2-(2-chloroethyl)-1-methylpyrrolidine;hydrochloride

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

実験手順: A mixture of 7-nitro-3,4-dihydro-2H-benzo[b][1,4]thiazine (1 g, 5.10 mmol), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (1.876 g, 10.19 mmol), and tetrabutylammonium bromide (0.082 g, 0.255 mmol) in dichloromethane (10 mL) and 50% NaOH solution (10 mL) was stirred at room temperature for 16 hours (overnight). The reaction was then diluted with dichloromethane (5 mL) and water (20 mL), and the mixture was transferred to a separatory funnel. The organic layer was removed, and the aqueous layer was extracted into dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The red crude material was subjected to column chromatography on silica gel using the Biotage purification system (80 g silicycle column; gradient: dichloromethane 3CV then ramp to 6:94 (2M NH3 in methanol):dichloromethane over 15CV; 254 nm; flow: 45 mL/min) to give the title compound as yellow-orange solid (0.827 g, 52.8%). 1H-NMR (DMSO-d6) δ 7.87 (dd, J=3.0, 9.0 Hz, 1H), 7.83 (d, J=3.0 Hz, 1H), 6.79 (d, J=9.3 Hz, 1H), 3.79-3.76 (m, 2H), 3.46 (t, J=8.1 Hz, 2H), 3.08-3.05 (m, 2H), 2.99-2.92 (m, 1H), 2.23 (s, 3H), 2.10-2.06 (m, 2H), 1.92-1.78 (m, 2H), 1.66-1.61 (m, 2H), 1.54-1.47 (m, 2H); ESI-MS (m/z, %): 308 (MH+, 100). the mixture was transferred to a separatory funnel The organic layer was removed the aqueous layer was extracted into dichloromethane (2×10 mL) The combined organic layers were dried (Na2SO4) filtered concentrated the Biotage purification system (80 g silicycle column

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

実験手順: A suspension of 7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (0.5 g, 2.575 mmol), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (0.94 g, 5.150 mmol), NaI (0.19 g, 1.287 mmol), and K2CO3 (2.13 g, 15.452 mmol) in dry DMF (10 mL) was stirred at room temperature overnight (18 hours). The reaction was diluted with water (150 mL), and the product was extracted into ethyl acetate (2×25 mL). The combined ethyl acetate layers were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the crude material was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2) to obtain the title compound (0.525 g, 67%) as a yellow solid. 1H NMR (DMSO-d6) δ 1.47-1.65 (m, 4H), 1.79-2.13 (m, 4H), 2.18 (s, 3H), 2.89-2.95 (m, 1H), 3.98 (t, 2H, J=7.8 Hz), 4.79 (s, 2H), 7.40 (d, 1H, J=9.0 Hz), 7.80 (d, 1H, J=2.7 Hz), 7.98 (dd, 1H, J=2.4, 9.0 Hz); ESI-MS (m/z, %): 306 (MH+, 100). the product was extracted into ethyl acetate (2×25 mL) The combined ethyl acetate layers were washed with brine (20 mL) dried (Na2SO4) The solvent was evaporated the crude material was purified by column chromatography (3:97 (2M NH3 in MeOH):CH2Cl2)

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

実験手順: 3-aminophenol (0.74 g, 6.8 mmol) in DMF (10 ml) was added dropwise to 95% NaH (0.49 g, 20.4 mmol) in 10 ml DMF at 0° C., under nitrogen. The reaction was stirred until H2(g) evolution ceased. 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (1.25 g, 6.8 mmol) was then added portionwise. The mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with 1N NaOH (50 ml) and the desired product extracted into ether (3×50 ml). The combined ether layers were washed (2×50 ml) with water, dried over MgSO4, and evaporated to dryness in vacuo. The residue was purified on silica gel by flash chromatography using 2% TEA in ethyl acetate to give an oil. The mixture was stirred at room temperature for 18 h The reaction mixture was quenched with 1N NaOH (50 ml) the desired product extracted into ether (3×50 ml) The combined ether layers were washed (2×50 ml) with water dried over MgSO4 evaporated to dryness in vacuo The residue was purified on silica gel by flash chromatography to give an oil

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

実験手順: According to Example 34, the compound (100 mg) produced in Example 37 was reacted with 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (54 mg) to obtain the ring expanding title compound (46 mg; 37%). to obtain the ring

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

実験手順: According to Example 34, the compound (100 mg) produced in Example 37 was reacted with 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (54 mg) to obtain the ring expanding title compound (46 mg; 37%). to obtain the ring

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

実験手順: 1.06 g of potassium t-butoxide were added to a solution of 1.00 g of 2-[2-(3-chlorophenyl)ethyl]phenol (prepared as described in Preparation 44) in 20 ml of dimethylacetamide, whilst cooling by ice and sodium chloride and stirring. 0.949 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochoride was then added to the solution, and the mixture was stirred at 50° C. for 3 hours. At the end of this time, the reaction mixture was cooled, and 100 ml of ethyl acetate and 50 ml of water were added to the mixture, which was then shaken. The ethyl acetate layer was separated, washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate layer was then concentrated by distillation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.770 g (yield 52%) of the title compound as a colorless oil. the mixture was stirred at 50° C. for 3 hours At the end of this time, the reaction mixture was cooled was then shaken The ethyl acetate layer was separated washed twice with a saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate The ethyl acetate layer was then concentrated by distillation under reduced pressure the concentrate was purified by column chromatography through silica gel by volume mixture of methylene chloride and methanol as the eluent

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

実験手順: 1.06 g of potassium t-butoxide were added to a solution of 1.00 g of 2-[2-(3-chlorophenyl)ethyl]phenol (prepared as described in Preparation 44) in 20 ml of dimethylacetamide, whilst cooling by ice and sodium chloride and stirring. 0.949 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochoride was then added to the solution, and the mixture was stirred at 50° C. for 3 hours. At the end of this time, the reaction mixture was cooled, and 100 ml of ethyl acetate and 50 ml of water were added to the mixture, which was then shaken. The ethyl acetate layer was separated, washed twice with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate layer was then concentrated by distillation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.770 g (yield 52%) of the title compound as a colorless oil. the mixture was stirred at 50° C. for 3 hours At the end of this time, the reaction mixture was cooled was then shaken The ethyl acetate layer was separated washed twice with a saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate The ethyl acetate layer was then concentrated by distillation under reduced pressure the concentrate was purified by column chromatography through silica gel by volume mixture of methylene chloride and methanol as the eluent

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

実験手順: 1.48 g of potassium t-butoxide were added to a solution of 1.35 g of 2-[4-(3-methoxyphenyl)butyl]phenol (prepared as described in Preparation 7) in 20 ml of dimethylacetamide, whilst ice-cooling and stirring. 1.45 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochoride were then added to the solution, and the mixture was stirred at 55° C. for 2 hours. At the end of this time, the reaction mixture was cooled, 200 ml of ethyl acetate and 100 ml of water were added to the mixture, and the mixture was shaken. The ethyl acetate layer was separated, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The ethyl acetate layer was then concentrated by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.92 g (yield 48%) of the title compound as an oil. cooling the mixture was stirred at 55° C. for 2 hours At the end of this time, the reaction mixture was cooled the mixture was shaken The ethyl acetate layer was separated washed with a saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate The ethyl acetate layer was then concentrated by distillation under reduced pressure the resulting residue was purified by column chromatography through silica gel by volume mixture of methylene chloride and methanol as the eluent

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

実験手順: Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(3,4,5-trimethoxyphenyl)ethyl]phenol (prepared as described in Preparation 28), 1.18 g of potassium t-butoxide and 0.958 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.900 g (yield 65%) of the title compound as a colorless oil. the crude product thus obtained was purified by column chromatography through silica gel by volume mixture of methylene chloride and methanol as the eluent

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

実験手順: Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(3,5-dimethoxyphenyl)ethyl]phenol (prepared as described in Preparation 27), 1.30 g of potassium t-butoxide and 1.06 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.15 g (yield 80%) of the title compound as a colorless oil. the crude product thus obtained was purified by column chromatography through silica gel by volume mixture of methylene chloride and methanol as the eluent

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

実験手順: Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(2-methylphenyl)ethyl]phenol (prepared as described in Preparation 24), 1.59 g of potassium t-butoxide and 1.73 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 350 mg (yield 23%) of the title compound as a solid. the crude product thus obtained was purified by column chromatography through silica gel by volume mixture of methylene chloride and methanol as the eluent

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

実験手順: Following a procedure similar to that described in Example 35(a), 1.00 g of 2-[2-(2-methylphenyl)ethyl]phenol (prepared as described in Preparation 24), 1.59 g of potassium t-butoxide and 1.73 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 10 ml of dimethylacetamide. The mixture was then worked up as described in Example 35(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 350 mg (yield 23%) of the title compound as a solid. the crude product thus obtained was purified by column chromatography through silica gel by volume mixture of methylene chloride and methanol as the eluent