2-[(2S)-piperazin-2-yl]ethanol

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

実験手順: In a manner such as that described in Example 300, combine 2-isopropyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.558 g, 1.89 mmol) and (S)-2-piperazin-2-yl-ethanol (0.493 g, 3.79 mmol) to obtain the title compound: mass spectrum (APCI): m/z=372.4 (M+1).

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

実験手順: Combine 2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.458 g, 1.72 mmol), (S)-2-piperazin-2-yl-ethanol (0.518, 3.98 mmol), diisopropylethylamine (0.346 mL, 1.99 mmol), dimethyl sulfoxide (1.5 mL) and toluene (4.5 mL) and heat to 110° C. for 48 hours. Evaporate the mixture and apply the material to 20 g of SCX, elute with methanol followed by 5% 2N ammonia-methanol in dichloromethane and finally 100% 2N ammonia-methanol. Purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 10% 2N ammonia-methanol in dichloromethane, to obtain (S)-2-[4-(2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-yl)-piperazin-2-yl]-ethanol (0.082 g, 0.239 mmol, 14%): mass spectrum (APCI): m/z=344.4 (M+1). Evaporate the mixture apply the material to 20 g of SCX, elute with methanol Purify by flash chromatography eluting with a step gradient

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

実験手順: By using a method similar to Example 258, using 7-chloro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride and (S)-2-(2-hydroxy-ethyl)-piperazine gives the title compound.

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve 6,7-difluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.51, 4.99 mmol), N,N-diisopropylethylamine (0.91 mL, 5.24 mmol) and (S)-2-piperazin-2-yl-ethanol (1.3 g, 9.99 mmol) in dimethylsulfoxide/toluene (1:2)(18 ml), stir under nitrogen and heat in an oil bath at 120° C. for 72 hours. Dilute the mixture with water (20 mL) and ethyl acetate (40 mL), separate layers and extract the aqueous with ethyl acetate. Combine all ethyl acetate extracts and wash with water and brine. Dry the organic phase (Na2SO4), filter and concentrate under reduced pressure. Purify by silica gel chromatography (eluent: 0-13% 2N ammonia in methanol/dichloromethane) to give 780 mg of impure product. Purify by silica gel chromatography (eluent: 85% dichloromethane/10% acetonitrile/0%2N ammonia in methanol to 80% dichloromethane/10% acetonitrile/10% 2N ammonia in methanol) to give the title compound (516 mg, 27%): Mass Spectrum (ESMS) 379 (M+1); 377 (M−1). separate layers extract the aqueous with ethyl acetate wash with water and brine Dry the organic phase (Na2SO4) filter concentrate under reduced pressure Purify by silica gel chromatography (eluent: 0-13% 2N ammonia in methanol/dichloromethane)

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

実験手順: Combine 6-fluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (2.94 g, 10.35 mmol), (S)-2-piperazin-2-yl-ethanol (2.7 g, 20.7 mmol), diisopropylethylamine (3.6 mL, 20.7 mmol), dimethyl sulfoxide (4.25 mL) and toluene (17 mL) and heat to 110° C. for 42 hours. Cool to ambient temperature and dilute with ethyl acetate (200 mL). Wash with saturated sodium bicarbonate solution, brine and evaporate to give 2.64 g of the crude product. Silica gel chromatography, eluting with methylene chloride: acetonitrile: 7N NH3/methanol (85:10:7), gives 0.523 g of the title compound as a brown solid foam: mass spectrum (ion spray): m/z=361 (M+1). Wash with saturated sodium bicarbonate solution, brine evaporate to give 2.64 g of the crude product Silica gel chromatography, eluting with methylene chloride

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

実験手順: Dissolve (S)-2-(1,4-dibenzylpiperazin-2-yl)ethanol (11.7 g, 0.038 mol) in 380 mL of ethanol, add 10% palladium on carbon (3.7 g of wet reagent, 50% by weight) as a suspension in a few mL of ethanol. Add excess ammonium formate (16.8 g, 0.27 mol) all at once. Heat at reflux for 5 h, cool to room temperature and filter through a celite pad, washing well with ethanol. Concentrate filtrate in vacuo to provide the title compound (5 g, quantitative) as a cloudy residue. Use directly on the next step without further purification: mass spectrum (APCI): m/z=131.1 (M+1). Heat at reflux for 5 h filter through a celite pad washing well with ethanol

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

実験手順: In a manner such as that described in Example 300, combine 2-isopropyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.558 g, 1.89 mmol) and (S)-2-piperazin-2-yl-ethanol (0.493 g, 3.79 mmol) to obtain the title compound: mass spectrum (APCI): m/z=372.4 (M+1).

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

実験手順: Combine 2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-ylamine hydrochloride (0.458 g, 1.72 mmol), (S)-2-piperazin-2-yl-ethanol (0.518, 3.98 mmol), diisopropylethylamine (0.346 mL, 1.99 mmol), dimethyl sulfoxide (1.5 mL) and toluene (4.5 mL) and heat to 110° C. for 48 hours. Evaporate the mixture and apply the material to 20 g of SCX, elute with methanol followed by 5% 2N ammonia-methanol in dichloromethane and finally 100% 2N ammonia-methanol. Purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 10% 2N ammonia-methanol in dichloromethane, to obtain (S)-2-[4-(2-methyl-4H-3-thia-1,4,9-triazabenzo[f]azulene-10-yl)-piperazin-2-yl]-ethanol (0.082 g, 0.239 mmol, 14%): mass spectrum (APCI): m/z=344.4 (M+1). Evaporate the mixture apply the material to 20 g of SCX, elute with methanol Purify by flash chromatography eluting with a step gradient

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

実験手順: By using a method similar to Example 258, using 7-chloro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride and (S)-2-(2-hydroxy-ethyl)-piperazine gives the title compound.

反応条件: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve 6,7-difluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (1.51, 4.99 mmol), N,N-diisopropylethylamine (0.91 mL, 5.24 mmol) and (S)-2-piperazin-2-yl-ethanol (1.3 g, 9.99 mmol) in dimethylsulfoxide/toluene (1:2)(18 ml), stir under nitrogen and heat in an oil bath at 120° C. for 72 hours. Dilute the mixture with water (20 mL) and ethyl acetate (40 mL), separate layers and extract the aqueous with ethyl acetate. Combine all ethyl acetate extracts and wash with water and brine. Dry the organic phase (Na2SO4), filter and concentrate under reduced pressure. Purify by silica gel chromatography (eluent: 0-13% 2N ammonia in methanol/dichloromethane) to give 780 mg of impure product. Purify by silica gel chromatography (eluent: 85% dichloromethane/10% acetonitrile/0%2N ammonia in methanol to 80% dichloromethane/10% acetonitrile/10% 2N ammonia in methanol) to give the title compound (516 mg, 27%): Mass Spectrum (ESMS) 379 (M+1); 377 (M−1). separate layers extract the aqueous with ethyl acetate wash with water and brine Dry the organic phase (Na2SO4) filter concentrate under reduced pressure Purify by silica gel chromatography (eluent: 0-13% 2N ammonia in methanol/dichloromethane)

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

実験手順: Combine 6-fluoro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride (2.94 g, 10.35 mmol), (S)-2-piperazin-2-yl-ethanol (2.7 g, 20.7 mmol), diisopropylethylamine (3.6 mL, 20.7 mmol), dimethyl sulfoxide (4.25 mL) and toluene (17 mL) and heat to 110° C. for 42 hours. Cool to ambient temperature and dilute with ethyl acetate (200 mL). Wash with saturated sodium bicarbonate solution, brine and evaporate to give 2.64 g of the crude product. Silica gel chromatography, eluting with methylene chloride: acetonitrile: 7N NH3/methanol (85:10:7), gives 0.523 g of the title compound as a brown solid foam: mass spectrum (ion spray): m/z=361 (M+1). Wash with saturated sodium bicarbonate solution, brine evaporate to give 2.64 g of the crude product Silica gel chromatography, eluting with methylene chloride

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

実験手順: Dissolve (S)-2-(1,4-dibenzylpiperazin-2-yl)ethanol (11.7 g, 0.038 mol) in 380 mL of ethanol, add 10% palladium on carbon (3.7 g of wet reagent, 50% by weight) as a suspension in a few mL of ethanol. Add excess ammonium formate (16.8 g, 0.27 mol) all at once. Heat at reflux for 5 h, cool to room temperature and filter through a celite pad, washing well with ethanol. Concentrate filtrate in vacuo to provide the title compound (5 g, quantitative) as a cloudy residue. Use directly on the next step without further purification: mass spectrum (APCI): m/z=131.1 (M+1). Heat at reflux for 5 h filter through a celite pad washing well with ethanol