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    • 专利摘要:
    PURPOSE: Provided is 2-aryl-2-methyl-2,3-dihydrobenzofuran with antioxidant activity which is useful for the prevention and treatment of various diseases associated with active oxygen species. CONSTITUTION: The 2-aryl-2-methyl-2,3-dihydrobenzofuran with antioxidant activity represented by formula(1) and its pharmaceutically acceptable salts are provided, wherein R' is hydrogen, acetyl, or t-butyldimethylsilyl; R is NO2, NH2, COOR1, CONR2R3 or NHC(Z)R4; R1 is hydrogen, C1 to C8 alkyl, C3 to C10 alkenyl, C3 to C6 cycloalkyl, phenyl or pyrimidine; R2 and R3 are independently C1 to C8 alkyl, phenyl, or pyridine; R4 is C1 to C8 alkyl, C3 to C10 alkenyl, phenyl, pyridine, C1 to C6 alkylamine, aniline, or aminopyridine; and Z is oxygen or sulfur. Its preparing method comprises the steps of: alkylation of a compound of formula(2) with a compound of formula(3) to form a compound of formula(4); Claisen reaction of the compound of formula(4) to form a compound of formula(5); and cyclization of the compound of formula(5) to prepare a compound of formula(1).
    公开号:KR20020076826A
    申请号:KR1020010016968
    申请日:2001-03-30
    公开日:2002-10-11
    发明作者:박노상；임희종；정영식；성철민；박준호；공재양
    申请人:한국화학연구원；
    IPC主号:
    专利说明:

    2-aryl-2-methyl-2,3-dihydrobenzofuran compound having antioxidant activity {2-Aryl-2-methyl-2,3-dihydrobenzofuranes as antioxidants}
    [1] The present invention relates to a 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by the following formula (1) having an antioxidant activity and a pharmaceutically acceptable salt thereof.
    [2]
    [3] In Formula 1 above:
    [4] R 'represents a hydrogen atom, an acetyl group or a t-butyldimethylsilyl group; R represents NO 2 , NH 2 , COOR 1 , CONR 2 R 3 , or NHC (Z) R 4 ; R 1 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, or a pyridine group; R 2 and R 3 each represent an alkyl group having 1 to 8 carbon atoms, a phenyl group, or a pyridine group; R 4 represents an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 10 carbon atoms, a phenyl group, a pyridine group, an alkylamine group having 1 to 6 carbon atoms, an aniline group, or an aminopyridine group; Z represents an oxygen atom or a sulfur atom.
    [5] Oxygen oxidizes the nutrients in the mitochondria in the cells involved in the generation of ATP, but the oxygen of 2-5% of which are O 2 - changes to harmful free radicals in the human body, such as -, H 2 O 2, OH . The free radicals naturally occurring in the energy generation process in vivo are eliminated by antioxidants such as in vivo antioxidant enzymes such as superoxide dismutase (SOD), catalase, peroxidase, or glutathione. In addition, free radicals are also eliminated through the food by antioxidants such as vitamin C or vitamin E. However, in certain circumstances, such as stroke, brain and spinal cord injury, if the capacity of the active oxygen defense system in excess is exceeded due to excessive production of free radicals, free radicals are the major constituents of living cells, such as lipids, proteins, and hexane (DNA, RNA). And carbohydrates, impairing their function, leading to disease and aging. In particular, it is known to cause diseases such as cancer, arteriosclerosis, diabetes, stroke, dementia, Parkinson's disease, and aging by attacking lipids, which are the main components of cell membranes, to produce cytotoxic lipid peroxide or destroying cell membranes. Therefore, sulfates that eliminate or inhibit free radicals produced by metabolic processes in the human body can be used as anticancer agents and anti-aging agents, as well as therapeutic agents for neurodegenerative diseases such as stroke, dementia, Parkinson's disease, and diabetes epilepsy. Can be used as
    [6] Recently, it has been reported that benzofuran has a structurally superior ability to eliminate radicals than vitamin B's benzopyrans [Ingold, KU FEBS Lett . 1990 , 267 , 63] There has been a great deal of research on benzofuran compounds as new antioxidants [Marion Merrell Dow Research Institute, France, J. Med. Chem. 1995 , 38 , 453; Takeda Chemical Industries, Japan, US Pat. No. 5,376,681; Biomedica Foscama Industria Chimico-Farmaceutica Spa, Italy, Drugs of Fut . 1999 , 24 , 735. Meanwhile, U-83839, a compound that combines piperazine with benzopyrane of vitamin E, developed by UpJohn, Inc., is a steroid derivative developed by the same company. The antioxidant effect has been reported to be superior to tirilazar mesylate.
    [7] The present inventors have tried to develop a novel benzofuran compound having an antioxidant effect better than the existing vitamin E. As a result, the 2-aryl-2-methyl-2,3-dihydrobenzofuran compound having an aryl group introduced into the benzofuran ring The present invention was completed by confirming that the antioxidant activity of the compound was superior.
    [8] It is therefore an object of the present invention to provide novel 2-aryl-2-methyl-2,3-dihydrobenzofuran compounds having antioxidant activity and pharmaceutically acceptable salts thereof.
    [9] Another object of the present invention is to contain the above-mentioned novel compound or a pharmaceutically acceptable salt thereof as an active ingredient to be used as an anti-aging agent and cancer, diabetes, epilepsy treatment and neurodegenerative diseases such as stroke, dementia, Parkinson's disease To provide a pharmaceutical composition that can be.
    [10] The present invention relates to a 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by the following formula (1) having an antioxidant activity and a pharmaceutically acceptable salt thereof.
    [11] Formula 1
    [12]
    [13] In Formula 1 above:
    [14] R 'represents a hydrogen atom, an acetyl group or a t-butyldimethylsilyl group; R represents NO 2 , NH 2 , COOR 1 , CONR 2 R 3 , or NHC (Z) R 4 ; R 1 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, or a pyridine group; R 2 and R 3 each represent an alkyl group having 1 to 8 carbon atoms, a phenyl group, or a pyridine group; R 4 represents an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 10 carbon atoms, a phenyl group, a pyridine group, an alkylamine group having 1 to 6 carbon atoms, an aniline group, or an aminopyridine group; Z represents an oxygen atom or a sulfur atom.
    [15] More specifically illustrating the 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by Formula 1 according to the present invention is as follows:
    [16] Methyl 3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [17] Methyl 3- (5-acetoxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [18] Ethyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [19] Ethyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [20] 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoic acid;
    [21] Butyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [22] Octyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [23] Geranyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [24] Cyclohexyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [25] Phenyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [26] Butyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [27] Octyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [28] Geranyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [29] Cyclohexyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [30] Phenyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [31] Ethyl 4- (5-acetoxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    [32] N1-propyl-4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzamide;
    [33] N1-phenyl-4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzamide;
    [34] 2- [4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenylcarboxamido] pyridine;
    [35] N1-phenyl-4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzamide;
    [36] 2,4,6,7-tetramethyl-2- (3-nitrophenyl) -2,3-dihydrobenzo [b] furan-5-ol;
    [37] 2,4,6,7-tetramethyl-2- (4-nitrophenyl) -2,3-dihydrobenzo [b] furan-5-ol;
    [38] 2- (3-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol;
    [39] 2- (4-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol;
    [40] N1- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] butanamide;
    [41] N1- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] octanamide;
    [42] N1- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] decanamide;
    [43] N1- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] butanamide;
    [44] N1- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] octanamide;
    [45] 3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) -1-phenylcarboxamidobenzene;
    [46] N2- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] -2-pyridinecarboxamide;
    [47] N2- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] -2-pyridinecarboxamide;
    [48] Anilino- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] methaneamide;
    [49] Anilino- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] methaneamide;
    [50] Anilino- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) anilino methanechione;
    [51] In addition, the 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by Chemical Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. . For example, salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid or formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gesty acid, fumaric acid, lactobionic acid, Forming salts of pharmaceutically acceptable salts of these acids with organic acids such as salicylic acid or acetylsalicylic acid (aspirin), or reacting with alkali metal ions such as sodium or potassium to form their metal salts, Or may be reacted with ammonium ions to form another form of a pharmaceutically acceptable salt.
    [52] In addition, 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by Chemical Formula 1 and pharmaceutically acceptable salts thereof according to the present invention may exhibit polymorphism crystals.
    [53] Meanwhile, the method of preparing the 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by Chemical Formula 1 and a pharmaceutically acceptable salt thereof according to the present invention will be described in the following Scheme 1.
    [54]
    [55] In Scheme 1: R 'and R are as defined in Formula 1, respectively.
    [56] The preparation method as shown in Scheme 1 includes three steps as follows: (i) converting the compound represented by Chemical Formula 2 into a compound represented by Chemical Formula 4 by alkylation reaction; (ii) preparing a compound represented by Chemical Formula 5 by claisen reaction of the compound represented by Chemical Formula 4; And (iii) preparing a compound represented by Chemical Formula 1 by cyclizing the compound represented by Chemical Formula 5.
    [57] The first process according to Scheme 1 is a reaction for converting the compound represented by Chemical Formula 2 and the compound represented by Chemical Formula 3 into a compound represented by Chemical Formula 4. This reaction is a kind of alkylation reaction, in which a compound represented by Chemical Formula 2 is made of sodium hydride in a N, N- dimethylformamide (DMF) solvent, and then reacted with a methanesulfonic acid ester compound represented by Chemical Formula 3.
    [58] In the second process, a compound represented by Chemical Formula 5 is obtained by subjecting the compound represented by Chemical Formula 4 to a chrysene reaction using a catalyst such as BCl 3 .
    [59] In the third process, the compound represented by Chemical Formula 5 is reacted with concentrated sulfuric acid in an ethyl alcohol solvent to thereby react 2-aryl-2-methyl-2,3-dihydrobenzofuran represented by Chemical Formula 1 according to the present invention. It is the process of obtaining a compound. As a result of the above cyclization reaction, a compound represented by Formula 1 wherein R 'is a hydrogen atom is obtained, and another derivative in which R' is an acetyl group or a t-butyldimethylsilyl group can be synthesized by a conventional method. . For example, a phenolic compound of which R 'is a hydrogen atom is reacted with acetic acid chloride to obtain an acetyl ester compound, or a t-butyldimethylsilyl trifluoromethanesulfonic acid ester (TBSOTf) to react with a t-butyldimethylsilyl ether compound Get
    [60] Meanwhile, the compounds represented by Formula 4 and Formula 5 synthesized as intermediates during the preparation process according to Scheme 1 are novel compounds, and the present invention is 2-aryl-2-methyl-2 represented by Formula 1, It includes a novel intermediate compound represented by the formula (4) and formula (5) useful for preparing 3-dihydrobenzofuran.
    [61] In addition, the compound represented by the formula (2) used in the preparation method according to Scheme 1 can be prepared by using a known method from trimethylhydroquinone [Tomkuljak D .; Baranek B .; Manduch M., Chem. Abstr. 1981 , 95 , 150164; Snuparek V .; Polak J .; Varga I .; Kmetty G., Chem. Abstr. 1988 , 109 , 22642.
    [62] In addition, as a compound used in the preparation method according to Scheme 1, the compound represented by the formula (3) can be prepared and used by the preparation method as shown in the following scheme 2.
    [63]
    [64] In Scheme 2: R is as defined in Chemical Formula 1, and OTf represents a trifluoromethylsulfonyloxy group.
    [65] According to the preparation method according to Scheme 2, the phenol derivative represented by Chemical Formula 6 is reacted with trifluoromethanesulfonic anhydride in a pyridine solvent to obtain a trifluoromethylsulfonyloxybenzene derivative represented by Chemical Formula 7, and Using a known method, a Heck reaction is carried out using a allyl alcohol and palladium as a catalyst in a DMF solvent to obtain a compound represented by Chemical Formula 8 [Cabri W .; Candiani I .; Bedeshi A., J. Org. Chem. 1992 , 57 , 3558]. In addition, the methanesulfonic acid ester compound represented by Chemical Formula 3 may be obtained by reacting the compound represented by Chemical Formula 8 with methanesulfonic acid chloride in a dichloromethane solvent.
    [66] In addition, in the 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by the general formula (1) of the present invention, the substituents R 'and R can be converted to each other.
    [67] For example, as shown in Scheme 3, in the case of a compound in which R is NO 2 , it may be converted to a compound in which R is NH 2 or NHCXR 4 .
    [68]
    [69] In Scheme 3: R 4 is as defined in Chemical Formula 1.
    [70] According to the preparation method according to Scheme 3, the nitro compound represented by Formula 1a is reduced to obtain an amine compound represented by Formula 1b, and the amine compound represented by Formula 1b, carboxylic acid, and carboxylic acid chloride using a known method. By reacting an alkyl isocyanate, an aryl isocyanate, an alkyl isothiocyanate or an aryl isothiocyanate, a corresponding compound represented by Chemical Formula 1c may be prepared.
    [71] As another derivative of the compound represented by Formula 1, which is an object of the present invention, the substituent R ′ is a hydrogen atom, an acetyl group, a t-butyldimethylsilyl group (t-Butyldimethylsilyl); and a compound wherein R is COOR 2 is represented by the following scheme Can switch each other based on 4.
    [72]
    [73] In Scheme 4: R 5 represents a methyl group or an ethyl group; R 6 is a substituent excluding the hydrogen atom in R 1 defined in Chemical Formula 1, TBS is a t-butyldimethylsilyl group, and Ac represents an acetyl group.
    [74] According to Scheme 4, the compound represented by Chemical Formula 1d is reacted with t-butyldimethylsilyl trifluoromethanesulfonic acid ester (TBSOTf) to obtain a t-butyldimethylsilyl ether compound represented by Chemical Formula 1e, and hydrolyzed to chemical formula The carboxylic acid compound represented by 1f is obtained. In addition, a compound represented by Chemical Formula 1g is obtained by reacting with alcohol using a known method. In addition, the t-butyldimethylsilyl substituent of the compound represented by the general formula (1 g) is removed by a known method to obtain another compound represented by the general formula (1h). In addition, by using a known method, the compound represented by the formula (1h) is reacted with acetic acid chloride to obtain a compound represented by the formula (1i).
    [75] As another derivative of the compound represented by Chemical Formula 1, which is an object of the present invention, a compound having a substituent R of CONR 1 R 2 may be prepared from a carboxylic acid compound represented by Chemical Formula 1f based on the following Scheme 5.
    [76]
    [77] In Scheme 5: R 2 and R 3 are as defined in Formula 1, respectively.
    [78] According to Scheme 5, the carboxylic acid compound represented by Chemical Formula 1f may be reacted with an amine using a known method to prepare a carboxamide compound represented by Chemical Formula 1j. In addition, the t-butyldimethylsilyl substituent of the compound represented by the general formula (1j) is removed by a known method to obtain another compound represented by the general formula (1k).
    [79] On the other hand, the 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by the formula (1) according to the present invention has excellent antioxidant activity, and thus, anti-aging agents and treatments for cancer, diabetes, epilepsy, and dementia, It is very effective as a therapeutic agent for neurodegenerative diseases such as Parkinson's disease, stroke, and hintinton. Therefore, the present invention is effective in the novel 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by the formula (1). Pharmaceutical compositions contained as ingredients. Pharmaceutical composition is conventional in the pharmaceutical field by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient to the 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by the formula (1) Formulations For example, it may be formulated into a formulation for oral administration such as tablets, capsules, troches, solutions, suspensions, or parenteral administration. In addition, the dosage of the compound represented by Chemical Formula 1 to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and is based on an adult patient having a weight of 70 kg. Generally, it is 0.01-1000 mg / day, and may be divided once a day or several times at regular time intervals according to the judgment of a doctor or a pharmacist.
    [80] The present invention as described above will be described in more detail based on the following Examples and Experimental Examples, but the present invention is not limited thereto.
    [81] Example 1 General Preparation of Compounds of Formula 8 [see Scheme 2].
    [82] The trifluoromethylsulfonyloxybenzene compound represented by the formula (7) was obtained by reacting with trifluoromethanesulfonic anhydride in a pyridine solvent according to a known method from the phenol derivative represented by the formula (6). A trifluoromethylsulfonyloxybenzene compound represented by the formula (7) was obtained (1 equivalent), allyl alcohol (2 equivalents), triethylamine (1.1 equivalents), and 1,1'-bis (diphenylphosphino) ferrocene ( DPPF, 2 mol%) was dissolved in anhydrous N, N-dimethylformamide (DMF, the concentration of the reactant was about 0.5 M) and stirred for 10 minutes under a nitrogen stream, followed by Pd (OAc) 2 (1.5-2.5 mol%). Was added to the reaction solution and stirred at 80 ° C. for 2 to 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (3 times the amount of DMF used), washed twice with 5% HCl (2 times the amount of DMF used), and then washed with water (2 times the amount of DMF used), and then MgSO. Dried over 4 and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give an oily compound of formula (8).
    [83] Example 1-1 Methyl 3- (1-hydroxymethylvinyl) benzoate.
    [84] Based on Example 1, 3.20 g (68%) of the title compound in an oil was obtained from methyl 3-trifluoromethylsulfonyloxybenzoate (7.00 g, 24.63 mmol) represented by Chemical Formula 7.
    [85] 1 H-NMR (CDCl 3 ) δ 8.09 (s, 1H), 7.94 (d, J = 7.6 Hz, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.60 Hz, 1H), 5.52 (s, 1H), 5.41 (s, 1H), 4.54 (bd, J = 4.0 Hz, 2H), 3.91 (s, 3H), 2.21 (bt, 1H); MS EI m / e 206 [M + ], 177 [M-CH 2 CH 3 ], 161 [M-CH 2 CH 3 , OH]
    [86] Example 1-2 ethyl 4- (1-hydroxymethylvinyl) benzoate.
    [87] Based on Example 1, 1.40 g (68%) of the title compound in the oil was obtained from ethyl 4-trifluoromethylsulfonyloxybenzoate (2.98 g, 24.63 mmol) represented by Chemical Formula 7.
    [88] 1 H-NMR (CDCl 3 ) δ 1.38 (t, 3H, J = 6.8 Hz, 7.4 Hz, Ethyl-H), 2.31 (brs, 1H, -OH), 4.42 to 4.31 (qt, 2H, J = 7.2 Hz, Ethyl-H), 4.53 (s, 2H, Methylene-H), 5.44 (s, 1H, Ethylene-H), 5.55 (s, 1H, Ethylene-H), 7.49 (d, 2H, J = 8.6 Hz , Ar-H), 8.00 (d, 2H, J = 8.4 Hz, Ar-H); MS EI m / e 206 [M + ], 177 [M-CH 2 CH 3 ], 161 [M-CH 2 CH 3 , OH].
    [89] Example 1-3: 2- (3-nitrophenyl) -2-propen-1-ol.
    [90] According to Example 1, 3.4 g (64%) of the title compound in oil was obtained from 3-nitrophenyl trifluoromethylsulfonate (8.0 g, 29.52 mmol) represented by Chemical Formula 7.
    [91] 1 HNMR (CDCl 3 ) δ1.78 (bs, 1H, -OH), 4.57 (s, 2H, Methylene-H), 5.51 (s, 1H, Ethylene-H), 5.61 (s, 1H, Ethylene-H) , 7.52 (t, 1H, J = 7.8Hz, 8Hz, Ar-H), 7.79 (d, 1H, J = 7.8Hz, Ar-H), 8.14 (d, 1H, J = 8.2Hz, Ar-H) , 8.31 (s, 1H, Ar-H); MS EI m / e 179 [M + ], 162 [M-OH].
    [92] Example 1-4: 2- (4-nitrophenyl) -2-propen-1-ol.
    [93] According to Example 1, 3.4 g (64%) of an oily compound was obtained from 4-nitrophenyl trifluoromethylsulfonate (8.0 g, 29.52 mmol) represented by Chemical Formula 7.
    [94] Example 2 General Preparation of Sulfonator Compounds of Formula 3 [See Scheme 2].
    [95] A solution of the compound of formula 8 and triethylamine in anhydrous dichloromethane was slowly added to a solution of methanesulfoic acid chloride in anhydrous dichloromethane at 0 ° C., the reaction mixture was allowed to warm to room temperature, poured into a 2N HCl solution and dichloromethane. After extraction three times with and dried with MgSO 4 and concentrated under reduced pressure to obtain a sulfonator compound represented by the formula (3) to obtain a compound represented by the formula (4) without purification.
    [96] Example 3: General preparation of compound of formula 4 [See Scheme 1]
    [97] The phenolic compound represented by Formula 2 was prepared using a known method. The phenol represented by the formula (2) (1.1 equivalents) was dissolved in anhydrous DMF, followed by NaH (1.2 equivalents). After addition at 30 ° C. and stirring for 30 minutes, the sulfonate compound (1 equivalent) prepared in Example 2 was added, followed by stirring at 40 ° C. for 2 to 4 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate (3 times the amount of DMF used), washed twice with 5% HCl (2 times the amount of DMF used), and then washed with water (2 times the amount of DMF used), and then MgSO.4Dried over and concentrated under reduced pressure. The residue was subjected to column chromatography (hexane / ethyl acetate = 2/1) to give a compound represented by the formula (4).
    [98] Example 3-1: 4- [2- (3-methyloxycarbonylphenyl) allyloxy] -2,3,6-trimethylphenyl acetate.
    [99] 5.59 g (85%) of the title compound was obtained from methyl 3- (1-methylsulfonyloxymethylvinyl) benzoate (4.92 g, 18.2 mmol) according to Example 3.
    [100] 1 HNMR (CDCl 3 ) δ2.05 (s, 3H), 2.08 (s, 3H), 2.13 (s, 3H), 2.33 (s, 3H), 3.93 (s, 3H), 4.85 (s, 2H), 5.55 (d, J = 1.0 Hz, 1H), 5.66 (d, J = 0.6 Hz, 1H), 6.65 (s, 1H), 7.43 (t, J = 7.7 Hz, 1H), 7.66 (dt, J = 8.0 , 1.6 Hz, 1H), 7.99 (dt, J = 7.6, 1.4 Hz, 1H), 8.17 (t, J = 1.8 Hz, 1H)
    [101] Example 3-2 4- [2- (4-ethyloxycarbonylphenyl) allyloxy] -2,3,6-trimethylphenylacetate.
    [102] According to Example 3, 1.9 g (86%) of the title compound was obtained as a white solid from methyl 4- (1-ethylsulfonyloxymethylvinyl) benzoate (1.91 g, 18.2 mmol).
    [103] 1 HNMR (CDCl 3 ) δ 1.40 (t, 3H, J = 7.2 Hz, Ethyl-H), 2.04 (s, 3H, Methyl-H), 2.06 (s, 3H, Methyl-H), 2.12 (s, 3H, Methyl-H), 2.33 (s, 3H, Acetyl-H), 4.43-4.33 (qt, 2H, J = 7.2 Hz, Ethyl-H), 4.85 (s, 2H, Methylene-H), 5.58 (s , 1H, Ethylene-H), 5.69 (s, 1H, Ethylene-H), 6.63 (s, 1H, Ar-H), 7.54 (d, 2H, J = 8.8Hz, Ar-H), 8.02 (d, 2H, J = 8.8 Hz, Ar-H); MS EI m / e 382 [M + ], 367 [M-CH 3 ], 340 [M-COCH 3 ], 325 [M-COCH 3 , CH 3 ]
    [104] Example 3-3 2,3,6-trimethyl-4- [2- (3-nitrophenyl) allyloxy] phenyl acetate.
    [105] 4.32 g (93%) of the title compound was obtained from 2- (3-nitrophenyl) allyl methanesulfonator (2.71 g) according to Example 3.
    [106] 1 HNMR (CDCl 3 ) δ2.04 (s, 3H, Methyl-H), 2.06 (s, 3H, Methyl-H), 2.14 (s, 3H, Methyl-H), 2.34 (s, 3H, Acetyl-H ), 4.86 (s, 2H, Methylene-H), 5.64 (s, 1H, Ethylene-H), 5.73 (s, 1H, Ethylene-H), 6.65 (s, 1H, Ar-H), 7.52 (t, 1H, J = 7.8Hz, 8.2Hz, Ar-H), 7.79 (d, 1H, J = 7.8Hz, Ar-H), 8.16 (d, 1H, J = 8.2Hz, Ar-H), 8.37 (s , 1H, Ar-H); MS EI m / e 355 [M + ], 313 [M-COCH 3 ].
    [107] Example 3-4 2,3,6-trimethyl-4- [2- (4-nitrophenyl) allyloxy] phenyl acetate.
    [108] 4.67 g (65%) of the title compound was obtained from 2- (4-nitrophenyl) allyl methanesulfonator (4.93 g, 19.16 mmol) according to Example 3.
    [109] Example 4 General Preparation of Compounds of Formula 1 [See Scheme 1].
    [110] The compound of formula 4 is dissolved in anhydrous dichloromethane and BCl3(1M, 2 equiv) slowly dropwise at room temperature followed by NaHCO3Pour into saturated aqueous solution and extract twice with dichloromethane.4And dried under reduced pressure to obtain a compound represented by the formula (5) in an oily phase. It is dissolved in ethyl alcohol without separating and refining sulfuric acid (EtOH / H2SO4Slowly add = 2/1) 60 Stir at about 2 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate and washed with water, and then MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 8/1) to give the compound represented by formula (1).
    [111] Example 4-1: Methyl 3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate.
    [112] 4.23 g of the title compound as a yellow solid from 4- [2- (3-methyloxycarbonylphenyl) allyloxy] -2,3,6-trimethylphenylacetate (5.20 g, 14.1 mmol) according to Example 4 above. (92%) obtained.
    [113] 1 HNMR (CDCl 3 ) δ 1.75 (s, 3H), 2.05 (s, 3H), 2.14 (s, 3H), 2.27 (s, 3H), 3.29 (s, 2H), 3.89 (s, 3H), 4.91 (s, 1H), 7.35 (t, J = 7.7 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 8.15 (s, 1H).
    [114] Example 4-2: Ethyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate.
    [115] Based on Example 4, 310 mg of the title compound as a yellow solid from 4- [2- (3-methyloxycarbonylphenyl) allyloxy] -2,3,6-trimethylphenylacetate (410 mg, 1.07 mmol). (85%).
    [116] 1 HNMR (CDCl 3 ) δ 1.38 (t, J = 7.2 Hz, 3H), 1.76 (s, 3H), 2.07 (s, 3H), 2.16 (s, 3H), 2.24 (s, 3H), 3.32 ( s, 2H), 4.26 (brs, 1H), 4.42 to 4.31 (qt, J = 7.2 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 8.01 (d, J = 8.8 Hz, 2H); MS EI m / e 340 [M + ], 325 [M-CH 3 ]
    [117] Example 4-3 2,4,6,7-tetramethyl-2- (3-nitrophenyl) -2,3-dihydrobenzo [b] furan-5-ol
    [118] Based on Example 4, 280 mg (78%) of the title compound was obtained as a yellow solid from 2,3,6-trimethyl-4- [2- (3-nitrophenyl) allyloxy] phenyl acetate (400 mg).
    [119] 1 HNMR (CDCl 3 ) δ 1.79 (s, 3H, Methyl-H), 2.08 (s, 3H, ArMethyl-H), 2.16 (s, 3H, ArMethyl-H), 2.25 (s, 3H, ArMethyl-H ), 3.34 (d, 2H, J = 5.4 Hz, Methylene-H), 4.44 (brs, 1H, -OH), 7.50 (t, 1H, J = 7.8 Hz, 8 Hz, Ar-H), 7.81 (d, 1H, J = 7.8 Hz, Ar-H), 8.10 (d, 1H, J = 8.1 Hz, Ar-H), 8.33 (s, 1H, Ar-H); MS EI m / e 313 [M + ], 296 [M-OH], 250 [M-OH, NO 2 ]; mp 132-134 ° C
    [120] Example 4-4 2,4,6,7-tetramethyl-2- (4-nitrophenyl) -2,3-dihydrobenzo [b] furan-5-ol
    [121] 0.62 g (84%) of the title compound as a yellow solid from 2,3,6-trimethyl-4- [2- (3-nitrophenyl) allyloxy] phenyl acetate (0.84 g, 2.35 mmol) according to Example 4. )
    [122] Example 5-1 Preparation of 2- (3-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (Formula 1b) Reference].
    [123] 2,4,6,7-tetramethyl-2- (3-nitrophenyl) -2,3-dihydrobenzo [b] furan-5-ol (700 mg, 2.23 mmol) obtained in Example 4-3. Was dissolved in ethyl acetate (50 mL) and 10% Pd-C (120 mg) was added and stirred in the presence of hydrogen for 14 hours. The reaction mixture was filtered through celite, concentrated and the residue was recrystallized (ethyl acetate-hexane) to give 0.57 g (90%) of the title compound as a brown solid.
    [124] 1 HNMR (CDCl 3 ) δ1.71 (s, 3H, Methyl-H), 2.06 (s, 3H, ArMethyl-H), 2.14 (s, 3H, ArMethyl-H), 2.21 (s, 3H, ArMethyl-H ), 3.27 (d, 2H, J = 3.6 Hz, Methylene-H), 4.14 (brs, 1H, -OH), 6.55 (d, 1H, J = 7.8 Hz, Ar-H), 6.84 to 6.81 (m, 2H, Ar-H), 7.11 (t, 1H, J = 8 Hz, Ar-H); MS EI m / e 283 [M + ], 296 [M-CH 3 ]; mp 163-164 캜.
    [125] Example 5-2 Preparation of 2- (4-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (Formula 1b) Reference].
    [126] 2,4,6,7-tetramethyl-2- (4-nitrophenyl) -2,3-dihydrobenzo [b] furan-5-ol (2.7 g, 8.62 mmol) obtained in Example 4-4. Was dissolved in ethyl acetate (60 mL) and 10% Pd-C (300 mg) was added and stirred in the presence of hydrogen for 14 hours. The reaction mixture was filtered through celite, concentrated and the residue was recrystallized (ethyl acetate-hexane) to give 1.6 g (90%) of the title compound as a brown solid.
    [127] 1 HNMR (CDCl 3 ) δ1.72 (s, 3H, methyl-H), 2.07 (s, 3H, Armethyl-H), 2.15 (s, 3H, Armethyl-H), 2.20 (s, 3H, Armethyl-H ), 3.25 (s, 2H, methylene-H), 3.62 (s, 2H, -NH 2 ), 4.15 (s, 1H, -OH), 6.64 (d, 2H, J = 8.6 Hz, Ar-H), 7.25 (d, 2H, J = 8.2 Hz, Ar-H); MS EI m / e 283 [M + ], 268 [M-CH 3 ]; mp 54-56 ℃
    [128] Example 6 General Preparation of Compounds of Formula 1c [See Scheme 3].
    [129] 2- (3-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol obtained in Example 5-1 or Example 5-2 2- (4-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol obtained from carboxylic acid, carboxylic acid chloride, carboxylic anhydride, phenyl isocyanate or phenyl Reaction with isothiocyanate afforded the title compound represented by Formula 1c.
    [130] Example 6-1 Preparation of N1- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] butanamide .
    [131] 2- (3-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (30 mg, 0.11 mmol) obtained in Example 5-1. Is dissolved in anhydrous dichloromethane (5 mL) and anhydrous butanoic acid (18 μL, 0.11 mmol) is added to 0 It was added at 캜 and stirred for 3 hours. The reaction mixture was poured into iced water (10 mL), extracted with dichloromethane (2 × 10 mL) and MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 5/1) to give 34 mg (91%) of the title compound as a white solid.
    [132] 1 HNMR (CDCl 3 ) δ1.00 (t, 3H, J = 7.4 Hz, methyl-H), 1.81-1.70 (m, 2H, methylene-H adjacent to methyl), 1.74 (s, 3H, methyl-H adjacent to aromatic), 2.06 (s, 3H, Armethyl-H), 2.15 (s, 3H, Armethyl-H), 2.23 (s, 3H, Armethyl-H), 2.33 (t, 2H, J = 7.2Hz, 7.8Hz , methylene-H adjacent to -CONH), 3.30 (s, 2H, methylene-H), 4.16 (brs, 1H, -OH), 7.12 (brs, 1H, -NH), 7.27-7.18 (m, 2H, Ar -H), 7.47 (d, 1H, J = 7.4 Hz, Ar-H), 7.57 (s, 1H, Ar-H); MS EI m / e 353 [M + ], 338 [M-CH 3 ]; mp 144-145 ° C
    [133] Example 6-2 Preparation of N1- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] octanamide .
    [134] 2- (3-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (20 mg, 0.07 mmol) obtained in Example 5-1. And triethylamine (20 μL, 0.14 mmol) in anhydrous dichloromethane (4 mL) and octanoyl chloride (13 μL, 0.078 mmol) at 0 It was added at 캜 and stirred for 3 hours. The reaction mixture was poured into iced water (10 mL), extracted with dichloromethane (2 × 10 mL) and MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 6/1) to give 31 mg (73%) of the title compound as a white solid.
    [135] 1 HNMR (CDCl 3 ) δ 0.88 (t, 3H, J = 6.6 Hz, methyl-H), 1.31-1.27 (m, 8H, methylene-H adjacent to methyl), 1.74 (s, 3H, methyl-H adjacent to aromatic), 2.06 (s, 3H, Armethyl-H), 2.15 (s, 3H, Armethyl-H), 2.23 (s, 3H, Armethyl-H), 2.34 (t, 2H, J = 7.4Hz, 7.8Hz , methylene-H adjacent to -CONH), 3.30 (s, 2H, methylene-H), 4.16 (brs, 1H, -OH), 7.11 (brs, 1H, -NH), 7.31-7.18 (m, 2H, Ar -H), 7.46 (d, 1H, J = 7.2 Hz, Ar-H), 7.57 (s, 1H, Ar-H); MS EI m / e 409 [M + ], 394 [M-CH 3 ], 309 [M- (CH 2 ) 6 CH 3 ]; mp 126-128 ℃
    [136] Example 6-3 Preparation of N1- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] decanamide .
    [137] 2- (3-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (30 mg, 0.11 mmol) obtained in Example 5-1. And triethylamine (16 μL, 0.12 mmol) in anhydrous dichloromethane (4 mL) and decanoyl chloride (24 μL, 0.12 mmol) at 0 It was added at 캜 and stirred for 3 hours. The reaction mixture was poured into iced water (10 mL), extracted with dichloromethane (2 × 10 mL) and MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 8/1) to give 36 mg (83%) of the title compound as a white solid.
    [138] 1 HNMR (CDCl 3 ) δ0.87 (t, 3H, J = 7Hz, methyl-H), 1.26 (m, 12H, Methylene-H adjacent to methyl), 1.70 (m, 2H, methylene-H adjacent to -CONHCH 2 ), 1.74 (s, 3H, methyl-H adjacent to aromatic), 2.06 (s, 3H, Armethyl-H), 2.15 (s, 3H, Armethyl-H), 2.23 (s, 3H, Armethyl-H), 2.37 to 2.30 (t, 2H, J = 7.2 Hz, 7.6 Hz, methylene-H adjacent to -CONH), 3.30 (s, 2H, methylene-H), 4.14 (brs, 1H, -OH), 7.10 (brs, 1H, -NH), 7.32-7.72 (m, 2H, Ar-H), 7.46 (d, 1H, J = 7 Hz, Ar-H), 7.57 (s, 1H, Ar-H); MS EI m / e 437 [M + ], 422 [M-CH 3 ], 283 [M-CO (CH 2 ) 8 CH 3 ]; mp 129-130 ℃
    [139] Example 6-4 Preparation of N1- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] benzamide .
    [140] 2- (3-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (30 mg, 0.11 mmol) obtained in Example 5-1. And triethylamine (16 μL, 0.12 mmol) in anhydrous dichloromethane (4 mL) and benzoyl chloride (14 μL, 0.12 mmol) at 0 It stirred at 1 degreeC and stirred for 1 hour. The reaction mixture was poured into iced water (10 mL), extracted with dichloromethane (2 × 10 mL) and MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 8/1) to give 34 mg (83%) of the title compound as a white solid.
    [141] 1 HNMR (CDCl 3 ) δ 1.77 (s, 3H, methyl-H), 2.15 (s, 3H, Armethyl-H), 2.07 (s, 3H, Armethyl-H), 2.24 (s, 3H, Armethyl-H ), 3.33 (s, 2H, methylene-H), 4.15 (brs, 1H, -OH), 7.38 to 7.33 (m, 2H, Ar-H), 7.63 to 7.44 (m, 3H, Ar-H), 7.70 (s, 1H, Ar-H), 7.81 (s, 1H, Ar-H), 7.89-7.84 (m, 2H, Ar-H); MS EI m / e 387 [M + ], 372 [M-CH 3 ], 282 [M-COC 6 H 5 ]; mp 167-169 ℃
    [142] Example 6-5 N2- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] pyridinecarboxamide Manufacturing.
    [143] 2- (3-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (30 mg, 0.11 mmol) obtained in Example 5-1. And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC; 14 mg, 74.1 μmol), hydroxybenzotriazole (HOBT; 10 mg, 74.1 μmol), triethylamine (16 μL, 0.12 mmol) is dissolved in anhydrous dichloromethane (4 mL) and picolinic acid (9 mg, 0.12 mmol) is added to 0 It was added at ℃ ℃ and warmed to room temperature and stirred for 20 hours. NaHCO reaction mixture3Pour into saturated aqueous solution (10 mL), extract with dichloromethane (2 × 10 mL), MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 8/1) to give 24 mg (88%) of the title compound as a yellow solid.
    [144] 1 HNMR (CDCl 3 ) δ1.78 (s, 3H, methyl-H), 2.08 (s, 3H, Armethyl-H), 2.15 (s, 3H, Armethyl-H), 2.25 (s, 3H, Armethyl-H ), 3.35 (s, 2H, methylene-H), 4.18 (brs, 1H, -OH), 7.38 to 7.25 (m, 2H, Ar-H), 7.47 (t, 1H, J = 6.8 Hz, 5.4 Hz, Ar-H), 7.71 (d, 1H, J = 7.4 Hz, Ar-H), 7.94-7.85 (m, 2H, Ar-H), 8.29 (d, 1H, J = 7.8 Hz, Ar-H), 8.60 (s, 1 H, Ar-H), 10.03 (brs, 1 H, -NH); MS EI m / e 388 [M + ], 373 [M-CH 3 ], 282 [M-COC 5 H 4 N].
    [145] Example 6-6 of anilino- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] methaneamide Produce.
    [146] 2- (3-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (30 mg, 0.11 mmol) obtained in Example 5-1. Was dissolved in anhydrous dichloromethane (4 mL) and phenylisocyanate (13 μL, 0.12 mmol) was added to 0 It was added at 占 폚 and stirred for 30 minutes. The reaction mixture is poured into water (10 mL), extracted with ethyl acetate (2 × 10 mL) and then MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 3/1) to give 37 mg (86%) of the title compound as a white solid.
    [147] 1 HNMR (CDCl 3 ) δ1.72 (s, 3H, methyl-H), 2.02 (s, 3H, Armethyl-H), 2.10 (s, 3H, Armethyl-H), 2.18 (s, 3H, Armethyl-H ), 3.26 (s, 2H, methylene-H), 4.18 (brs, 1H, -OH), 6.82 (d, 2H, J = 4.4 Hz, Ar-H), 7.28 to 7.05 (m, 6H, Ar-H) ), 7.47 (s, 1 H, Ar-H); MS EI m / e 402 [M + ], 387 [M-CH 3 ], 309 [M-CH 3 , C 6 H 5 ]; mp 115-120 ° C.
    [148] Example 6-7 of anilino- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) anilino methanechione Produce.
    [149] 2- (3-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (25 mg, 0.09 mmol) obtained in Example 5-1. Is dissolved in anhydrous pyridine (4 mL) and phenylisothiocyanate (13 μL, 0.12 mmol) is added to 0. It was added at 占 폚 and stirred for 30 minutes. The reaction mixture is poured into water (10 mL), extracted with ethyl acetate (2 × 10 mL) and then MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 3/1) to give 34 mg (92%) of the title compound as a white solid.
    [150] 1 HNMR (CDCl 3 ) δ1.75 (s, 3H, methyl-H), 2.06 (s, 3H, Armethyl-H), 2.12 (s, 3H, Armethyl-H), 2.18 (s, 3H, Armethyl-H ), 3.30 (s, 2H, methylene-H), 4.19 (brs, 1H, -OH), 7.40-7.28 (m, 6H, Ar-H), 7.47 (s, 1H, Ar-H), 7.76 (d , 2H, J = 3.6 Hz, Ar-H); MS EI m / e 418 [M + ] 403 [M-CH 3 ], 325 [M-CH 3 , C 6 H 5 ]; mp 163-165 deg.
    [151] Example 6-8 Preparation of N1- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] butanamide .
    [152] 2- (4-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (35 mg, 0.12 mmol) obtained in Example 5-2. Is dissolved in anhydrous dichloromethane (5 mL) and anhydrous butanoic acid (21 μL, 0.13 mmol) is added to 0 It was added at 캜 and stirred for 3 hours. The reaction mixture was poured into iced water (10 mL), extracted with dichloromethane (2 × 10 mL) and MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 5/1) to give 39 mg (85%) of the title compound as a white solid.
    [153] 1 HNMR (CDCl 3 ) δ 0.99 (t, 3H, J = 7.4 Hz, 7.2 Hz, methyl-H), 1.80-1.69 (m, 2H, methylene-H adjacent to methyl), 1.73 (s, 3H, methyl -H adjacent to aromatic), 2.07 (s, 3H, Armethyl-H), 2.15 (s, 3H, Armethyl-H), 2.21 (s, 3H, Armethyl-H), 2.32 (t, 2H, J = 7Hz, 7.8 Hz, methylene-H adjacent to -CONH), 3.28 (s, 2H, methylene-H), 4.14 (brs, 1H, -OH), 7.08 (brs, 1H, -NH), 7.49 to 7.38 (m, 4H , Ar-H) ,; MS EI m / e 353 [M + ], 338 [M-CH 3 ], 283 [M-CO (CH 2 ) 2 CH 3 ], [M-CH 3 , C 6 H 5 ]; mp79-81 degreeC.
    [154] Example 6-9 Preparation of N1- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] octanamide .
    [155] 2- (4-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (35 mg, 0.12 mmol) obtained in Example 5-2. And triethylamine (18 μL, 0.13 mmol) in anhydrous dichloromethane (4 mL) and octanoyl chloride (22 μL, 0.13 mmol) at 0 It was added at 캜 and stirred for 3 hours. The reaction mixture was poured into iced water (10 mL), extracted with dichloromethane (2 × 10 mL) and MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 6/1) to give 32 mg (83%) of the title compound as a white solid.
    [156] 1 HNMR (CDCl 3 ) δ 0.91 to 0.84 (m, 3H, methyl-H), 1.30 to 1.27 (m, 8H, methylene-H adjacent to methyl), 1.70 (m, 2H, methylene-H adjacent to -CONHCH 2 ), 1.73 (s, 3H, methyl-H adjacent to aromatic), 2.06 (s, 3H, Armethyl-H), 2.15 (s, 3H, Armethyl-H), 2.21 (s, 3H, Armethyl-H), 2.33 (t, 2H, J = 7.2 Hz, 8 Hz, methylene-H adjacent to -CONH), 3.28 (s, 2H, methylene-H), 4.14 (brs, 1H, -OH), 7.07 (brs, 1H,- NH), 7.49-77.3 (m, 4H, Ar-H); MS EI m / e 409 [M + ], 394 [M-CH 3 ], 283 [M-CO (CH 2 ) 6 CH 3 ]; mp 75-76 ° C.
    [157] Example 6-10: N2- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] pyridinecarboxamide Manufacturing.
    [158] 2- (4-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (50 mg, 0.18 mmol) obtained in Example 5-1. And 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC; 35 mg, 0.19 mmol), hydroxybenzotriazole (HOBT; 25 mg, 0.19 mmol), triethylamine (27 μL, 0.19 mmol) is dissolved in anhydrous dichloromethane (5 mL) and picolinic acid (23 mg, 0.19 mmol) is added to 0 It was added at ℃ and stirred at room temperature for 20 hours. NaHCO reaction mixture3Pour into saturated aqueous solution (10 mL), extract with dichloromethane (2 × 10 mL), MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 3/1) to give 48 mg (70%) of the title compound as a yellow solid.
    [159] 1 HNMR (CDCl 3 + CD 3 OD) δ 1.77 (s, 3H, methyl-H), 2.08 (s, 3H, Armethyl-H), 2.16 (s, 3H, Armethyl-H), 2.22 (s, 3H , Armethyl-H), 3.31 (s, 2H, methylene-H), 7.54-7.47 (m, 3H, Ar-H), 7.75-77.7 (m, 2H, Ar-H), 7.94 (t, 1H, J) = 7.8 Hz, Ar-H), 8.26 (d, 1H, J = 7.6 Hz, Ar-H), 8.65-8.62 (m, 1H, Ar-H); MS EI m / e 388 [M + ], 373 [M-CH 3 ]; mp 206-210 ° C.
    [160] Example 6-11 of anilino- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] methaneamide Produce.
    [161] 2- (4-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol (50 mg, 0.18 mmol) obtained in Example 5-2. Was dissolved in anhydrous pyridine (4 mL) and phenylisocyanate (20 μL, 0.19 mmol) was added to 0 It was added at ℃ and stirred at room temperature for 20 hours. The reaction mixture is poured into water (10 mL), extracted with ethyl acetate (2 × 10 mL) and then MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 3/1) to give 59 mg (83%) of the title compound as a white solid.
    [162] 1 HNMR (CDCl 3 + CD 3 OD) δ 1.73 (s, 3H, methyl-H), 2.07 (s, 3H, Armethyl-H), 2.15 (s, 3H, Armethyl-H), 2.20 (s, 3H , Armethyl-H), 3.27 (s, 2H, methylene-H), 7.05 to 6.98 (t, 1H, J = 7.4 Hz, J = 6.8 Hz, Ar-H), 7.42 to 7.24 (m, 8H, Ar- H); MS EI m / e 403 [M + ], 388 [M-CH 3 ], 310 [M-CH 3 , C 6 H 5 ]; mp 108-112 ° C.
    [163] Example 7 ethyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate (Formula 1e) Preparation of [see Scheme 4].
    [164] Ethyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate (0.34 g, obtained in Example 4-2); 1.00 mmol) and 2,6-lutidine (0.214 g, 2.00 mmol) in anhydrous dichloromethane (10 mL) and t-butyldimethylsilyltrifluoromethanesulfonic acid ester (TBSOTf; 0.28 mL, 1.2 mmol) It was added at ℃ ℃ and stirred for 14 hours at room temperature. The reaction mixture was washed with 1N HCl (20 mL) and water (20 mL), followed by MgSO.4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 20/1) to give 0.45 g (99%) of the title compound on the oil.
    [165] 1 HNMR (CDCl 3 ) δ0.09 (s, 3H, SiMethyl-H), 0.10 (s, 3H, SiMethyl-H), 1.01 (s, 9H, tert-butyl-H), 1.36 (t, 3H, J = 7.2 Hz, 7 Hz, Ethyl-H), 1.73 (s, 3H, Methyl-H), 1.99 (s, 3H, ArMethyl-H), 2.08 (s, 3H, ArMethyl-H), 2.18 (s, 3H, ArMethyl-H), 3.26 (s, 2H, Methylene-H), 4.40 to 4.29 (qt, 2H, J = 7 Hz, Ethyl-H), 7.52 (d, 2H, J = 6.7 Hz, Ar-H), 7.99 (d, 2H, J = 6.6 Hz, Ar-H); MS EI m / e 454 [M + ], 425 [M-CH 2 CH 3 ], 409 [M-OCH 2 CH 3 ]
    [166] Example 8: Preparation of 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoic acid (Formula 1f) See Scheme 4.
    [167] Ethyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate obtained in Example 7 (0.444) g, 0.98 mmol) was dissolved in tetrahydrofuran-water-methanol (12 mL; 4/1/1), 2N LiOH (1.46 mL) was added, and the mixture was stirred at room temperature for 3 hours. 1N HCl (5 mL) was added to the reaction mixture, followed by extraction with ethyl acetate (2 × 20 mL). The organic layer was washed with water (2 × 20 mL), dried over MgSO 4 , and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 1/1) to give 0.39 g (94%) of the title compound as a white solid.
    [168] 1 HNMR (CDCl 3 ) δ0.14 (s, 5H), 1.04 (s, 9H), 1.78 (s, 3H), 2.02 (s, 3H), 2.11 (s, 3H), 2.21 (s, 3H), 3.30 (s, 2H), 7.59 (d, J = 8.2 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H).
    [169] Example 9: of 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate (Formula 1 g) General preparation method [see Scheme 4].
    [170] 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoic acid obtained in Example 8 was used as React with butanol, octanol, geraniol, cyclohexanol and phenol in dichloromethane using bodyimide (DCC) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC) Got
    [171] Example 9-1 Preparation of Butyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate .
    [172] The benzoic acid (50 mg, 0.117 mmol), butanol (17.4 mg, 0.234 mmol) and dimethylaminopyridine (2.0 mg, 0.016 mmol) obtained in Example 8 were dissolved in anhydrous dichloromethane (2 mL), followed by DCC (27 mg). , 0.129 mmol) to 0 It was added at 占 폚 and stirred for 30 minutes. Water (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (2 x 10 mL), and the organic layer was washed with water (2 x 10 mL) and MgSO.4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 20/1) to give 34 mg (60%) of the title compound on oil.
    [173] 1 HNMR (CDCl 3 ) δ 0.11 (s, 3H), 0.12 (s, 3H), 0.97 (t, J = 7.4 Hz, 3H), 1.04 (s, 9H), 1.41 to 1.56 (m, 2H), 1.66 to 1.85 (m, 5H), 2.02 (s, 3H), 2.10 (s, 3H), 2.20 (s, 3H), 3.28 (s, 2H), 4.31 (t, J = 6.5 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H).
    [174] Example 9-2 Preparation of Octyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate .
    [175] 37 mg (69%) of the title compound in oil form was obtained from benzoic acid (50 mg, 0.117 mmol) in the same manner as in Example 9-1.
    [176] 1 HNMR (CDCl 3 ) δ 0.11 (s, 3H), 0.12 (s, 3H), 0.88 (t, J = 6.8 Hz, 3H), 1.03 (s, 9H), 1.26 to 1.45 (m, 10H), 1.76 (s, 3H), 2.01 (s, 3H), 2.10 (s, 3H), 2.20 (s, 3H), 3.28 (s, 2H), 4.40 (t, J = 6.8 Hz, 2H), 7.54 (d , J = 8.4 Hz, 2H), 8.00 (d, J = 8.2 Hz, 2H).
    [177] Example 9-3 of geranyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate Produce.
    [178] 25 mg (51%) of the title compound was obtained from benzoic acid (50 mg, 0.117 mmol) in the same manner as in Example 9-1.
    [179] 1 HNMR (CDCl 3 ) δ0.11 (s, 3H), 0.12 (s, 3H), 1.03 (s, 9H), 1.58 (s, 4H), 1.68 (s, 3H), 1.75 (s, 6H), 2.01 (s, 3H), 2.10 (s, 5H), 2.20 (s, 3H), 3.28 (s, 2H), 4.82 (d, J = 6.8 Hz, 2H), 5.06 ~ 5.11 (m, 1H), 5.42 5.49 (m, 1H), 7.53 (d, J = 9.0 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H).
    [180] Example 9-4 of cyclohexyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate Produce.
    [181] The benzoic acid (70 mg, 0.16 mmol) obtained in Example 8 was dissolved in anhydrous dichloromethane (5 mL), cyclohexanol (19 μL, 0.18 mmol), dimethylaminopyridine (4.0 mg, 20 mol%), 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC; 35 mg, 0.18 mmol) was added to 0 It was added at ℃ ℃ and warmed to room temperature and stirred for 20 hours. NaHCO reaction mixture3Pour into saturated aqueous solution (10 mL), extract with dichloromethane (2 × 10 mL), MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 8/1) to give 55 mg (66%) of the title compound on oil.
    [182] 1 HNMR (CDCl 3 ) δ 0.12 (s, 3H), 0.13 (s, 3H), 1.26 (s, 9H), 1.46 to 2.18 (m, 10H), 1.99 (s, 3H), 2.24 (s, 3H ), 2.33 (s, 3H), 2.43 (s, 3H), 3.51 (s, 2H), 5.24 (m, 1H), 7.76 (d, J = 8.0 Hz, 2H), 8.24 (d, J = 8.2 Hz , 2H); MS EI m / e 508 [M + ],
    [183] Example 9-5 Preparation of Phenyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate .
    [184] The benzoic acid (50 mg, 0.12 mmol) obtained in Example 8 was dissolved in anhydrous dichloromethane (5 mL), phenol (11 μL, 0.13 mmol), dimethylaminopyridine (3.0 mg, 20 mol%), 1- (3- Dimethylaminopropyl) -3-ethylcarbodiimide (EDC; 25 mg, 0.13 mmol) was added to 0 It was added at ℃ ℃ and warmed to room temperature and stirred for 20 hours. NaHCO reaction mixture3Pour into saturated aqueous solution (10 mL), extract with dichloromethane (2 × 10 mL), MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 8/1) to give 45 mg (76%) of the title compound on oil.
    [185] 1 HNMR (CDCl 3 ) δ0.12 (s, 3H), 0.13 (s, 3H), 1.03 (s, 9H), 1.79 (s, 3H), 2.03 (s, 3H), 2.10 (s, 3H), 2.20 (s, 3H), 3.32 (s, 2H), 7.19-7.31 (m, 3H), 7.77 (d, J = 7.0 Hz, 2H), 8.08 (d, J = 8.2 Hz, 2H), 8.28 (s , 1H); MS EI m / e 502 [M + ],
    [186] Example 10: General preparation of 4- (hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate (Formula 1f) Reference].
    [187] The compounds obtained in Examples 9-1, 9-2, 9-3, 9-4, and 9-5 were dissolved in anhydrous tetrahydrofuran, and then tetrabutylammonium fluoride (TBAF; 1.2 equivalents) was 0. It was added at 占 폚 and stirred for 30 minutes. Water (10 mL) was added to the reaction mixture, neutralized with 1N HCl, extracted with ethyl acetate (2 × 10 mL), the organic layer was sieved with water (2 × 10 mL), and then MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 8/1) to give the title compound.
    [188] Example 10-1 Preparation of Butyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate.
    [189] 25 mg (96%) of the title compound in an oil was obtained from the compound (34.0 mg, 0.07 mmol) obtained in Example 9-1.
    [190] 1 HNMR (CDCl 3 ) δ 0.97 (t, J = 7.2 Hz, 3H), 1.41 to 1.52 (m, 2H), 1.62 to 1.81 (m, 7H), 2.07 (s, 3H), 2.16 (s, 3H ), 2.23 (s, 3H), 3.31 (s, 2H), 4.02 (s, 1H), 4.31 (t, J = 6.6 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 8.00 (d , J = 8.2 Hz, 2H).
    [191] Example 10-2 Preparation of Octyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate.
    [192] 14 mg (89%) of the title compound in oil were obtained from the compound (34.0 mg, 0.07 mmol) obtained in Example 9-2.
    [193] 1 HNMR (CDCl 3 ) δ 0.88 (t, J = 6.5 Hz, 3H), 1.22 to 1.50 (m, 10H), 1.68 to 1.82 (m, 2H), 1.76 (s, 3H), 2.07 (s, 3H ), 2.16 (s, 3H), 2.24 (s, 3H), 3.32 (s, 2H), 4.19 (bs, 1H), 4.30 (t, J = 6.7 Hz, 2H), 7.53 (d, J = 8.6 Hz) , 2H), 8.00 (d, J = 8.6 Hz, 2H).
    [194] Example 10-3 Preparation of Geranyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate.
    [195] 18 mg (90%) of the title compound in oil was obtained from the compound (25.0 mg, 0.044 mmol) obtained in Example 9-3.
    [196] 1 HNMR (CDCl 3 ) δ 1.60 (s, 4H), 1.67 (s, 3H), 2.07 (s, 6H), 2.16 (s, 3H), 2.23 (s, 3H), 3.31 (s, 3H), 4.19 (bs, 1H), 4.82 (d, J = 6.8 Hz, 2H), 4.95-5.18 (m, 1H), 5.45 (t, J = 7.1 Hz, 1H), 7.52 (d, J = 8.2 Hz, 2H ), 8.01 (d, J = 8.6 Hz, 2H).
    [197] Example 10-4:
    [198] Preparation of cyclohexyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate.
    [199] 32 mg (83%) of the title compound in an oil was obtained from the compound (50.0 mg, 0.10 mmol) obtained in Example 9-4.
    [200] 1 HNMR (CDCl 3 ) δ 1.25 to 1.89 (m, 10H), 1.76 (s, 3H), 2.06 (s, 3H), 2.15 (s, 3H), 2.23 (s, 3H), 3.31 (s, 2H ), 4.15 (bs, 1H), 5.01 (m, 1H), 7.52 (d, J = 8.2 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H); MS EI m / e 394 [M + ],
    [201] Example 10-5 Preparation of Phenyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate.
    [202] 12 mg (39%) of the title compound in an oil was obtained from the compound (40.0 mg, 0.08 mmol) obtained in Example 9-5.
    [203] 1 HNMR (CDCl 3 ) δ 1.80 (s, 3H), 2.08 (s, 3H), 2.15 (s, 3H), 2.25 (s, 3H), 3.36 (s, 2H), 4.15 (bs, 1H), 7.18-7.31 (m, 3H), 7.40-7.51 (m, 3H), 7.77 (d, J = 8.0 Hz, 2H), 8.08 (d, J = 8.0 Hz, 2H), 8.28 (s, 1H); MS EI m / e 388 [M + ].
    [204] Example 11 Preparation of Methyl 3- (5-acetoxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate (Formula 1i) 4].
    [205] The compound obtained in Example 4-1 (100.0 mg, 0.31 mmol) was dissolved in anhydrous dichloromethane (10 mL), and then 0. Pyridine (125 μL, 1.53 mmol) and acetic acid chloride (55 μL, 0.77 mmol) were added at ° C. and stirred at room temperature for 24 hours. 2N HCl (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (2 × 10 mL), followed by MgSO.4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 5/1) to give 110.0 mg (97%) of the title compound.
    [206] 1 HNMR (CDCl 3 ) δ 1.77 (s, 3H), 1.95 (s, 3H), 2.03 (s, 3H), 2.22 (s, 3H), 2.31 (s, 3H), 3.33 (s, 2H), 3.92 (s, 3H), 7.40 (t, J = 7.9 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 8.11 (s, 1H); MS EI m / e 368 [M + ].
    [207] Example 12 Preparation of ethyl 4- (5-acetoxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate (Formula 1i) 4].
    [208] The compound obtained in Example 4-2 (100.0 mg, 0.29 mmol) was dissolved in anhydrous dichloromethane (10 mL), and then 0. Pyridine (120 μL, 1.47 mmol) and acetic acid chloride (53 μL, 0.737 mmol) were added at 캜, and the mixture was stirred at room temperature for 24 hours. 2N HCl (10 mL) was added to the reaction mixture, followed by extraction with dichloromethane (2 × 10 mL), followed by MgSO.4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 5/1) to give 110 mg (98%) of the title compound on oil.
    [209] 1 HNMR (CDCl 3 ) δ 1.38 (t, J = 7.2 Hz, 3H), 1.76 (s, 3H), 1.95 (s, 3H), 2.03 (s, 3H), 2.22 (s, 3H), 2.31 ( s, 3H), 3.32 (s, 2H), 4.36 (q, J = 7.1 Hz, 2H), 7.52 (d, J = 7.8 Hz, 2H), 8.01 (d, J = 7.8 Hz, 2H); MS EI m / e 382 [M + ].
    [210] Example 13 of 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzamide (Formula 1j) General preparation method [see Scheme 5].
    [211] 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) represented by Chemical Formula 1f obtained in Example 8 Benzoic acid was dissolved in chloromethane using 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC), hydroxybenzotriazole (HOBT), triethylamine, and aniline, propylamine, 2-aminopyridine. And an amide compound represented by formula 1j was obtained.
    [212] Example 13-1 N1-phenyl-4- (5-t-butyldimethylsilyloxy-2,4,6,8-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benz Preparation of an amide (Formula 1j) [see Scheme 5].
    [213] 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) represented by Chemical Formula 1f obtained in Example 8 Benzoic acid (50.0 mg, 0.12 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDC; 25 mg, 0.13 mmol), hydroxybenzotriazole (HOBT; 17 mg, 0.13 mmol), Triethylamine (18 μL, 0.13 mmol) was dissolved in anhydrous dichloromethane (5 mL) and aniline (12 μL, 0.13 mmol) was 0 It was added at ℃ ℃ and warmed to room temperature and stirred for 20 hours. NaHCO reaction mixture3Pour into saturated aqueous solution (10 mL), extract with dichloromethane (2 × 10 mL), MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 8/1) to give 72.0 mg (100%) of the title compound on oil.
    [214] 1 HNMR (CDCl 3 ) δ0.12 (s, 3H), 0.13 (s, 3H), 1.03 (s, 9H), 1.78 (s, 3H), 2.02 (s, 3H), 2.10 (s, 3H), 2.21 (s, 3H), 3.31 (s, 2H), 7.15 (t, J = 7.8 Hz, 2H), 7.34-7.49 (m, 3H), 7.61-7.72 (m, 4H), 8.00 (s, 1H) 8.08 (d, J = 8.0 Hz, 2H), 8.00 (s, 1H); MS EI m / e 501 [M + ].
    [215] Example 13-2 N1-propyl-4- (5-t-butyldimethylsilyloxy-2,4,6,8-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benz Preparation of an amide (Formula 1j) [see Scheme 5].
    [216] 35 mg (64%) of the title compound in oil form was obtained from benzoic acid (50.0 mg, 0.12 mmol) in the same manner as in Example 13-1.
    [217] 1 HNMR (CDCl 3 ) δ 0.11 (s, 3H), 0.12 (s, 3H), 0.95 to 0.99 (m, 3H), 1.02 (s, 9H), 1.59 to 1.70 (m, 2H), 1.76 (s , 3H), 2.01 (s, 3H), 2.10 (s, 3H), 2.19 (s, 3H), 3.28 (s, 2H), 3.42 (q, J = 13.6 Hz, 2H), 6.33 (s, 1H) 7.38 (t, J = 7.8 Hz, 1H), 7.57-77.6 (m, 2H), 7.89 (s, 1H); MS EI m / e 467 [M + ].
    [218] Example 13-3: N2- [4- (5-t-butyldimethylsilyloxy-2,4,6,8-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] Preparation of 2-pyridinecarboxamide (Formula 1j) [see Scheme 5].
    [219] In the same manner as in Example 13-1, 10 mg (17%) of an oily title compound was obtained from benzoic acid (50.0 mg, 0.12 mmol).
    [220] 1 HNMR (CDCl 3 ) δ0.12 (s, 3H), 0.13 (s, 3H), 1.03 (s, 9H), 1.81 (s, 3H), 2.04 (s, 3H), 2.10 (s, 3H), 2.20 (s, 3H), 3.34 (s, 2H), 7.45-7.82 (m, 4H), 7.88-7.74 (m, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1 H), 8.37 (s, 1 H); MS EI m / e 502 [M + ].
    [221] Example 14 of N1-phenyl-4- (5-hydroxy-2,4,6,8-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzamide (Formula 1k) Preparation [see Scheme 5].
    [222] The compound (67.0 mg, 0.13 mmol) obtained in Example 13-1 was dissolved in anhydrous tetrahydrofuran (5 mL), and then tetrabutylammonium fluoride (1M; 0.13 mL, 0.13 mmol) was 0. It was added at 占 폚 and stirred for 30 minutes. Water (10 mL) was added to the reaction mixture, neutralized with 1N HCl, extracted with ethyl acetate (2 × 10 mL), the organic layer was sieved with water (2 × 10 mL), and then MgSO4Dried over and concentrated under reduced pressure. The residue was separated by column chromatography (hexane / ethyl acetate = 8/1) to give 30 mg (66%) of the title compound.
    [223] 1 HNMR (CDCl 3 ) δ 1.79 (s, 3H), 2.08 (s, 3H), 2.16 (s, 3H), 2.25 (s, 3H), 3.35 (s, 2H), 4.15 (bs, 1H), 7.15 (t, J = 7.3 Hz, 1H), 7.34-7.49 (m, 3H), 7.61-7.72 (m, 4H), 8.00 (s, 1H), 7.99 (s, 1H); MS EI m / e 388 [M + ].
    [224] Chemical structures of the 2-aryl-2-methyl-2,3-dihydrobenzofuran compound obtained by the method according to Examples 4 to 14 are shown in Table 1 below.
    [225] ExampleR 'RExampleR 'R 4-1H3-CO 2 CH 3 7 4-CO 2 Et 4-2H4-CO 2 CH 2 CH 3 8 4-CO 2 H 4-3H3-NO 2 9-1 4-CO 2 CH 2 CH 2 CH 2 CH 34-4H4-NO 2 9-2 4-CO 2- (CH 2 ) 7 -CH 35-1H3-NH 2 9-3 4-; 5-2H4-NH 2 9-4 4-; 6-1H3-NHCOCH 2 CH 2 CH 3 9-5 4-; 6-2H3-NHCO- (CH 2 ) 6 -CH 3 10-1H4-CO 2 CH 2 CH 2 CH 2 CH 36-3H3-NHCO- (CH 2 ) 8 -CH 3 10-2H4-CO 2- (CH 2 ) 7 -CH 36-4H3-; 10-3H4-; 6-5H3-; 10-4H4-; 6-6H3-; 10-5H4-; 6-7H3-; 11CH 3 CO3-CO 2 CH 36-8H4-NHCOCH 2 CH 2 CH 3 12CH 3 CO4-CO 2 CH 2 CH 36-9H4-NHCO- (CH 2 ) 6 -CH 3 13-1 4-; 6-10H4-; 13-2 4-CONHCH 2 CH 2 CH 36-11H4-; 13-3 4-;14H4-;
    [226] Meanwhile, the 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by Chemical Formula 1 according to the present invention may be formulated in various forms according to the purpose. The following illustrates some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.
    [227] Formulation 1 : tablet (direct pressure)
    [228] After sifting 5.0 mg of active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.
    [229] Formulation 2 : Tablet (Wet Granulation)
    [230] After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.
    [231] Formulation 3 : Powders and Capsules
    [232] 5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.
    [233] Formulation 4 : Injection
    [234] Injectables were prepared by containing 100 mg as the active ingredient, followed by 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water.
    [235] Experimental Example 1 Antioxidant Activity Test
    [236] 1. Preparation of brain homogenate
    [237] SD rats (males, 10 to 12 weeks old) were singled out and brains were quickly removed and homogenized by adding 10 ml / brain of 10 mM Tris-HCl buffer (pH 7.4) containing 150 mM KCl. The homogenized brain mixture was centrifuged at 2,200 rpm and 4 ° C. for 10 minutes, and only the supernatant was taken to measure the exact amount of protein by protein assay and then stored at −20 ° C.
    [238] 2. Lipid Peroxidation Assay
    [239] Dispense 250 μl of brain homogenate (5 mg protein / ml), 10 μl of test substance, and 20 μl of buffer solution in 96-well microplates, and incubate at 37 ° C. for 20 min in 20 μM FeCl 2 and 250 μM. 10 μl each of ascorbic acid was added thereto and then incubated at 37 ° C. for 30 minutes. 50 μl of 35% HClO 4 was added to stop the reaction, and the microplate was centrifuged at 2000 rpm and 4 ° C. for 10 minutes to transfer 240 μl of the supernatant to 96-well microplate. / Ml in 50% acetic acid) was added in 120 mu l. The microplates were reacted at 80 ° C. for 1 hour and then cooled at room temperature, and then absorbance was measured at 520 nm of TBARS (thiobarbituric acid reactive substances (MDA)) produced by the reaction.
    [240] Quantitative reaction curves of TBARS generated using tetraethoxypropane, a reactant of TBA, were used to calculate the amount of reaction product MDA of the test substance, and the inhibitory effect of the test drug was calculated by Equation 1 below. In addition, 50% inhibition concentration (IC 50 ) was calculated by calculating the dose response curve.
    [241]
    [242] In Equation 1: A represents the concentration (nmol) of the control protein (MDA / mg), B represents the concentration (nmol) of the test protein (MDA / mg).
    [243] Therefore, the smaller the value of IC 50 , the stronger the antioxidant activity.
    [244] The experimental results are shown in Table 2 below, and it is determined that the compound according to the present invention has superior antioxidant activity compared to the conventional vitamin E.
    [245] Experimental compoundLipid Peroxidation Assay (IC 50 ) Vitamin E4.68 μM Ethyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzofuran-2-yl) benzoate (Example 4-1)0.28 μM 2,4,6,7-tetramethyl-2- (3-nitrophenyl) -2,3-dihydrobenzofuran-5-ol (Example 4-3)0.25 μM
    [246] Test Example 2: Oral Toxicity Test
    [247] Some compounds according to the invention were subjected to acute toxicity testing in rats. As a result, up to 10 mg / kg oral dose did not cause serious toxicity symptoms, and up to 100 mg / kg oral dose did not cause any death.
    [248] As described above, the 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by Chemical Formula 1 according to the present invention has excellent antioxidant activity and is effective for preventing and treating various diseases related thereto. .
    权利要求:
    Claims (8)
    [1" claim-type="Currently amended] 2-aryl-2-methyl-2,3-dihydrobenzofuran compound or a pharmaceutically acceptable salt thereof, characterized in that represented by the following formula (1).
    Formula 1

    In Formula 1 above:
    R 'represents a hydrogen atom, an acetyl group or a t-butyldimethylsilyl group; R represents NO 2 , NH 2 , COOR 1 , CONR 2 R 3 , or NHC (Z) R 4 ; R 1 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group, or a pyridine group; R 2 and R 3 each represent an alkyl group having 1 to 8 carbon atoms, a phenyl group, or a pyridine group; R 4 represents an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 3 to 10 carbon atoms, a phenyl group, a pyridine group, an alkylamine group having 1 to 6 carbon atoms, an aniline group, or an aminopyridine group; Z represents an oxygen atom or a sulfur atom.
    [2" claim-type="Currently amended] The compound of claim 1, wherein R 'is a hydrogen atom.
    [3" claim-type="Currently amended] The method of claim 1,
    Methyl 3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Methyl 3- (5-acetoxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Ethyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Ethyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoic acid;
    Butyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Octyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Geranyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Cyclohexyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Phenyl 4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Butyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Octyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Geranyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Cyclohexyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Phenyl 4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    Ethyl 4- (5-acetoxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzoate;
    N1-propyl-4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzamide;
    N1-phenyl-4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzamide;
    2- [4- (5-t-butyldimethylsilyloxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenylcarboxamido] pyridine;
    N1-phenyl-4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) benzamide;
    2,4,6,7-tetramethyl-2- (3-nitrophenyl) -2,3-dihydrobenzo [b] furan-5-ol;
    2,4,6,7-tetramethyl-2- (4-nitrophenyl) -2,3-dihydrobenzo [b] furan-5-ol;
    2- (3-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol;
    2- (4-aminophenyl) -2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-5-ol;
    N1- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] butanamide;
    N1- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] octanamide;
    N1- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] decanamide;
    N1- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] butanamide;
    N1- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] octanamide;
    3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) -1-phenylcarboxamidobenzene;
    N2- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] -2-pyridinecarboxamide;
    N2- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] -2-pyridinecarboxamide;
    Anilino- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] methaneamide;
    Anilino- [4- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) phenyl] methaneamide; And
    Anilino- [3- (5-hydroxy-2,4,6,7-tetramethyl-2,3-dihydrobenzo [b] furan-2-yl) anilino methanechione
    The compound characterized in that it is selected from.
    [4" claim-type="Currently amended] A pharmaceutical composition having an antioxidant activity, characterized in that it contains a 2-aryl-2-methyl-2,3-dihydrobenzofuran compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
    Formula 1

    In Formula 1: R 'and R are as defined in claim 1, respectively.
    [5" claim-type="Currently amended] The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is used as an anti-aging agent, an anticancer agent, a diabetes treatment agent, an epilepsy treatment or a neurodegenerative disease treatment agent.
    [6" claim-type="Currently amended] Converting the compound represented by Formula 2 into an alkylation reaction with the compound represented by Formula 3 below to a compound represented by Formula 4;
    Preparing a compound represented by Chemical Formula 5 by performing a Claisen reaction on the compound represented by Chemical Formula 4; And
    Method for producing a compound represented by the following formula 1 by the cyclization reaction of the compound represented by the formula (5).

    In the above: R 'and R are as defined in claim 1, respectively.
    [7" claim-type="Currently amended] The intermediate represented by the following formula (4), characterized in that it is used to prepare a compound represented by the formula (1).
    Formula 1

    Formula 4

    In the formula: R 'and R are as defined in claim 1, respectively.
    [8" claim-type="Currently amended] The intermediate represented by the following formula (5), characterized in that used to prepare a compound represented by the formula (1).
    Formula 1

    Formula 5

    In the formula: R 'and R are as defined in claim 1, respectively.
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    同族专利:
    公开号 | 公开日
    KR100402054B1|2003-10-17|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2001-03-30|Application filed by 한국화학연구원
    2001-03-30|Priority to KR10-2001-0016968A
    2002-10-11|Publication of KR20020076826A
    2003-10-17|Application granted
    2003-10-17|Publication of KR100402054B1
    优先权:
    申请号 | 申请日 | 专利标题
    KR10-2001-0016968A|KR100402054B1|2001-03-30|2001-03-30|2-Aryl-2-methyl-2,3-dihydrobenzofuranes as antioxidants|
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