KR20130077451A - Method of preparing aminobenzylamine - Google Patents

Abstract

PURPOSE: A producing method of aminobenzylamine is provided to simplify production processes, and to mass-produce aminobenzylamine with high yield by not using an expensive catalyst. CONSTITUTION: A producing method of aminobenzylamine comprises the following steps: producing a compound denoted by chemical formula 2 by the substitution reaction between a compound denoted by chemical formula 3 and metallic azide; and a producing a compound denoted by chemical formula 1 by the reduction reaction between a nitro group of the compound denoted by the chemical formula 2 with an azide group. In the chemical formula 1: R1 is an alkyl group, an aryl group, a cycloalkyl group, and a heteroaryl group; l is a fixed number selected from 0-4; and R2 is selected from hydrogen, an alkyl group, an aryl group, a cycloalkyl group, and a heteroaryl group.

Description

Method for preparing aminobenzylamine {METHOD OF PREPARING AMINOBENZYLAMINE}

The present invention relates to a novel method for preparing aminobenzylamine that can be used as an intermediate in the manufacture of various pharmaceuticals, such as schizophrenia and sedatives.

Regarding the conventional method for preparing aminobenzylamine, a method of preparing by reducing 2-aminobenzamide as a starting material with lithium aluminum hydride or dimethylsulfide borane complex (Scheme I) Is reported.

[Reaction Scheme I]

However, lithium aluminum hydride used as a reducing agent in the above method is an anhydrous condition is essential, flammable, explosive is very unsuitable for mass production, dimethyl sulfide borane complex is an expensive reagent, it is unsuitable for mass production.

In addition, 2-aminobenzonitrile (2-aminobenzonitrile) as a starting material to reduce the hydrogenation reaction using a platinum (IV) or nickel (nickel) catalyst and a method of reducing by using lithium aluminum hydride Although the following method (Scheme II) is reported, the platinum (IV) or nickel catalyst used in the above method is an expensive reagent and is not suitable for mass production.

[Reaction Scheme II]

Therefore, in order to mass-produce aminobenzylamine, it is necessary to solve the above-mentioned problems in the related art. Therefore, it is required to develop a new method for preparing aminobenzylamine, which is economical and safe because the production process is simple and does not use an expensive catalyst.

US 2008293749 A KR 1087002017 B

Journal of medicinal chemistry, vol 23 (1980), 1261-1264 Bulletin de la Societe Chimique de France, 1939, 1663-1667 Journal of American Chemical Society, 1977, 5716-5725

Accordingly, an object of the present invention is to provide a method for preparing aminobenzylamine, which is economical and suitable for mass production, since the production process can be simplified to reduce the production cost, and expensive catalysts are not used.

In order to achieve the above object, the preparation method of the aminobenzylamine according to an embodiment of the present invention to prepare a compound represented by the formula (2) by substitution reaction of the compound represented by the formula (3) and alkali metal azide (azide) And reducing the nitro group and the azide group of the compound represented by the following Chemical Formula 2 to prepare a compound represented by the following Chemical Formula 1.

[Formula 1]

(In Formula 1, R ₁ is any one selected from the group consisting of alkyl group, aryl group, cyclo alkyl group and hetero aryl group, l is an integer of 0 to 4, R ₂ is hydrogen, alkyl group, aryl group, cyclo alkyl group and Is any one selected from the group consisting of heteroaryl groups)

(2)

(In Formula 2, R ₃ is any one selected from the group consisting of alkyl group, aryl group, cyclo alkyl group and hetero aryl group, m is an integer of 0 to 4, R ₄ is hydrogen, alkyl group, aryl group, cyclo alkyl group and Is any one selected from the group consisting of heteroaryl groups)

 (3)

이고, R₁₁은 알킬기 또는 아릴기이다)(In Formula 3, R ₅ is any one selected from the group consisting of an alkyl group, an aryl group, a cyclo alkyki and a heteroaryl group, n is an integer of 0 to 4, R ₆ is hydrogen, an alkyl group, an aryl group, a cyclo alkyl group And hetero aryl group selected from the group consisting of, R ₇ is a halogen atom or

R ₁₁ is an alkyl group or an aryl group)

로 이루어지는 군에서 선택되는 어느 하나이고, R₁₁은 메틸기,　톨릴기, 2-클로로톨릴기 및 2-니트로톨릴기로 이루어지는 군에서 선택되는 어느 하나 일 수 있다.In the compound represented by Formula 3, R ₇ is Cl, Br, I and

It may be any one selected from the group consisting of, R ₁₁ may be any one selected from the group consisting of methyl group, tolyl group, 2-chlorotolyl group and 2-nitrotolyl group.

In the method for preparing aminobenzylamine, the compound represented by Chemical Formula 3 may be prepared by reacting nitrobenzyl alcohol and alkylsulfonyl halide, and the reaction may be performed in the presence of a base. The base may be any one selected from the group consisting of triethylamine and diisopropylethylamine.

In the method for preparing aminobenzylamine, the reduction reaction may be performed in the presence of any one selected from the group consisting of metals and reducing agents, and the metals and reducing agents may be Pd / C, Zn, Fe, Sn, NaBH ₄ , LiAlH ₄ And it may be any one selected from the group consisting of a combination thereof.

The preparing of the compound represented by Chemical Formula 2 may include the compound represented by Chemical Formula 3 and the alkali metal azide in 1: 0.25 to 1: 0.5, and the substitution reaction may be performed at 0 to 100 ° C. And, the reduction reaction may be made at 0 to 100 ℃.

In addition, in the method for preparing aminobenzylamine, the reduction reaction may be performed under a hydrogen atmosphere, and the reduction reaction may be performed under a pressure of 1 atm to 40 atm.

Hereinafter, the present invention will be described in more detail.

Unless stated otherwise in the specification, alkyl is a monovalent atomic group subtracting one hydrogen atom from an alkane, and may be represented by the general formula —C _n H _{2n + 1} , wherein n is 1 to 30. Means an integer of. The alkanes include linear alkanes, branched alkanes and include primary alkanes, secondary alkanes and tertiary alkanes.

Unless stated otherwise in the present specification, aryl refers to a monovalent atomic group in which one hydrogen atom is removed from an arene, and the arene includes not only one benzene ring but also two to seven atoms. Hydrocarbons and derivatives thereof.

In the present specification, all the compounds or substituents may be substituted or unsubstituted unless otherwise specified. Herein, the substituted hydrogen atom represents a halogen atom, a hydroxy group, a carboxy group, a cyano group, a nitro group, an amino group, a thio group, a methyl thio group, an alkoxy group, a nitrile group, an aldehyde group, an epoxy group, an ether group, an ester group, an ester group, Substituted one selected from the group consisting of carbonyl group, acetal group, ketone group, alkyl group, cycloalkyl group, heterocycloalkyl group, benzyl group, aryl group, heteroaryl group, pofluoroalkaline group, derivatives thereof and combinations thereof it means.

A method for preparing aminobenzylamine according to an embodiment of the present invention includes preparing a compound represented by the following Chemical Formula 2 by a substitution reaction between a compound represented by the following Chemical Formula 3 and an alkali metal azide (azide) and the following Chemical Formula 2 It comprises the step of preparing a compound represented by the formula (1) by reducing the nitro group and the azide group of the compound represented.

In the method for preparing aminobenzylamine, first, a compound represented by Chemical Formula 2 is prepared by substituting an alkali metal azide for a compound represented by Chemical Formula 3.

(3)

In Formula 3, R ₅ is any one selected from the group consisting of alkyl group, aryl group, cyclo alkyl group and hetero aryl group, n is an integer of 0 to 4, R ₆ is hydrogen, alkyl group, aryl group, cyclo alkyl group and hetero Any one selected from the group consisting of an aryl group, preferably hydrogen. More preferably, the compound represented by Formula 3 may be a compound in which n is 0 and R ₆ is hydrogen.

일 수 있고, 바람직하게는 Cl, Br, I 및　

로 이루어지는 군에서 선택되는 어느 하나일 수 있고, 더더욱 바람직하게는

일 수 있다.In Formula 3, R ₇ is a halogen atom or

May be preferably Cl, Br, I and

It may be any one selected from the group consisting of, even more preferably

Lt; / RTI >

In Formula 3, R ₁₁ may be an alkyl group or an aryl group, and the aryl group may be preferably an aryl group in which a hydrogen atom is substituted with a halogen atom or a nitro group, and more preferably R ₁₁ is a methyl group, a tolyl group (tolyl), chlorotolyl group (chlorotolyl) and nitrotolyl group (nitrotolyl) may be any one selected from the group, more preferably in the group consisting of methyl, tolyl, 2-chloro tolyl and 2-nitro tolyl group It may be any one selected, and most preferably may be a methyl group.

R ₇ in Formula 3 may be present at any one position selected from the group consisting of o, m and p of the compound, preferably may be present in the o position.

The compound represented by Formula 3 may preferably be 2-nitrobenzyl methanesulfonate.

The compound represented by Chemical Formula 3 may be prepared by, for example, dissolving nitrobenzyl alcohol in a solvent and then reacting by dropwise addition of alkylsulfonyl halide, and 100 parts by weight of the nitrobenzyl. Alcohol may be included in an amount of 1.0 to 1.2 parts by weight and the alkylsulfonyl halide in an amount of 0.7 to 1.2 parts by weight to prepare a compound represented by Formula 3, but the present invention is not limited thereto. If the nitrobenzyl alcohol is less than 1.0 parts by weight, a problem of yield reduction may occur, and if it is more than 1.2 parts by weight, difficulty in removing unreacted nitrobenzyl alcohol may occur. In addition, when the alkylsulfonyl halide is less than 0.7 parts by weight, problems of yield reduction and unreacted nitrobenzyl alcohol removal may occur, and when exceeding 1.2 parts by weight, problems of alkylsulfonyl halide removal may occur. It is preferable to use.

In addition, the compound represented by Formula 3 may preferably be prepared in the presence of a base, and the base may be a base commonly used in the preparation of the compound represented by Formula 3, and may be triethylamine or Diisopropylethylamine (diisopropylethlylamine) can be preferably used, and triethylamine can be most preferably used.

In addition, the base may be made in the presence of 0.9 to 1.5 parts by weight of the base with respect to 100 parts by weight of the solvent. If the base is less than 0.9 parts by weight, a problem of lowering yield may occur, and if the base is more than 1.5 parts by weight, a problem of removing base used in excess may occur.

The alkali metal azide can be represented by the general formula of MeN ₃ , wherein Me is lithium (Li), sodium (Na), potassium (K), rubidium (Rb), cesium (Cs) and francium (Fr). It may be any one selected from the group consisting of, preferably sodium azide which is sodium. When using the sodium azide it is possible to reduce the production cost because the price is low.

In the step of preparing the compound represented by Formula 2, the substitution reaction may be performed by mixing the compound represented by Formula 3 with an alkali metal azide in an organic solvent and then refluxing. For example, the organic solvent may be any one selected from the group consisting of acetone, ethyl acetate, hexane, THF, chloroform, thichloromethane, acetonitrile, and a combination thereof, and acetonitrile may be preferably used.

In the step of preparing the compound represented by Formula 2, the substitution reaction may be performed by refluxing for 1 to 24 hours by adding the compound represented by Formula 3 and the alkali metal azide to 1: 0.25 to 1: 0.5. And, the substitution reaction may be carried out at 0 to 100 ℃, preferably 40 to 80 ℃. When the weight ratio of the alkali metal azide to the compound represented by Formula 3 is less than 1.0, a problem of lowering yield may occur, and when it exceeds 2.0, a problem of removing alkali metal azide may occur, and the reflux time is 1 If less than time may cause a problem of yield decrease, if more than 24 hours may cause a problem of side reactions production, if the substitution reaction is made in 0 to 100? Since the compound represented by 2 can be obtained, the effect is excellent.

Next, the nitro group and azide group of the compound represented by Formula 2 are reduced to prepare a compound represented by Formula 1.

(2)

In Formula 2, R ₃ is any one selected from the group consisting of an alkyl group, an aryl group, a cyclo alkyl group and a hetero aryl group, m is an integer of 0 to 4, R ₄ is hydrogen, an alkyl group, an aryl group, a cyclo alkyl group and a hetero Any one selected from the group consisting of an aryl group, preferably hydrogen. More preferably, in the compound represented by Formula 2, m may be 0 and R ₄ may be hydrogen.

In Formula 2, the azide group (-C (R ₄ ) (N ₃ )) may be present at any one position selected from the group consisting of o, m, and p of the compound, and preferably present at the o position. have.

The compound represented by Formula 2 may preferably be 1- (azidomethyl) -2-nitrobenzene.

The reduction reaction means reducing the nitro group and the azide group of the compound represented by Formula 2, and the reduction reaction may be performed in the presence of any one selected from the group consisting of metals and reducing agents. The metal and reducing agent are preferably Pd / C, Zn, Fe, Sn, NaBH _{4 ,} LiAlH ₄ And it may be any one selected from the group consisting of a combination thereof, more preferably may be Pd / C or Fe.

The reducing agent may be included in an amount of 0.1 to 10 parts by weight based on 10 parts by weight of the compound represented by Formula 2, preferably 0.1 to 0.5 parts by weight for Pd / C or 0.5 to 5 parts by weight for Fe.

In addition, the reduction reaction may be carried out under a hydrogen atmosphere, preferably by injecting hydrogen to a pressure of 1 atm to 40 atm to reduce the nitro and azide groups of the compound represented by the formula (2). As an example, the nitro group and the azide group of the compound represented by Chemical Formula 2 may be reduced by adding hydrogen so that the atmospheric pressure is 5 atm to 20 atm. When the reduction reaction is carried out in a hydrogen atmosphere it is possible to effectively obtain a compound without any additional process.

Compounds represented by Chemical Formula 3 and Chemical Formula 2, which are intermediates synthesized in each preparation step of the method for preparing aminobenzylamine, may be obtained by further performing a process of separately separating and purifying, and separating and purifying. Without passing through the compound represented by the following formula (1) as the final target compound can be obtained. In order to simplify the production process and reduce the production cost, a method that does not separate and purify may be preferably used.

Through the method for preparing aminobenzylamine, a compound represented by Chemical Formula 1 may be prepared.

[Formula 1]

In Formula 1, R ₁ is any one selected from the group consisting of an alkyl group, an aryl group, a cyclo alkyl group and a hetero aryl group, l may be an integer of 0 to 4. R ₂ is any one selected from the group consisting of hydrogen, an alkyl group, an aryl group, a cycloalkyl group and a hetero aryl group, preferably hydrogen. More preferably, the compound represented by Formula 1 may be a compound in which l is 0 and R ₂ is hydrogen.

The amino group (NH ₂ ) in Formula 1 may be present at any one position selected from the group consisting of o, m and p of the compound represented by Formula 1, preferably may be present in the o position. The compound represented by Formula 1 prepared according to one embodiment of the present invention may be 2-aminobenzylamine.

According to the aminobenzylamine production method of the present invention, it is possible to simplify the production process and mass-produce aminobenzylamine with economical and high yield without using an expensive catalyst.

Hereinafter, embodiments of the present invention will be described in detail so that those skilled in the art can easily practice the present invention. The present invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein.

< Example  1> 2- Nitrobenzyl Methanesulfonate  Produce

2-nitrobenzyl alcohol (10.0 g, 0.0653 mol) and triethylamine (9.90 g, 0.098 mol) were dissolved in 100 mL of methylene chloride, and the reaction temperature was cooled to 5 degrees or less. Methanesulfonyl chloride (8.23 g, 0.0718 mol) was added dropwise and stirred for 30 minutes. Water was added to stop the reaction, and the water layer was extracted with 30 mL of methylene chloride. The organic layer was washed with 30 mL of 1N HCl and 30 mL of brine, the organic layer was dried over magnesium sulfate, filtered and concentrated, and then the reaction was carried out (yield: 97%).

¹ H NMR (CDCl ₃ ): 8.19 (t, 1 H), 7.76 (m, 2 H), 7.73 (m, 1 H), 5.66 (s, 2 H), 3.13 (s, 3 H)

< Example  2> 1- ( Azidomethyl Preparation of 2-nitrobenzene

2-nitrobenzyl methanesulfonate (8.0 g, 0.0346 mol) obtained above was dissolved in 40 mL of acetonitrile, and sodium azide (2.7 g, 0.0415 mol) was added thereto and refluxed for 3 hours. The reaction solution was concentrated, diluted with 100 mL of methylene chloride, and washed twice with 50 mL of water. The organic layer was dried over magnesium sulfate, filtered and concentrated to proceed with the next reaction (yield: 96%).

¹ H NMR (CDCl ₃ ): 8.11 (d, 1H), 7.69 (m, 2H), 7.50 (m, 1H), 4.84 (s, 2H)

< Example  3> 2- Of aminobenzylamine  Produce

1- (azidomethyl) -2-nitrobenzene (5.0 g, 0.0337 mol) obtained above was diluted with 25 mL of ethyl acetate, Pd / C (0.1 g) was added thereto, and hydrogen was added at atmospheric pressure. After checking whether the reaction proceeded in TLC, the reaction was terminated, and filtered to remove Pd / C, and then concentrated under reduced pressure to obtain 2-aminobenzylamine (yield: 92%).

¹ H NMR (CDCl ₃ ): 7.04 (m, 2H), 6.66 (m, 2H), 3.82 (s, 2H)

< Example  4> 2- Of aminobenzylamine  Produce

In 50 mL of tetrahydrofuran (THF), 1- (azidomethyl) -2-nitrobenzene (5.0 g, 0.0337 mol) and Fe (1.0 g) obtained in Example 2 were added and refluxed for 12 hours. After confirming the completion of the reaction in thin layer chromatography (Thin Layer Chromatography, TLC), the reaction solution was filtered through Celite. The filtrate was washed with 1N HCl (50 mL), and the aqueous layer was neutralized to pH 6-8 with NaOH 1N aqueous solution and extracted with methylene chloride (MC). The organic layer was washed with water (50 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-aminobenzylamine (yield: 83%).

¹ H NMR (CDCl ₃ ): 7.04 (m, 2H), 6.66 (m, 2H), 3.82 (s, 2H)

< Comparative example > 2- Of aminobenzylamine  Produce

LiAlH ₄ (15.2g, 0.04mol) was dissolved in THF (100mL) under nitrogen atmosphere, and aminobenzylamide (16.3g, 0.1mol) was dissolved carefully in THF (50mL). The reaction solution was refluxed under a nitrogen atmosphere for 52 hours and then terminated. 15 mL of water was added to quench the reaction, followed by 2N NaOH (15 mL) and water (45 mL). The by-products were filtered off and concentrated under reduced pressure to remove THF. MC was added and extracted, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 2-aminobenzylamine (yield: 87%).

¹ H NMR (CDCl ₃ ): 7.04 (m, 2H), 6.66 (m, 2H), 3.82 (s, 2H)

Claims (10)

Preparing a compound represented by the following Chemical Formula 2 by substitution reaction of a compound represented by the following Chemical Formula 3 with an alkali metal azide;
To prepare a compound represented by the formula (1) by reducing the nitro group and the azide group of the compound represented by the formula (2)
Method for producing aminobenzylamine comprising a.
[Chemical Formula 1]

(In Formula 1, R ₁ is any one selected from the group consisting of alkyl group, aryl group, cyclo alkyl group and hetero aryl group, l is an integer of 0 to 4,
R ₂ is any one selected from the group consisting of hydrogen, an alkyl group, an aryl group, a cycloalkyl group and a heteroaryl group)
(2)

(In Formula 2, R ₃ is any one selected from the group consisting of an alkyl group, an aryl group, a cyclo alkyl group and a hetero aryl group, m is an integer of 0 to 4,
R ₄ is any one selected from the group consisting of hydrogen, an alkyl group, an aryl group, a cycloalkyl group and a heteroaryl group)
(3)

(In Chemical Formula 3, R ₅ is any one selected from the group consisting of an alkyl group, an aryl group, a cyclo alkyl and a heteroaryl group, n is an integer of 0 to 4,
R ₆ is any one selected from the group consisting of hydrogen, an alkyl group, an aryl group, a cycloalkyl group and a heteroaryl group,
R ₇ is a halogen atom or

R ₁₁ is an alkyl group or an aryl group) The method of claim 1,
R ₇ is Cl, Br, I and

Any one selected from the group consisting of, and R ₁₁ is any one selected from the group consisting of methyl group, tolyl group, 2-chlorotolyl group and 2-nitrotolyl group. The method of claim 1,
Compound represented by the formula (3) is prepared by reacting nitrobenzyl alcohol (nitrobenzylalcohol) and alkylsulfonyl halide (alkylsulfonylhalide). The method of claim 3,
The reaction for preparing the compound represented by Formula 3 is made in the presence of a base,
The base is any one selected from the group consisting of triethylamine (triethylamine) and diisopropylethylamine (diisopropylethylamine). The method of claim 1,
The reduction reaction is a method for producing aminobenzylamine that is made in the presence of any one selected from the group consisting of metals and reducing agents. The method of claim 5,
The metal and reducing agent are Pd / C, Zn, Fe, Sn, NaBH _{4 ,} LiAlH ₄ And any one selected from the group consisting of a combination thereof. The method of claim 1,
The preparing of the compound represented by Chemical Formula 2 may include the compound represented by Chemical Formula 3 and the alkali metal azide as 1: 0.25 to 1: 0.5. The method of claim 1,
The substitution reaction is made at 0 to 100 ℃,
The reduction reaction is a method for producing aminobenzylamine that is made at 0 to 100 ℃. The method of claim 1,
The reduction reaction is a method for producing aminobenzylamine is carried out in a hydrogen atmosphere. 10. The method of claim 9,
The reduction reaction is a method for producing aminobenzylamine that is carried out under a pressure of 1atm to 40atm.