ethyl azetidine-3-carboxylate;hydrochloride

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.45 g, 1.57 mmol) was dissolved in dichloromethane (15 ml), then diisopropylethylamine (0.6 ml, 3.53 mmol) and ethyl azetidine-3-carboxylate hydrochloride (I-147) (0.55 g) were added. After heated under reflux for 3 hours, this was diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a brown oil (0.60 g, quant). After heated under reflux for 3 hours After washing with water drying over anhydrous sodium sulfate the solvent was evaporated away under reduced pressure the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a brown oil (0.60 g, quant)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.45 g, 1.57 mmol) was dissolved in dichloromethane (15 ml), then diisopropylethylamine (0.6 ml, 3.53 mmol) and ethyl azetidine-3-carboxylate hydrochloride (I-147) (0.55 g) were added. After heated under reflux for 3 hours, this was diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a brown oil (0.60 g, quant). After heated under reflux for 3 hours After washing with water drying over anhydrous sodium sulfate the solvent was evaporated away under reduced pressure the resulting residue was purified by silica gel column chromatography (dichloromethane to dichloromethane:methanol=70:1) to obtain a brown oil (0.60 g, quant)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of {4-[3-(4-isobutylphenyl)isoxazol-5-yl]-2-thienyl}methanol (0.43 g, 1.4 mmol) that was obtained in Example 9 (9g), carbon tetrabromide (0.68 g, 2.1 mmol) and triphenylphosphine (0.54 g, 2.1 mmol) in dichloromethane (15 ml) was stirred at 0° C. for 5 minutes. Subsequently, to the reaction mixture were added successively ethyl 3-azetidinecarboxylate hydrochloride (0.34 mg, 2.1 mmol) and N,N-diisopropylethylamine (0.60 ml, 3.4 mmol) with stirring, and the resulting mixture was stirred at room temperature for 18 hours. After stirring, a saturated aqueous solution of sodium hydrogencarbonate (5 ml) was added to the reaction mixture to quench the reaction, and the resulting mixture was poured into water (50 ml) and extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:4 to 3:2) as the eluent to afford the title compound (0.48 g) in a yield of 82% as a white crystalline solid. with stirring the resulting mixture was stirred at room temperature for 18 hours After stirring to quench the reaction extracted with dichloromethane The extract was washed with a saturated aqueous solution of sodium chloride dried over magnesium sulfate After filtration the filtrate was evaporated in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using 2-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-4,5,6,7-tetrahydro-1-benzothiophen-4-ol (92 mg, 0.26 mmol) that was obtained in Example 8 (8f), carbon tetrabromide (0.10 g, 0.31 mmol), triphenylphosphine (81 mg, 0.31 mmol), ethyl 3-azetidinecarboxylate hydrochloride (65 mg, 0.39 mmol), and N,N-diisopropylethylamine (0.14 ml, 0.78 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1) as the eluent to afford the title compound (44 mg) in a yield of 36% as a colourless oily product. the similar reaction to

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using 2-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-4,5,6,7-tetrahydro-1-benzofuran-4-ol (0.15 g, 0.45 mmol) that was obtained in Example 7 (7e), carbon tetrabromide (0.30 g, 0.90 mmol), triphenylphosphine (0.24 g, 0.90 mmol), ethyl 3-azetidinecarboxylate hydrochloride (0.11 g, 0.68 mmol), and N,N-diisopropylethylamine (0.20 ml, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:3) as the developing solvent to afford the title compound (27 mg) in a yield of 13% as a white crystalline solid. the similar reaction to

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using 2-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-4,5,6,7-tetrahydro-1-benzofuran-4-ol (0.15 g, 0.45 mmol) that was obtained in Example 7 (7e), carbon tetrabromide (0.30 g, 0.90 mmol), triphenylphosphine (0.24 g, 0.90 mmol), ethyl 3-azetidinecarboxylate hydrochloride (0.11 g, 0.68 mmol), and N,N-diisopropylethylamine (0.20 ml, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:3) as the developing solvent to afford the title compound (27 mg) in a yield of 13% as a white crystalline solid. the similar reaction to

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using {4-[5-(4-benzylphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (95 mg, 0.27 mmol) that was obtained in Example 6 (6a), carbon tetrabromide (0.18 g, 0.54 mmol), triphenylphosphine (0.14 g, 0.54 mmol), ethyl 3-azetidinecarboxylate hydrochloride (67 mg, 0.41 mmol), and N,N-diisopropylethylamine (0.12 ml, 0.68 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (6:4) as the developing solvent to afford the title compound (84 mg) in a yield of 68% as a white crystalline solid. the similar reaction to

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using {5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (97 m g, 0.28 mmol) that was obtained in Example 5 (5a), carbon tetrabromide (0.19 g, 0.56 mmol), triphenylphosphine (0.15 g, 0.56 mmol), ethyl 3-azetidinecarboxylate hydrochloride (70 mg, 0.42 mmol), and N,N-diisopropylethylamine (0.18 ml, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:3) as the developing solvent to afford the title compound (93 mg) in a yield of 72% as a colourless oily product. the similar reaction to

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using {5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol (97 m g, 0.28 mmol) that was obtained in Example 5 (5a), carbon tetrabromide (0.19 g, 0.56 mmol), triphenylphosphine (0.15 g, 0.56 mmol), ethyl 3-azetidinecarboxylate hydrochloride (70 mg, 0.42 mmol), and N,N-diisopropylethylamine (0.18 ml, 1.1 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:3) as the developing solvent to afford the title compound (93 mg) in a yield of 72% as a colourless oily product. the similar reaction to

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using (5-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.12 g, 0.29 mmol) that was obtained in Example 4 (4c), carbon tetrabromide (0.19 g, 0.58 mmol), triphenylphosphine (0.15 g, 0.58 mmol), ethyl 3-azetidinecarboxylate hydrochloride (62 mg, 0.38 mmol), and N,N-diisopropylethylamine (0.13 ml, 0.73 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:5) as the developing solvent to afford the title compound (0.12 g) in a yield of 80% as a colourless oily product. the similar reaction to

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using (5-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.12 g, 0.29 mmol) that was obtained in Example 4 (4c), carbon tetrabromide (0.19 g, 0.58 mmol), triphenylphosphine (0.15 g, 0.58 mmol), ethyl 3-azetidinecarboxylate hydrochloride (62 mg, 0.38 mmol), and N,N-diisopropylethylamine (0.13 ml, 0.73 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (4:5) as the developing solvent to afford the title compound (0.12 g) in a yield of 80% as a colourless oily product. the similar reaction to

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1f) using (4-{5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-1,2,4-oxadiazol-3-yl}-2-thienyl)methanol (0.10 g, 0.25 mmol) that was obtained in Example 3 (3c), carbon tetrabromide (0.17 g, 0.50 mmol), triphenylphosphine (0.13 g, 0.50 mmol), ethyl 3-azetidinecarboxylate hydrochloride (62 mg, 0.38 mmol), and N,N-diisopropylethylamine (0.11 ml, 0.63 mmol). Subsequently, the crude product of the title compound thus obtained was purified by thin layer chromatography on a silica gel plate using a mixed solvent of ethyl acetate and hexane (2:3) as the developing solvent to afford the title compound (73 mg) in a yield of 56% as a white crystalline solid. the similar reaction to