2-[(2S)-4-benzylpiperazin-2-yl]ethanol

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared as the trifluoroacetic acid salt according to the procedure outlined in Example 133 substituting 1-bromo-2-fluorobenzene for 1-bromo-2-fluoro-4-methylbenzene and Example 255E for (S)-2-(4-benzylpiperazin-2-yl)ethanol. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.85-7.05 (m, 3H), 6.74-6.85 (m, 1H), 4.29-4.45 (m, 1H), 4.01-4.16 (m, 1H), 3.21-3.48 (m, 4H), 2.89-3.21 (m, 3H), 1.87-2.14 (m, 2H); MS (ESI) m/z 223 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round bottom flask was charged with (S)-2-(4-benzylpiperazin-2-yl)ethanol (1.0 g, 4.5 mmol), 2-bromo-5-methoxyphenol (1.0 g, 5.0 mmol), di-tert-butyl azodicarboxylate (1.57 g, 6.81 mmol), polymer-supported triphenylphosphine resin (4.354 g, 9.08 mmol) and tetrahydrofuran (30 mL). The reaction stirred for 16 hours. The resin was removed via filtration and the solution was concentrated. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. The resin was removed via filtration the solution was concentrated Purification via flash chromatography (0-30% methanol/dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round bottom flask was charged with (S)-2-(4-benzylpiperazin-2-yl)ethanol (1.5 g, 6.8 mmol), 2-bromo-6-methylphenol (1.4 g, 7.5 mmol), di-tert-butyl azodicarboxylate (DBAD, 2.4 g, 10.2 mmol), polymer supported-triphenylphosphine (3.8 g, 13.6 mmol) and tetrahydrofuran (30 mL). The reaction stirred for 16 hours. The resin was removed via filtration and the solution was concentrated. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. The resin was removed via filtration the solution was concentrated Purification via flash chromatography (0-30% methanol/dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round bottom flask was charged with (S)-2-(4-benzylpiperazin-2-yl)ethanol (1.5 g, 6.8 mmol), 2-bromo-6-methylphenol (1.4 g, 7.5 mmol), di-tert-butyl azodicarboxylate (DBAD, 2.4 g, 10.2 mmol), polymer supported-triphenylphosphine (3.8 g, 13.6 mmol) and tetrahydrofuran (30 mL). The reaction stirred for 16 hours. The resin was removed via filtration and the solution was concentrated. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. The resin was removed via filtration the solution was concentrated Purification via flash chromatography (0-30% methanol/dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 0° C. solution of (S)-(4-benzyl-3,6-dioxopiperazin-2-yl)acetic acid methyl ester (31.9 g, 0.12 mol) in tetrahydrofuran (1 L), add lithium aluminum hydride via slow cannulation (350 mL of a commercial 1.0 M solution in tetrahydrofuran). Stir at room temperature overnight, quench by successive careful addition of 13.3 mL of water, 13.3 mL of 15% aqueous sodium hydroxyde, and 39.9 mL of water, all the while with vigourous stirring to ensure formation of a fine precipitate. Filter through a fritted funnel, washing the solids well with tetrahydrofuran and dichloromethane. Concentrate in vacuo to provide 26.5 g of an oily residue, apply directly to a silica gel column. Elute with a 5% mixture of 7N ammonia-methanol in dichloromethane, to obtain the desired product as an orange oil which solidifies under vacuum. Take up the solid in acetonitrile and sonicate for a few minutes. Filter the resulting precipitate to obtain 7.5 g (25%) of the title compound as an off-white crystalline solid, mp 78.9-80.4° C. Concentrate the mother liquor to obtain 6.8 g (23%) of slightly less pure material as an amorphous solid: mass spectrum (ES): m/e 221.3 (M+1); specific Rotation: −7.84. quench by successive careful addition of 13.3 mL of water, 13.3 mL of 15% aqueous sodium hydroxyde, and 39.9 mL of water, all the while with vigourous stirring Filter through a fritted funnel washing the solids well with tetrahydrofuran and dichloromethane Concentrate in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 0° C. solution of (S)-(4-benzyl-3,6-dioxopiperazin-2-yl)acetic acid methyl ester (31.9 g, 0.12 mol) in tetrahydrofuran (1 L), add lithium aluminum hydride via slow cannulation (350 mL of a commercial 1.0 M solution in tetrahydrofuran). Stir at room temperature overnight, quench by successive careful addition of 13.3 mL of water, 13.3 mL of 15% aqueous sodium hydroxyde, and 39.9 mL of water, all the while with vigourous stirring to ensure formation of a fine precipitate. Filter through a fritted funnel, washing the solids well with tetrahydrofuran and dichloromethane. Concentrate in vacuo to provide 26.5 g of an oily residue, apply directly to a silica gel column. Elute with a 5% mixture of 7N ammonia-methanol in dichloromethane, to obtain the desired product as an orange oil which solidifies under vacuum. Take up the solid in acetonitrile and sonicate for a few minutes. Filter the resulting precipitate to obtain 7.5 g (25%) of the title compound as an off-white crystalline solid, mp 78.9-80.4° C. Concentrate the mother liquor to obtain 6.8 g (23%) of slightly less pure material as an amorphous solid: mass spectrum (ES): m/e 221.3 (M+1); specific Rotation: −7.84. quench by successive careful addition of 13.3 mL of water, 13.3 mL of 15% aqueous sodium hydroxyde, and 39.9 mL of water, all the while with vigourous stirring Filter through a fritted funnel washing the solids well with tetrahydrofuran and dichloromethane Concentrate in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-2-(4-benzylpiperazin-2-yl)ethanol (150 mg, 0.681 mmol) and 1-bromo-2-fluoro-4-methylbenzene (167 mg, 885 mmol) in dimethyl sulfoxide (5 mL) was added sodium tert-butoxide (164 mg, 1.70 mmol). The reaction mixture was allowed to stir for 16 hours at room temperature before addition of water and ethyl acetate. The organic layer was separated and concentrated onto silica gel. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.40 (d, J=7.80 Hz, 1 H), 7.18-7.35 (m, 5 H), 6.92 (d, J=1.36 Hz, 1 H), 6.65-6.73 (m, 1 H), 4.08 (t, J=6.44 Hz, 2 H), 3.36-3.51 (m, 2 H), 2.55-2.89 (m, 6 H), 1.87-1.99 (m, 1 H), 1.68-1.77 (m, 2 H); MS (APCI+) m/z 389, 391 (M+H)+. The organic layer was separated concentrated onto silica gel Purification via flash chromatography (0-30% methanol/dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of (S)-2-(4-benzylpiperazin-2-yl)ethanol (150 mg, 0.681 mmol) and 1-bromo-2-fluoro-4-methylbenzene (167 mg, 885 mmol) in dimethyl sulfoxide (5 mL) was added sodium tert-butoxide (164 mg, 1.70 mmol). The reaction mixture was allowed to stir for 16 hours at room temperature before addition of water and ethyl acetate. The organic layer was separated and concentrated onto silica gel. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.40 (d, J=7.80 Hz, 1H), 7.18-7.35 (m, 5H) 6.92 (d, J=1.36 Hz, 1H), 6.65-6.73 (m, 1H), 4.08 (t, J=6.44 Hz, 2H), 3.36-3.51 (m, 2H), 2.55-2.89 (m, 6H),1.87-1.99 (m, 1H), 1.68-1.77 (m, 2H); MS (APCI+) m/z 389, 391 (M+H)+. The organic layer was separated concentrated onto silica gel Purification via flash chromatography (0-30% methanol/dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared as the trifluoroacetic acid salt according to the procedure outlined in Example 133 substituting 1-bromo-2-fluorobenzene for 1-bromo-2-fluoro-4-methylbenzene and Example 255E for (S)-2-(4-benzylpiperazin-2-yl)ethanol. 1H NMR (300 MHz, DMSO-d6) δ ppm 6.85-7.05 (m, 3H), 6.74-6.85 (m, 1H), 4.29-4.45 (m, 1H), 4.01-4.16 (m, 1H), 3.21-3.48 (m, 4H), 2.89-3.21 (m, 3H), 1.87-2.14 (m, 2H); MS (ESI) m/z 223 (M+H)+.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round bottom flask was charged with (S)-2-(4-benzylpiperazin-2-yl)ethanol (1.0 g, 4.5 mmol), 2-bromo-5-methoxyphenol (1.0 g, 5.0 mmol), di-tert-butyl azodicarboxylate (1.57 g, 6.81 mmol), polymer-supported triphenylphosphine resin (4.354 g, 9.08 mmol) and tetrahydrofuran (30 mL). The reaction stirred for 16 hours. The resin was removed via filtration and the solution was concentrated. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. The resin was removed via filtration the solution was concentrated Purification via flash chromatography (0-30% methanol/dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A round bottom flask was charged with (S)-2-(4-benzylpiperazin-2-yl)ethanol (1.5 g, 6.8 mmol), 2-bromo-6-methylphenol (1.4 g, 7.5 mmol), di-tert-butyl azodicarboxylate (DBAD, 2.4 g, 10.2 mmol), polymer supported-triphenylphosphine (3.8 g, 13.6 mmol) and tetrahydrofuran (30 mL). The reaction stirred for 16 hours. The resin was removed via filtration and the solution was concentrated. Purification via flash chromatography (0-30% methanol/dichloromethane) afforded the title compound. The resin was removed via filtration the solution was concentrated Purification via flash chromatography (0-30% methanol/dichloromethane)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 0° C. solution of (S)-(4-benzyl-3,6-dioxopiperazin-2-yl)acetic acid methyl ester (31.9 g, 0.12 mol) in tetrahydrofuran (1 L), add lithium aluminum hydride via slow cannulation (350 mL of a commercial 1.0 M solution in tetrahydrofuran). Stir at room temperature overnight, quench by successive careful addition of 13.3 mL of water, 13.3 mL of 15% aqueous sodium hydroxyde, and 39.9 mL of water, all the while with vigourous stirring to ensure formation of a fine precipitate. Filter through a fritted funnel, washing the solids well with tetrahydrofuran and dichloromethane. Concentrate in vacuo to provide 26.5 g of an oily residue, apply directly to a silica gel column. Elute with a 5% mixture of 7N ammonia-methanol in dichloromethane, to obtain the desired product as an orange oil which solidifies under vacuum. Take up the solid in acetonitrile and sonicate for a few minutes. Filter the resulting precipitate to obtain 7.5 g (25%) of the title compound as an off-white crystalline solid, mp 78.9-80.4° C. Concentrate the mother liquor to obtain 6.8 g (23%) of slightly less pure material as an amorphous solid: mass spectrum (ES): m/e 221.3 (M+1); specific Rotation: −7.84. quench by successive careful addition of 13.3 mL of water, 13.3 mL of 15% aqueous sodium hydroxyde, and 39.9 mL of water, all the while with vigourous stirring Filter through a fritted funnel washing the solids well with tetrahydrofuran and dichloromethane Concentrate in vacuo