The present invention is explained in more detail by the following Examples. However, these Examples seek to illustrate the present invention only, and the scope of the present invention is not limited by them.
Hereinafter, M means molar concentration and N means normal concentration. Furthermore, abbreviations used in the following Preparations and Examples are as follows:
BBr3: boron tribromide
CH3CN: acetonitrile
(CH3)3P: trimethyl phosphine
Cs2CO3: cesium carbonate
DCM, MC: dichloromethane, methylene chloride
Dioxane: dioxane
DMAP: 4-dimethylaminopyridine
DMF: N,N-dimethylformamide
DMSO: dimethylsulfoxide
EtOAc: ethylacetate
EtOH: ethanol
Et2O: diethylether
HCl: hydrochloric acid
Hex: n-hexane
K2CO3: potassium carbonate
KOH: potassium hydroxide
KHMDS: potassium hexamethyldisilane
LAH: lithium aluminum hydride
LDA: lithium diisopropylamide
LiBH4: lithium borohydride
LiOH: lithium hydroxide
MeI: methyl iodide
MeOH: methanol
MgSO4: magnesium sulfate
NaBH4: sodium borohydride
NaCl: sodium chloride
NaH: sodium hydride
NaOH: sodium hydroxide
Na2S2O3·5H2O: sodium thiosulfate· pentahydrate
Pd/C: palladium/carbon
Pd2(dba)3: tris(dibenzylidene acetone)dipalladium(0)
SOCl2: thionyl chloride
TEA: triethylamine
TFA: trifluoroacetic acid
THF: tetrahydrofurane
Preparation Example 1: 3-chloromethyl-2-isopropylsulfanyl-pyridine
Step A: 2-isopropylsulfanyl-nicotinic acid
2-Mercapto-nicotinic acid (5.0 g, 32.22 mmol) was dissolved in DMF (40 mL), and the solution was cooled to 0~5℃. NaH (6.4 g, 161.1 mmol) was added thereto slowly, and the mixture was stirred at 0~5℃ for 30 minutes. 2-Iodo-propane (9.65 mL, 96.66 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure and water was added to dilute the residue. 3N HCl was added to adjust the pH of the aqueous solution to 2~3, and the mixture was extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The reaction product was used in the next step without a separate purification process.
1H-NMR (DMSO-d6) δ 8.57(1H, m), 8.12(1H, m), 7.16(1H, m), 3.96(1H, m), 1.28(6H, d)
Step B: (2-isopropylsulfanyl-pyridin-3-yl)-methanol
2-Isopropylsulfanyl-nicotinic acid obtained in Step A was dissolved in THF (50 mL), and the solution was cooled to 0~5℃. LAH (3.06 g, 80.55 mmol) was added thereto slowly, and the mixture was stirred at 0~5℃ for 30 minutes and then at room temperature for 2 hours. After the termination of the reaction, saturated sodium sulfate aqueous solution was added thereto and the mixture was stirred for 30 minutes. After the addition of EtOAc, solid material was removed by using cellite. The organic layer was dried with MgSO4, filtrated and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex = 1/3) to obtain the title compound (3.94 g, 67%).
1H-NMR (CDCl3) δ 8.37(1H, m), 7.61(1H, m), 7.02(1H, m), 4.66(2H, s), 4.16(1H, m), 1.42(6H, d)
Step C: 3-chloromethyl-2-isopropylsulfanyl-pyridine
(2-Isopropylsulfanyl-pyridin-3-yl)-methanol (3.0 g, 16.37 mmol) obtained in Step B was dissolved in CH3CN (20 mL), and SOCl2 (2.39 mL, 32.74 mmol) was added thereto dropwise at 0℃. The mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure. After the addition of EtOAc, the organic layer was washed with water, dried with MgSO4, filtrated and concentrated under reduced pressure to obtain the title compound (3.04 g, 92%).
1H-NMR (CDCl3) δ 8.41(1H, m), 7.61(1H, m), 7.01(1H, m), 4.6 0(2H, s), 4.17(1H, m), 1.41(6H, d)
Preparation Example 2: 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester
Step A: 3,5-difluoro-4-hydroxy-benzaldehyde
TFA (7 mL) was added to 2,6-difluoro-phenol (1.0 g, 7.69 mmol) and hexamethylenetetraamine (1.08 g, 7.69 mmol), and the mixture was stirred at 75~80℃ for 12 hours. The reactant was cooled, diluted with water, and then extracted with DCM/MeOH (9:1) solution three or four times. The organic layer was concentrated under reduced pressure, and DCM was added to the residue. The mixture was dried with MgSO4 and concentrated under reduced pressure. The reaction product was used in the next step without a separate purification process.
Step B: 4-benzyloxy-3,5-difluoro-benzaldehyde
3,5-Difluoro-4-hydroxy-benzaldehyde obtained in Step A was dissolved in CH3CN (15 mL), and Cs2CO3 (6.3 g, 19.23 mmol) was added to the solution. The mixture was cooled to 0~5℃. Benzylbromide (1.1 mL, 9.23 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was filtered and then concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex = 1/7) to obtain the title compound (1.76 g, 92%).
1H NMR (400 MHz, CDCl3) δ 9.81(t, 1H), 7.46-7.31(m, 7H), 5.32(s, 2H)
Step C: (
E
)-3-(4-benzyloxy-3,5-difluoro-phenyl)-acrylic acid ethyl ester
4-Benzyloxy-3,5-difluoro-benzaldehyde (1.2 g, 4.83 mmol) obtained in Step B and carbethoxymethylene triphenylphosphorane (2.0 g, 5.78 mmol) was dissolved in THF (10 mL), and the solution was stirred at 65~75℃ for 1 hour. After the termination of the reaction, the reactant was cooled and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex = 1/10) to obtain the title compound (1.2 g, 78%).
1H NMR (400 MHz, CDCl3) δ 7.48(d, 1H), 7.45-7.40(m, 2H), 7.39-7.29(m, 3H), 7.02(d, 2H), 6.29(d, 1H), 5.21(s, 2H), 4.25(q, 2H), 1.32(t, 3H)
Step D: 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester
(E)-3-(4-Benzyloxy-3,5-difluoro-phenyl)-acrylic acid ethyl ester (1.2 g, 3.77 mmol) obtained in Step C was dissolved in EtOH (20 mL), and 10% Pd/C (120 mg) was added to the solution. The mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. The reactant was filtered by using celite and concentrated under reduced pressure to obtain the title compound (0.85 g, 98%).
1H NMR (400 MHz, CDCl3) δ 6.77(d, 2H), 4.11(q, 2H), 2.83(t, 2H), 2.59(t, 2H), 1.22(t, 3H)
Preparation Example 3: 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester
Step A: (
E
)-3-(4-benzyloxy-phenyl)-2-methyl-acrylic acid ethyl ester
Carbethoxyethylidene triphenylphosphorane (1.02 g, 2.81 mmol) was dissolved in anhydrous THF (25 mL), and 4-benzyloxy-benzaldehyde (0.5 g, 2.36 mmol)/THF (10 mL) solution was added dropwise thereto at -78℃. The mixture was heated slowly to room temperature and then stirred for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure. The residue was added with water and then extracted with EtOAc. The organic layer was dried with MgSO4 and purified by column chromatography (eluent, EtOAc/Hex = 1/9) to obtain the title compound (0.68 g, 97.4%).
1H NMR (400 MHz, CDCl3) δ 1.28 and 1.34 (2t, 3H), 2.05 and 2.13 (2s, 3H), 4.18-4.30 (2q, 2H), 5.10 (s, 2H), 6.97-7.02 (m, 2H), 7.31-7.45 (m, 7H), 7.64 (br. s, 1H)
Step B: 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester
(E)-3-(4-Benzyloxy-phenyl)-2-methyl-acrylic acid ethyl ester (0.68 g, 2.29 mmol) obtained in Step A was reacted in the same manner as in Step D of Preparation Example 2 to obtain the title compound (0.47 g, 98.4%).
1H NMR (400 MHz, CDCl3) δ 1.14 (d, 3H), 1.19 (t, 3H), 2.57-2.75 (m, 2H), 2.85-2.30 (m, 1H), 4.09 (d, 2H), 6.74(d, 2H), 7.03(d, 2H)
Preparation Example 4: 3-(4-hydroxy-phenyl)-propionic acid methyl ester
After 3-(4-hydroxy-phenyl)propionic acid (3 g, 18 mmol) was added with MeOH (6 mL), 4M HCl/dioxane solution (18 mL, 72 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reactant was concentrated, added with EtOAc, and then washed with NaCl aqueous solution. The organic layer was separated, dried with MgSO4, and filtered to obtain the title compound (3.26 g, 99%).
1H-NMR (CDCl3) δ 7.06(2H, m), 6.75(2H, m), 4.79(1H, brs, OH), 3.66(3H, s), 2.88(2H, t), 2.59(2H, t)
Preparation Example 5: 2-sec-butylsulfanyl-6-chloromethyl-pyridine
Step A: 6-sec-butylsulfanyl-pyridine-2-carboxylic acid ethyl ester
6-Mercapto-pyridine-2-carboxylic acid ethyl ester (0.25 g, 1.3 mmol) was added with DMF (7 mL), and the mixture was cooled to 0℃. NaH (0.065 g, 1.56 mmol) was added thereto, and the mixture was stirred for 30 minutes. 2-Iodobutane (0.2 mL, 1.56 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reactant was added with water and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and purified by column chromatography to obtain the title compound (0.17 g, 52%).
1H-NMR (CDCl3) δ 7.74(1H, d), 7.56(1H, t), 7.28(1H, d), 4.40(2H, q), 3.96(1H, m), 1.80(1H, m), 1.70(1H, m), 1.40(3H+3H), 1.03(3H, t)
Step B: (6-sec-butylsulfanyl-pyridin-2-yl)-methanol
6-sec-Butylsulfanyl-pyridine-2-carboxylic acid ethyl ester (0.17 g, 0.71 mmol) obtained in Step A was dissolved in anhydrous THF (3 mL). 2.0 M LiBH4 solution (0.5 mL, 1.0 mmol) was added thereto, and the mixture was stirred at 40℃ for 1 hour. After the termination of the reaction, the reactant was cooled to room temperature. The reactant was added with water and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.126 g, 90%).
1H-NMR (CDCl3) δ 7.47(1H, m), 7.06(1H, m), 6.86(1H, m), 4.70(2H, d), 3.84(1H, m), 3.71(1H, t, OH), 1.76(1H, m), 1.70(1H, m), 1.40(3H, d), 1.03(3H, t)
Step C: 2-sec-butylsulfanyl-6-chloromethyl-pyridine
(6-sec-Butylsulfanyl-pyridin-2-yl)-methanol (0.126 g, 0.64 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 1 to obtain the title compound (0.128 g, 93%).
1H-NMR (CDCl3) δ 7.47(1H, m), 7.09(2H, m), 4.59(2H, s), 3.87(1H, m), 1.73(1H, m), 1.67(1H, m), 1.38(3H, d), 1.02(3H, t)
Preparation Example 6: 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester
Step A: 1-benzyloxy-4-bromo-2-fluoro-benzene
DMF (12 mL), K2CO3 (1.19 g, 8.55 mmol) and benzyl bromide (0.75 mL, 6.27 mmol) was added to 4-bromo-2-fluorophenol (1.1 g, 5.7 mmol), and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated and the residue was diluted with 20mL water. The mixture was extracted with EtOAc. The organic layer was separated and dried with MgSO4 to obtain the title compound (1.62 g, 100%).
Step B: (
E
)-3-(4-benzyloxy-3-fluoro-phenyl)-acrylic acid methyl ester
1-Benzyloxy-4-bromo-2-fluoro-benzene (1.62 g, 5.7 mmol) obtained in Step A was added with methyl acrylate (1 mL), 1,4-dioxane (19 mL), Pd2(dba)3 (0.1 g, 0.11 mmol), TEA (1.6 mL, 11.4 mmol) and tri-t-butylphosphine tetrafluoroborate (0.16 g, 0.57 mmol), and the mixture was stirred at 100℃ for 6 hours. The reactant was filtered by using celite, and the filtrate was washed with EtOAc and purified by column chromatography to obtain the title compound (0.37 g, 22%).
1H-NMR (CDCl3) δ 7.58(1H, d, J=15.9Hz), 7.44-7.28(6H, m), 7.19(1H, m), 6.98(1H, t), 6.28(1H, d, J=15.9Hz), 5.18(2H, s), 3.79(3H, s)
Step C: 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester
(E)-3-(4-Benzyloxy-3-fluoro-phenyl)-acrylic acid methyl ester (0.37 g, 1.2 mmol) obtained in Step B was dissolved in EtOAc (4 mL) and MeOH (2 mL). The solution was added with 10% Pd/C (0.03 g), and the mixture was stirred under hydrogen atmosphere for 18 hours. The reactant was filtered by using celite, and the filtrate was washed with EtOAc to obtain the title compound (0.25 g, 98%).
1H-NMR (CDCl3) δ 6.93(1H, m), 6.91(1H, m), 6.85(1H, m), 5.02(1H, brs, OH), 3.67(3H, s), 2.87(2H, t), 2.59(2H, t)
Preparation Example 7: 3-(2-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester
Step A: (
E
)-3-(2-fluoro-4-methoxy-phenyl)-acrylic acid ethyl ester
2-Fluoro-4-methoxy-benzaldehyde (2 g, 12.98 mmol) was reacted in the same manner as in Step C of Preparation Example 2 to obtain the title compound (2.90 g, 99.7%).
1H NMR (400 MHz, CDCl3) δ 7.75(1H, d, 16Hz), 7.45(1H, t, 8Hz), 6.71(1H, dd, 8 and 2 Hz), 6.64(1H, dd, 12 and 2 Hz), 6.41(1H, d, 16Hz), 4.26(2H, q, 7Hz), 3.83(3H, s), 1.33(3H, t, 7Hz)
Step B: 3-(2-fluoro-4-methoxy-phenyl)-propionic acid ethyl ester
(E)-3-(2-Fluoro-4-methoxy-phenyl)-acrylic acid ethyl ester (2.90 g, 12.93 mmol) obtained in Step A was reacted in the same manner as in Step D of Preparation Example 2 to obtain the title compound (2.85 g, 97%).
1H NMR (400 MHz, CDCl3) δ 7.10(1H, t, 8Hz), 6.63-6.57(2H, m), 4.12(2H, q, 7Hz), 3.83(3H, s), 2.90(2H, t, 8Hz), 2.58(2H, t, 8Hz), 1.23(3H, t, 7Hz)
Step C: 3-(2-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester
3-(2-Fluoro-4-methoxy-phenyl)-propionic acid ethyl ester (2.5 g, 11.05 mmol) obtained in Step B was dissolved in anhydrous DCM (10 mL). 1M BBr3 solution (33 mL, 33.15 mmol) was added thereto at -78℃, and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, MeOH was added to the reactant. The mixture was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex = 1/2) to obtain the title compound (1.88 g, 80%).
1H NMR (400 MHz, CDCl3) δ 7.03(1H, t, 8Hz), 6.55-6.51(2H, m), 5.38(1H, brs), 4.13(2H, q, 7Hz), 2.89(2H, t, 8Hz), 2.59(2H, t, 8Hz), 1.24(3H, t, 7Hz)
Preparation Example 8: 3-chloromethyl-2-cyclopentylsulfanyl-pyridine
Step A: 2-cyclopentylsulfanyl-nicotinic acid
2-Mercapto-nicotinic acid (1.0 g, 6.44 mmol) and bromo-cyclopentane (2 mL, 19.33 mmol) were reacted in the same manner as in Step A of Preparation Example 1 to obtain the title compound, which was used in the next step without a separate purification process.
Step B: (2-cyclopentylsulfanyl-pyridin-3-yl)-methanol
2-Cyclopentylsulfanyl-nicotinic acid obtained in Step A was reacted in the same manner as in Step B of Preparation Example 1 to obtain the title compound (0.65 g, 47%).
1H-NMR (CDCl3) δ 8.41-8.40(1H, m), 7.64-7.62(1H, m), 7.06-7.03(1H, q), 4.70-4.69(2H, d), 4.27-4.20(1H, m), 2.28-2.19(2H, m), 1.81-1.78(2H, m), 1.69-1.63(4H, m)
Step C: 3-chloromethyl-2-cyclopentylsulfanyl-pyridine
(2-Cyclopentylsulfanyl-pyridin-3-yl)-methanol (0.6 g, 2.87 mmol) obtained in Step B was dissolved in CH3CN (5 mL), and SOCl2 (0.42 mL, 5.74 mmol) was added thereto at 0℃. The mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Preparation Example 9: 3-chloromethyl-2-isopropylsulfanyl-6-methyl-pyridine
Step A: 2-chloro-6-methyl-nicotinic acid methyl ester
2-Chloro-6-methyl-nicotinic acid (3.58 g, 20.86 mmol) was dissolved in DMF (34 mL). MeI (5.8 mL, 93.88 mmol) and K2CO3 (7.78 g, 56.33 mmol) were added thereto, and the mixture was stirred at room temperature for 2 hours. The reactant was distilled under reduced pressure to remove the solvent and extracted with EtOAc. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent EtOAc/Hex = 1/2) to obtain the title compound (3.68 g, 94%).
NMR: 1H-NMR (CDCl3) 8.08(1H, d), 7.16(1H, d), 3.92(3H, s), 2.57(3H, s)
Step B: 2-isopropylsulfanyl-6-methyl-nicotinic acid methyl ester
2-Chloro-6-methyl-nicotinic acid methyl ester (1.39 g, 7.44 mmol) obtained in Step A was dissolved in DMF (15 mL). Cs2CO3 (4.88 g, 14.99 mmol) and propane-2-thiol (1.39 mL, 14.99 mmol) were added to the solution, and the mixture was stirred at room temperature for 2 hours. The reactant was concentrated under reduced pressure to remove the solvent. The residue was added with water and then extracted with EtOAc. The organic layer was dried with MgSO4, filtered and concentrated under reduced pressure. The obtained residue was purified by column chromatography (eluent EtOAc/Hex = 1/5) to obtain the title compound (1.17 g, 69%).
NMR: 1H-NMR (CDCl3) 8.06(1H, d), 6.86(1H, d), 4.15(1H, m), 3.90(3H, s), 2.53(3H, s), 1.40(6H, d)
Step C: (2-isopropylsulfanyl-6-methyl-nicotinic acid-3-yl)-methanol
2-Isopropylsulfanyl-6-methyl-nicotinic acid methyl ester (498 mg, 2.35 mmol) obtained in Step B was reacted in the same manner as in Step B of Preparation Example 1 to obtain the title compound (384 mg, 82%).
NMR: 1H-NMR (CDCl3) 7.46(1H, d), 6.86(1H, d), 4.63(2H, d), 4.17(1H, m), 2.49(3H, s), 2.01(1H, t), 1.40(6H, d)
Step D: 3-chloromethyl-2-isopropylsulfanyl-6-methyl-pyridine
(2-Isopropylsulfanyl-6-methyl-nicotinic acid-3-yl)-methanol (184 mg, 0.931 mmol) obtained in Step C was reacted in the same manner as in Step C of Preparation Example 8 to obtain the title compound, which was used in the next step without a separate purification process.
Preparation Example 10: 2-butylsulfanyl-3-chloromethyl-pyridine
Step A: 2-butylsulfanyl-nicotinic acid
After MeOH (20 mL) was added to 2-mercapto-nicotinic acid (1 g, 6 mmol), the mixture was cooled to 0℃, and 6 M NaOH aqueous solution (3.2 mL) was added slowly thereto. The reactant was stirred at 0℃ for 30 minutes. 1-Iodobutane (0.74 mL, 6 mmol) was added to the reactant, and the mixture was stirred under reflux at 80℃ for 16 hours. The reactant was concentrated under reduced pressure, and 6 M HCl aqueous solution was added thereto to adjust the pH of the solution to 7. The resulting precipitate was filtered and dried to obtain the title compound (1.27 g, 93%).
1H-NMR (DMSO-d6) δ 13.3(1H, brs), 8.61(1H, m), 8.18(1H, m), 7.21(1H, m), 3.08(2H, t), 1.59(2H, m), 1.44(2H, m), 0.90(3H, t)
Step B: (2-butylsulfanyl-pyridin-3-yl)-methanol
Anhydrous THF (30 mL) in dried flask was cooled to 0℃, LAH (1.14 g, 30 mmol) was added slowly thereto, and the mixture was stirred for 30 minutes. 2-Butylsulfanyl-nicotinic acid (1.27 g, 5.58 mmol) obtained in Step A which is dissolved in anhydrous THF (10 mL) was added slowly thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, water (10 mL) was added slowly thereto at 0℃, and the mixture was stirred for 30 minutes. The reactant was extracted with EtOAc, and the organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.85 g, 77%).
1H-NMR (CDCl3) δ 8.36(1H, m), 7.60(1H, m), 7.00(1H, m), 4.68(2H, s), 3.25(2H, t), 2.10(1H, brs), 1.68(2H, m), 1.47(2H, m), 0.94(3H, t)
Step C: 2-butylsulfanyl-3-chloromethyl-pyridine
(2-Butylsulfanyl-pyridin-3-yl)-methanol (0.85 g, 4.3 mmol) obtained in Step B was dissolved in CH3CN (20 mL). SOCl2 (0.63 mL, 8.6 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to remove the solvent and then added with EtOAc. The organic layer was washed with water, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.77 g, 82%).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.58(1H, m), 7.02(1H, m), 4.62(2H, s), 3.26(2H, t), 1.70(2H, m), 1.47(2H, m), 0.95(3H, t)
Preparation Example 11: chloromethyl-2-ethylsulfanyl-pyridine
Step A: 2-ethylsulfanyl-nicotinic acid
2-Mercapto-nicotinic acid (2 g, 12.8 mmol) and bromoethane were reacted in the same manner as in Step A of Preparation Example 1 to obtain the title compound (1.9 g, 80%).
1H-NMR (CDCl3) δ 8.61(1H, m), 8.31(1H, m), 7.08(1H, m), 3.20(2H, q), 1.38(3H, t)
Step B: (2-ethylsulfanyl-pyridin-3-yl)-methanol
2-Ethylsulfanyl-nicotinic acid (0.44 g, 2.4 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 10 to obtain the title compound (0.2 g, 49%).
1H-NMR (CDCl3) δ 8.37(1H, m), 7.60(1H, m), 7.02(1H, m), 4.68(2H, s), 3.26(2H, q), 2.00(1H, brs, OH), 1.38(3H, t)
Step C: 3-chloromethyl-2-ethylsulfanyl-pyridine
(2-Ethylsulfanyl-pyridin-3-yl)-methanol (0.2 g, 1.1 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 10 to obtain the title compound (0.2 g, 90%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.60(1H, m), 7.02(1H, m), 4.61(2H, s), 3.27(2H, q), 1.38(3H, t)
Preparation Example 12: 3-chloromethyl-2-isobutylsulfanyl-pyridine
Step A: 2-isobutylsulfanyl-nicotinic acid
2-Mercapto-nicotinic acid (2 g, 12.8 mmol) and isobutyliodide were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (2.175 g, 92%).
1H-NMR (CDCl3) δ 8.59(1H, m), 8.29(1H, m), 7.07(1H, m), 3.12(2H, d), 1.97(1H, m), 1.07(6H, d)
Step B: (2-isobutylsulfanyl-pyridin-3-yl)-methanol
2-Isobutylsulfanyl-nicotinic acid (0.43 g, 2 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 10 to obtain the title compound (0.18g, 46%).
1H-NMR (CDCl3) δ 8.36(1H, m), 7.61(1H, m), 7.01(1H, m), 4.72(2H, s), 3.20(2H, d), 1.95(1H, m), 1.06(6H, d)
Step C: 3-chloromethyl-2-isobutylsulfanyl-pyridine
(2-Isobutylsulfanyl-pyridin-3-yl)-methanol (0.18 g, 0.9 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 10 to obtain the title compound (0.18 g, 92%).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.58(1H, m), 7.01(1H, m), 4.64(2H, s), 3.19(2H, d), 1.96(1H, m), 1.06(6H, d)
Preparation Example 13: 4-(4-hydroxy-phenyl)-butyric acid ethyl ester
Step A: (4-benzyloxy-phenyl)-acetic acid methyl ester
(4-Hydroxy-phenyl)-acetic acid methyl ester (1.0 g, 6.02 mmol) was dissolved in DMF (10 mL), and K2CO3 (2.5 g, 18.06 mmol) was added thereto. Benzyl chloride (0.83 mL, 7.22 mmol) was added slowly thereto, and the mixture was stirred at 40~50℃ for 12 hours. The reactant was cooled and concentrated under reduced pressure. The residue was added with water and then extracted with EtOAc. The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent, EtOAc/Hex = 1/4) to obtain the title compound (1.4 g, 91%).
1H NMR (400 MHz, CDCl3) δ 7.43-7.27(m, 5H), 7.18(d, 2H), 6.92(d, 2H), 5.02(s, 2H), 3.66(s, 3H), 3.55(s, 2H)
Step B: 2-(4-benzyloxy-phenyl)-ethanol
(4-Benzyloxy-phenyl)-acetic acid methyl ester (1.4 g, 5.46 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 1 to obtain the title compound (0.71 g, 57%).
1H NMR (400 MHz, CDCl3) δ 7.45-7.29(m, 5H), 7.14(d, 2H), 6.93(d, 2H), 5.04(s, 2H), 3.82(q, 2H), 2.81(t, 2H), 1.39(t, 1H)
Step C: (4-benzyloxy-phenyl)-acetaldehyde
2-(4-Benzyloxy-phenyl)-ethanol (0.64 g, 2.80 mmol) obtained in Step B was dissolved in DCM (10 mL), and Dess-Martin periodinane (2.38 g, 5.60 mmol) was added thereto. The reactant was stirred at room temperature for 2 hours, diluted with DCM, and washed with Na2S2O3·5H2O aqueous solution. The remained organic solution was dried with MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex = 1/5) to obtain the title compound (0.50 g, 79%).
1H NMR (400 MHz, CDCl3) δ 9.70(t, 1H), 7.44-7.29(m, 5H), 7.12(d, 2H), 6.97(d, 2H), 5.02(s, 2H), 3.61(d, 2H)
Step D: (
E
)-4-(4-benzyloxy-phenyl)-2-betenoic acid ethyl ester
(4-Benzyloxy-phenyl)-acetaldehyde (0.5 g, 2.21 mmol) obtained in Step C was reacted in the same manner as in Step C of Preparation Example 2 to obtain the title compound (0.55 g, 84%).
Step E: 4-(4-hydroxy-phenyl)-butyric acid ethyl ester
(E)-4-(4-Benzyloxy-phenyl)-2-betenoic acid ethyl ester (0.55 g, 1.86 mmol) obtained in Step D was reacted in the same manner as in Step D of Preparation Example 2 to obtain the title compound (0.37 g, 96%).
1H NMR (400 MHz, CDCl3) δ 7.02(d, 2H), 6.75(d, 2H), 4.13(q, 2H), 2.57(t, 2H), 2.31(t, 2H), 1.91(m, 2H), 1.25(t, 3H)
Preparation Example 14: 3-chloromethyl-2-propylsulfanyl-pyridine
Step A: 2-propylsulfanyl-nicotinic acid
2-Mercapto-nicotinic acid (1 g, 6.4 mmol) and 1-iodopropane were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (1.22 g, 96%).
1H-NMR (DMSO-d6) δ 13.3(1H, brs), 8.60(1H, dd), 8.18(1H, dd), 7.20(1H, dd), 3.06(2H, t), 1.66(2H, m), 1.00(3H, t)
Step B: (2-propylsulfanyl-pyridin-3-yl)-methanol
2-Propylsulfanyl-nicotinic acid (1.22 g, 6.2 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 10 to obtain the title compound (0.9 g, 80%).
1H-NMR (CDCl3) δ 8.37(1H, m), 7.60(1H, m), 7.02(1H, m), 4.69(2H, s), 3.24(2H, t), 1.74(2H, m), 1.05(3H, t)
Step C: 3-chloromethyl-2-propylsulfanyl-pyridine
(2-Propylsulfanyl-pyridin-3-yl)-methanol (0.9 g, 4.9 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 10 to obtain the title compound (0.9 g, 91%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.59(1H, m), 7.01(1H, m), 4.62(2H, s), 3.24(2H, t), 1.74(2H, m), 1.05(3H, t)
Preparation Example 15: 3-chloromethyl-2-phenylsulfanyl-pyridine
Step A: 2-phenylsulfanyl-nicotinic acid
2-Mercapto-nicotinic acid (100 mg, 0.64 mmol) was dissolved in DMF (5 mL), and then Cu powder (82 mg, 1.28 mmol) and Cs2CO3 (630 mg, 1.92 mmol) were added in turn thereto. The mixture was stirred at 150~160℃ for 2 hours, cooled to room temperature, and concentrated under reduced pressure. After the residue was diluted with water, 1N HCl was added to adjust the pH of the solution to 2~3. EtOAc was added to the solution, and the mixture was stirred and then filtered. The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Step B: (2-phenylsulfanyl-pyridin-3-yl)-methanol
2-Phenylsulfanyl-nicotinic acid obtained in Step A was reacted in the same manner as in Step B of Preparation Example 1 to obtain the title compound (20 mg, 14%).
1H NMR (400 MHz, CDCl3) δ 8.37-8.32(m, 1H), 7.76-7.71(m, 1H), 7.49-7.44(m, 2H), 7.40-7.32(m, 3H), 7.15-7.10(m, 1H), 4.79(d, 2H), 2.14(t, 1H)
Step C: 3-chloromethyl-2-phenylsulfanyl-pyridine
(2-Phenylsulfanyl-pyridin-3-yl)-methanol (20 mg, 0.09 mmol) obtained in StepB was dissolved in CH3CN (20 mL), and SOCl2 (13 uL, 0.18 mmol) was added dropwise thereto at 0℃. The mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Preparation Example 16: 2-chloromethyl-6-isopropylsulfanyl)-pyridine
Step A: 6-isopropylsulfanyl-pyridine-2-carboxylic acid methyl ester
6-Bromo-pyridine-2-carboxylic acid methyl ester (0.15 g, 0.69 mmol) was added with DMF (2.3 mL), Cs2CO3 (0.45 g, 1.38 mmol) and 2-propanethiol (0.064 mL, 0.69 mmol) in turn, and the mixture was stirred at room temperature for 18 hours. After the termination of the reaction, the reactant was filtered and concentrated under reduced pressure to obtain the title compound (0.13 g, 88%).
1H-NMR (CDCl3) δ 7.76(1H, d), 7.58(1H, t), 7.30(1H, d), 4.07(1H, m), 3.96(3H, s), 1.40(6H, d)
Step B: (6-isopropylsulfanyl-pyridin-2-yl)-methanol
6-Isopropylsulfanyl-pyridine-2-carboxylic acid methyl ester (0.13 g, 0.61 mmol) obtained in Step A was dissolved in anhydrous THF (3 mL). 2.0M LiBH4 solution (0.5 mL, 1 mmol) was added thereto, and the mixture was stirred at 40℃ for 1 hour. After the termination of the reaction, the reactant was cooled to room temperature, added with water, and extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.08 g, 70%).
1H-NMR (CDCl3) δ 7.47(1H, t), 7.07(1H, d), 6.89(1H, d), 4.71(2H, s), 4.01(1H, m), 3.70(1H, brs, OH), 1.42(6H, d)
Step C: 2-chloromethyl-6-isopropylsulfanyl-pyridine
(6-Isopropylsulfanyl-pyridin-2-yl)-methanol (0.08 g, 0.43 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 10 to obtain the title compound (0.081 g, 92%).
1H-NMR (CDCl3) δ 7.49(1H, t), 7.13(1H, d), 7.08(1H, d), 4.61(2H, s), 4.00(1H, m), 1.40(6H, d)
Preparation Example 17: 2-t-butylsulfanyl-3-chloromethyl-pyridine
Step A: 2-t-butylsulfanyl-nicotinic acid ethyl ester
2-Chloro-nicotinic acid ethyl ester (0.23 g, 1.2 mmol) and t-butylthiol were reacted in the same manner as in Step B of Preparation Example 9 to obtain the title compound (0.125 g, 42%).
1H-NMR (CDCl3) δ 8.53(1H, m), 8.11(1H, m), 7.00(1H, m), 4.36(2H, q), 1.63(9H, s), 1.39(3H, t)
Step B: (2-t-butylsulfanyl-pyridin-3-yl)-methanol
2-t-Butylsulfanyl-nicotinic acid ethyl ester (0.125 g, 0.52 mmol) obtained in Step A was reacted in the same manner as in Step C of Preparation Example 9 to obtain the title compound (0.094 g, 91%).
1H-NMR (CDCl3) δ 8.42(1H, m), 7.62(1H, m), 7.07(1H, m), 4.70(2H, s), 1.58(9H, s)
Step C: 2-t-butylsulfanyl-3-chloromethyl-pyridine
(2-t-Butylsulfanyl-pyridin-3-yl)-methanol (0.093 g, 0.47 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 8 to obtain the title compound (0.082 g, 80%).
1H-NMR (CDCl3) δ 8.44(1H, m), 7.64(1H, m), 7.06(1H, m), 4.68(2H, s), 1.58(9H, s)
Preparation Example 18: 3-chloromethyl-2-cyclopropylmethylsulfanyl-pyridine
Step A: 2-cyclopropylmethylsulfanyl-nicotinic acid
2-Mercapto-nicotinic acid (1 g, 6.4 mmol) and bromomethyl cyclopropane were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (1.19 g, 88%).
1H-NMR (DMSO-d6) δ 8.61(1H, m), 8.20(1H, m), 7.22(1H, m), 3.01(2H, d), 1.07(1H, m), 0.53(2H, m), 0.27(2H, m)
Step B: (2-cyclopropylmethylsulfanyl-pyridin-3-yl)-methanol
2-Cyclopropylmethylsulfanyl-nicotinic acid (0.53 g, 2.5 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 10 to obtain the title compound (0.45 g, 90%).
1H-NMR (CDCl3) δ 8.36(1H, m), 7.62(1H, m), 7.03(1H, m), 4.70(2H, s), 3.21(2H, d), 2.06(1H, brs, OH), 1.15(1H, m), 0.58(2H, m), 0.32(2H, m)
Step C: 3-chloromethyl-2-cyclopropylmethylsulfanyl-pyridine
(2-Cyclopropylmethylsulfanyl-pyridin-3-yl)-methanol (0.427 g, 2.1 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 10 to obtain the title compound (0.044 g, 94%).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.60(1H, m), 7.03(1H, m), 4.64(2H, s), 3.21(2H, d), 1.17(1H, m), 0.61(2H, m), 0.34(2H, m)
Preparation Example 19: 3-chloromethyl-2-(2,2,2-trifluoro-ethylsulfanyl)-pyridine
Step A: 2-(2,2,2-trifluoro-ethylsulfanyl)-nicotinic acid
2-Mercapto-nicotinic acid (1 g, 6.4 mmol) was reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (0.46 g, 30%)
1H-NMR (DMSO-d6) δ 13.69(1H, brs), 8.70(1H, m), 8.30(1H, m), 7.36(1H, m), 4.30(2H, q)
Step B: [2-(2,2,2-trifluoro-ethylsulfanyl)-pyridin-3-yl]-methanol
2-(2,2,2-trifluoro-ethylsulfanyl)-nicotinic acid (0.46 g, 1.93 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 10 to obtain the title compound (0.38 g, 89%).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.70(1H, m), 7.11(1H, m), 4.70(2H, s), 4.12(2H, q), 1.91(1H, brs, OH)
Step C: 3-chloromethyl-2-(2,2,2-trifluoro-ethylsulfanyl)-pyridine
[2-(2,2,2-trifluoro-ethylsulfanyl)-pyridin-3-yl]-methanol (0.38 g, 1.7 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 10 to obtain the title compound (0.039 g, 95%).
1H-NMR (CDCl3) δ 8.42(1H, m), 7.65(1H, m), 7.10(1H, m), 4.60(2H, s), 4.14(2H, q)
Preparation Example 20: 2-chloromethyl-6-cyclopropylmethylsulfanyl-pyridine
Step A: 6-mercapto-pyridine-2-carboxylic acid ethyl ester
6-Hydroxy-pyridine-2-carboxylic acid ethyl ester (1.8 g, 10.7 mmol) was dissolved in THF (50 mL), and Lawesson’s reagent (2.18 g, 5.35 mmol) was added thereto. The mixture was stirred at room temperature for 24 hours. After the termination of the reaction, the reactant was added with water and then extracted with DCM. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure and then separated by column chromatography to obtain the title compound (1.17 g, 59%).
1H-NMR (DMSO-d6) δ 13.0(1H, brs), 7.47(2H, d), 7.29(1H, m), 4.33(2H, q), 1.32(3H, t)
Step B: 6-cyclopropylmethylsulfanyl-pyridine-2-carboxylic acid ethyl ester
6-Mercapto-pyridine-2-carboxylic acid ethyl ester (0.54 g, 2.94 mmol) obtained in Step A and bromomethyl cyclopropane were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (0.568 g, 81%).
1H-NMR (CDCl3) δ 7.76(1H, d), 7.59(1H, t), 7.33(1H, d), 4.42(2H, q), 3.22(2H, d), 1.43(3H, t), 1.20(1H, m), 0.60(2H, m), 0.39(2H, m)
Step C: (6-cyclopropylmethylsulfanyl-pyridin-2-yl)-methanol
6-Cyclopropylmethylsulfanyl-pyridine-2-carboxylic acid ethyl ester (0.56 g, 2.35 mmol) obtained in Step B was reacted in the same manner as in Step B of Preparation Example 16 to obtain the title compound (0.446 g, 95%).
1H-NMR (CDCl3) δ 7.48(1H, t), 7.11(1H, d), 6.90(1H, d), 4.72(2H, d), 3.68(1H, t, OH), 3.13(2H, d), 1.16(1H, d), 0.62(2H, d), 0.32(2H, d)
Step D: 2-chloromethyl-6-cyclopropylmethylsulfanyl-pyridine
(6-Cyclopropylmethylsulfanyl-pyridin-2-yl)-methanol (0.446 g, 2.28 mmol) obtained in Step C was reacted in the same manner as in Step C of Preparation Example 16 to obtain the title compound (0.43 g, 88%).
1H-NMR (CDCl3) δ 7.49(1H, t), 7.12(2H, m), 4.60(2H, s), 3.12(2H, d), 1.25(1H, m), 0.58(2H, m), 0.32(2H, m)
Preparation Example 21: 2-chloromethyl-3-isopropylsulfanyl-pyrazine
Step A: 3-mercapto-pyrazine-2-carboxylic acid methyl ester
After 3-chloro-pyrazine-2-carboxylic acid methyl ester (0.4 g, 2.3 mmol) was dissolved in MeOH (46 mL), sodium hydrosulfide monohydrate (0.65 g, 6.9 mmol) was added thereto, and the mixture was stirred at room temperature for 9 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and 1N HCl aqueous solution was used to adjust the pH of the reactant to 3. The reactant was extracted with EtOAc, and the organic layer was separated to obtain the title compound (0.35 g, 89%).
1H-NMR (CDCl3) δ 8.43(1H, m), 8.42(1H, m), 5.18(1H, brs), 4.04(3H, s)
Step B: 3-isopropylsulfanyl-pyrazine-2-carboxylic acid methyl ester
3-Mercapto-pyrazine-2-carboxylic acid methyl ester(0.35 g, 2.0 mmol) obtained in Step A and 2-iodopropane were reacted in the same manner as in Step A of Preparation Example 5 to obtain the title compound (0.267 g, 61%).
1H-NMR (CDCl3) δ 8.57(1H, d), 8.35(1H, d), 4.12(1H, m), 4.05(3H, s), 1.45(6H, d)
Step C: (3-isopropylsulfanyl-pyrazin-2-yl)-methanol
3-Isopropylsulfanyl-pyrazine-2-carboxylic acid methyl ester (0.135 g, 0.63 mmol) obtained in Step B was reacted in the same manner as in Step B of Preparation Example 16 to obtain the title compound (0.08 g, 65%).
1H-NMR (CDCl3) δ 8.32(1H, d), 8.18(1H, d), 4.62(2H, s), 4.12(1H, m), 3.96(1H, brs, OH), 1.42(6H, d)
Step D: 2-chloromethyl-3-isopropylsulfanyl-pyrazine
(3-Isopropylsulfanyl-pyrazin-2-yl)-methanol (0.08 g, 0.4 mmol) obtained in Step C was reacted in the same manner as in Step C of Preparation Example 16 to obtain the title compound (0.04 g, 49%).
1H-NMR (CDCl3) δ 8.35(1H, d), 8.21(1H, d), 4.68(2H, s), 2.10(1H, m), 1.43(6H, d)
Preparation Example 22: 3-chloromethyl-2-cyclohexylsulfanyl-pyridine
Step A: 2-cyclohexylsulfanyl-nicotinic acid
2-Mercapto-nicotinic acid (0.5 g, 3.22 mmol) was dissolved in DMF (5 mL), and the solution was cooled to 0~5℃. NaH (0.64 g, 16.11 mmol) was added slowly thereto, and the mixture was stirred at 0~5℃ for 30 minutes. Bromo-cyclohexane (1.19 mL, 9.66 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and the residue was diluted with water. 3N HCl was used to adjust the pH of the solution to 2~3, and the solution was extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Step B: (2-cyclohexylsulfanyl-pyridin-3-yl)-methanol
2-Cyclohexylsulfanyl-nicotinic acid obtained in Step A was reacted in the same manner as in Step B of Preparation Example 1 to obtain the title compound (0.29 g, 40%).
1H NMR (400 MHz, CDCl3) δ 8.36(d, 1 H), 7.59(d, 1H), 7.03-6.98(m, 1H), 4.66(d, 2H), 4.07-3.97(m, 1H), 2.31-2.24(m, 1H), 2.12-2.01(m, 2H), 1.82-1.71(m, 2H), 1.69-1.60(m, 1H), 1.56-1.40(m, 3H), 1.38-1.23(m, 2H)
Step C: 3-chloromethyl-2-cyclohexylsulfanyl-pyridine
(2-Cyclohexylsulfanyl-pyridin-3-yl)-methanol (0.25 g, 1.12 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 14 to obtain the title compound, which was used in the next step without a separate purification process.
Preparation Example 23: 3-chloromethyl-2-cyclobutylsulfanyl-pyridine
Step A: 2-cyclobutylsulfanyl-nicotinic acid
2-Mercapto-nicotinic acid (0.1 g, 0.64 mmol) was dissolved in DMF (2 mL), and the solution was cooled to 0~5℃. NaH (0.13 g, 3.2 mmol) was added slowly thereto, and the mixture was stirred at 0~5℃ for 30 minutes. Bromo-cyclobutane (0.12 mL, 1.28 mmol) was added thereto, and the mixture was stirred at 55~65℃ for 3 hours, and then stirred at room temperature for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure. The residue was diluted with water, and then 3N HCl was used to adjust the pH of the solution to 2~3. The solution was extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Step B: (2-cyclobutylsulfanyl-pyridin-3-yl)-methanol
2-Cyclobutylsulfanyl-nicotinic acid obtained in Step A was reacted in the same manner as in Step B of Preparation Example 1 to obtain the title compound (0.066 g, 52%).
1H NMR (400 MHz, CDCl3) δ 8.36-8.30(m, 1 H), 7.62-7.57(m, 1H), 7.02-6.97(m, 1H), 4.63(d, 2H), 4.54-4.45(m, 1H), 2.59-2.47(m, 3H), 2.18-1.98(m, 4H)
Step C: 3-chloromethyl-2-cyclobutylsulfanyl-pyridine
(2-Cyclobutylsulfanyl-pyridin-3-yl)-methanol (0.06 g, 0.31 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 14 to obtain the title compound, which was used in the next step without a separate purification process.
Preparation Example 24: (2-isopropylsulfanyl-pyrimidin-4-yl)-methanol
Step A: 2-chloropyrimidine-4-carboxylic acid ethyl ester
After 2-chloropyrimidin-4-carboxylic acid (0.223 g, 1.4 mmol) was dissolved in DCM (7 mL), dicyclohexylcarbodiimide (0.29 g, 1.4 mmol), DMAP (0.017 g, 0.14 mmol) and EtOH (0.1 mL, 1.4 mmol) were added thereto, and the mixture was stirred at room temperature for 24 hours. After the termination of the reaction, the reactant was filtered and separated by column chromatography to obtain the title compound (0.13 g, 50%).
Step B: 2-isopropylsulfanyl-pyrimidine-4-carboxylic acid ethyl ester
2-Chloropyrimidine-4-carboxylic acid ethyl ester (0.024 g, 0.13 mmol) obtained in Step A and 2-propanethiol were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (0.02 g, 68%).
1H-NMR (CDCl3) δ 8.72(1H, d), 7.57(1H, d), 4.46(2H, q), 3.99(1H, m), 1.44(6H, d), 1.42(3H, t)
Step C: (2-isopropylsulfanyl-pyrimidin-4-yl)-methanol
After 2-isopropylsulfanyl-pyrimidine-4-carboxylic acid ethyl ester (0.1 g, 0.44 mmol) obtained in Step B was dissolved in MeOH (4 mL), NaBH4 (0.033 g, 0.9 mmol) was added to the solution, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was added with water, and then extracted with EtOAc. The separated organic layer was dried with MgSO4 and separated by column chromatography to obtain the title compound (0.063 g, 77%).
1H-NMR (CDCl3) δ 8.46(1H, d), 6.92(1H, d), 4.68(2H, d), 3.96(1H, m), 3.24(1H, t, OH), 1.44(6H, d)
Preparation Example 25: 3-chloromethyl-2-(3,3,3-trifluoro-propylsulfanyl)-pyridine
Step A: 2-(3,3,3-trifluoro-propylsulfanyl)-nicotinic acid
2-Mercapto-nicotinic acid (1 g, 6.4 mmol) and 3-bromo-1,1,1-trifluoropropane were reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (0.16 g, 10%).
1H-NMR (DMSO-d6) δ 8.65(1H, m), 8.22(1H, m), 7.25(1H, m), 3.26(2H, m), 2.63(2H, m)
Step B: [2-(3,3,3-trifluoro-propylsulfanyl)-pyridin-3-yl]-methanol
2-(3,3,3-Trifluoro-propylsulfanyl)-nicotinic acid (0.16 g, 0.64 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 10 to obtain the title compound (0.12 g, 79%).
1H-NMR (CDCl3) δ 8.37(1H, m), 7.65(1H, m), 7.06(1H, m), 4.72(2H, s), 3.40(2H, m), 2.57(2H, m), 2.06(1H, brs, OH)
Step C: 3-chloromethyl-2-(3,3,3-trifluoro-propylsulfanyl)-pyridine
[2-(3,3,3-trifluoro-propylsulfanyl)-pyridin-3-l]-methanol obtained in Step B was reacted in the same manner as in Step C of Preparation Example 10 to obtain the title compound (0.12 g, 92%).
1H-NMR (CDCl3) δ 8.41(1H, m), 7.61(1H, m), 7.05(1H, m), 4.58(2H, s), 3.41(2H, m), 2.57(2H, m)
Preparation Example 26: 3-chloromethyl-2-(2,2-dimethyl-propylsulfanyl)-pyridine
Step A: 2-(2,2-dimethyl-propylsulfanyl)pyridine-3-carboxylic acid
2-Mercapto-nicotinic acid (0.5 g, 3.2 mmol) and 1-iodo-2,2-dimethyl-propanol weres reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (0.12 g, 16%).
1H-NMR (DMSO-d6) δ 8.60(1H, m), 8.18(1H, m), 7.20(1H, m), 3.17(2H, s), 1.00(9H, s)
Step B: [2-(2,2-dimethyl-propylsulfanyl)pyridin-3-yl]-methanol
2-(2,2-dimethyl-propylsulfanyl)pyridine-3-carboxylic acid (0.12 g, 0.53 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 10 to obtain the title compound (0.1 g, 89%).
1H-NMR (CDCl3) δ 8.35(1H, m), 7.60(1H, m), 7.02(1H, m), 4.73(2H, s), 3.30(2H, s), 1.00(9H, s)
Step C: 3-chloromethyl-2-(2,2-dimethyl-propylsulfanyl)-pyridine
[2-(2,2-dimethyl-propylsulfanyl)pyridin-3-yl]-methanol (0.1 g, 0.47 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 10 to obtain the title compound (0.035 g, 32%).
1H-NMR (CDCl3) δ 8.37(1H, m), 7.60(1H, m), 7.00(1H, m), 4.67(2H, s), 3.31(2H, s), 1.05(9H, s)
Preparation Example 27: 2-chloromethyl-6-cyclopentylsulfanyl-pyridine
Step A: 6-cyclopentylsulfanyl-pyridine-2-carboxylic acid methyl ester
6-Bromo-pyridine-2-carboxylic acid methyl ester (0.5 g, 2.3 mmol) and bromocyclopentane were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (0.45 g, 77%).
1H-NMR (CDCl3) δ 7.76(1H, dd), 7.59(1H, t), 7.32(1H, dd), 4.08(1H, m), 3.97(3H, s), 2.25(2H, m), 1.78(2H, m), 1.65(4H, m)
Step B: (6-cyclopentylsulfanyl-pyridin-2-yl)-methanol
6-Cyclopentylsulfanyl-pyridine-2-carboxylic acid methyl ester (0.45 g, 1.9 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 16 to obtain the title compound (0.276 g, 73%).
1H-NMR (CDCl3) δ 7.47(1H, t), 7.07(1H, d), 6.87(1H, d), 4.70(2H, d), 4.04(1H, m), 3.79(1H, t, OH), 2.20(2H, m), 1.79(2H, m), 1.66(4H, m)
Step C: 2-chloromethyl-6-cyclopentylsulfanyl-pyridine
(6-Cyclopentylsulfanyl-pyridin-2-yl)-methanol (0.276 g, 1.3 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 16 to obtain the title compound (0.276 g, 92%).
1H-NMR (CDCl3) δ 7.49(1H, t), 7.12(1H, d), 7.09(1H, d), 4.60(2H, s), 4.02(1H, m), 2.21(2H, m), 1.78(2H, m), 1.64(4H, m)
Preparation Example 28: 2-chloromethyl-6-cyclohexylsulfanyl-pyridine
Step A: 6-cyclohexylsulfanyl-pyridine-2-carboxylic acid methyl ester
After 6-bromo-pyridine-2-carboxylic acid methyl ester (0.30 g, 1.39 mmol) was dissolved in DMF (4 mL), K2CO3 (0.575 g, 4.16 mmol) and cyclohexanethiol (0.25 mL, 2.08 mmol) were added thereto in turn, and the mixture was stirred at 70℃ for 18 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, extracted with EtOAc, and purified by column chromatography (eluent, EtOAc/Hex = 1/5) to obtain the title compound (0.162 g, 46%).
1H-NMR (CDCl3) δ 7.77-7.75(1H, d), 7.60-7.56(1H, t), 7.31-7.29(1H, d), 3.97(3H, s), 3.90-3.89(1H, m), 2.12-2.09(2H, m), 1.79-1.77(2H, m), 1.66-1.63(1H, m), 1.56-1.43(4H, m), 1.34-1.32(1H, m)
Step B: (6-cyclohexylsulfanyl-pyridin-2-yl)-methanol
6-Cyclohexylsulfanyl-pyridine-2-carboxylic acid methyl ester (0.162g, 0.64 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 1 to obtain the title compound (0.025 g, 17%).
1H-NMR (CDCl3) δ 7.48-7.42(1H, t), 7.08-7.06(1H, d), 6.89-6.87(1H, d), 4.70(2H, s), 3.83-3.78(1H, m), 2.11-2.07(2H, m), 1.81-1.77(2H, m), 1.63-1.62(1H, m), 1.53-1.31(5H, m)
Step C: 2-chloromethyl-6-cyclohexylsulfanyl)-pyridine
(6-Cyclohexylsulfanyl-pyridin-2-yl)-methanol (0.025 g, 0.11 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 1 to obtain the title compound, which was used in the next step without a separate purification process.
Preparation Example 29: 3-chloromethyl-6-ethyl-2-isopropylsulfanyl-pyridine
Step A: 6-ethyl-2-isopropylsulfanyl-nicotinic acid methyl ester
After 2-isopropylsulfanyl-6-methyl-nicotinic acid methyl ester (105 mg, 0.46 mmol) was dissolved in THF (3 mL), KHMDS (1 mL, 0.51 mmol) was added slowly thereto at -78℃, and the mixture was stirred for 30 minutes. MeI (72 mg, 0.51 mmol) was added slowly to the reactant at -78℃, and the mixture was stirred at room temperature for 1 hour. The reactant was cooled, diluted with water, and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (eluent EtOAc/Hex = 1/5) to obtain the title compound (60 mg, 54%).
NMR: 1H-NMR (CDCl3) 8.09(1H, d), 6.85(1H, d), 4.15(1H, m), 3.90(3H, s), 2.80(2H, q), 1.40(6H, d), 1.32(3H, t)
Step B: (6-ethyl-2-isopropylsulfanyl-pyridin-3-yl)-methanol
6-Ethyl-2-isopropylsulfanyl-nicotinic acid methyl ester (60 mg, 0.25 mmol) ) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 16 to obtain the title compound (29 mg, 55%).
NMR: 1H-NMR (CDCl3) 7.47(1H, d), 6.85(1H, d), 4.63(1H, d), 4.19(1H, m), 2.76(2H, q), 1.99(1H, t), 1.41(6H, d), 1.29(3H, t)
Step C: 3-chloromethyl-6-ethyl-2-isopropylsulfanyl-pyridine
(6-Ethyl-2-isopropylsulfanyl-pyridin-3-yl)-methanol (29 mg, 0.13mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 16 to obtain the title compound, which was used in the next step without a separate purification process.
Preparation Example 30: 3-chloromethyl-2-isopropylsulfanyl-5-methyl-pyridine
Step A: 2-isopropylsulfanyl-5-methyl-pyridine-3-carbonitrile
5-Methyl-2-sulfanyl-pyridine-3-carbonitrile (0.2 g, 1.3 mmol) and 2-bromopropane were reacted in the same manner as in Step A of Preparation Example 5 to obtain the title compound (0.18 g, 70%).
1H-NMR (CDCl3) δ 8.42(1H, dd), 7.60(1H, dd), 4.10(1H, m), 2.31(3H, s), 1.42(6H, d)
Step B: 2-isopropylsulfanyl-5-methyl-nicotinic acid
After 2-isopropylsulfanyl-5-methyl-pyridine-3-carbonitrile (0.186 g, 0.97 mmol) obtained in Step A was dissolved in water (0.4 mL) and DMSO (0.04 mL), KOH (0.76 g) was added thereto, and the mixture was stirred at 100℃ for 16 hours. After the termination of the reaction, 6N HCl aqueous solution was added thereto to adjust the pH of the reactant to 2, and the mixture was extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.15 g, 73%).
1H-NMR (DMSO-d6) δ 13.29(1H, brs), 8.46(1H, d), 8.01(1H, d), 3.97(1H, m), 2.28(3H, s), 1.30(6H, d)
Step C: (2-isopropylsulfanyl-5-methyl-pyridin-3-yl)-methanol
2-Isopropylsulfanyl-5-methyl-nicotinic acid (0.075 g, 0.35 mmol) obtained in Step B was reacted in the same manner as in Step B of Preparation Example 10 to obtain the title compound (0.038 g, 54%).
1H-NMR (CDCl3) δ 8.23(1H, m), 7.44(1H, m), 4.65(2H, d), 4.11(1H, m), 2.29(3H, s), 2.07(1H, brs, OH), 1.39(6H, d)
Step D: 3-chloromethyl-2-isopropylsulfanyl-5-methyl-pyridine
(2-Isopropylsulfanyl-5-methyl-pyridin-3-yl)-methanol (0.037 g, 0.18 mmol) obtained in Step C was reacted in the same manner as in Step C of Preparation Example 10 to obtain the title compound (0.031 g, 77%).
1H-NMR (CDCl3) δ 8.25(1H, s), 7.43(1H, s), 4.59(3H, s), 4.10(1H, m), 2.29(3H, s), 1.40(6H, d)
Preparation Example 31: 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane-carboxylic acid ethyl ester
Step A: 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropane-carboxylic acid ethyl ester
After (E)-3-(4-benzyloxy-3,5-difluoro-phenyl)-acrylic acid ethyl ester (2.5 g, 7.85 mmol) obtained in Step C of Preparation Example 2 was dissolved in THF (10 mL), diazomethane solution (94 mL, 23.55 mmol, 0.25M ether) was added thereto. After the reactant was cooled to 0~5℃, palladium(Ⅱ) acetate (0.29 g, 1.30 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 5 hours. After the termination of the reaction, the reactant was added with water and then extracted. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography (eluent EtOAc/Hex = 1/10) to obtain the title compound (2.27 g, 87%).
1H NMR (400 MHz, CDCl3) δ 7.45-7.40(m, 2H), 7.38-7.29(m, 3H), 6.62(d, 2H), 5.11(s, 2H), 4.16(q, 2H), 2.44-2.38(m, 1H), 1.85-1.79(m, 1H), 1.60-1.54(m, 1H), 1.28(t, 3H), 1.23-1.18(m, 1H)
Step B: 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane-carboxylic acid ethyl ester
2-(4-Benzyloxy-3,5-difluoro-phenyl)-cyclopropane-carboxylic acid ethyl ester (0.65 g, 1.96 mmol) obtained in Step A was dissolved in EtOH (15 mL), and 10% Pd/C (65 mg) was added thereto. The mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. The reactant was filtered by using celite and concentrated under reduced pressure to obtain the title compound (0.46 g, 97%).
1H NMR (400 MHz, CDCl3) δ 6.66(d, 2H), 4.18(q, 2H), 2.47-2.38(m, 1H), 1.84-1.78(m, 1H), 1.60-1.53(m, 1H), 1.28(t, 3H), 1.25-1.18(m, 1H)
Preparation Example 32: 3-(3-fluoro-4-hydroxy-phenyl]-2-methyl-propionic acid methyl ester
Step A: (E)-3-(3-fluoro-4-methoxy-phenyl)-2-methyl-acrylic acid ethyl ester
After 3-fluoro-4-methoxy-benzaldehyde (0.50 g, 3.24 mmol) was dissolved in anhydrous THF (10 mL), carbethoxyethylidene triphenylphosphorane (1.75 g, 4.86 mmol) was added thereto at 0℃, and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex = 1/2) to obtain the title compound (0.768 g, 99%).
1H-NMR (CDCl3) δ 7.57(1H, s), 7.21-7.14(2H, m), 7.06-6.99(1H, t), 4.29-4.20(2H, q), 3.92(3H, s), 2.12(3H, s), 1.36-1.33(3H, t)
Step B: 3-(3-fluoro-4-methoxy-phenyl)-2-methyl-propionic acid ethyl ester
After (E)-3-(3-fluoro-4-methoxy-phenyl)-2-methyl-acrylic acid ethyl ester (0.728 g, 3.0 mmol) obtained in Step A was dissolved in EtOH (10 mL), 10% Pd/C (0.073 g) was added thereto, and the mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. After the termination of the reaction, the reactant was filtered by using celite, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex = 1/2) to obtain the title compound (0.726 g, 98%).
1H-NMR (CDCl3) δ 6.91-6.84(3H, m), 4.15-4.08(2H, q), 3.86(3H, s), 2.95-2.91(1H, q), 2.71-2.58(2H, m), 1.23-1.20(3H, t), 1.15-1.14(3H, d)
Step C: 3-(3-fluoro-4-hydroxy-phenyl]-2-methyl-propionic acid methyl ester
After 3-(3-fluoro-4-methoxy-phenyl)-2-methyl-propionic acid ethyl ester (0.728 g, 3.03 mmol) obtained in Step B was dissolved in anhydrous DCM (10 mL), 1M BBr3 solution (4.5 mL, 4.5 mmol) was added thereto at -78℃, and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with MeOH, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex = 1/2) to obtain the title compound (0.64 g, 99%).
1H-NMR (CDCl3) δ 6.91-6.80(2H, m), 6.69-6.67(1H, m), 5.29-5.28(1H, d), 3.64(3H, s), 2.95-2.90(1H, q), 2.73-2.65(1H, m), 2.62-2.57(1H, m), 1.16-1.14(3H, d)
Preparation Example 33: 2-sec-butylsulfanyl-3-chloromethyl-pyridine
Step A: 2-sec-butylsulfanyl-nicotinic acid
2-Mercapto-nicotinic acid (1.0 g, 6.4 mmol) was reacted in the same manner as in Step A of Preparation Example 10 to obtain the title compound (0.89 g, 66%).
1H-NMR (DMSO-d6) δ 13.32(1H, brs), 8.59(1H, m), 8.17(1H, m), 7.19(1H, m), 3.91(1H, m), 1.70(1H, m), 1.58(1H, m), 1.29(3H, d), 0.95(3H, t)
Step B: (2-sec-butylsulfanyl-pyridin-3-yl)-methanol
2-sec-Butylsulfanyl-nicotinic acid (0.89 g, 4.2 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 10 to obtain the title compound (0.76 g, 90%).
1H-NMR (CDCl3) δ 8.36(1H, m), 7.61(1H, m), 7.01(1H, m), 4.67(2H, s), 4.04(1H, m), 2.20(1H, brs, OH), 1.76(1H, m), 1.69(1H, m), 1.39(3H, d), 1.04(3H, t)
Step C: 2-sec-butylsulfanyl-3-chloromethyl-pyridine
(2-sec-Butylsulfanyl-pyridin-3-yl)-methanol (0.76 g, 3.8 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 10 to obtain the title compound (0.072 g, 87%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.60(1H, m), 7.01(1H, m), 4.62(2H, s), 4.06(1H, m), 1.76(1H, m), 1.69(1H, m), 1.42(3H, d), 1.03(3H, t)
Preparation Example 34: 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester
Step A: (
E
)-3-(4-benzyloxy-3,5-difluoro-phenyl)-2-methyl-acrylic acid ethyl ester
4-Benzyloxy-3,5-difluoro-benzaldehyde (1.68 g, 6.77 mmol) was reacted in the same manner as in Step A of Preparation Example 3 to obtain the title compound (2.19 g, 97%).
1H NMR (400 MHz, CDCl3) δ 7.50-7.43(3H, m), 7.39-7.31(3H, m), 6.97-6.90(2H, m), 5.21(2H, s), 4.26(2H, q, 7Hz), 2.10(3H, s), 1.34(3H, t, 7Hz)
Step B: 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester
(E)-3-(4-Benzyloxy-3,5-difluoro-phenyl)-2-methyl-acrylic acid ethyl ester (2.19 g, 6.59 mmol) obtained in Step A was reacted in the same manner as in Step D of Preparation Example 2 to obtain the title compound (1.60 g, 99%).
1H NMR (400 MHz, DMSO-d6) δ 9.93(1H, brs), 6.89-6.81(2H, m), 4.01(2H, q, 7Hz), 2.79-2.65(2H, m), 2.58(1H, dd, 12 and 6 Hz), 1.11(3H, t, 7Hz), 1.04(3H, d, 7Hz)
Preparation Example 35: 3-chloromethyl-2-isopropylsulfanyl-6-methoxy-pyridine
Step A: 2-chloro-6-methoxy-nicotinic acid
Potassium botoxide (483 mg, 4.31 mmol) and MeOH (8 mL) were added to 2,6-dichloro-nicotinic acid (207 mg, 1.07 mmol), and the mixture was stirred using microwave at 60℃ for 1 hour. After the termination of the reaction, the reactant was filtered, and 1N HCl was added thereto at 0℃ to adjust the pH to 3. The solid was dried by N2 gas to obtain the title compound (106 mg, 52%).
1H-NMR (DMSO-d6) δ 8.17(1H, d), 6.92(1H, d), 3.92(3H, s)
Step B: 2-chloro-6-methoxy-nicotinic acid methyl ester
2-Chloro-6-methoxy-nicotinic acid (106 mg, 0.56 mmol) obtained in Step A and K2CO3 (156 mg, 1.13 mmol) were reacted in the same manner as in Step A of Preparation Example 9 to obtain the title compound (61 mg, 53%).
1H-NMR (CDCl3) δ 8.13(1H, d), 6.70(1H, d), 4.00(3H, s), 3.91(3H, s)
Step C: 2-isopropylsulfanyl-6-methoxy-nicotinic acid methyl ester
2-Chloro-6-methoxy-nicotinic acid methyl ester (52 mg, 0.26 mmol) obtained in Step B and isopropylthiol were reacted in the same manner as in Step B of Preparation Example 9 to obtain the title compound (54 mg, 87%).
NMR: 1H-NMR (CDCl3) 8.10(1H, d), 6.42(1H, d), 4.13(1H, m), 4.00(3H, s), 3.87(3H, s), 1.43(6H, d)
Step D: (2-isopropylsulfanyl-6-methoxy-pyridin-3-yl)-methanol
2-Isopropylsulfanyl-6-methoxy-nicotinic acid methyl ester (54 mg, 0.22 mmol) obtained in Step C was reacted in the same manner as in Step C of Preparation Example 9 to obtain the title compound (17 mg, 96%).
1H-NMR (CDCl3) δ 7.47(1H, d), 6.44(1H, d), 4.60(1H, d), 4.12(1H, m), 3.94(3H, s), 1.87(1H, t), 1.44(6H, d)
Step E: 3-chloromethyl-2-isopropylsulfanyl-6-methoxy-pyridin
(2-Isopropylsulfanyl-6-methoxy-pyridin-3-yl)-methanol (27 mg, 0.12 mmol) obtained in Step D was reacted in the same manner as in Step C of Preparation Example 8 to obtain the title compound, which was used in the next step without a separate purification process.
Preparation Example 36: 3-chloromethyl-2-cyclopentylsulfanyl-6-methyl-pyridine
Step A: 2-cyclopentylsulfanyl-6-methyl-nicotinic acid methyl ester
2-Chloro-6-methyl-nicotinic acid methyl ester (511 mg, 2.75 mmol) was reacted in the same manner as in Step B of Preparation Example 9 to obtain the title compound (418 mg, 60%).
1H-NMR (CDCl3) δ 8.06(1H, d), 6.86(1H, d), 4.15(1H, m), 3.89(3H, s), 2.53(3H, s), 2.23(2H, m), 1.75(2H, m), 1.65(4H, m)
Step B: (2-cyclopentylsulfanyl-6-methyl-pyridin-3-yl)-methanol
2-Cyclopentylsulfanyl-6-methyl-nicotinic acid methyl ester (210 mg, 0.83 mmol) obtained in Step A was reacted in the same manner as in Step C of Preparation Example 9 to obtain the title compound (168 mg, 90%).
1H-NMR (CDCl3) δ 7.42(1H, d), 6.83(1H, d), 4.16(2H, d), 4.19(1H, m), 2.48(3H, s), 2.21(2H, m), 1.76(2H, m), 1.65(4H, m)
Step C: 3-chloromethyl-2-cyclopentylsulfanyl-6-methyl-pyridine
(2-Cyclopentylsulfanyl-6-methyl-pyridin-3-yl)-methanol (35 mg, 0.15 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 8 to obtain the title compound, which was used in the next step without a separate purification process.
Preparation Example 37: 2-chloromethyl-6-cyclobutylsulfanyl-pyridine
Step A: 6-cyclobutylsulfanyl-pyridine-2-carboxylic acid ethyl ester
After 6-mercapto-pyridine-2-carboxylic acid ethyl ester (0.40 g, 2.18 mmol) was dissolved in CH3CN (9 mL), Cs2CO3 (2.667 g, 6.54 mmol) and bromo cyclobutane (0.385 mL, 3.27 mmol) were added thereto, and the mixture was stirred at 50℃ for 18 hours. After the termination of the reaction, the reactant was filtered, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex = 1/5) to obtain the title compound (0.481 g, 92%).
Step B: (6-cyclobutylsulfanyl-pyridin-2-yl)-methanol
6-Cyclobutylsulfanyl-pyridine-2-carboxylic acid ethyl ester (0.481 g, 2.03 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 16 to obtain the title compound (0.377 g, 95%).
1H-NMR (CDCl3) δ 7.75-7.73(1H, d), 7.59-7.56(1H, t), 7.22-7.20(1H, d), 4.45-4.33(3H, m), 2.59-2.56(2H, m), 2.21-2.03(4H, m), 1.44-1.40(3H, t)
Step C: 2-chloromethyl-6-cyclobutylsulfanyl-pyridin
(6-Cyclobutylsulfanyl-pyridin-2-yl)-methanol (0.04 g, 0.20 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 16 to obtain the title compound, which was used in the next step without a separate purification process.
1H-NMR (CDCl3) δ 7.49-7.45(1H, t), 7.01-6.99(1H, d), 6.88-6.86(1H, d), 4.70-4.69(2H, d), 4.35-4.27(1H, m), 3.78-3.75(1H, t), 2.60-2.53(2H, m), 2.21-2.03(4H, m)
Preparation Example 38: 3-(4-hydroxy-3-methoxy-phenyl]-propionic acid ethyl ester
Step A: 4-benzyloxy-3-methoxy-benzaldehyde
4-Hydroxy-3-methoxy-benzaldehyde (2.17 g, 14.26 mmol) was reacted in the same manner as in Step B of Preparation Example 2 to obtain the title compound (3.40 g, 98%).
1H-NMR (CDCl3) δ 9.87(1H, s), 7.52~7.31(7H, m), 6.99(1H, d), 5.30(2H, s), 3.95(3H, s)
Step B: (E)-3-(4-benzyloxy-3-methoxy-phenyl)-acrylic acid ethyl ester
4-Benzyloxy-3-methoxy-benzaldehyde (1.17 g, 4.85 mmol) obtained in Step A was reacted in the same manner as in Step C of Preparation Example 2 to obtain the title compound (1.0 g, 66%).
1H-NMR (CDCl3) δ 7.70(1H, d), 7.52~7.29(5H, m), 7.07~7.02(2H, m), 6.97(1H, d), 6.30(1H, d), 5.19(2H, s), 4.25(2H, q), 3.92(3H, s), 1.25(3H, t)
Step C: 3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester
(E)-3-(4-Benzyloxy-3-methoxy-phenyl)-acrylic acid ethyl ester (1.0 g, 3.20 mmol) obtained in Step B was reacted in the same manner as in Step D of Preparation Example 2 to obtain the title compound (679 mg, 94%).
1H-NMR (CDCl3) δ 7.00(1H, d), 6.69(2H, m), 5.47(1H, s), 4.13(2H, q), 3.87(3H, s), 2.88(2H, t), 2.59(2H, t), 1.24(3H, t)
Preparation Example 39: 3-(4-hydroxy-phenyl)-2,2-dimethyl-propionic acid ethyl ester
Step A: 4-benzyloxy-benzaldehyde
4-Hydroxy-benzaldehyde (1.0 g, 8.19 mmol) was reacted in the same manner as in Step B of Preparation Example 2 to obtain the title compound (1.70 g, 98%).
Step B: 3-(4-benzyloxy-phenyl)-3-hydroxy-2,2-dimethyl-propionic acid ethyl ester
Ethyl isobutyrate (2.5 mL, 18.42 mmol) was dissolved in THF (8 mL), and the solution was cooled to -78℃. LDA (9.2 mL, 18.42 mmol) was added thereto, and the mixture was stirred at the corresponding temperature for 2 hours. After 4-benzyloxy-benzaldehyde (1.7 g, 8.01 mmol) obtained in Step A was added thereto at -78℃, the mixture was heated to room temperature, and then stirred for 2 days. The reactant was added with water, and then extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex = 1/5) to obtain the title compound (1.77 g, 67%).
1H NMR (400 MHz, CDCl3) δ 7.42-7.38(m, 2H), 7.37-7.32(m, 2H), 7.31-7.26(m, 1H), 7.19(d, 2H), 6.89(d, 2H), 5.00(s, 2H), 4.81(d, 1H), 4.13(q, 2H), 3.26(d, 1H), 1.23(t, 3H),1.11(s, 3H), 1.06(s, 3H)
Step C: 3-(4-benzyloxy-phenyl)-2,2-dimethyl-propionic acid ethyl ester
3-(4-Benzyloxy-phenyl)-3-hydroxy-2,2-dimethyl-propionic acid ethyl ester (1.5 g, 4.57 mmol) obtained in Step B was dissolved in DCM (20 mL). Triethylsilane (0.81 mL, 5.03 mmol) was added thereto, and the reactant was cooled to 0~5℃. After boron trifluoride diethylether (0.62 mL, 5.03 mmol) was added thereto at 0~5℃, the mixture was heated to room temperature and stirred for 2 hours. Saturated sodium bicarbonate was added thereto, and the reactant was stirred. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent, EtOAc/Hex = 1/5) to obtain the title compound (1.34 g, 94%).
Step D: 3-(4-hydroxy-phenyl)-2,2-dimethyl-propionic acid ethyl ester
3-(4-benzyloxy-phenyl)-2,2-dimethyl-propionic acid ethyl ester (1.3 g, 4.16 mmol) obtained in Step C was reacted in the same manner as in Step D of Preparation Example 2 to obtain the title compound (0.92 g, 99%).
1H NMR (400 MHz, CDCl3) δ 6.96(d, 2H), 6.70(d, 2H), 4.11(q, 2H), 2.78(s, 2H), 1.24(t, 3H), 1.16(s, 6H)
Preparation Example 40: (4-isopropylsulfanyl-2-methyl-pyrimidin-5-yl)-methanol
Step A: 4-isopropylsulfanyl-2-methyl-pyrimidine-5-carboxylic acid methyl ester
4-Chloro-2-methyl-pyrimidine-5-carboxylic acid methyl ester (0.105 g, 0.56 mmol) and 2-propanethiol were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (0.114 g, 90%).
1H-NMR (CDCl3) δ 8.89(1H, s), 4.17(1H, m), 3.92(3H, s), 2.69(3H, s), 1.41(6H, d)
Step B: (4-isopropylsulfanyl-2-methyl-pyrimidin-5-yl)-methanol
4-Isopropylsulfanyl-2-methyl-pyrimidine-5-carboxylic acid methyl ester (0.057 g, 0.25 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 16 to obtain the title compound (0.006 g, 12%).
1H-NMR (CDCl3) δ 8.30(1H, s), 4.61(2H, d), 4.22(1H, m), 2.65(3H, s), 1.94(1H, brs, OH), 1.43(6H, d)
Preparation Example 41: (2-cyclopentylsulfanyl-6-methoxy-pyridin-3-yl)-methanol
Step A: 2-cyclopentylsulfanyl-6-methoxy-nicotinic acid methyl ester
2-Chloro-6-methoxy-nicotinic acid methyl ester (54 mg, 0.26 mmol) and cyclopentanethiol were reacted in the same manner as in Step A of Preparation Example 16 to obtain the title compound (55 mg, 77%).
1H-NMR (CDCl3) δ 8.09(1H, d), 6.42(1H, d), 4.16(1H, m), 4.00(3H, s), 3.87(3H, s), 2.22(2H, m), 1.82~1.60(6H, m)
Step B: (2-cyclopentylsulfanyl-6-methoxy-pyridin-3-yl)-methanol
2-Cyclopentylsulfanyl-6-methoxy-nicotinic acid methyl ester (55 mg, 0.20 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 16 to obtain the title compound (36 mg, 73%).
1H-NMR (CDCl3) δ 7.46(1H, d), 6.43(1H, d), 4.60(1H, d), 4.17(1H, m), 3.94(3H, s), 2.22(2H, m), 1.82~1.60(6H, m)
Preparation Example 42: 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester
Step A: 4-benzyloxy-3-chloro-benzaldehyde
4-Hydroxy-3-chloro-benzaldehyde (1.13 g, 14.26 mmol) was reacted in the same manner as in Step B of Preparation Example 2 to obtain the title compound (2.12 g, 99%).
1H-NMR (CDCl3) δ 9.84(1H, s), 7.93(1H, s), 7.73(1H, d), 7.52~7.31(5H, m), 7.07(1H, d), 5.25(2H, s)
Step B: (E)-3-(4-benzyloxy-3-chloro-phenyl)-acrylic acid ethyl ester
4-Benzyloxy-3-chloro-benzaldehyde (814 mg, 3.29 mmol) obtained in Step A was reacted in the same manner as in Step C of Preparation Example 2 to obtain the title compound (843 mg, 80%).
1H-NMR (CDCl3) δ 7.60~7.50(2H, m), 7.47~7.29(6H, m), 6.94(1H, d), 6.30(1H, d), 5.19(2H, s), 4.23(2H, q), 1.32(3H, t)
Step C: 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester
(E)-3-(4-Benzyloxy-3-chloro-phenyl)-acrylic acid ethyl ester (1.1 g, 3.32 mmol) obtained in Step B was reacted in the same manner as in Step D of Preparation Example 2 to obtain the title compound (807 mg, 99%).
1H-NMR (CDCl3) δ 7.16(1H, s), 7.02(1H, d), 6.93(1H, d), 5.40(1H, s), 4.13(2H, q), 2.86(2H, t), 2.57(2H, t), 1.23(3H, t)
Preparation Example 43: 3-(4-hydroxy-2,3-dimethyl-phenyl]-propionic acid ethyl ester
Step A: 4-hydroxy-2,3-dimethyl-benzaldehyde
4-Methoxy-2,3-dimethyl-benzaldehyde (2.0 g, 12.18 mmol) was dissolved in DCM (48 mL), and the solution was cooled to -78℃. 1M BBr3 (24 mL, 24.13 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 12 hours. After the termination of the reaction, the residue was diluted with water and extracted with DCM. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex = 1/5) to obtain the title compound (187 mg, 10%).
1H-NMR (CDCl3) δ 10.16(1H, s), 7.60(1H, d), 6.75(1H, d), 5.23(1H, s), 2.61(3H, s), 2.22(3H, s)
Step B: 4-benzyloxy-2,3-dimethyl-benzaldehyde
4-Hydroxy-2,3-dimethyl-benzaldehyde (187 mg, 1.24 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 2 to obtain the title compound (256 mg, 84%).
1H-NMR (CDCl3) δ 10.15(1H, s), 7.64(1H, d),7.50~7.30(6H, m), 6.88(1H, d), 5.15(2H, s), 2.61(3H, s), 2.25(3H, s)
Step C: (
E
)-3-(4-benzyloxy-2,3-dimethyl-phenyl)-acrylic acid ethyl ester
4-Benzyloxy-2,3-dimethyl-benzaldehyde (256 mg, 1.05 mmol) obtained in Step A was reacted in the same manner as in Step C of Preparation Example 2 to obtain the title compound (306 mg, 93%).
1H-NMR (CDCl3) δ 8.03(1H, d), 7.52~7.31(6H, m), 6.78(1H, d), 6.23(1H, d), 5.10(2H, s), 4.26(2H, q), 2.36(3H, s), 2.23(3H, s), 1.34(3H, t)
Step D: 3-(4-hydroxy-2,3-dimethyl-phenyl]-propionic acid ethyl ester
(E)-3-(4-Benzyloxy-2,3-dimethyl-phenyl)-acrylic acid ethyl ester (306 mg, 0.98 mmol) obtained in Step C was reacted in the same manner as in Step D of Preparation Example 2 to obtain the title compound (131 mg, 59%).
1H-NMR (CDCl3) δ 6.88(1H, d), 6.57(1H, d), 4.56(1H, s), 4.14(2H, q), 2.91(2H, t), 2.52(2H, t), 2.22(3H, s), 2.18(3H, s), 1.25(t, 3H)
Preparation Example 44: 2-[3-fluoro-4-hydroxy-phenyl]-cyclopropane carboxylic acid ethyl ester
Step A: (
E
)-3-(3-fluoro-4-methoxy-phenyl)-acrylic acid ethyl ester
3-Fluoro-4-methoxy-benzaldehyde (0.50 g, 3.2 mmol) was reacted in the same manner as in Step C of Preparation Example 2 to obtain the title compound (0.60 g, 82%).
1H-NMR (CDCl3) δ 7.60-7.56(1H, d), 7.30-7.23(2H, m), 6.97-6.93(1H, t), 6.31-6.27(1H, d), 4.28-4.23(2H, q), 3.92(3H, s), 1.35-1.31(3H, t)
Step B: 2-(3-fluoro-4-methoxy-phenyl)-cyclopropanecarboxylic acid ethyl ester
(E)-3-(3-Fluoro-4-methoxy-phenyl)-acrylic acid ethyl ester (0.39 g, 1.74 mmol) obtained in Step A was reacted in the same manner as in Step A of Preparation Example 31 to obtain the title compound (0.367 g, 88%).
1H-NMR (CDCl3) δ 6.89-6.80(3H, m), 4.19-4.14(2H, q), 3.86(3H, s), 2.48-2.43(1H, m), 1.84-1.79(1H, m), 1.59-1.54(1H, m), 1.30-1.26(3H, t), 1.25-1.21(1H, m)
Step C: 2-[3-fluoro-4-hydroxy-phenyl]-cyclopropanecarboxylic acid ethyl ester
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (0.494 g, 2.07 mmol) obtained in Step B was dissolved in anhydrous DCM (7 mL), BBr3 1M DCM solution (3 mL, 3.11 mmol) was added thereto at -78℃, and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with MeOH, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex = 1/2) to obtain the title compound (0.424 g, 91%).
1H-NMR (CDCl3) δ 6.93-6.88(1H, t), 6.84-6.78(2H, m), 5.00-5.01(1H, d), 4.19-4.13(2H, q), 2.46-2.44(1H, m), 1.82-1.79(1H, m), 1.58-1.54(1H, m), 1.30-1.26(3H, t), 1.25-1.21(1H, m)
Preparation Example 45: 2-(2-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester
Step A: 2-chloro-4-hydroxy-benzaldehyde
After 2-chloro-4-hydroxy-benzonitrile (2 g, 0.013 mol) was dissolved in anhydrous THF (40 mL), DIBAL-H 1M hexane solution (21.7 mL, 0.032 mol) was added thereto at -78℃, and the mixture was stirred for 1 hour, and then stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was added with 1M HCl at 0℃ and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Step B: 4-benzyloxy-2-chloro-benzaldehyde
2-Chloro-4-hydroxy-benzaldehyde obtained in Step A was dissolved in CH3CN (20 mL). After Cs2CO3 (8.7 g, 0.027 mol) was added thereto, benzyl bromide (1.5 mL, 0.013 mol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was filtered by using celite, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex = 1/5) to obtain the title compound (1.89g, 59%).
1H-NMR (CDCl3) δ 10.33(1H, s), 7.91-7.88(1H, m), 7.42-7.35(5H, m), 7.02(1H, m), 6.97-6.94(1H, m), 5.18(2H, s)
Step C: (
E
)-3-(4-benzyloxy-2-chloro-phenyl)-acrylic acid ethyl ester
4-Benzyloxy-2-chloro-benzaldehyde (0.50 g, 2.02 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 2 to obtain the title compound (0.61 g, racemic mixture, 95%).
1H-NMR (CDCl3) δ 8.05-8.01(1H, d), 7.57-7.55(1H, d), 7.41-7.34(5H, m), 7.03(1H, m), 6.90-6.88(1H, m), 6.35-6.31(1H, d), 5.07(2H, s), 4.29-4.24(2H, q), 1.35-1.32(3H, t)
1H-NMR (CDCl3) δ 7.61-7.59(1H, d), 7.41-7.34(5H, m), 7.11-7.08(1H, d), 7.01(1H, m), 6.87-6.84(1H, m), 6.00-5.97(1H, d), 5.06(2H, s), 4.16-4.11(2H, q), 1.23-1.20(3H, t)
Step D: 2-(4-benzyloxy-2-chloro-phenyl)-cyclopropanecarboxylic acid ethyl ester
(E)-3-(4-Benzyloxy-2-chloro-phenyl)-acrylic acid ethyl ester (0.612 g, 1.93 mmol) obtained in Step C was reacted in the same manner as in Step A of Preparation Example 31 to obtain the title compound (0.415 g, 64%).
1H-NMR (CDCl3) δ 7.41-7.32(5H, m), 7.02-7.01(1H, m), 6.94-6.92(1H, m), 6.80-6.78(1H, m), 5.03(2H, s), 4.25-4.15(2H, q), 2.67-2.62(1H, m), 1.77-1.72(1H, m), 1.60-1.56(1H, m), 1.31-1.24(4H, m)
Step E: 2-(2-chloro-4-hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester
2-(4-Benzyloxy-2-chloro-phenyl)-cyclopropane carboxylic acid ethyl ester (0.415 g, 1.25 mmol) obtained in Step D was reacted in the same manner as in Step B of Preparation Example 31 to obtain the title compound (0.30 g, 99%).
1H-NMR (CDCl3) δ 6.91-6.89(2H, m), 6.67-6.65(1H, m), 4.85(1H, m), 4.23-4.16(2H, q), 2.66-2.61(1H, m), 1.76-1.72(1H, m), 1.60-1.55(1H, m), 1.31-1.24(4H, m)
Preparation Example 46: 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester
Step A: (
E
)-3-(4-benzyloxy-3-chloro-phenyl)-2-methyl-acrylic acid ethyl ester
4-Benzyloxy-3-chloro-benzaldehyde (814 mg, 3.29 mmol) was reacted in the same manner as in Step C of Preparation Example 2 to obtain the title compound (843 mg, 80%).
1H-NMR (CDCl3) δ 7.60~7.50(2H, m), 7.47~7.29(6H, m), 6.94(1H, d), 6.30(1H, d), 5.19(2H, s), 4.23(2H, q), 1.32(3H, t)
Step B: 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester
(E)-3-(4-benzyloxy-3-chloro-phenyl)-acrylic acid ethyl ester (1.1 g, 3.32 mmol) obtained in Step A was reacted in the same manner as in Step D of Preparation Example 2 to obtain the title compound (807 mg, 99%).
Preparation Example 47: 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester
Step A: 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropanecarboxylic acid ethyl ester
(E)-3-(4-benzyloxy-3-chloro-phenyl)-acrylic acid ethyl ester (1.03 g, 3.26 mmol) obtained in Step B of Preparation Example 42 was reacted in the same manner as in Step A of Preparation Example 31 to obtain the title compound (805 mg, 74%).
1H-NMR (CDCl3) δ 7.52~7.27(5H, m), 7.12(1H, s), 6.92(1H, m), 6.86(1H, d), 5.13(2H, s), 4.14(2H, q), 2.44(1H, m), 1.82(1H, m), 1.57(1H, m), 1.34~1.20(4H, m)
Step B: 2-(3-chloro-4-hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester
2-(4-Benzyloxy-3-chloro-phenyl)-cyclopropanecarboxylic acid ethyl ester (847 mg, 2.56 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 31 to obtain the title compound (500 mg, 81%).
1H-NMR (CDCl3) δ 7.13(1H, s), 6.93(2H, s), 5.40(1H, s), 4.15(2H, q), 2.44(1H, m), 1.82(1H, m), 1.54(1H, m), 1.30~1.20(4H, m)
Preparation Example 48: 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester
Step A: (
E
)-3-(4-methoxy-2,3-dimethyl-phenyl)-acrylic acid ethyl ester
4-Methoxy-2,3-dimethyl-benzaldehyde (1.0 g, 6.09 mmol) was reacted in the same manner as in Step C of Preparation Example 2 to obtain the title compound (1.3 g, 91%).
Step B: 2-(4-methoxy-2,3-dimethyl-phenyl)-cyclopropanecarboxylic acid ethyl ester
(E)-3-(4-Methoxy-2,3-dimethyl-phenyl)-acrylic acid ethyl ester (0.98 g, 4.18 mmol) obtained in Step A was reacted in the same manner as in Step A of Preparation Example 31 to obtain the title compound (0.80 g, 77%).
1H NMR (400 MHz, CDCl3) δ 6.86(d, 2H), 6.59(d, 2H), 4.23-4.14(m, 2H), 3.75(s, 3H), 2.5-2.43(m, 1H), 2.28(s, 3H), 2.15(s, 3H),1.71-1.66(m, 1H), 1.56-1.50(m, 1H), 1.28(t, 3H), 1.27-1.20(m, 1H)
Step C: 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropanecarboxylic acid ethyl ester
2-(4-Methoxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.32 g, 1.29 mmol) obtained in Step B was dissolved in DCM (5 mL), and the reactant was cooled to 0~5℃. BBr3 solution (3.90 mL, 3.87 mmol, 1M/DCM) was added dropwise thereto, and the mixture was stirred at 0~5℃ for 2 hours. After the termination of the reaction, EtOH and saturated sodium bicarbonate solution were added thereto in turn, and the mixture was stirred. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent, EtOAc/Hex = 1/5) to obtain the title compound (0.24 g, 79%).
1H NMR (400 MHz, CDCl3) δ 6.77(d, 2H), 6.56(d, 2H), 5.48(s, 1H), 4.25-4.17(m, 2H), 2.5-2.42(m, 1H), 2.29(s, 3H), 2.18(s, 3H),1.72-1.67(m, 1H), 1.57-1.50(m, 1H), 1.30(t, 3H), 1.27-1.20(m, 1H)
Preparation Example 49: 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane-carboxylic acid ethyl ester
Step A: (4-benzyloxy-3,5-difluoro-phenyl)-acetaldehyde
After methoxymethyl triphenyl phosphonium chloride (1.04 g, 3.02 mmol) was dissolved in anhydrous THF (9 mL), LiHMDS 1.0M THF solution (3 mL, 3.02 mmol) was added thereto at 0℃, and the mixture was stirred for 15 minutes. 4-Benzyloxy-3,5-difluoro-benzaldehyde (0.50 g, 2.01 mmol) obtained in Step B of Preparation Example 2 was dissolved in anhydrous THF (6 mL), and the solution was added thereto. The mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure, and then purified by column chromatography (eluent, EtOAc/Hex = 1/5). After the obtained product was dissolved in THF (7.68 mL), 2N HCl (3.84 mL) was added thereto, and the mixture was stirred at 70℃ for 5 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure, and the purified by column chromatography (eluent, EtOAc/Hex = 1/5) to obtain the title compound (0.107 g, 20%).
1H-NMR (CDCl3) δ 9.82(1H, s), 7.45-7.30(7H, m), 5.22(2H, s)
Step B: (
E
)-4-(4-benzyloxy-3,5-difluoro-phenyl)-2-butenoic acid ethyl ester
(4-Benzyloxy-3,5-difluoro-phenyl)-acetaldehyde (0.107 mg, 0.40 mmol) obtained in Step A was reacted in the same manner as in Step C of Preparation Example 2 to obtain the title compound (0.10 g, 74%).
1H-NMR (CDCl3) δ 7.47-7.43(2H, m), 7.39-7.33(3H, m), 7.03-6.97(1H, m), 6.71-6.69(2H, m), 5.82-5.77(1H, d), 5.14(2H, s), 4.22-4.14(2H, q), 3.43-3.41(2H, d), 1.31-1.27(3H, t)
Step C: 2-(4-benzyloxy-3,5-difluoro-benzyl)-cyclopropanecarboxylic acid ethyl ester
(E)-4-(4-Benzyloxy-3,5-difluoro-phenyl)-2-butenoic acid ethyl ester (0.10 g, 0.30 mmol) obtained in Step B was reacted in the same manner as in Step A of Preparation Example 31 to obtain the title compound (0.082 g, 78%).
1H-NMR (CDCl3) δ 7.46-7.33(5H, m), 6.76-6.74(2H, m), 5.13(2H, s), 4.19-4.10(2H, m), 2.66-2.61(1H, m), 2.53-2.47(1H, m), 1.60-1.58(1H, m), 1.52-1.48(1H, m), 1.28-1.24(4H, m), 0.84-0.80(1H, m)
Step D: 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropanecarboxylic acid ethyl ester
2-(4-Benzyloxy-3,5-difluoro-benzyl)-cyclopropane carboxylic acid ethyl ester (0.082 g, 0.24 mmol) obtained in Step C was reacted in the same manner as in Step B of Preparation Example 31 to obtain the title compound (0.026 g, 43%).
1H-NMR (CDCl3) δ 6.78-6.77(2H, m), 4.97(1H, s), 4.19-4.10(2H, m), 2.66-2.61(1H, m), 2.53-2.47(1H, m), 1.60-1.58(1H, m), 1.52-1.48(1H, m), 1.28-1.24(4H, m), 0.84-0.80(1H, m)
Preparation Example 50: (5,7-difluoro-6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester
Step A: 4-chloromethyl-6,8-difluoro-7-hydroxy-2-chromenone
Sulfuric acid (2 mL) in a flask was cooled to 0℃. After ethyl 4-chloroacetoacetate (0.62 g, 3.8 mmol) was added thereto, 2,4-difluororesorcinol (0.5 g, 3.4 mmol) was added dropwise thereto. The mixture was stirred at room temperature for 2 hours, and the reactant was placed in ice water. The precipitate was filtered, washed with water, and dried by nitrogen gas to obtain the title compound (0.2 g, 24%).
Step B: (5,7-difluoro-6-hydroxy-benzofuran-3-yl)-acetic acid
4-Chloromethyl-6,8-difluoro-7-hydroxy-2-chromenone (0.2 g, 0.81 mmol) obtained in Step A was dissolved in 1N NaOH aqueous solution (8 mL), and the mixture was stirred under reflux for 2 hours. The reactant was acidified by the addition of sulfuric acid, and then extracted with EtOAc. The organic layer was dried with MgSO4, and distilled under reduced pressure to obtain the title compound (0.16 g).
Step C: (5,7-difluoro-6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester
(5,7-Difluoro-6-hydroxy-benzofuran-3-yl)-acetic acid obtained in Step B, without purification, was dissolved in MeOH (1 mL), and SOCl2 (0.10 mL, 1.4 mmol) was added slowly thereto. The mixture was stirred at room temperature for 30 minutes, and the reactant was distilled under reduced pressure. The residue was purified by column chromatography using EtOAc/Hex (1:4) solution to obtain the title compound (0.16 g, 89%).
1H-NMR (CDCl3) δ 7.62(1H, s), 7.02(1H, m), 3.70(2H, s), 2.39(3H, s)
Preparation Example 51: (5,7-difluoro-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester
(5,7-Difluoro-6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester (0.16 g, 0.66 mmol) obtained in Step C of Preparation Example 50 was dissolved in MeOH, and 10% Pd/C (30 mg) was added thereto. The mixture was stirred at room temperature under hydrogen atmosphere for 3 hours and then filtered. The filtrate was distilled under reduced pressure and then purified using EtOAc/Hex (1:4) solution by column chromatography to obtain the title compound (0.13 g, 81%).
1H-NMR (CDCl3) δ 6.73(1H, d), 4.83(1H, t), 4.35(1H, m), 3.86(1H, m), 3.72(3H, s), 2.72(1H, m), 2.60(1H, m)
Preparation Example 52: (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester
Resorcinol (1.0g, 9.1 mmol) was reacted in the same manner as in Preparation Example 50 and Preparation Example 51 in turn to obtain the title compound (0.45 g, 24%).
1H-NMR (CDCl3) δ 7.07(1H, m), 6.48(2H, m), 4.78(1H, t), 4.31(1H, m), 3.82(1H, m), 3.72(3H, s), 2.80(1H, m), 2.65(1H, m)
Preparation Example 53: [2-(3-fluoro-4-hydroxy-phenyl)-cyclopropyl]-acetic acid methyl ester
Step A: [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-methanol
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid-ethyl ester (0.71 g, 2.98 mmol) was dissolved in anhydrous THF (10 mL), LiBH4-2.0M THF solution (3 mL, 5.96 mmol) was added thereto, and the mixture was stirred at 50℃ for 2 hours. After the termination of the reaction, the reactant was cooled to room temperature, added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, and then concentrated under reduced pressure to obtain the title compound (0.519 g, 88%).
1H-NMR (CDCl3) δ 6.88-6.77(3H, m), 3.86(3H, s), 3.63-3.60(2H, m), 1.80-1.75(1H, m), 1.40-1.35(2H, m), 0.92-0.88(2H, m)
Step B: 2-(3-fluoro-4-methoxy-phenyl)-cyclopropanecarbaldehyde
After [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-methanol (0.30 g, 1.52 mmol) obtained in Step A was dissolved in DMSO (5 mL), 2-iodoxybenzoic acid (1.248 g, 4.58 mmol) was added thereto at 0℃, and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, added with water, and then extracted with EtOAc. The organic layer was separated, dried with MgSO4, concentrated under reduced pressure, and then purified by column chromatography (eluent, EtOAc/Hex = 1/3) to obtain the title compound (0.265 g, 89%).
1H-NMR (CDCl3) δ 9.34(1H, s), 6.90-6.81(3H, m), 3.87(3H, s), 2.57-2.55(1H, m), 2.12-2.09(1H, m), 1.73-1.68(1H, m), 1.48-1.43(1H, m)
Step C: [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-acetaldehyde
2-(3-Fluoro-4-methoxy-phenyl)-cyclopropanecarbaldehyde (0.265 g, 1.36 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 48 to obtain the title compound (0.088 g, 31%).
1H-NMR (CDCl3) δ 9.84(1H, s), 6.88-6.80(3H, m), 3.86(3H, s), 2.50(2H, m), 1.72-1.68(1H, m), 1.26(1H, m), 1.02-0.97(1H, m), 0.87-0.82(1H, m)
Step D: [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-acetic acid
[2-(3-Fluoro-4-methoxy-phenyl)-cyclopropyl]-acetaldehyde (0.088 g, 0.42 mmol) obtained in Step C was dissolved in EtOH (2 mL). AgNO3 (0.143 g, 0.84 mmol) dissolved in water (0.26 mL) and NaOH (0.067 g, 1.69 mmol) dissolved in water (0.26 mL) was added thereto in turn, and the mixture was stirred for 3 hours. After the termination of the reaction, the reactant was filtered by using celite to remove solid material, and 1N HCl aqueous solution was added to adjust the pH of the solution to 2. The organic layer obtained by the extraction with EtOAc was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.075 g, 79%).
1H-NMR (CDCl3) δ 6.88-6.81(3H, m), 3.85(3H, s), 2.45-2.43(2H, dd), 1.76-1.71(1H, m), 1.33-1.29(1H, m), 0.98-0.93(1H, m), 0.88-0.83(1H, m)
Step E: [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-acetic acid methyl ester
After [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-acetic acid (0.075 g, 0.33 mmol) obtained in Step D was dissolved in THF (1 mL), diazomethane (2.7 ml, 0.66 mmol, 0.25M ether) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex = 1/2) to obtain the title compound (0.063 g, 79%).
1H-NMR (CDCl3) δ 6.87-6.80(3H, m), 3.85(3H, s), 3.70(3H, s), 2.40-2.38(2H, dd), 1.72-1.68(1H, m), 1.31-1.27(1H, m), 0.95-0.90(1H, m), 0.85-0.80(1H, m)
Step F: [2-(3-fluoro-4-hydroxy-phenyl)-cyclopropyl]-acetic acid methyl ester
After [2-(3-fluoro-4-methoxy-phenyl)-cyclopropyl]-acetic acid methyl ester (0.067 g, 0.28 mmol) obtained in Step E was dissolved in anhydrous DCM (2 mL), BBr3 1M DCM solution (0.42 mL, 0.42 mmol) was added thereto at -78℃, and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with MeOH, concentrated under reduced pressure, and then purified by column chromatography (eluent, EtOAc/Hex = 1/2) to obtain the title compound (0.053 g, 84%).
1H-NMR (CDCl3) δ 6.90-6.78(3H, m), 4.92-4.91(1H, d), 3.71(3H, s), 2.40-2.38(2H, dd), 1.71-1.67(1H, m), 1.29-1.26(1H, m), 0.94-0.89(1H, m), 0.84-0.79(1H, m)
Preparation Example 54: (6-hydroxy-7-methyl-benzofuran-3-yl)-acetic acid methyl ester
2-Methyl resorcinol (1.2 g, 9.7 mmol) was reacted in the same manner as in Preparation Example 50 to obtain the title compound (0.6g, 28%).
1H-NMR (CDCl3) δ 7.53(1H, s), 7.22(1H, d), 6.77(1H, d), 4.79(1H, s), 3.71(3H, s), 3.65(2H, s), 2.38(3H, s)
Preparation Example 55: ((R)-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester
(6-Hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (40 mg, 0.19 mmol) obtained in Preparation Example 52 was separated by Prep-HPLC (CHIRALPAK AD, hexane/2-propanol (90/10)) to obtain the title compound (18 mg, 45%) eluted at 27 minute of elution time.
1H-NMR (CDCl3) δ 7.07(1H, m), 6.48(2H, m), 4.78(1H, t), 4.31(1H, m), 3.82(1H, m), 3.72(3H, s), 2.80(1H, m), 2.65(1H, m)
Preparation Example 56: ((S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester
(6-Hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (40 mg, 0.19 mmol) obtained in Preparation Example 52 was separated by Prep-HPLC (CHIRALPAK AD, hexane/2-propanol (90/10)) to obtain the title compound (18 mg, 45%) eluted at 29 minute of elution time.
1H-NMR (CDCl3) δ 7.07(1H, m), 6.48(2H, m), 4.78(1H, t), 4.31(1H, m), 3.82(1H, m), 3.72(3H, s), 2.80(1H, m), 2.65(1H, m)
Preparation Examples 57 and 58: (R)-4-benzyl-3-[2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarbonyl]-oxazolidin-2-on (57, more polar) (58, less polar)
Step A: 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarbonyl chloride
After 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarboxylic acid (75 mg, 0.246 mmol) was dissolved in anhydrous MC (5 ml), SOCl2 (0.58 g, 4.92 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process.
Step B: (R)-4-benzyl-3-[2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropane carbonyl]-oxazolidin-2-on (57, more polar), (58, less polar)
After (R)-4-benzyl-oxazolidin-2-on (52 mg, 0.295 mmol) was dissolved in anhydrous THF (2 ml), NaH (60%, 14 mg, 0.344 mmol) was added thereto, and the mixture was stirred for 30 minutes. Next, 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarnoyl chloride obtained in Step A was added thereto at -78℃, and the mixture was stirred for 15 minutes, and then stirred at room temperature for 1 hour. After the termination of the reaction, NH4Cl solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was separated, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain each title compound [(more polar, 41 mg, 36%), (less polar, 44 mg, 38%)].
(57, more polar) NMR (400 MHz, CDCl3) 1.32-1.38 (m, 1H), 1.71-1.77 (m, 1H), 2.57-2.63 (m, 1H), 2.80 (dd, 13.2 and 9.6 Hz, 1H), 3.30 (dd, 13.2 and 3.2 Hz, 1H), 3.46-3.51 (m, 1H), 4.17-4.26 (m, 2H), 4.65-4.73 (m, 1H), 5.13 (s, 2H), 6.71-6.77 (m, 2H), 7.18-7.22 (m, 2H), 7.27-7.39 (m, 6H), 7.42-7.46 (m, 2H) ppm.
(58, less polar) NMR (400 MHz, CDCl3) 1.37-1.43 (m, 1H), 1.75-1.81 (m, 1H), 2.54-2.60 (m, 1H), 2.79 (dd, 13.2 and 9.6 Hz, 1H), 3.30 (dd, 13.2 and 3.2 Hz, 1H), 3.46-3.52 (m, 1H), 4.16-4.25 (m, 2H), 4.66-4.72 (m, 1H), 5.12 (s, 2H), 6.67-6.73 (m, 2H), 7.18-7.22 (m, 2H), 7.27-7.39 (m, 6H), 7.42-7.46 (m, 2H) ppm.
Preparation Example 59: 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar)
Step A: 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropane carboxylic acid
After LiOH (6.4 mg, 0.152 mmol) was dissolved in water (1 mL), H2O2 (35%, 37 mg, 0.38 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes, and then cooled to 0℃. The reactant was added to the solution of (R)-4-benzyl-3-[2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarbonyl]-oxazolidin-2-on (less polar, 44 mg, 0.095 mmol) obtained in Step B of Preparation Example 58 dissolved in THF/H2O (2 mL/0.5 mL), and the mixture was stirred for 1 hour. After the termination of the reaction, Na2SO3 solution (0.1 g in 1 mL of H2O) was added thereto, and the mixture was stirred at 0℃ for 1 hour, and then concentrated under reduced pressure. The residue was added with water, and 6N HCl aqueous solution was added to adjust the pH of the solution to 2. The organic layer otained by the extraction with ethyl acetate was separated, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the mixture (41 mg) of the title compound and 4-benzyloxazolidin-2-on, which which was used in the next step without a separate purification process.
Step B: 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropane carboxylic acid methyl ester
Mixture (41 mg) of 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropane carboxylic acid obtained in Step A and 4-benzyloxazolidine-2-on was dissolved in THF (2 mL), and CH2N2 (0.25M in Et2O, 1 mL, 0.158 mmol) was added thereto. The mixture was reacted at room temperature for 1 hour, and then the reactant was concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex = 1/2) to obtain the title compound (22.7 mg, two-step yield 75%).
NMR (400 MHz, CDCl3) 1.20-1.26 (m, 1H), 1.56-1.62 (m, 1H), 1.80-1.86 (m, 1H), 2.39-2.45 (m, 1H), 3.72 (s, 3H), 5.12 (s, 2H), 6.58-6.66 (m, 2H), 7.30-7.39 (m, 3H), 7.42-7.46 (m, 2H) ppm.
Step C: 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester
2-(4-Benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarboxylic acid methyl ester (21 mg, 0.066 mmol) obtained in Step B was dissolved in THF/MeOH (1 mL/1 mL), and Pd/C (10%, 10 mg) was added thereto. The mixture was stirred under hydroten atmosphere for 12 hours, filtered by using celite, and concentrated under reduced pressure to obtain the title compound (17 mg, 99%).
NMR (400 MHz, CDCl3) 1.20-1.26 (m, 1H), 1.55-1.61 (m, 1H), 1.78-1.84 (m, 1H), 2.40-2.46 (m, 1H) 3.72 (s, 3H), ~3.8-3.9 (brs, 1H), 6.62-6.70 (m, 2H) ppm.
Preparation Example 60: 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester(more polar)
Step A: 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropane carboxylic acid
(R)-4-Benzyl-3-[2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarbonyl]-oxazolidin-2-on (more polar, 41 mg, 0.088 mmol) obtained in Step B of Preparation Example 57 was was reacted in the same manner as Step A of Preparation Example 59 to obtain the mixture (44 mg) of the title compound and 4-benzyloxazolidin-2-on, which which was used in the next step without a separate purification process.
Step B: 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropane carboxylic acid methyl ester
The mixture (44 mg) of 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropane carboxylic acid and 4-benzyloxazolidin-2-on obtained in Step A was reacted in the same manner as in Step B of Preparation Example 59 to obtain the title compound (26.75 mg, two-step yield 95%).
NMR (400 MHz, CDCl3) 1.20-1.26 (m, 1H), 1.56-1.62 (m, 1H), 1.80-1.86 (m, 1H), 2.39-2.45 (m, 1H), 3.72 (s, 3H), 5.12 (s, 2H), 6.58-6.66 (m, 2H), 7.30-7.39 (m, 3H), 7.42-7.46 (m, 2H) ppm.
Step C: 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester
2-(4-Benzyloxy-3,5-difluoro-phenyl)-cyclopropane carboxylic acid methyl ester (26 mg, 0.082 mmol) obtained in Step B was reacted in the same manner as in Step C of Preparation Example 59 to obtain the title compound (17 mg, 89%).
NMR (400 MHz, CDCl3) 1.20-1.26 (m, 1H), 1.55-1.61 (m, 1H), 1.78-1.84 (m, 1H), 2.40-2.46 (m, 1H), 3.72 (s, 3H), 3.8-3.9 (brs, 1H), 6.62-6.70 (m, 2H) ppm.
Preparation Examples 61 and 62: (R)-4-benzyl-3-[2-(3-fluoro-4-methoxy-phenyl)-cyclopropanecarbonyl]-oxazolidin-2-on (61, more polar) (62, less polar)
Step A: 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid ethyl ester (1.15 g, 4.83 mmol) was dissolved in THF (6 mL), methyl alcohol (1 mL) and water (1 mL), an excess amount of sodium hydroxide was added, and then the mixture was stirred at room temperature for 4 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and 1N HCl was added to adjust the pH of the solution to 2. The organic layer obtained by the extraction with ethyl acetate was separated, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (0.985g, 97%).
1H NMR (CDCl3) δ 6.90-6.81 (3H, m), 3.86 (3H, s), 2.56-2.51 (1H, m), 1.85-1.81 (1H, m), 1.65-1.61 (1H, m), 1.36-1.31 (1H, m)
Step B: 2-(3-fluoro-4-methoxy-phenyl)-cyclopropanecarbonyl chloride
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid (0.848 g, 4.03 mmol) obtained in Step A was dissolved in anhydrous MC (10 mL), SOCl2 (3 mL, 40.34 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process
Step C: (R)-4-benzyl-3-[2-(3-fluoro-4-methoxy-phenyl)-cyclopropanecarbonyl] -oxazolidin-2-on (61, more polar) (62, less polar)
After (R)-4-benzyl-oxazolidin-2-on (0.858 g, 4.84 mmol) was dissolved in anhydrous THF (15 mL), NaH (0.226 g, 5.64 mmol) was added thereto, and the mixture was stirred for 30 minutes. 2-(3-Fluoro-4-methoxy-phenyl)-cyclopropanecarbonyl chloride obtained in Step B was added thereto at -78℃, and the mixture was stirred for 15 minutes, and then stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was added with NH4Cl and extracted with ethyl acetate. The organic layer was separated, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex/MC = 1/5/10) to obtain the title compounds [(more polar, 33 mg, 49%), (less polar, 33 mg, 49%)].
(61, more polar) 1H NMR (CDCl3) δ 7.36-7.33 (2H, m), 7.30-7.28 (1H, m), 7.23-7,21 (2H, m), 6.92-6.84 (3H, m), 4.72-4.68 (1H, m), 4.24-4.17 (2H, m), 3.86 (3H, s), 3.50-3.46 (1H, m), 3.33-3.29 (1H, dd), 2.83-2.77 (1H, q), 2.63-2.60 (1H, m), 1.80-1.75 (1H, m), 1.44-1.40 (1H, m)
(62, less polar) 1H NMR (CDCl3) δ 7.36-7.33 (2H, m), 7.30-7.28 (1H, m), 7.23-7,21 (2H, m), 6.92-6.84 (3H, m), 4.72-4.68 (1H, m), 4.24-4.17 (2H, m), 3.86 (3H, s), 3.50-3.46 (1H, m), 3.33-3.29 (1H, dd), 2.83-2.77 (1H, q), 2.63-2.60 (1H, m), 1.80-1.75 (1H, m), 1.44-1.40 (1H, m)
Preparation Example 63: 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar)
Step A: 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid
After LiOH (0.059 g, 1.40 mmol) was dissolved in water (5 mL), H2O2 (0.3 mL, 3.52 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reactant was added to the solution of (R)-4-benzyl-3-[2-(3-fluoro-4-methoxy-phenyl)-cyclopropanecarbonyl]-oxazolidin-2-on (0.325 g, 0.88 mmol) obtained in Step C of Preparation Example 61 in THF/H2O (17 mL/4.4 mL) at 0℃, and the mixture was stirred for 1 hour. After the termination of the reaction, Na2SO3 (1 g) dissolved in water (5 mL) was added thereto, and the mixture was stirred at 0℃ for 1 hour. 6N HCl was added thereto to adjust the pH to 2, and the reactant was extracted with ethyl acetate. The organic layer was separated, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process
1H NMR (CDCl3) δ 6.90-6.81 (3H, m), 3.86 (3H, s), 2.56-2.51 (1H, m), 1.85-1.81 (1H, m), 1.65-1.61 (1H, m), 1.36-1.31 (1H, m)
Step B: 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid methyl ester
2-(3-Fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid obtained in Step A was reacted in the same manner as in Step B of Preparation Example 59 to obtain the title compound (0.173 g, two-step yield 87%).
Step C: 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester
2-(3-Fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid methyl ester obtained in Step B was reacted in the same manner as in Step C of Preparation Example 32 to obtain the title compound (0.034 g, 21%).
1H NMR (CDCl3) δ 6.92-6.88 (1H, m), 6.83-6.78 (2H, m), 4.97 (1H, m), 3.71 (3H, s), 2.46 (1H, m), 1.84-1.79 (1H, m), 1.59-1.54 (1H, m), 1.25-1.21 (1H, m)
Preparation Example 64: 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar)
Step A: 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid
After LiOH (0.059 g, 1.40 mmol) was dissolved in water (5 mL), H2O2 (0.3 mL, 3.52 mmol) was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reactant was added to the solution of (R)-4-benzyl-3-[2-(3-fluoro-4-methoxy-phenyl)-cyclopropanecarbonyl]-oxazolidin-2-on (0.325 g, 0.88 mmol) obtained in Step C of Preparation Example 62 in THF/H2O (17 mL/4.4 mL) at 0℃, and the mixture was stirred for 1 hour. After the termination of the reaction, Na2SO3 (1 g) dissolved in water (5 mL) was added thereto, and the mixture was stirred at 0℃ for 1 hour. 6N HCl was added thereto to adjust the pH to 2, and the reactant was extracted with ethyl acetate. The organic layer was separated, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound, which was used in the next step without a separate purification process
1H NMR (CDCl3) δ 6.90-6.81 (3H, m), 3.86 (3H, s), 2.56-2.51 (1H, m), 1.85-1.81 (1H, m), 1.65-1.61 (1H, m), 1.36-1.31 (1H, m)
Step B: 2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid methyl ester
(1S,2S)-2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid obtained in Step A was reacted in the same manner as in Step B of Preparation Example 59 to obtain the title compound (0.170 g, two-step yield 86%).
Step C: 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester
(1S,2S)-2-(3-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid methyl ester obtained in Step B was reacted in the same manner as in Step C of Preparation Example 59 to obtain the title compound (0.080 g, 50%).
1H NMR (CDCl3) δ 6.92-6.88 (1H, m), 6.83-6.78 (2H, m), 4.97 (1H, m), 3.71 (3H, s), 2.46 (1H, m), 1.84-1.79 (1H, m), 1.59-1.54 (1H, m), 1.25-1.21 (1H, m)
Preparation Example 65: 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar)
Step A: 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid
2-(4-Benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid ethyl ester (4.64 g, 14.02 mmol) was reacted in the same manner as in Step A of Preparation Example 61 to obtain the title compound (4.14 g, 97%).
1H NMR (CDCl3) 7.45~7.27(5H, m), 7.12(1H, s), 6.93(1H, m), 6.86(1H, d), 5.14(2H, s), 2.52(1H, m), 1.82(1H, m), 1.62(1H, m), 1.32(1H, m)
Step B: 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carbonyl chloride
2-(4-Benzyloxy-3-chloro-phenyl)-cyclopropanecarboxylic acid (2.02 g, 6.67 mmol) obtained in Step A was reacted in the same manner as in Step B of Preparation Example 61, and concentrated under reduced pressure to to obtain the title compound, which was used in the next step without a separate purification process.
Step C: (R)-4-benzyl-3-[2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carbonyl]-oxazolidin-2-on
2-(4-Benzyloxy-3-chloro-phenyl)-cyclopropanecarbonyl chloride obtained in Step B was reacted in the same manner as in Step C of Preparation Example 61 to obtain the title compound (0.91 g, 59%).
1H NMR (CDCl3) 7.52~7.20(11H, m), 7.00(1H, m), 6.88(1H, d), 5.15(2H, s), 4.70(1H, m), 4.20(2H, m), 3.47(1H, m), 3.28(1H, m), 2.81(1H, m), 2.63(1H, m), 1.74(1H, m), 1.32(1H, m)
Step D: 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid
(R)-4-benzyl-3-[2-(4-benzyloxy-3-chloro-phenyl)-cyclopropanecarbonyl]-oxazolidin-2-on (918 mg, 1.98 mmol) obtained in Step C was reacted in the same manner as in Step A of Preparation Example 59 to obtain the mixture (650 mg) of the title compound and 4-benzyloxazolidin-2-on.
1H NMR (CDCl3) 7.45~7.27(5H, m), 7.12(1H, s), 6.93(1H, m), 6.86(1H, d), 5.14(2H, s), 2.52(1H, m), 1.82(1H, m), 1.62(1H, m), 1.32(1H, m)
Step E: 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid methyl ester
The mixture (650 mg) of 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid and 4-benzyloxazolidin-2-on obtained in Step D was reacted in the same manner as in Step B of Preparation Example 59 to obtain the title compound (379 mg, two-step yield 38%).
1H NMR (CDCl3) 7.45~7.27(5H, m), 7.12(1H, s), 6.93(1H, m), 6.86(1H, d), 5.13(2H, s), 3.71(3H, s), 2.45(1H, m), 1.82(1H, m), 1.62(1H, m), 1.24(1H, m)
Step F: 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester
2-(4-Benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid methyl ester obtained in Step E was reacted in the same manner as in Step C of Preparation Example 59 to obtain the title compound (0.034g, 21%).
1H NMR (CDCl3) 7.07(1H, s), 6.93(2H, s), 5.44(1H, s), 3.72(3H, s), 2.45(1H, m), 1.82(1H, m), 1.24(2H, m)
Preparation Example 66: 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar)
Step A: 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid
(R)-4-Benzyl-3-[2-(4-benzyloxy-3-chloro-phenyl)-cyclopropanecarbonyl]-oxazolidin-2-on (132 mg, 0.28 mmol) was reacted in the same manner as in Step A of Preparation Example 59 to obtain the mixture (85 mg) of the title compound and 4-benzyloxazolidin-2-on.
1H NMR (CDCl3) 7.45~7.26(5H, m), 7.14(1H, s), 6.93(1H, m), 6.85(1H, d), 5.14(2H, s), 2.52(1H, m), 1.82(1H, m), 1.62(1H, m), 1.32(1H, m)
Step B: 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid methyl ester
The mixture (85 mg) of 2-(4-benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid and 4-benzyloxazolidin-2-on obtained in Step A was reacted in the same manner as in Step B of Preparation Example 59 to obtain the title compound (54 mg, two-step yield 60%).
1H NMR (CDCl3) 7.45~7.27(5H, m), 7.12(1H, s), 6.93(1H, m), 6.86(1H, d), 5.13(2H, s), 3.71(3H, s), 2.45(1H, m), 1.82(1H, m), 1.62(1H, m), 1.24(1H, m)
Step C: 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester
2-(4-Benzyloxy-3-chloro-phenyl)-cyclopropane carboxylic acid methyl ester (54 mg, 0.17 mmol) obtained in Step E was reacted in the same manner as in Step C of Preparation Example 59 to obtain the title compound (37 mg, 97%).
1H NMR (CDCl3) 7.07(1H, s), 6.93(2H, s), 5.42(1H, s), 3.72(3H, s), 2.45(1H, m), 1.82(1H, m), 1.24(2H, m)
Preparation Example 67: 3-(4-amino-phenyl)-propionic acid methyl ester
SOCl2 (1.5 mL) was added slowly to MeOH (6 mL) at 0 ~ 5℃, and the mixture was stirred for 10 minutes. 3-(4-Amino-phenyl)-propionic acid (1 g, 6.05 mmol) was added thereto at the same temperature. After the temperature was elevated to room temperature, the mixture was stirred for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, added with saturated sodium bicarbonate aqueous solution, and extracted with EtOAc. The organic layer was added with NaCl aqueous solution, extracted again, and then filtered by using celite. The filtrate was concentrated under reduced pressure. The residue was added with n-Hex, and then concentrated under reduced pressure again. n-Hex (20 mL) was added to the obtained solid, and the mixture was stirred under reflux for 1 hour, and then stirred at room temperature for 2 hours. The mixture was filtered to obtain the title compound (0.85 g, 78%).
1H NMR (500 MHz, CDCl3) δ 6.98(d, 2H), 6.61(d, 2H), 3.65(s, 3H), 2.83(t, 2H), 2.56(t, 2H)
Preparation Example 68: 2-(2-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester
Step A: (
E
)-3-(2-fluoro-4-methoxy-phenyl)-acrylic acid ethyl ester
2-Fluoro-4-methoxy-benzaldehyde (1.24 g, 3.56 mmol) and carbethoxy methylene triphenylphosphorane (2.0 g, 5.78 mmol) were dissolved in THF (10 mL), and the mixture was stirred at 65 ~ 75℃ for 1 hour. After the termination of the reaction, the reactant was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex = 1/10) to obtain the title compound (0.6 g, 83%).
1H NMR (400 MHz, CDCl3) δ 7.73(d, 1H), 7.43(t, 1H), 6.71-6.67(m, 1H), 6.64-6.59(m, 1H), 6.35(d, 1H), 4.29(q, 2H), 3.80(s, 3H), 1.33(t, 3H)
Step B: 2-(2-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid ethyl ester
(E)-3-(2-Fluoro-4-methoxy-phenyl)-acrylic acid ethyl ester (0.3 g, 1.34 mmol) obtained in Step A was dissolved in THF (10 mL), and diazomethane solution (21.4 mL, 5.36 mmol, 0.25M ether) was added thereto. After the reactant was cooled to 0 ~ 5℃, palladium(Ⅱ) acetate (45 mg, 0.2 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 5 hours. After the termination of the reaction, the reactant was filtered by using celite, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex = 1/10) to obtain the title compound (0.16 g, 51%).
1H NMR (400 MHz, CDCl3) δ 6.91-6.84(m, 1H), 6.63-6.56(m, 2H), 4.17(q, 2H), 3.76(s, 3H), 2.60-2.52(m, 1H), 1.88-1.82(m, 1H), 1.58-1.50(m, 1H), 1.31-1.25(m, 1H), 1.28(t, 3H)
Step C: 2-(2-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester
After 2-(2-fluoro-4-methoxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.16 g, 0.67 mmol) obtained in Step B was dissolved in anhydrous DCM (10 mL), 1M BBr3 solution (3.36 mL, 3.35 mmol) was added thereto at -78℃, and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, EtOH was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reactant was concentrated under reduced pressure, added with saturated sodium bicarbonate aqueous solution, and extracted with DCM. The organic layer was concentrated under reduced pressure and purified by column chromatography (eluent, EtOAc/Hex = 1/4) to obtain the title compound (0.25 g, 97%).
1H NMR (400 MHz, CDCl3) δ 6.85-6.78(m, 1H), 6.59-6.51(m, 2H), 4.19(q, 2H), 2.61-2.52(m, 1H), 1.88-1.82(m, 1H), 1.59-1.52(m, 1H), 1.33-1.27(m, 1H), 1.29(t, 3H)
Example 1: 3-[3,5-difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
Step A: 3-[3,5-difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)phenyl]-propionic acid ethyl ester
After 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (40 mg, 0.174 mmol) obtained in Step D of Preparation Example 2 was dissolved in CH3CN (5 mL), Cs2CO3 (171 mg, 0.52 mmol) was added thereto, and then 3-chloromethyl-2-isopropyl sulfanyl-pyridin (35 mg, 0.174 mmol) obtained in Step C of Preparation Example 1 was added thereto. The mixture was stirred at 80 ~ 85℃ for 1 hour. After the termination of the reaction, the reactant was cooled and then filtered by celite. The filtrate was concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex = 1/10) to obtain the title compound (66 mg, 96%).
1H NMR (400 MHz, CDCl3) δ 8.44-8.38(m, 1H), 7.83-7.77(m, 1H), 7.07-7.02(m, 1H), 6.76(d, 2H), 5.10(s, 2H), 4.19-4.09(m, 3H), 2.88(t, 2H), 2.58(t, 2H), 1.39(d, 6H), 1.24(t, 3H)
Step B: 3-[3,5-difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
After 3-[3,5-difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)phenyl]-propionic acid ethyl ester (66 mg, 0.167 mmol) obtained in Step A was dissolved in THF/MeOH/water (2:2:1, 5 mL), lithium hydroxide (12 mg, 0.50 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and the residue was diluted with water. The aqueous layer was added with diethyl ether, stirred, and then extracted. The aqueous layer was added with 1N HCl to adjust pH to 2~3, and then extracted with EtOAc. The organic layer was dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (56 mg, 91%).
1H NMR (400 MHz, CDCl3) δ 8.45-8.40(m, 1H), 7.84-7.79(m, 1H), 7.10-7.02(m, 1H), 6.77(d, 2H), 5.12(s, 2H), 4.20-4.08(m, 1H), 2.89(t, 2H), 2.66(t, 2H), 1.39(d, 6H)
Example 2: 3-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
Step A: 3-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)phenyl]-propionic acid methyl ester
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.056 g, 0.27 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-phenyl)-propionic acid methyl ester (0.05 g, 0.27 mmol) obtained in Preparation Example 4 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.066 g, 69%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.68(1H, m), 7.12(2H, d), 7.02(1H, m), 6.88(2H, d), 4.98(2H, s), 4.18(1H, m), 3.66(3H, s), 2.89(2H, t), 2.60(2H, t), 1.42(3H, t)
Step B: 3-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)phenyl]-propionic acid methyl ester (0.064 g, 0.18 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.027 mg, 44%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.68(1H, m), 7.14(2H, d), 7.02(1H, m), 6.90(2H, d), 4.99(2H, s), 4.18(1H, m), 2.93(2H, t), 2.66(2H, t), 1.42(6H, d)
Mass(EI): 332(M+1)
Example 3: 3-[4-(2-isopropylsulfanyl-5-methyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid
Step A: 3-[4-(2-isopropylsulfanyl-5-methyl-pyridin-3-ylmethoxy)phenyl]-2-methyl-propionic acid ethyl ester
3-Chloromethyl-2-isopropylsulfanyl-5-methyl-pyridine (0.02 g, 0.09 mmol) obtained in Step D of Preparation Example 30 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester obtained in Step B of Preparation Example 3 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.012 g, 33%).
1H-NMR (CDCl3) δ 8.24(1H, s), 7.53(1H,s), 7.10(2H, d), 6.90(2H, d), 4.97(2H, s), 4.13(1H, m), 4.08(2H, q), 2.94(1H, m), 2.67(2H, m), 2.28(3H, s), 1.39(6H, d), 1.19(3H, t), 1.14(3H, d)
Step B 3-[4-(2-isopropylsulfanyl-5-methyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid
3-[4-(2-Isopropylsulfanyl-5-methyl-pyridin-3-ylmethoxy)phenyl]-2-methyl-propionic acid ethyl ester (0.012 g, 0.03 mmol) obtained in Step A was reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.007 g, 63%).
1H-NMR (CDCl3) δ 8.25(1H, s), 7.54(1H, s), 7.11(2H, d), 6.90(2H, d), 4.97(2H, s), 4.11(1H, m), 3.01(1H, m), 2.72(1H, m), 2.62(1H, m), 2.28(3H, s), 1.40(6H, d), 1.18(3H, d)
Example 4: 3-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid
Step A: 3-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid ethyl ester
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.063 g, 0.31 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (0.065 g, 0.31 mmol) obtained in Step B of Preparation Example 3 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.062 g, 53%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.70(1H, m), 7.08(2H, d), 7.02(1H, m), 6.88(2H, d), 4.98(2H, s), 4.19(1H, m), 4.06(2H, q), 2.95(1H, m), 2.63(2H, m), 1.43(6H, d), 1.20(3H, t), 1.14(3H, d)
Step B 3-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid
3-[4-(2-Isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid ethyl ester (0.06 g 0.16 mmol) obtained in Step A was reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.037 g, 66%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.69(1H, m), 7.11(2H, d), 7.02(1H, m), 6.89(2H, d), 4.99(2H, s), 4.18(1H, m), 3.00(1H, m), 2.72(1H, m), 2.64(1H, m), 1.43(6H, d), 1.19(3H, d)
Example 5: 3-[4-(2-isopropylsulfanyl-5-methyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-5-methyl-pyridine (0.052g, 0.24mmol) obtained in Step D of Preparation Example 30 and 3-(4-hydroxy-phenyl)-propionic acid methyl ester (0.043g, 0.24mol) obtained in Preparation Example 4 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (55%).
1H-NMR (CDCl3) δ8.25(1H, s), 7.54(1H, s), 7.14(2H, d), 6.91(2H, d), 4.98(2H, s), 4.12(1H, m), 2.92(2H, t), 2.66(2H, t), 2.28(3H, s), 1.39(6H, d)
Example 6: 3-[3-fluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.041g, 0.2mmol) obtained in Step C of Preparation Example 1 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.04g, 0.2mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (47% yield).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.74(1H, m), 7.04(1H, m), 6.95(1H, m), 6.90(2H, m), 5.05(2H, s), 4.17(1H, m), 2.88(2H, t), 2.65(2H, t), 1.42(6H, d)
Example 7: 3-[2-fluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.043g, 0.21mmol) obtained in Step C of Preparation Example 1 and 3-(2-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.045g, 0.21mmol) obtained in Step D of Preparation Example 7 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (27% yield).
1H-NMR (CDCl3) δ 8.41(1H, m), 7.66(1H, m), 7.12(1H, m), 7.02(1H, m), 6.68(2H, m), 4.97(2H, s), 4.18(1H, m), 2.92(2H, t), 2.66(2H, t), 1.43(6H, d)
Example 8: 3-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.205 g, 0.9 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-phenyl)-propionic acid methyl ester (0.162 g, 0.9 mmol) obtained in Preparation Example 4 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.270 g, 83%).
1H-NMR (CDCl3) δ 8.40-8.39(1H, m), 7.68- 7.67(1H, m), 7.14-7.12(2H, d), 7.03-7.01(1H, q), 6.91- 6.89(2H, d), 4.99(2H, s), 4.26-4.18(1H, m), 2.93-2.89(2H, t), 2.67-2.63(2H, t), 2.25-2.19(2H, m), 1.79-1.77(2H, m), 1.71-1.60(4H, m)
Example 9: 3-[3,5-difluoro-4-(2-isopropylsulfanyl-6-methyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-6-methyl-pyridine obtained in Step D of Preparation Example 9 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (236 mg, 1.02 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (278 mg, 78%).
1H-NMR (CDCl3) δ 7.62(1H, d), 6.87(1H, d), 6.74(2H, m), 5.10(2H, s), 4.13(1H, m), 2.86(2H, t), 2.65(2H, t), 2.48(3H, s), 1.35(6H, d)
Example 10: 3-[4-(2-ethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
3-Chloromethyl-2-ethylsulfanyl-pyridine (0.1g, 0.53mmol) obtained in Step C of Preparation Example 11 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.12g, 0.53mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtai the title compound (76% yield).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.78(1H, m), 7.04(1H, m), 6.77(2H, m), 5.11(2H, s), 3.25(2H, q), 2.87(2H, t), 2.66(2H, t), 1.35(3H, t)
Example 11: 3-[3,5-difluoro-4-(2-isobutylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-isobutylsulfanyl-pyridine (0.048g, 0.22mmol) obtained in Step C of Preparation Example 12 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.051g, 0.22mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (60% yield).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.78(1H, m), 7.03(1H, m), 6.78(2H, m), 5.14(2H, s), 3.17(2H, d), 2.88(2H, t), 2.66(2H, t), 1.92(1H, m), 1.03(6H, d)
Example 12: 3-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.037 g, 0.16 mmol) obtained in Step C of Preparation Example 8 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.037 g, 0.16 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.050 g, 79%).
1H-NMR (CDCl3) δ 8.41-8.40(1H, m), 7.79-7.78(1H, m), 7.06- 7.03(1H, q), 5.11(2H, s), 4.22-4.15(1H, m), 2.91-2.87(2H, t), 2.68-2.64(2H, t), 2.22-2.19(2H, m), 1.76-1.75(2H, m), 1.67-1.59(4H, m)
Example 13: 4-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-butyric acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.04 g, 0.20 mmol) obtained in Step C of Preparation Example 1 and 4-(4-hydroxy-phenyl)-butyric acid ethyl ester (0.041 g, 0.20 mmol) obtained in Step E of Preparation Example 13 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.06 g, 88%).
1H NMR (400 MHz, CDCl3) δ 8.42-8.38(m, 1H), 7.72-7.67(m, 1H), 7.10(d, 2H), 7.05-7.00(m, 1H), 6.89(d, 2H), 4.99(s, 2H), 4.23-4.12(m, 1H), 2.62(t, 2H), 2.36(t, 2H), 1.98-1.88(m, 2H), 1.42(d, 6H)
Example 14: 3-[3,5-difluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
Step A: 3-[3,5-difluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid ethyl ester
3-Chloromethyl-2-propylsulfanyl-pyridine (0.1 g, 0.49 mmol) obtained in Step C of Preparation Example 14 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (0.155 g, 79%).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.78(1H, m), 7.04(1H, m), 6.76(2H, m), 5.12(2H, s), 4.13(2H, q), 3.22(2H, t), 2.87(2H, t), 2.58(2H, t), 1.73(2H, m), 1.24(3H, t), 1.03(3H, t)
Step B: 3-[3,5-difluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-[3,5-Difluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid ethyl ester (0.155 g, 0.39 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.139 g, 96%).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.78(1H, m), 7.04(1H, m), 6.77(2H, m), 5.13(2H, s), 3.22(2H, t), 2.88(2H, t), 2.68(2H, t), 1.73(2H, m), 1.03(3H, t)
Example 15: 3-[3,5-difluoro-4-(2-phenylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-phenylsulfanyl-pyridine obtained in Step C of Preparation Example 15 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (21 mg, 0.09 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (19 mg, 51%).
1H-NMR (CDCl3) δ 8.39(1H, d), 7.91(1H, d), 7.50(2H, m), 7.30(3H, m), 7.10(1H, m), 6.76(2H, m), 5.26(2H, s), 2.89(2H, t), 2.65(2H, t)
Example 16: 3-[4-(2-t-butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
Step A: 3-[4-(2-t-butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid ethyl ester
2-t-Butylsulfanyl-3-chloromethyl-pyridine (0.08 g, 0.37 mmol) obtained in Step C of Preparation Example 17 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (0.13 g, 86%).
1H-NMR (CDCl3) δ 8.45(1H, m), 7.88(1H, m), 7.11(1H, m), 6.76(2H, m), 5.17(2H, m), 4.13(2H, q), 2.87(2H, t), 2.58(2H, t), 1.54(9H, s), 1.24(3H, t)
Step B: 3-[4-(2-
t
-butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
3-[4-(2-t-Butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid ethyl ester (0.13 g, 0.31 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.108 g, 89%).
1H-NMR (CDCl3) δ 8.47(1H, m), 7.89(1H, m), 7.14(1H, m), 6.76(2H, m), 5.19(2H, s), 2.87(2H, t), 2.67(2H, t), 1.53(9H, s)
Example 17: 3-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
Step A: 3-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid ethyl ester
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (0.07 g, 0.32 mmol) obtained in Step C of Preparation Example 18 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.1 g, 80%).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.80(1H, m), 7.05(1H, m), 6.75(2H, m), 5.13(2H, s), 4.13(2H, q), 3.20(2H, d), 2.88(2H, t), 2.59(2H, t), 1.24(3H, t), 1.15(1H, m), 0.58(2H, m), 0.32(2H, m)
Step B: 3-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
3-[4-(2-Cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid ethyl ester (0.1 g, 0.24 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.08 g, 85%).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.80(1H, m), 7.05(1H, m), 6.76(2H, m), 5.14(2H, s), 3.18(2H, d), 2.87(2H, t), 2.66(2H, t), 1.14(1H, m), 0.56(2H, m), 0.29(2H, m)
Example 18: 3-{3,5-difluoro-4-[2-(2,2,2-trifluoro-ethylsulfanyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid
Step A: 3-{3,5-difluoro-4-[2-(2,2,2-trifluoro-ethylsulfanyl)-pyridin-3-yl methoxy]-phenyl}-propionic acid ethyl ester
3-Chloromethyl-2-(2,2,2-trifluoro-ethylsulfanyl)-pyridine (0.07 g, 0.28 mmol) obtained in Step C of Preparation Example 19 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.082 g, 65%).
1H-NMR (CDCl3) δ 8.42(1H, m), 7.82(1H, m), 7.14(1H, m), 6.75(2H, m), 5.14(2H, s), 4.15(2H, q), 4.12(2H, q), 2.87(2H, t), 2.58(2H, t), 1.24(3H, t)
Step B: 3-{3,5-difluoro-4-[2-(2,2,2-trifluoro-ethylsulfanyl)-pyridin-3-yl methoxy]-phenyl}-propionic acid
3-{3,5-Difluoro-4-[2-(2,2,2-trifluoro-ethylsulfanyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid ethyl ester (0.082 g, 0.18 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.043 g, 56%).
1H-NMR (CDCl3) δ 8.41(1H. m), 7.81(1H, m), 7.13(1H, m), 6.76(2H, m), 5.15(2H, s), 4.10(2H, q), 2.88(2H, t), 2.65(2H, t)
Example 19: 3-[4-(2-sec-butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
Step A: 3-[4-(2-sec-butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid ethyl ester
2-sec-Butylsulfanyl-3-chloromethyl-pyridine (0.06 g, 0.27 mmol) obtained in Step C of Preparation Example 33 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.074 g, 65%).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.79(1H, m), 7.04(1H, m), 6.76(2H, m), 5.11(2H, s), 4.12(2H, q), 4.03(1H, m), 2.87(2H, t), 2,58(2H, t), 1.74(1H, m), 1.66(1H, m), 1.38(3H, d), 1.24(3H, t), 1.02(3H, t)
Step B: 3-[4-(2-sec-butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
3-[4-(2-sec-Butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid ethyl ester (0.074 g, 0.18 mmol) obtained in Step A wase reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.068 g, 98%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.79(1H, m), 7.04(1H, m), 6.77(2H, m), 5.12(2H, s), 4.04(1H, m), 2.89(2H, t), 2.65(2H, t), 1.74(1H, m), 1.66(1H, m), 1.38(3H, d), 1.01(3H, t)
Example 20: 3-[3,5-difluoro-4-(3-isopropylsulfanyl-pyrazin-2-ylmethoxy)-phenyl]-propionic acid
Step A: 3-[3,5-difluoro-4-(3-isopropylsulfanyl-pyrazin-2-ylmethoxy)-phenyl]-propionic acid ethyl ester
2-Chloromethyl-3-isopropylsulfanyl-pyrazine (0.04 g, 0.2 mmol) obtained in Step D of Preparation Example 21 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.06 g, 75%).
1H-NMR (CDCl3) δ 8.34(1H, d), 8.20(1H, d), 6.73(2H, m), 5.21(2H, s), 4.12(2H, q), 4.07(1H, m), 2.86(2H, t), 2.57(2H, t), 1.40(6H, d), 1.23(3H, t)
Step B: 3-[3,5-difluoro-4-(3-isopropylsulfanyl-pyrazin-2-ylmethoxy)-phenyl]-propionic acid
3-[3,5-Difluoro-4-(3-isopropylsulfanyl-pyrazin-2-ylmethoxy)-phenyl]-propionic acid ethyl ester (0.06 g, 0.15 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.05 g, 90%).
1H-NMR (CDCl3) δ 8.36(1H, d), 8.21(1H, d), 6.74(2H, m), 5.22(2H, s), 4.10(1H, m), 2.88(2H, t), 2.65(2H, t), 1.41(6H, d)
Example 21: 4-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-butyric acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.020 g, 0.09 mmol) obtained in Step C of Preparation Example 8 and 4-(4-hydroxy-phenyl)-butyric acid ethyl ester (0.018g, 0.09mmol) obtained in Step E of Preparation Example 13 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.031 g, 94%).
1H-NMR (CDCl3) δ 8.42-8.41(1H, m), 7.71- 7.69(1H, m), 7.11-7.09(2H, d), 7.04-7.01(1H, q), 6.90- 6.88(2H, d), 4.99(2H, s), 4.25- 4.22(1H, m), 2.63-2.59(2H, t), 2.38-2.34(2H, t), 2.24-2.22(2H, m), 1.97-1.89(2H, m), 1.89(2H, m), 1.66(4H, m)
Example 22: 3-[4-(2-cyclohexylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
3-Chloromethyl-2-cyclohexylsulfanyl-pyridine (0.074 mmol) obtained in Step C of Preparation Example 22 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (17.5 mg, 0.074 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (23 mg, 74%).
1H NMR (400 MHz, CDCl3) δ 8.42-8.39(m, 1H), 7.83-7.79(m, 1H), 7.08-7.01(m, 1H), 6.77(d, 2H), 5.12(s, 2H), 4.04-3.95(m, 1H), 2.89(t, 3H), 2.66(t, 3H), 2.10-2.00(m, 2H), 1.80-1.70(m, 1H), 1.69-1.58(m, 1H), 1.53-1.39(m, 4H), 1.37-1.25(m, 1H)
Example 23: 3-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.113 mmol) obtained in Step C of Preparation Example 23 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (26 mg, 0.113 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (35 mg, 82%).
1H NMR (400 MHz, CDCl3) δ 8.42-8.37(m, 1H), 7.82-7.74(m, 1H), 7.09-7.00(m, 1H), 6.77(d, 2H), 5.10(s, 2H), 4.56-4.44(m, 1H), 2.89(t, 2H), 2.66(t, 2H), 2.60-2.49(m, 2H), 2.20-1.99(m, 4H)
Example 24: 3-[3,5-difluoro-4-(2-isopropylsulfanyl-pyrimidin-4-ylmethoxy)-phenyl]-propionic acid
Step A: 3-[3,5-difluoro-4-(2-isopropylsulfanyl-pyrimidin-4-ylmethoxy)phenyl]-propionic acid ethyl ester
(2-Isopropylsulfanyl-pyrimidin-4-yl)-methanol (0.08g, 0.43mmol) obtained in Step C of Preparation Example 24, 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.1g, 0.43mmol) obtained in Step D of Preparation Example 2 and triphenyl phosphine (0.114g, 0.43mmol) were dissolved in anhydrous THF (3 mL), and the mixture was stirred at room temperature for 10 minutes. Diisopropyl azodicarboxylate (0.085 mL, 0.43 mmol) was added slowly thereto. The mixture was stirred at room temperature for 18 hours, concentrated under reduced pressure, and separated by column chromatography (eluent: 100% DCM) to obtain the title compound (0.14 g, 81%).
1H-NMR (CDCl3) δ 8.56(1H, d), 7.36(1H, d), 6.78(2H, m), 5.13(2H, s), 4.14(2H, q), 3.93(1H, m), 2.88(2H, t), 2.59(2H, t), 1.41(6H, d), 1.25(3H, t)
Step B: 3-[3,5-difluoro-4-(2-isopropylsulfanyl-pyrimidin-4-ylmethoxy)-phenyl]-propionic acid
3-[3,5-Difluoro-4-(2-isopropylsulfanyl-pyrimidin-4-ylmethoxy)phenyl]-propionic acid ethyl ester (0.14 g, 0.35 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.09 g, 69%).
1H-NMR (CDCl3) δ 8.56(1H, d), 7.36(1H, d), 6.79(2H, m), 5.14(2H, s), 3.93(1H, m), 2.88(2H, t), 2.66(2H, t), 1.41(6H, d)
Example 25: 3-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.056 g, 0.24 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester obtained in Step B of Preparation Example 3 A were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.035 g, 40%).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.67(1H, m), 7.10(2H, d), 7.01(1H, m), 6.88(2H, d), 4.98(2H, s), 4.22(1H, m), 3.01(1H, m), 2.72(1H, m), 2.63(1H, m), 2.22(2H, m), 1.77(2H, m), 1.65(4H, m), 1.17(3H, d)
Example 26: 3-[4-(2-butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
Step A: 3-[4-(2-butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid ethyl ester
2-Butylsulfanyl-3-chloromethyl-pyridine (0.069 g, 0.32 mmol) obtained in Step C of Preparation Example 10 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.12 g, 91%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.78(1H, m), 7.04(1H, m), 6.77(2H, m), 5.12(2H, s), 4.13(2H, q), 3.25(2H, t), 2.88(2H, t), 2.59(2H, t), 1.67(2H, m), 1.48(2H, m), 1.25(3H, t), 0.94(3H, t)
Step B: 3-[4-(2-butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
3-[4-(2-Butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid ethyl ester (0.12 g, 0.29 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.071 g, 64%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.79(1H, m), 7.04(1H, m), 6.76(2H, m), 5.13(2H, s), 3.24(2H, t), 2.88(2H, t), 2.68(2H, t), 1.67(2H, m), 1.47(2H, m), 0.93(3H, t)
Example 27: 3-{3,5-difluoro-4-[2-(3,3,3-trifluoro-propylsulfanyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid
Step A: 3-{3,5-difluoro-4-[2-(3,3,3-trifluoro-propylsulfanyl)-pyridin-3-yl methoxy]-phenyl}-propionic acid ethyl ester
3-Chloromethyl-2-(3,3,3-trifluoro-propylsulfanyl)-pyridine (0.058 g, 0.22 mmol) obtained in Step C of Preparation Example 25 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.079 g, 77%).
1H-NMR (CDCl3) δ 8.42(1H, m), 7.78(1H, m), 7.09(1H, m), 6.77(2H, m), 5.10(2H, s), 4.13(2H, q), 3.40(2H, m), 2.88(2H, t), 2.61(2H, t), 2.55(2H, m), 1.25(3H, t)
Step B: 3-{3,5-difluoro-4-[2-(3,3,3-trifluoro-propylsulfanyl)-pyridin-3-yl methoxy]-phenyl}-propionic acid
3-{3,5-Difluoro-4-[2-(3,3,3-trifluoro-propylsulfanyl)-pyridin-3-ylmethoxy]-phenyl}-propionic acid ethyl ester (0.079 g, 0.17 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.035 g, 49%).
1H-NMR (CDCl3) δ 8.42(1H, m), 7.79(1H, m), 7.08(1H, m), 6.78(2H, m), 5.10(2H, s), 3.39(2H, m), 2.89(2H, t), 2.66(2H, t), 2.55(2H, m)
Example 28: 3-{4-[2-(2,2-dimethyl-propylsulfanyl)-pyridin-3-ylmethoxy]-3,5-difluoro-phenyl}-propionic acid
Step A: 3-{4-[2-(2,2-dimethyl-propylsulfanyl)-pyridin-3-ylmethoxy]-3,5-difluoro-phenyl}-propionic acid ethyl ester
3-Chloromethyl-2-(2,2-dimethyl-propylsulfanyl)-pyridine (0.034 g, 0.15 mmol) obtained in Step C of Preparation Example 26 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.06 g, 95%).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.79(1H, m), 7.03(1H, m), 6.75(2H, m), 5.16(2H, s), 4.13(2H, q), 3.29(2H, s), 2.87(2H, t), 2.58(2H, t), 1.25(3H, t), 1.02(9H, s)
Step B: 3-{4-[2-(2,2-dimethyl-propylsulfanyl)-pyridin-3-ylmethoxy]-3,5-difluoro-phenyl}-propionic acid
3-{4-[2-(2,2-Dimethyl-propylsulfanyl)-pyridin-3-ylmethoxy]-3,5-difluoro-phenyl}-propionic acid ethyl ester (0.06 g, 0.14 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.022 g, 40%).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.79(1H, m), 7.03(1H, m), 6.78(2H, m), 5.17(2H, s), 3.29(2H, s), 2.88(2H, t), 2.66(2H, t), 1.02(9H, s)
Example 29: 3-[4-(6-cyclopentylsulfanyl)-pyridin-2-ylmethoxy]-phenyl]-propionic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.094 mmol) obtained in Step C of Preparation Example 27 and 3-(4-hydroxy-phenyl)-propionic acid methyl ester (17 mg, 0.094 mmol) obtained in Preparation Example 4 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.03 g, 89%).
1H NMR (400 MHz, CDCl3) δ 7.48(t, 1H), 7.18-7.06(m, 4H), 6.90(d, 2H), 5.12(s, 2H), 4.04-3.96(m, 1H), 2.90(t, 2H), 2.64(t, 2H), 2.25-2.12(m, 2H), 1.85-1.73(m, 2H), 1.71-1.59(m, 4H)
Example 30: 3-[4-(6-cyclopentylsulfanyl)-pyridin-2-ylmethoxy]-3,5-difluoro-phenyl]-propionic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.096 mmol) obtained in Step C of Preparation Example 27 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.022 g, 0.096 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.031 g, 82%).
1H NMR (400 MHz, CDCl3) δ 7.52(t, 1H), 7.31(d, 1H), 7.09(d, 1H), 6.76(d, 2H), 5.20(s, 2H), 4.01-3.91(m, 1H), 2.88(t, 2H), 2.65(t, 2H), 2.23-2.10(m, 2H), 1.83-1.70(m, 2H), 1.69-1.55(m, 4H)
Example 31: 3-[4-(6-cyclohexylsulfanyl)-pyridin-2-ylmethoxy]-3,5-difluoro-phenyl]-propionic acid
2-Chloromethyl-6-cyclohexylsulfanyl-pyridine (0.027 g, 0.11 mmol) obtained in Step C of Preparation Example 28 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.026 g, 0.11 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.017 g, 37%).
1H-NMR (CDCl3) δ 7.53-7.49(1H, t), 7.32-7.30(1H, d), 7.09- 7.07(1H, d), 6.79-6.74(2H, m), 5.19(2H, s), 3.75-3.74(1H, m), 2.90-2.86(2H, t), 2.67-2.63(2H, t), 2.04-2.02(2H, m), 1.76-1.74(2H, m), 1.61(1H, m), 1.50-1.36(5H, m)
Example 32: 3-[4-(6-ethyl-2-isopropylsulfanyl)-pyridin-3-ylmethoxy]-3,5-difluoro-phenyl]-propionic acid
3-Chloromethyl-6-ethyl-2-isopropylsulfanyl-pyridine obtained in Step C of Preparation Example 29 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (35 mg, 0.15 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (34 mg, 63%).
1H-NMR (CDCl3) δ 7.66(1H, d), 6.87(1H, d), 6.76(2H, m), 5.09(2H, s), 4.17(1H, m), 2.88(2H, t), 2.78(2H, q), 2.65(2H, t), 1.39(6H, d) 1.28(3H, t)
Example 33: 3-[3,5-difluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.043 g, 0.21 mmol) obtained in Step C of Preparation Example 16 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.047 g, 60%).
1H-NMR (CDCl3) δ 7.51(1H, m), 7.31(1H, d), 7.07(1H, d), 6.74(2H, m), 5.19(2H, s), 3.92(1H, m), 2.85(2H, t), 2.65(2H, t), 1.34(6H, d)
Example 34: 3-[4-(6-sec-butylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
2-sec-Butylsulfanyl-6-chloromethyl-pyridine (0.06 g, 0.27 mmol) obtained in Step C of Preparation Example 5 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester obtained in Step D of Preparation Example 2 were used to react in the same manner as in Step A Example 1 to obtain the title compound (0.074 g, 65%).
1H-NMR (CDCl3) δ 7.51(1H, t), 7.31(1H, d), 7.08(1H, d), 6.75(2H, m), 5.20(2H, s), 3.78(1H, m), 2.88(2H, t), 2.65(2H, t), 1.72(1H, m), 1.62(1H, m), 1.34(3H, d), 1.00(3H, t)
Example 35: 2-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.033 g, 0.143 mmol) obtained in Step C of Preparation Example 27 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (0.033 g, 0.143 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.045 g, 77%).
1H NMR (400 MHz, CDCl3) δ 7.52(t, 1H), 7.29(d, 1H), 7.09(d, 1H), 6.66(d, 2H), 5.20(s, 2H), 3.98-3.89(m, 1H), 2.54-2.47(m, 1H), 2.20-2.09(m, 2H), 1.87-1.81(m, 1H), 1.81-1.70(m, 2H), 1.69-1.54(m, 5H), 1.37-1.29(m, 1H)
Example 36: 2-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.024 g, 0.113 mmol) obtained in Step C of Preparation Example 23 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.026 g, 0.113 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.036 g, 81%).
1H NMR (400 MHz, CDCl3) δ 8.41-8.37(m, 1H), 7.78-7.72(m, 1H), 7.07-7.00(m, 1H), 6.67(d, 2H), 5.10(s, 2H), 4.54-4.44(m, 1H), 2.59-2.48(m, 3H), 2.18-1.98(m, 4H), 1.88-1.82(m, 1H), 1.70-1.62(m, 1H), 1.37-1.29(m, 1H)
Example 37: 3-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.022 g, 0.10 mmol) obtained in Step C of Preparation Example 23 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.022 g, 0.10 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.037 g, 97%).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.72-7.70(1H, m), 7.03-7.00(1H, q), 6.97-6.85(3H, m), 5.04(2H, s), 4.56-4.51(1H, m), 3.01-2.96(1H, q), 2.74-2.71(1H, m), 2.65-2.54(3H, m), 2.17-2.05(4H, m), 1.19-1.18(3H, d)
Example 38: 3-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.054 g, 0.24 mmol) obtained in Step C of Preparation Example 8 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.050 g, 0.24 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.091 g, 98%).
1H-NMR (CDCl3) δ 8.41-8.40(1H, m), 7.75-7.73(1H, m), 7.05-7.02(1H, q), 6.97-6.85(3H, m), 5.06(2H, s), 4.26-4.24(1H, m), 3.01-2.96(1H, q), 2.75-2.70(1H, m), 2.65-2.60(1H, m), 2.25-2.22(2H, m), 1.79-1.77(2H, m), 1.66-1.63(4H, m), 1.19-1.18(3H, d)
Example 39: 3-[4-(2-sec-butylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-2-methyl-propionic acid
2-sec-Butylsulfanyl-3-chloromethyl-pyridine (0.050 g, 0.23 mmol) obtained in Step C of Preparation Example 33 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.050 g, 0.23 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.060 g, 64%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.75-7.73(1H, m), 7.05-7.02(1H, q), 6.96-6.87(3H, m), 5.07(2H, s), 4.11-4.08(1H, m), 3.01-2.96(1H, q), 2.75-2.73(1H, m), 2.66-2.60(1H, m), 1.78-1.69(2H, m), 1.41-1.39(3H, d), 1.20-1.18(3H, d), 1.06-1.02(3H, t)
Example 40: 3-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-cyclomethylsulfanyl-pyridine (0.050 g, 0.23 mmol) obtained in Step C of Preparation Example 18 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.050 g, 0.23 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.084 g, 96%).
1H-NMR (CDCl3) δ 8.39-8.38(1H, m), 7.75-7.73(1H, m), 7.05-7.02(1H, q), 6.97-6.85(3H, m), 5.09(2H, s), 3.24-3.22(2H, d), 3.01-2.96(1H, q), 2.76-2.71(1H, m), 2.66-2.60(1H, m), 1.20-1.17(4H, m), 0.62-0.57(2H, m), 0.35-0.32(2H, m)
Example 41: 3-[3,5-difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.045 g, 0.22 mmol) obtained in Step C of Preparation Example 1 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (0.055 g, 0.22 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.046 g, 54%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.80(1H, m), 7.06(1H, m), 6.74(2H, m), 5.11(2H, s), 4.14(1H, m), 2.97(1H, m), 2.72(1H, m), 2.61(1H, m), 1.39(6H, d), 1.21(3H, d)
Example 42: 3-[4-(2-sec-butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid
2-sec-Butylsulfanyl-3-chloromethyl-pyridine (0.049 g, 0.22 mmol) obtained in Step C of Preparation Example 33 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (0.055 g, 0.22 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.036 g, 56%).
1H-NMR (CDCl3) δ 8.40(1H, m) 7.79(1H, m), 7.05(1H, m), 6.74(2H, m), 5.12(2H, s), 4.03(1H, m), 2.97(1H, m), 2.73(1H, m), 2.64(1H, m), 1.74(1H, m), 1.65(1H, m), 1.36(3H, d), 1.20(3H, d), 1.02(3H, t)
Example 43: 3-[3,5-difluoro-4-(2-isopropylsulfanyl-6-methoxy-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-6-methoxy-pyridine obtained in Step E of Preparation Example 35 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (33 mg, 0.14 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 66%).
1H-NMR (CDCl3) δ 7.58(1H, d), 6.75(2H, m), 6.44(1H, d), 5.06(2H, s), 4.11(1H, m), 3.94(3H, s), 2.89(2H, t), 2.66(2H, t), 1.41(6H, d)
Example 44: 3-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (40 mg, 0.17 mmol) obtained in Step C of Preparation Example 27 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (43 mg, 0.17 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.054 g, 75%).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.78(1H, m), 7.03(1H, m), 6.73(2H, m), 5.10(2H, s), 4.27(1H, m), 4.11(2H, q), 2.97(1H, m), 2.74(1H, m), 2.60(1H, m), 2.20(2H, m), 1.74(2H, m), 1.63(4H, m), 1.20(3H, d)
Example 45: 3-[4-(2-cyclopentylsulfanyl-6-methyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-6-methyl-pyridine obtained in Step C of Preparation Example 36 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (39 mg, 0.17 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (33 mg, 57%).
1H-NMR (CDCl3) δ 7.61(1H, d), 6.87(1H, d), 6.75(2H, m), 5.09(2H, s), 4.19(1H, m), 2.88(2H, t), 2.65(2H, t), 2.49(3H, s), 2.20(2H, m), 1.76(2H, m), 1.62(4H, m)
Example 46: 3-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid
Step A: 3-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid ethyl ester
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.018 g, 0.08 mmol) obtained in Step C of Preparation Example 37 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (0.021 g, 0.08 mmol) obtained in Step B of Preparation Example 34 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (0.024 g, 67%).
1H-NMR (CDCl3) δ 7.52(1H, t), 7.32(1H, d), 7.00(1H, d), 6.72(2H, m), 5.18(2H, s), 4.25(1H, m), 4.10(2H, q), 2.92(1H, m), 2.67(1H, m), 2.61(1H, m), 2.49(2H, m), 2.08(4H, m), 1.20(3H, t), 1.15(3H, d)
Step B: 3-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid
3-[4-(6-Cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid ethyl ester (0.024 g, 0.057 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.0023 g, 10%).
1H-NMR (CDCl3) δ 7.52(1H, t), 7.32(1H, d), 7.00(1H, d), 6.74(2H, m), 5.19(2H, s), 4.23(1H, m), 2.97(1H, m), 2.74(1H, m), 2.62(1H, m), 2.49(2H, m), 2.08(4H, m), 1.19(3H, d)
Example 47: 3-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.035 g, 0.15 mmol) obtained in Step C of Preparation Example 8 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (35mg, 0.13 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.027 g, 46% yield).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.78(1H, m), 7.04(1H, m), 6.73(2H, m), 5.10(2H, s), 4.18(1H, m), 2.96(1H, m), 2.72(1H, m), 2.63(1H, m), 2.19(2H, m), 1.74(2H, m), 1.63(4H, m), 1.20(3H, d)
Example 48: 3-[4-(6-sec-butylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid
Step A: 3-[4-(6-sec-butylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid ethyl ester
2-sec-Butylsulfanyl-6-chloromethyl-pyridine (28 mg, 0.13mmol) in Step C of Preparation Example 5 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (30mg, 0.13 mmol) in Step B of Preparation Example 34 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (50 mg, 96%).
Step B: 3-[4-(6-sec-butylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid
3-[4-(6-sec-Butylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid ethyl ester (50mg, 0.12 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (35 mg, 75%).
1H-NMR (CDCl3) δ 7.53(1H, t), 7.31(1H, d), 7.08(1H, d), 6.74(2H, m), 5.19(2H, s), 3.81(1H, m), 2.97(1H, m), 2.73(1H, m), 2.62(1H, m), 1.71(1H, m), 1.63(1H, m), 1.34(3H, d), 1.20(3H, d), 1.00(3H, t)
Example 49: 3-[3,5-difluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-2-methyl-propionic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (26 mg, 0.13 mmol) obtained in Step C of Preparation Example 16 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (30 mg, 0.13 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (40 mg, 80%).
1H-NMR (CDCl3) δ 7.51(1H, t), 7.32(1H, d), 7.08(1H, d), 6.74(2H, m), 5.20(2H, s), 3.93(1H, m), 2.97(1H, m), 2.73(1H, m), 2.62(1H, m), 1.36(6H, d), 1.20(3H, d)
Example 50: 3-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (0.037 g, 0.17 mmol) obtained in Step C of Preparation Example 18 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (39 mg, 0.17 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.047 g, 70%).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.80(1H, m), 7.05(1H, m), 6.76(2H, m), 5.14(2H, s), 3.20(2H, d), 2.98(1H, m), 2.73(1H, m), 2.63(1H, m), 1.21(3H, d), 1.14(1H, m), 0.58(2H, m), 0.31(2H, m)
Example 51: 3-[3,5-difluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-propylsulfanyl-pyridine (0.031 g, 0.15 mmol) obtained in Step C of Preparation Example 14 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (35 mg, 0.15 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.04 g, 68%).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.78(1H, m), 7.04(1H, m), 6.75(2H, m), 5.13(2H, s), 3.22(2H, t), 2.97(1H, m), 2.74(1H, m), 2.63(1H, m), 1.71(2H, m), 1.21(3H, d), 1.02(3H, t)
Example 52: 3-[3-fluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-2-methyl-propionic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.030 g, 0.15 mmol) obtained in Step C of Preparation Example 16 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.031 g, 0.15 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.047 g, 87%).
1H-NMR (CDCl3) δ 7.52-7.48(1H, t), 7.23-7.21(1H, d), 7.09-7.07(1H, d), 6.96-6.90(2H, m), 6.85-6.83(1H, m), 5.19(2H, s), 4.00-3.93(1H, m), 3.01-2.96(1H, q), 2.76-2.67(1H, m), 2.64-2.58(1H, m), 1.40-1.39(6H, d), 1.18-1.17(3H, d)
Example 53: 3-[4-(6-sec-butylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-2-methyl-propionic acid
2-sec-Butylsulfanyl-6-chloromethyl-pyridine (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 5 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.052 g, 99%).
1H-NMR (CDCl3) δ 7.50-7.46(1H, t), 7.21-7.19(1H, d), 7.09-7.07(1H, d), 6.96-6.89(2H, m), 6.84-6.82(1H, m), 5.17(2H, s), 3.88-3.79(1H, m), 3.00-2.95(1H, q), 2.72-2.58(1H, m), 1.76-1.64(2H, m), 1.38-1.36(3H, d), 1.18-1.16(3H, d), 0.88-0.83(3H, t)
Example 54: 3-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-2-methyl-propionic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.030 g, 0.13 mmol) obtained in Step C of Preparation Example 27 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.028 g, 0.13 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.050 g, 98%).
1H-NMR (CDCl3) δ 7.52-7.48(1H, t), 7.22-7.20(1H, d), 7.09-7.07(1H, d), 6.96-6.84(3H, m), 5.18(2H, s), 4.03-3.96(1H, m), 3.00-2.97(1H, q), 2.71-2.66(1H, m), 2.63-2.60(1H, m), 2.22-2.16(2H, m), 1.79-1.76(2H, m), 1.66-1.60(4H, m), 1.19-1.16(3H, d)
Example 55: 3-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-2-methyl-propionic acid
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.050 g, 0.23 mmol) obtained in Step C of Preparation Example 37 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.050 g, 0.23 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.070 g, 81%).
1H-NMR (CDCl3) δ 7.52-7.48(1H, t), 7.22-7.20(1H, d), 7.00-6.98(1H, d), 6.97-6.83(3H, m), 5.17(2H, s), 4.32-4.24(1H, m), 3.00-2.95(1H, q), 2.75-2.70(1H, m), 2.64-2.59(1H, m), 2.56-2.51(2H, m), 2.16-2.00(4H, m), 1.19-1.17(3H, d)
Example 56: 3-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.045 g, 0.21 mmol) obtained in Step C of Preparation Example 23 and 3-(3,5-difluoro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (49 mg, 0.21 mmol) obtained in Step B of Preparation Example 34 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.026 g, 31%).
1H-NMR (CDCl3) δ 8.36(1H, m), 7.76(1H, m), 7.02(1H, m), 6.75(2H, m), 5.09(2H, s), 4.49(1H, m), 2.97(1H, m), 2.74(1H, m), 2.63(1H, m), 2.51(2H, m), 2.10(2H, m), 2.05(2H, m), 1.20(3H, d)
Example 57: 3-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-3-methoxy-phenyl]-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (33 mg, 0.16 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-3-methoxy-phenyl]-propionic acid ethyl ester (40 mg, 0.17 mmol) obtained in Step C of Preparation Example 38 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (34 mg, 72%).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.72(1H, d), 7.00(1H, m), 6.77(2H, m), 6.69(1H, m), 5.06(2H, s), 4.18(1H, m), 3.89(3H, s), 2.91(2H, t), 2.66(2H, t), 1.43(6H, d)
Example 58: 3-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3-methoxy-phenyl]-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (40 mg, 0.16 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-3-methoxy-phenyl]-propionic acid ethyl ester (48 mg, 0.21 mmol) obtained in Step C of Preparation Example 38 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (36 mg, 64%).
1H-NMR (CDCl3) δ 8.37(1H, m), 7.72(1H, d), 7.00(1H, m), 6.76(2H, m), 6.68(1H, m), 5.06(2H, s), 4.22(1H, m), 3.89(3H, s), 2.91(2H, t), 2.67(2H, t), 2.24(2H, m), 1.79(2H, m), 1.54(4H, m)
Example 59: [6-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (20 mg, 0.10mmol) obtained in Step C of Preparation Example 1 and (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.10mmol) obtained in Preparation Example 52 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (25 mg, 70%).
1H-NMR (CDCl3) δ 8.41(1H, d), 7.68(1H, d), 7.07(2H, m), 6.48(2H, m), 4.97(2H, s), 4.78(1H, t), 4.31(1H, m), 4.16(1H, m), 3.82(1H, m), 2.80(1H, m), 2.65(1H, m), 1.41(6H, d)
Example 60: 3-[3-fluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.028 g, 0.14 mmol) obtained in Step C of Preparation Example 1 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.029 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.039 g, 78%).
1H-NMR (CDCl3) δ 8.41-8.40(1H, m), 7.75-7.73(1H, m), 7.05-7.02(1H, q), 6.97-6.84(3H, m), 5.05(2H, s), 4.22-4.15(1H, m), 3.01-2.96(1H, q), 2.75-2.70(1H, m), 2.65-2.60(1H, m), 1.43-1.41(6H, d), 1.19-1.18(3H, d)
Example 61: 3-[4-(2-butylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-2-methyl-propionic acid
2-Butylsulfanyl-3-chloromethyl-pyridine (0.020 g, 0.09 mmol) obtained in Step C of Preparation Example 10 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.019 g, 0.09 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.034 g, 97%).
1H-NMR (CDCl3) δ 8.44(1H, m), 7.77-7.75(1H, m), 7.07(1H, m), 6.97-6.85(3H, m), 5.08(2H, s), 3.33-3.29(2H, m), 3.01-2.96(1H, q), 2.75-2.70(1H, m), 2.65-2.60(1H, m), 1.73-1.67(2H, m), 1.51-1.46(2H, m), 1.19-1.18(3H, d), 0.97-0.93(3H, t)
Example 62: 2-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.030 g, 0.13 mmol) obtained in Step C of Preparation Example 8 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.032 g, 0.13 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.054g, 99%).
1H-NMR (CDCl3) δ 8.41-8.40(1H, m), 7.77-7.75(1H, m), 7.05-7.02(1H, q), 6.68-6.66(2H, m), 5.11(2H, s), 4.21-4.19(1H, m), 2.51-2.48(1H, m), 2.21(2H, m), 1.88-1.84(1H, m), 1.76(2H, m), 1.68-1.60(5H, m), 1.36-1.31(1H, m)
Example 63: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (0.020 g, 0.09 mmol) obtained in Step C of Preparation Example 18 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.023 g, 0.09 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.028 g, 77%).
1H-NMR (CDCl3) δ 8.40-8.39(1H, m), 7.79-7.77(1H, m), 7.06-7.03(1H, q), 6.69-6.66(2H, m), 5.15(2H, s), 3.21-3.19(2H, d), 2.51(1H, m), 1.87-1.84(1H, m), 1.67-1.65(1H, m), 1.35-1.33(1H, m), 1.14(1H, m), 0.59-0.57(2H, m), 0.32-0.30(2H, m)
Example 64: 2-[3,5-difluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.020 g, 0.10 mmol) obtained in Step C of Preparation Example 16 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.024 g, 0.10 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.022 g, 59%).
1H-NMR (CDCl3) δ 7.53-7.50(1H, t), 7.30-7.28(1H, d), 7.09-7.07(1H, d), 6.66-6.64(2H, m), 5.19(2H, s), 3.92-3.89(1H, m), 2.49(1H, m), 1.84(1H, m), 1.65(1H, m), 1.36-1.35(6H, d), 1.34(1H, m)
Example 65: 2-[3,5-difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cycloprppane carboxylic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.020 g, 0.10 mmol) obtained in Step C of Preparation Example 1 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.024 g, 0.10 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.035 g, 94%).
1H-NMR (CDCl3) δ 8.43-8.42(1H, m), 7.80-7.78(1H, m), 7.07-7.04(1H, q), 6.68-6.64(2H, m), 5.11(2H, s), 4.18-4.11(1H, m), 2.54-2.50(1H, m), 1.88-1.83(1H, m), 1.68-1.64(1H, m), 1.40-1.38(6H, d), 1.36-1.31(1H, m)
Example 66: 2-[4-(2-butylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid
2-Butylsulfanyl-3-chloromethyl-pyridine (0.020 g, 0.09 mmol) obtained in Step C of Preparation Example 10 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.022 g, 0.09 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.024 g, 66%).
1H-NMR (CDCl3) δ 8.42-8.41(1H, m), 7.78-7.76(1H, m), 7.07-7.04(1H, q), 6.69-6.64(2H, m), 5.12(2H, s), 3.27-3.23(2H, t), 2.54-2.50(1H, m), 1.86-1.83(1H, m), 1.69-1.65(3H, m), 1.49-1.43(2H, m), 1.35-1.30(1H, m), 0.95-0.91(3H, t)
Example 67: [6-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (20 mg, 0.10 mmol) obtained in Step C of Preparation Example 16 and (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.10mmol) obtained in Preparation Example 52 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 84%).
1H-NMR (CDCl3) δ 7.49(1H, t), 7.15(1H, d), 7.07(2H, t), 6.49(2H, m), 5.10(2H, s), 4.77(1H, t), 4.28(1H, m), 3.98(1H, m), 3.81(1H, m), 2.79(1H, m), 2.64(1H, m), 1.40(6H, d)
Example 68: [6-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (23 mg, 0.10 mmol) obtained in Step C of Preparation Example 27 and (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.10 mmol) obtained in Preparation Example 52 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 78%).
1H-NMR (CDCl3) δ 7.49(1H, t), 7.15(1H, d), 7.06(2H, m), 6.48(2H, m), 5.09(2H, s), 4.77(1H, t), 4.28(1H, m), 4.01(1H, m), 3.81(1H, m), 2.81(1H, m), 2.64(1H, m), 2.19(2H, m), 1.78(2H, m), 1.64(4H, m)
Example 69: 3-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2,2-dimethyl-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.02 g, 0.099 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-phenyl)-2,2-dimethyl-propionic acid ethyl ester (0.022 g, 0.099 mmol) obtained in Step D of Preparation Example 39 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.029 g, 81%).
1H NMR (400 MHz, CDCl3) δ 8.42-8.38(m, 1H), 7.72-7.67(m, 1H), 7.09(d, 2H), 7.04-6.99(m, 1H), 6.88(d, 2H), 4.99(s, 2H), 4.23-4.12(m, 1H), 2.84(s, 2H), 1.41(d, 6H), 1.20(s, 6H)
Example 70: 3-[4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-2,2-dimethyl-propionic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.02 g, 0.099 mmol) obtained in Step C of Preparation Example 16 and 3-(4-hydroxy-phenyl)-2,2-dimethyl-propionic acid ethyl ester (0.022 g, 0.099 mmol) obtained in Step D of Preparation Example 39 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.029 g, 81%).
1H NMR (400 MHz, CDCl3) δ 7.47(t, 1H), 7.17(d, 1H), 7.10-7.02(m, 3H), 6.89(d, 2H), 5.12(s, 2H), 4.02-3.90(m, 1H), 2.83(s, 2H), 1.39(d, 6H), 1.19(s, 6H)
Example 71: 3-[3,5-difluoro-4-(4-isopropylsulfanyl-2-methyl-pyrimidin-5-ylmethoxy)-phenyl]-propionic acid
Step A: 3-[3,5-difluoro-4-(4-isopropylsulfanyl-2-methyl-pyrimidin-5-yl methoxy)-phenyl]-propionic acid ethyl ester
(4-Isopropylsulfanyl-2-methyl-pyrimidin-5-yl)-methanol (0.006 g, 0.03 mmol) obtained in Step B of Preparation Example 40 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.007g, 0.03mmol) obtained in Step D of Preparation Example 2 were reacted in the same manner as in Step A of Example 24 to obtain the title compound (0.009 g, 72%).
1H-NMR (CDCl3) δ 8.36(1H, s), 6.74(2H, m), 5.03(2H, s), 4.21(2H, q), 2.85(2H, t), 2.65(3H, s), 2.58(2H, t), 1.42(6H, d), 1.24(3H, t)
Step B: 3-[3,5-difluoro-4-(4-isopropylsulfanyl-2-methyl-pyrimidin-5-yl methoxy)-phenyl]-propionic acid
3-[3,5-Difluoro-4-(4-isopropylsulfanyl-2-methyl-pyrimidin-5-ylmethoxy)-phenyl]-propionic acid ethyl ester (0.009 g, 0.02 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (0.0035 g, 42%).
1H-NMR (CDCl3) δ 8.34(1H, s), 6.76(2H, m), 5.02(2H, s), 4.21(1H, m), 2.88(2H, t), 2.64(3H, s), 2.63(2H, t), 1.41(6H, d)
Example 72: 3-[4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-3-methoxy-phenyl]-propionic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (32 mg, 0.15 mmol) obtained in Step C of Preparation Example 16 and 3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester (39 mg, 0.17 mmol) obtained in Step C of Preparation Example 38 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 61%).
1H-NMR (CDCl3) δ 7.49(1H, t), 7.20(1H, d), 7.06(1H, d), 6.77(2H, m), 6.68(1H, m), 5.21(2H, s), 4.00(1H, m), 3.90(3H, s), 2.90(2H, t), 2.66(2H, t), 1.40(6H, d)
Example 73: 3-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3-methoxy-phenyl]-propionic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (33 mg, 0.14 mmol) obtained in Step C of Preparation Example 27 and 3-(4-hydroxy-3-methoxy-phenyl)-propionic acid ethyl ester (36 mg, 0.15 mmol) obtained in Step C of Preparation Example 38 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (32 mg, 69%).
1H-NMR (CDCl3) δ 7.49(1H, t), 7.19(1H, d), 7.06(1H, d), 6.77(2H, m), 6.68(1H, m), 5.20(2H, s), 4.00(1H, m), 3.90(3H, s), 2.90(2H, t), 2.66(2H, t), 2.18(2H, m), 1.79(2H, m), 1.54(4H, m)
Example 74: [6-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.21 g, 0.92 mmol) obtained in Step C of Preparation Example 8 and (6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (0.19 g, 0.92 mmol) obtained in Preparation Example 52 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.25 g, 70%).
1H-NMR (CDCl3) δ 8.39(1H, d), 7.66(1H, d), 7.07(1H, d), 7.01(1H, m), 6.49(2H, m), 4.97(2H, s), 4.76(1H, t), 4.30(1H, m), 4.20(1H, m), 3.82(1H, m), 2.80(1H, m), 2.65(1H, m), 2.23(2H, m), 1.77(2H, m), 1.65(4H, m)
Example 75: 2-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.040 g, 0.18 mmol) obtained in Step C of Preparation Example 37 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.045 g, 0.18 mmol) obtained in Step B of Preparation Example 31 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.050 g, 69%).
1H-NMR (CDCl3) δ 7.55-7.51(1H, t), 7.31-7.29(1H, d), 7.01-6.99(1H, d), 6.68-6.64(2H, m), 5.19(2H, s), 4.27-4.19(1H, m), 2.52-2.50(3H, m), 2.13-2.05(4H, m), 1.86-1.84(1H, m), 1.67-1.65(1H, m), 1.34-1.31(1H, m)
Example 76: 3-[4-(2-cyclopentylsulfanyl-6-methoxy-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (40 mg, 0.16 mmol) obtained in Step C of Preparation Example 8 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (38 mg, 0.16 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (64 mg, 98%).
1H-NMR (CDCl3) δ 7.56(1H, d), 6.75(2H, m), 6.43(1H, d), 5.06(2H, s), 4.16(1H, m), 3.94(3H, s), 2.99(2H, t), 2.65(2H, t), 2.20(2H, m), 1.77(2H, m), 1.54(4H, m)
Example 77: 3-[3-chloro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (23 mg, 0.11 mmol) obtained in Step C of Preparation Example 1 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (29 mg, 0.12 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (41 mg, 93%).
1H-NMR (CDCl3) δ 8.41(1H, m), 7.83(1H, d), 7.27(1H, m), 7.05(2H, m), 6.89(1H, d), 5.05(2H, s), 4.20(1H, m), 2.89(2H, t), 2.66(2H, t), 1.43(6H, d)
Example 78: 3-[3-chloro-4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (28 mg, 0.13 mmol) obtained in Step C of Preparation Example 8 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (33 mg, 0.14 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (41 mg, 91%).
1H-NMR (CDCl3) δ 8.40(1H, m), 7.81(1H, d), 7.27(1H, m), 7.05(2H, m), 6.89(1H, d), 5.05(2H, s), 4.25(1H, m), 2.89(2H, t), 2.65(2H, t), 2.20(2H, m), 1.78(2H, m), 1.55(4H, m)
Example 79: 3-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-2,3-dimethyl-phenyl]-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (25 mg, 0.12 mmol) obtained in Step C of Preparation Example 1 and 3-(4-hydroxy-2,3-dimethyl-phenyl)-propionic acid ethyl ester (30 mg, 0.13 mmol) obtained in Step D of Preparation Example 43 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (34 mg, 85%).
1H-NMR (CDCl3) δ 8.41(1H, m), 7.83(1H, d), 7.01(1H, m), 6.97(1H, m), 6.69(1H, d), 4.97(2H, s), 4.18(1H, m), 2.95(2H, t), 2.60(2H, t), 2.25(d, 6H), 1.42(6H, d)
Example 80: 3-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2,3-dimethyl-phenyl]-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (28 mg, 0.10 mmol) obtained in Step C of Preparation Example 8 and 3-(4-hydroxy-2,3-dimethyl-phenyl)-propionic acid ethyl ester (27 mg, 0.12 mmol) obtained in Step D of Preparation Example 43 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (37 mg, 84%).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.72(1H, d), 7.05(1H, m), 6.96(1H, m), 6.70(1H, d), 5.14(2H, s), 4.22(1H, m), 2.94(2H, t), 2.59(2H, t), 2.23(m, 8H), 1.78(2H, m), 1.55(4H, m)
Example 81: [(S)-6-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (11 mg, 0.05 mmol) obtained in Step C of Preparation Example 8 and ((S)-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (10 mg, 0.05 mmol) obtained in Preparation Example 56 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (13 mg, 70%).
1H-NMR (CDCl3) δ 8.39(1H, d), 7.66(1H, d), 7.07(1H, d), 7.01(1H, m), 6.49(2H, m), 4.97(2H, s), 4.78(1H, t), 4.30(1H, m), 4.20(1H, m), 3.82(1H, m), 2.80(1H, m), 2.65(1H, m), 2.23(2H, m), 1.77(2H, m), 1.65(4H, m)
Example 82: [(R)-6-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2,3-dihydro-benzofuran-3-yl]-acetic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (11 mg, 0.05 mmol) obtained in Step C of Preparation Example 8 and ((R)-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (10 mg, 0.05 mmol) obtained in Preparation Example 55 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (15 mg, 89%).
1H-NMR (CDCl3) δ 8.39(1H, d), 7.66(1H, d), 7.07(1H, d), 7.01(1H, m), 6.49(2H, m), 4.97(2H, s), 4.78(1H, t), 4.30(1H, m), 4.20(1H, m), 3.81(1H, m), 2.84(1H, m), 2.65(1H, m), 2.23(2H, m), 1.77(2H, m), 1.65(4H, m)
Example 83: 2-[3-fluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.040 g, 0.20 mmol) obtained in Step C of Preparation Example 1 and 2-[3-fluoro-4-hydroxy-phenyl]-cyclopropane carboxylic acid ethyl ester (0.044 g, 0.20 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.060 g, 84%).
1H-NMR (CDCl3) δ 8.42-8.40(1H, m), 7.73-7.71(1H, m), 7.05-7.03(1H, q), 6.94-6.81(3H, m), 5.06(2H, s), 4.22-4.15(2H, m), 2.53-2.51(1H, m), 1.85-1.81(1H, m), 1.66-1.61(1H, m), 1.61-1.43(6H, d), 1.36-1.31(1H, m)
Example 84: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-cyclopropylmethyl sulfanyl-pyridine (0.040 g, 0.18 mmol) obtained in Step C of Preparation Example 18 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.042 g, 0.18 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.050 g, 72%).
1H-NMR (CDCl3) δ 8.39-8.38(1H, m), 7.73-7.71(1H, m), 7.05-7.02(1H, q), 6.94-6.81(3H, m), 5.09(2H, s), 3.24-3.22(2H, d), 2.53-2.51(1H, m), 1.86-1.81(1H, m), 1.66-1.61(1H, m), 1.34-1.32(1H, m), 1.19-1.15(1H, m), 0.61-0.57(2H, m), 0.35-0.32(2H, m)
Example 85: 2-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 27 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.061 g, 89%).
1H-NMR (CDCl3) δ 7.52-7.48(1H, t), 7.20-7.19(1H, d), 7.10-7.08(1H, d), 6.93-6.78(3H, m), 5.19(2H, s), 4.02-3.97(1H, m), 2.55-2.50(1H, m), 2.19-2.17(2H, m), 1.84-1.79(3H, m), 1.65-1.61(5H, m), 1.35-1.30(1H, m)
Example 86: 2-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.044 g, 0.20 mmol) obtained in Step C of Preparation Example 37 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.046 g, 0.20 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.069 g, 90%).
1H-NMR (CDCl3) δ 7.53-7.50(1H, t), 7.22-7.20(1H, d), 7.01-6.99(1H, d), 6.93-6.79(3H, m), 5.22(2H, s), 4.32-4.24(1H, m), 2.56-2.50(3H, m), 2.15-2.03(4H, m), 1.83-1.81(1H, m), 1.64-1.61(1H, m), 1.35-1.30(1H, m)
Example 87: 2-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 8 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.067 g, 98%).
1H-NMR (CDCl3) δ 8.40-8.39(1H, m), 7.71-7.70(1H, m), 7.04-7.01(1H, q), 6.93-6.81(3H, m), 5.06(2H, s), 4.24-4.21(1H, m), 2.53(1H, m), 2.24-2.22(2H, m), 1.86-1.81(3H, m), 1.65-1.62(5H, m), 1.36-1.31(1H, m)
Example 88: 2-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.040 g, 0.18 mmol) obtained in Step C of Preparation Example 23 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.046 g, 0.18 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.069 g, 98%).
1H-NMR (CDCl3) δ 8.38-8.37(1H, m), 7.70-7.68(1H, m), 7.03-7.01(1H, q), 6.93-6.81(3H, m), 5.04(2H, s), 4.56-4.52(1H, m), 2.56-2.54(3H, m), 2.17-2.06(4H, m), 1.86-1.82(1H, m), 1.66-1.61(1H, m), 1.36-1.33(1H, m)
Example 89: 2-[2-chloro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.040 g, 0.20 mmol) obtained in Step C of Preparation Example 1 and 2-(2-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.047 g, 0.20 mmol) obtained in Step E of Preparation Example 45 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.041 g, 55%).
1H-NMR (CDCl3) δ 8.42-8.41(1H, m), 7.66-7.64(1H, m), 7.04-7.03(2H, m), 6.97-6.95(1H, d), 6.81-6.79(1H, m), 4.98(2H, s), 4.21-4.17(1H, m), 2.72(1H, m), 1.78-1.75(1H, m), 1.67-1.64(1H, m), 1.44-1.42(6H, d), 1.39-1.37(1H, m)
Example 90: 2-[2-chloro-4-(6-chlorobutylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.040 g, 0.18 mmol) obtained in Step C of Preparation Example 37 and 2-(2-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.045 g, 0.18 mmol) obtained in Step E of Preparation Example 45 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.042 g, 58%).
1H-NMR (CDCl3) δ 7.50-7.46(1H, t), 7.12-7.10(1H, d), 7.05(1H, s), 7.02-7.00(1H, d), 6.96-6.93(1H, m), 6.81-6.78(1H, m), 5.11(2H, s), 4.33-4.25(1H, m), 2.74-2.69(1H, m), 2.55- 2.50(2H, m), 2.16-2.07(4H, m), 1.77-1.72(1H, m), 1.66-1.61(1H, m), 1.39-1.34(1H, m)
Example 91: 3-[3-chloro-4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy) -phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-cyclopropylmethyl sulfanyl-pyridine (33 mg, 0.15 mmol) obtained in Step C of Preparation Example 18 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (42 mg, 0.17 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (41 mg, 77%).
1H-NMR (CDCl3) δ 8.38(1H, m), 7.83(1H, d), 7.26(1H, m), 7.05(2H, m), 6.90(1H, d), 5.04(2H, s), 3.24(2H, d), 3.00(1H, m), 2.73(1H, m), 2.61(1H, m), 1.20(4H, m), 0.61(2H, m), 0.34(2H, m)
Example 92: 3-[3-chloro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-propylsulfanyl-pyridine (32 mg, 0.15 mmol) obtained in Step C of Preparation Example 14 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (42 mg, 0.17 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (40 mg, 75%).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.80(1H, d), 7.26(1H, m), 7.05(2H, m), 6.89(1H, d), 5.07(2H, s), 3.28(2H, t), 3.00(1H, m), 2.74(1H, m), 2.63(1H, m), 1.76(2H, m), 1.19(3H, d), 1.05(3H, t)
Example 93: 3-[3-chloro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-2-methyl-propionic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (35 mg, 0.17 mmol) obtained in Step C of Preparation Example 16 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (47 mg, 0.19 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (50 mg, 89%).
1H-NMR (CDCl3) δ 7.51(1H, m), 7.25(2H, m), 7.08(1H, m), 7.00(1H, m), 6.89(1H, d), 5.19(2H, s), 3.96(1H, m), 2.98(1H, m), 2.75(1H, m), 2.61(1H, m), 1.40(6H, d), 1.18(3H, d)
Example 94: 3-[3-chloro-4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-2-methyl-propionic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (37 mg, 0.16 mmol) obtained in Step C of Preparation Example 27 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (43 mg, 0.17 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (51 mg, 85%).
1H-NMR (CDCl3) δ 7.51(1H, t), 7.25(2H, m), 7.09(1H, d), 6.99(1H, m), 6.88(1H, d), 5.19(2H, s), 4.00(1H, m), 3.00(1H, m), 2.98(1H, m), 2.74(1H, m), 2.61(1H, m), 2.19(2H, m), 1.79(2H, m), 1.64(4H, m), 1.18(3H, d)
Example 95: 3-[3-chloro-4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-2-methyl-propionic acid
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (50 mg, 0.25 mmol) obtained in Step C of Preparation Example 23 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (60 mg, 0.28 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (76 mg, 81%).
1H-NMR (CDCl3) δ 8.36(1H, m), 7.80(1H, d), 7.24(1H, m), 7.04(2H, m), 6.89(1H, d), 5.04(2H, s), 4.55(1H, m), 2.98(1H, m), 2.73(1H, m), 2.69~2.65(3H, m), 2.20~2.00(4H, m), 1.19(3H, d)
Example 96: 3-[3-chloro-4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-2-methyl-propionic acid
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (50 mg, 0.25 mmol) obtained in Step C of Preparation Example 37 and 3-(3-chloro-4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (60 mg, 0.28 mmol) obtained in Step B of Preparation Example 46 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (77 mg, 85%).
1H-NMR (CDCl3) δ 7.52(1H, t), 7.25(2H, m), 7.01(2H, m), 6.89(1H, m), 5.18(2H, s), 4.29(1H, m), 2.98(1H, m), 2.73(1H, m), 2.69~2.45(3H, m), 2.20~2.00(4H, m), 1.19(3H, d)
Example 97: 2-[3-chloro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (33 mg, 0.16 mmol) obtained in Step C of Preparation Example 1 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (43 mg, 0.17 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (42 mg, 80%).
1H-NMR (CDCl3) δ 8.41(1H, m), 7.80(1H, d), 7.14(1H, m), 7.05(1H, m), 6.97(1H, m), 6.87(1H, d), 5.05(2H, s), 4.20(1H, m), 2.52(1H, m), 1.83(1H, m), 1.62(1H, m), 1.43(6H, d), 1.33(1H, m)
Example 98: 2-[3-chloro-4-(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy) -phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (36 mg, 0.17 mmol) obtained in Step D of Preparation Example 20 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (45 mg, 0.18 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (59 mg, 83%).
1H-NMR (CDCl3) δ 7.51(1H, t), 7.25(2H, m), 7.15(1H, m), 7.10(1H, m), 6.88(1H, m), 5.19(2H, s), 3.11(2H, d), 2.52(1H, m), 1.84(1H, m), 1.62(1H, m), 1.30(1H, m), 1.10(1H, m), 0.60(2H, m), 0.30(2H, m)
Example 99: 2-[3-chloro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (40 mg, 0.19 mmol) obtained in Step C of Preparation Example 16 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (52 mg, 0.21 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (42 mg, 65%).
1H-NMR (CDCl3) δ 7.51(1H, t), 7.25(1H, m), 7.15(1H, m), 7.08(1H, m), 6.89(2H, m), 5.20(2H, s), 3.97(1H, m), 2.52(1H, m), 1.83(1H, m), 1.62(1H, m), 1.40(6H, d), 1.34(1H, m)
Example 100: 2-[3-chloro-4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (42 mg, 0.18 mmol) obtained in Step C of Preparation Example 27 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (49 mg, 0.20 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (47 mg, 72%).
1H-NMR (CDCl3) δ 7.51(1H, t), 7.25(1H, m), 7.15(1H, m), 7.08(1H, m), 6.93(1H, m), 6.89(1H, d), 5.19(2H, s), 3.99(1H, m), 2.52(1H, m), 2.18(2H, m), 1.90~1.75(3H, m), 1.70~50(5H, m), 1.34(1H, m)
Example 101: 2-[3-chloro-4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (49 mg, 0.23 mmol) obtained in Step C of Preparation Example 8 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (62 mg, 0.25 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (65 mg, 75%).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.79(1H, d), 7.15(1H, m), 7.05(1H, m), 6.90(1H, m), 6.88(1H, d), 5.05(2H, s), 4.13(1H, m), 2.53(1H, m), 2.22(2H, m), 1.90~1.75(3H, m), 1.70~50(5H, m), 1.35(1H, m)
Example 102: 2-[3-chloro-4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (52 mg, 0.26 mmol) obtained in Step C of Preparation Example 23 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (70 mg, 0.29 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (77 mg, 84%).
1H-NMR (CDCl3) δ 8.37(1H, m), 7.78(1H, d), 7.15(1H, m), 7.05(1H, m), 6.90(1H, m), 6.88(1H, d), 5.04(2H, s), 4.55(1H, m), 2.60~2.45(3H, m), 2.22~2.00(4H, m), 1.84(1H, m), 1.63(1H, m), 1.34(1H, m)
Example 103: 2-[3-chloro-4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (52 mg, 0.26 mmol) obtained in Step C of Preparation Example 37 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (70 mg, 0.29 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (77 mg, 84%).
1H-NMR (CDCl3) δ 7.51(1H, t), 7.25(1H, m), 7.10(1H, m), 6.95(2H, m), 6.87(1H, d), 5.18(2H, s), 4.27(1H, m), 2.59~2.45(3H, m), 2.22~2.00(4H, m), 1.83(1H, m), 1.61(1H, m), 1.35(1H, m)
Example 104: 2-[2-chloro-4-(6-chloropentylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 27 and 2-(2-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.042 g, 0.17 mmol) obtained in Step E of Preparation Example 45 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043 g, 61%).
1H-NMR (CDCl3) δ 7.52-7.48(1H, t), 7.17-7.09(2H, q), 7.05(1H, s), 6.95-6.93(1H, d), 6.82-6.79(1H, m), 5.12(2H, s), 4.04-3.97(1H, m), 2.74-2.69(1H, m), 2.21- 2.18(2H, m), 1.79-1.73(3H, m), 1.66-1.62(5H, m), 1.39-1.34(1H, m)
Example 105: 2-[4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-2,3-dimethyl-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.030 g, 0.149 mmol) obtained in Step C of Preparation Example 1 and 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.035 g, 0.149 mmol) obtained in Step C of Preparation Example 48 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.045 g, 81%).
1H NMR (400 MHz, CDCl3) δ 8.43-8.39(m, 1H), 7.74-7.70(m, 1H), 7.07-7.01(m, 1H), 6.88(d, 1H), 6.67(d, 1H), 4.98(s, 2H), 4.23-4.12(m, 1H), 2.62-2.53(m, 1H), 2.35(s, 3H), 2.27(s, 3H),1.76-1.69(m, 1H), 1.65-1.58(m, 1H), 1.42(d, 6H), 1.40-1.33(m, 1H)
Example 106: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-2,3-dimethyl-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (0.032 g, 0.149 mmol) obtained in Step D of Preparation Example 20 and 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.035 g, 0.149 mmol) obtained in Step C of Preparation Example 48 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.044 g, 77%).
1H NMR (400 MHz, CDCl3) δ 8.42-8.38(m, 1H), 7.77-7.69(m, 1H), 7.09-7.01(m, 1H), 6.88(d, 1H), 6.69(d, 1H), 5.01(s, 2H), 3.23(d, 2H), 2.63-2.55(m, 1H), 2.35(s, 3H), 2.27(s, 3H), 1.77-1.69(m, 1H), 1.67-1.59(m, 1H), 1.42-1.33(m, 1H), 1.23-1.11(m, 1H), 0.65-0.57(m, 1H), 0.40-0.30(m, 1H)
Example 107: 2-[3-chloro-4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (41 mg, 0.19 mmol) obtained in Step C of Preparation Example 18 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (50 mg, 0.21 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (72 mg, 90%).
1H-NMR (CDCl3) δ 8.37(1H, m), 7.88(1H, d), 7.14(1H, m), 7.05(1H, m), 6.99(1H, m), 6.98(1H, m), 5.08(2H, s), 3.23(2H, d), 2.52(1H, m), 1.83(1H, m), 1.62(1H, m), 1.34(1H, m), 1.16(1H, m), 0.60(2H, m), 0.32(2H, m)
Example 108: 2-[3-chloro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-propylsulfanyl-pyridine (47 mg, 0.23 mmol) obtained in Step C of Preparation Example 14 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (61 mg, 0.25 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (60 mg, 73%).
1H-NMR (CDCl3) δ 8.39(1H, m), 7.79(1H, d), 7.15(1H, m), 7.05(1H, m), 6.96(1H, m), 6.89(1H, d), 5.08(2H, s), 3.27(2H, t), 2.51(1H, m), 1.84(1H, m), 1.75(2H, m), 1.62(1H, m), 1.34(1H, m), 1.16(1H, m), 1.60(3H, t)
Example 109: 2-[3-chloro-4-(2-isopropylsulfanyl-6-methoxy-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-isopropylsulfanyl-6-methoxy-pyridine (20 mg, 0.09 mmol) obtained in Step E of Preparation Example 36 and 3-(3,5-difluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (21 mg, 0.09 mmol) obtained in Step D of Preparation Example 2 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (19 mg, 66%).
1H-NMR (CDCl3) δ 7.64(1H, d), 7.12(1H, m), 6.95(1H, m), 6.88(1H, d), 6.47(1H, d), 5.01(2H, s), 4.15(1H, m), 3.94(3H, s), 2.52(1H, m), 1.83(1H, m), 1.62(1H, m), 1.44(6H, d), 1.35(1H, m)
Example 110: 2-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-benzyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.023 g, 0.10 mmol) obtained in Step C of Preparation Example 27 and 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane carboxylic acid ethyl ester (0.026 g, 0.10 mmol) obtained in Step D of Preparation Example 49 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.037 g, 88%).
1H-NMR (CDCl3) δ 7.54-7.51(1H, t), 7.33-7.31(1H, d), 7.10-7.08(1H, d), 6.78-6.76(2H, m), 5.20(2H, s), 3.98-3.94(1H, m), 2.68-2.62(1H, m), 2.57-2.51(1H, m), 2.15(2H, m), 1.70(2H, m), 1.67(1H, m), 1.62(4H, m), 1.54-1.51(1H, m), 1.36-1.32(1H, m), 0.94-0.89(1H, m)
Example 111: [6-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-5,7-difluoro-2,3-dihydro-benzofuran-3-yl]-acetic acid
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (18 mg, 0.08 mmol) obtained in Step C of Preparation Example 23 and (5,7-difluoro-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.08 mmol) obtained in Preparation Example 51 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (26 mg, 78%).
1H-NMR (CDCl3) δ 8.38(1H, d), 7.77(1H, d), 7.04(1H, m), 6.78(1H, d), 5.13(2H, s), 4.86(1H, t), 4.49(1H, m), 4.38(1H, m), 3.90(1H, m), 2.82(1H, m), 2.69(1H, m), 2.53(2H, m), 2.11(2H, m), 2.03(2H, m)
Example 112: 2-[2,3-dimethyl-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (0.03 g, 0.149 mmol) obtained in Step D of Preparation Example 20 and 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.035 g, 0.149 mmol) obtained in Step C of Preparation Example 48 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.046 g, 83%).
1H NMR (400 MHz, CDCl3) δ 8.43-8.37(m, 1H), 7.74-7.68(m, 1H), 7.06-7.00(m, 1H), 6.88(d, 1H), 6.68(d, 1H), 5.00(s, 2H), 3.26(t, 2H), 2.62-2.54(m, 1H), 2.35(s, 3H), 2.27(s, 3H), 1.80-1.69(m, 3H), 1.65-1.58(m, 1H), 1.40-1.32(m, 1H), 1.05(t, 3H)
Example 113: 2-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-2,3-dimethyl-phenyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.032 g, 0.149 mmol) obtained in Step C of Preparation Example 23 and 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.035 g, 0.149 mmol) obtained in Step C of Preparation Example 48 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.047 g, 82%).
1H NMR (400 MHz, CDCl3) δ 8.40-8.37(m, 1H), 7.72-7.67(m, 1H), 7.05-6.99(m, 1H), 6.88(d, 1H), 6.67(d, 1H), 4.97(s, 2H), 4.59-4.49(m, 1H), 2.62-2.51(m, 3H), 2.35(s, 3H), 2.26(s, 3H), 2.20-2.10(m, 2H), 2.10-2.00(m, 2H), 1.75-1.69(m, 1H), 1.66-1.58(m, 1H), 1.40-1.33(m, 1H)
Example 114: 2-[4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-2,3-dimethyl-phenyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.030 g, 0.149 mmol) obtained in Step C of Preparation Example 16 and 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.035 g, 0.149 mmol) obtained in Step C of Preparation Example 48 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.046 g, 83%).
1H NMR (400 MHz, CDCl3) δ 7.49(t, 1H), 7.19(d, 1H), 7.07(d, 1H), 6.86(d, 1H), 6.67(d, 1H), 5.12(s, 2H), 4.03-3.92(m, 1H), 2.61-2.53(m, 1H), 2.34(s, 3H), 2.28(s, 3H), 1.73-1.67(m, 1H), 1.64-1.57(m, 1H), 1.40(d, 6H), 1.38-1.31(m, 1H)
Example 115: 2-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-benzyl]-cyclopropane carboxylic acid
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.021 g, 0.10 mmol) obtained in Step C of Preparation Example 37 and 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane carboxylic acid ethyl ester (0.024 g, 0.10 mmol) obtained in Step D of Preparation Example 49 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.026 g, 66%).
1H-NMR (CDCl3) δ 7.55-7.51(1H, t), 7.34-7.32(1H, d), 7.02-7.00(1H, d), 6.78-6.76(2H, m), 5.20(2H, s), 4.27-4.23(1H, m), 2.68-2.63(1H, m), 2.57-2.47(3H, m), 2.14-2.02(4H, m), 1.70(1H, m), 1.54-1.52(1H, m), 1.37-1.34(1H, m), 0.94-0.89(1H, m)
Example 116: 2-[3,5-difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-benzyl]-cyclopropane carboxylic acid
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.019 g, 0.09 mmol) obtained in Step C of Preparation Example 1 and 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane carboxylic acid ethyl ester (0.023 g, 0.09 mmol) obtained in Step D of Preparation Example 49 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.028 g, 75%).
1H-NMR (CDCl3) δ 8.42-8.41(1H, m), 7.82-7.80(1H, m), 7.07-7.04(1H, q), 6.80-6.75(2H, m), 5.12(2H, s), 4.18-4.10(1H, m), 2.64-2.52(2H, m), 1.71-1.69(1H, m), 1.55-1.51(1H, m), 1.40-1.38(6H, d), 1.37-1.32(1H, m), 0.94-0.89(1H, m)
Example 117: 2-[3,5-difluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-benzyl]-cyclopropane carboxylic acid
3-chloromethyl-2-propylsulfanyl-pyridine (0.016 g, 0.08 mmol) obtained in Step C of Preparation Example 14 and 2-(3,5-difluoro-4-hydroxy-benzyl]-cyclopropane carboxylic acid ethyl ester (0.02 g, 0.08 mmol) obtained in Step D of Preparation Example 49 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.024 g, 77%).
1H-NMR (CDCl3) δ 8.41-8.40(1H, m), 7.81-7.79(1H, m), 7.07-7.04(1H, q), 6.81-6.74(2H, m), 5.14(2H, s), 3.25-3.21(2H, m), 2.66-2.56(2H, m), 1.75-1.68(3H, m), 1.54-1.52(1H, m), 1.37-1.32(1H, m), 1.05-1.01(1H, t), 0.94-0.89(1H, m)
Example 118: [6-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-7-methyl-benzofuran-3-yl]-acetic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (21 mg, 0.09 mmol) obtained in Step C of Preparation Example 8 and (6-hydroxy-7-methyl-benzofuran-3-yl)-acetic acid methyl ester (21 mg, 0.09 mmol) obtained in Preparation Example 54 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 83%).
1H-NMR (CDCl3) δ 8.41(1H, d), 7.73(1H, d), 7.57(1H, s), 7.29(1H, d), 7.04(1H, m), 6.91(1H, d), 5.06(2H, s), 4.24(1H, m), 3.70(2H, s), 2.44(3H, s), 2.22(2H, m), 1.78(2H, m), 1.66(4H, m)
Example 119: 2-[3-fluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (less polar)
3-Chloromethyl-2-propylsulfanyl-pyridine (0.016 g, 0.08 mmol) obtained in Step C of Preparation Example 14 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.017 g, 0.08 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.014 g, 48%).
1H-NMR (CDCl3) δ 8.42-8.41(1H, m), 7.74-7.72(1H, m), 7.06-7.03(1H, q), 6.94-6.81(3H, m), 5.08(2H, s), 3.29-3.25(2H, t), 2.55-2.52(1H, m), 1.84-1.81(1H, m), 1.78-1.72(2H, m), 1.66-1.61(1H, m), 1.36-1.31(1H, m), 1.07-1.04(3H, t)
Example 120: {2-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropyl}-acetic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.026 g, 0.11 mmol) obtained in Step C of Preparation Example 27 and [2-(3-fluoro-4-hydroxy-phenyl)-cyclopropyl]-acetic acid methyl ester (0.026 g, 0.11 mmol) obtained in Step F of Preparation Example 53 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.040 g, 87%).
1H-NMR (CDCl3) δ 7.51-7.47(1H, t), 7.21-7.19(1H, d), 7.09-7.07(1H, d), 6.90-6.76(3H, m), 5.17(2H, s), 4.00-3.97(1H, m), 2.44-2.42(2H, m), 2.19-2.17(2H, m), 1.79(2H, m), 1.73-1.70(1H, m), 1.66-1.63(4H, m), 1.31-1.30(1H, m), 0.95-0.93(1H, m), 0.86-0.84(1H, m)
Example 121: {2-[3-fluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropyl}-acetic acid
3-Chloromethyl-2-propylsulfanyl-pyridine (0.024 g, 0.12 mmol) obtained in Step C of Preparation Example 14 and [2-(3-fluoro-4-hydroxy-phenyl)-cyclopropyl]-acetic acid methyl ester (0.027 g, 0.12 mmol) obtained in Step F of Preparation Example 53 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043 g, 96%).
1H-NMR (CDCl3) δ 8.40-8.39(1H, m), 7.73-7.71(1H, m), 7.04-7.01(1H, q), 6.91-6.79(3H, m), 5.07(2H, s), 3.27-3.23(2H, m), 2.45-2.43(2H, m), 1.77-1.71(3H, m), 1.31-1.28(1H, m), 1.07-1.02(3H, m), 0.96-0.94(1H, m), 0.87-0.85(1H, m)
Example 122: [6-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-5,7-difluoro-benzofuran-3-yl]-acetic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (19 mg, 0.08 mmol) obtained in Step C of Preparation Example 8 and (5,7-difluoro-6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.08 mmol) obtained in Step C of Preparation Example 50 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (28 mg, 81%).
1H-NMR (CDCl3) δ 8.42(1H, d), 7.82(1H, d), 7.66(1H, s), 7.06(2H, m), 5.17(2H, s), 4.18(1H, m), 3.69(2H, s), 2.19(2H, m), 1.74(2H, m), 1.62(4H, m)
Example 123: [6-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-5,7-difluoro-2,3-dihydro-benzofuran-3-yl]-acetic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (19 mg, 0.08 mmol) obtained in Step C of Preparation Example 8 and (5,7-difluoro-6-hydroxy-2,3-dihydro-benzofuran-3-yl)-acetic acid methyl ester (20 mg, 0.08 mmol) obtained in Preparation Example 51 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.25 mg, 72%).
1H-NMR (CDCl3) δ 8.40(1H, d), 7.79(1H, d), 7.05(1H, m), 6.77(1H, d), 5.12(2H, s), 4.86(1H, t), 4.38(1H, m), 4.19(1H, m), 3.88(1H, m), 2.82(1H, m), 2.69(1H, m), 2.20(2H, m), 1.75(2H, m), 1.64(4H, m)
Example 124: 2-[3-chloro-4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (less polar)
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (27 mg, 0.13 mmol) obtained in Step C of Preparation Example 23 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (37 mg, 0.15 mmol) obtained in Preparation Example 66 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (36 mg, 80%).
1H NMR (CDCl3) 8.37(1H, m), 7.77(1H, d), 7.15(1H, m), 7.03(1H, m), 6.97(1H, m), 6.87(1H, d), 5.04(2H, s), 4.55(1H, m), 2.60~2.45(3H, m), 2.22~2.00(4H, m), 1.84(1H, m), 1.63(1H, m), 1.34(1H, m)
Example 125: 2-[3-chloro-4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (more polar)
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (26 mg, 0.13 mmol) obtained in Step C of Preparation Example 23 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (33 mg, 0.14 mmol) obtained in Step F of Preparation Example 65 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (39 mg, 90%).
1H NMR (CDCl3) 8.37(1H, m), 7.77(1H, d), 7.15(1H, m), 7.03(1H, m), 6.97(1H, m), 6.87(1H, d), 5.04(2H, s), 4.55(1H, m), 2.60~2.45(3H, m), 2.22~2.00(4H, m), 1.84(1H, m), 1.63(1H, m), 1.34(1H, m)
Example 126: 2-[3-chloro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl] -cyclopropane carboxylic acid (more polar)
3-Chloromethyl-2-isopropylsulfanyl-pyridine (17 mg, 0.08 mmol) obtained in Step C of Preparation Example 1 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (20 mg, 0.09 mmol) obtained in Step F of Preparation Example 65 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (23 mg, 79%).
1H NMR (CDCl3) 8.39(1H, d), 7.79(1H, d), 7.13(1H, m), 7.04(1H, m), 6.87(1H, m), 6.86(1H, d), 5.04(2H, s), 4.18(1H, m), 2.52(1H, m), 1.82(1H, m), 1.61(1H, m), 1.41(6H, d), 1.33(1H, m)
Example 127: 2-[3-chloro-4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (more polar)
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (21 mg, 0.10mmol) obtained in Step C of Preparation Example 18 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (25 mg, 0.11 mmol) obtained in Step F of Preparation Example 65 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (24 mg, 74%).
1H NMR (CDCl3) 8.38(1H, m), 7.80(1H, d), 7.14(1H, m), 7.05(1H, m), 6.99(1H, m), 6.88(1H, m), 5.09(2H, s), 3.24(2H, d), 2.52(1H, m), 1.85(1H, m), 1.62(1H, m), 1.35(1H, m), 1.17(1H, m), 0.61(2H, m), 0.33(2H, m)
Example 128: 2-[3-chloro-4-(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (more polar)
2-Chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (21 mg, 0.10mmol) obtained in Step D of Preparation Example 20 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (25 mg, 0.11 mmol) obtained in Step F of Preparation Example 65 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (21 mg, 77%).
1H NMR (CDCl3) 7.51(1H, t), 7.25(1H, m), 7.15(2H, m), 7.00(1H, m), 6.88(1H, m), 5.19(2H, s), 3.11(2H, d), 2.51(1H, m), 1.82(1H, m), 1.62(1H, m), 1.32(1H, m), 1.15(1H, m), 0.58(2H, m), 0.31(2H, m)
Example 129: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid (less polar)
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (0.026 g, 0.12 mmol) obtained in Step C of Preparation Example 18 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.025 g, 0.12 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.042 g, 95%).
1H NMR (CDCl3) δ 8.38 (1H, m), 7.72 (1H, m), 7.04 (1H, m), 6.92 (1H, t), 6.90~6.80 (2H, m), 5.09 (2H, s), 3.23 (2H, d), 2.53 (1H, m), 1.84 (1H, m), 1.63 (1H, m), 1.33 (1H, m), 1.17 (1H, m), 0.59 (2H, m), 0.33 (2H, m)
Example 130: 2-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid (less polar)
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.032 g, 0.14 mmol) obtained in Step C of Preparation Example 8 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.033 g, 71%).
1H NMR (CDCl3) δ 8.40 (1H, m), 7.70 (1H, m), 7.03 (1H, m), 6.90 (1H, t), 6.88~6.80 (2H, m), 5.05 (2H, s), 4.22 (1H, m), 2.52 (1H, m), 2.23 (2H, m), 1.83 (1H, m), 1.79 (2H, m), 1.65 (5H, m), 1.33 (1H, m)
Example 131: 2-[3-fluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl] -cyclopropane carboxylic acid (less polar)
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.029 g, 0.14 mmol) obtained in Step C of Preparation Example 16 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.048 g, 93%).
1H NMR (CDCl3) δ 7.49 (1H, t), 7.19 (1H, d), 7.07 (1H, d), 6.90 (1H, t), 6.84 (1H, m), 6.80 (1H, m), 5.18 (2H, s), 3.96 (1H, m), 2.52 (1H, m), 1.82 (1H, m), 1.63 (1H, m), 1.39 (6H, d), 1.32 (1H, m)
Example 132: 2-[3-chloro-4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (more polar)
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (32 mg, 0.16 mmol) obtained in Step C of Preparation Example 37 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (41 mg, 0.18 mmol) obtained in Step F of Preparation Example 65 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (32 mg, 68%).
1H NMR (CDCl3) 7.51(1H, t), 7.25(1H, m), 7.15(1H, m), 7.08(1H, m), 6.93(1H, m), 6.89(1H, d), 5.18(2H, s), 4.27(1H, m), 2.53(3H, m), 2.20~2.00(4H, m), 1.84(1H, m), 1.61(1H, m), 1.33(1H, m)
Example 133: 2-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid (less polar)
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.032 g, 0.15 mmol) obtained in Step C of Preparation Example 23 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.037 g, 84%).
1H NMR (CDCl3) δ 8.37 (1H, m), 7.68 (1H, m), 7.02 (1H, m), 6.90 (1H, t), 6.88~6.80 (2H, m), 5.04 (2H, s), 4.53 (1H, m), 2.55 (3H, m), 2.20~2.05 (4H, m), 1.83 (1H, m), 1.64 (1H, m), 1.34 (1H, m)
Example 134: 2-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid (less polar)
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.033 g, 0.14 mmol) obtained in Step C of Preparation Example 27 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043g, 77%).
1H NMR (CDCl3) δ 7.50 (1H, t), 7.19 (1H, d), 7.09 (1H, d), 6.90 (1H, t), 6.84 (1H, m), 6.80 (1H, m), 5.18 (2H, s), 4.00 (1H, m), 2.53 (1H, m), 2.19 (2H, m), 1.80 (3H, m), 1.64 (5H, m), 1.33 (1H, m)
Example 135: 2-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid (less polar)
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.018 g, 0.08 mmol) obtained in Step C of Preparation Example 37 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (0.018 g, 0.08 mmol) obtained in Step C of Preparation Example 64 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.022 g, 71%).
1H NMR (CDCl3) δ 7.53-7.50 (1H, t), 7.22-7.20 (1H, d), 7.01-6.99 (1H, d), 6.93-6.79 (3H, m), 5.22 (2H, s), 4.32-4.24 (1H, m), 2.56-2.50 (3H, m), 2.15-2.03 (4H, m), 1.83-1.81 (1H, m), 1.64-1.61 (1H, m), 1.35-1.30 (1H, m)
Example 136: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid (less polar)
Step A: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3,5-Difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (less polar) (8 mg, 0.035 mmol) obtained in Step C of Preparation Example 59 and 3-chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (7.5 mg, 0.035 mmol) obtained in Step C of Preparation Example 18 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (13 mg, 90%).
NMR (400 MHz, CDCl3): 0.28-0.33 (m., 2H), 0.55-0.60 (m., 2H), 1.12-1.16 (m., 1H), 1.22-1.27 (m., 1H), 1.57-1.63 (m., 1H), 1.82-1.87 (m., 1H), 2.42-2.47 (m., 1H), 3.20 (d., 7.2 Hz, 2H), 3.72 (s., 3H), 5.14 (s., 2H), 6.62-6.70 (m., 2H), 7.04 (d.d., 7.6 and 4.8 Hz, 1H), 7.77 (d.d., 7.6 and 1.6 Hz, 1H), 8.39 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Step B: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid
After 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid methyl ester (13 mg, 0.031 mmol) obtained in Step A was dissolved in THF/MeOH (1 mL/1 mL), 10N sodium hydroxide solution (30 mg, 0.31 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and the residue was diluted with water. The aqueous layer was added with 1N HCl to adjust the pH to 2~3, and then extracted with EtOAc. The organic layer was dried with MgSO4, concentrated under reduced pressure, and purified by column chromatography (eluent, MeOH/DCM = 5/95) to obtain the title compound (12 mg, 97%).
NMR (400 MHz, CDCl3): 0.28-0.33 (m., 2H), 0.55-0.60 (m., 2H), 1.09-1.19 (m., 1H), 1.28-1.35 (m., 1H), 1.63-1.68 (m., 1H), 1.83-1.88 (m., 1H), 2.49-2.53 (m., 1H), 3.20 (d., 7.2 Hz, 2H), 5.14 (s., 2H), 6.64-6.70 (m., 2H), 7.05 (d.d., 7.6 and 4.8 Hz, 1H), 7.78 (d.d., 7.6 and 1.6 Hz, 1H), 8.39 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Example 137: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropanecarboxylic acid methyl ester
2-(3,5-Difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (8 mg, 0.035 mmol) obtained in Step C of Preparation Example 60 and 3-chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (7.5 mg, 0.035 mmol) obtained in Step C of Preparation Example 18 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (15 mg, 99%).
NMR (400 MHz, CDCl3): 0.28-0.33 (m., 2H), 0.55-0.60 (m., 2H), 1.12-1.16 (m., 1H), 1.22-1.27 (m., 1H), 1.57-1.63 (m., 1H), 1.82-1.87 (m., 1H), 2.42-2.47 (m., 1H), 3.20 (d., 7.2 Hz, 2H), 3.72 (s., 3H), 5.14 (s., 2H), 6.62-6.70 (m., 2H), 7.04 (d.d., 7.6 and 4.8 Hz, 1H), 7.77 (d.d., 7.6 and 1.6 Hz, 1H), 8.39 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Step B: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid
2-[4-(2-Cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid methyl ester (15 mg, 0.035 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (12 mg, 85%).
NMR (400 MHz, CDCl3): 0.28-0.33 (m., 2H), 0.55-0.60 (m., 2H), 1.09-1.19 (m., 1H), 1.28-1.35 (m., 1H), 1.63-1.68 (m., 1H), 1.83-1.88 (m., 1H), 2.49-2.53 (m., 1H), 3.20 (d., 7.2 Hz, 2H), 5.14 (s., 2H), 6.64-6.70 (m., 2H), 7.05 (d.d., 7.6 and 4.8 Hz, 1H), 7.78 (d.d., 7.6 and 1.6 Hz, 1H), 8.39 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Example 138: 2-[3,5-difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[3,5-difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3,5-Difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (22.5 mg, 0.1 mmol) obtained in Step C of Preparation Example 60 was used to react in the same manner as in Step A of Example 1 to obtain the title compound (38.5 mg, 98%).
NMR (400 MHz, CDCl3): 1.22-1.27 (m., 1H), 1.39 (d., 6.4 Hz, 6H), 1.57-1.63 (m., 1H), 1.82-1.87 (m., 1H), 2.41-2.47 (m., 1H), 3.72 (s., 3H), 4.13 (sep., 6.4 Hz, 1H), 5.10 (s., 2H), 6.62-6.70 (m., 2H), 7.04 (d.d., 7.6 and 4.8 Hz, 1H), 7.77 (d.d., 7.6 and 1.6 Hz, 1H), 8.40 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Step B: 2-[3,5-difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
2-[3,5-Difluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester (38 mg, 0.098 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (28 mg, 76%).
NMR (400 MHz, CDCl3): 1.22-1.27 (m., 1H), 1.38 (d., 6.4 Hz, 6H), 1.55-1.65 (m., 1H), 1.79-1.87 (m., 1H), 2.44-2.50 (m., 1H), 4.15 (sep., 6.4 Hz, 1H), 5.10 (s., 2H), 6.62-6.70 (m., 2H), 7.03 (d.d., 7.6 and 4.8 Hz, 1H), 7.77 (d.d., 7.6 and 1.6 Hz, 1H), 8.40 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Example 139: 2-[3,5-difluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[3,5-difluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3,5-Difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (20 mg, 0.088 mmol) obtained in Step C of Preparation Example 60 and 3-chloromethyl-2-propylsulfanyl-pyridine (17.7 mg, 0.088 mmol) obtained in Step C of Preparation Example 14 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (33.5 mg, 97%).
NMR (400 MHz, CDCl3): 1.03 (t., 7.6 Hz., 3H), 1.22-1.27 (m., 1H), 1.57-1.63 (m., 1H), 1.71 (sex., 7.6 Hz, 2H), 1.82-1.87 (m., 1H), 2.41-2.47 (m., 1H), 3.22 (t., 7.6 Hz, 2H), 3.72 (s., 3H), 5.12 (s., 2H), 6.62-6.69 (m., 2H), 7.03 (d.d., 7.6 and 4.8 Hz, 1H), 7.74 (d.d., 7.6 and 1.6 Hz, 1H), 8.39 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Step B: 2-[3,5-difluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
2-[3,5-difluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester (33 mg, 0.085 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (25 mg, 77%).
NMR (400 MHz, CDCl3): 1.01 (t., 7.6 Hz., 3H), 1.22-1.27 (m., 1H), 1.52-1.62 (m., 1H), 1.69 (sex., 7.6 Hz, 2H), 1.75-1.85 (m., 1H), 2.38-2.47 (m., 1H), 3.19 (t., 7.6 Hz, 2H), 5.10 (s., 2H), 6.62-6.69 (m., 2H), 7.00 (d.d., 7.6 and 4.8 Hz, 1H), 7.73 (d.d., 7.6 and 1.6 Hz, 1H), 8.38 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Example 140: 2-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl] -cyclopropane carboxylic acid methyl ester
2-(3,5-Difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (20.8 mg, 0.091 mmol) obtained in Step C of Preparation Example 60 and 3-chloromethyl-2-cyclopentylsulfanyl-pyridine (20.76 mg, 0.091 mmol) obtained in Step C of Preparation Example 8 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (38 mg, 99%).
NMR (400 MHz, CDCl3): 1.23-1.27 (m., 1H), 1.57-1.70 (m., 5H), 1.70-1.80 (m., 2H), 1.82-1.87 (m., 1H), 2.17-2.22 (m., 2H), 2.41-2.47 (m., 1H), 3.72 (s., 3H), 4.15-4.22 (m., 1H), 5.10 (s., 2H), 6.62-6.69 (m., 2H), 7.03 (d.d., 7.6 and 4.8 Hz, 1H), 7.73 (d.d., 7.6 and 1.6 Hz, 1H), 8.39 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Step B: 2-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid
2-[4-(2-Cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid methyl ester (38 mg, 0.09 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (34 mg, 93%).
NMR (400 MHz, CDCl3): 1.23-1.27 (m., 1H), 1.55-1.86 (m., 8H), 2.17-2.22 (m., 2H), 2.45-2.51 (m., 1H), 4.15-4.22 (m., 1H), 5.10 (s., 2H), 6.62-6.69 (m., 2H), 7.03 (d.d., 7.6 and 4.8 Hz, 1H), 7.75 (d.d., 7.6 and 1.6 Hz, 1H), 8.39 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Example 141: 3-[3-chloro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (41 mg, 0.20 mmol) obtained in Step C of Preparation Example 16 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (51 mg, 0.22 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (38 mg, 59%).
1H NMR (CDCl3) 7.52(1H, t), 7.26(1H, m), 7.08(1H, m), 6.90(1H, m), 6.88(1H, d), 5.19(2H, s), 3.97(1H, m), 2.88(2H, t), 2.65(2H, t), 1.40(6H, d)
Example 142: 3-[3-chloro-4-(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid
2-Chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (43 mg, 0.20 mmol) obtained in Step D of Preparation Example 20 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (51 mg, 0.22 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (48 mg, 72%).
1H NMR (CDCl3) 7.50(1H, t), 7.25(2H, m), 7.11(1H, m), 6.90(1H, m), 6.88(1H, m), 5.19(2H, s), 3.11(2H, d), 2.89(2H, t), 2.65(2H, t), 1.15(1H, m), 0.60(1H, m), 0.32(1H, m)
Example 143: 3-[3-chloro-4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (46 mg, 0.20 mmol) obtained in Step C of Preparation Example 27 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (51 mg, 0.22 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (45 mg, 71%).
1H NMR (CDCl3) 7.51(1H, t), 7.25(1H, m), 7.09(1H, m), 6.99(1H, m), 6.88(1H, d), 5.19(2H, s), 4.00(1H, m), 2.88(2H, m), 2.64(2H, m), 2.19(2H, m), 1.67(3H, m), 1.64(4H, m)
Example 144: 3-[3-fluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-propylsulfanyl-pyridine (0.030 g, 0.15mmol) obtained in Step C of Preparation Example 14 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.031 g, 0.15 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.038g, 73%).
1H NMR (CDCl3) δ 8.40-8.39 (1H, m), 7.74-7.72 (1H, m), 7.05-7.01 (1H, q), 6.99-6.87 (3H, m), 5.08 (2H, s), 3.27-3.24 (2H, t), 2.91-2.88 (2H, t), 2.67-2.63 (2H, t), 1.79-1.70 (2H, m), 1.07-1.03 (3H, m)
Example 145: 3-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-propionic acid
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 23 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.041g, 82%).
1H NMR (CDCl3) δ 8.38-8.37 (1H, m), 7.72-7.70 (1H, m), 7.03-7.00 (1H, q), 6.99-6.87 (3H, m), 5.04 (2H, s), 4.58-4.50 (1H, m), 2.92-2.88 (2H, t), 2.67-2.63 (2H, t), 2.60-2.53 (2H, m), 2.20-2.02 (4H, m)
Example 146: 3-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-pyridine (0.032 g, 0.14 mmol) obtained in Step C of Preparation Example 8 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.045 g, 84%).
1H NMR (CDCl3) δ 8.40-8.39 (1H, m), 7.73-7.71 (1H, m), 7.04-7.01 (1H, q), 6.98-6.87 (3H, m), 5.05 (2H, s), 4.22 (1H, m), 2.92-2.88 (2H, t), 2.67-2.63 (2H, t), 2.24 (2H, m), 1.79 (2H, m), 1.66 (4H, m)
Example 147: 3-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-propionic acid
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 18 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.031 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.044 g, 86%).
1H NMR (CDCl3) δ 8.39 (1H, m), 7.74-7.72 (1H, m), 7.03-7.02 (1H, q), 6.99-6.87 (3H, m), 5.09 (2H, s), 3.24-3.22 (2H, d), 2.92-2.88 (2H, t), 2.67-2.63 (2H, t), 1.17 (1H, m), 0.61-0.59 (2H, m), 0.34-0.32 (2H, m)
Example 148: 3-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-propionic acid
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 37 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043 g, 84%).
1H NMR (CDCl3) δ 7.52-7.48 (1H, t), 7.21-7.19 (1H, d), 7.00-6.98 (1H, d), 6.96-6.85 (3H, m), 5.17 (2H, s), 4.30-4.24 (1H, m), 2.91-2.87 (2H, t), 2.66-2.62 (2H, t), 2.56-2.51 (2H, m), 2.17-2.02 (4H, m)
Example 149: 3-[3-fluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid
2-Chloromethyl-6-isopropylsulfanyl-pyridine (0.028 g, 0.14 mmol) obtained in Step C of Preparation Example 16 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.041 g, 83%).
1H NMR (CDCl3) δ 7.52-7.48 (1H, t), 7.22-7.20 (1H, d), 7.09-7.07 (1H, d), 6.99-6.85 (3H, m), 5.18 (2H, s), 4.00-3.93 (1H, m), 2.91-2.87 (2H, t), 2.66-2.62 (2H, t), 1.40-1.39 (6H, d)
Example 150: 3-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-propionic acid
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.032 g, 0.14 mmol) obtained in Step C of Preparation Example 27 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.045 g, 84%).
1H NMR (CDCl3) δ 7.52-7.48 (1H, t), 7.21-7.20 (1H, d), 7.09-7.07 (1H, d), 6.98-6.85 (3H, m), 5.18 (2H, s), 4.01-3.98 (1H, m), 2.90-2.87 (2H, t), 2.66-2.62 (2H, t), 2.21-2.19 (2H, m), 1.79 (2H, m), 1.67-1.63 (4H, m)
Example 151: 3-[4-(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-propionic acid
2-Chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (0.030 g, 0.14 mmol) obtained in Step D of Preparation Example 20 and 3-(3-fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (0.030 g, 0.14 mmol) obtained in Step C of Preparation Example 6 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043 g, 86%).
1H NMR (CDCl3) δ 7.51-7.47 (1H, t), 7.22-7.20 (1H, d), 7.11-7.09 (1H, d), 6.99-6.85 (3H, m), 5.18 (2H, s), 3.12-3.10 (2H, d), 2.91-2.87 (2H, t), 2.66-2.62 (2H, t), 1.15 (1H, m), 0.61-0.56 (2H, m), 0.33-0.29 (2H, m)
Example 152: 2-[3,5-difluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[3,5-difluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3,5-Difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (20.3 mg, 0.089 mmol) obtained in Step C of Preparation Example 60 and 2-chloromethyl-6-isopropylsulfanyl-pyridine (17.94 mg, 0.089 mmol) obtained in Step C of Preparation Example 16 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (32 mg, 91%).
NMR (400 MHz, CDCl3): 1.22-1.27 (m., 1H), 1.35 (d., 6.8 Hz, 6H), 1.57-1.63 (m., 1H), 1.82-1.87 (m., 1H), 2.41-2.46 (m., 1H), 3.72 (s., 3H), 3.91 (sep., 6.8 Hz, 1H), 5.19 (s., 2H), 6.62-6.70 (m., 2H), 7.08 (d., 8 Hz, 1H), 7.29 (d., 8 Hz, 1H), 7.51 (t., 8 Hz, 1H) ppm.
Step B: 2-[3,5-difluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropanecarboxylic acid
2-[3,5-Difluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester (32 mg, 0.081 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (27 mg, 87%).
NMR (400 MHz, CDCl3): 1.22-1.36 (m.+d. (overlaps), 7H), 1.62-1.68 (m., 1H), 1.82-1.87 (m., 1H), 2.48-2.53 (m., 1H), 3.91 (sep., 6.8 Hz, 1H), 5.20 (s., 2H), 6.62-6.70 (m., 2H), 7.08 (d., 8 Hz, 1H), 7.29 (d., 8 Hz, 1H), 7.51 (t., 8 Hz, 1H) ppm.
Example 153: 2-[4-(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[4-(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3,5-Difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (21 mg, 0.092 mmol) obtained in Step C of Preparation Example 60 and 2-chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (19.67 mg, 0.092 mmol) obtained in Step D of Preparation Example 20 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (37 mg, 99%).
NMR (400 MHz, CDCl3): 0.26-0.30 (m., 2H), 0.53-0.58 (m., 2H), 1.08-1.13 (m., 1H), 1.22-1.27 (m., 1H), 1.57-1.63 (m., 1H), 1.82-1.87 (m., 1H), 2.41-2.46 (m., 1H), 3.05 (d., 7.2 Hz, 2H), 3.72 (s., 3H), 5.18 (s., 2H), 6.62-6.68 (m., 2H), 7.10 (d., 8 Hz, 1H), 7.29 (d., 8 Hz, 1H), 7.51 (t., 8 Hz, 1H) ppm.
Step B: 2-[4-(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropanecarboxylic acid
2-[4-(6-Cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid methyl ester (37 mg, 0.091 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (31.5 mg, 88%).
NMR (400 MHz, CDCl3): 0.26-0.30 (m., 2H), 0.53-0.58 (m., 2H), 1.06-1.16 (m., 1H), 1.29-1.35 (m., 1H), 1.62-1.68 (m., 1H), 1.82-1.87 (m., 1H), 2.48-2.53 (m., 1H), 3.05 (d., 7.2 Hz, 2H), 5.19 (s., 2H), 6.62-6.69 (m., 2H), 7.10 (d., 8 Hz, 1H), 7.28 (d., 8 Hz, 1H), 7.51 (t., 8 Hz, 1H) ppm.
Example 154: 2-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl] -cyclopropane carboxylic acid methyl ester
2-(3,5-Difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (21.7 mg, 0.095 mmol) obtained in Step C of Preparation Example 60 and 2-chloromethyl-6-cyclopentylsulfanyl-pyridine (21.66 mg, 0.095 mmol) obtained in Step C of Preparation Example 27 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (37 mg, 93%).
NMR (400 MHz, CDCl3): 1.23-1.27 (m., 1H), 1.57-1.70 (m., 5H), 1.70-1.80 (m., 2H), 1.82-1.87 (m., 1H), 2.10-2.18 (m., 2H), 2.41-2.46 (m., 1H), 3.72 (s., 3H), 3.90-3.97 (m., 1H), 5.18 (s., 2H), 6.62-6.68 (m., 2H), 7.08 (d., 8 Hz, 1H), 7.29 (d., 8 Hz, 1H), 7.51 (t., 8 Hz, 1H) ppm.
Step B: 2-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl] -cyclopropanecarboxylic acid
2-[4-(6-Cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid methyl ester (37 mg, 0.089 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (33 mg, 92%).
NMR (400 MHz, CDCl3): 1.29-1.35 (m., 1H), 1.55-1.68 (m., 5H), 1.70-1.80 (m., 2H), 1.82-1.88 (m., 1H), 2.10-2.18 (m., 2H), 2.48-2.53 (m., 1H), 3.90-3.97 (m., 1H), 5.19 (s., 2H), 6.62-6.69 (m., 2H), 7.09 (d., 8 Hz, 1H), 7.29 (d., 8 Hz, 1H), 7.52 (t., 8 Hz, 1H) ppm.
Example 155: 2-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid (more polar)
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (0.018 g, 0.08 mmol) obtained in Step C of Preparation Example 37 amd 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (0.020 g, 0.08 mmol) obtained in Step C of Preparation Example 60 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.030g, 88%).
1H-NMR (CDCl3) δ 7.54-7.50 (1H, t), 7.30-7.29 (1H, d), 7.01-6.99 (1H, d), 6.70-6.64 (2H, m), 5.18 (2H, s), 4.27-4.19 (1H, m), 2.53-2.48 (3H, m), 2.13-2.04 (4H, m), 1.86-1.84 (1H, m), 1.67-1.64 (1H, m), 1.34-1.32 (1H, m)
Example 156: 2-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid (more polar)
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (0.018 g, 0.08 mmol) obtained in Step C of Preparation Example 23 and 2-(3,5-difluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (0.020 g, 0.08 mmol) obtained in Step C of Preparation Example 60 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.030 g, 88%).
1H-NMR (CDCl3) δ 8.39-8.38 (1H, m), 8.05-8.03 (1H, m), 7.05-7.02 (1H, q), 6.70-6.65 (2H, m), 5.10 (2H, s), 4.54-4.46 (1H, m), 2.54-2.50 (3H, m), 2.14-2.03 (4H, m), 1.87-1.84 (1H, m), 1.67-1.65 (1H, m), 1.34-1.32 (1H, m)
Example 157: 3-[3-chloro-4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (35 mg, 0.16 mmol) obtained in Step C of Preparation Example 18 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (42 mg, 0.18 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (38 mg, 74%).
1H NMR (CDCl3) 8.38(1H, m), 7.82(1H, d), 7.26(1H, m), 7.05(2H, m), 6.90(1H, d), 5.09(2H, s), 3.24(2H, d), 2.91(2H, t), 2.66(2H, t), 1.17(1H, m), 0.59(2H, m), 0.34(2H, m)
Example 158: 3-[3-chloro-4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-cyclobutylsulfanyl-pyridine (34 mg, 0.17 mmol) obtained in Step C of Preparation Example 23 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (43 mg, 0.19 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (39 mg, 73%).
1H NMR (CDCl3) 8.37(1H, m), 7.80(1H, d), 7.26(1H, m), 7.04(2H, m), 6.88(1H, d), 5.04(2H, s), 4.55(1H, m), 2.98(2H, t), 2.64(2H, t), 2.55(2H, m), 2.20~2.00(4H, m)
Example 159: 3-[3-chloro-4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid
2-Chloromethyl-6-cyclobutylsulfanyl-pyridine (34 mg, 0.17 mmol) obtained in Step C of Preparation Example 37 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (43 mg, 0.19 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (35 mg, 63%).
1H NMR (CDCl3) 7.52(1H, m), 7.25(2H, m), 7.04(2H, m), 6.88(1H, m), 5.18(2H, s), 4.27(1H, m), 2.89(2H, m), 2.65(2H, m), 2.54(2H, m), 2.12(4H, m)
Example 160: 3-[3-chloro-4-(2-isopropylsulfanyl-6-methyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-6-methyl-pyridine (34 mg, 0.17 mmol) obtained in Step D of Preparation Example 9 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (43 mg, 0.18 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (32 mg, 58%).
1H NMR (CDCl3) 7.66(1H, m), 7.26(1H, m), 7.02(1H, m), 6.88(2H, m), 5.04(2H, s), 4.20(1H, m), 2.88(2H, t), 2.65(2H, t), 2.50(3H, s), 1.42(6H, d)
Example 161: 3-[3-chloro-4-(2-cyclopentylsulfanyl-6-methyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-6-methyl-pyridine (35 mg, 0.15 mmol) obtained in Step C of Preparation Example 36 and 3-(3-chloro-4-hydroxy-phenyl)-propionic acid ethyl ester (36 mg, 0.17 mmol) obtained in Step C of Preparation Example 42 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (30 mg, 58%).
1H NMR (CDCl3) 7.66(1H, m), 7.26(2H, m), 7.02(1H, m), 6.89(2H, d), 5.04(2H, s), 4.24(1H, m), 2.88(2H, t), 2.65(2H, t), 2.50(3H, s), 2.23(2H, m), 1.78(2H, m), 1.55(4H, m)
Example 162: 2-[3-fluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[3-fluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3-Fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (32 mg, 0.153 mmol) obtained in Step C of Preparation Example 63 and 3-chloromethyl-2-isopropylsulfanyl-pyridine (31 mg, 0.153 mmol) obtained in Step C of Preparation Example 1 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (56 mg, 97%).
NMR (400 MHz, CDCl3): 1.22-1.27 (m., 1H), 1.42 (d., 6.4 Hz, 6H), 1.54-1.60 (m., 1H), 1.80-1.85 (m., 1H), 2.43-2.49 (m., 1H), 3.72 (s., 3H), 4.18 (sep., 6.4 Hz, 1H), 5.05 (s., 2H), 6.77-6.88 (m., 2H), 6.92 (t., 8.4 Hz, 1H), 7.02 (d.d., 7.6 and 4.8 Hz, 1H), 7.71 (d.d., 7.6 and 1.6 Hz, 1H), 8.40 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Step B: 2-[3-fluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
2-[3-Fluoro-4-(2-isopropylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester(56 mg, 0.148 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (52 mg, 97%).
NMR (400 MHz, CDCl3): 1.27-1.35 (m., 1H), 1.42 (d., 6.4 Hz, 6H), 1.60-1.66 (m., 1H), 1.81-1.85 (m., 1H), 2.51-2.56 (m., 1H), 4.18 (sep., 6.4 Hz, 1H), 5.06 (s., 2H), 6.80-6.88 (m., 2H), 6.91 (t., 8.4 Hz, 1H), 7.03 (d.d., 7.6 and 4.8 Hz, 1H), 7.72 (d.d., 7.6 and 1.6 Hz, 1H), 8.40 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Example 163: 2-[3-fluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[3-fluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3-Fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (30 mg, 0.142 mmol) obtained in Step C of Preparation Example 63 and 3-chloromethyl-2-propylsulfanyl-pyridine (28.79 mg, 0.142 mmol) obtained in Step C of Preparation Example 14 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (50 mg, 95%).
NMR (400 MHz, CDCl3): 1.05 (t., 7.6 Hz., 3H), 1.22-1.27 (m., 1H), 1.55-1.60 (m., 1H), 1.74 (sex., 7.6 Hz, 2H), 1.82-1.87 (m., 1H), 2.43-2.49 (m., 1H), 3.26 (t., 7.6 Hz, 2H), 3.72 (s., 3H), 5.07 (s., 2H), 6.77-6.89 (m., 2H), 6.92 (t., 8.4 Hz, 1H), 7.02 (d.d., 7.6 and 4.8 Hz, 1H), 7.71 (d.d., 7.6 and 1.6 Hz, 1H), 8.39 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Step B: 2-[3-fluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid
2-[3-Fluoro-4-(2-propylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester (51 mg, 0.135 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (47 mg, 97%).
NMR (400 MHz, CDCl3): 1.05 (t., 7.6 Hz., 3H), 1.31-1.36 (m., 1H), 1.61-1.66 (m., 1H), 1.74 (sex., 7.6 Hz, 2H), 1.81-1.86 (m., 1H), 2.51-2.56 (m., 1H), 3.26 (t., 7.6 Hz, 2H), 5.08 (s., 2H), 6.81-6.87 (m., 2H), 6.92 (t., 8.4 Hz, 1H), 7.02 (d.d., 7.6 and 4.8 Hz, 1H), 7.71 (d.d., 7.6 and 1.6 Hz, 1H), 8.39 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Example 164: 2-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3-Fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (33 mg, 0.158 mmol) obtained in Step C of Preparation Example 63 and 3-chloromethyl-2-cyclopentylsulfanyl-pyridine (35.76 mg, 0.158 mmol) obtained in Step C of Preparation Example 8 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (61 mg, 97%).
NMR (400 MHz, CDCl3): 1.23-1.27 (m., 1H), 1.56-1.72 (m., 5H), 1.72-1.84 (m., 3H), 2.17-2.22 (m. 2H), 2.43-2.49 (m., 1H), 3.71 (s., 3H), 4.19-4.26 (m., 1H), 5.05 (s., 2H), 6.77-6.89 (m., 2H), 6.92 (t., 8.4 Hz, 1H), 7.02 (d.d., 7.6 and 4.8 Hz, 1H), 7.70 (d.d., 7.6 and 1.6 Hz, 1H), 8.39 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Step B: 2-[4-(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid
2-[4-(2-Cyclopentylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid methyl ester (61 mg, 0.153 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (58 mg, 97%).
NMR (400 MHz, CDCl3): 1.32-1.36 (m., 1H), 1.58-1.72 (m., 5H), 1.72-1.84 (m., 3H), 2.17-2.25 (m., 2H), 2.51-2.56 (m., 1H), 4.19-4.26 (m., 1H), 5.06 (s., 2H), 6.80-6.87 (m., 2H), 6.91 (t., 8.4 Hz, 1H), 7.02 (d.d., 7.6 and 4.8 Hz, 1H), 7.70 (d.d., 7.6 and 1.6 Hz, 1H), 8.39 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Example 165: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3-Fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (32 mg, 0.152 mmol) obtained in Step C of Preparation Example 63 and 3-chloromethyl-2-cyclopropylmethylsulfanyl-pyridine (32.54 mg, 0.152 mmol) obtained in Step C of Preparation Example 18 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (56 mg, 95%).
NMR (400 MHz, CDCl3): 0.31-0.35 (m., 2H), 0.57-0.62 (m., 2H), 1.13-1.20 (m., 1H), 1.22-1.27 (m., 1H), 1.55-1.60 (m., 1H), 1.81-1.86 (m., 1H), 2.43-2.49 (m., 1H), 3.23 (d., 7.2 Hz, 2H), 3.72 (s., 3H), 5.09 (s., 2H), 6.77-6.89 (m., 2H), 6.91 (t., 8.4 Hz, 1H), 7.03 (d.d., 7.6 and 4.8 Hz, 1H), 7.71 (d.d., 7.6 and 1.6 Hz, 1H), 8.38 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Step B: 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid
2-[4-(2-Cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid methyl ester (56 mg, 0.144 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (47 mg, 87%).
NMR (400 MHz, CDCl3): 0.31-0.35 (m., 2H), 0.57-0.62 (m., 2H), 1.12-1.21 (m., 1H), 1.31-1.36 (m., 1H), 1.61-1.66 (m., 1H), 1.81-1.86 (m., 1H), 2.51-2.56 (m., 1H), 3.23 (d., 7.2 Hz, 2H), 5.09 (s., 2H), 6.80-6.87 (m., 2H), 6.92 (t., 8.4 Hz, 1H), 7.03 (d.d., 7.6 and 4.8 Hz, 1H), 7.71 (d.d., 7.6 and 1.6 Hz, 1H), 8.38 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Example 166: 2-[3-fluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[3-fluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3-Fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (29 mg, 0.140 mmol) obtained in Step C of Preparation Example 63 was reacted in the same manner as in Step A of Example 1 to obtain the title compound (50 mg, 96%).
NMR (400 MHz, CDCl3): 1.22-1.27 (m., 1H), 1.39 (d., 6.8 Hz, 6H), 1.54-1.59 (m., 1H), 1.80-1.84 (m., 1H), 2.43-2.48 (m., 1H), 3.71 (s., 3H), 3.96 (sep., 6.8 Hz, 1H), 5.18 (s., 2H), 6.77-6.85 (m., 2H), 6.90 (t., 8.4 Hz, 1H), 7.07 (d., 8 Hz, 1H), 7.19 (d., 8 Hz, 1H), 7.49 (t., 8 Hz, 1H) ppm.
Step B: 2-[3-fluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropanecarboxylic acid
2-[3-Fluoro-4-(6-isopropylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-cyclopropane carboxylic acid methyl ester (50 mg, 0.134 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (39 mg, 81%).
NMR (400 MHz, CDCl3): 1.30-1.35 (m., 1H), 1.39 (d., 6.8 Hz, 6H), 1.60-1.65 (m., 1H), 1.80-1.85 (m., 1H), 2.50-2.55 (m., 1H), 3.96 (sep., 6.8 Hz, 1H), 5.18 (s., 2H), 6.78-6.87 (m., 2H), 6.91 (t., 8.4 Hz, 1H), 7.07 (d., 8 Hz, 1H), 7.19 (d., 8 Hz, 1H), 7.49 (t., 8 Hz, 1H) ppm.
Example 167: 2-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3-Fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (30 mg, 0.143 mmol) obtained in Step C of Preparation Example 63 and 2-chloromethyl-6-cyclobutylsulfanyl-pyridine (30.5 mg, 0.143 mmol) obtained in Step C of Preparation Example 37 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (52 mg, 95%).
NMR (400 MHz, CDCl3): 1.23-1.27 (m., 1H), 1.54-1.59 (m., 1H), 1.80-1.84 (m., 1H), 2.02-2.20 (m., 4H), 2.42-2.47 (m., 1H), 2.47-2.55 (m., 2H), 3.71 (s., 3H), 4.28 (quin., 7.6 Hz, 1H), 5.16 (s., 2H), 6.77-6.86 (m., 2H), 6.90 (t., 8.4 Hz, 1H), 6.98 (d., 8 Hz, 1H), 7.18 (d., 8 Hz, 1H), 7.49 (t., 8 Hz, 1H) ppm.
Step B: 2-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid
2-[4-(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid methyl ester (52 mg, 0.135 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (44 mg, 87%).
NMR (400 MHz, CDCl3): 1.30-1.35 (m., 1H), 1.60-1.65 (m., 1H), 1.80-1.85 (m., 1H), 2.02-2.20 (m., 4H), 2.50-2.58 (m., 3H), 4.28 (quin., 7.6 Hz, 1H), 5.17 (s., 2H), 6.78-6.87 (m., 2H), 6.91 (t., 8.4 Hz, 1H), 6.99 (d., 8 Hz, 1H), 7.18 (d., 8 Hz, 1H), 7.49 (t., 8 Hz, 1H) ppm.
Example 168: 2-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3-Fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (33 mg, 0.159 mmol) obtained in Step C of Preparation Example 63 and 2-chloromethyl-6-cyclopentylsulfanyl-pyridine (35.76 mg, 0.159 mmol) obtained in Step C of Preparation Example 27 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (59 mg, 93%).
NMR (400 MHz, CDCl3): 1.23-1.27 (m., 1H), 1.54-1.70 (m., 5H), 1.70-1.87 (m., 3H), 2.12-2.22 (m., 2H), 2.43-2.48 (m., 1H), 3.71 (s., 3H), 3.95-4.03 (m., 1H), 5.17 (s., 2H), 6.77-6.85 (m., 2H), 6.90 (t., 8.4 Hz, 1H), 7.08 (d., 8 Hz, 1H), 7.18 (d., 8 Hz, 1H), 7.49 (t., 8 Hz, 1H) ppm.
Step B: 2-[4-(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid
2-[4-(6-Cyclopentylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid methyl ester (59 mg, 0.148 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (52 mg, 91%).
NMR (400 MHz, CDCl3): 1.30-1.35 (m., 1H), 1.58-1.70 (m., 5H), 1.70-1.85 (m., 3H), 2.13-2.22 (m., 2H), 2.50-2.55 (m., 1H), 3.95-4.03 (m., 1H), 5.18 (s., 2H), 6.77-6.86 (m., 2H), 6.91 (t., 8.4 Hz, 1H), 7.08 (d., 8 Hz, 1H), 7.18 (d., 8 Hz, 1H), 7.49 (t., 8 Hz, 1H) ppm.
Example 169: 2-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropanecarboxylic acid methyl ester
2-(3-Fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid methyl ester (more polar) (31 mg, 0.149 mmol) obtained in Step C of Preparation Example 63 and 3-chloromethyl-2-cyclobutylsulfanyl-pyridine (31.52 mg, 0.149 mmol) obtained in Step C of Preparation Example 23 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (57 mg, 99%).
NMR (400 MHz, CDCl3): 1.22-1.27 (m., 1H), 1.57-1.60 (m., 1H), 1.81-1.85 (m., 1H), 2.03-2.20 (m., 4H), 2.42-2.47 (m., 1H), 2.53-2.58 (m., 2H), 3.72 (s., 3H), 4.54 (quin., 7.6 Hz, 1H), 5.04 (s., 2H), 6.78-6.86 (m., 2H), 6.90 (t., 8.4 Hz, 1H), 7.01 (d.d., 7.6 and 4.8 Hz, 1H), 7.68 (d.d., 7.6 and 1.6 Hz, 1H), 8.37 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Step B: 2-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid
2-[4-(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid methyl ester (57 mg, 0.148 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (52 mg, 94%).
NMR (400 MHz, CDCl3): 1.31-1.36 (m., 1H), 1.61-1.66 (m., 1H), 1.81-1.86 (m., 1H), 2.03-2.20 (m., 4H), 2.53-2.60 (m., 3H), 4.54 (quin., 7.6 Hz, 1H), 5.04 (s., 2H), 6.80-6.87 (m., 2H), 6.91 (t., 8.4 Hz, 1H), 7.01 (d.d., 7.6 and 4.8 Hz, 1H), 7.69 (d.d., 7.6 and 1.6 Hz, 1H), 8.37 (d.d., 4.8 and 1.6 Hz, 1H) ppm.
Example 170: 2-[4-(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid (more polar)
Step A: 2-[4-(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid methyl ester
2-(3-Fluoro-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (more polar) (31 mg, 0.146 mmol) obtained in Step C of Preparation Example 63 and 2-chloromethyl-6-cyclopropylmethylsulfanyl-pyridine (31.52 mg, 0.146 mmol) obtained in Step D of Preparation Example 20 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (50 mg, 89%).
NMR (400 MHz, CDCl3): 0.29-0.33 (m., 2H), 0.56-0.61 (m., 2H), 1.11-1.17 (m., 1H), 1.22-1.28 (m., 1H), 1.54-1.59 (m., 1H), 1.80-1.84 (m., 1H), 2.43-2.48 (m., 1H), 3.10 (d., 7.2 Hz, 2H), 3.71 (s., 3H), 5.18 (s., 2H), 6.77-6.85 (m., 2H), 6.90 (t., 8.4 Hz, 1H), 7.10 (d., 8 Hz, 1H), 7.18 (d., 8 Hz, 1H), 7.49 (t., 8 Hz, 1H) ppm.
Step B: 2-[4-(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid
2-[4-(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-3-fluoro-phenyl]-cyclopropane carboxylic acid methyl ester (50 mg, 0.130 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (38 mg, 79%).
NMR (400 MHz, CDCl3): 0.29-0.33 (m., 2H), 0.56-0.61 (m., 2H), 1.11-1.17 (m., 1H), 1.30-1.35 (m., 1H), 1.60-1.65 (m., 1H), 1.80-1.85 (m., 1H), 2.50-2.55 (m., 1H), 3.11 (d., 7.2 Hz, 2H), 5.18 (s., 2H), 6.78-6.87 (m., 2H), 6.91 (t., 8.4 Hz, 1H), 7.10 (d., 8 Hz, 1H), 7.18 (d., 8 Hz, 1H), 7.49 (t., 8 Hz, 1H) ppm.
Example 171: 3-{4-[(2-cyclopentylsulfanyl-pyridin-3-ylmethyl)-amino]-phenyl]-propionic acid
Step A: 3-{4-[(2-cyclopentylsulfanyl-pyridin-3-ylmethyl)-amino]-phenyl]-propionic acid methyl ester
3-(4-Amino-phenyl)-propionic acid methyl ester (50 mg, 0.28 mmol) obtained in Preparation Example 67 was dissolved in CH3CN (5 mL), and Cs2CO3 (227 mg, 0.7 mmol) was added thereto. After 3-chloromethyl-2-cyclopentylsulfanyl-pyridine (64 mg, 0.28 mmol) obtained in Step C of Preparation Example 8 was added thereto, the mixture was stirred at 80 ~ 85℃ for 5 hours. After the termination of the reaction, the reactant was cooled and then filtered by using celite. The filtrate was concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex = 1/7) to obtain the title compound (28 mg, 27%).
1H NMR (400 MHz, CDCl3) δ 8.37-8.31(m, 1H), 7.54-7.48(m, 1H), 6.99(d, 2H), 6.97-6.90(m, 1H), 6.52(d, 2H), 4.25(s, 2H), 4.25-4.18(m, 1H), 4.12(s, 1H), 3.66(s, 3H), 2.83(t, 2H), 2.56(t, 2H), 2.30-2.18(m, 2H), 1.85-1.72(m, 2H), 1.72-1.59(m, 4H)
Step B: 3-{4-[(2-cyclopentylsulfanyl-pyridin-3-ylmethyl)-amino]-phenyl]-propionic acid
3-{4-[(2-Cyclopentylsulfanyl-pyridin-3-ylmethyl)-amino]-phenyl]-propionic acid methyl ester (28 mg, 0.076 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (26 mg, 97%).
1H NMR (400 MHz, CDCl3) δ 8.49-8.43(m, 1H), 7.79-7.71(m, 1H), 7.10-7.02(m, 1H), 7.06(d, 2H), 6.65(d, 2H), 4.40-4.33(m, 1H), 4.33(s, 2H), 2.85(t, 2H), 2.62(t, 2H), 2.32-2.21(m, 2H), 1.83-1.57(m, 6H)
Example 172: 3-{4-[(6-cyclopentylsulfanyl-pyridin-2-ylmethyl)-amino]-phenyl]-propionic acid
3-(4-Amino-phenyl)-propionic acid methyl ester (50 mg, 0.28 mmol) obtained in Preparation Example 67 and 2-chloromethyl-6-cyclopentylsulfanyl-pyridine (64 mg, 0.28mmol) obtained in Step C of Preparation Example 27 were used to react sequentially in the same manner as in Steps A and B of Example 171 to obtain the title compound (36 mg, 36%).
1H NMR (500 MHz, CDCl3) δ 7.42(t, 1H), 7.07-7.00(m, 3H), 6.98-6.94(m, 1H), 6.63-6.58(m, 2H), 4.36(s, 2H), 4.05-3.97(m, 1H), 2.84(t, 2H), 2.61(t, 2H), 2.26-2.14(m, 2H), 1.84-1.74(m, 2H), 1.72-1.60(m, 4H)
Example 173: 3-[4-[(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid
Step A: 3-[4-[(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester
3-(2-Fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (28 mg, 0.13 mmol) obtained in Step C of Preparation Example 7 and 3-chloromethyl-2-cyclopentylsulfanyl -pyridine (30 mg, 0.13 mmol) obtained in Step C of Preparation Example 8 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (45 mg, 85%).
1H NMR (400 MHz, CDCl3) δ 8.42-8.37(m, 1H), 7.67-7.61(m, 1H), 7.11(t, 1H), 7.04-6.99(m, 1H), 6.77-6.63(m, 2H), 4.97(s, 2H), 4.28-4.18(m, 1H), 4.12(q, 2H), 2.90(t, 2H), 2.58(t, 2H), 2.29-2.18(m, 2H), 1.83-1.73(m, 2H), 1.71-1.59(m, 4H), 1.23(t, 3H)
Step B: 3-[4-[(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid
3-[4-[(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester (45 mg, 0.11 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (41 mg, 98%).
1H NMR (400 MHz, CDCl3) δ 8.45-8.39(m, 1H), 7.69-7.61(m, 1H), 7.12(t, 1H), 7.06-7.00(m, 1H), 6.75-6.65(m, 2H), 4.97(s, 2H), 4.28-4.18(m, 1H), 2.92(t, 2H), 2.65(t, 2H), 2.33-2.18(m, 2H), 1.87-1.73(m, 2H), 1.73-1.59(m, 4H)
Example 174: 2-[4-[(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-cyclopropane carboxylic acid
Step A: 2-[4-[(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-cyclopropane carboxylic acid ethyl ester
2-(2-Fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (29.5 mg, 0.13 mmol) obtained in Step C of Preparation Example 68 and 3-chloromethyl-2-cyclopentylsulfanyl-pyridine (30 mg, 0.13 mmol) obtained in Step C of Preparation Example 8 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (52 mg, 95%).
1H NMR (400 MHz, CDCl3) δ 8.42-8.37(m, 1H), 7.65-7.60(m, 1H), 7.04-6.98(m, 1H), 6.88(t, 1H), 6.70-6.63(m, 2H), 4.99(s, 2H), 4.28-4.18(m, 1H), 4.17(q, 2H), 2.60-2.52(m, 1H), 2.28-2.17(m, 2H), 1.89-1.81(m, 1H), 1.81-1.71(m, 2H), 1.71-1.59(m, 4H), 1.59-1.51(m, 1H), 1.31-1.22(m, 1H), 1.28(t, 3H)
Step B: 2-[4-[(2-cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-cyclopropane carboxylic acid
2-[4-[(2-Cyclopentylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-cyclopropane carboxylic acid ethyl ester (52 mg, 0.125 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (48 mg, 99%).
1H NMR (400 MHz, CDCl3) δ 8.44-8.38(m, 1H), 7.67-7.60(m, 1H), 7.07-6.99(m, 1H), 6.90(t, 1H), 6.71-6.63(m, 2H), 4.98(s, 2H), 4.28-4.18(m, 1H), 2.69-2.60(m, 1H), 2.30-2.17(m, 2H), 1.90-1.82(m, 1H), 1.82-1.71(m, 2H), 1.71-1.59(m, 4H), 1.45-1.34(m, 1H), 1.30-1.20(m, 1H)
Example 175: 3-[4-[(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid
Step A: 3-[4-[(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester
3-(2-Fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (20 mg, 0.094 mmol) obtained in Step C of Preparation Example 7 and 3-chloromethyl-2-cyclobutylsulfanyl-pyridine (20.14 mg, 0.094 mmol) obtained in Step C of Preparation Example 23 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (35 mg, 95%).
1H NMR (400 MHz, CDCl3) δ 8.40-8.34(m, 1H), 7.67-7.60(m, 1H), 7.11(t, 1H), 7.03-6.98(m, 1H), 6.71-6.65(m, 2H), 4.96(s, 2H), 4.59-4.49(m, 1H), 4.12(q, 2H), 2.91(t, 2H), 2.59(t, 2H), 2.59-2.50(m, 2H), 2.20-2.09(m, 2H), 2.09-2.00(m, 2H), 1.23(t, 3H)
Step B: 3-[4-[(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid
3-[4-[(2-Cyclobutylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester (35 mg, 0.09 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (31 mg, 95%).
1H NMR (400 MHz, CDCl3) δ 8.41-8.36(m, 1H), 7.67-7.61(m, 1H), 7.12(t, 1H), 7.05-6.99(m, 1H), 6.72-6.65(m, 2H), 4.96(s, 2H), 4.58-4.49(m, 1H), 2.92(t, 2H), 2.66(t, 2H), 2.61-2.50(m, 2H), 2.20-2.00(m, 4H)
Example 176: 3-[4-[(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid
Step A: 3-[4-[(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester
3-(2-Fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (20 mg, 0.094 mmol) obtained in Step C of Preparation Example 7 and 2-chloromethyl-6-cyclobutylsulfanyl-pyridine (20.14 mg, 0.094 mmol) obtained in Step C of Preparation Example 37 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (36 mg, 98%).
1H NMR (400 MHz, CDCl3) δ 7.49(t, 1H), 7.16-7.05(m, 2H), 6.99(d, 1H), 6.72-6.65(m, 2H), 5.09(s, 2H), 4.35-4.25(m, 1H), 4.12(q, 2H), 2.90(t, 2H), 2.58(t, 2H), 2.58-2.49(m, 2H), 2.20-2.00(m, 4H), 1.23(t, 3H)
Step B: 3-[4-[(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid
3-[4-[(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester (36 mg, 0.092 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (32 mg, 96%).
1H NMR (400 MHz, CDCl3) δ 7.49(t, 1H), 7.17-7.08(m, 2H), 6.99(d, 1H), 6.72-6.66(m, 2H), 5.09(s, 2H), 4.33-4.23(m, 1H), 2.91(t, 2H), 2.64(t, 2H), 2.60-2.49(m, 2H), 2.20-1.99(m, 4H)
Example 177: 3-[4-[(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid
Step A: 3-[4-[(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester
3-(2-Fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (20 mg, 0.094 mmol) obtained in Step C of Preparation Example 7 and 2-chloromethyl-6-cyclopentyl sulfanyl-pyridine (21.46 mg, 0.094 mmol) obtained in Step C of Preparation Example 27 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (34 mg, 89%).
1H NMR (400 MHz, CDCl3) δ 7.48(t, 1H), 7.16-7.05(m, 3H), 6.71-6.65(m, 2H), 5.10(s, 2H), 4.12(q, 2H), 4.06-3.97(m, 1H), 2.90(t, 2H), 2.58(t, 2H), 2.24-2.13(m, 2H), 1.83-1.71(m, 2H), 1.70-1.58(m, 4H), 1.23(t, 3H)
Step B: 3-[4-[(6-cyclopentylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid
3-[4-[(6-Cyclopentylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester (34 mg, 0.082 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (30 mg, 95%).
1H NMR (400 MHz, CDCl3) δ 7.49(t, 1H), 7.16-7.07(m, 3H), 6.72-6.66(m, 2H), 5.11(s, 2H), 4.05-3.96(m, 1H), 2.90(t, 2H), 2.64(t, 2H), 2.25-2.11(m, 2H), 1.84-1.71(m, 2H), 1.71-1.58(m, 4H)
Example 178: 3-[4-[(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid
Step A: 3-[4-[(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester
3-(2-Fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (20 mg, 0.094 mmol) obtained in Step C of Preparation Example 7 and 3-chloromethyl-2-cyclopropylmethyl sulfanyl-pyridine (20.14 mg, 0.094 mmol) obtained in Step C of Preparation Example 18 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (36 mg, 98%).
1H NMR (400 MHz, CDCl3) δ 8.41-8.37(m, 1H), 7.69-7.63(m, 1H), 7.11(t, 1H), 7.05-6.99(m, 1H), 6.72-6.65(m, 2H), 5.01(s, 2H), 4.12(q, 2H), 3.23(d, 2H), 2.91(t, 2H), 2.59(t, 2H), 1.23(t, 3H), 1.20-1.11(m, 1H), 0.63-0.57(m, 2H), 0.36-0.30(m, 2H)
Step B: 3-[4-[(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid
3-[4-[(2-Cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester (36 mg, 0.092 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (33 mg, 99%).
1H NMR (400 MHz, CDCl3) δ 8.42-8.37(m, 1H), 7.70-7.62(m, 1H), 7.12(t, 1H), 7.08-7.00(m, 1H), 6.74-6.65(m, 2H), 5.01(s, 2H), 3.23(d, 2H), 2.92(t, 2H), 2.66(t, 2H), 1.22-1.10(m, 1H), 0.64-0.56(m, 2H), 0.37-0.30(m, 2H)
Example 179: 3-[4-[(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid
Step A: 3-[4-[(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester
3-(2-Fluoro-4-hydroxy-phenyl)-propionic acid ethyl ester (20 mg, 0.094 mmol) obtained in Step C of Preparation Example 7 and 2-chloromethyl-6-cyclopropylmethyl sulfanyl-pyridine (20.14 mg, 0.094 mmol) obtained in Step D of Preparation Example 20 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (36 mg, 98%).
1H NMR (400 MHz, CDCl3) δ 7.48(t, 1H), 7.15-7.06(m, 3H), 6.71-6.66(m, 2H), 5.10(s, 2H), 4.12(q, 2H), 3.12(d, 2H), 2.90(t, 2H), 2.58(t, 2H), 1.23(t, 3H), 1.20-1.10(m, 1H), 0.62-0.55(m, 2H), 0.35-0.29(m, 2H)
Step B: 3-[4-[(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid
3-[4-[(6-Cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-2-fluoro-phenyl]-propionic acid ethyl ester (36 mg, 0.092 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (33 mg, 99%).
1H NMR (400 MHz, CDCl3) δ 7.48(t, 1H), 7.16-7.07(m, 3H), 6.72-6.66(m, 2H), 5.10(s, 2H), 3.12(d, 2H), 2.91(t, 2H), 2.64(t, 2H), 1.20-1.10(m, 1H), 0.63-0.55(m, 2H), 0.35-0.28(m, 2H)
Example 180: 3-[4-[(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
Step A: 3-[4-[(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid methyl ester
3-(4-Hydroxy-phenyl)-propionic acid methyl ester (20 mg, 0.11 mmol) obtained in Preparation Example 4 and 3-chloromethyl-2-cyclobutylsulfanyl-pyridine (23.72 mg, 0.11 mmol) obtained in Step C of Preparation Example 23 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (35 mg, 88%).
1H NMR (400 MHz, CDCl3) δ 8.39-8.33(m, 1H), 7.68-7.62(m, 1H), 7.15-7.09(m, 2H), 7.01-6.97(m, 1H), 6.92-6.87(m, 2H), 4.97(s, 2H), 4.59-4.49(m, 1H), 3.66(s, 3H), 2.90(t, 2H), 2.60(t, 2H), 2.59-2.51(m, 2H), 2.20-2.09(m, 2H), 2.09-2.00(m, 2H)
Step B: 3-[4-[(2-cyclobutylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-[4-[(2-Cyclobutylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid methyl ester (35 mg, 0.098 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (31 mg, 95%).
1H NMR (500 MHz, CDCl3) δ 8.40-8.34(m, 1H), 7.69-7.63(m, 1H), 7.18-7.09(m, 2H), 7.04-6.97(m, 1H), 6.94-6.86(m, 2H), 4.97(s, 2H), 4.57-4.48(m, 1H), 2.90(t, 2H), 2.65(t, 2H), 2.60-2.49(m, 2H), 2.20-2.08(m, 2H), 2.08-1.97(m, 2H)
Example 181: 3-[4-[(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid
Step A: 3-[4-[(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid methyl ester
3-(4-Hydroxy-phenyl)-propionic acid methyl ester (20 mg, 0.11 mmol) obtained in Preparation Example 4 and 2-chloromethyl-6-cyclobutylsulfanyl-pyridine (23.72 mg, 0.11 mmol) obtained in Step C of Preparation Example 37 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (37 mg, 93%).
1H NMR (400 MHz, CDCl3) δ 7.47(t, 1H), 7.18-7.13(m, 1H), 7.13-7.08(m, 2H), 6.99-6.95(m, 1H), 6.92-6.87(m, 2H), 5.11(s, 2H), 4.33-4.24(m, 1H), 3.66(s, 3H), 2.89(t, 2H), 2.59(t, 2H), 2.58-2.49(m, 2H), 2.20-2.00(m, 4H)
Step B: 3-[4-[(6-cyclobutylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid
3-[4-[(6-Cyclobutylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid methyl ester (37 mg, 0.092 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (33 mg, 93%).
1H NMR (500 MHz, CDCl3) δ 7.48(t, 1H), 7.18-7.13(m, 1H), 7.13-7.08(m, 2H), 7.00-6.95(m, 1H), 6.93-6.86(m, 2H), 5.11(s, 2H), 4.32-4.23(m, 1H), 2.89(t, 2H), 2.64(t, 2H), 2.60-2.47(m, 2H), 2.20-1.98(m, 4H)
Example 182: 3-[4-[(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
Step A: 3-[4-[(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid methyl ester
3-(4-Hydroxy-phenyl)-propionic acid methyl ester (20 mg, 0.11 mmol) obtained in Preparation Example 4 and 3-chloromethyl-2-cyclopropylmethyl sulfanyl-pyridine (23.72 mg, 0.11 mmol) obtained in Step C of Preparation Example 18 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (37 mg, 93%).
1H NMR (400 MHz, CDCl3) δ 8.40-8.34(m, 1H), 7.70-7.65(m, 1H), 7.15-7.10(m, 2H), 7.05-6.99(m, 1H), 6.93-6.88(m, 2H), 5.02(s, 2H), 3.66(s, 3H), 3.23(d, 2H), 2.90(t, 2H), 2.60(t, 2H), 1.22-1.10(m, 1H), 0.63-0.56(m, 2H), 0.38-0.30(m, 2H)
Step B: 3-[4-[(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-[4-[(2-Cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid methyl ester (37 mg, 0.104 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (34 mg, 96%).
1H NMR (500 MHz, CDCl3) δ 8.41-8.35(m, 1H), 7.71-7.66(m, 1H), 7.18-7.10(m, 2H), 7.05-6.99(m, 1H), 6.95-6.86(m, 2H), 5.02(s, 2H), 3.22(d, 2H), 2.90(t, 2H), 2.64(t, 2H), 1.21-1.10(m, 1H), 0.64-0.54(m, 2H), 0.37-0.27(m, 2H)
Example 183: 3-[4-[(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid
Step A: 3-[4-[(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid methyl ester
3-(4-Hydroxy-phenyl)-propionic acid methyl ester (20 mg, 0.11 mmol) obtained in Preparation Example 4 and 2-chloromethyl-6-cyclopropylmethyl sulfanyl-pyridine (23.72 mg, 0.11 mmol) obtained in Step D of Preparation Example 20 were used to react in the same manner as in Step A of Example 1 to obtain the title compound (36 mg, 91%).
1H NMR (400 MHz, CDCl3) δ 7.47(t, 1H), 7.17-7.14(m, 1H), 7.13-7.07(m, 3H), 6.93-6.88(m, 2H), 5.12(s, 2H), 3.66(s, 3H), 3.12(d, 2H), 2.89(t, 2H), 2.59(t, 2H), 1.20-1.10(m, 1H), 0.62-0.56(m, 2H), 0.35-0.29(m, 2H)
Step B: 3-[4-[(6-cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid
3-[4-[(6-Cyclopropylmethylsulfanyl-pyridin-2-ylmethoxy)-phenyl]-propionic acid methyl ester (36 mg, 0.10 mmol) obtained in Step A was reacted in the same manner as in Step B of Example 1 to obtain the title compound (34 mg, 98%).
1H NMR (500 MHz, CDCl3) δ 7.47(t, 1H), 7.19-7.14(m, 1H), 7.14-7.06(m, 3H), 6.93-6.87(m, 2H), 5.11(s, 2H), 3.12(d, 2H), 2.89(t, 2H), 2.64(t, 2H), 1.20-1.10(m, 1H), 0.62-0.54(m, 2H), 0.35-0.28(m, 2H)
Example 184: 3-[4-[(2-cyclopentylsulfanyl-6-methyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-cyclopentylsulfanyl-6-methyl-pyridine (31 mg, 0.13 mmol) obtained in Step C of Preparation Example 36 and 3-(4-hydroxy-phenyl)-propionic acid methyl ester (27 mg, 0.15 mmol) obtained in Preparation Example 4 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (32 mg, 63%).
1H NMR (CDCl3) 7.53(1H, m), 7.13(2H, m), 6.87(3H, m), 4.97(2H, s), 4.22(1H, m), 2.91(2H, t), 2.65(2H, t), 2.49(3H, s), 2.22(2H, m), 1.78(2H, m), 1.55(4H, m)
Example 185: 3-[4-[(2-isopropylsulfanyl-6-methyl-pyridin-3-ylmethoxy)-phenyl]-propionic acid
3-Chloromethyl-2-isopropylsulfanyl-6-methyl-pyridine (30 mg, 0.15 mmol) obtained in Step D of Preparation Example 9 and 3-(4-hydroxy-phenyl)-propionic acid methyl ester (30 mg, 0.16 mmol) obtained in Preparation Example 4 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (29 mg, 56%).
1H NMR (CDCl3) 7.54(1H, m), 7.13(1H, m), 6.87(3H, m), 4.97(2H, s), 4.19(1H, m), 2.91(2H, t), 2.66(2H, t), 2.50(3H, s), 1.41(6H, d)
Experimental Example 1: Measurement of activity of GPR120 agonist (cell-based assay)
CHO-K1 cells expressing Ga16 and hGPR120 were dispensed into each well of a 96-well plate (3 × 104 cells/100 ㎕/well) and then incubated in 5% CO2, 37℃ incubator for 18 hours. Each well was treated with 100 ㎕ of Calcium 5 dye (Molecular Devices) solution including 2% DMSO and then incubated in 5% CO2, 37℃ incubator for 1 hour. Serially diluted GPR120 agonists were prepared to a final concentration of 0.5% DMSO in a 96-well plate. Each well was treated with 50 ㎕ of the agonist compounds using Plexstation II, and then fluorescence was measured at Ex 485 ㎚, Em 525 ㎚.
Fluorescence increased by the serially diluted GPR120 agonists is calculated as a relative percent (%) value based on the fluorescence represented by the treatment of 0.1% DMSO only. EC50 refers to the concentration of agonist which shows 50% of maximum fluorescence increased by the treatment of agonist. The calculation of measurement was carried out by using statistical software (Prizm).
The agonistic effects of the Example compounds obtained by the above experiment are shown in the following Table 1 with EC50 unit (μM). Activity is denoted based on the following criteria:
A = >20 μM, B = 20~2 μM, C = 2~0.2 μM, D = <0.2 μM
As shown in the table, most of the novel compounds according to the present invention have superior GPR120 agonistic effects (EC50), lower than 0.2 μM.