JP7257985B2 - Method for producing benzonitrile derivative - Google Patents

Description

The present disclosure relates to methods for producing benzonitrile derivatives.

Benzonitrile derivatives, especially 2-aminobenzonitrile derivatives, are useful as intermediates for pharmaceuticals, reagents and the like.
Benzonitrile derivatives are commercially available, and various studies have been made on methods for producing benzonitrile derivatives.
Conventionally, a method of decomposing isatin oxime to obtain a benzonitrile derivative has also been used industrially. As a method for obtaining a benzonitrile derivative in high yield, a method for obtaining a benzonitrile derivative by reacting isatin oxime with a carbonate in an amide solvent is disclosed (see Patent Document 1). According to the method described in Patent Document 1, it is described that the yield of the benzonitrile derivative exceeds 80%. Non-Patent Document 1 discloses a method of obtaining a 2-aminobenzonitrile derivative as an intermediate by reacting isatin oxime with sodium carbonate in the presence of dimethylformamide.
As another method for obtaining a 2-aminobenzonitrile derivative, a method has been proposed in which isatin oxime is decomposed using sodium methoxide in nonaethylene glycol (see Patent Document 2).

JP-A-2003-64039 Japanese Patent Publication No. 46-15611

European Journal of Medicinal Chemistry, Vol. 64, pp401-409 (2013)

According to the production methods described in Patent Document 1 and Non-Patent Document 1, a benzonitrile derivative can be obtained with a yield exceeding 80%. However, in these production methods, since a carbonate is used in the reaction, the product contains an inorganic salt as a by-product together with the benzonitrile derivative. For this reason, when isolating the benzonitrile derivative after the completion of the reaction, distillation causes problems such as foaming. There are problems such as less
In the method described in Patent Document 2, the desired reaction proceeds and a yield of 85% to 90% can be expected. However, since the reaction is carried out under strongly basic conditions, there is a problem that post-treatment such as purification promotes hydrolysis, which reduces the yield of the purified benzonitrile derivative.
Therefore, in any production method, there is a problem that undesirable side reactions and generation of impurities resulting from the side reactions occur.

The problem to be solved by one embodiment of the present invention is to provide a method for producing a benzonitrile derivative that suppresses the generation of side reactions and impurities caused by the side reactions and can obtain the desired benzonitrile derivative with high purity. to provide.

Means for solving the above problems include the following aspects.

<1> A compound represented by general formula I below is treated in the presence of at least one tertiary amine selected from the group consisting of compounds represented by general formula III and compounds represented by general formula IV below. A method for producing a benzonitrile derivative, comprising the step of reacting to obtain a benzonitrile derivative represented by the following general formula II.

In general formula I, R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a halogen atom, an alkoxy group having 1 to 5 carbon atoms, or a phenyl group. .
In general formula II, R ²¹ , R ²² , R ²³ and R ²⁴ each independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a halogen atom, an alkoxy group having 1 to 5 carbon atoms, or a phenyl group. .
In general formula III, R ³¹ , R ³² and R ³³ each independently represent an alkyl group or a phenyl group.
In general formula IV, R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ each independently represent an alkyl group. R ⁴¹ and R ⁴³ , and R ⁴² and R ⁴⁴ may be linked together to form a cyclic alkyl group.

<2> The method for producing a benzonitrile derivative according to <1>, wherein the amount of the tertiary amine used is in the range of 0.1 mol % to 100 mol % per 1 mol of the compound represented by formula I.
<3> The step of obtaining the benzonitrile derivative is carried out in the presence of at least one solvent selected from the group consisting of water and an aprotic polar solvent. Production method.
<4> The benzonitrile derivative according to any one of <1> to <3>, wherein the compound represented by Formula I is isatin oxime in which R ¹ , R ² , R ³ and R ⁴ are hydrogen atoms. Production method.

According to one embodiment of the present invention, it is possible to provide a method for producing a benzonitrile derivative that suppresses the generation of side reactions and impurities resulting from the side reactions and that can obtain the desired benzonitrile derivative with high purity. can.

The contents of the present disclosure will be described below.
The description of the constituent elements described below may be made based on representative embodiments of the present disclosure, but the present invention is not limited to the following embodiments.
In the present disclosure, a numerical range described using "to" represents a numerical range including numerical values before and after "to" as lower and upper limits.
The amount of each component described in the present disclosure means the total amount of the multiple substances unless otherwise specified when there are multiple substances corresponding to the component.
In the numerical ranges described stepwise in the present disclosure, the upper limit value or lower limit value described in a certain numerical range may be replaced with the upper limit value or lower limit value of another numerical range described stepwise. In addition, in the numerical ranges described in the present disclosure, upper or lower limits described in a certain numerical range may be replaced with values shown in Examples.
In the present disclosure, a combination of two or more preferred aspects is a more preferred aspect.
The chemical structural formulas in this specification may be represented by simplified structural formulas in which hydrogen atoms are omitted.
In the present disclosure, the term "process" includes not only an independent process, but also a process that cannot be clearly distinguished from other processes as long as the intended purpose of the process is achieved.

<Method for producing benzonitrile derivative>
The method for producing a benzonitrile derivative of the present disclosure (hereinafter sometimes simply referred to as the production method of the present disclosure) is a compound represented by the following general formula I, a compound represented by the following general formula III and a compound represented by the following general formula IV A step of reacting in the presence of at least one tertiary amine selected from the group consisting of compounds represented by to obtain a benzonitrile derivative represented by the following general formula II (hereinafter referred to as step A may occur).
At least one tertiary amine selected from the group consisting of compounds represented by the following general formula III and compounds represented by the general formula IV is hereinafter sometimes referred to as a specific tertiary amine.

In general formula I, R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a halogen atom, an alkoxy group having 1 to 5 carbon atoms, or a phenyl group. .
In general formula II, R ²¹ , R ²² , R ²³ and R ²⁴ each independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a halogen atom, an alkoxy group having 1 to 5 carbon atoms, or a phenyl group. .
In general formula III, R ³¹ , R ³² and R ³³ each independently represent an alkyl group or a phenyl group.
In general formula IV, R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ each independently represent an alkyl group. R ⁴¹ and R ⁴³ , and R ⁴² and R ⁴⁴ may be linked together to form a cyclic alkyl group.

Step A is considered to include the reaction shown below in which the oximated isatin is reacted in the presence of a specified tertiary amine, or preferably in the presence of a specified amine and a solvent, to give a 2-aminobenzonitrile. there is

In the above reaction, even if water is by-produced due to the function of the specific tertiary amine, hydrolysis is unlikely to occur in the next reaction. Therefore, it is considered that the production of by-products in the reaction is suppressed and the target product of high purity can be obtained.
Shown below is a reaction scheme using isatin oxime in which R ¹ , R ² , R ³ and R ⁴ are all hydrogen atoms as a starting material.

It is believed that the above reaction proceeds as follows.

(Compound represented by general formula I)
The compounds represented by general formula I are oximated isatins (isatin oximes), and the six-membered ring may or may not have a substituent.
In general formula I, R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a halogen atom, an alkoxy group having 1 to 5 carbon atoms, or a phenyl group. .
When R ¹ , R ² , R ³ and R ⁴ represent an alkyl group having 1 to 5 carbon atoms, the alkyl group includes a methyl group, an ethyl group, a butyl group, a propyl group and the like, and a methyl group or an ethyl group. is preferred.
A halogen atom includes a fluorine atom, a chlorine atom, an iodine atom and the like, and a chlorine atom or a bromine atom is preferable.
The alkoxy group having 1 to 5 carbon atoms includes methoxy, ethoxy, butoxy, propoxy and the like, with methoxy and ethoxy being preferred.
Among them, compounds in which all of R ¹ , R ² , R ³ and R ⁴ are hydrogen atoms are preferred from the viewpoint of better reactivity.

Isatin oxime can be obtained by synthesis using isatin as a starting material.
A method of obtaining isatin oxime by synthesis includes a method of reacting isatin with hydroxylamine hydrochloride.
Isatin is commercially available from Fuji Film Wako Pure Chemical Industries, Ltd., Tokyo Chemical Industry Co., Ltd., and the like.
The production method of the present disclosure may further include a step of oximating isatin (step B) in addition to step A, as described below.

(Specific tertiary amine)
In step A, the compound represented by general formula I is reacted with at least one compound selected from the group consisting of compounds represented by general formula III and compounds represented by general formula IV (specific tertiary amine).

In general formula III, R ³¹ , R ³² and R ³³ each independently represent an alkyl group or a phenyl group.
In general formula IV, R ⁴¹ , R ⁴² , R ⁴³ and R ⁴⁴ each independently represent an alkyl group. R ⁴¹ and R ⁴³ , and R ⁴² and R ⁴⁴ may be linked together to form a cyclic alkyl group.
The compound represented by the general formula III is an alkyl group represented by R ³¹ , R ³² and R ³³ in the general formula III, or an alkylene group obtained by removing one hydrogen atom from a phenyl group, or a phenylene group. It may be a dimer or trimer in which 2 or 3 tertiary amine structures are bonded.
In step A, the reaction is carried out in the presence of at least one selected from the above specific tertiary amines.
Specific tertiary amines include tertiary amines having chain alkyl groups (group a below), and dimers or trimers in which a plurality of tertiary amines are bonded via alkylene groups derived from chain alkyl groups. It may be either a tertiary amine (group b below), a cyclic tertiary amine (group c below), or the like. A cyclic tertiary amine may be a compound having a plurality of ring structures.
Specific tertiary amines that can be used in step A are exemplified below, but the specific tertiary amines are not limited to the following examples. In the structures below, Bu represents a butyl group.

The names of the compounds abbreviated in the above group c are as follows.
DABCO: 1,4-diazabicyclo[2,2,2]octane DBN: 1,5-diazabicyclo[4,3,0]-5-nonene DBU: 1,8-diazabicyclo[5,4,0]-7- Undecene

Among tertiary amines, tri-n-butylamine included in group a, N, N, and N',N'-tetramethylethylenediamine, N,N,N',N'-tetraethylethylenediamine, N,N,N',N'-tetramethyl-1,3-diaminopropane, N,N,N', N′-pentamethyldiethylenetriamine, DBU, DBN included in group c are preferred, and among them, N,N,N′,N′-tetraethylethylenediamine, N,N,N′,N′-tetramethyl-1, More preferred are 3-aminopropane, N,N,N',N'-pentamethyldiethylenetriamine, DBU, etc. N,N,N',N'-tetraethylethylenediamine, N,N,N',N'-tetramethyl -1,3-aminopropane, DBU are more preferred.

In step A, only one type of specific tertiary amine may be used, or two or more types may be used in combination.
The amount of the specific tertiary amine used in step A is not particularly limited, and the reaction proceeds regardless of the amount of the specific tertiary amine used. Among them, from the viewpoint that the reactivity is better and a higher yield can be expected, the specific tertiary amine is used in the range of 0.1 mol% to 100 mol% with respect to 1 mol of the compound represented by the general formula I. It is preferably used in the range of 1 mol % to 50 mol %, more preferably in the range of 1.5 mol % to 20 mol %.
The amount used means the total amount used when two or more kinds of specific tertiary amines are included.

In the reaction system in step A, in addition to the compound represented by general formula I and the specific tertiary amine, other components such as a solvent may be used within a range that does not impair the effect.

(solvent)
In step A, it is preferred to use a solvent for the reaction. Examples of solvents include water and aprotic polar solvents. Step A is preferably carried out in the presence of at least one solvent selected from the group consisting of water and aprotic polar solvents.
Examples of solvents include water, amide solvents, sulfone solvents, sulfoxide solvents, ureide solvents, ether solvents, ketone solvents, hydrocarbon solvents, halogen solvents, alcohol solvents, pyridine solvents, esters solvent, carboxylic acid solvent and nitrile solvent.

Water as a solvent is preferably ion-exchanged water, distilled water, pure water, ultrapure water, or the like, from the viewpoint of containing few impurities.

Amide solvents include, for example, N,N-dimethylformamide, N,N-dimethylacetamide, and 1-methyl-2-pyrrolidone. Examples of sulfone-based solvents include sulfolane. Examples of sulfoxide solvents include dimethylsulfoxide. Ureido solvents include, for example, tetramethylurea. Ether solvents include, for example, dioxane and cyclopentyl methyl ether. Ketone solvents include, for example, acetone and cyclohexanone. Hydrocarbon solvents include, for example, toluene, xylene, and n-decane. Examples of halogen-based solvents include tetrachloroethane and chlorobenzene. Alcoholic solvents include, for example, methanol, ethanol, isopropyl alcohol, ethylene glycol, cyclohexanol, and phenol. Pyridine-based solvents include, for example, pyridine, γ-picoline, and 2,6-lutidine. Ester solvents include, for example, ethyl acetate and butyl acetate. Carboxylic acid solvents include, for example, acetic acid and propionic acid. Examples of nitrile solvents include acetonitrile.
When using a solvent for the reaction, only one type may be used, or two or more types may be used in combination.
From the viewpoint of better reactivity, the solvent is preferably an amide solvent, a sulfone solvent, a sulfoxide solvent, a ureide solvent, or a nitrile solvent, and more preferably an amide solvent or a sulfoxide solvent.

Specifically, in step A, a mixed liquid containing a solvent and a tertiary amine is stored in a reactor such as a flask, and the internal temperature is raised to 100°C to 150°C.
A solution of the compound represented by general formula I dissolved in a separately prepared solvent is added dropwise into the container. Dropping is carried out at a rate that does not cause foaming, and the internal temperature is maintained at 100° C. to 150° C., and the reaction is allowed to proceed for 1 to 3 hours.
After completion of the reaction, cool to 15°C to 30°C. After confirming the presence of the reaction product represented by the general formula II, the reaction product is distilled under reduced pressure to obtain the compound represented by the general formula II.
The presence of the compound represented by general formula II can be confirmed by NMR or the like.

The temperature of the mixture is preferably 100°C to 150°C, preferably 110°C to 140°C, more preferably 110°C to 130°C.
The dropping speed of the solution of the compound represented by general formula I is preferably a speed that does not cause foaming as described above. A mode of dripping can be mentioned.

The reaction temperature is preferably 100°C to 150°C, more preferably 110°C to 140°C, more preferably 110°C to 130°C, as the internal temperature of the mixture.
The reaction time can be 1 hour to 3 hours, preferably 1.5 hours to 2.5 hours.

The fact that the aminobenzonitrile derivative obtained by the production method of the present disclosure has few by-products and high purity can be confirmed by analyzing the resulting product by High Performance Liquid Chromatography (HPLC). can be confirmed.
The purity of the benzonitrile derivative obtained by the present disclosure is preferably 90% or higher, preferably 95% or higher, and more preferably 99% or higher.
An apparatus used for HPLC analysis includes, for example, high performance liquid chromatography LC-2010 (Shimadzu Corporation).

In the present disclosure, HPLC analysis adopts values obtained under the following conditions.
Apparatus; LC-2010 manufactured by Shimadzu Corporation
Column; Tosoh Corporation, ODS-80Ts
Flow rate; 1 ml/min Oven temperature; 40°C
Detection wavelength; 254 nm
Eluent; acetonitrile/water (volume ratio) = 60/40, triethylamine, 0.1% by mass each of acetic acid

The production method of the present disclosure can include other steps in addition to step A. Other steps include a step of synthesizing the compound represented by general formula I (step B), a step of purifying the obtained compound represented by general formula II (step C), and the like.

(Step B)
Step B includes, for example, a step of oximating isatin as a raw material to obtain isatin oxime included in the compound represented by general formula I.
In step B, for example, a mixed solution containing isatin which may have a substituent, hydroxylamine hydrochloride, and water is mixed, and the internal temperature of the mixed solution is raised to 70° C. to 90° C. A step of heating and stirring for about 1 hour while maintaining the warmed temperature can be mentioned.
After the reaction is completed, the internal temperature of the mixed solution is cooled to 15° C. to 20° C., stirred for 10 to 20 minutes, and the formed isatin oxime crystals are collected by filtration.
The obtained isatin oxime crystals can be washed with water and dried at 50° C. for 12 hours to obtain purified isatin oxime.

(Process C)
Step C is a step of purifying the compound represented by general formula II obtained in step A.
The compound represented by general formula II obtained in step A may be used in the next step while containing a solvent, but generally, the solvent is removed by distillation under reduced pressure to obtain general formula II as a solid component. to obtain the indicated compound.

According to the production method of the present disclosure, generation of impurities caused by side reactions and side reactions is suppressed, and the desired benzonitrile derivative can be obtained with high purity. Furthermore, by adjusting the amount of the tertiary amine used, the target benzonitrile derivative can be obtained in a higher yield than the conventional method.
Since the benzonitrile derivative obtained by the production method of the present disclosure has few impurities, it can be easily purified and can be suitably used for various purposes such as production of pharmaceuticals.

The present invention will be described in detail below with reference to examples. Materials, usage amounts, ratios, processing details, processing procedures, and the like shown in the following examples can be changed as appropriate without departing from the scope of the invention. Accordingly, the scope of embodiments of the present invention is not limited to the specific examples shown below. In the examples, "parts" and "%" mean "mass parts" and "mass%" unless otherwise specified.

[Example 1]
<Synthesis of oximated isatin>
17.03 g of isatin, 8.0 g of hydroxylamine hydrochloride, and 82.4 mL of water were placed in a three-necked flask, and the internal temperature of the mixed liquid was raised to 80°C.
Heating and stirring were continued for 1 hour while the internal temperature of the mixed solution was maintained at 80° C., and completion of the reaction was confirmed by HPLC analysis under the conditions described above.
Thereafter, the internal temperature of the reaction-completed liquid was cooled to 15° C. to 20° C. and stirred for 15 minutes. Crystals were dispersed in the reaction-completed liquid.
Crystals were filtered from the liquid. The filtered crystals were washed with 160 mL of water and dried at 50° C. for 12 hours to obtain 18.2 g of isatin oxime. Yield was 97%. (Step B)

(Confirmation of isatin oxime)
When the obtained crystals were analyzed by HPLC under the conditions described above, it was confirmed to be isatin oxime with a purity of 99.3%.
Spectra obtained by nuclear magnetic resonance (NMR) of isatin oxime: ¹ H-NMR (CDCl ₃ ) 8.06 (1H, d), 7.32 (1H, t), 7.06 (1H, t), 6 .88(1H,d)
The NMR spectrum confirmed that the obtained compound had the structure of isatin oxime.

<Preparation of benzonitrile derivative>
A mixed liquid containing 28 mL of N,N-dimethylacetamide and 0.3 g of DBU (1.5 mol % with respect to 1 mol of isatin oxime) was stored in a three-necked flask, and the liquid temperature (inner temperature) was raised to 115°C to 120°C.
In the following examples, the amount of specific tertiary amine used indicates the amount used per 1 mol of isatin oxime.
Separately, 18.2 g of isatin oxime obtained in step B was dissolved in 28 mL of N,N-dimethylacetamide to prepare a solution. The prepared isatin oxime solution was added dropwise over 30 minutes to the three-necked flask containing the mixed solution. The mixture was added dropwise while paying attention to foaming, reacted at 115°C to 120°C for 2 hours, and then cooled to 20°C.
Quantification by the internal standard method confirmed that 12.8 g of 2-aminobenzonitrile was produced (yield 97%). (Step A)
A liquid containing 2-aminobenzonitrile was distilled under reduced pressure to obtain 12.0 g of 2-aminobenzonitrile. Yield was 91%. (Process C)
Analysis by HPLC indicated that the purity of the 2-aminobenzonitrile obtained was 99.5%.

(Confirmation of 2-aminobenzonitrile)
NMR spectrum of the obtained 2-aminobenzonitrile: ¹ H-NMR (CDCl ₃ ) 7.32-7.36 (2H, m), 6.72-6.74 (2H, m), 4.45 ( 2H, s)
The NMR spectrum confirmed that the obtained compound had the structure of 2-aminobenzonitrile.

[Example 2]
2-Aminobenzonitrile was obtained in the same manner as in Example 1, except that the solvent used for preparing the isatin oxime solution in Step A of Example 1 was changed from N,N-dimethylacetamide to sulfolane.
Quantification by the internal standard method confirmed that 2-aminobenzonitrile was produced with a yield of 96%.
Thereafter, distillation under reduced pressure was carried out in the same manner as in Step C of Example 1, and the yield of isolated 2-aminobenzonitrile was 86%.
According to HPLC analysis, the purity of the 2-aminobenzonitrile obtained in Example 2 was 99.3%.

According to Examples 1 and 2, the yield after isolation is high, and 2-aminobenzonitrile with a purity of 99% or more can be obtained in both cases. Further, from a comparison between Example 1 and Example 2, it can be seen that a higher yield can be achieved by using N,N-dimethylacetamide, which is an amide solvent, as the solvent.

[Example 3]
2-Aminobenzonitrile was obtained in the same manner as in Example 1, except that the amount of DBU, which is a tertiary amine used in Step A of Example 1, was changed from 1.5 mol% to 20 mol%.
Quantification by the internal standard method confirmed that 2-aminobenzonitrile was produced with a yield of 94%.
Thereafter, distillation under reduced pressure was carried out in the same manner as in Step C of Example 1, and the yield of isolated 2-aminobenzonitrile was 86%.
According to HPLC analysis, the purity of the 2-aminobenzonitrile obtained in Example 3 was 98.2%.

[Example 4]
2-Aminobenzonitrile was obtained in the same manner as in Example 1, except that the amount of DBU, which is a tertiary amine used in Step A of Example 1, was changed from 1.5 mol% to 50 mol%.
Quantification by the internal standard method confirmed that 2-aminobenzonitrile was produced with a yield of 72%.
Thereafter, distillation under reduced pressure was carried out in the same manner as in Step C of Example 1, and the yield of isolated 2-aminobenzonitrile was 66%.
According to HPLC analysis, the purity of the 2-aminobenzonitrile obtained in Example 4 was 96.1%.

[Example 5]
2-Aminobenzonitrile was prepared in the same manner as in Example 1, except that the amount of DBU, which is a tertiary amine used in Step A of Example 1, was changed from 1.5 mol% to 100 mol% (1 equivalent). Obtained.
Quantification by the internal standard method confirmed that 2-aminobenzonitrile was produced with a yield of 69%.
Thereafter, vacuum distillation was performed in the same manner as in Step C of Example 1, and the yield of isolated 2-aminobenzonitrile was 62%.
According to HPLC analysis, the purity of the 2-aminobenzonitrile obtained in Example 5 was 95.7%.

From the results of Examples 1 and 3 to 5, it can be seen that high-purity 2-aminobenzonitrile can be obtained when the amount of DBU, which is a tertiary amine, is in the range of 1.5 mol % to 100 mol %. . Also, it can be seen that a higher yield of 2-aminobenzonitrile can be achieved when the amount of DBU used is in the range of 1.5 mol % to 20 mol %.

[Example 6]
2-Aminobenzonitrile was obtained in the same manner as in Example 1, except that the tertiary amine DBU used in Step A of Example 1 was changed to 110 mol% (1.1 equivalents) of tri-n-butylamine. rice field.
Quantification by the internal standard method confirmed that 2-aminobenzonitrile was produced with a yield of 84%.
Thereafter, distillation under reduced pressure was carried out in the same manner as in Step C of Example 1, and the yield of isolated 2-aminobenzonitrile was 76%.
According to HPLC analysis, the purity of the 2-aminobenzonitrile obtained in Example 6 was 98.6%.

[Example 7]
The procedure of Example 1 was repeated except that the tertiary amine DBU used in Step A of Example 1 was changed to 110 mol% (1.1 equivalents) of N,N,N',N'-tetramethylethylenediamine. to give 2-aminobenzonitrile.
Quantification by the internal standard method confirmed that 2-aminobenzonitrile was produced with a yield of 69%.
Thereafter, vacuum distillation was performed in the same manner as in Step C of Example 1, and the yield of isolated 2-aminobenzonitrile was 62%.
According to HPLC analysis, the purity of the 2-aminobenzonitrile obtained in Example 7 was 99.0%.

[Example 8]
In the same manner as in Example 1, except that the tertiary amine DBU used in Step A of Example 1 was changed to 110 mol% (1.1 equivalents) of N,N,N',N'-tetraethylethylenediamine. , to give 2-aminobenzonitrile.
Quantification by the internal standard method confirmed that 2-aminobenzonitrile was produced with a yield of 90%.
Thereafter, distillation under reduced pressure was carried out in the same manner as in Step C of Example 1, and the yield of isolated 2-aminobenzonitrile was 82%.
According to HPLC analysis, the purity of the 2-aminobenzonitrile obtained in Example 8 was 98.4%.

[Example 9]
Except for changing the tertiary amine DBU used in Step A of Example 1 to 110 mol% (1.1 equivalents) of N,N,N',N'-tetramethyl-1,3-diaminopropane, Analogously to Example 1, 2-aminobenzonitrile was obtained.
Quantification by the internal standard method confirmed that 2-aminobenzonitrile was produced with a yield of 73%.
Thereafter, distillation under reduced pressure was carried out in the same manner as in Step C of Example 1, and the yield of isolated 2-aminobenzonitrile was 65%.
According to HPLC analysis, the purity of the 2-aminobenzonitrile obtained in Example 9 was 98.9%.

[Example 10]
Same as Example 1, except that DBU, which is a tertiary amine used in Step A of Example 1, was changed to 110 mol% (1.1 equivalents) of N,N,N',N'-pentamethylethylenetriamine. to give 2-aminobenzonitrile.
Quantification by the internal standard method confirmed that 2-aminobenzonitrile was produced with a yield of 82%.
Thereafter, vacuum distillation was performed in the same manner as in Step C of Example 1, and the yield of isolated 2-aminobenzonitrile was 74%.
According to HPLC analysis, the purity of the 2-aminobenzonitrile obtained in Example 10 was 98.8%.

[Comparative Example 1]
2-Aminobenzonitrile was obtained in the same manner as in Example 1 except that DBU, which is the specific tertiary amine used in Step A of Example 1, was not used and only N,N-dimethylacetamide was used.
Quantification by the internal standard method confirmed that 2-aminobenzonitrile was produced in a yield of 25%.
Thereafter, distillation under reduced pressure was carried out in the same manner as in Step C of Example 1, and the yield of isolated 2-aminobenzonitrile was 18%.
According to HPLC analysis, the purity of the 2-aminobenzonitrile obtained in Comparative Example 1 was 95.3%.

The yield in each Example and Comparative Example 1 and the purity of the obtained 2-aminobenzonitrile are shown in Table 1 below.

As is clear from Table 1 above, according to the production methods of Examples 1 to 10, an aminobenzonitrile derivative with a higher purity than the production method of Comparative Example 1 that did not use a specific tertiary amine was produced. It can be seen that high yields are obtained.

Claims (4)

A compound represented by the following general formula I, at least one tertiary amine selected from the group consisting of a compound represented by the following general formula III and 1,8-diazabicyclo[5,4,0]-7-undecene A method for producing a benzonitrile derivative, comprising the step of reacting in the presence of a species to obtain a benzonitrile derivative represented by general formula II below.

In general formula I, R ¹ , R ² , R ³ and R ⁴ each independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a halogen atom, an alkoxy group having 1 to 5 carbon atoms, or a phenyl group. .
In general formula II, R ²¹ , R ²² , R ²³ and R ²⁴ each independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, a halogen atom, an alkoxy group having 1 to 5 carbon atoms, or a phenyl group. .
In general formula III, R ³¹ , R ³² and R ³³ each independently represent an alkyl group . The method for producing a benzonitrile derivative according to claim 1, wherein the amount of the tertiary amine used is in the range of 0.1 mol% to 100 mol% with respect to 1 mol of the compound represented by the general formula I. The method for producing a benzonitrile derivative according to claim 1 or 2, wherein the step of obtaining the benzonitrile derivative is performed in the presence of at least one solvent selected from the group consisting of water and an aprotic polar solvent. . 4. The benzo according to any one of claims 1 to 3, wherein the compound represented by general formula I is isatin oxime in which R ¹ , R ² , R ³ and R ⁴ in general formula I are hydrogen atoms. A method for producing a nitrile derivative.