WO2007004753A1

WO2007004753A1 - Alkylphenol derivatives having phytopathogenic fungi activities

Info

Publication number: WO2007004753A1
Application number: PCT/KR2005/002069
Authority: WO
Inventors: Won Sik Choi; Bong Jin Chung; Seung Sik Jang; Hee Jun Kwon; Lae Hong Cho; Do Yeon Jang
Original assignee: Dongbu Hitek Co., Ltd.
Priority date: 2005-06-30
Filing date: 2005-06-30
Publication date: 2007-01-11

Abstract

Disclosed herein is an alkylphenol derivative having inhibitory activities on the growth of phytopathogenic fungi, represented by Formula 1, and a growth inhibitor for phytopathogenic fungi containing the alkylphenol derivative as an effective component. The alkylphenol derivative of this invention may exhibit excellent inhibitory activities on the growth of phytopathogenic fungi, for example, Phytophthora infestans, Pyrcularia grisea, Alternaria alternata f. sp. mali, Colletotrichum orbiculare, Rhizoctonia solini, Colletotrichum gloeasporioid.es, Botrytis cinerea, and Phytophthora capsici, and thus, may be used as an environmentally friendly disinfecting agent.

Description

[DESCRIPTION]

[invention Title]

ALKYLPHENOL DERIVATIVES HAVING PHYTOPATHOGENIC FUNGI ACTIVITIES

[Technical Field]

The present invention relates, generally, to alkylphenol derivatives having inhibitory activities on the growth of phytopathogenic fungi, represented by Formula 1 below, and to uses thereof. More particularly, the present invention relates to an alkylphenol derivative having inhibitory activities on the growth of phytopathogenic fungi, represented by Formula 1, and to a growth inhibitor for specific phytopathogenic fungi, containing the alkylphenol derivative as an effective component . Formula 1

(wherein Ri is any one selected from the group consisting of H, a Ci~C₆ aliphatic hydrocarbon including a linear or branched alkyl group or haloalkyl group, a Ci~C₆ aliphatic hydrocarbon, an aromatic hydrocarbon or a heterocyclic compound including at least one element selected tic hydrocarbon, and a heterocyclic compound, and preferably includes

in which Z is any one selected from the group consisting of a Ci~C₆ linear or branched alkyl group or haloalkyl group, an aryl group, and a substituted aryl group, in which the substituted aryl group is 1 to 3 substituted aryl groups with any one substituent selected from the group consisting of a halogen atom, a nitro group, a Ci~ Cε alkyl group, a Ci~C₆ alkoxy group, and a Ci-C₆ haloalkyl group, and R₂ is H or CH₃. ) .

[Background Art] While agricultural products having excellent qualities according to recent economic growth are required along with the stable assurance of food resources due to a drastic population increase since the 1960s, importance of pesticides is increasing. Although organic synthetic pesticides have been actively used to increase food production, to correspond to the drastic population increase, they are disadvantageous because they kill natural enemies, useful microorganisms, and insects, negatively affect wild animals and fish, are harmful to human beings and animals, remain in soil and food, and cause various side effects such as environmental pollution. Eventually, at the Environmental Conference held in Rio at 1992, each country endorsed an international agreement to decrease the amounts of organic synthetic pesticides used by 50% by 2004.

Therefore, as interest in alternative pesticides rises, thorough attempts have been made to develop various pesticide resistant crops, insect pest resistant crops, stress resistant crops and disease resistant crops by controlling insect pests using natural enemy insects and microorganisms, by using sexual pheromones or functional materials between organisms present in an ecosystem, that is, natural physiologically active materials, or by biotechnologically recombining genes. Moreover, some attempts have already been applied in practice.

Recently, pesticides, in particular, environmentally friendly pesticides, are mainly required, and thus, research into the development of derivatives using natural material alone or a mixture of natural material and chemical pesticides, or using natural material as a precursor has been mainly conducted. As the natural material, plant oil is revealed to have aroitiatherapeutic effects, and is variously used in functional food, functional cosmetics, aromatherapeutic agents, and aromatics for environmental improvement, in addition to using the unique favor thereof. Hence, physiological activities of various constituents in plant oils have been extensively and intensively studied.

Plant oil may be extracted from leaves, flowers, skins, roots, rinds or all plant organs, according to the type of plant, and contains large amounts of highly volatile mono- and sesquiterpenes. In this regard, antibiotic activities of rosemary, lavender, Eucalyptus, lemongrass, peppermint oil, etc., have been reported [Larrondo J. V., Agut M. and Calvo Torras M. A. Microbios., 1995, 82, 171-172].

The present inventors have confirmed antibiotic activities of plant oil, such as thyme, clove bud, sassafras and Rosen-geranium, on phytopathogenic fungi.

In particular, thyme oil is confimred to exhibit excellent physiological activities on Alternaria alternata f. sp. mali, Phytophthora capsici, Colletotrichum gloeasporioides, Botrytis cinerea, and Trichoderma virens, that is, excellent inhibitory activities on the growth and germination of the spores of the above phytopathogenic fungi, and also to manifest the prevention and treatment effects as a result of crop application tests. Further, main components of the thyme oil having physiological activities on phytopathogenic fungi are analyzed to be thymol or carvacrol, and derivatives derived from the above components are known.

Leading to the present invention, intensive and thorough research into the development of novel environmentally friendly pesticides using plant oils having physiological activities on phytopathogenic fungi, aiming to avoid the problems encountered in the related art, resulted in the provision of an alkylphenol derivative having a structure similar to thymol or carvacrol, derived from thyme oil, in which excellent physiological activities of the alkylphenol derivative on phytopathogenic fungi are confirmed.

[Disclosure] [Technical Problem]

An object of the present invention is to provide an alkylphenol derivative having inhibitory activities on the growth of phytopathogenic fungi, represented by Formula 1.

Another object of the present invention is to provide a method of preparing an alkylphenol derivative having inhibitory activities on the growth of phytopathogenic fungi, represented by Formula 1.

A further object of the present invention is to provide a growth inhibitor for phytopathogenic fungi, which contains an alkylphenol derivative having inhibitory activities on the growth of phytopathogenic fungi, represented by Formula 1, as an effective component .

[Technical Solution] In order to achieve the above objects, the present invention provides an alkylphenol derivative having inhibitory activities on the growth of phytopathogenic fungi, represented by Formula 1: Formula 1

in which Z is any one selected from the group consisting of a Ci~C₆ linear or branched alkyl group or haloalkyl group, an aryl group, and a substituted aryl group, in which the substituted aryl group is 1 to 3 substituted aryl groups with any one substituent selected from the group consisting of a halogen atom, a nitro group, a Ci~ C_δ alkyl group, a Ci~C₆ alkoxy group, and a Ci~C₆ haloalkyl group, and R₂ is H or CH₃.) . The alkylphenol derivative of the present invention may be prepared from 4-isopropylphenol or 2- isopropylphenol, in which Ri and R₂ are H, or 4-isopropyl- 3-methylphenol or 5-isopropyl-3-methylphenol, in which Ri is H and R₂ is CH₃. Preferably, in the alkylphenol derivative of the present invention, Ri may be substituted by any one functional group selected from the group consisting of an ester group, a sulfonyl ester group, a carbamate group, and an ether group.

In addition, the present invention provides a method of preparing an alkylphenol derivative having inhibitory activities on the growth of phytopathogenic fungi, represented by Formula 1. Specifically, the method comprises dissolving a thymol or carvacrol derivative derived from thyme oil, represented by Formula 1, in an acetonitrile solvent or a solvent mixture of methanol and water, adding triethylamine to prepare a basic solution, adding the basic solution with a compound having any one functional group selected from the group consisting of an ester group, a sulfonyl ester group, a carbamate group, an ether group, and a phosphoyl group at 0~25^°C to conduct a substitution reaction for 2 ~10 hr, and extracting the reacted solution to separate an organic layer, which is then dried. In addition, the present invention provides a growth inhibitor for specific phytopathogenic fungi, containing the alkylphenol derivative having inhibitory activities on the growth of phytopathogenic fungi. As such, the phytopathogenic fungi are any one selected from the group consisting of Phytophthora infestans, Pyrcularia grisea, Alternaria alternata f. sp. mali, Colletotrichum orbiculare, Rhizoctonia solini, Colletotrichum gloeasporioides, Botrytis cinerea, and Phytophthora capsici.

[Advantageous Effects]

In the present invention, an alkylphenol derivative having a structure similar to thymol or carvacrol derived from thyme oil is confirmed to exhibit excellent inhibitory activities on the growth of phytopathogenic fungi, and thus, may be provided as a precursor for an environmentally friendly disinfecting agent.

[Description of Drawings] FIG. 1 is a photograph showing the inhibitory activities of the alkylphenol derivatives of the present invention on the growth of Phytophthora infestans;

FIG. 2 is a photograph showing the inhibitory activities of the alkylphenol derivatives of the present invention on the growth of Phrcularia grisea;

FIG. 3 is a photograph showing the inhibitory activities of the alkylphenol derivatives of the present invention on the growth of Alternaria alternata f. sp. maIi; and FIG. 4 is a photograph showing the inhibitory activities of the alkylphenol derivatives of the present invention on the growth of Colletotrichum orbiculare.

[Best Mode] Hereinafter, a detailed description will be given of the present invention.

The present invention provides an alkylphenol derivative represented by Formula 1 below: Formula 1

(wherein Ri and R₂ are as defined above.) .

In the present invention, since excellent inhibitory activities of thymol or carvacrol derived from thyme oil on the growth of phytopathogenic fungi are used, the alkylphenol derivative having a structure similar to thymol or carvacrol was determined as a precursor.

Preferably, the alkylphenol derivative of the present invention is prepared from 4-isopropylphenol or 2- isopropylphenol when Ri and R₂ in the above Formula are H, or 4-isopropyl-3-methylphenol or 5-isopropyl-3- methylphenol when Ri is H and R₂ is CH₃.

Particularly, the alkylphenol derivative of the present invention has Ri, which is substituted by any one functional group selected from the group consisting of an ester group, a sulfonyl ester group, a carbamate group, and an ether group. More particularly, the alkylphenol derivative of the present invention may be exemplified by: ^■ 1) 4-isopropylphenyl 2, 2-dimethylpropionate,

2) 4-isopropylphenyl piperonyloylate,

3) 2-isopropylphenyl bromoacetate, 4) 2-isopropylphenyl piperonyloylate,

5) 4-isopropyl-3-methylphenyl (1, 2, 3, 4-tetrazol-l- yl) acetate,

6) 4-isopropyl-3-methylphenyl (2-aminothiazol-4- yl)methoxyiminoacetate,

7) 4-isopropyl-3-methylphenyl phenylacetate,

8) 5-isopropyl-3-methylphenyl phenylacetate,

9) 2-isopropyl-5-methylphenyl 2, β-dimethoxy benzoate,

10) 4-isopropylphenyl 3, 5-dimethoxybenzoate, 11) 2-isopropylphenyl 3, 4, 5-trimethoxybenzoate,

12) 4-isopropyl 3-methylphenyl 3, 5-dichloro benzoate,

13) 4-isopropylphenyl 3, 5-dichloro benzoate,

14) 4-isopropyl-3-methylphenyl 2, 4, 5-trifluoro benzoate,

15) 2-isopropyl-5-methylphenyl 2, 3, 6-trifluoro benzoate, 16) 5-isopropyl-3-methylphenyl 2, 3, 6-trifluoro benzoate,

18) 2-isopropyl 4-methoxybenzenesulfonate,

19) 4-isopropyl-3-methylphenyl N- (4-ethyl-2, 3-dioxo-l- piperazine) carbamate,

20) 4-isopropyl-3-methylphenylbenzyl ether, 21) 4-isopropyl-3-methylphenylaryl ether,

22) methyl (4-isopropyl-3-methylphenoxy) acetate,

23) 5-isopropyl-3-methylphenylbenzyl ether, or

24) methyl (5-isopropyl-3-methylphenoxy) acetate.

Further, the present invention provides a method of preparing an alkylphenol derivative, comprising dissolving a thymol or carvacrol derivative derived from thyme oil, represented by Formula 1, in an acetonitrile solvent or a solvent mixture of methanol and water, and then adding triethylamine, to prepare a basic solution; adding the basic solution with a compound having any one functional group selected from the group consisting of an ester group, a sulfonyl ester group, a carbamate group, an ether group, and a phosphoyl group at 0~25^°C to conduct a substitution reaction for 2~10 hr; and extracting the reacted solution to separate an organic layer, which is then dried.

1. When the functional group is an ester group, the present invention provides a method of preparing an alkylphenol derivative according to Reaction 1 below:

(wherein Ri is any one selected from the group consisting of H, a Ci~C₆ aliphatic hydrocarbon, an aromatic hydrocarbon or a heterocyclic compound including a linear or branched alkyl group or haloalkyl group and preferably, said Ri is any one selected from the group consisting of a Ci~C₆ linear or branched alkyl group or haloalkyl group, an aryl group, a Ci~C₆ linear or branched alkyl group or haloalkyl group, an aryl group, a substituted aryl group,

^N°^CH3 ,

in which the substituted aryl group is 1 to 3 substituted aryl groups with any one substituent selected from the group consisting of a halogen atom, a nitro group, a Ci~ Ce alkyl group, a Cχ~C6 alkoxy group, and a Ci~Cδ haloalkyl group, and R₂ is H or CH₃, and X is Cl or Br.) .

2. When the functional group is a sulfonyl ester group, the present invention provides a method of preparing an alkylphenol derivative according to Reaction 2 below:

Reaction 2

(wherein Ri, R₂ and X are as defined above.)

More preferably, said Ri is any one selected from the group consisting of an alkyl group, an aryl group, a substituted aryl group, and -Λ //-0-CH₃

in which the substituted aryl group is 1 to 3 substituted aryl groups with any one substituent selected from the group consisting of a halogen atom, a nitro group, a Ci~ Ce alkyl group, a Ci~C_δ alkoxy group, and a Ci~C₆ haloalkyl group, and R₂ is H or CH₃, and X is Cl or Br.) .

3. When the functional group is a carbamate group, the present invention provides a method of preparing an alkylphenol derivative according to Reaction 3 below: Reaction 3

(wherein Ri, R₂ and X are as defined above.)

More preferably, said Ri is any one selected from the group consisting of an alkyl group, an aryl group, a substituted aryl group, and

in which the substituted aryl group is 1 to 3 substituted aryl groups with any one substituent selected from the group consisting of a halogen atom, a nitro group, a Ci~ C₆ alkyl group, a Ci~C₆ alkoxy group, and a Ci~C₆ haloalkyl group, and R₂ is H or CH₃, and X is Cl or Br.) . 4. When the functional group is an ether group, the present invention provides a method of preparing an alkylphenol derivative according to Reaction 4 below: Reaction 4

(wherein Ri, R₂ and X are as defined above.)

More preferably, said Ri is any one selected from the group consisting of H, a Ci~C₆ linear or branched alkyl group, an aryl group, a substituted aryl group,

K2$CH=C&, and

in which the substituted aryl group is 1 to 3 substituted aryl groups with any one substituent selected from the group consisting of a halogen atom, a nitro group, a Ci~ C₆ alkyl group, a Ci~C₆ alkoxy group, and a Ci-C₆ haloalkyl group, and R₂ is H or CH₃, and X is Cl or Br.) .

Further, the present invention provides a growth inhibitor containing the alkylphenol derivative as an effective component, to effectively inhibit the growth of Phytophthora infestans, Pyrcularia grisea, Alternaria alternata f. sp. mail, Colletotrichum orbiculare, Rhizoctonia solini, Colletotrichum gloeasporioides, Botrytis cinerea, and Phytophthora capsici.

Preferably, to exhibit excellent inhibitory activities on the growth of Phytophthora infestans, the alkylphenol derivatives of the present invention, in particular, any one selected from the group consisting of 4-isopropylphenyl piperonyloylate (compound of Example 2) , 2-isopropylphenyl piperonyloylate (compound of Example 4), methyl (4-isopropyl-3-methylphenoxy) acetate (compound of Example 22), and methyl (5-isopropyl-3- methylphenoxy) acetate (compound of Example 23) may be used, and, more preferably, 2-isopropylphenyl piperonyloylate may be used (FIG. 1) .

In addition, to exhibit excellent inhibitory activities on the growth of Pyrcularia grisea, the alkylphenol derivatives of the present invention, in particular, 4-isopropyl-3-methylphenyl (1, 2, 3, 4-tetrazol- 1-yl) acetate (compound of Example 5) or 4-isopropyl-3- methylphenyl (2-aminothiazol-4-yl) methoxyiminoacetate (compound of Example 6) may be used (FIG. 2) .

In addition, to exhibit excellent inhibitory activities on the growth of Alternaria alternata f. sp. mail, the alkylphenol derivatives of the present invention, in particular, any one selected from the group consisting of 4-isopropylphenol, 4-isopropyl-3- methylphenyl phenylacetate (compound of Example 7), 5- isopropyl-3-methylphenyl phenylacetate (compound of Example 8), and 4-isopropyl-3-methylphenyl N-(4-ethyl- 2, 3-dioxo-l-piperazine) carbamate (compound of Example 19) may be used, which is confirmed through the observation of the fungal growth diameter (FIG. 3) .

In addition, to exhibit excellent inhibitory activities on the growth of Colletotrichum orbiculare, the alkylphenol derivatives of the present invention, in particular, any one selected from the group consisting of 4-isopropylphenyl 3, 5-dimethoxybenzoate (compound of Example 10), 4-isopropyl 3-methylphenyl 3,5-dichloro benzoate (compound of Example 12), 4-isopropylphenyl 3,5- dichloro benzoate (compound of Example 13) , 4-isopropyl- 3-methylphenyl 2, 4, 5-trifluoro benzoate (compound of Example 14), 2-isopropyl-5-methylphenyl 2, 3, 6-trifluoro benzoate (compound of Example 15) , 5-isopropyl-3- methylphenyl 2, 3, 6-trifluoro benzoate (compound of Example 16), 4-isopropyl-3-methylphenyl 2, 3, 6-trifluoro benzoate (compound of Example 17), and 2-isopropyl 4- methoxybenzenesulfonate (compound of Example 18) may be used (FIG. 4) .

In addition, to exhibit excellent inhibitory activities on the growth of Colletotrichum gloeasporioides, the alkylphenol derivatives of the present invention, in particular, any one selected from the group consisting of 4-isopropylphenol, 4- isopropylphenyl 2, 2-dimethylpropionate (compound of Example 1) , and 4-isopropyl-3-methylphenyl (2- aminothiazol-4-yl)methoxyiminoacetate (compound of Example 6) may be used.

In addition, to exhibit excellent inhibitory activities on the growth of Rhizoctonia solini, the alkylphenol derivatives of the present invention, in particular, 2-isopropylphenyl bromoacetate (compound of Example 3) may be used.

In addition, to exhibit excellent inhibitory activities on the growth of Phytophthora capsici, the alkylphenol derivatives of the present invention, in particular, 2-isopropyl-5-methylphenyl 2, 6-dimethoxy benzoate (compound of Example 9) or 2-isopropylphenyl 3, 4 , 5-trimethoxybenzoate (compound of Example 11) may be used, and thus, may be included in a disinfecting agent being able to effectively inhibit the growth of Phytophthora capsici.

Moreover, the alkylphenol derivatives of the present invention may exhibit excellent inhibitory activities on the growth of Phytophthora capsici, Botrytis cinerea, Pythium ultimum, and Trichoderma virens. [Mode for Invention]

Hereinafter, the present invention is specifically explained using the following examples which are set forth to illustrate, but are not to be construed to limit the present invention. a) Synthesis of Ester Derivatives

<Example 1> Synthesis of 4-isopropylphenyl 2,2- dimethylpropionate

I g (7.34 mmol) of 4-isopropylphenol was dissolved in 30 ml of methanol, and then 0.82 g of potassium hydroxide were added. Subsequently, the reaction mixture was stirred for 30 min and filtered, after which the filtrate was concentrated. The concentrate was added with 20 ml of methylene chloride to be dissolved therein, and was then allowed to react for 2 hr while 1.1 ml (8.81 mmol) of trimethylacetyl chloride were slowly added. After the completion of the reaction, the resultant reaction solution was added with 30 ml of distilled water and then stirred for 30 min. The organic layer was separated, added with 0.8 g of anhydrous magnesium sulfate, and filtered to obtain a filtrate, which was then subjected to column chromatography using silica gel to remove impurities. The obtained eluate was concentrated under reduced pressure at 50 ^°C or lower, thus yielding 1.07 g (66.7%) of 4-isopropylphenyl 2, 2-dimethylpropionate as a title compound.

IR(KBr, cm^"1) : 1750 (C=O)

GC/MS(m/e) : 220(M⁺), 136, 121 (base peak) RT(min) : 12.2 ¹H-NMR (CDCl₃, ppm) : 1.19 (s, 9H C(CH₃J₃), 1.29 (m, 6H, isopropyl CH(CH₃)₂), 3.12 (m, IH, -CH(CH₃)₂), 6.99(s, 4H, aromatic H)

<Example 2> Synthesis of 4-isopropylphenyl piperonyloylate

1.75 g (83.89%) of 4-isopropylphenyl piperonyloylate as a title compound were prepared in the same manner as in Example 1, with the exception that 1 g

(7.34 mmol) of 4-isopropylphenol and 1.62 g (8.81 mmol) of piperonyloyl chloride were used.

IR(KBr, cm^"1) : 1725 (C=O)

GC/MS(m/e) : 284(M⁺), 241, 149 (base peak)

RT(min) : 21.2

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH (CH₃) ₂), 3.12 (m, IH, -CH(CH₃J₂), 5.90(s, 2H, heteroaromatic) ,

7.07 (s, 4H, aromatic H), 7.20 (m, 3H, piperonyl aromatic)

<Example 3> Synthesis of 2-isopropylphenyl bromoacetate

1.58 g (84.2%) of 2-isopropylphenyl bromoacetate as a title compound were prepared in the same manner as in Example 1, with the exception that I g (7.34 mmol) of 2- isopropylphenol and 0.7 ml (8.81 mmol) of bromoacetyl chloride were used.

IR(KBr, cm^"1) : 1760(C=O), 1265(C-O) GC/MS(m/e) : 256(M⁺), 177, 121 (base peak)

RT(min) : 12.0

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂),

3.12 (m, IH, -CH (CH₃) ₂)_/ 4.12 (s, 2H, CH₂-Br), 7.10(m, 4H, aromatic)

<Example 4> Synthesis of 2-isopropylphenyl piperonyloylate

1.81 g (86.82%) of 2-isopropylphenyl piperonyloylate as a title compound were prepared in the same manner as in Example 1, with the exception that 1 g

(7.34 mmol) of 2-isopropylphenol and 1.62 g (8.81 mmol) of piperonyloyl chloride were used.

IR(KBr, cm^"1) : 1725 (ester -COO-)

GC/MS(m/e) : 284(M⁺), 183, 149 (base peak) RT(min) : 20.2

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂),

3.12 (m, IH, -CH (CH₃) ₂), 5.90(s, 2H, heteroaromatic) ,

7.07 (s, 4H, aromatic H), 7.20 (m, 3H, piperonyl aromatic)

<Example 5> Synthesis of 4-isopropyl-3-methylphenyl (1,2,3, 4-tetrazol-l-yl) acetate

1.94 g (15.16 mmol) of 1, 2, 3, 4-tetrazolyl acetic acid were dissolved in 8.5 ml of N,N-dimethylacetamide and 2.5 ml of acetonitrile. The temperature of the solution was controlled to 0~5^°C, and 1.49 ml (19.16 mmol) of N, N-dimethylformamide and 1.49 ml (15.98 mmol) of POCl₃ were added, after which the reaction mixture was stirred at 0~5^°C for 30 min. The reaction solution thus obtained was added in droplets with a solution prepared by dissolving 2 g (13.31 mmol) of 4-isopropyl-3- methylphenol in 5.0 ml of acetonitrile and then adding 2.22 ml (15.97 mmol) of triethylamine, after which the reaction mixture was stirred for 3 hr. After the completion of the reaction, the same procedures as in Example 1 were conducted. Subsequently, the solvent was completely removed, and the resultant material was crystallized using 10 ml of butylacetate and 80 ml of cyclohexane. The precipitated crystals were filtered and dried, thus yielding 1.83 g (53.0%) of 4-isopropyl-3- methylphenyl (1, 2, 3, 4-tetrazol-l-yl) acetate as a title compound.

IR(KBr, cm^"1) : 1776(C=O), 1492(-CH₂-) GC/MS(m/e) : 260(M⁺), 135 (base peak) RT (min) : 21.7 ¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH (CH₃) ₂) , 2.35 (s, 3H, aromatic-CH₃) , 3.12 (m, IH, -CH(CH₃J₂), 6.83(s, 3H, aromatic H), 8.92 (s, IH, N-CH=N)

<Example 6> Synthesis of 4-isopropyl-3-methylphenyl (2- aminothiazol-4-yl)methoxyiminoacetate

2 g (13.31 mmol) of 4-isopropyl-3-methylphenol and 5.57 g (15.89 mmol) of 2-mercaptobenzenethiazolyl-2- (2- aminothiazol-4-yl) -2-methoxyiminoacetate were added to a solvent mixture of 13.5 ml of methylene chloride and 10.8 ml of methanol, and 2.22 ml (15.97 mmol) of triethylamine were added, and then the reaction mixture was stirred for 8 hr. After the completion of the reaction, the same procedures as in Example 5 were conducted. Subsequenly, the resultant material was crystallized, thus yielding 3.34 g (75.2%) of 4-isopropyl-3-methylphenyl (2- aminothiazol-4-yl) methoxyiminoacetate as a title compound. IR(KBr, cm^"1) : 1739 (C=O) ¹H-NMR (CDCl₃, ppm) : 1.25 (m, 6H, isopropyl CH (CH₃) ₂), 3.49(m, IH, isopropyl CH(CH₃)₂), 3.89(s, 3H, 3-CH₃), 4.10(s, 3H, 0-CH₃), 6.82 (s_f 2H, aromatic 2-H, 6-H) , 6.85 (s, IH, aromatic 5-H) , 7.00 (s, IH, aminothiazole CH) <Example 7> Synthesis of 4-isopropyl-3-methylphenyl phenylacetate

2 g (13.31 mmol) of 4-isopropyl-3-methylphenol were dissolved in 15 ml of acetonitrile, to obtain a solution which was then added in droplets with 2.22 ml (15.97 mmol) of triethylamine and 2.11 ml (15.97 mmol) of phenylacetyl chloride, and the reaction mixture was stirred at room temperature for 5 hr. After the completion of the reaction, the same procedures as in Example 1 were conducted, thus yielding 3.30 g (92.3%) of 4-isopropyl-3-methylphenyl phenylacetate as a title compound. IR(KBr, cm^"1) : 1750(C=O), 1235 (C-O) GC/MS(m/e) : 268(M⁺), 135 (base peak) RT(min) : 20.5

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 2.35 (s, 3H, aromatic-CH₃) , 3.12 (m, IH, -CH (CH₃) ₂), 6.83 (s, 3H, aromatic H), 7.15 (m, 4H, aromatic)

<Example 8> Synthesis of 5-isopropyl-3-methylphenyl phenylacetate

2 g (13.31 mmol) of 5-isopropyl-3-methylphenol were dissolved in 15 ml of acetonitrile, to obtain a solution which was then added in droplets with 2.22 ml (15.97 mmol) of triethylamine and 2.11 ml (15.97 imtiol) of phenylacetyl chloride, and the reaction mixture was stirred at room temperature for 5 hr. After the completion of the reaction, the same procedures as in Example 1 were conducted, thus yielding 3.35 g (93.7%) of 5-isopropyl-3-methylphenyl phenylacetate as a title compound.

IR(KBr, cm^"1) : 1757(-OCO-), 1237 (C-O) GC/MS(m/e) : 268(M⁺), 135 (base peak) RT(min) : 20.5

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 2.35 (s, 3H, aromatic-CH₃) , 3.12 (m, IH, -CH (CH₃) ₂) , 6.83(s, 3H, aromatic H) , 7.15 (m, 4H, aromatic)

<Example 9> Synthesis of 2-isopropyl-5-methγlphenyl 2,6- dimethoxy benzoate

0.5 g (3.32 mmol) of thymol were completely- dissolved in 30 ml of acetonitrile, to obtain a reaction solution, which was then added with 1.1 ml of triethylamine and stirred for 30 min. Subsequently, the reaction temperature was controlled to 0^°C, and 0.88 g (4.38 mmol) of 2, 6-dimethoxybenzoyl chloride were slowly added in droplets at 0^°C or lower. The reaction temperature was increased to room temperature, and the reaction solution was allowed to react for 3 hr. The resultant reaction solution was added with 20 ml of distilled water and 30 ml of methylene chloride and stirred for 20 min, after which the organic layer was separated. The separated organic layer was added with 20 ml of water, and it was washed with water for 30 min.

The separated organic layer was added with 1 g of anhydrous magnesium sulfate (MgSO₄) and then filtered. The filtrate was concentrated under reduced pressure at 50 ^°C or lower and purified using silica gel column chromatography, thus yielding 0.93 g (89.3%) of 2- isopropyl-5-methylphenyl 2, 6-dimethoxy benzoate as a title compound.

IR(KBr, cm^"1) : 1748(C=O), 1257 (C-O) GC/MS(m/e) : 314(M⁺), 91 (base peak) RT (min) : 21.2

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 2.35 (s, 3H, aromatic-CH₃) , 3.12 (m, IH, -CH(CH₃J₂)_/ 3.73 (s, 6H, OCH₃ ), 6.62(m, 3H, aromatic H), 7.15 (m, 3H, aromatic)

<Example 10> Synthesis of 4-isopropylphenyl 3,5- dimethoxybenzoate

0.5 g (3.67 mmol) of 4-isopropylphenol were completely dissolved in 30 ml of acetonitrile, to obtain a reaction solution, which was then added with 1.1 ml of triethylamine and stirred for 30 min. Subsequently, the reaction temperature was controlled to 0^°C, and 0.88 g (4.38 iranol) of 3, 5-dimethoxybenzoyl chloride were slowly added in droplets at 0^°C or lower. The reaction temperature was increased to room temperature, and the reaction solution was allowed to react for 3 hr. The resultant reaction solution was added with 20 ml of distilled water and 30 ml of methylene chloride and stirred for 20 min, after which the organic layer was separated. The separated organic layer was added with 20 ml of water, and it was washed with water for 30 min.

The separated organic layer was added with 1 g of anhydrous magnesium sulfate (MgSCU) and then filtered. The filtrate was concentrated under reduced pressure at 50°C or lower and purified using silica gel column chromatography, thus yielding 0.89 g (89.9%) of A- isopropylphenyl 3, 5-dimethoxy benzoate as a title compound.

IR(KBr, cm^"1) : 1735(C=O), 1255 (C-O) GC/MS(m/e) : 300(M⁺), 135 (base peak) RT(min) : 26.2

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH (CH₃) ₂) , 3.12 (m, IH, -CH (CH₃) ₂), 3.73(s, 6H, OCH₃ ), 7.14 (m, 3H, aromatic H), 7.21 (m, 3H, aromatic)

<Example 11> Synthesis of 2-isopropylphenyl 3,4,5- trimethoxybenzoate

0.5 g (3.67 iranol) of 2-isopropylphenol were completely dissolved in 30 ml of acetonitrile, to obtain a reaction solution, which was then added with 1.1 ml of triethylamine and stirred for 30 min. Subsequently, the reaction temperature was controlled to 0^°C, and 1.01 g

(4.37 mmol) of 3, 4, 5-trimethoxybenzoyl chloride were slowly added in droplets at 0^°C or lower. The reaction temperature was increased to room temperature, and the reaction solution was allowed to react for 3 hr. The resultant reaction solution was added with 20 ml of distilled water and 30 ml of methylene chloride and stirred for 20 min, after which the organic layer was separated. The separated organic layer was added with 20 ml of water, and it was washed with water for 30 min. The separated organic layer was added with 1 g of anhydrous magnesium sulfate (MgSU₄) and then filtered. The filtrate was concentrated under reduced pressure at 50 ^°C or lower and purified using silica gel column chromatography, thus yielding 0.82 g (75.2%) of 2- isopropylphenyl 3, 4, 5-trimethoxy benzoate as a title compound.

IR(KBr, cm^"1) : 1726(C=O), 1249(C-O) GC/MS(m/e) : 300(M⁺), 91 (base peak) RT (min) : 27.3 ¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH (CH₃) ₂) , 3.12 (m_f IH, -CH(CH₃)₂), 3.73(S, 9H, OCH₃ ), 7.10 (m, 2H, aromatic H), 7.18 (m, 4H, aromatic)

<Example 12> Synthesis of 4-isopropyl 3-methylphenyl 3,5- dichloro benzoate

0.5 g (3.32 mmol) of 4-isopropyl 3-methylphenol were completely dissolved in 30 ml of acetonitrile, to obtain a reaction solution, which was then added with 1.1 ml of triethylamine and stirred for 30 min. Subsequently, the reaction temperature was controlled to 0^°C, and 0.83 ml (3.96 mmol) of 3, 5-dichlorobenzoyl chloride were slowly added in droplets at 0^°C or lower. The reaction temperature was increased to room temperature, and the reaction solution was allowed to react for 3 hr. The resultant reaction solution was added with 20 ml of distilled water and 30 ml of methylene chloride and stirred for 20 min, after which the organic layer was separated. The separated organic layer was added with 20 ml of water, and it was washed with water for 30 min.

The separated organic layer was added with 1 g of anhydrous magnesium sulfate (MgSC^) and then filtered. The filtrate was concentrated under reduced pressure at 50 ^°C or lower and purified using silica gel column chromatography, thus yielding 0.87 g (81.3%) of 4- isopropyl 3-methylphenyl 3,5-dichloro benzoate as a title compound.

IR(KBr, cm^"1) : 1745(C=O), 1243 (C-O) GC/MS(m/e) : 323(M⁺), 121 (base peak) RT(min) : 15.2

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH (CH₃) ₂), 2.35 (s, 3H, aromatic-CHs) , 3.12 (m, IH, -CH (CH₃J₂), 3.73(s, 9H, OCH₃ ), β.7(d, 2H, aromatic H) , 7.02 (m, 3H, aromatic)

<Example 13> Synthesis of 4-isopropylphenyl 3,5-dichloro benzoate

0.5 g (3.67 mmol) of 4-isopropylphenol were completely dissolved in 30 ml of acetonitrile, to obtain a reaction solution, which was then added with 1.1 ml of triethylamine and stirred for 30 min. Subsequently, the reaction temperature was controlled to 0^°C, and 0.92 ml (4.39 mmol) of 3, 5-dichlorobenzoyl chloride were slowly added in droplets at 0^°C or lower. The reaction temperature was increased to room temperature, and the reaction solution was allowed to react for 3 hr. The resultant reaction solution was added with 20 ml of distilled water and 30 ml of methylene chloride and stirred for 20 min, after which the organic layer was separated. The separated organic layer was added with 20 ml of water, and it was washed with water for 30 min. The separated organic layer was added with 1 g of anhydrous magnesium sulfate (MgSO₄) and then filtered.

The filtrate was concentrated under reduced pressure at 50^°C or lower and purified using silica gel column chromatography, thus yielding 0.89 g (86.5%) of 4- isopropylphenyl 3,5-dichloro benzoate as a title compound. IR(KBr, cm^"1) : 1744(C=O), 1254 (C-O) GC/MS(m/e) : 310(M⁺), 121 (base peak) RT(min) : 15.2 ¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 3.12 (m, IH, -CH (CH₃) ₂), 3.73(s, 9H, OCH₃ ), 6.7 (d, 2H, aromatic H), 7.02 (m, 3H, aromatic)

<Example 14> Synthesis of 4-isopropyl-3-methylphenyl 2 ,4,5-trifluoro benzoate

0.5 g (3.32 mmol) of 4-isopropyl-3-methylphenol were completely dissolved in 30 ml of acetonitrile, to obtain a reaction solution, which was then added with 1.1 ml of triethylamine and stirred for 30 min. Subsequently, the reaction temperature was controlled to 0^°C, and 0.72 ml (5.65 mmol) of 2, 4, 5-trichlorobenzoyl chloride were slowly added in droplets at 0^°C or lower. The reaction temperature was increased to room temperature, and the reaction solution was allowed to react for 3 hr. The resultant reaction solution was added with 20 ml of distilled water and 30 ml of methylene chloride and stirred for 20 min, after which the organic layer was separated. The separated organic layer was added with 20 ml of water, and it was washed with water for 30 min. The separated organic layer was added with 1 g of anhydrous magnesium sulfate (MgSO₄) and then filtered. The filtrate was concentrated under reduced pressure at 50 ^°C or lower and purified using silica gel column chromatography, thus yielding 0.92 g (90.2%) of 4- isopropyl-3-methylphenyl 2, 4, 5-trifluoro benzoate as a title compound.

IR(KBr, cm^"1) : 1744(C=O), 1254 (C-O) GC/MS(m/e) : 308(M⁺), 159 (base peak) RT (min) : 15.8 ¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 2.35 (s, 3H, aromatic-CH₃) , 3.12 (m, IH, -CH (CH₃) ₂) , 6.94(d, 2H, aromatic H), 7.02 (m, 3H, aromatic)

<Example 15> Synthesis of 2-isopropyl-5-methylphenyl 2,3,6—trifluoro benzoate

0.5 g (3.32 mmol) of thymol were completely dissolved in 30 ml of acetonitrile, to obtain a reaction solution, which was then added with 1.1 ml of triethylamine and stirred for 30 min. Subsequently, the reaction temperature was controlled to 0^°C, and 0.53 ml (3.99 itimol) of 2, 3, 6-trifluorobenzoyl chloride were slowly added in droplets at 0^°C or lower. The reaction temperature was increased to room temperature, and the reaction solution was allowed to react for 3 hr. The resultant reaction solution was added with 20 ml of distilled water and 30 ml of methylene chloride and stirred for 20 min, after which the organic layer was separated. The separated organic layer was added with 20 ml of water, and it was washed with water for 30 min. The separated organic layer was added with 1 g of anhydrous magnesium sulfate (MgSCj) and then filtered. The filtrate was concentrated under reduced pressure at 50 ^°C or lower and purified using silica gel column chromatography, thus yielding 0.86 g (84.3%) of 2- isopropyl-5-methylphenyl 2, 3, 6-trifluoro benzoate as a title compound.

IR(KBr, cm^"1) : 1744(C=O), 1254 (C-O) GC/MS(m/e) : 308(M⁺), 159 (base peak) RT (min) : 15.3 ¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH (CH₃) ₂) , 2.35 (s, 3H, aromatic-CH₃) , 3.12 (m, IH, -CH(CH₃J₂), 6.94 (d, 2H, aromatic H), 7.02 (m, 3H, aromatic)

<Example 16> Synthesis of 5-isopropyl-3-methylphenyl 2 ,3, 6-trifluoro benzoate 0.5 g (3.32 mmol) of 5-isopropyl-3-methylphenol were completely dissolved in 30 ml of acetonitrile, to obtain a reaction solution, which was then added with 1.1 ml of triethylamine and stirred for 30 min. Subsequently, the reaction temperature was controlled to 0^°C, and 0.53 ml (3.99 mmol) of 2, 3, 6-trifluorobenzoyl chloride were slowly added in droplets at 0^°C or lower. The reaction temperature was increased to room temperature, and the reaction solution was allowed to react for 3 hr. The resultant reaction solution was added with 20 ml of distilled water and 30 ml of methylene chloride and stirred for 20 min, after which the organic layer was separated. The separated organic layer was added with 20 ml of water, and it was washed with water for 30 min. The separated organic layer was added with 1 g of anhydrous magnesium sulfate (MgSO₄) and then filtered. The filtrate was concentrated under reduced pressure at 50^°C or lower and purified using silica gel column chromatography, thus yielding 0.91 g (89.2%) of 5- isopropyl-3-methylphenyl 2, 3, 6-trifluoro benzoate as a title compound.

IR(KBr, cm^"1) : 1744(C=O), 1254 (C-O) GC/MS(m/e) : 308(M⁺), 159 (base peak) RT (min) : 15.2 ¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 2.35 (s, 3H, aromatic-CH₃) , 3.12 (m, IH, -CH(CH₃)₂), 6.94(d, 2H, aromatic H), 7.02 (m, 3H, aromatic)

<Example 17> Synthesis of 4-isopropyl-3-methylphenyl 2 , 3 , 6-trifluoro benzoate

*2240.5 g (3.32 πunol) of 4-isopropyl-3-methylphenol were completely dissolved in 30 ml of acetonitrile, to obtain a reaction solution, which was then added with 1.1 ml of triethylamine and stirred for 30 min. Subsequently, the reaction temperature was controlled to 0^°C, and 0.53 ml (3.99 mmol) of 2, 3, 6-trifluorobenzoyl chloride were slowly added in droplets at 0°C or lower. The reaction temperature was increased to room temperature, and the reaction solution was allowed to react for 3 hr. The resultant reaction solution was added with 20 ml of distilled water and 30 ml of methylene chloride and stirred for 20 min, after which the organic layer was separated. The separated organic layer was added with 20 ml of water, and it was washed with water for 30 min.

The separated organic layer was added with 1 g of anhydrous magnesium sulfate (MgSO₄) and then filtered. The filtrate was concentrated under reduced pressure at 50 ^°C or lower and purified using silica gel column chromatography, thus yielding 0.87 g (85.3%) of 4- isopropyl-3-methylphenyl 2, 3, 6-trifluoro benzoate as a title compound.

IR(KBr, cm^"1) : 1744(C=O), 1254 (C-O) GC/MS(m/e) : 308(M⁺), 159 (base peak) RT(min) : 16.1

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 2.35 (s, 3H, aromatIc-CH₃) , 3.12 (m, IH, -CH (CH₃) 2)/ 6.94(d, 2H, aromatic H), 7.02 (m, 3H, aromatic)

b) Synthesis of Sulfonyl Ester Derivative

<Example 18> Synthesis of 2-isopropylphenyl 4- methoxybenzenesulfonate

1.87 g (83.26%) of 2-isopropylphenyl 4- methoxybenzenesulfonate as a title compound were prepared in the same manner as in Example 1, with the exception that 1 g (7.34 mmol) of 2-isopropylphenol and 1.82 g (8.81 mmol) of 4-methoxybenzenesulfonyl chloride were used. IR(KBr, cm^"1) : 1377, 1190(O=S=O) GC/MS(m/e) : 306(M⁺), 291, 171 (base peak) RT(min) : 21.7

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 3.12 (m, IH, -CH(CH₃)₂), 3.73(s, 3H, -OCH₃), 6.94(d, 2H, aromatic H), 7.02 (in, 3H, aromatic) c) Synthesis of Carbamate Derivative

<Example 19> Synthesis of 4-isopropyl-3-methylphenyl N- (4-ethyl-2 , 3-dioxo-l-piperazine) carbamate

2 g (13.31 mmol) of 4-isopropyl-3-methylphenol were dissolved in 15 ml of acetonitrile, to obtain a reaction solution, which was then added with 2.22 ml of triethylamine and 3.02 g (14.75 mmol) of 4-ethyl-2,3- dioxo-1-piperazinecarbonyl chloride and stirred at room temperature for 4 hr. After the completion of the reaction, the same procedures as in Example 1 were conducted, thus yielding 3.90 g (92.0%) of 4-isopropyl-3- methylphenyl N- (4-ethyl-2, 3-dioxo-l-piperazine) carbamate as a title compound. IR(KBr, cm^"1) : 1783(C=O), 1675 (C=O) ¹H-NMR (CDCl₃, ppm) : 1.19(m, 9H, isopropyl CH (CH₃) ₂, N- CH₂CH₃), 2.31 (s, 3H, 3-CH₃), 3.10 (m, IH, isopropyl CH(CH₃J₂), 3.60(m, 4H, piperazine ring CH₂CH₂), 4.12 (m, 2H, N-CH₂CH₃), 6.95(s, 2H, aromatic 2-H, 6-H) , 7.21 (s, IH, aromatic 5-H)

d) Synthesis of Ether Derivatives

<Example 20> Synthesis of 4-isopropyl-3- methylphenylbenzyl ether

2 g (13.31 mmol) of 4-isopropyl-3-methylphenol were completely dissolved in a solvent mixture of 5 ml of dimethylsulfoxide and 5 ml of tetrahydrofuran. The resultant reaction solution was added with 1.89 ml (15.91 mmol) of benzyl bromide and 0.89 g (15.86 mmol) of KOH, and then stirred at room temperature for 2 hr. After the completion of the reaction, the same procedures as in Example 1 were conducted, thus yielding 3.03 g (94.7%) of 4-isopropyl-3-methylphenylbenzyl ether as a title compound. IR(KBr, cm^"1) : 1456(-CH₂-), 1249, 1151 (C-O) GC/MS(m/e) : 240(M⁺), 91 (base peak) RT(min) : 17.6

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH (CH₃) ₂), 2.35 (s, 3H, aromatic-CH₃) , 3.12 (m, IH, -CH(CH₃J₂), 6.7 (m, 3H, aromatic H), 7.19(m, 5H, aromatic)

<Example 21> Synthesis of 4-isopropyl-3-methylphenylaryl ether

2 g (13.31 mmol) of 4-isopropyl-3-methylphenol were completely dissolved in a solvent mixture of 5 ml of dimethylsulfoxide and 5 ml of tetrahydrofuran. The resultant reaction solution was added with 1.38 ml (15.97 mmol) of aryl bromide and 0.89 g (15.86 mmol) of KOH, and then stirred at room temperature for 2 hr. After the completion of the reaction, the same procedures as in Example 1 were conducted, thus yielding 2.32 g (91.6%) of 4-isopropyl-3-methylphenylaryl ether as a title compound. IR(KBr, cm^"1) : 1291, 1159 (C-O) GC/MS(m/e) : 190(M⁺), 175 (base peak) RT(min) : 11.5 ¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 2.35 (s, 3H, aromatIc-CH₃) , 3.12 (m, IH, -CH (CH₃) 2), 4.61(d, 2H, 0-CH₂-), 5.24 (s, 6H, =C-CH₃ ), 6.54 (mlH, =CH-) , 6.7 (m, 2H, aromatic H)

<Example 22> Synthesis of methyl (4-isopropyl-3- methylphenoxy) acetate

2 g (13.31 ramol) of 4-isopropyl-3-methylphenol were completely dissolved in a solvent mixture of 5 ml of dimethylsulfoxide and 5 ml of tetrahydrofuran. The resultant reaction solution was added with 1.51 ml (15.97 ramol) of methyl bromoacetate and 0.89 g (15.86 mmol) of KOH, and then stirred at room temperature for 2 hr. After the completion of the reaction, the same procedures as in Example 1 were conducted, thus yielding 2.50 g (84.4%) of methyl (4-isopropyl-3-methylphenoxy) acetate as a title compound.

IR(KBr, cm^"1) : 1205,1168(C-O), 1730 (C=O) GC/MS(m/e) : 222(M⁺), 207 (base peak) RT(min) : 15.0 ¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 2.35 (s, 3H, aromatJ-C-CH₃) , 3.12 (m, IH, -CH (CH₃J₂), 3.67(s, 3H, -OCH₃), 4.49(d, 2H, o-CH₂-) , 6.62(m, 2H, aromatic H)

<Example 23> Synthesis of 5-isopropyl-3- methylphenylbenzyl ether

2 g (13.31 mmol) of 5-isopropyl-3-methylphenol were completely dissolved in a solvent mixture of 5 ml of dimethylsulfoxide and 5 ml of tetrahydrofuran. The resultant reaction solution was added with 1.89 ml (15.91 mmol) of benzyl bromide and 0.89 g (15.86 mmol) of KOH, and then stirred at room temperature for 2 hr. After the completion of the reaction, the same procedures as in Example 1 were conducted, thus yielding 3.10 g (96.9%) of 5-isopropyl-3-methylphenylbenzyl ether as a title compound.

IR(KBr, cm^"1) : 1455(-CH₂-), 1291, 1164 (C=C-O-)

GC/MS(m/e) : 206(M⁺), 135 (base peak)

RT(min) : 17.6

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 2.35 (s, 3H, aromatic-CH₃) , 3.12 (m, IH, -CH(CH₃J₂), 6.7 (m, 3H, aromatic H), 7.19(m, 5H, aromatic)

<Example 24> Synthesis of methyl (5-isopropyl-3- methylphenoxy) acetate 2 g (13.31 mmol) of 5-isopropyl-3-methylphenol were completely dissolved in a solvent mixture of 5 ml of dimethylsulfoxide and 5 ml of tetrahydrofuran. The resultant reaction solution was added with 1.51 ml (15.97 itimol) of methyl bromoacetate and 0.89 g (15.86 mmol) of KOH, and then stirred at room temperature for 2 hr.

After the completion of the reaction, the same procedures as in Example 1 were conducted, thus yielding 2.52 g (85.1%) of methyl (5-isopropyl-3- methylphenoxy) acetate as a title compound. IR(KBr, cm^"1) : 1231, 1160 (C=C-O-)

GC/MS(m/e) : 222(M⁺), 207 (base peak)

*277RT(min) : 15.0

¹H-NMR (CDCl₃, ppm) : 1.29 (m, 6H, isopropyl CH(CH₃)₂), 2.35 (s, 3H, aromatic-CH₃) , 3.12(m, IH, -CH(CH₃J₂), 3.67 (s, 3H, -OCH₃), 4.49 (d, 2H, 0-CH₂-), 6.62(m, 2H, aromatic H)

Experimental Example 1> Physiological Activity Test of Alkylphenol Derivatives on Phytopathogenic Fungi Step 1: Subculture of Phytopathogenic Fungi

As phytopathogenic fungi, Phytophthora infestans, Pyrcularia grisea, Alternaria alternata f. sp. mali, Colletotrichum orbiculare, Rhizoctonia solini, Colletotrichum gloeasporioid.es, Botrytis cinerea and Phytophthora capsici were subcultured on PDA solid media. Step 2: Measurement of Fungal Growth Diameter of Phytopathogenic Fungi

To measure physiological activities on phytopathogenic fungi, each sample was preapred as follows .

A control sample was composed of only 0.1 ml of DMSO, whereas each derivative sample was prepared by dissolving 0.1 g of each derivative in 0.9 ml of DMSO. A commercial chemical sample of Alternaria alternata f. sp. mali was prepared by dissolving 1 g of Polyoxin wettable powder (WP) (Polyoxin B purity 10%) in 0.9 ml of distilled water. As the other commercial chemicals, Panmasi WP (Thiabendazole 60%) and Forum WP (Dimethomorph 25%) were available from Dongbang Agro Corp., Korea, while Antha emulsion (Etridiazole 25%), Antracol

(Propineb 70%), Monceren (Pency-curon 25%), Euparen

(Dichlofluanid 50%), and Bim WP (Tricyclazole 75%) were available from Dongbu Hannong Chemical Co. Ltd., Korea, each of which was diluted corresponding to its purity to prepare a 10000 ppm sample.

For the preparation of a PDA solid medium, 3.9 g of PDA were dissolved in 100 ml of distilled water and then sterilized at 121^"C and 1.5 atm for 15 min using a high- temperature sterilizer. Thereafter, the temperature of the medium was decreased to 60 ^°C , after which 10 μJL of each sample prepared as above were supplemented into the medium and then uniformly aliquotted into petri dishes, to prepare a control medium, derivative media, and commercial chemical media. The spherical cores of subcultured phytopathogenic fungi were inoculated into each prepared medium, and thereafter, cultured under darkroom conditions of 20~25^°C and 70% humidity for 4 days, to measure a fungal lesion size. All experiments were conducted three times or more. The results are given in Table 1 below.

[Table l]

Measurement of Phytopathogenic Fungal Growth Diameter in Alkylphenol Derivatives of the Present Invention

As a result of directly applying the alkylphenol derivatives of the present invention on test crops to test resistance to the above phytopathogenic fungi, these derivatives were confirmed to exhibit excellent inhibitory effects on the growth of the above phytopathogenic fungi. Particularly, FIG. 1 is a photograph showing the inhibitory activities of 2- isopropylphenyl piperonyloylate of Example 4 on the growth of Phytophthora infestans, in which A shows the untreated control, B shows the result treated using the commercial chemical, C shows the result treated using the derivative of Example 4, and D shows the result treated using 2-isopropylphenol. As shown in FIG. 1 and Table 1, the fungal growth diameter was 52 mm upon treatment using the commercial chemical, whereas it was 25 mm upon treatment using the derivative of Example 4.

Thereby, the derivative of the present invention was confirmed to exhibit excellent growth inhibitory activities.

FIG. 2 is a photograph showing the inhibitory activities of 2-isopropylphenyl piperonyloylate of Example 6 on the growth of Pyrcularia grisea, in which A shows the untreated control, B shows the result treated using the commercial chemical, C shows the result treated using 4-isopropyl-3-methylphenol, and D shows the result treated using the derivative of Example 6. As is apparent from FIG. 2, the derivative of Example 6 was confirmed to exhibit stronger growth inhibitory activities than the commercial chemical.

FIG. 3 is a photograph showing the physiological activities on Alternaria alternata f. sp. mail, in which A shows the untreated control, B shows the result treated using the derivative of Example 8, C shows the result treated using the commercial chemical, and D shows the result treated using 5-isopropyl-3-methylphenol. From these results, the alkylphenol derivatives of the present invention were confirmed to exhibit excellent growth inhibitory activities. FIG. 4 is a photograph showing the physiological activities of the alkylphenol derivatives of the present invention on Colletotrichum orbiculare, in which A shows the untreated control, B shows the result treated using isopropylphenol, C shows the result treated using 2- isopropyl 4-methoxybenzene sulfonate of Example 18, and D shows the result treated using the commercial chemical.

As shown in FIG. 1 and Table 1, the fungal growth diameter was 40 mm upon treatment using the commercial chemical, whereas it was 34 mm upon treatment using the derivative of Example 4. Thereby, the derivatives of the present invention were confirmed to exhibit excellent growth inhibitory activities.

Step 3: Disinfecting Effects on Phytopathogenic Fungi The disinfecting effects of the alkylphenol derivatives of the present invention on Colletotrichum orbiculare were assayed as follows.

For assaying the effects on Colletotrichum orbiculare, as disinfected cucumber seeds (Baecdadaki) , one cucumber seed was implanted in a plastic pot having soil using bedding soil available from Dongbu Hannong Chemical Co. Ltd., Korea. Water was added two times, in the morning and the afternoon, and the cucumber crop was grown in a glasshouse at 27 ^°C and 80% humidity for 2 weeks. As the crop, cucumber seedings, having 2~3 uniformly grown true leaves and an average size of about 10 cm, were used.

To culture the strains, the strains were inoculated in the PDA medium, and then cultured using a thermostat in the dark at 25^°C for 7 days, and then for a further 6 days while light was radiated for 12 hr each, thus forming spores. The sample of each of the commercial chemical (Dithianon) and the derivative was prepared in such a manner that 0.01 g of each material, 4 ml of acetone and 1 ml of polypropyleneglycol were loaded into an erlenmeyer flask, and then 95 ml of a 250 ppm twin-20 solution were added to realize 100 ml total volume. As such, the concentration of each of the chemical and the derivative was 100 ppm. 30 ml of each of the commercial chemical and the sample were uniformly sprayed on the front and rear surfaces of the leaf using a sprayer. In addition, for inoculation of pathogens, the spores formed in the medium were collected by being added with 10 ml of sterile distilled water and then scraped three times using a brush. Subsequently, the collected spores were made to have a concentration of 2 x 10³ spores/ml using a hematocytometer of an optical microscope, loaded into a sprayer, and were then sufficiently sprayed onto young cucumber plants in an amount of 30 ml. For the induction of disease, the spores were cultured in an incubator at 25°C and 95% humidity for 48 hr after inoculation, after which disease was induced in a constant temperature and humidity room under conditions of 25^°C and 85% humidity for 5 days . The control results of the commercial chemicals and the test groups treated using the alkylphenol derivatives of the present invention are given in Table 2 below.

[Table 2] Control Effects of Alkylphenol Derivatives of the Present Invention on Colletotrichum orbiculare

As is apparent from Table 2, the alkylphenol derivatives of the present invention were confirmed to exhibit control effects equal or superior to presently available commercial chemicals, thus manifesting antibiotic activities equal to commercial chemicals.

Step 4: Disinfecting Effects on Phytopathogenic Fungi

To assay the disinfecting control effects of the alkylphenol derivatives of the present invention on

Phytophthora capsici, the following test was conducted.

The present step was carried out in the same manner as in

Step 3, with the exception of using a commercial chemical

(Dimethomorph) on Phytophthora capsici. Subsequently, the control effects of the commercial chemical and the test groups treated using the alkylphenol derivatives of the present invention were measured.

As a result, of the alkylphenol derivatives of the present invention, 2-isopropyl-5-methylphenyl 2,6- dimethoxy benzoate of Example 9 or 2-isopropylphenyl

3, 4, 5-trimethoxybenzoate of Example 11 were confirmed to have 90% control effects, thus exhibiting antibiotic activities equal to commercial chemicals.

As is apparent from the physiological activity experiments of the alkylphenol derivatives of the present invention on phytopathogenic fungi, the alkylphenol derivatives of the present invention may exhibit inhibitory activities on the growth of phytopathogenic fungi equal or superior to conventional disinfecting agents, and therefore, may be used as environmentally friendly disinfecting agents substitutable for conventional pesticides.

[industrial Applicability]

As described hereinbefore, the present invention provides an alkylphenol derivative having inhibitory activities on the growth of phytopathogenic fungi. The alkylphenol derivative of the present invention, which has a structure similar to thymol or carvacrol, derived from thyme oil, is confirmed to exhibit excellent inhibitory activities on the growth of phytopathogenic fungi, and is thus provided as a precursor for environemntally friendly disinfecting agents. In particular, the alkylphenol derivatives of the present invention may be provided as growth inhibitors having inhibitory activities on the growth of Phytophthora infestans, Pyrcularia grisea, Alternaria alternata f. sp. mali, Colletotrichum orbiculare, Rhizoctonia solini, Colletotrichum. gloeasporioid.es, and Phytophthora capsici. Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

Claims

[CLAIMS]

[Claim l]

An alkylphenol derivative having inhibitory activities on the growth of phytopathogenic fungi, which is represented by Formula 1 below: Formula 1

(wherein Ri is any one selected from the group consisting of H, a Ci~C6 aliphatic hydrocarbon including a linear or branched alkyl group or haloalkyl group, a Ci~C6 aliphatic hydrocarbon, an aromatic hydrocarbon or a heterocyclic compound including at least one element selected from the group consisting of N, 0, P and S, and preferably includes

in which Z is any one selected from the group consisting of a Ci~C6 linear or branched alkyl group or haloalkyl group, an aryl group, and a substituted aryl group, in which the substituted aryl group is 1 to 3 substituted aryl groups with any one substituent selected from the group consisting of a halogen atom, a nitro group, a Cχ~C₆ alkyl group, a Cχ~C₆ alkoxy group, and a Ci~C6 haloalkyl group, and R₂ is H or CH₃.) .

[Claim 2] The alkylphenol derivative according to claim 1, wherein the alkylphenol derivative is 4-isopropylphenol or 2-isopropylphenol, in which Ri and R₂ are H, or 4- isopropyl-3-methylphenol or 5-isopropyl-3-methylphenol, in which Ri is H and R₂ is CH₃.

[Claim 3]

The alkylphenol derivative according to claim 1, wherein the Ri of the alkylphenol derivative is substituted with any one functional group selected from the group consisting of an ester group, a sulfonyl ester group, a carbamate group, and an ether group.

[Claim 4]

The alkylphenol derivative according to claim 1, wherein the alkylphenol derivative is any one selected from the group consisting of:

1) 4-isopropylphenyl 2, 2-dimethylpropionate,

2) 4-isopropylphenyl piperonyloylate,

*3323) 2-isopropylphenyl bromoacetate, 4) 2-isopropylphenyl piperonyloylate,

5) 4-isopropyl-3-methylphenyl (1, 2, 3, 4-tetrazol-l- yl) acetate,

6) 4-isopropyl-3-methylphenyl (2-aminothiazol-4-yl)methoxyiminoacetate,

7) 4-isopropyl-3-methylphenyl phenylacetate,

8) 5-isopropyl-3-methylphenyl phenylacetate,

9) 2-isopropyl-5-methylphenyl 2, 6-diinethoxy benzoate,

12) 4-isopropyl 3-methylphenyl 3,5-dichloro benzoate,

13) 4-isopropylphenyl 3,5-dichloro benzoate,

14) 4-isopropyl-3-methylphenyl 2, 4, 5-trifluoro benzoate,

15) 2-isopropyl-5-methylphenyl 2, 3, β-trifluoro benzoate, 16) 5-isopropyl-3-methylphenyl 2, 3, 6-trifluoro benzoate,

17) 4-isopropyl-3-methylphenyl 2, 3, 6-trifluoro benzoate,

18) 2-isopropyl 4-methoxybenzenesulfonate,

19) 4-isopropyl-3-methylphenyl

N- (4-ethyl-2, 3-dioxo-l-piperazine) carbamate, 20) 4-isopropyl-3-methylphenylbenzyl ether,

21) 4-isopropyl-3-methylphenylaryl ether,

22) methyl (4-isopropyl-3-methylphenoxy) acetate,

23) 5-isopropyl-3-methylphenylbenzyl ether, and

24) methyl (5-isopropyl-3-methylphenoxy) acetate . [Claim 5]

A method of preparing an alkylphenol derivative, comprising: dissolving a thymol or carbacrol derivative derived from thyme oil, represented by Formula 1, in an acetonitrile solvent or a solvent mixture of methanol and water, and then adding triethylamine, to prepare a basic solution; adding the basic solution with a compound having any one functional group selected from the group consisting of an ester group, a sulfonyl ester group, a carbamate group, an ether group, and a phosphoyl group at 0~25°C to conduct a substitution reaction for 2~10 hr; and extracting the reacted solution to separate an organic layer, which is then dried.

[Claim 6]

A disinfecting agent, inhibitory of the growth of Phytophthora infestans, containing any one selected from the group consisting of 4-isopropylphenyl piperonyloylate, 2-isopropylphenyl piperonyloylate, methyl (4-isopropyl-3- methylphenoxy) acetate, and methyl (5-isopropyl-3- methylphenoxy) acetate, among the alkylphenol derivatives of claim 4.

[Claim 7] A disinfecting agent, inhibitory of the growth of

Pyrcularia grisea, containing 4-isopropyl-3-methylphenyl

(1, 2, 3, 4-tetrazol-l-yl) acetate or 4-isopropyl-3- methylphenyl (2-aminothiazol-4-yl)methoxyiminoacetate, among the alkylphenol derivatives of claim 4.

[Claim 8]

A disinfecting agent, inhibitory of the growth of Alternaria alternata f. sp. mali, containing any one selected from the group consisting of 4-isopropylphenol, 4-isopropyl-3-methylphenyl phenylacetate, 5-isopropyl-3- methylphenyl phenylacetate, and 4-isopropyl-3- methylphenyl N- (4-ethyl-2, 3-dioxo-l-piperazine) carbamate, among the alkylphenyl derivatives of claim 4.

[Claim 9]

A disinfecting agent, inhibitory of the growth of

Colletotrichum orbiculare, containing any one selected from the group consisting of 4-isopropylphenyl 3,5- dimethoxybenzoate, 4-isopropyl 3-methylphenyl 3,5- dichloro benzoate, 4-isopropylphenyl 3,5-dichloro benzoate, 4-isopropyl-3-methylphenyl 2, 4, 5-trifluoro benzoate, 2-isopropyl-5-methylphenyl 2, 3, 6-trifluoro benzoate, 5-isopropyl-3-methylphenyl 2, 3, 6-trifluoro benzoate, 4-isopropyl-3-methylphenyl 2, 3, 6-trifluoro benzoate, and 2-isopropyl 4-methoxybenzenesulfonate, among the alkylphenol derivatives of claim 4.

[Claim 10] A disinfecting agent, inhibitory of the growth of Rhizoctonia solini, containing 2-isopropylphenyl bromoacetate, among the alkylphenol derivatives of claim 4.

[Claim 11]

A disinfecting agent, inhibitory of the growth of Colletotrichum gloeasporioides, containing any one selected from the group consisting of 4-isopropylphenol, 4-isopropylphenyl 2, 2-dimethylpropionate, and 4- isopropyl-3-methylphenyl (2-aminothiazol-4- yl)methoxyiminoacetate, among the alkylphenol derivatives of claim 4.

[Claim 12] A disinfecting agent, inhibitory of the growth of Phytophthora capsici, containing 2-isopropyl-5- methylphenyl 2, 6-dimethoxy benzoate or 2-isopropylphenyl 3, 4, 5-trimethoxybenzoate, among the alkylphenol derivatives of claim 4.