Mode for carrying out the invention
[95]
Hereinafter, examples will be described in detail to help understanding of the present invention. However, the following examples are provided to more fully explain the present invention to those having average knowledge in the art, and are merely illustrative of the contents of the present invention, so the scope of the present invention is limited to the following examples. no.
[96]
[97]
< Synthesis Example 1> General reaction process of 4- benzopyranone compound derivative
[98]
[Scheme 1]
[99]

[100]
First, 2-hydroxybenzophosphorane derivative compound (2) was dissolved in carbon dichloride, pyridine (2 equivalents) was added dropwise, then heteroaromatic or benzoic acid chloride derivative (1.5 equivalents) was added dropwise, and 4-dimethylaminopyridine (0.05 Equivalent) was added dropwise. Thereafter, the reaction was stirred for 1 to 5 hours under a nitrogen atmosphere. Upon completion of the reaction, acetic acid (1 mL) was added to the reaction solution, and Girard reagent T (1 eq) was added dropwise, followed by stirring under nitrogen atmosphere for 1 hour. This was again extracted with a saturated solution of 1N HCl and NaHCO 3, and the organic layer was dried over anhydrous MgSO 4 , filtered, and distilled under reduced pressure to dissolve Compound (3) in a solvent toluene. After heating to reflux for 5 to 18 hours under a nitrogen atmosphere, when the reaction was completed, the solvent was distilled off under reduced pressure, and the reaction product was purified by chromatography. The thus obtained 4-benzopyranone compound (4) was dissolved in carbon dichloride, TFA was added dropwise, and stirred for 1 to 5 hours under nitrogen atmosphere. When the reaction was completed, the solvent was removed by distillation under reduced pressure, crystallized with ether, and the resulting crystal was filtered and dried in a vacuum oven to obtain the final target compounds (5).
[101]
[102]
< Example 1> Synthesis of methyl 2- (3- fluorophenyl ) -3- carboxy -7- methoxy - (4 H ) -4- benzopyranyl discussed Synthesis
[103]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphorane compound (150 mg, 0.28 mmol), pyridine (0.05 mL, 0.57 mmol, 2 eq), 3-fluorobenzoic acid chloride ( 0.05 mL, 0.43 mmol, 1.5 eq) was stirred in carbon dichloride (5 mL) for 4 hours and 30 minutes, stirred in toluene (10 mL) for 2 hours and 30 minutes, TFA (2 mL), carbon dichloride (2 mL) for 1 hour and 30 minutes to obtain the final target compound, 2-(3-fluorophenyl)-3-carboxy-7-methoxy-(4 H )-4-benzopyranone 60 mg (67.0%) Got it.
[104]
mp 214-215 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 3.96 (s, 3H), 6.97 (d, J = 2.3 Hz, 1H), 7.15 (dd, J = 9.1, 2.3 Hz, 1H), 7.26-7.50 (m , 4H), 8.24 (d, J=9.1 Hz, 1H); 13 C NMR (75 MHz, CDCl 3 ): δ 56.22, 100.21, 110.10, 115.48, 116.14, 116.91, 118.53, 124.96, 127.77, 129.86, 134.56, 157.54, 160.45, 163.56, 166.12, 172.04, 179.62.
[105]
[106]
Synthesis of 2-(2 -furanyl )-3-carboxy-8-methoxy-( 4H )-4-benzopyranone
[107]
Through the synthesis method of Preparation Example 1, 2-hydroxy-3-methoxybenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (diisopropylethylamine; 0.068 mL, 0.40 mmol, 2 eq), 2-puro One chloride (furoyl chloride; 0.029 mL, 0.30 mmol, 1.5 eq), 4-(dimethylamino) pyridine (4-(dimethylamino) pyridine; 5 mg) was stirred in methylene chloride (3 mL) for 2 hours And, after stirring for 50 hours in toluene (6 mL), TFA (3 mL), methylene chloride (methylene chloride; 3 mL) stirred for 1 hour to final target compound 2-(2-furanyl)-3- 25.2 mg (47.6%) of carboxy-8-methoxy-( 4H )-4-benzopyranone was obtained.
[108]
mp 195-197 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.53 (s, 3H), 6.71 (dd, J = 3.7, 1.7 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.66 (dd, J = 8.6, 2.0 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 3.7 Hz, 1H), 8.09 (s, 1H), 14.55 (s, 1H).
[109]
[110]
Synthesis of 2-(2 -furanyl )-3-carboxy-7-methoxy-( 4H )-4-benzopyranone
[111]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphorane compound (200 mg, 0.38 mmol), pyridine (0.06 mL, 0.76 mmol, 2 equivalents), 2-furoyl chloride (2- furoyl chloride; 0.05 mL, 0.57 mmol, 1.5 eq) was stirred in carbon dichloride (4 mL) for 1 hour, stirred in toluene (15 mL) for 10 hours, TFA (2 mL), carbon dichloride (2 mL) After stirring for 4 hours, the final target compound 2-(2 -furanyl )-3-carboxy-7-methoxy-( 4H )-4-benzopyranone 50 mg (46.0%) was obtained.
[112]
mp 217-219 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 3.99 (s, 3H), 6.71 (dd, J = 3.7, 1.6 Hz, 1H), 7.03 (d, J = 2.3 Hz, 1H), 7.11 (dd, J = 9.0, 2.3 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 8.01 (d, J = 3.7 Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 15.00 (s, 1H ).
[113]
[114]
Synthesis of 2-(2 -furanyl )-3-carboxy-6-methoxy-( 4H )-4-benzopyranone
[115]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-methoxybenzophosphoran compound (200 mg, 0.38 mmol), pyridine (0.06 mL, 0.76 mmol, 2 eq), 2-furoyl chloride (0.05 mL) , 0.57 mmol, 1.5 eq) was stirred in methylene chloride (4 mL) for 1 hour, stirred in toluene (15 mL) for 10 hours, and then stirred in TFA (2 mL) and methylene chloride (2 mL) for 4 hours. This gave 70 mg (64.0%) of the final target compound 2-(2 -furanyl )-3-carboxy-6-methoxy-( 4H )-4-benzopyranone.
[116]
mp 205-207 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 3.97 (s, 3H), 6.71 (dd, J = 3.7, 1.7 Hz, 1H), 7.43 (dd, J = 9.2, 3.1 Hz, 1H), 7.60 (d , J = 9.2 Hz, 1H), 7.64 (d, J = 3.1 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 3.7 Hz, 1H), 14.60 (s, 1H) ).
[117]
[118]
Synthesis of 2-(3-methylphenyl)-3-carboxy-8-methoxy-( 4H )-4-benzopyranone
[119]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-3-methoxybenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), m-toluyl Chloride (m-toluoly chloride; 0.031 mL, 0.24 mmol, 1.2 eq), 4-(dimethylamino)pyridine (4-(dimethylamino)pyridine; 5 mg) was stirred for 24 hours in metlene chloride (3 mL). , After stirring in toluene (6 mL) for 14 hours, then stirred in TFA (3 mL) and methylene chloride (3 mL) for 1 hour 30 minutes to obtain the final target compound 2-(3-methylphenyl)-3-carboxy-8 -Methoxy-( 4H )-4-benzopyranone 23.1 mg (40.1%) was obtained.
[120]
mp 192-195 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.46 (s, 3H), 2.55 (s, 3H), 7.41-7.47 (m, 4H), 7.52 (d, J= 8.6 Hz, 1H), 7.67 (dd , J= 8.6, 2.1 Hz, 1H), 8.14 (d, J= 0.9 Hz, 1H), 14.30 (s, 1H).
[121]
[122]
Synthesis of 2-(3-methylphenyl)-3-carboxy-7-methoxy-( 4H )-4-benzopyranone
[123]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphorane compound (200 mg, 0.38 mmol), pyridine (0.06 mL, 0.76 mmol, 2 equivalents), m-toluoyl chloride (0.05 mL) , 0.57 mmol, 1.5 eq) was stirred in methylene chloride (4 mL) for 19 hours, stirred in toluene (15 mL) for 17 hours, and then in TFA (5 mL), methylene chloride (5 mL) for 2 hours. After stirring, the final target compound 2-(3-methylphenyl)-3-carboxy-7-methoxy-( 4H )-4-benzopyranone 76.3 mg (65.0%) was obtained.
[124]
mp 183-184 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.46 (s, 3H), 3.96 (s, 3H), 6.98 (d, J = 2.3 Hz, 1H), 7.14 (dd, J = 9.0, 2.3 Hz, 1H ), 7.40-7.46 (m, 4H), 8.25 (d, J = 9.0 Hz, 1H), 14.45 (s, 1H).
[125]
[126]
2-(3-methylphenyl)-3-carboxy-6-methoxy-( 4H )-4-benzopyranone sum
[127]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-methoxybenzophosphorane compound (200 mg, 0.38 mmol), pyridine (0.06 mL, 0.76 mmol, 2 eq), m-toluoyl chloride (0.05 mL) , 0.57 mmol, 1.5 eq) was stirred in methylene chloride (4 mL) for 2 hours, stirred in toluene (15 mL) for 71 hours, and then in TFA (5 mL), methylene chloride (5 mL) for 2 hours. Stirring gave 49.5 mg (42.0%) of the final target compound 2-(3-methylphenyl)-3-carboxy-6-methoxy-( 4H )-4-benzopyranone.
[128]
mp 198-199 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.46 (s, 3H), 3.98 (s, 3H), 7.27-7.46 (m, 5H), 7.56 (d, J = 9.2 Hz, 1H), 7.67 (d , J = 3.0 Hz, 1H), 14.35 (s, 1H).
[129]
[130]
Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-( 4H )-4-benzopyranone
[131]
Through the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphorane compound (200 mg, 0.4 mmol), pyridine (0.05 mL, 0.6 mmol, 1.5 eq), 3,4-dimethoxybenzoyl chloride (dimethoxybenzoyl chloride) ; 96 mg, 0.48 mmol, 1.2 eq) was stirred in methylene chloride (4 mL) for 150 hours, stirred in toluene (15 mL) for 72 hours, and then in TFA (5 mL), methylene chloride (5 mL) After stirring for 2 hours, the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-( 4H )-4-benzopyranone 34.9 mg (63.0%) was obtained.
[132]
mp 237-238 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 3.94 (s, 3H), 3.99 (s, 3H), 7.00 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 2.1 Hz, 1H), 7.39 (dd, J = 8.4, 2.1 Hz, 1H), 7.56-7.64 (m, 2H), 7.64-7.90 (m, 1H), 8.36 (dd, J = 8.0, 1.6 Hz, 1H), 14.50 (s, 1H).
[133]
[134]
Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methoxy-( 4H )-4-benzopyranone
[135]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphorane compound (200 mg, 0.38 mmol), pyridine (0.05 mL, 0.57 mmol, 1.5 eq), 3,4-dimethoxybenzoyl chloride (92 mg, 0.46 mmol, 1.2 eq) was stirred in methylene chloride (4 mL) for 12 hours, stirred in benzene (10 mL) for 45 hours, and then in TFA (5 mL), methylene chloride (5 mL) After stirring for 2 hours, the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methoxy-( 4H )-4-benzopyranone 59.7 mg (89.0%) was obtained.
[136]
mp 208-210 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 3.94 (s, 3H), 3.96 (s, 3H), 3.97 (s, 3H), 6.97-6.99 (m, 2H), 7.12 (dd, J = 8.9, 2.3 Hz, 1H), 7.20 (d, J = 1.9 Hz, 1H), 7.34 (dd, J = 8.4, 1.9 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H).
[137]
[138]
Synthesis of 2-(2-chlorophenyl)-3-carboxy-7-methoxy-( 4H )-4-benzopyranone
[139]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphoran compound (200 mg, 0.38 mmol), pyridine (0.05 mL, 0.57 mmol, 1.5 eq), 2-chlorobenzoyl chloride (0.06 mL) , 0.46 mmol, 1.2 eq) was stirred in methylene chloride (4 mL) for 1 hour, stirred in toluene (15 mL) for 8 hours, and then in TFA (5 mL), methylene chloride (5 mL) for 2 hours. After stirring, 70 mg (88.0%) of the target compound 2-(2-chlorophenyl)-3-carboxy-7-methoxy-( 4H )-4-benzopyranone was obtained.
[140]
mp 130-132 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 3.96 (s, 3H), 6.98 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 9.0, 2.4 Hz, 1H), 7.43-7.44 (m , 2H), 7.48-7.56 (m, 2H), 8.28 (d, J = 9.0 Hz, 1H), 14.40 (s, 1H).
[141]
[142]
Synthesis of 2-(2-chlorophenyl)-3-carboxy-( 4H )-4-benzopyranone
[143]
Through the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphorane compound (200 mg, 0.40 mmol), pyridine (0.05 mL, 0.60 mmol, 1.5 eq), 2-chlorobenzoyl chloride (0.06 mL, 0.48 mmol, 1.2) eq) was stirred in methylene chloride (4 mL) for 1 hour, stirred in toluene (15 mL) for 120 hours, and then stirred in TFA (5 mL) and methylene chloride (5 mL) for 6 hours and 30 minutes to final The target compound 2-(2-chlorophenyl)-3-carboxy-( 4H )-4-benzopyranone 34 mg (44.0%) was obtained.
[144]
mp 133-135 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.44-7.46 (m, 2H), 7.49-7.55 (m, 2H), 7.61-7.66 (m, 2H), 7.87-7.93 (m, 1H), 8.40 ( dd, J = 8.3, 1.7 Hz, 1H).
[145]
[146]
Synthesis of 2-(2-thiophenyl)-3-carboxy-8-methoxy-( 4H )-4-benzopyranone
[147]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-3-methoxybenzophosphorane compound (200 mg, 0.38 mmol), pyridine (0.05 mL, 0.57 mmol, 1.5 eq), 2-thiophenecarbonyl chloride (2-thiophenecarbonyl chloride; 0.05 mL, 0.46 mmol, 1.2 eq) was stirred in methylene chloride (4 mL) for 2 hours and 30 minutes, stirred in toluene (15 mL) for 36 hours, and then TFA (5 mL), Stirring in methylene chloride (5 mL) for 2 hours to obtain the final target compound 2-(2-thiophenyl)-3-carboxy-8-methoxy-(4 H )-4-benzopyranone 52.4 mg (56.0%) Got it.
[148]
mp 196-198 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 4.07 (s, 3H), 7.25 (dd, J = 5.0, 4.0 Hz, 1H), 7.31 (dd, J = 8.1, 1.3 Hz, 1H), 7.46 (dd , J = 8.1, 8.1 Hz, 1H), 7.81-7.85 (m, 2H), 8.38 (dd, J = 4.0, 1.2 Hz, 1H), 14.80 (s, 1H).
[149]
[150]
Synthesis of 2-(2-thiophenyl)-3-carboxy-7-methoxy-( 4H )-4-benzopyranone
[151]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methoxybenzophosphorane compound (200 mg, 0.38 mmol), pyridine (0.05 mL, 0.57 mmol, 1.5 eq), 2-thiophenecarbonyl chloride (0.05 mL, 0.46 mmol, 1.2 eq) was stirred in methylene chloride (4 mL) for 2 hours and 30 minutes, and after stirring in toluene (15 mL) for 28 hours, TFA (5 mL), methylene chloride (5 mL) ), and stirred for 2 hours to obtain 41 mg (77.0%) of the final target compound 2-(2-thiophenyl)-3-carboxy-7-methoxy-( 4H )-4-benzopyranone.
[152]
mp 205-207 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 3.97 (s, 3H), 6.95 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 9.0, 2.3 Hz, 1H), 7.22 (dd, J = 5.0, 4.0 Hz, 1H), 7.79 (dd, J = 5.0, 1.1 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H), 8.25 (dd, J = 4.0, 1.1 Hz, 1H), 14.98 (s, 1H).
[153]
[154]
Synthesis of 2-(2-thiophenyl)-3-carboxy-6-methoxy-( 4H )-4-benzopyranone
[155]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-methoxybenzophosphorane compound (200 mg, 0.38 mmol), pyridine (0.05 mL, 0.57 mmol, 1.5 eq), 2-thiophenecarbonyl chloride (0.05 mL, 0.46 mmol, 1.2 eq) was stirred in methylene chloride (4 mL) for 2 h 30 min, stirred in toluene (15 mL) for 42 h, then TFA (5 mL), methylene chloride (5 mL) ) Was stirred for 1 hour and 30 minutes to obtain 50 mg (68.0%) of the final target compound 2-(2-thiophenyl)-3-carboxy-6-methoxy-( 4H )-4-benzopyranone.
[156]
mp 172-174 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 3.96 (s, 3H), 7.24 (dd, J = 5.0, 4.0 Hz, 1H), 7.43 (dd, J = 9.2, 3.0 Hz, 1H), 7.55 (d , J = 9.2 Hz, 1H), 7.63 (d, J = 3.0 Hz, 1H), 7.81 (dd, J = 5.0, 1.2 Hz, 1H), 8.25 (dd, J = 4.0, 1.2 Hz, 1H), 14.78 (s, 1H).
[157]
[158]
Synthesis of 2-(2-thiophenyl)-3-carboxy-( 4H )-4-benzopyranone
[159]
Through the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphorane compound (200 mg, 0.40 mmol), pyridine (0.05 mL, 0.60 mmol, 1.5 eq), 2-thiophenecarbonyl chloride (0.05 mL, 0.48) mmol, 1.2 eq) was stirred in methylene chloride (4 mL) for 3 hours, stirred in toluene (15 mL) for 23 hours 30 minutes, and then in TFA (5 mL) and methylene chloride (5 mL) for 2 hours. Stirring gave 52.3 mg (78.0%) of the final target compound 2-(2-thiophenyl)-3-carboxy-( 4H )-4-benzopyranone.
[160]
mp 175-176 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.25 (dd, J= 5.0, 4.1 Hz, 1H), 7.55-7.64 (m, 2H), 7.83-7.89 (m, 2H), 8.29-8.34 (m, 2H), 14.70 (s, 1H).
[161]
[162]
Synthesis of 2-(3-fluorophenyl)-3-carboxy-( 4H )-4-benzopyranone
[163]
Through the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphorane compound (300 mg, 0.6 mmol), diisopropylethylamine (diisopropylethylamine; 0.314 mL, 1.8 mmol, 3 eq), 3-fluorobenzoyl chloride ( 0.118 mL, 1.2 mmol, 2 eq), 4-(dimethylamino)pyridine (10 mg) was stirred in methylene chloride (5 mL) for 1 hour, and then in toluene (15 mL) for 4 hours 30 minutes, TFA (7 mL), stirred in methylene chloride (7 mL) for 1 hour 30 minutes, the final target compound 2-(3-fluorophenyl)-3-carboxy-(4 H )-4-benzopyranone 154 mg ( 90.0%) was obtained.
[164]
mp 193-196 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.29-7.55 (m, 4H), 7.60-7.65 (m, 2H), 7.87-7.93 (m, 1H), 8.37-8.40 (m, 1H), 14.19 ( s, 1H).
[165]
[166]
Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-( 4H )-4-benzopyranone
[167]
Through the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphorane compound (300 mg, 0.6 mmol), diisopropylethylamine (0.314 mL, 1.8 mmol, 3 eq), 3,5-difluorobenzoyl chloride (0.15 mL, 1.2 mmol, 2 eq), 4-(dimethylamino) pyridine (10 mg) was stirred in methylene chloride (5 mL) for 1 hour, and then stirred in toluene (15 mL) for 2 hours 30 minutes. , TFA (7 mL), stirred in methylene chloride (7 mL) for 1 hour to final target compound 2-(3,5-difluorophenyl)-3-carboxy-( 4H )-4-benzopyranone 22 mg (12.0%) was obtained.
[168]
mp 208-209 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.02-7.08 (m, 1H), 7.16-7.19 (m, 2H), 7.62-66 (m, 2H), 7.89-7.94 (m, 1H), 8.38 ( d, J = 8.3 Hz, 1H).
[169]
[170]
Synthesis of 2-(2 -furanyl )-3-carboxy-( 4H )-4-benzopyranone
[171]
Through the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphorane compound (300 mg, 0.6 mmol), diisopropylethylamine (0.314 mL, 1.8 mmol, 3 eq), 2-furoyl chloride (0.118 mL, 1.2 mmol, 2 eq), 4-(dimethylamino) pyridine (10 mg) was stirred in methylene chloride (5 mL) for 1 hour, stirred in toluene (15 mL) for 8 hours, and then TFA (7 mL) , Stirred in methylene chloride (7 mL) for 1 hour to obtain 96 mg (62.0%) of the final target compound 2-(2 -furanyl )-3-carboxy-( 4H )-4-benzopyranone.
[172]
mp 202-205 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 6.72 (dd, J = 3.8, 1.7 Hz, 1H), 7.54-7.60 (m, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.81-7.89 (m, 2H), 8.01-8.03 (m, 1H), 8.32 (dd, J = 8.0, 1.5 Hz, 1H), 14.45 (s, 1H).
[173]
[174]
Synthesis of 2-(3-methylphenyl)-3-carboxy-( 4H )-4-benzopyranone
[175]
Through the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphorane compound (300 mg, 0.6 mmol), diisopropylethylamine (0.314 mL, 1.8 mmol, 3 eq), m-toluoyl chloride (0.158 mL, 1.2 mmol, 2 eq), 4-(dimethylamino) pyridine (10 mg) was stirred in methylene chloride (5 mL) for 1 hour, stirred in toluene (15 mL) for 72 hours, and then TFA (7 mL) , By stirring in methylene chloride (7 mL) for 1 hour, the final target compound 2-(3-methylphenyl)-3-carboxy-( 4H )-4-benzopyranone 73 mg (43.0%) was obtained.
[176]
mp 162-164 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.48 (s, 3H), 7.43-7.50 (m, 4H), 7.59-7.65 (m, 2H), 7.86-7.92 (m, 1H), 8.38 (dd, J = 8.0, 1.5 Hz, 1H), 14.20 (s, 1H).
[177]
[178]
Synthesis of 2-(2 -furanyl )-3-carboxy-8-methyl-( 4H )-4-benzopyranone
[179]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-furoyl chloride (0.029 mL, 0.30 mmol, 1.5 eq), 4-dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 2 hours, stirred in toluene (6 mL) for 50 hours, and then TFA ( 3 mL), and stirred in methylene chloride (3 mL) for 1 hour to final target compound 2-(2 -furanyl )-3-carboxy-8-methyl-(4 H )-4-benzopyranone 31.4 mg (59.3) %).
[180]
mp 227-228 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.58 (s, 3H), 6.69 (dd, J = 3.6, 1.7 Hz, 1H), 7.32-7.36 (m, 2H), 7.59 (d, J = 7.3 Hz , 1H), 7.76-7.77 (m, 1H), 7.98 (d, J = 7.3 Hz, 1H).
[181]
[182]
Synthesis of 2-(2 -furanyl )-3-carboxy-7-methyl-( 4H )-4-benzopyranone
[183]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-furoyl chloride (0.029 mL, 0.30 mmol, 1.5 eq), 4-(dimethylamino)pyridine (5 mg) was stirred in methylene chloride (3 mL) for 2 hours, and then stirred in toluene (6 mL) for 50 hours, followed by TFA. (3 mL), stirred in methylene chloride (3 mL) for 1 hour, and the final target compound 2-(2 -furanyl )-3-carboxy-7-methyl-(4 H )-4-benzopyranone 19.1 mg ( 36.1%).
[184]
mp 217-218 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.57 (s, 3H), 6.71 (dd, J = 3.7, 1.7 Hz, 1H), 7.37 (dd, J = 8.2, 0.8 Hz, 1H), 7.46 (s , 1H), 7.79 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 3.7 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 14.55 (s, 1H).
[185]
[186]
Synthesis of 2-(2 -furanyl )-3-carboxy-6-methyl-( 4H )-4-benzopyranone
[187]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-furoyl chloride (0.029 mL, 0.30 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 2 hours, stirred in toluene (6 mL) for 50 hours, and then TFA (3 mL), stirred in methylene chloride (3 mL) for 1 hour to give the final target compound 2-(2 -furanyl )-3-carboxy-6-methyl-( 4H )-4-benzopyranone 25.2 mg ( 47.6%) was obtained.
[188]
mp 195-197 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.53 (s, 3H), 6.71 (dd, J = 3.7, 1.7 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.66 (dd, J = 8.6, 2.0 Hz, 1H), 7.79 (d, J = 1.7 Hz, 1H), 7.99 (d, J = 3.7 Hz, 1H), 8.09 (s, 1H), 14.55 (s, 1H).
[189]
[190]
Synthesis of 2-(2 -furanyl )-3-carboxy-6-chloro-( 4H )-4-benzopyranone
[191]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphorane compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 2-furoyl chloride (0.028 mL, 0.29 mmol, 1.5 eq), 4-(dimethylamino)pyridine (5 mg) was stirred in methylene chloride (3 mL) for 2 hours, and then stirred in toluene (6 mL) for 50 hours, followed by TFA. (3 mL), stirred in methylene chloride (3 mL) for 1 hour to give the final desired compound 2-(2 -furanyl )-3-carboxy-6-chloro-( 4H )-4-benzopyranone 20.20 mg ( 36.9%) was obtained.
[192]
mp 196-198 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 6.73 (dd, J = 3.8, 1.7 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.77-7.81 (m, 2H), 8.04 (dd , J = 3.8, 0.5 Hz, 1H), 8.27 (d, J = 2.5 Hz, 1H), 14.00 (s, 1H).
[193]
[194]
Synthesis of 2-(2 -furanyl )-3-carboxy-6-bromo-( 4H )-4-benzopyranone
[195]
2-hydroxy-5-bromobenzophosphoran compound (100 mg, 0.17 mmol), diisopropylethylamine (0.061 mL, 0.34 mmol, 2 eq), 2-furoyl through the general synthesis method of Preparation Example 1 above. Chloride (0.026 mL, 0.26 mmol, 1.5 eq), 4-(dimethylamino)pyridine (5 mg) was stirred in methylene chloride (3 mL) for 2 hours, and then stirred in toluene (6 mL) for 50 hours, TFA (3 mL), stirred in methylene chloride (3 mL) for 1 hour to final target compound 2-(2 -furanyl )-3-carboxy-6-bromo-( 4H )-4-benzopyranone 41.9 mg (71.9%) was obtained.
[196]
mp 209-211 ℃. 1 H NMR (300 MHz, CDCl 3 ): δ 6.73 (dd, J = 3.8, 1.6 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.80-7.81 (m, 1H), 7.93 (dd , J = 8.9, 2.4 Hz, 1H), 8.03 (d, J = 3.8 Hz, 1H), 8.43 (d, J = 2.4 Hz, 1H), 14.25 (s, 1H).
[197]
[198]
Synthesis of 2-(3-methylphenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone
[199]
2-hydroxy-3-methylbenzophosphoran compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), m-toluoyl chloride through the general synthesis method of Preparation Example 1 (0.031 mL, 0.24 mmol, 1.2 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 24 hours, stirred in toluene (6 mL) for 144 hours, and then TFA (3 mL), stirred in methylene chloride (3 mL) for 1 hour 30 minutes, and the final target compound 2-(3-methylphenyl)-3-carboxy-8-methyl-(4 H )-4-benzopyranone 14.0 mg (24.3%).
[200]
mp 209-211 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.47 (s, 3H), 2.55 (s, 3H), 7.42-7.51 (m, 5H), 7.70 (d, J = 7.1 Hz, 1H), 8.19 (d , J = 7.1 Hz, 1H), 14.25 (s, 1H).
[201]
[202]
2-(3-methylphenyl)-3-carboxy-7-methyl-( 4H )-4-benzopyranone
[203]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), m-toluoyl chloride (0.031 mL, 0.24 mmol, 1.2 eq), 4-dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 24 hours, stirred in toluene (6 mL) for 144 hours, and then TFA ( 3 mL), stirred in methylene chloride (3 mL) for 1 hour 30 minutes, and the final target compound 2-(3-methylphenyl)-3-carboxy-7-methyl-(4 H )-4-benzopyranone 23.2 mg ( 40.4%) was obtained.
[204]
mp 152-155 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.46 (s, 3H), 2.57 (s, 3H), 7.39-7.47 (m, 6H), 8.24 (d, J = 8.5 Hz, 1H), 14.30 (s , 1H).
[205]
[206]
Synthesis of 2-(3-methylphenyl)-3-carboxy-6-methyl-( 4H )-4-benzopyranone
[207]
2-hydroxy-5-methylbenzophosphoran compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), m-toluoyl chloride through the general synthesis method of Preparation Example 1 (0.031 mL, 0.24 mmol, 1.2 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 24 hours, stirred in toluene (6 mL) for 144 hours, and then TFA (3 mL), stirred in methylene chloride (3 mL) for 1 h 30 min to give the final desired compound 2-(3-methylphenyl)-3-carboxy-6-methyl-( 4H )-4-benzopyranone 23.1 mg (40.1%) was obtained.
[208]
mp 192-195 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.46 (s, 3H), 2.55 (s, 3H), 7.41-7.47 (m, 4H), 7.52 (d, J = 8.6 Hz, 1H), 7.67 (dd , J = 8.6, 2.1 Hz, 1H), 8.14 (d, J = 0.9 Hz, 1H), 14.30 (s, 1H).
[209]
[210]
Synthesis of 2-(3-methylphenyl)-3-carboxy-7-chloro-( 4H )-4-benzopyranone
[211]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphorane compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), m-toluoyl chloride (0.030 mL, 0.23 mmol, 1.2 eq), 4-(dimethylamino)pyridine (5 mg) was stirred in methylene chloride (3 mL) for 24 hours, stirred in toluene (6 mL) for 144 hours, and then TFA. (3 mL), stirred in methylene chloride (3 mL) for 1 hour 30 minutes, and the final target compound 2-(3-methylphenyl)-3-carboxy-7-chloro-( 4H )-4-benzopyranone 28.4 mg (48.0%) was obtained.
[212]
mp 179-181 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.46 (s, 3H), 7.43-7.46 (m, 4H), 7.56 (dd, J = 8.6, 1.5 Hz, 1H), 7.66 (s, 1H), 8.30 (d, J = 8.6 Hz, 1H), 13.95 (s, 1H).
[213]
[214]
Synthesis of 2-(3-methylphenyl)-3-carboxy-6-chloro-( 4H )-4-benzopyranone
[215]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphorane compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), m-toluoyl chloride (0.030 mL, 0.23 mmol, 1.2 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 24 hours, stirred in toluene (6 mL) for 144 hours, and then TFA (3 mL), stirred in methylene chloride (3 mL) for 1 hour 30 minutes, and the final target compound 2-(3-methylphenyl)-3-carboxy-6-chloro-(4 H )-4-benzopyranone 13.4 mg (22.6%) was obtained.
[216]
mp 218-220 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.46 (s, 3H), 7.44-7.47 (m, 4H), 7.52 (d, J = 8.9 Hz, 1H), 7.95 (dd, J = 8.9, 2.4 Hz , 1H), 8.49 (d, J = 2.4 Hz, 1H), 13.80 (s, 1H).
[217]
[218]
Synthesis of 2-(3-methylphenyl)-3-carboxy-6-bromo-( 4H )-4-benzopyranone
[219]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphorane compound (100 mg, 0.17 mmol), diisopropylethylamine (0.061 mL, 0.34 mmol, 2 eq), m-toluoyl Chloride (0.027 mL, 0.20 mmol, 1.2 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 24 hours, and then stirred in toluene (6 mL) for 144 hours, TFA (3 mL), stirred in methylene chloride (3 mL) for 1 hour 30 minutes, the final target compound 2-(3-methylphenyl)-3-carboxy-6-bromo-( 4H )-4-benzopyranone 21.6 mg (34.6%) was obtained.
[220]
mp 208-210 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.47 (s, 3H), 7.42-7.47 (m, 4H), 7.59 (d, J = 8.9 Hz, 1H), 7.80 (dd, J = 8.9, 2.5 Hz , 1H), 8.32 (d, J = 2.5 Hz, 1H), 13.90 (s, 1H).
[221]
[222]
Synthesis of 2-(2-thiophenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone
[223]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-thiophene Carbonyl chloride (0.031 mL, 0.30 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 1 hour, and then in toluene (6 mL) for 21 hours. Then, the final target compound 2-(2-thiophenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone by stirring for 1 hour in TFA (3 mL) and methylene chloride (3 mL) 26.5 mg (47.3%) was obtained.
[224]
mp 205-206 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.63 (s, 3H), 7.25-7.26 (m, 4H), 7.45 (dd, J = 7.7, 7.7 Hz, 1H), 7.68 (d, J = 7.7 Hz , 1H), 7.83 (dd, J = 5.0, 1.0 Hz, 1H), 8.14 (d, J = 7.7 Hz, 1H), 8.38 (dd, J = 4.0, 1.0 Hz, 1H).
[225]
[226]
Synthesis of 2-(2-thiophenyl)-3-carboxy-7-methyl-( 4H )-4-benzopyranone
[227]
2-hydroxy-4-methylbenzophosphoran compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-thiophene through the general synthesis method of Preparation Example 1 above. Carbonyl chloride (0.031 mL, 0.30 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 1 hour, and in toluene (6 mL) for 21 hours. Then, the final target compound 2-(2-thiophenyl)-3-carboxy-7-methyl-( 4H )-4-benzopyranone by stirring for 1 hour in TFA (3 mL) and methylene chloride (3 mL) 30.1 mg (53.8%) was obtained.
[228]
mp 202-203 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.58 (s, 3H), 7.24 (dd, J = 5.0, 4.0 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H ), 7.82 (dd, J = 5.0, 1.1 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 8.28 (dd, J = 4.0, 1.1 Hz, 1H), 14.80 (s, 1H).
[229]
[230]
Synthesis of 2-(2-thiophenyl)-3-carboxy-6-methyl-( 4H )-4-benzopyranone
[231]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 2-thiophene Carbonyl chloride (0.031 mL, 0.30 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 1 hour, and stirred in toluene (6 mL) for 30 hours. Then, the final target compound 2-(2-thiophenyl)-3-carboxy-6-methyl-( 4H )-4-benzopyranone by stirring for 1 hour in TFA (3 mL) and methylene chloride (3 mL) 50 mg (89%) were obtained.
[232]
mp 153-155 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.54 (s, 3H), 7.24 (dd, J = 5.0, 4.0 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.66 (dd, J = 8.6, 2.0 Hz, 1H), 7.82 (dd, J = 5.0, 1.1 Hz, 1H), 8.09 (s, 1H), 8.28 (dd, J = 4.0, 1.1 Hz, 1H), 14.75 (s, 1H) .
[233]
[234]
Synthesis of 2-(2-thiophenyl)-3-carboxy-7-chloro-( 4H )-4-benzopyranone
[235]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphorane compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 2-thiophene Carbonyl chloride (0.030 mL, 0.29 mmol, 1.5 eq), 4-(dimethylamino)pyridine (5 mg) was stirred for 1 hour in methylene chloride (3 mL), and stirred for 24 hours in toluene (6 mL). Then, the mixture was stirred in TFA (3 mL) and methylene chloride (3 mL) for 1 hour to give the final target compound 2-(2-thiophenyl)-3-carboxy-7-chloro-( 4H )-4-benzopyranone. 37.0 mg (63.8%) was obtained.
[236]
mp 232-233 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.20 (dd, J = 5.0, 4.0 Hz, 1H), 7.42 (dd, J = 8.5, 1.8 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H ), 7.73 (dd, J = 5.0, 1.0 Hz, 1H), 7.93 (dd, J = 4.0, 1.0 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H).
[237]
[238]
Synthesis of 2-(2-thiophenyl)-3-carboxy-6-chloro-( 4H )-4-benzopyranone
[239]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphorane compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 2-thiophene Carbonyl chloride (0.030 mL, 0.29 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 1 hour, and in toluene (6 mL) for 72 hours. Then, the mixture was stirred in TFA (3 mL) and methylene chloride (3 mL) for 1 hour to give the final target compound 2-(2-thiophenyl)-3-carboxy-6-chloro-( 4H )-4-benzopyranone. 36.7 mg (63.3%) was obtained.
[240]
mp 202-204 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.24 (dd, J = 5.0, 4.0 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 7.77 (dd, J = 8.9, 2.5 Hz, 1H ), 7.84 (dd, J = 5.0, 1.1 Hz, 1H), 8.25 (d, J = 2.5 Hz, 1H), 8.28 (dd, J = 4.0, 1.1 Hz, 1H), 14.45 (s, 1H).
[241]
[242]
Synthesis of 2-(2-thiophenyl)-3-carboxy-6-bromo-( 4H )-4-benzopyranone
[243]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphorane compound (100 mg, 0.17 mmol), diisopropylethylamine (0.061 mL, 0.34 mmol, 2 eq), 2-thiophene Necarbonyl chloride (0.028 mL, 0.26 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 1 hour, and in toluene (6 mL) for 72 hours Then, by stirring for 1 hour in TFA (3 mL) and methylene chloride (3 mL), the final target compound 2-(2-thiophenyl)-3-carboxy-6-bromo-( 4H )-4-benzo Pyranone 46.2 mg (75.7%) was obtained.
[244]
mp 210-212 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.25 (dd, J = 5.0, 4.1 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.86 (dd, J = 5.0, 1.1 Hz, 1H ), 7.93 (dd, J = 8.9, 2.4 Hz, 1H), 8.30 (dd, J = 4.1, 1.1 Hz, 1H), 8.44 (d, J = 2.4 Hz, 1H), 14.30 (s, 1H).
[245]
[246]
Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone
[247]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 3,4-dime Toxoxybenzoyl chloride (3,4-dimethoxybenzoyl chloride; 59 mg, 0.30 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 24 hours, and toluene ( 6 mL), followed by stirring for 96 hours in TFA (3 mL) and methylene chloride (3 mL) for 1 hour to obtain the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-8- 20.3 mg (30.3%) of methyl-( 4H )-4-benzopyranone was obtained.
[248]
mp 210-212 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.58 (s, 3H), 3.96 (s, 3H), 4.00 (s, 3H), 7.01 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.43 (dd, J = 8.5, 2.1 Hz, 1H), 7.48 (dd, J = 7.7, 7.7 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 8.18 (d , J = 7.7 Hz, 1H), 14.45 (s, 1H).
[249]
[250]
Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methyl-( 4H )-4-benzopyranone
[251]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 3,4-dime Toxibenzoyl chloride (59 mg, 0.30 mmol, 1.5 eq), 4-(dimethylamino)pyridine (5 mg) was stirred in methylene chloride (3 mL) for 24 hours, and stirred in toluene (6 mL) for 96 hours. Then, the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methyl-( 4H )-4- by stirring for 1 hour in TFA (3 mL) and methylene chloride (3 mL) Benzopyranone 28.4 mg (42.4%) was obtained.
[252]
mp 200-201 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.58 (s, 3H), 3.96 (s, 3H), 3.99 (s, 3H), 6.99 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.36-7.43 (m, 3H), 8.22 (d, J = 8.1 Hz, 1H), 14.45 (s, 1H).
[253]
[254]
Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-7-chloro-( 4H )-4-benzopyranone
[255]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphorane compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 3,4-dime Toxoxybenzoyl chloride (57 mg, 0.29 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 2 hours, and then in toluene (6 mL) for 100 hours. Then, the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-7-chloro-( 4H )-4- by stirring for 1 hour in TFA (3 mL) and methylene chloride (3 mL) 34.8 mg (51.2%) of benzopyranone was obtained.
[256]
mp 226-227 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 3.95 (s, 3H), 3.99 (s, 3H), 6.99 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.54 (dd, J = 8.6, 1.8 Hz, 1H), 7.66 (dd, J = 1.8 Hz, 1H), 8.28 (d, J = 8.6 Hz, 1H ), 14.10 (s, 1H).
[257]
[258]
Synthesis of 2-(3,4-dimethoxyphenyl)-3-carboxy-6-bromo-( 4H )-4-benzopyranone
[259]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphorane compound (100 mg, 0.17 mmol), diisopropylethylamine (0.061 mL, 0.34 mmol, 2 eq), 2-thiophene Necarbonyl chloride (0.028 mL, 0.26 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 1 hour, and in toluene (6 mL) for 92 hours Then, by stirring for 1 hour in TFA (3 mL) and methylene chloride (3 mL), the final target compound 2-(3,4-dimethoxyphenyl)-3-carboxy-6-bromo-( 4H )- 34 mg (48%) of 4-benzopyranone was obtained.
[260]
mp 242-243 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 3.95 (s, 3H), 3.99 (s, 3H), 6.99 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.4, 2.1 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.94 (dd, J = 8.9, 2.4 Hz, 1H), 8.48 (d, J = 2.4 Hz, 1H ).
[261]
[262]
Synthesis of 2-(3-fluorophenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone
[263]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 3-fluorobenzoyl Chloride (0.036 mL, 0.30 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 1 hour, and then stirred in toluene (6 mL) for 12 hours, TFA (3 mL), stirred in methylene chloride (3 mL) for 2 hours to final target compound 2-(3-fluorophenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone 18.7 mg (32.2%) was obtained.
[264]
mp 227-229 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.54 (s, 3H), 7.28-7.33 (m, 1H), 7.39 (d, J = 9.3 Hz, 1H), 7.46-7.49 (m. 3H), 7.71 (d, J = 7.5 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H).
[265]
[266]
Synthesis of 2-(3-fluorophenyl)-3-carboxy-7-methyl-( 4H )-4-benzopyranone
[267]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 3-fluorobenzoyl Chloride (0.036 mL, 0.30 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 1 hour, and then stirred in toluene (6 mL) for 10 hours, TFA (3 mL), stirred in methylene chloride (3 mL) for 2 hours to final target compound 2-(3-fluorophenyl)-3-carboxy-7-methyl-(4 H )-4-benzopyranone 16.1 mg (27.8%) was obtained.
[268]
mp 178-181 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.58 (s, 3H), 7.28-7.38 (m, 2H), 7.42-7.44 (m, 3H), 7.47-7.54 (m. 1H), 8.23-8.26 ( m, 1H), 14.33 (s, 1H).
[269]
[270]
Synthesis of 2-(3-fluorophenyl)-3-carboxy-6-methyl-( 4H )-4-benzopyranone
[271]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphorane compound (100 mg, 0.20 mmol), diisopropylethylamine (0.068 mL, 0.40 mmol, 2 eq), 3-fluorobenzoyl Chloride (0.036 mL, 0.30 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 1 hour, and then stirred in toluene (6 mL) for 21 hours, TFA (3 mL), stirred in methylene chloride (3 mL) for 2 hours to final target compound 2-(3-fluorophenyl)-3-carboxy-6-methyl-(4 H )-4-benzopyranone 34.2 mg (59.0%).
[272]
mp 214-215 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.56 (s, 3H), 7.30-7.33 (m, 1H), 7.35-7.39 (m, 1H), 7.42-7.45 (m, 1H), 7.47-7.54 ( m. 2H), 7.69 (dd, J = 8.6, 2.0 Hz, 1H), 8.14 (s, 1H), 14.30 (s, 1H).
[273]
[274]
Synthesis of 2-(3-fluorophenyl)-3-carboxy-7-chloro-( 4H )-4-benzopyranone
[275]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphorane compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 3-fluorobenzoyl Chloride (0.034 mL, 0.29 mmol, 1.5 eq), 4-(dimethylamino)pyridine (5 mg) was stirred in methylene chloride (3 mL) for 2 hours, and then stirred in toluene (6 mL) for 19 hours, TFA (3 mL), stirred in methylene chloride (3 mL) for 2 hours, the final target compound 2-(3-fluorophenyl)-3-carboxy-7-chloro-(4 H )-4-benzopyranone 43 mg (71.6%) was obtained.
[276]
mp 160-163 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.30-7.44 (m, 2H), 7.51 (dd, J = 8.0, 5.4 Hz, 1H), 7.58 (dd, J = 8.6, 1.8 Hz, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.71-7.75 (m, 1H), 8.31 (d, J = 8.6 Hz, 1H), 15.35 (s, 1H).
[277]
[278]
Synthesis of 2-(3-fluorophenyl)-3-carboxy-6-chloro-( 4H )-4-benzopyranone
[279]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphorane compound (100 mg, 0.19 mmol), diisopropylethylamine (0.066 mL, 0.38 mmol, 2 eq), 3-fluorobenzoyl Chloride (0.034 mL, 0.29 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 2 hours, and then stirred in toluene (6 mL) for 24 hours, TFA (3 mL), stirred in methylene chloride (3 mL) for 2 hours to final target compound 2-(3-fluorophenyl)-3-carboxy-6-chloro-( 4H )-4-benzopyranone 48.0 mg (80.0%) was obtained.
[280]
mp 216-217 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.29-7.39 (m, 2H), 7.42-7.46 (m, 1H), 7.49-7.56 (m, 1H), 7.60 (d, J = 8.9 Hz, 1H) , 7.83 (dd, J = 8.9, 2.5 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 13.80 (s, 1H).
[281]
[282]
Synthesis of 2-(3-fluorophenyl)-3-carboxy-6-bromo-( 4H )-4-benzopyranone
[283]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphorane compound (100 mg, 0.17 mmol), diisopropylethylamine (0.061 mL, 0.34 mmol, 2 eq), 3-fluoro Benzoyl chloride (0.032 mL, 0.26 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (3 mL) for 1 hour, and then stirred in toluene (6 mL) for 24 hours. , TFA (3 mL), stirred in methylene chloride (3 mL) for 1 hour to obtain the final target compound 2-(3-fluorophenyl)-3-carboxy-6-bromo-( 4H )-4-benzopyra 44.9 mg (71.3%) of paddy fields were obtained.
[284]
mp 222-223 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.32-7.38 (m, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.48-7.55 (m. 2H), 7.97 (dd, J = 9.7, 2.3 Hz, 1H), 8.50 (d, J = 2.3 Hz, 1H), 13.85 (s, 1H).
[285]
[286]
Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone
[287]
2-hydroxy-3-methylbenzophosphoran compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3,5-di through the general synthesis method of Preparation Example 1 Fluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino)pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 hour 30 min, and 7 hours in toluene (9 mL) After stirring for 2 hours in TFA (6 mL) and methylene chloride (6 mL), the final target compound 2-(3,5-difluorophenyl)-3-carboxy-8-methyl-(4 H )-4-benzopyranone 92.2 mg (75.0%) was obtained.
[288]
mp 243-244 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.53 (s, 3H), 7.01-7.06 (m, 1H), 7.26-7.33 (m, 2H), 7.42-7.47 (m. 1H), 7.67 (d, J = 7.0 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H).
[289]
[290]
Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-7-methyl-( 4H )-4-benzopyranone
[291]
2-hydroxy-4-methylbenzophosphoran compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3,5-di through the general synthesis method of Preparation Example 1 Fluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred for 1 hour 30 minutes in methylene chloride (4 mL), and 7 hours in toluene (9 mL). After stirring for 2 hours, TFA (6 mL) and methylene chloride (6 mL) were stirred for 2 hours to obtain the final target compound 2-(3,5-difluorophenyl)-3-carboxy-7-methyl-(4 H )-4-benzopyranone 77.3 mg (62.9%) was obtained.
[292]
mp 220-222 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.65 (s, 3H), 7.07-7.15 (m, 1H), 7.18-7.26 (m, 2H), 7.50 (d, J = 8.2 Hz, 2H), 8.31 (d, J = 8.2 Hz, 1H), 14.34 (s, 1H).
[293]
[294]
Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-6-methyl-( 4H )-4-benzopyranone
[295]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphorane compound (200 mg, 0.40 mml), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3,5-di Fluorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred for 1 hour 30 minutes in methylene chloride (4 mL), and 10 hours in toluene (9 mL). After stirring for 2 hours, TFA (6 mL) and methylene chloride (6 mL) were stirred for 2 hours to obtain the final target compound 2-(3,5-difluorophenyl)-3-carboxy-6-methyl-(4 H )-4-benzopyranone 75.7 mg (61.5%) was obtained.
[296]
mp 238-240 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.63 (s, 3H), 7.07-7.15 (m, 1H), 7.20-7.34 (m, 2H), 7.59 (d, J = 8.6 Hz, 1H), 7.77 (dd, J = 8.6, 2.1 Hz, 1H), 8.21 (s, 1H), 14.12 (s, 1H).
[297]
[298]
Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-( 4H )-4-benzopyranone
[299]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphorane compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 3,5-di Fluorobenzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and in toluene (9 mL) for 10 hours Then, by stirring in TFA (6 mL) and methylene chloride (6 mL) for 2 hours, the final target compound 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-( 4H )- To obtain 99.0 mg (78.6%) of 4-benzopyranone.
[300]
mp 207-209 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.09-7.17 (m, 1H), 7.20-7.12 (m, 2H), 7.66 (d, J = 8.9 Hz, 1H), 7.91 (dd, J = 8.9, 2.5 Hz, 1H), 8.40 (d, J = 2.5 Hz, 1H), 14.00 (s, 1H).
[301]
[302]
Synthesis of 2-(3,5-difluorophenyl)-3-carboxy-6-bromo-( 4H )-4-benzopyranone
[303]
2-hydroxy-5-bromobenzophosphoran compound (200 mg, 0.35 mmol), diisopropylethylamine (0.121 mL, 0.70 mmol, 2 eq), 3,5- Difluorobenzoyl chloride (0.066 mL, 0.52 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and in toluene (9 mL) for 10 hours. After stirring, TFA (6 mL) and methylene chloride (6 mL) were stirred for 2 hours to obtain the final target compound 2-(3,5-difluorophenyl)-3-carboxy-6-bromo-(4 H )-4-benzopyranone 91.3 mg (69.2%) was obtained.
[304]
mp 216-218 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.01-7.08 (m, 1H), 7.14-7.18 (m, 2H), 7.51 (d, J = 8.9 Hz, 1H), 7.97 (dd, J = 8.9, 2.3 Hz, 1H), 8.48 (d, J = 2.3 Hz, 1H), 13.60 (s, 1H).
[305]
[306]
Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone
[307]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphorane compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.3-difluoro Benzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 hour 30 minutes, and stirred in toluene (9 mL) for 15 hours Then, by stirring in TFA (6 mL) and methylene chloride (6 mL) for 2 hours, the final target compound 2-(2,3-difluorophenyl)-3-carboxy-8-methyl-( 4H )- 4-benzopyranone 68.0 mg (55.3%) was obtained.
[308]
mp 167-169 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.51 (s, 3H), 7.26-7.31 (m, 2H), 7.36-7.43 (m, 1H), 7.48-7.53 (m, 1H), 7.71 (d, J = 7.3 Hz, 1H), 8.20 (d, J = 7.9 Hz, 1H), 14.21 (s, 1H).
[309]
[310]
Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-7-methyl-( 4H )-4-benzopyranone
[311]
2-hydroxy-4-methylbenzophosphoran compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.3-difluoro through the general synthesis of Preparation Example 1 Benzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino)pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 h 30 min, in toluene (9 mL) for 15 h After that, the mixture was stirred in TFA (6 mL) and methylene chloride (6 mL) for 2 hours to give the final target compound 2-(2,3-difluorophenyl)-3-carboxy-7-methyl-(4 H )- 4-benzopyranone 78.0 mg (63.4%) was obtained.
[312]
mp 155-156 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.57 (s, 3H), 7.17-7.27 (m, 3H), 7.42 (d, J = 8.2 Hz, 2H), 8.24 (d, J = 8.2 Hz, 1H ), 14.20 (s, 1H).
[313]
[314]
Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-6-methyl-( 4H )-4-benzopyranone
[315]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphorane compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.3-difluoro Benzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 hour 30 minutes, and stirred in toluene (9 mL) for 15 hours Then, by stirring in TFA (6 mL) and methylene chloride (6 mL) for 2 hours, the final target compound 2-(2,3-difluorophenyl)-3-carboxy-6-methyl-( 4H )- 4-benzopyranone 32.0 mg (26.0%) was obtained.
[316]
mp 120-122 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.55 (s, 3H), 7.24-7.30 (m, 2H), 7.35-7.43 (m, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.0 Hz, 1H), 8.14 (s, 1H), 14.15 (s, 1H).
[317]
[318]
Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-7-chloro-( 4H )-4-benzopyranone
[319]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphorane compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 2.3-difluoro Benzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 hour 30 minutes, and stirred in toluene (9 mL) for 15 hours Then, by stirring for 2 hours in TFA (6 mL) and methylene chloride (6 mL), the final target compound 2-(2,3-difluorophenyl)-3-carboxy-7-chloro-( 4H )- 2-benzopyranone 26.0 mg (20.6%) was obtained.
[320]
mp 220℃ or higher. 1 H NMR (300 MHz, CDCl 3 ): δ 6.95-7.31 (m, 2H), 7.38-7.46 (m, 1H), 7.69 (dd, J = 8.6, 1.8 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 13.85 (s, 1H).
[321]
[322]
Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-( 4H )-4-benzopyranone
[323]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphorane compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 2.3-difluoro Benzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 hour 30 minutes, and stirred in toluene (9 mL) for 15 hours Then, by stirring in TFA (6 mL) and methylene chloride (6 mL) for 2 hours, the final target compound 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-( 4H )- 34.0 mg (27.0%) of 4-benzopyranone was obtained.
[324]
mp 120℃ or higher. 1 H NMR (300 MHz, CDCl 3 ): δ 7.24-7.32 (m, 2H), 7.38-7.47 (m, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.84 (dd, J = 8.9, 2.5 Hz, 1H), 8.35 (d, J = 2.5 Hz, 1H), 13.81 (s, 1H).
[325]
[326]
Synthesis of 2-(2,3-difluorophenyl)-3-carboxy-6-bromo-( 4H )-4-benzopyranone
[327]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphorane compound (200 mg, 0.35 mmol), diisopropylethylamine (0.121 mL, 0.70 mmol, 2 eq), 3,5- Difluorobenzoyl chloride (0.066 mL, 0.52 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 hour 30 minutes, and 15 in toluene (9 mL). After stirring for an hour, TFA (6 mL) and methylene chloride (6 mL) were stirred for 2 hours to obtain the final target compound 2-(2,3-difluorophenyl)-3-carboxy-6-bromo-( 4 H ) -4- benzo obtain a non-pyrazol 90.0 mg (68.2%).
[328]
mp 120℃ or higher. 1 H NMR (300 MHz, CDCl 3 ): δ 7.17-7.53 (m, 3H), 7.61 (dd, J = 8.8, 2.3 Hz, 1H), 7.91-7.98 (m, 1H), 8.43 (d, J = 2.3 Hz, 1H), 11.80 (s, 1H).
[329]
[330]
Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone
[331]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphorane compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.5-difluoro Benzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and then stirred in toluene (9 mL) for 15 hours. , TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours to obtain the final target compound 2-(2,5-difluorophenyl)-3-carboxy-8-methyl-( 4H )-4- 104.5 mg (85.0%) of benzopyranone was obtained.
[332]
mp 170-172 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.54 (s, 3H), 7.20-7.31 (m, 3H), 7.51 (dd, J = 7.6, 7.6 Hz, 1H), 7.73 (d, J = 7.6 Hz , 1H), 8.21 (d, J = 7.6 Hz, 1H), 14.19 (s, 1H).
[333]
[334]
Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-7-methyl-( 4H )-4-benzopyranone
[335]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphorane compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.5-difluoro Benzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and then stirred in toluene (9 mL) for 15 hours. , TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours to final target compound 2-(2,5-difluorophenyl)-3-carboxy-7-methyl-( 4H )-4- 84.9 mg (69.0%) of benzopyranone was obtained.
[336]
mp 156-158 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.59 (s, 3H), 7.15-7.29 (m, 3H), 7.43 (d, J = 8.0 Hz, 2H), 8.12 (d, J = 8.0 Hz, 1H ), 14.21 (s, 1H).
[337]
[338]
Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-6-methyl-( 4H )-4-benzopyranone
[339]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphorane compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 2.5-difluoro Benzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and then stirred in toluene (9 mL) for 15 hours. , TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours to obtain the final target compound 2-(2,5-difluorophenyl)-3-carboxy-6-methyl-( 4H )-4- 82.3 mg (66.9%) of benzopyranone was obtained.
[340]
mp 120 ℃ or higher. 1 H NMR (300 MHz, CDCl 3 ): δ 2.57 (s, 3H), 7.15-7.30 (m, 3H), 7.52 (d, J = 8.6 Hz, 1H), 7.70 (dd, J = 8.6, 1.9 Hz , 1H), 8.15 (s, 1H), 14.17 (s, 1H).
[341]
[342]
Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-7-chloro-( 4H )-4-benzopyranone
[343]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-chlorobenzophosphorane compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 2.5-difluoro Benzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and then stirred in toluene (9 mL) for 15 hours. , TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours to obtain the final target compound 2-(2,5-difluorophenyl)-3-carboxy-7-chloro-( 4H )-4- 37.6 mg (29.8%) of benzopyranone was obtained.
[344]
mp 147-150 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.26-7.43 (m, 3H), 7.69 (dd, J = 8.6, 1.8 Hz, 1H), 7.75 (d, J = 1.8 Hz, 1H), 8.41 (d , J = 8.6 Hz, 1H), 13.94 (s, 1H).
[345]
[346]
Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-( 4H )-4-benzopyranone
[347]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphorane compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 2.5-difluoro Benzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq) and 4-(dimethylamino) pyridine (5 mg) were stirred in methylene chloride (4 mL) for 2 hours, and then stirred in toluene (9 mL) for 15 hours. , TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours to obtain the final target compound 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-( 4H )-4- 108.8 mg (86.4%) of benzopyranone was obtained.
[348]
mp 168-170 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.16-7.33 (m, 3H), 7.60 (d, J = 8.9 Hz, 1H), 7.84 (dd, J = 8.9, 2.5 Hz, 1H), 8.34 (d , J = 2.5 Hz, 1H), 13.77 (s, 1H).
[349]
[350]
Synthesis of 2-(2,5-difluorophenyl)-3-carboxy-6-bromo-( 4H )-4-benzopyranone
[351]
2-hydroxy-5-bromobenzophosphoran compound (200 mg, 0.35 mmol), diisopropylethylamine (0.121 mL, 0.70 mmol, 2 eq), 2,5- Difluorobenzoyl chloride (0.066 mL, 0.52 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and in toluene (9 mL) for 15 hours. After stirring, TFA (6 mL) and methylene chloride (6 mL) were stirred for 2 hours to obtain the final target compound 2-(2,5-difluorophenyl)-3-carboxy-6-bromo-(4 H )-4-benzopyranone 65.2 mg (49.4%) was obtained.
[352]
mp 152-153 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.16-7.32 (m, 3H), 7.53 (d, J = 8.9 Hz, 1H), 7.98 (dd, J = 8.9, 2.3 Hz, 1H), 8.50 (d , J = 2.3 Hz, 1H), 13.77 (s, 1H).
[353]
[354]
Synthesis of 2-(3,4-difluorophenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone
[355]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-3-methylbenzophosphorane compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3.4-difluoro Benzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and then stirred in toluene (9 mL) for 10 hours. , TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours to obtain the final target compound 2-(3,4-difluorophenyl)-3-carboxy-8-methyl-( 4H )-4- 81 mg (66%) of benzopyranone was obtained.
[356]
mp 203-204 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.55 (s, 3H), 7.29-7.38 (m, 1H), 7.45-7.58 (m, 3H), 7.73 (d, J = 6.7 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 14.30 (s, 1H).
[357]
[358]
Synthesis of 2-(3,4-difluorophenyl)-3-carboxy-7-methyl-( 4H )-4-benzopyranone
[359]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphorane compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3.4-difluoro Benzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and then stirred in toluene (9 mL) for 10 hours. , TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours to obtain the final target compound 2-(3,4-difluorophenyl)-3-carboxy-7-methyl-( 4H )-4- 47 mg (38%) of benzopyranone were obtained.
[360]
mp 202-204 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.30-7.36 (m, 1H), 7.43 (d, J = 6.9 Hz, 3H), 7.49-7.55 (m, 1H), 8.24 (d, J = 8.7 Hz , 1H), 14.30 (s, 1H).
[361]
[362]
Synthesis of 2-(3,4-difluorophenyl)-3-carboxy-6-methyl-( 4H )-4-benzopyranone
[363]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphorane compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 3.4-difluoro Benzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and then stirred in toluene (9 mL) for 10 hours. , Stirred in TFA (6 mL), methylene chloride (6 mL) for 2 hours to give the final target compound 2-(3,4-difluorophenyl)-3-carboxy-6-methyl-( 4H )-4- 70.9 mg (57.6%) of benzopyranone was obtained.
[364]
mp 222-223 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.56 (s, 3H), 7.30-7.36 (m, 1H), 7.42-7.47 (m, 1H), 7.49-7.56 (m, 2H), 7.70 (dd, J = 8.5, 1.8 Hz, 1H), 8.14 (s, 1H), 14.20 (s, 1H).
[365]
[366]
Synthesis of 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-( 4H )-4-benzopyranone
[367]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphoran compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 3,4-di Fluorobenzoyl chloride (0.071 mL, 0.57 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and in toluene (9 mL) for 10 hours Then, by stirring in TFA (6 mL) and methylene chloride (6 mL) for 2 hours, the final target compound 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-( 4H )- 100.8 mg (80.0%) of 4-benzopyranone was obtained.
[368]
mp 195-198 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.31-7.37 (m, 1H), 7.43-7.47 (m, 1H), 7.50-7.61 (m, 2H), 7.83 (dd, J = 8.9, 2.4 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H).
[369]
[370]
Synthesis of 2-(4-chlorophenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone
[371]
2-hydroxy-3-methylbenzophosphoran compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 4-chlorobenzoyl chloride through the general synthesis method of Preparation Example 1 above. (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 hour, stirred in toluene (9 mL) for 40 hours, and then TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours to provide final target compound 2-(4-chlorophenyl)-3-carboxy-8-methyl-( 4H )-4-benzopyranone 99 mg ( 81%).
[372]
mp 217-219 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.53 (s, 3H), 7.46-7.53 (m, 3H), 7.63 (dd, J = 6.7, 2.0 Hz, 2H), 7.70 (d, J = 6.7 Hz , 1H), 8.18 (d, J = 8.0 Hz, 1H), 14.35 (s, 1H).
[373]
[374]
Synthesis of 2-(4-chlorophenyl)-3-carboxy-7-methyl-( 4H )-4-benzopyranone
[375]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-4-methylbenzophosphorane compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 4-chlorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 hour, stirred in toluene (9 mL) for 70 hours, and then TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours, and the final target compound 2-(4-chlorophenyl)-3-carboxy-7-methyl-(4 H )-4-benzopyranone 105 mg ( 85%).
[376]
mp 220-222 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.56 (s, 3H), 7.40 (d, J = 6.7 Hz, 2H), 7.48 (dd, J = 6.7, 2.0 Hz, 2H), 7.60 (dd, J = 6.7, 2.0 Hz, 2H), 8.22 (d, J = 8.6 Hz, 1H), 14.35 (s, 1H).
[377]
[378]
Synthesis of 2-(4-chlorophenyl)-3-carboxy-6-methyl-( 4H )-4-benzopyranone
[379]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-methylbenzophosphorane compound (200 mg, 0.40 mmol), diisopropylethylamine (0.136 mL, 0.80 mmol, 2 eq), 4-chlorobenzoyl chloride (0.074 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 hour, stirred in toluene (9 mL) for 60 hours, and then TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours, and the final target compound 2-(4-chlorophenyl)-3-carboxy-6-methyl-(4 H )-4-benzopyranone 57.0 mg ( 46.3%) was obtained.
[380]
mp 212-227 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 2.54 (s, 3H), 7.49 (dd, J = 8.6, 2.7 Hz, 3H), 7.60 (dd, J = 8.6, 1.8 Hz, 2H), 7.67 (dd , J = 8.6, 2.1 Hz, 1H), 8.12 (s, 1H), 14.50 (s, 1H).
[381]
[382]
Synthesis of 2-(4-chlorophenyl)-3-carboxy-6-chloro-( 4H )-4-benzopyranone
[383]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-chlorobenzophosphorane compound (200 mg, 0.38 mmol), diisopropylethylamine (0.131 mL, 0.75 mmol, 2 eq), 4-chlorobenzoyl chloride (0.072 mL, 0.57 mmol, 1.5 eq), 4-(dimethylamino)pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 hour, and then stirred in toluene (9 mL) for 80 hours, followed by TFA. (6 mL), stirred in methylene chloride (6 mL) for 2 hours, and the final target compound 2-(4-chlorophenyl)-3-carboxy-6-chloro-( 4H )-4-benzopyranone 48.2 mg ( 38.3%) was obtained.
[384]
mp 227-228 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.50 (d, J = 8.5 Hz, 2H), 7.55-7.62 (m, 3H), 7.80 (dd, J = 8.9, 2.5 Hz, 1H), 8.30 (d , J = 2.5 Hz, 1H), 14.20 (s, 1H).
[385]
[386]
Synthesis of 2-(4-chlorophenyl)-3-carboxy-6-bromo-( 4H )-4-benzopyranone
[387]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-5-bromobenzophosphorane compound (200 mg, 0.35 mmol), diisopropylethylamine (0.121 mL, 0.70 mmol, 2 eq), 4-chlorobenzoyl Chloride (0.066 mL, 0.52 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 1 hour, and then stirred in toluene (9 mL) for 40 hours, TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours to final target compound 2-(4-chlorophenyl)-3-carboxy-6-bromo-( 4H )-4-benzopyranone 61.4 mg (46.5%) was obtained.
[388]
mp 211-213 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.47-7.50 (m, 3H), 7.73 (d, J = 8.5 Hz, 2H), 7.87 (dd, J = 8.8, 2.3 Hz, 1H), 8.39 (d , J = 2.3 Hz, 1H).
[389]
[390]
Synthesis of 2-(4-chlorophenyl)-3-carboxy-( 4H )-4-benzopyranone
[391]
Through the general synthesis method of Preparation Example 1, 2-hydroxybenzophosphorane compound (200 mg, 0.40 mmol), diisopropylethylamine (0.140 mL, 0.80 mmol, 2 eq), 4-chlorobenzoyl chloride (0.077 mL, 0.60 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, stirred in toluene (9 mL) for 17 hours, and then TFA (6 mL) , By stirring in methylene chloride (6 mL) for 2 hours, the final target compound 2-(4-chlorophenyl)-3-carboxy-( 4H )-4-benzopyranone 47.1 mg (38.9%) was obtained.
[392]
mp 212-213 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 7.50 (d, J= 8.6 Hz, 2H), 7.58-7.63 (m, 4H), 7.84-7.90 (m, 1H), 8.35 (dd, J = 8.2, 1.7 Hz, 1H), 14.35 (s, 1H).
[393]
[394]
Synthesis of 2-(4-chlorophenyl)-3-carboxy-8-methoxy-( 4H )-4-benzopyranone
[395]
Through the general synthesis method of Preparation Example 1, 2-hydroxy-3-methoxybenzophosphorane compound (200 mg, 0.38 mmol), diisopropylethylamine (0.132 mL, 0.76 mmol, 2 eq), 4-chlorobenzoyl Chloride (0.072 mL, 0.57 mmol, 1.5 eq), 4-(dimethylamino) pyridine (5 mg) was stirred in methylene chloride (4 mL) for 2 hours, and then stirred in toluene (9 mL) for 20 hours, TFA (6 mL), stirred in methylene chloride (6 mL) for 2 hours to final target compound 2-(4-chlorophenyl)-3-carboxy-8-methoxy-(4 H )-4-benzopyranone 30.8 mg (24.4%) was obtained.
[396]
mp 238-239 °C. 1 H NMR (300 MHz, CDCl 3 ): δ 4.02 (s, 3H), 7.34 (d, J = 8.0 Hz, 1H), 7.49-7.54 (m, 3H), 7.67 (d, J = 8.5 Hz, 2H ), 7.88 (dd, J = 8.0, 1.2 Hz, 1H), 14.30 (s, 1H).
[397]
[398]
Measurement of TNF-induced apoptosis inhibitory activity of the synthesized 4-benzopyranone derivative compound
[399]
First, apoptosis is induced when recombinant TNF is added to mouse fibroblast LM cells, and a TNF-neutralizing bioassay was constructed using this. That is, TNF (20 ng/ml) and various concentrations of the compound synthesized in the above examples were pretreated on LM cells together (5 × 10 4 cells/well), and actinomycin D (actinomycin) as a sensitizer D; 0.5 μg/ml) was added and incubated in a CO 2 incubator for 24 hours, followed by MTT assay. At this time, 10 μl of MTT (5 mg/ml stock) was added and reacted for 4 hours, dissolved in DMSO, and absorbance was measured at 570 nm. First, a single concentration (50 or 10 μM) of TNF-target predicted compounds was measured for inhibiting/neutralizing TNF apoptosis, and secondly, IC50 values ​​were obtained by treating compounds with various concentrations for the compounds having excellent effects. % inhibition of TNF was calculated by the following formula;
[Claim 1]
4-benzopyranone derivatives, characterized in that represented by the following formula (1), pharmaceutically acceptable salts, solvates, racemates or stereoisomers thereof; [Formula 1] In Formula 1, R 1 is heteroaryl or substituted phenyl; R 2 is hydrogen or lower alkyl of (C1-C4); R 3 , R 4 , R 5 and R 6 are each independently hydrogen, halogen or (C1 to C4)alkoxy.
[Claim 2]
The method of claim 1, wherein in Formula 1, R 1 is furanyl, thiophenyl, or substituted phenyl represented by R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, chloro, bromo, fluoro or methoxy 4-benzopyranone derivative, a pharmaceutically acceptable salt, solvate, racemate or stereoisomer thereof .
[Claim 3]
The method of claim 1, wherein the 4-benzopyranone derivative is 2-(2-chlorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyranone; 2-(2-chlorophenyl)-3-carboxy-(4H)-4-benzopyranone; 2-(2-furanyl)-3-carboxy-(4H)-4-benzopyranone; 2-(2-furanyl)-3-carboxy-8-methoxy-(4H)-4-benzopyranone; 2-(2-furanyl)-3-carboxy-7-methoxy-(4H)-4-benzopyranone; 2-(2-furanyl)-3-carboxy-6-methoxy-(4H)-4-benzopyranone; 2-(2-furanyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(2-furanyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(2-furanyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(2-furanyl)-3-carboxy-7-chloro-(4H)-4-benzopyranone; 2-(2-furanyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(2-furanyl)-3-carboxy-6-bromo-(4H)-4-benzopyranone; 2-(3-methylphenyl)-3-carboxy-(4H)-4-benzopyranone; 2-(3-methylphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyranone; 2-(3-methylphenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyranone; 2-(3-methylphenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyranone; 2-(3-methylphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(3-methylphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(3-methylphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(3-methylphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyranone; 2-(3-methylphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(3-methylphenyl)-3-carboxy-6-bromo-(4H)-4-benzopyranone; 2-(2-thiophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyranone; 2-(2-thiophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyranone; 2-(2-thiophenyl)-3-carboxy-6-methoxy-(4H)-4-benzopyranone; 2-(2-thiophenyl)-3-carboxy-(4H)-4-benzopyranone; 2-(2-thiophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(2-thiophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(2-thiophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(2-thiophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyranone; 2-(2-thiophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(2-thiophenyl)-3-carboxy-6-bromo-(4H)-4-benzopyranone; 2-(3,4-dimethoxyphenyl)-3-carboxy-(4H)-4-benzopyranone; 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-chloro-(4H)-4-benzopyranone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(3,4-dimethoxyphenyl)-3-carboxy-6-bromo-(4H)-4-benzopyranone; 2-(3,4-dimethoxyphenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyranone; 2-(3,4-dimethoxyphenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyranone; 2-(3-fluorophenyl)-3-carboxy-(4H)-4-benzopyranone; 2-(3-fluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(3-fluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(3-fluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(3-fluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyranone; 2-(3-fluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(3-fluorophenyl)-3-carboxy-6-bromo-(4H)-4-benzopyranone; 2-(3-fluorophenyl)-3-carboxy-7-methoxy-(4H)-4-benzopyranone; 2-(3,5-difluorophenyl)-3-carboxy-(4H)-4-benzopyranone; 2-(3,5-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(3,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(3,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(3,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(3,5-difluorophenyl)-3-carboxy-6-bromo-(4H)-4-benzopyranone; 2-(2,3-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(2,3-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(2,3-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(2,3-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyranone; 2-(2,3-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(2,3-difluorophenyl)-3-carboxy-6-bromo-(4H)-4-benzopyranone; 2-(2,5-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(2,5-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(2,5-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(2, 5-difluorophenyl)-3-carboxy-7-chloro-(4H)-4-benzopyranone; 2-(2,5-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(2,5-difluorophenyl)-3-carboxy-6-bromo-(4H)-4-benzopyranone; 2-(3,4-difluorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(3,4-difluorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(3,4-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-6-bromo-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-(4H)-4-benzopyranone; And 2-(4-chlorophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyranone derivative, characterized in that it is selected from the group consisting of, its pharmaceutically acceptable Possible salts, solvates, racemates or stereoisomers. 4-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-6-bromo-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-(4H)-4-benzopyranone; And 2-(4-chlorophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyranone derivative, characterized in that it is selected from the group consisting of, pharmaceutically acceptable thereof Possible salts, solvates, racemates or stereoisomers. 4-difluorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(3,4-difluorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-8-methyl-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-7-methyl-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-6-methyl-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-6-chloro-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-6-bromo-(4H)-4-benzopyranone; 2-(4-chlorophenyl)-3-carboxy-(4H)-4-benzopyranone; And 2-(4-chlorophenyl)-3-carboxy-8-methoxy-(4H)-4-benzopyranone derivative, characterized in that it is selected from the group consisting of, its pharmaceutically acceptable Possible salts, solvates, racemates or stereoisomers.
[Claim 4]
It contains a 4-benzopyranone derivative represented by the following formula (1), a pharmaceutically acceptable salt, solvate, racemate, or stereoisomer thereof as an active ingredient, and directly binds to tumor necrosis factor (TNF) to activate TNF. A pharmaceutical composition for preventing or treating TNF-related diseases, characterized in that it inhibits; [Formula 1] In Formula 1, R 1 is heteroaryl or substituted phenyl; R 2 is hydrogen or lower alkyl of (C1-C4); R 3 , R 4 , R 5 and R 6 are each independently hydrogen, halogen or (C1 to C4)alkoxy.
[Claim 5]
The method of claim 4, wherein in Formula 1, R 1 is furanyl, thiophenyl, or substituted phenyl represented by R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, chloro, bromo, fluoro or methoxy, characterized in that the TNF-related disease prevention or treatment pharmaceutical composition.
[Claim 6]
The method of claim 4, wherein the TNF-related disease is selected from the group consisting of autoimmune diseases, inflammatory diseases, cardiovascular diseases, metabolic diseases, immune disorders, neurological diseases, ophthalmic diseases, skin diseases, mental diseases, infectious diseases and cancer. A pharmaceutical composition for preventing or treating TNF-related diseases, characterized in that any one.
[Claim 7]
The method of any one of claims 4 to 6, wherein the TNF-related disease is rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, plaque psoriasis, juvenile plaque psoriasis, psoriatic arthritis. , Polyarticular pediatric idiopathic arthritis, Behcet's enteritis, ankylosing spondylitis, axial spondyloarthritis, pediatric bone-attached arthritis, multiple rheumatoid myalgia, multiple sclerosis, thyroiditis, delayed hypersensitivity, allergy, contact dermatitis, atopic dermatitis, systemic lupus erythematosus , Systemic sclerosis, adult still disease, asthma, autoimmune thyroid disorder, Sjogren's syndrome, Kawasaki disease, pancreatitis, nephritis, hepatitis, pneumonia, chronic obstructive pulmonary disease, otitis media, vasculoplastic nephritis, myelodysplastic syndrome, osteoarthritis, sarcoidosis, Cyclic granuloma, Wegener's granulomatosis, lupus, hemolytic uremic syndrome, arteriosclerosis, vasculitis, heart failure, stroke, myocardial infarction, myocardial ischemia-reperfusion injury, sexual dysfunction, obesity, hypertension, diabetes and diabetes complications, hyperlipidemia, preeclampsia, kidney disease, liver disease , Kidney damage, liver damage, snake bite, allograft rejection, organ transplant, graft versus host disease, dementia, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, pain, central nervous system disease, uveitis, Behcet's disease, diabetic macular edema, Macular degeneration, orbital disease, glaucoma, purulent cholecystitis, multiple psychotic reticular hyperplasia, porous red nasal hyperplasia, eosinophilic fasciitis, fatty stratitis, diabetic oligodendrogenic necrosis, scarlike celestial ulcer, necrotizing pyoderma, sweet syndrome, keratinocytes Arous dermatosis, sclerosis, neutrophilic dermatitis, toxic epidermal necrosis fusion, pustular dermatitis, dermatitis, polymyositis, blister dermatitis, erythema nodosa, alopecia, depression, bipolar disorder, anxiety disorder, tuberculosis, viral infection, bacterial infection, Fungal infection, protozoal infection, brain malaria, sepsis, septic shock, prostate cancer, skin cancer, colon cancer, kidney cancer, pancreatic cancer, ovarian cancer, breast cancer, bladder cancer,TNF-related disease prevention or treatment pharmaceutical composition, characterized in that selected from the group consisting of prostate cancer, lymphoma, gliomas, osteosarcoma, leukemia, multiple myeloma and cachexia.
[Claim 8]
[6] The pharmaceutical composition for preventing or treating TNF-related diseases according to claim 4, wherein the composition further comprises a drug.
[Claim 9]
The anti-rheumatic agent (DMARDs), non-steroidal anti-inflammatory agents (NSAIDs), steroids, anti-metabolites, anti-inflammatory substances, antibiotics, signaling / enzyme inhibitors, receptor inhibitors, HMGB1 inhibitors, anti A pharmaceutical composition for the prevention or treatment of TNF-related diseases, characterized in that it is selected from thrombus, autophagy agonist, cytokine inhibitor, HMG-CoA reductase inhibitor, antihypertensive agent, anticancer agent, immune activator, B cell inhibitor and T cell inhibitor .
[Claim 10]
The drug according to claim 8 or 9, wherein the drug is methotrexate, hydrochloroquine, sulfasalazine, leflunomide, bushramin, cyclosporine, tacrolimus, azathioprine, cyclophosphamide, mizoribine, penicillamine, oral gold Formulations, antimalarial agents, 6-mercaptopurine, indomethacin, naproxen, sulindac, diclofenac, aceclofenac, mefenamic acid, aspirin, fenoprofen, salsalate, piroxicam, etodolac, flubiprofen, eve Propene, loxoprofen, nabumetone, ronazolac, meloxicam, fenbufen, ketorolac tromethamine, indoprofen, ketoprofen, suprofen, carprofen, thiapropenic acid, flufenamic Acid, Eveselene, Felbinac, Tolmethine, Flunixin, Celecoxib, Rofecoxib, Hydrocortisone, Cortisone, Prednisolone, Methylprednisolone, Triamcinolone, Betamethasone, Dexamethasone, Fludrocortisone, Entocot, 5-Aminosalicil Late, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine, mechloretamine, thioepaclorambucil, melphalan, carmustine, lomustine, busulfan, cestrin2, witferrin A, Celastrol, Quercetin, Luteolin, Curcumin, Meformin, Dibromomannitol, GR270773, Pentoxifylline, N-acetylcysteine, Melatonin, Resveratrol, Mesilamine, Short Chain Fatty Acids, Glutamine, Gemfibrozil, Retinoid , Hydroxyurea, trihydroxyisoflavone, deoxycampferol, camperol, gingerol, caffeic acid, cyanidine, cryptotansinone, deguelin, delphinidin, equol, ficetin, myricetin, procyanidine B2, Metronidazole, ciprofloxacin, niclosamide, thiabendazole, imifenam-cilastatin, fluoroquinolone, tofacitinib, glyburide, rolipram, doxycycline, VX-166, zVAD, L-97-1, ISO- One,Taurorusodeoxycholic acid, HK-156, A-285222, CP-0127, Bis-N-norgliovictin, aurintricarboxylic acid, chloroamidine, ouabine, terazosin, prazosin, Tranilast, apremilast, monobenzone, phenazopyridine, 546C88, NOX-100, gabexate mesylate, ulinastatin, somatostanin, octrotide, IKK inhibitor, caspase inhibitor, TAK- 242, erythoran, ki16425, camptothecin, caffeic acid phenethyl ester, sulforaphane, Tim-3, BN-52021, BB-882, TCV-309, CT-400, ethylpyruvate, hemin, CORM-2, tansy Non-IIA sulfonate, nicotine, EGCG, isoramnetin-3-O-galactoside, pulcicarin, catechin, carbenoxolone, glycyrrhizin, emodin-6-ObD-glucoside, acteoside, forcytoside B, Rosmarinic acid, chlorogenic acid, inflachromin, cilostazol, clopidogrel, sapogrylate, drotrecoginalfa, carbamazepine, chloroquine, anakinra, tocilizumab, LMT-28, 1-(30dimethylaminopropyl) )-3-ethylurea, gp130Fc, Beta-Arrestin2, IL-30, Diaserine, Secukinumab, Ustekinumab, Ixekizumab, Thalidomide, Adalimumab, Infliximab, Pravastatin, Ato Vastatin, rosuvastatin, simvastatin, losartan, telmisartan, hydrochlorothiazide, furosemide, propranolol, metoprolol, captopril, amlodipine, clonidine, methyldopa, minoxidil, streptozotocin, mitomycin, cisplatin, daunoru Bicine, doxorubicin, dactinomycin, bleomycin, mithramycin, anthramycin, calicheamicin, duocarmycinvincristine, taxol, docetaxel, cytocalacin B, gramicidine D,Ethidium bromide, emethine, mitomycin, etoposide, tenofoside, vincristine, vinblastine, colchicine, dihydroxy anthracene dione, mitoxantrone, mitramicin, actinomycin D, 1-dehydrotestosterone , Procaine, tetracaine, lidocaine, propranolol, tamoxifen, bazedoxifen, furomycin, anetholtrithione, nivolumab, pembrolizumab, ipilimumab, atezolizumab, alphagalatosylceramide, SRT3025, DTA- 1, IL-7, IL-2, IL-15, CXCL1, ATRA, gemcitabine, carboplanin, NCX-4016, CDDO-Me, sunitinib, zoledronic acid, astragalus polysaccharide, rituximab , Immuran, avatarcept, GW9662, rosiglitazone, Y-27632, and a pharmaceutical composition for the prevention or treatment of TNF-related diseases, characterized in that selected from the group consisting of alefacept.
[Claim 11]
A 4-benzopyranone derivative represented by the following Formula 1, a pharmaceutically acceptable salt, solvate, racemate, or stereoisomer thereof is included as an active ingredient, and the activity of TNF by binding directly to tumor necrosis factor (TNF) A health functional food composition for preventing or improving TNF-related diseases, characterized in that to inhibit the; [Formula 1] In Formula 1, R 1 is heteroaryl or substituted phenyl; R 2 is hydrogen or lower alkyl of (C1-C4); R 3 , R 4 , R 5 and R 6 are each independently hydrogen, halogen or (C1 to C4)alkoxy.
[Claim 12]
The method of claim 11, wherein in Formula 1, R 1 is furanyl, thiophenyl, or substituted phenyl represented by R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently hydrogen, chloro, bromo, fluoro or methoxy TNF-related disease prevention or improvement health functional food composition, characterized in that.
[Claim 13]
Treatment of TNF-related diseases, comprising treating a 4-benzopyranone derivative represented by the following Formula 1, a pharmaceutically acceptable salt, solvate, racemate, or stereoisomer thereof in a pharmaceutically effective amount How to; [Formula 1] In Formula 1, R 1 is heteroaryl or substituted phenyl; R 2 is hydrogen or lower alkyl of (C1-C4); R 3 , R 4 , R 5 and R 6 are each independently hydrogen, halogen or (C1 to C4)alkoxy.
[Claim 14]
4-benzopyranone derivatives represented by the following formula (1), including pharmaceutically acceptable salts, solvates, racemates or stereoisomers thereof as active ingredients, and inhibiting the activity of TNF in vitro Reagent composition; [Formula 1] In Formula 1, R 1 is heteroaryl or substituted phenyl; R 2 is hydrogen or lower alkyl of (C1-C4); R 3 , R 4 , R 5 and R 6 are each independently hydrogen, halogen or (C1 to C4)alkoxy.
[Claim 15]
A method for inhibiting TNF activity, comprising treating a 4-benzopyranone derivative represented by the following formula (1), a pharmaceutically acceptable salt, solvate, racemate, or stereoisomer thereof in animals other than humans; [Formula 1] In Formula 1, R 1 is heteroaryl or substituted phenyl; R 2 is hydrogen or lower alkyl of (C1-C4); R 3 , R 4 , R 5 and R 6 are each independently hydrogen, halogen or (C1 to C4)alkoxy.