KR101582955B1 - Preparation of aniline derivatives - Google Patents

Abstract

[화학식 2]

[화학식 3]

(상기 화학식 1 내지 3에서 A는 질소 또는 CR이며; 상기 R 및 R₁은 서로 독립적으로 수소, 할로겐, (C1-C10)알킬, (C1-C10)알케닐, (C3-C10)시클로알킬, (C3-C10)헤테로시클로알킬, (C6-C12)아릴, (C3-C12)헤테로아릴, 니트로, 또는 티올이며; 상기 R₂는 (C1-C5)알킬렌이며; 상기 n은 1 내지 4의 정수이며; 상기 X는 할로겐, 또는 OR₃이며; 상기 R₃은 p-톨루엔술포닐 또는 메틸술포닐이다.)
본 발명에 따른 아닐린 유도체 제조방법은, 단일 단계를 통해 제조할 수 있어서, 보다 간단하며, 반응 후에 감압증류로 용매를 용이하게 제거할 수 있으며, 생성물은 플래시컬럼크로마토그래피 방법으로 쉽게 분리할 수 있으며, 또한 공정이 간단하여 에너지를 절약할 수 있어서 환경 친화적이며, 제조비용을 절약할 수 있다.The method for preparing an aniline derivative according to the present invention may include the step of reacting the following general formula (2) with the following general formula (3) in the presence of a catalyst, a base and a solvent to prepare the general formula (1).
[Chemical Formula 1]

(2)

(3)

Wherein R and R ₁ are independently of each other hydrogen, halogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkenyl, (C 3 -C 10) cycloalkyl, (C3-C10) heterocycloalkyl, (C6-C12) aryl, (C3-C12) heteroaryl, nitro, or thiol group and; wherein R ₂ is (C1-C5) alkylene, and; n is from 1 to 4 Wherein X is halogen or OR _3, and R ₃ is p -toluenesulfonyl or methylsulfonyl.
The process for preparing aniline derivatives according to the present invention can be prepared through a single step, which is simpler. After the reaction, the solvent can be easily removed by distillation under reduced pressure, and the product can be easily separated by flash column chromatography , And the process can be simplified to save energy, so that it is environmentally friendly, and the manufacturing cost can be saved.

Description

Preparation of aniline derivatives < RTI ID = 0.0 >

The present invention relates to a method for producing an aniline derivative by converting a hydroxyl group (-OH) of a phenol into an amine group (-NH ₂ ) using the Smile transfer reaction.

Aniline is a kind of aromatic amine which is widely used in various fields and is used in the manufacture of many dyes such as azine, azo and azoxy which are of commercial importance and have electric conductivity Therefore, it is also used as a raw material of a conductive polymer such as an organic solar cell, an organic EL, and a transparent conductive film. In addition, phenacetin, an acetylated ethoxyaniline, is known as an analgesic antipyretic agent and is also manufactured as a main raw material for a biosensor, a metal catalyst polymer, and an agricultural chemical.

Several methods for synthesizing aniline are known, and there is also a Smiles rearrangement using an aromatic compound having a substituent. The smile transfer reaction is a substituent of a nucleophilic aromatic within a molecule that causes a transfer from a heteroatom linked to a substituent on the aromatic ring to another heteroatom, and is directed to various heteroatoms such as oxygen, sulfur and nitrogen. In particular, the smile transfer reaction of phenols, including heterocyclic phenols, is described in IGC Coutts and MR Southcott, J. Chem . Soc . Perkin Trans . I , 1990: 767-771). This describes a three-step process as shown in the following reaction scheme 1, including optionally purifying each intermediate by substituting an amino group for a hydroxy group on an aromatic ring fused to a larger ring system.

[Reaction Scheme 1]

However, using this method, the synthesis of phenol to aniline has serious drawbacks. For example, the conversion of 4-chloro-2-phenylquinazoline is only possible in high temperature and basic conditions, and similarly, the conversion of phenol by diethyl phosphate ester is carried out in liquid ammonia , Toxic diethylchlorophosphate and potassium should be used. Since Bucherer reaction uses naphthalene and related heterocycle compounds such as sodium hydride (NaH) or dimethylformamide (DMF) which proceed well but cause an exothermic reaction in the reaction, the reaction control Is difficult. In order to solve this problem, sodium hydroxide / dimethylformamide (NaOH / DMF) or sodium hydroxide / dimethylamine (NaOH / DMA) may be used. However, since excess water is used in the reaction, There are difficult disadvantages. Therefore, mass production of aniline through such reactions is practically difficult to commercialize.

Coutts, Ian G. C .; Southcott, Mark R. J. Chem. Soc., Perkin Trans. 1, 1990, 767-771. Mizuno, M., Yamano, M. Org. Lett. 2005, 7 (17), 3629-3631. Buckley, J .; Webb, R. L .; Laird, T .; Ward, R. J. Chem. Eng. News, 1982, 60 (28), 5. Zhang, T. Y .; Stout, J. R .; Keay, J. G .; Scriven, E. F. V .; Toomey, J. E .; Goe, G. L. Tetrahedron 1995, 51, 13177; Choi, H. Y .; Chi, D. Y. J. Am. Chem. Soc. 2001, 123, 9202; Lee, D.-Y .; Hartwig, J. F. Org. Lett. 2005, 7, 1169; Wu, Z .; Jiang, Z .; Wu, D .; Xiang, H .; Zhou, X. Eur. J. Org. Chem. 2010, 2010, 1854; Moon, B.-S .; Choi, H.-Y .; Koh, H.-Y .; Chi, D.-Y. Bull. Korean Chem. Soc. 2011, 32, 472.

In order to solve the above-described problems, the present invention provides a method of synthesizing aniline using a catalyst, which is simpler, environmentally friendly, and cost-effective than an aniline synthesis method by using a catalyst in the process of synthesizing aniline using the Smile- And an object of the present invention is to provide a novel process for producing an aniline derivative.

The present invention relates to a process for preparing aniline derivatives.

In the reaction of the present invention, the following formula 2 is reacted with the formula 3 in the presence of a catalyst, a base and a solvent to synthesize the formula 1, that is, a process for producing an aniline derivative.

[Chemical Formula 1]

(2)

(3)

(Wherein A is nitrogen or C;

Wherein R and R ₁ independently represent hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkenyl, (C3-C10) cycloalkyl, (C3-C10) heterocycloalkyl, (C6-C12) Aryl, (C3-C12) heteroaryl, nitro, or thiol;

Wherein R < ₂ > is (C1-C5) alkylene;

N is an integer of 1 to 4;

X is halogen, or OR < _{3 &} gt ;;

Wherein R < ₃ > is p-toluenesulfonyl or methylsulfonyl.

Another embodiment of the present invention relates to a process for producing an aniline derivative wherein the above-mentioned formula (3) is any one selected from the following formulas (4) to (6).

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(Wherein R ₁₁ to R ₁₆ , R ₂₁ to R ₂₅ and R ₃₁ to R ₃₇ in the general formulas 4 to 6 are each independently hydrogen, (C 1 -C 5) alkyl or halogen;

Any one of R ₁₁ to R ₁₆ , R ₂₁ to R _25, and R ₃₁ to R ₃₇ is necessarily hydroxy.

Another embodiment of the present invention is a compound represented by any one of the above formulas (1) to (6), wherein the compounds represented by formulas (4) to (6) are 1- (4-hydroxyphenyl) ethanone, 1- -Dichlorophenol, 2,4-dichlorophenol, 4-nitrophenol, 2-nitrophenol, 2-chloropyridin-3-ol, 5-chloroquinolin-8-ol, 5,7-dichloroquinolin- 5,7-dichloro-2-methylquinolin-8-ol. ≪ / RTI >

The catalyst may be one or two or more of potassium iodide, sodium iodide, potassium bromide, sodium bromide and the like. When 1 mole of the compound of Formula 3 is used, the catalyst may be added in a ratio of 0.01 to 1 mole.

The base may also be selected from the group consisting of sodium hydroxide, cesium carbonate, cesium acetate, cesium bicarbonate, cesium bromide, cesium fluoride, cesium fluoride, cesium iodide, potassium carbonate, sodium hydride, potassium hydride, lithium hydride, lithium-bis- n -butyl lithium, sec -butyl lithium, iso -butyl lithium and tert -butyl lithium, and the compound of formula 3 may be used in an amount of 1 mole In use, the base may be added in a ratio of 1 to 5 moles.

Further, the process for producing an aniline derivative according to the present invention may be carried out at a reaction temperature of 50 to 200 ° C, more specifically at 80 to 100 ° C for 10 to 90 minutes, To < / RTI > 6 hours.

The method for producing an aniline derivative according to the present invention can be produced through a one-pot process, which is simpler. After the reaction, the solvent can be easily removed by distillation under reduced pressure. The product is adsorbed on silica or the like, Is very simple. In addition, the process can be simplified to save energy, be environmentally friendly, and save manufacturing cost.

The present invention relates to a process for preparing an aniline derivative capable of proceeding in a one-pot process in the presence of a catalyst in the process of synthesizing aniline using the Smile's shift reaction. More specifically, Reacting a compound represented by the formula (2) with a compound represented by the following formula (3) to produce an aniline derivative.

First, in the present invention, alkyl means an aliphatic saturated hydrocarbon group on the carbon number of 1 to 10 straight-chain or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert - butyl, hexyl, heptyl And the like.

The alkenyl means a linear or branched unsaturated aliphatic group having 1 to 10 carbon atoms, and may include one or more double bonds. For example ethenyl, propenyl, cis-2-butenyl, trans-2-butenyl, 3-butenyl, cis-2-pentenyl, trans-2-pentenyl, cis-3-pentenyl, trans Pentenyl, 4-pentenyl, 2-methyl-3-butenyl, hexenyl, heptenyl, octenyl, nonenyl,

Said cycloalkyl, by itself or in combination with other terms, unless otherwise indicated, refers to a cyclic form of alkyl, alkenyl or alkynyl having from 3 to 10 carbon atoms, or mixtures thereof. In addition, cycloalkyl may contain fused rings, but with the exception of the fused aryl and heteroaryl groups, the cycloalkyl groups may be substituted, unless otherwise stated as unsubstituted. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

Said heterocycloalkyl, by itself or in combination with other terms, is a group consisting of 3 to 10 carbon atoms annular carbon atoms and O, N, P, Si and S, preferably N, O and S ≪ / RTI > wherein the ring is not aromatic, but may contain an unsaturated moiety. The term " cycloalkyl " Such as pyrrolidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydrofuryl, 2,3-dihydrofuryl, tetrahydrothiophenyl and 2,3-dihydrothiophenyl , Imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, oxazolidinyl, oxazolidinyl, isoxazolidinyl, isoxazolidinyl, thiazolidinyl, thiazolidinyl, isothiazolidinyl, Isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl and 1,4,2-dithiazolyl, and the like.

Unless otherwise indicated, the aryl refers to an aromatic hydrocarbon group of 5 to 12 carbon atoms, which may be a single ring or multiple fused rings (e.g., one to three rings). For example, phenyl, 1-naphthyl, 2-naphthyl, tetrahydronaphthyl, and the like.

Wherein said heteroaryl refers to a single ring having 3 to 12 carbon atoms or a group comprising two or three fused rings wherein one or more of the rings is optionally substituted with one to four heteroatoms selected from N, (I.e., it contains one or more heteroaromatic rings), wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom (s) are optionally quaternized. Pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2- 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-isoxazolyl, Pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, 2-benzimidazolyl , 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl and 6-quinolyl and the like.

Also, in the present invention, the halogen includes fluorine (F), chlorine (Cl), bromine (Br) and iodine (I) elements.

The aniline derivative according to the present invention can be prepared by reacting an aniline derivative represented by the following general formula (2) with the following general formula (3) in the presence of a catalyst, a base and a solvent.

[Chemical Formula 1]

(2)

(3)

Wherein A is nitrogen or C and R and R ₁ are independently of each other hydrogen, halogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkenyl, (C 3 -C 10) cycloalkyl, C3-C10) heterocycloalkyl, (C6-C12) aryl, (C3-C12) heteroaryl, and nitro, or thiol, wherein R ₂ is (C1-C5) alkylene, wherein n is an integer from 1 to 4 , X is halogen or OR ₃ , and R ₃ may be p -toluenesulfonyl or methylsulfonyl.

The formula 3 may be a simple hydroxy aromatic compound which is a single aromatic ring and may be a complex hydroxy aromatic compound capable of forming a multi-carbon fused ring having various degrees of saturation due to the R ₁ group, or a complex hydroxy aromatic compound having a ring structure attached thereto as a substituent Lt; / RTI >

In the above-mentioned formula (3), the complex ring structure may include not only wholly aromatic complex ring structures such as pyridine, isoquinoline, quinoline, and acridine but also partially and completely saturated complex structures such as tetrahydroisoquinoline, tetrahydroquinoline, tetrahydrocuridine, Ring structure.

More specifically, the formula (3) may be any one selected from the following formulas (4) to (6).

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

In the formulas 4 to 6, R ₁₁ to R ₁₆ , R ₂₁ to R _25, and R ₃₁ to R ₃₇ are each independently hydrogen, (C 1 -C 5) alkyl or halogen, and R ₁₁ to R ₁₆ , R ₂₁ to R ₂₅ And any one of R ₃₁ to R ₃₇ is necessarily hydroxy.

The above-mentioned formulas 4 to 6 are preferably 1- (4-hydroxyphenyl) ethanone, 1- (4-hydroxyphenyl) butan-1-one, 4- hydroxybenzonitrile, 4-nitrophenol, 2-nitrophenol, 2-chloropyridin-3-ol, 5-chloroquinolin-8-ol, 5,7-dichloroquinolin- Dichloro-2-methylquinolin-8-ol.

The formula (2) may serve as an alkylating agent in the present invention. The alkylating agent acts as a donor of a substituent that can undergo nucleophilic substitution or a Smile transfer reaction in the molecule.

In the formula (2), R ₂ may be (C 1 -C 5) alkylene, more preferably (C 1 -C 3) alkylene. Further, X may be a leaving group, for example, halogen or OR < ₃ >. R ₃ is preferably p -toluenesulfonyl or methylsulfonyl.

Examples of the alkylating agent according to the present invention include acetamides such as 2-chloroacetamide, 2-bromo-2-methylpropanamide and 2-bromo-2-ethylbutanamide, -Chloroacetamide is advantageous in terms of yield.

The alkylating agent may be added in an equivalent ratio of the formula (3) as the raw material. Preferably, the alkylating agent is added in a ratio of 1 to 2 mol, more preferably 1 to 1.5 mol, per mol of the compound of the formula (3).

The base according to the present invention can remove the hydroxy group of the hydroxy aromatic compound participating in the reaction or act as an electron transfer promoter. The base is preferably selected from the group consisting of sodium hydroxide (NaOH), cesium carbonate (Cs ₂ CO ₃ ), cesium acetate, cesium bicarbonate (CsHCO ₃ ), cesium bromide (CsBr), cesium chloride (CsCl), cesium fluoride cesium (CsI), potassium carbonate (K ₂ CO _3), sodium hydride (NaH), potassium hydride (KH), lithium hydride (LiH), lithium -bis- trimethylsilyl amide, sodium -bis- trimethylsilyl amide, potassium n -butyllithium, sec -butyllithium, iso -butyllithium, and tert -butyllithium.

In the present invention, the addition amount of the base is not limited, but may be added in an equivalent ratio of the compound of the formula (3), preferably 1 to 5 mol, more preferably 1.5 to 2.5 mol per mol of the compound of the formula A stable yield can be obtained.

In the present invention, the solvent can easily dissolve the reactants containing the alkylating agent and the base, and an amide solvent or a nitrile solvent which can be commonly used in the art can be used. As the solvent, any one selected from, for example, 1-methyl-2-pyrrolidinone, dimethylformamide, dimethylacetamide and acetonitrile or a mixture thereof may be used.

In the present invention, the addition amount of the solvent is not limited, but may be added in an equivalent ratio of the compound of the formula (3), and preferably the concentration of the compound of the formula (3) is 0.1 molar to 0.1 molar.

The catalyst according to the present invention may be added with a metal halide compound (MX) to improve the yield and yield of the invention. As the catalyst, any one or two or more selected from potassium iodide, sodium iodide, potassium bromide and sodium bromide may be used, and potassium iodide is preferably used.

The amount of the catalyst to be used in the present invention may be added in an equivalent ratio of the compound of the formula (3). When 1 mole of the compound of the formula (3) is used, the catalyst is used in a range of 0.01 to 1 mol, preferably 0.05 to 0.5 good. When it is added in an amount less than 0.01 molar ratio, it is difficult to obtain the effect of increasing the yield depending on the addition of the catalyst, and when it is added in excess of 1 molar amount, the meaning as a catalyst is lost.

The aniline derivative according to the present invention can be prepared by adding a catalyst, a base and monomers corresponding to the general formulas (2) and (3) to a solvent and reacting them. The reaction is preferably carried out at 50 ° C or higher, preferably 50 to 200 ° C. If the reaction temperature is lower than 50 ° C, the reaction does not occur properly. If the reaction temperature is higher than 200 ° C, by-products may be generated, which may cause economic problems.

Further, the reaction may proceed at a single temperature without changing the temperature. However, in order to accelerate the reaction at the second step, it is preferable to proceed at a temperature of more than two stages. However, It is preferably carried out at a temperature of 50 to 200 ° C.

The reaction is preferably carried out in two or more stages, preferably two stages. More preferably, the reaction is carried out at 80 to 100 ° C for 10 to 90 minutes, and then the reaction is carried out at 140 to 160 ° C It is preferable to carry out the reaction for 2 to 6 hours.

[Reaction Scheme 2]

Hereinafter, a method of preparing an aniline derivative according to the present invention will be described in more detail with reference to Examples. However, the following examples are only illustrative of the present invention in more detail, and the present invention is not limited by the following examples.

(Example 1)

(2.72 g, 20 mmol, 1 equiv.), Cesium carbonate (16.25 g, 50 mmol, 2.5 equiv.), 2-chloroacetamide (2.23 g , 24 mmol, 1.2 equiv.) And dimethylformamide (30 mL) as a solvent. At this time, the reaction was allowed to proceed at 90 ° C for 1 hour and then at 150 ° C for 4 hours. After the progress of the reaction, the dimethylformamide was removed by distillation under reduced pressure, and the residue was separated by flash column chromatography to obtain aniline (1- (4-aminophenyl) ethanone) The yields are shown in Table 1 below.

(Examples 2 to 5)

The reaction was carried out in the same manner as in Example 1 except that the base, the solvent, the catalyst and the reaction conditions were changed as shown in the following Table 1, and aniline was prepared. The yield of the produced aniline was measured, Respectively.

[Table 1]

Examples 1, 2 and 5 in which the reaction was carried out at a different reaction temperature as shown in Table 1 were higher than those in Examples 3 and 4 in which the reaction was carried out at a single reaction temperature. In Example 5 in which KI was added as a catalyst The best yield was obtained.

(Examples 6 to 16)

The hydroxyaromatic compound / 2-chloroacetamide / potassium carbonate / potassium iodide described in the following Table 2 were added to the dimethylformamide solvent at a molar ratio of 1 / 1.2 / 2.5 / 0.2, respectively, and after 1 hour at 90 ° C , And reacted at 150 DEG C for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was separated by flash column chromatography using ethyl acetate: hexanes (1: 9, v / v) to obtain the aniline derivatives shown in Table 2 below.

[Table 2]

[Table 3]

Claims (9)

Catalysts such as sodium hydroxide, cesium carbonate, cesium acetate, cesium bicarbonate, cesium bromide, cesium fluoride, cesium fluoride, cesium iodide, potassium carbonate, sodium hydride, potassium hydride, lithium hydride, lithium-bis-trimethylsilylamide, Butyllithium, isobutyllithium, tert-butyllithium, and 1-methyl-2-pyrrolidinone , Dimethylformamide, dimethylacetamide and acetonitrile at a temperature of from 80 to 100 ° C for 10 to 90 minutes and then reacting at a temperature of from 140 to 160 ° C for 2 to 10 hours, And reacting the compound of formula (I) for 6 hours to prepare an aniline derivative.
[Chemical Formula 1]

(2)

(3)

(Wherein A is nitrogen or C;
Wherein R ₁ is independently selected from the group consisting of hydrogen, halogen, (C 1 -C 10) alkyl, (C 1 -C 10) alkenyl, (C 3 -C 10) cycloalkyl, (C 3 -C 10) heterocycloalkyl, (C3-C12) heteroaryl, nitro, or thiol;
Wherein R < ₂ > is (C1-C5) alkylene;
N is an integer of 1 to 4;
X is halogen, or OR < _{3 &} gt ;;
Wherein R < ₃ > is p -toluenesulfonyl or methylsulfonyl. The method according to claim 1,
Wherein the formula (3) is any one selected from the following formulas (4) to (6).
[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(Wherein R ₁₁ to R ₁₆ , R ₂₁ to R ₂₅ and R ₃₁ to R ₃₇ in the general formulas 4 to 6 are each independently hydrogen, (C 1 -C 5) alkyl or halogen;
Any one of R ₁₁ to R ₁₆ , R ₂₁ to R _25, and R ₃₁ to R ₃₇ is necessarily hydroxy. delete The method according to claim 1,
Wherein the catalyst is at least one selected from potassium iodide, sodium iodide, potassium bromide, sodium bromide and the like. The method according to claim 1,
Wherein the catalyst is added in an amount of 0.01 to 1 mole based on 1 mole of the compound of Formula 3 to produce the aniline derivative. delete The method according to claim 1,
Wherein the base is added in an amount of 1 to 5 mol per 1 mol of the compound of Formula 3 to produce an aniline derivative. delete delete