WO2023249414A1 - Method for producing benzoamine derivative - Google Patents

Abstract

The present invention relates to a method for producing a benzoamine derivative, and more specifically, to a method for producing a benzoamine derivative at high yield and purity using 1,1'-carbonyldiimidazole as a coupling catalyst in order to improve the safety of the reaction and ease of operation. The production method according to the present invention uses cost-effective and safe reagents, thus providing a high degree of operational safety and being well-suited for commercial-scale production without the risk of equipment corrosion, and improves reaction yield and purity, thus maximizing production efficiency and being useful for mass production.

Description

Method for producing benzoamine derivatives

The present invention relates to a method for producing benzoamine derivatives, and more specifically, to improve the safety of the reaction and the ease of operation, 1,1'-carbonyldiimidazole, a coupling catalyst, is used to produce benzoamine in high yield and purity. It relates to a method for producing amine derivatives.

Niclosamide (5-Chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide, CAS NO. 50-65-7) treats tapeworm, tapeworm, tapeworm, and dwarf tapeworm infections. It is a benzoamine derivative used as an effective anthelmintic. Niclosamide is also being studied as an anticancer drug and an antiviral agent in addition to being an antihelminthic drug (Cellular Signalling, Volume 41, 89~96, 2018, ACS Infect. Dis. 2020, 6, 5, 909-915).

Niclosamide crystallizes in hydrated or anhydrous form. In particular, in the case of anhydride, it has a low-energy crystal structure, has the highest density, and has a small amount of voids, making it easy to store. In addition, when stored for a long period of time, it can maintain a stable hydrate form without interaction with moisture (Talanta, Volume 199, 1 July 2019, Pages 679-688).

Anhydrous type 1 crystals are a crystal structure that can be obtained at temperatures below 100℃, and anhydrous type 2 crystals are dehydrated at high temperatures above 140℃ and have a structurally rearranged crystal structure (AAPS PharmSciTech, volume 5, 2004, Article number: 101).

Regarding the manufacturing method of benzoamine derivatives, the following prior literature discloses a manufacturing method using PCl ₃ , SOCl ₂ , etc.

In Chinese Patent No. 105566147, as shown in Scheme a below, Compound 1 and Compound 2 were reacted with PCl ₃ in a chlorbenzene solvent at high temperature, and after the reaction was completed, the resulting product was filtered and recrystallized with ethyl acetate or acetone. A method for preparing compound 3, niclosamide, is disclosed.

[Scheme a]

In Chinese Patent No. 106957298, as shown in Scheme b below, a compound of Formula IV and a compound of Formula III are dissolved in toluene and reacted with PCl ₃ under reflux, and after the reaction is completed, the resulting product is filtered and recrystallized to prepare a benzoamine derivative. A method is disclosed.

[Scheme b]

In Chinese Patent No. 106431949, 5-chloro-salicylic acid and o-chloro-p nitroaniline are reacted with SOCl ₂ in methylene chloride and xylene solvents, and after the reaction is completed, the resulting product is filtered and purified with ethanol to obtain a benzoamine derivative. A method for manufacturing is disclosed.

International journal Medicinal Chemistry Research, 2019, vol. 28, #3, 387-393 describes a method of preparing a benzoamine derivative by reacting a compound of Formula 1 and a compound of Formula 2 with EDCI in a methylene chloride solvent at room temperature, as shown in Scheme c below.

[Scheme c]

International academic journal Pharmaceutical Research, 2016, vol. 33, #12, 1 to 13, as shown in Scheme d below, a benzoamine derivative is prepared using PCl ₃ in a xylene solvent at high temperature using a compound of Formula 1 and a compound of Formula 2.

[Scheme d]

However, this method uses highly toxic and corrosive reagents (PCl ₃ or SOCl ₂ ), which poses a risk of corrosion of equipment and the safety of workers due to the generation of toxic gases, and not only is waste liquid treatment complicated, but the yield is low. In addition, the yield is low and the purification process is complicated due to the use of an expensive and low-reactivity catalyst. Therefore, the prior art method had a problem in that it was not suitable for commercial mass production.

Accordingly, the present inventors completed the present invention by identifying a manufacturing method suitable for mass production that is not only economical but also can produce the final compound with improved yield using reagents that are inexpensive and have low toxicity and risk.

[Prior art literature]

[Patent Document]

(Patent Document 0001) China Registered Patent No. 105566147

(Patent Document 0002) China Registered Patent No. 106957298

(Patent Document 0003) China Registered Patent No. 106431949

[Non-patent literature]

(Non-patent document 0001) Medicinal Chemistry Research, 2019, vol. 28, #3, 387~393

(Non-patent document 0002) Pharmaceutical Research, 2016, vol. 33, #12, 1~13

The purpose of the present invention is to provide a manufacturing method of benzoamine derivatives that is safe and easy to operate, is easy to apply to mass production, and has no problems in equipment use, in order to solve the problems of the prior art as described above. Do it as

In order to achieve the stated objectives, the present invention provides a method for producing benzoamine derivatives that is not only safe and easy to operate, but also has high yield.

Hereinafter, the method for producing benzoamine derivatives according to the present invention will be described in more detail.

The final target compound, a benzoamine derivative, is the same as the compound of formula 1 below.

[Formula 1]

In the above equation,

X is halogen (eg F, Cl, Br or I);

R ₁ is independently hydrogen or hydroxy;

R ₂ is independently hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, or nitro.

For example, the compound of Formula 1 may be a compound of Formula 1a below.

[Formula 1a]

The present invention provides a method for preparing the compound of Formula 1, comprising the following.

Obtaining a compound of Formula 1 by coupling the compound of Formula 2 and the compound of Formula 3 under basic conditions using the compound of Formula 4 as a catalyst (Step 1).

[Formula 2]

[Formula 3]

[Formula 4]

In the above equation,

X is halogen (eg F, Cl, Br or I);

R ₁ is independently hydrogen or hydroxy;

R ₂ is independently hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, or nitro.

For example, the compound of Formula 2 may be a compound of Formula 2a below.

[Formula 2a]

For example, the compound of Formula 3 may be a compound of Formula 3a below.

[Formula 3a]

In Chinese Patent No. 105566147, the process of manufacturing the compound of Chemical Formula 1 involves reacting with PCl ₃ , which is highly toxic and corrosive, at a high temperature of 135°C, which generates toxic hydrochloric acid gas and not only complicates the process of treating waste liquid, but also reduces product yield ( 68.7%), so it has the disadvantage of being unsuitable for commercial mass production.

Likewise, in Chinese Patent No. 106957298, the process of preparing the compound of Chemical Formula 1 involves reacting with highly toxic and corrosive PCl ₃ under reflux, which generates toxic hydrochloric acid gas and not only complicates the process of disposing the waste liquid, but also reduces the product yield ( 70%), so it has the disadvantage of being unsuitable for commercial mass production.

In Chinese Patent No. 106431949, the process of manufacturing the compound of Chemical Formula 1 is not suitable for commercial mass production because it reacts with highly toxic and corrosive SOCl ₂ , which generates toxic hydrochloric acid gas and the waste treatment process is complicated. There is a downside.

International journal Medicinal Chemistry Research, 2019, vol. 28, # 3, 387-393, the process of preparing the compound of Formula 1 uses EDCI, a low-reactivity and expensive reagent, and proceeds without hydroxy benzotriazole (HOBt), producing acyl as a by-product. It has the disadvantage of being unsuitable for commercial mass production because the process of producing urea (Acylurea) and separating it after completion of the reaction to purify the product is complicated.

International academic journal Pharmaceutical Research, 2016, vol. 33, #12, 1~13, the process of manufacturing the compound of formula 1 involves reacting with PCl ₃ , which is highly toxic and corrosive at high temperature, generating toxic hydrochloric acid gas and the process of treating waste liquid is complicated, so commercial mass production is required. It has the disadvantage of not being suitable for .

In order to solve these problems of the prior art, the production method of the present invention uses carbonyldiimidazole (compound of formula 4) and a base, so no hydrochloric acid gas is generated during the reaction, so the safety of the work is high and there is no risk of equipment corrosion. . Under these safe conditions, not only is reactivity further increased, but mass production is also possible, and economic feasibility can also be greatly improved as production is possible with high yield.

In one embodiment, the method for producing a compound of Formula 1 according to the present invention includes the step of coupling a compound of Formula 2 and a compound of Formula 3 under basic conditions using a compound of Formula 4 as a catalyst to obtain a compound of Formula 1 ( It can be prepared including step 1).

The solvent used in step 1 is one selected from the group consisting of toluene, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, methylene chloride, water, methanol, ethanol, isopropyl alcohol, ethyl acetate, and acetone. It may be more than this, and it is preferable to use methylene chloride, acetonitrile, tetrahydrofuran, or toluene, considering the reaction temperature and the ease of later concentration and removal of the solvent.

Although not limited thereto, the solvent is used in an amount of 5 to 25w/v, for example, 5 to 8w/v, 8 to 10w/v, 10 to 12.5w/v, 12.5 to 15w/v, 15 to 18w/v, relative to the starting material. v, may range from 18 to 20 w/v, 20 to 23 w/v, and 23 to 25 w/v. Preferably, using it in the range of 8w/v to 18w/v may be advantageous when considering reactivity.

The base may be one or more selected from the group consisting of N,N-diisopropylethylamine, triethylamine, diethylamine, diisopropylamine, and pyridine, and is preferably N,N-diisopropylethylamine. Using amines, or triethylamine, may be advantageous when considering reactivity.

Although not limited thereto, the amount of the base used is 0.5 to 2.0 equivalents, for example, 0.5 to 0.7 equivalents, 0.7 to 0.9 equivalents, 0.9 to 1.1 equivalents, 1.1 to 1.3 equivalents, 1.3 to 1.5 equivalents, based on the compound of Formula 2. , 1.5 to 1.7 equivalents, 1.7 to 2.0 equivalents. Preferably, it may be advantageous to use it in the range of 0.9 to 1.5 equivalents when considering reactivity.

Step 1 is not limited thereto, but may be performed at 20 to 120°C, for example, 20 to 30°C, 30 to 50°C, 50 to 70°C, 70 to 90°C, 90 to 100°C, 100 to 100°C. It may be 120℃. Preferably it may be 30°C to 100°C. Depending on the selection of the solvent, the reflux temperature of the solvent can be set.

Step 1 may be prepared including the following steps 1-1 to 1-2.

Reacting a compound of Formula 2 using a compound of Formula 4 as a catalyst (step 1-1),

Obtaining a compound of Formula 1 by coupling with a compound of Formula 3 in the presence of a base (Step 1-2).

Step 1-1 is not limited thereto, but the amount of 1,1'-carbonyldiimidazole (compound of Formula 4) used is 0.5 to 2.0 equivalents, for example, 0.5 to 0.7 equivalents, 0.7 equivalents, based on the compound of Formula 2. to 0.9 equivalents, 0.9 to 1.1 equivalents, 1.1 to 1.3 equivalents, 1.3 to 1.5 equivalents, 1.5 to 1.7 equivalents, 1.7 to 2.0 equivalents. Preferably, it may be advantageous to use it in the range of 0.9 to 1.5 equivalents when considering reactivity.

Step 1-1 is not limited thereto, but can be performed for a reaction time of 1 to 6 hours, for example, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, or 5 to 6 hours. there is. Preferably it may be 1 to 3 hours. If the time range is outside the above time range, the reaction may not occur sufficiently or an addition reaction may occur, resulting in a decrease in yield.

The steps 1-2 are not limited thereto, but the reaction time is 1 to 12 hours, for example, 1 to 2 hours, 2 to 3 hours, 3 to 4 hours, 4 to 5 hours, 5 to 6 hours, or 6 to 6 hours. It can be performed for 7 hours, 7 to 8 hours, 8 to 9 hours, 9 to 10 hours, 10 to 11 hours, and 11 to 12 hours. If the time range is outside the above time range, there is a problem that the reaction is not sufficiently carried out or an addition reaction occurs, resulting in a decrease in yield.

In step 1, step 1-2 can be performed without performing a separate post-treatment or purification process after step 1-1 is completed.

In one embodiment of the present invention, the step of reacting a compound of Formula 2 with a compound of Formula 4 below and then coupling the compound of Formula 2 with a compound of Formula 3 to obtain a compound of Formula 1 is performed in toluene, and the reaction temperature is Can be carried out at 30°C to 100°C.

The carboxyl group of the compound of Formula 2 is converted to ester using 1,1'-carbonyldiimidazole (compound of Formula 4), and then the amidated compound of Formula 2' is obtained, and N,N-diisopropylethylamine In the presence of the carbonyl of the compound of Formula 2' and the amine group of the compound of Formula 3, an amide is formed, and the process of synthesizing the compound of Formula 1 is illustratively expressed as the reaction formula below.

[Scheme 1]

DIPEA(N,N-Diisopropylethylamine): N,N-Diisopropylethylamine

The present invention may further include a purification step (step 2) using a solvent to obtain a high-purity product that can be used as a raw drug product.

Step 2 can be purified by adding an organic acid to obtain high purity niclosamide, and the organic acid can be one or more selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid.

The solvent used in step 2 may be one or more selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, ethyl acetate, and acetone, and preferably methanol, ethanol, or acetone is used to ensure the purity of the product. This may be advantageous when considering the ease of increasing the concentration or removing the solvent in the future.

The amount of solvent used in step 2 can be within the range of 15 to 50w/v based on the benzoamine derivative, for example, 15 to 18w/v, 18 to 20w/v, 20 to 23w/v, 23 to 25w. /v, 25 to 30w/v, 30 to 33w/v, 33 to 35w/v, 35 to 40w/v, 40 to 43w/v, 43 to 45w/v, 45 to 50w/v. Preferably, using it within the range of 15 v/w to 30 v/w may be advantageous in increasing purification yield.

The amount of organic acid used in step 2 may be within the range of 0.3 to 2 v/w compared to the amount of starting material introduced, for example, 0.3 to 0.5 v/w, 0.5 to 0.8 v/w, 0.8 to 1.0 v/w, It may be in the range of 1.0 to 1.3v/w, 1.3 to 1.5v/w, 1.5 to 1.8v/w, 1.8 to 2.0v/w, preferably 0.5v/w to 1.0v/w.

Step 2 is not limited thereto, but may be performed at 20 to 120°C, for example, 20 to 30°C, 30 to 50°C, 50 to 70°C, 70 to 90°C, 90 to 100°C, 100 to 100°C. It may be 120℃. Preferably it may be 30°C to 100°C. Depending on the selection of the solvent, the reflux temperature of the solvent can be set.

Step 2 is not limited thereto, but may be performed at pH less than 6.0. In one embodiment according to the present invention, it was carried out in the pH range of 0.3 to 5.0.

The manufacturing method according to the present invention has high operational safety by using inexpensive and safe reagents, and is suitable for commercial production as there is no risk of equipment corrosion. It is also useful for mass production by maximizing production efficiency by improving reaction yield and purity. can be used

Figure 1 shows XRD data of niclosamide prepared by the method of Example 1 according to the present invention.

Figure 2 is DSC data of niclosamide prepared by the method of Example 1 according to the present invention.

Hereinafter, the present invention will be described in more detail by examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited to these examples.

[Example]

(Comparative Example 1)

10.0 g (0.06 mol) of 5-chloro-salicylic acid, 11.0 g (0.06 mol) of 2-chloro-4-nitroaniline, and 80.0 mL of toluene were added to a 250 mL reactor, heated to 80°C, and stirred. Phosphoryl chloride 14.1 g (0.09 mol) was added and stirred at 80-90°C for 3 hours. When the reaction was completed, the internal temperature was cooled to room temperature and then 40.0 mL of methanol was slowly added, and when the addition was completed, 100.0 mL of purified water was added. The mixture was stirred at room temperature for 1 hour, and the precipitated crystals were filtered and washed with purified water. The washed crystals were dissolved in 90.0 mL of acetone, refluxed for 1 hour, cooled, and the crystals were filtered to obtain 12.4 g (65%, purity 99.0%) of niclosamide.

(Comparative Example 2)

Add 10.0 g (0.06 mol) of 5-chloro-salicylic acid, 11.0 g (0.06 mol) of 2-chloro-4-nitroaniline, and 80.0 mL of toluene to a 250 mL reactor, raise the temperature to 80°C, and stir. Phosphoryl chloride 14.1 g (0.09 mol) was added and stirred at 80-90°C for 3 hours. When the reaction was completed, the internal temperature was cooled to room temperature and then 40.0 mL of methanol was slowly added, and when the addition was completed, 100.0 mL of purified water was added. After stirring at room temperature for 1 hour, the precipitated crystals were filtered and washed with purified water to obtain 14.9 g (79%, purity 96.8%) of niclosamide.

(Example 1)

10.0 g (0.06 mol) of 5-chloro-salicylic acid, 9.9 g (0.06 mol) of 1,1'-carbonyldiimidazole, and 80.0 mL of toluene were added to a 250 mL reactor and stirred at 40°C for 1 hour. When stirring is complete, 10.0 g (0.06 mol) of 2-chloro-4-nitroaniline and 9.0 g (0.07 mol) of N,N-diisopropylethylamine are added to the reaction solution, and the reaction temperature is raised to 90 ° C. It was stirred for some time. When the reaction was completed, it was cooled to room temperature, and the precipitated crystals (98% purity) were filtered and washed with purified water to obtain 17.7 g (93%, 98% purity) of niclosamide.

The washed niclosamide crystals were added to 150.0 mL of methanol and the pH was adjusted to 1.0 by adding concentrated hydrochloric acid. The pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 14.1 g (74%, purity 99.9%) of niclosamide.

^1H NMR (DMSO-d ₆ ) δ 11.47 (s, 1H, OH), 8.82 (d, 3J = 9.2 Hz, 1H, CH), 8.43 (d, 4J = 2.8 Hz, 1H, CH), 8.30 (dd , J = 9.2 Hz, 4J = 2.7 Hz, 1H, CH), 7.97 (d, 4J = 2.8 Hz, 1H, CH), 7.55 (dd, 3J = 8.7 Hz, 4J = 2.8 Hz, 1H, CH), 7.10 (d, 3J = 8.7 Hz, 1H, CH)

The purity of Comparative Example 1 and Example 1 according to the present invention was analyzed using liquid chromatography (HPLC) according to the analysis method of the European Pharmacopoeia (EP10).

Figure 1 is XRD data of niclosamide prepared by the method of Example 1 according to the present invention, and Figure 2 is DSC data of niclosamide prepared by the method of Example 1 according to the present invention.

As shown in Figure 1, as a result of analyzing the niclosamide crystals prepared by the method of Example 1 according to the present invention, it was confirmed that the niclosamide crystal structure corresponds to anhydrous type 1, and in Figure 2, the melting point is according to the European Pharmacopoeia It was confirmed that it was the target compound as it matched the melting point of niclosamide registered in .

(Example 2)

10.0 g (0.06 mol) of 5-chloro-salicylic acid, 11.3 g (0.07 mol) of 1,1'-carbonyldiimidazole, and 80.0 mL of toluene were added to a 250 mL reactor and stirred at 40°C for 1 hour. When stirring is complete, 10.0 g (0.06 mol) of 2-chloro-4-nitroaniline and 7.7 g (0.06 mol) of N,N-diisopropylethylamine are added to the reaction solution, and the reaction temperature is raised to 80° C. It was stirred for some time. When the reaction was completed, it was cooled to room temperature, and the precipitated crystals were filtered and washed with purified water. The washed crystals were added to 150.0 mL of methanol and the pH was adjusted to 1.0 by adding concentrated hydrochloric acid. The pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 14.7 g (77%) of niclosamide.

(Example 3)

10.0 g (0.06 mol) of 5-chloro-salicylic acid, 11.3 g (0.07 mol) of 1,1'-carbonyldiimidazole, and 50.0 mL of acetonitrile were added to a 250 mL reactor and stirred at 40°C for 1 hour. When stirring is complete, 11.0 g (0.06 mol) of 2-chloro-4-nitroaniline and 9.0 g (0.07 mol) of N,N-diisopropylethylamine are added to the reaction solution, and the reaction temperature is raised to 80° C. It was stirred for some time. When the reaction was completed, it was cooled to room temperature, and the precipitated crystals were filtered and washed with purified water. The washed crystals were added to 150.0 mL of methanol and adjusted to pH 1.0 by adding concentrated hydrochloric acid. The pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 14.4 g (76%) of niclosamide.

(Example 4)

10.0 g (0.06 mol) of 5-chloro-salicylic acid, 11.3 g (0.07 mol) of 1,1'-carbonyldiimidazole, and 100.0 mL of toluene were added to a 250 mL reactor and stirred at 40°C for 1 hour. When stirring is complete, 10.0 g (0.06 mol) of 2-chloro-4-nitroaniline and 9.0 g (0.07 mol) of N,N-diisopropylethylamine are added to the reaction solution, and the reaction temperature is raised to 80° C. It was stirred for some time. When the reaction was completed, it was cooled to room temperature, and the precipitated crystals were filtered and washed with purified water. The washed crystals were added to 150.0 mL of methanol and adjusted to pH 1.0 by adding concentrated hydrochloric acid. The pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 13.8 g (73%) of niclosamide.

(Example 5)

10.0 g (0.06 mol) of 5-chloro-salicylic acid, 9.9 g (0.06 mol) of 1,1'-carbonyldiimidazole, and 80.0 mL of toluene were added to a 250 mL reactor and stirred at 40°C for 1 hour. When stirring is complete, 10.0 g (0.06 mol) of 2-chloro-4-nitroaniline and 9.0 g (0.07 mol) of N,N-diisopropylethylamine are added to the reaction solution, and the reaction temperature is raised to 80° C. It was stirred for some time. When the reaction was completed, it was cooled to room temperature, and the precipitated crystals were filtered and washed with purified water. The washed crystals were added to 150.0 mL of methanol, and the pH was adjusted to 0.3 by adding concentrated hydrochloric acid. The pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 14.4 g (76%) of niclosamide.

(Example 6)

10.0 g (0.06 mol) of 5-chloro-salicylic acid, 9.9 g (0.06 mol) of 1,1'-carbonyldiimidazole, and 60.0 mL of acetonitrile were added to a 250 mL reactor and stirred at 60°C for 1 hour. When stirring was completed, 11.0 g (0.06 mol) of 2-chloro-4-nitroaniline and 7.0 g (0.07 mol) of trimethylamine were added to the reaction solution, the reaction temperature was raised to 85°C, and the mixture was stirred for 4 hours. When the reaction is complete, it is cooled to room temperature, and the precipitated crystals are filtered and washed with purified water. The washed crystals were added to 150.0 mL of ethanol and adjusted to pH 5.0 by adding concentrated hydrochloric acid. The pH-adjusted mixture was refluxed for 1 hour, cooled, and the crystals were filtered to obtain 14.4 g (76%) of niclosamide.

Examples 1 to 6 according to the present invention used carbonyldiimidazole (compound of formula 4) and a base, so no hydrochloric acid gas was generated during the reaction, so the safety of work was high and there was no risk of equipment corrosion. Under these safe conditions, niclosamide, a benzoamine derivative, could be produced in high yield within a short period of time.

The method for producing benzoamine derivatives according to the present invention uses 1,1'-carbonyldiimidazole, a coupling catalyst, to not only improve the safety of the reaction and ease of operation, but also to produce benzoamine derivatives in high yield and purity. You can.

Claims (9)

A method for producing a benzoamine derivative, comprising the step of coupling a compound of Formula 2 and a compound of Formula 3 under basic conditions using a compound of Formula 4 as a catalyst to obtain a compound of Formula 1. [Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

In the above equation, X is halogen; R ₁ is independently hydrogen or hydroxy; R ₂ is independently hydrogen, halogen, C _1-6 alkyl, C _1-6 haloalkyl, -OC _1-6 alkyl, -OC _1-6 haloalkyl, or nitro. The method of claim 1, wherein the compound of Formula 1 is a compound of Formula 1a. [Formula 1a]

The method of claim 1, wherein the base is at least one selected from the group consisting of N,N-diisopropylethylamine, triethylamine, diethylamine, diisopropylamine, and pyridine. . The method of claim 1, wherein the compound of Formula 4 is used in an amount of 0.5 to 2.0 equivalents based on the compound of Formula 2. The method of claim 1, wherein the solvent used is selected from the group consisting of toluene, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, methylene chloride, water, methanol, ethanol, isopropyl alcohol, ethyl acetate, and acetone. A method for producing one or more benzoamine derivatives. The method for producing a benzoamine derivative according to claim 1, further comprising the step of purifying by adding an organic acid. The method of claim 6, wherein the solvent used in the purification step is at least one selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, ethyl acetate, and acetone. The method of claim 6, wherein the organic acid is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid. The method of claim 1 or 6, wherein the benzoamine derivative has an anhydrous type 1 crystal structure.

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