KR100902236B1 - Phenethyl benzoate derivatives and process for preparing the same - Google Patents

Abstract

The present invention relates to a phenethyl benzoate derivative and a method for producing the same, and more particularly, to a phenethyl benzoate derivative substituted with a hydroxy group at positions 2 and / or 3 of a phenethyl group and a method for producing the same.

Description

Phenethyl benzoate derivatives and process for preparing the same {Phenethyl benzoate derivatives and process for preparing the same}

1 shows an NMR spectrum of 2-hydroxyphenethyl 3,4,5-trihydroxybenzoate obtained in Example 1 of the present invention.

Fig. 2 shows the IR spectrum of 2-hydroxyphenethyl 3,4,5-trihydroxybenzoate obtained in Example 1 of the present invention.

Fig. 3 shows the NMR spectrum of 3-hydroxyphenethyl 3,4,5-trihydroxybenzoate obtained in Example 2 of the present invention.

4 shows the IR spectrum of 3-hydroxyphenethyl 3,4,5-trihydroxybenzoate obtained in Example 2 of the present invention.

The present invention relates to a phenethyl benzoate derivative and a method for producing the same, and more particularly, to a phenethyl benzoate derivative substituted with a hydroxy group at positions 2 and / or 3 of a phenethyl group and a method for producing the same.

In general, pharmacologically important ingredients in Rhodiola saline are known as salidroside and p-tyrosol, and are effective for arthritis, pain, pulmonary tuberculosis, anemia, neuralgia, hepatitis and hypotension. Calm, hematopoietic, cold, anti-inflammatory effect is better than ginseng, but has the advantage of fewer side effects than ginseng. In particular, p-tyrosol having a structure of Formula (A) has a phenethyl benzoate structure and is known to be excellent in antioxidant activity and anti-inflammatory activity per se, and has a skeleton similar to the phenethyl benzoate. In the case of compounds, it is expected to have various activities.

<Formula A>

The technical problem to be achieved by the present invention is to provide a phenethyl benzoate derivative.

Another object of the present invention is to provide a method for preparing the phenethyl benzoate derivative.

The present invention to achieve the above technical problem,

There is provided a phenethyl benzoate derivative of the formula:

<Formula 1>

Food,

R ₁ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are the same as or different from each other, and each represents a hydrogen, a halogen atom, a carboxyl group, an amino group and a nitro. Groups, cyano groups, substituted or unsubstituted C ₁ -C ₂₀ alkyl groups, substituted or unsubstituted C ₁ -C ₂₀ alkoxy groups, substituted or unsubstituted C ₂ -C ₂₀ alkenyl groups, substituted or unsubstituted C ₂ -C ₂₀ alkynyl group, substituted or unsubstituted C ₁ -C ₂₀ heteroalkyl group, substituted or unsubstituted C ₆ -C ₃₀ aryl group, substituted or unsubstituted C ₇ -C ₃₀ arylalkyl group, substituted or unsubstituted A C ₅ -C ₃₀ heteroaryl group, or a substituted or unsubstituted C ₃ -C ₃₀ heteroarylalkyl group, two or more of them may be fused to each other to form a 5- to 7-membered fused ring,
R ₂ , R ₃ and R ₄ represent a hydroxy group,

Provided that at least one of R ₆ , R ₇ , R ₉ and R ₁₀ represents a hydroxy group.

The present invention to achieve the above other technical problem,

Provided is a preparation method of preparing the compound of Formula 1 by condensation of a compound of Formula 11 with a compound of Formula 21 in the presence of an organic solvent:

<Formula 11>

<Formula 21>

Food,

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are as defined above.

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

The present invention provides a compound of formula 1 having a phenethyl benzoate backbone, which has a variety of activities by having a backbone similar to the p-tyrosol known in the art:

<Formula 1>

Food,

R ₁ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are the same as or different from each other, and each represents a hydrogen, a halogen atom, a carboxyl group, an amino group and a nitro. Groups, cyano groups, substituted or unsubstituted C ₁ -C ₂₀ alkyl groups, substituted or unsubstituted C ₁ -C ₂₀ alkoxy groups, substituted or unsubstituted C ₂ -C ₂₀ alkenyl groups, substituted or unsubstituted C ₂ -C ₂₀ alkynyl group, substituted or unsubstituted C ₁ -C ₂₀ heteroalkyl group, substituted or unsubstituted C ₆ -C ₃₀ aryl group, substituted or unsubstituted C ₇ -C ₃₀ arylalkyl group, substituted or unsubstituted A C ₅ -C ₃₀ heteroaryl group, or a substituted or unsubstituted C ₃ -C ₃₀ heteroarylalkyl group, two or more of them may be fused to each other to form a 5- to 7-membered fused ring,
R ₂ , R ₃ and R ₄ represent a hydroxy group,

Provided that at least one of R ₆ , R ₇ , R ₉ and R ₁₀ represents a hydroxy group.

The phenethyl benzoate derivative of Chemical Formula 1 according to the present invention has a hydroxy group in at least one of ortho or meta of the right phenyl ring, and at the position of such hydroxy, p-tyrosol Is distinguished from. Conventionally known p-tyrosols have a hydroxyl group at position 4, para. Preferably, the hydroxy group is present alone at position 2 or position 3 of the right phenyl group.

Preferred compounds as compounds of Formula 1 have the structure of Formula 2:

<Formula 2>

Wherein R ₂ , R ₃ and R ₄ are as defined above,

R ₉ and R ₁₀ represent hydrogen or a hydroxy group,

However, when R ₉ is hydrogen, R ₁₀ is a hydroxy group, and when R ₉ is a hydroxy group, R ₁₀ represents hydrogen.

The most preferred compound as the compound of Formula 1 is 2-hydroxyphenethyl 3,4,5-trihydroxybenzoate of Formula 3 or 3-hydroxyphenethyl 3,4,5-trihydride of Formula 4 Oxybenzoate.

<Formula 3>

<Formula 4>

The phenethyl benzoate derivative of Formula 1 according to the present invention may be prepared by various methods, an example of which is shown in Scheme 1 below:

<Scheme 1>

In Scheme 1, the benzoic acid derivative of Formula 11 is condensed with the phenethyl alcohol derivative of Formula 21 in the presence of an organic solvent to produce the phenethyl benzoate derivative of Formula 1 according to the present invention. More specifically, the compound of Formula 11 and the compound of Formula 21, which are reactants, are added to the container, and then, by adding an organic solvent, at a temperature of 20 to 25 ° C, preferably at room temperature for 1 to 10 hours, preferably 3 The reaction is carried out under stirring for about 7 hours. After completion of the reaction, the product was washed and dried, followed by further purification to prepare a high purity phenethyl benzoate derivative. The washing, drying and purification processes can be carried out by conventional methods known in the art.

The organic solvent used in the manufacturing process can be used without limitation as long as it can be used in the condensation reaction as described above, for example, chloroform, dichloromethane containing dichlorocarbene (DCC) is more preferred.

In the method for preparing a phenethyl benzoate derivative of Chemical Formula 1 according to the present invention, as the compound of Chemical Formula 11, which is a reactant, preferably, the compound of Chemical Formula 12, and more preferably the compound of Chemical Formula 13 may be used:

<Formula 12>

Food,

R ₂ , R ₃ and R ₄ are as defined above.

<Formula 13>

In addition, the compound of formula 21, which is a raw material in the method for preparing a phenethyl benzoate derivative of formula 1 according to the present invention, preferably a compound of formula 22, more preferably a compound of formula 23 or a formula 24 Can be used.

<Formula 22>

Food,

R ₉ and R ₁₀ are the same as or different from each other, and each represents a hydrogen, a halogen atom, a carboxyl group, an amino group, a nitro group, a cyano group, a substituted or unsubstituted C ₁ -C ₂₀ alkyl group, a substituted or unsubstituted C ₁ -C ₂₀ Alkoxy group, substituted or unsubstituted C ₂ -C ₂₀ alkenyl group, substituted or unsubstituted C ₂ -C ₂₀ alkynyl group, substituted or unsubstituted C ₁ -C ₂₀ heteroalkyl group, substituted or unsubstituted C _6- A C ₃₀ aryl group, a substituted or unsubstituted C ₇ -C ₃₀ arylalkyl group, a substituted or unsubstituted C ₅ -C ₃₀ heteroaryl group, or a substituted or unsubstituted C ₃ -C ₃₀ heteroarylalkyl group, and At least one represents a hydroxyl group.

<Formula 23>

<Formula 24>

Among the terms of the substituent used in the present invention, the alkyl group is preferably a straight or branched alkyl group having 1 to 20 carbon atoms, more preferably a straight or branched alkyl group having 1 to 12 carbon atoms, and a straight chain having 1 to 6 carbon atoms. Or branched alkyl groups are most preferred. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isoamyl, hexyl and the like. One or more hydrogen atoms included in these alkyl groups may be further substituted with halogen atoms to constitute a haloalkyl group.

Among the terms of the substituents used in the present invention, an alkoxy group is preferably an oxygen-containing straight or branched alkoxy group each having an alkyl moiety of 1 to 20 carbon atoms. More preferred are alkoxy groups having 1 to 6 carbon atoms and most preferred are alkoxy groups having 1 to 3 carbon atoms. Examples of such alkoxy groups include methoxy, ethoxy, propoxy, butoxy, and t-butoxy. The alkoxy group may be further substituted with one or more halo atoms such as fluoro, chloro or bromo to provide a haloalkoxy group. Examples thereof include fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, fluoropropoxy and the like.

In the term of the substituent used in the present invention, an alkenyl group means a straight or branched aliphatic hydrocarbon group having 2 to 20 carbon atoms having a carbon-carbon double bond. Preferred alkenyl groups have 2 to 12 carbon atoms in the chain, more preferably 2 to 6 carbon atoms in the chain. Branched means that one or more lower alkyl or lower alkenyl groups are attached to the alkenyl straight chain. Such alkenyl groups may be unsubstituted or may be independently substituted by one or more groups including but not limited to halo, carboxy, hydroxy, formyl, sulfo, sulfino, carbamoyl, amino and imino. Examples of such alkenyl groups include ethenyl, propenyl, carboxyethenyl, carboxypropenyl, sulfinoethenyl, sulfonoethenyl and the like.

In the terminology of a substituent used in the present invention, a heteroalkyl group is a heteroatom in the main chain of 1 to 20, preferably 1 to 12, more preferably 1 to 6 carbon atoms in the alkyl group, for example N, O, P , S and the like.

Among the terms of the substituents used in the present invention, an aryl group is used alone or in combination to mean a carbocycle aromatic system having 6 to 30 carbon atoms containing one or more rings, which rings may be attached or fused together in a pendant manner. The term aryl includes aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl. More preferably phenyl. The aryl group may have 1 to 3 substituents such as hydroxy, halo, haloalkyl, nitro, cyano, alkoxy and lower alkylamino.

In the term of the substituent used in the present invention, an arylalkyl group means that one or more hydrogen atoms of the alkyl group are substituted with the aryl group.

In the term of the substituent used in the present invention, the heteroarylalkyl group means that at least one hydrogen atom of the alkyl group as defined above is substituted with the heteroaryl group as defined above, and means a carbocycle aromatic system having 3 to 30 carbon atoms.

In the compounds of Formulas 1 to 3, the heteroaryl group includes 1, 2, or 3 hetero atoms selected from N, O, or S, and the remaining ring atoms are C to monovalent monocyclic or non-carbon monovalent having 5 to 30 ring atoms. Cyclic aromatic radicals. The term also refers to monovalent monocyclic or bicyclic aromatic radicals in which heteroatoms in the ring are oxidized or quaternized to form, for example, N-oxides or quaternary salts. Representative examples include thienyl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, quinoxalinyl, imidazolyl, furanyl, benzofuranyl, thiazolyl, isoxazolin, Benzisoxazolin, benzimidazolyl, triazolyl, pyrazolyl, pyrrolyl, indolyl, 2-pyridonyl, N-alkyl-2-pyridonyl, pyrazinyl, pyridazininyl, pyrimidinyl , Oxazoloyl and their corresponding N-oxides (eg pyridyl N-oxides, quinolinyl N-oxides), quaternary salts thereof, and the like.

The phenethyl benzoate derivative of Formula 1 of the present invention as described above is expected to have various activities, for example, it can be used for treating arthritis, analgesic, tuberculosis, neuralgia, hepatitis, blood pressure, anti-inflammatory, cardiac, cosmetics, etc. have.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it is to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. Will be self-evident.

Example 1 Synthesis of 2-hydroxyphenethyl 3,4,5-trihydroxybenzoate

20 mL of THF is added with gallic acid (0.02 mol) of formula 13 and 2-hydroxyphenethyl alcohol (0.025 mol) of formula 23 to dissolve. The solution is placed in a flask equipped with a CaCl ₂ filled tube. After mounting the ice bath DCC solution (DCC 0.02mol / CH ₂ Cl ₂ 10mL) was slowly added. After removing the ice bath, the reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction was filtered to remove urea. The filtrate was washed several times with water and further with 5% acetic acid. Washed again with water, dried over MgSO ₄ and the solvent was removed. The reaction was separated by silica gel column chromatography and dried. The product was washed with chloroform and filtered and dried. As a result, 1.5095 g, 26% of an ivory 2-hydroxyphenethyl 3,4,5-trihydroxybenzoate of Chemical Formula 3 was obtained. As a result of elemental analysis, the weight% values of C, H, and O were 61.89, 4.644, and 32.74%, respectively, which were almost in agreement with the theoretical values. ^The structure was analyzed using ¹ H-NMR and FT-IR.

As shown in FIG. 1, the ¹ H-NMR spectrum is shown in FIG. 1, and as the raw material becomes an ester, it can be seen that the peak of hydrogen next to -OH moves to a region where the peak is low. As shown in FIG. 2, ester functional groups can be confirmed in the vicinity of 1735 cm ⁻¹ from FIG. 2.

<Formula 13>

<Formula 23>

<Formula 3>

Example 2: Synthesis of 3-hydroxyphenethyl 3,4,5-trihydroxybenzoate

20 mL of THF is added with gallic acid (0.02 mol) of the following formula (13) and the following formula 24 3-hydroxyphenethyl alcohol (0.025 mol) to dissolve. The solution is placed in a flask equipped with a CaCl ₂ filled tube. After mounting an ice bath, DCC solution (DCC 0.025mol / CH ₂ Cl ₂ 10mL) was slowly added. After removing the ice bath, the reaction was stirred at room temperature for 5 hours. After completion of the reaction, the reaction was filtered to remove urea. The filtrate was washed several times with water and further with 5% acetic acid. Washed again with water, dried over MgSO ₄ and the solvent was removed. The reaction was separated by silica gel column chromatography and dried. The product was washed with chloroform and filtered and dried. As a result, 1.655 g, 28.5% of 3-hydroxyphenethyl 3,4,5-trihydroxybenzoate of Chemical Formula 4 was obtained as a pale yellow powder. The structure was analyzed by elemental analysis, ¹ H-NMR and FT-IR.

Elemental analysis showed that the weight percent values of C, H, and O were 58.19, 5.61, and 36.24%, respectively, which were almost in agreement with the theoretical values. In addition, as shown in FIG. 1, the ¹ H-NMR spectrum is shown in FIG. 1, and as the reactant becomes an ester, it can be seen that the peak of hydrogen next to -OH moves to a region where the peak is low. As shown in FIG. 4, ester functional groups can be confirmed in the vicinity of 1735 cm ⁻¹ .

<Formula 13>

<Formula 24>

<Formula 4>

The present invention provides a novel structure of phenethyl benzoate derivative having various activities, and a method for preparing the same.

Claims (6)

Fenethyl benzoate derivative of formula <Formula 1>

Food, R ₁ , R ₅ , R ₈ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are the same or different from each other, and each represents a hydrogen, a halogen atom, a carboxyl group, an amino group, a nitro group, a cyano group, a C ₁ -C ₂₀ alkyl group, C ₁ -C ₂₀ alkoxy group, C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₁ -C ₂₀ heteroalkyl group, C ₆ -C ₃₀ aryl group, C ₇ -C ₃₀ arylalkyl group, C ₅ -C ₃₀ heteroaryl group, or C ₃ -C ₃₀ heteroarylalkyl group, two or more of them may be fused to each other to form a 5- to 7-membered fused ring, R ₂ , R ₃ and R ₄ represent a hydroxy group, R ₆ , R ₇ , R ₉ and R ₁₀ are the same or different from each other, and each hydrogen, halogen atom, carboxyl group, amino group, nitro group, cyano group, hydroxy group, C ₁ -C ₂₀ alkyl group, C ₁ -C ₂₀ alkoxy group , C ₂ -C ₂₀ alkenyl group, C ₂ -C ₂₀ alkynyl group, C ₁ -C ₂₀ heteroalkyl group, C ₆ -C ₃₀ aryl group, C ₇ -C ₃₀ arylalkyl group, C ₅ -C ₃₀ heteroaryl group, Or a C ₃ -C ₃₀ heteroarylalkyl group, two or more of them may be fused to each other to form a 5- to 7-membered fused ring, Provided that at least one of R ₆ , R ₇ , R ₉ and R ₁₀ represents a hydroxy group. The method of claim 1, A phenethyl benzoate derivative according to claim 1, wherein the phenethyl benzoate derivative is a compound of Formula 2: <Formula 2>

Wherein R ₂ , R ₃ and R ₄ are as defined in claim 1, R ₉ and R ₁₀ represent hydrogen or a hydroxy group, However, when R ₉ is hydrogen, R ₁₀ is a hydroxy group, and when R ₉ is a hydroxy group, R ₁₀ represents hydrogen. The method of claim 1, The phenethyl benzoate derivative of Formula 1 is a compound of Formula 3 or 4 below. <Formula 3>

<Formula 4>

A process for preparing a compound represented by formula 1 according to claim 1 comprising the step of condensing a compound of formula 11 with a compound of formula 21 in the presence of an organic solvent: <Formula 11>

<Formula 21>

Food, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are the same as defined in claim 1. . The method of claim 4, wherein Process for producing a compound of formula 11 is characterized in that the compound of formula 13. <Formula 13>

The method of claim 4, wherein Method for producing a compound of formula 21 is characterized in that the compound of formula 23 or 24. <Formula 23>

<Formula 24>

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