to 2-naphthyl acetic acid) at 100 ° C. ) Was added dropwise, and the mixture was stirred at 100 ° C. for 4.5 hours to react. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 84.1 Area%.
[0119]
Comparative Example 10: Synthetic
　nitrogen-substituted reaction vessel of 2-naphthylacetonitrile 0.5 g of the carboxylic acid compound (2-naphthylacetic acid) obtained in Example 2 and 1.5 mL of sulfolane (3 relative to 2-naphthylacetic acid). 0.284 g of sulfamide (1.1 mol times with respect to 2-naphthyl acetic acid) and mixed, and 0215 μL of thionyl chloride (1.1 mol times with respect to 2-naphthyl acetic acid) at 100 ° C. Dropped. Further, 0.25 mL of sulfolane (0.5 volume-fold with respect to 2-naphthylacetic acid) was added, and the mixture was stirred at 100 ° C. for 7.5 hours for reaction. As a result of analyzing the reaction product by HPLC (HPLC analysis condition-3), 2-naphthylacetonitrile was produced with a purity of 79.2 Area%.
[0120]
[Table 2]

[0121]
　As is clear from Table 2, high-purity 2-naphthylacetonitrile can be obtained when the amount of sulfamide is greater than the amount of thionyl chloride (Example 12). On the other hand, when the amount of sulfamide is smaller than the amount of thionyl chloride, a large amount of highly polar impurities are produced as a by-product, and the purity of the obtained 2-naphthylacetonitrile is also low (Comparative Example 9). When the amount of sulfamide is the same as the amount of thionyl chloride, the amount of highly polar impurities produced as a by-product is relatively small, but the purity of 2-naphthylacetonitrile is low, and it is considered that the reaction did not proceed sufficiently. ..
[0122]
Comparative Example 11: Bromination method
　A method for synthesizing 2- (bromomethyl) naphthalene from 2-methylnaphthalene was examined.
[0123]
(1) Synthesis of 2- (bromomethyl) naphthalene In a
　nitrogen-substituted reaction vessel, 1.0 g of commercially available 2-Methylnaphthalene and 4.0 mL of cyclohexane (4.0 volumes of 2-methylnaphthalene) ), N-Bromosuccinimide (NBS) 1.00 g-1.46 g (0.80-1.17 mol times as much as 2-methylnaphthalene) and azobisisobutyronitrile (AIBN) 3.5 mg (2- It was added 0.003 mol times with respect to methylnaphthalene) 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 wt% sodium hydroxide aqueous solution was added to stop the reaction. Then, the upper layer was analyzed by HPLC (HPLC analysis condition-1) to analyze the reaction composition. The results are shown in Table 3.
　In Tables 3 to 5 below, MR is a molar ratio to 2-methylnaphthalene, VR is a volume ratio to 2-methylnaphthalene, c-Hex is cyclohexane, and Product is 2- (bromomethyl) naphthalene, S. cerevisiae. M. Is 2-methylnaphthalene, DiBr is a dibromo compound, A% is Area% by HPLC analysis, N.I. D. Means that it was not detected.
[0124]
[Table 3]

[0125]
(2) Synthesis of 2- (bromomethyl) naphthalene In a
　nitrogen-substituted reaction vessel, 1.0 g of commercially available 2-methylnaphthalene, 4.0 mL of cyclohexane (4.0 volumes of 2-methylnaphthalene), 1,3 -Dibromo-5,5-dimethylhydranthin (DBMH) 0.91-1.21 g (0.45-0.60 mol times as much as 2-methylnaphthalene), azobisisobutyronitrile (AIBN) 3.5 mg (0.003 mol times based on 2-methylnaphthalene) was added, and 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 wt% sodium hydroxide aqueous solution was added to stop the reaction. Then, the upper layer was analyzed by HPLC (HPLC analysis condition-1) to analyze the reaction composition. The results are shown in Table 4.
[0126]
[Table 4]

[0127]
(3) Synthesis of 2- (bromomethyl) naphthalene In a
　nitrogen-substituted reaction vessel, 1.0 g of commercially available 2-methylnaphthalene, 4.0 mL of solvent (4.0 volumes of 2-methylnaphthalene), 1,3 -Dibromo-5,5-dimethylhydranthin (DBMH) 1.21 g (0.60 mol times relative to 2-methylnaphthalene), azobisisobutyronitrile (AIBN) 3.5 mg (against 2-methylnaphthalene) 0.003 mol times) was added, and the mixture was reacted at 80 ° C. for 2 hours. After the reaction, the mixture was cooled to room temperature and 2.0 mL of a 20 wt% sodium hydroxide aqueous solution was added to stop the reaction. Then, the upper layer was analyzed by HPLC (HPLC analysis condition-1) to analyze the reaction composition. The results are shown in Table 5.
[0128]
[Table 5]

[0129]
　From the above examination results, when the yield of the target product (2- (bromomethyl) naphthalene) is increased, the by-product dibromo form increases, and it is necessary to lower the yield of the target product in order to suppress the production of the dibromo form. I was able to confirm that there is. Subsequent studies also revealed that it was difficult to improve this relationship, and it was difficult to improve the yield in the synthesis of 2- (bromomethyl) naphthalene by bromination of 2-methylnaphthalene.
[0130]
(4) Synthesis of 2-naphthylacetonitrile from 2-
　(bromomethyl) naphthalene 2.0 g of 2- (bromomethyl) naphthalene (containing 17Area% of dibromo compound) synthesized by the same method as in Run 6 above, 10.0 mL of dimethyl sulfoxide (2-). (5.0 times by volume based on (bromomethyl) naphthalene) and 0.89 g of sodium cyanide (2.0 times by volume based on 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 volumes by volume with respect to 2- (bromomethyl) naphthalene) was added dropwise to precipitate crystals. After cooling and stirring at 13 ° C. for 2.5 hours, crystals were recovered by filtration. As a result of analyzing the obtained crystals by HPLC (HPLC analysis condition-1), 2-naphthylacetonitrile was produced with a purity of 60.2 Area%, and a dibromo compound was contained in an amount of 5.4 Area%.
Industrial applicability
[0131]
　According to the present invention, aromatic nitrile compounds such as 2-naphthylacetonitrile and aromatic carboxylic acid compounds such as 2-naphthylacetic acid, which are useful as raw materials for synthesis of various pharmaceuticals, pesticides and chemical products, and intermediates for synthesis, are industrialized. Therefore, it is possible to provide a novel method for producing with high purity, safely and inexpensively, with high efficiency. Furthermore, by using the aromatic nitrile compound such as 2-naphthylacetonitrile thus obtained, it is safe and inexpensive (1R, 5S) -1- (naphthalene-2-yl) -3-azabicyclo [3]. .1.0] Pharmaceuticals such as hexane can be produced.
[0132]
　This application is filed with US Provisional Patent Application No. 62 / 663,014 (Filing Date: April 26, 2018) and US Provisional Patent Application No. 62 / 780,445 (Filing Date: December 17, 2018). It is the basis, the contents of which are incorporated herein by reference in their entirety.
The scope of the claims
[Claim 1]
　General formula (1)
Np-R 5- CN (1)
(In general formula (1), Np is a naphthyl group which may have a substituent," which comprises the following steps 1 and 2. Shown , R 5
represents an alkylene group having 1 to 3 carbon atoms.) A method for producing a nitrile compound represented by.
Step 1:
　General formula
(2) Np-CO-R　　1 (2)
(In the general formula (2), Np is the same as defined above, R 1 represents an alkyl group having 1 to 3 carbon atoms.)
Table with General formula (3)
Np-R 5- C (= X) -NR 3 R 4　　(3)
(general formula (1 )) obtained by reacting the compound to be obtained by Wilgerot reaction in the presence of an additive, if necessary. ), Np and R 5 are synonymous with the above, X indicates an oxygen atom or a sulfur atom, and R 3 and R 4Independently indicate an alkyl group or a hydrogen atom having 1 to 3 carbon atoms which may have a nitrogen atom, an oxygen atom or a sulfur atom, and R 3 and R 4 are bonded to form a ring. You may. ) Is
hydrolyzed and then neutralized. General formula (4)
Np-R 5- COOH (4)
(In the general formula (4), Np and R 5 are described above. . synonymous)
obtaining a carboxylic acid compound represented by;
step 2: any of the steps of step 2A or step 2B
step 2A:
　represented by the general formula obtained in the step 1 (4) The general formula (5)
Np-R 5- CONH 2　　(5 ) obtained by reacting a carboxylic acid compound with a halogenating agent in an organic solvent in the presence of a catalyst, if necessary, and further reacting with an amidating agent. )
in (formula (5), Np and R 5 are as defined above.)
or general formula (6)
Np-R 5 -CONHOH (6)
(In the general formula (6), Np and R 5 has the same meaning as defined above.)
Step a compound represented by is reacted with a dehydrating agent to obtain a represented by a nitrile compound by the general formula (1);
Step 2B: The
　carboxylic acid compound represented by the general formula (4) obtained in the above step 1 is subjected to a halogenating agent and the general formula (7)
R 6 SO in an organic solvent in the presence of a catalyst, if necessary. 2 R 7　　(7)
(In the general formula (7), R 6 and R 7 each independently represent a chlorine atom, a hydroxyl group, an amino group, an isocyanate group or a p-tolyl group)
and a compound represented by the compound . A step of reacting to obtain a nitrile compound represented by the general formula (1).
[Claim 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: The
　carboxylic acid compound represented by the general formula (4) is subjected to a halogenating agent and the general formula (7) at 80 ° C. to 180 ° C. in an organic solvent in the presence of a catalyst, if necessary. in reacted with a compound represented by, obtaining a nitrile compound represented by the general formula (1);
step 2B-2:
　carboxylic acid compound represented by the general formula (4), halogenating agents, the The reaction raw material 1 in which one organic solvent and, if necessary, a catalyst are mixed, and the reaction raw material 2 in which the compound represented by the general formula (7) and the second organic solvent are mixed are reacted at 80 ° C. to 180 ° C. A step of obtaining a nitrile compound represented by the general formula (1).
[Claim 3]
　General formula (1)
Np-R 5- CN (1) including any of the following steps 2A or 2B
(In general formula (1), Np indicates a naphthyl group which may have a substituent. , R 5
represents an alkylene group having 1 to 3 carbon atoms.) A method for producing a nitrile compound represented by.
Step 2A: A carboxylic acid compound represented by the
　general formula (4)
Np-R 5- COOH (4)
(in the general formula (4), Np and R 5 have the same meanings as described above)
, if necessary. General formula (5)
Np-R 5- CONH 2　　(5) obtained by reacting with a halogenating agent and further reacting with an amidating agent in an organic solvent in the presence of a catalyst
(in the general formula (5), Np and R 5 are synonymous with the above.)
Or general formula (6)
Np-R 5- CONHOH (6)
(In the general formula (6), Np and R 5 has the same meaning as defined above.)
Step a compound represented by is reacted with a dehydrating agent to obtain a represented by a nitrile compound by the general formula (1);
Step 2B: A carboxylic acid compound represented by the
　general formula (4)
Np-R 5- COOH (4)
(in the general formula (4), Np and R 5 are synonymous with the above)
, if necessary. In the presence of a catalyst, in an organic solvent, a halogenating agent and the general formula (7)
R 6 SO 2 R 7　(7)
(In the general formula (7), R 6 and R 7 are independently chlorine atoms and hydroxyl groups, respectively. , Amino group, isocyanate group or p-tolyl group
) to obtain a nitrile compound represented by the general formula (1).
[Claim 4]
　The method for producing a nitrile compound according to claim 3, wherein the step 2B is the following step 2B-1 or step 2B-2.
Step 2B-1: The
　carboxylic acid compound represented by the general formula (4) is subjected to a halogenating agent and the general formula (7) at 80 ° C. to 180 ° C. in an organic solvent in the presence of a catalyst, if necessary. in reacted with a compound represented by, obtaining a nitrile compound represented by the general formula (1);
step 2B-2:
　carboxylic acid compound represented by the general formula (4), halogenating agents, the The reaction raw material 1 in which one organic solvent and, if necessary, a catalyst are mixed, and the reaction raw material 2 in which the compound represented by the general formula (7) and the second organic solvent are mixed are reacted at 80 ° C. to 180 ° C. A step of obtaining a nitrile compound represented by the general formula (1).
[Claim 5]
　General formula (2)
Np-CO-R 1　　(2)
(In 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. The
compound represented by ( shown) is subjected to a Wilgerot reaction in the presence of an additive, if necessary, to obtain a general formula (3)
Np-R 5- C (= X) -NR 3 R 4　　(3).
(In the general formula (1), Np is synonymous with the above, X represents an oxygen atom or a sulfur atom, R 5 represents an alkylene group having 1 to 3 carbon atoms, and R 3 and R 4 are independent of each other. It represents an alkyl group or a hydrogen atom having 1 to 3 carbon atoms which may have a nitrogen atom, an oxygen atom or a sulfur atom, and R 3 and R 4 may be bonded to form a ring.)
The compound represented by (4)
Np-R 5- COOH (4) , which is characterized by hydrolyzing and then neutralizing the compound represented by.
(In the general formula (4), Np and R 5 has the same meaning as defined above.)
Method for producing a carboxylic acid compound represented by.
[Claim 6]
　After the hydrolysis, the reaction product obtained by the hydrolysis is brought into contact with a hydrocarbon solvent, the hydrocarbon solvent is present at the time of the neutralization, or the reaction product obtained by the neutralization is carbonized. The method for producing a carboxylic acid compound according to claim 5, which comprises contacting with a hydrogen solvent.
[Claim 7]
　The sulfur content is 0.001 mol% to 1 mol%, and the purity is 98 mol% or more. General formula (4)
Np-R 5- COOH (4)
(In the 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.) A carboxylic acid compound represented by.