哌嗪-2,6-二酮盐酸盐

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N,N-Diisopropylethylamine (0.29 mL, 1.7 mmol), piperazine-2,6-dione hydrochloride (88 mg, 0.58 mmol), EDCI (112 mg, 0.58 mmol) and HOBt (79 mg, 0.58 mmol) were successively added to a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (which may be prepared in accordance with the experimental described in Example 4, step 4; 150 mg, 0.48 mmol) in dichloromethane (1.6 mL). The reaction mixture was stirred at room temperature overnight then diluted by addition of dichloromethane (20 mL) and a saturated solution of ammonium chloride (20 mL). After separation, the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were washed with a saturated solution of sodium hydrogen carbonate (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (95:5 to 90:10) as eluent. The title product was obtained as a beige solid (130 mg, 66%). may be prepared in accordance with the After separation the aqueous layer was extracted with dichloromethane (2×20 mL) The combined organic phases were washed with a saturated solution of sodium hydrogen carbonate (20 mL) dried over sodium sulfate filtered concentrated under vacuum The residue was purified by chromatography on silica gel

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-benzylpiperazine-2,6-dione (which may be prepared in accordance with the experimental described in Example 4, step 1; 2.0 g, 9.8 mmol) in a mixture of methanol/H2O (65 mL/28 mL) were added a solution of HCl 1N in methanol (23.8 mL) and Pd/C (10% wet, 0.2% wt., 400 mg). The reaction mixture was degassed 3 times with hydrogen/vacuum prior to its overnight stirring under hydrogen (P=1 atm). The reaction mixture was then filtered on Clarcel® and washed with methanol. The filtrate was finally concentrated to dryness and the residue was precipitated from a mixture of methanol and ether. The title product was obtained as a beige solid (418 mg, 28%). The reaction mixture was degassed 3 times with hydrogen/vacuum The reaction mixture was then filtered on Clarcel® washed with methanol The filtrate was finally concentrated to dryness the residue was precipitated from a mixture of methanol and ether

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N,N-Diisopropylethylamine (0.29 mL, 1.7 mmol), piperazine-2,6-dione hydrochloride (88 mg, 0.58 mmol), EDCI (112 mg, 0.58 mmol) and HOBt (79 mg, 0.58 mmol) were successively added to a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (which may be prepared in accordance with the experimental described in Example 4, step 4; 150 mg, 0.48 mmol) in dichloromethane (1.6 mL). The reaction mixture was stirred at room temperature overnight then diluted by addition of dichloromethane (20 mL) and a saturated solution of ammonium chloride (20 mL). After separation, the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were washed with a saturated solution of sodium hydrogen carbonate (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (95:5 to 90:10) as eluent. The title product was obtained as a beige solid (130 mg, 66%). may be prepared in accordance with the After separation the aqueous layer was extracted with dichloromethane (2×20 mL) The combined organic phases were washed with a saturated solution of sodium hydrogen carbonate (20 mL) dried over sodium sulfate filtered concentrated under vacuum The residue was purified by chromatography on silica gel

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-benzylpiperazine-2,6-dione (which may be prepared in accordance with the experimental described in Example 4, step 1; 2.0 g, 9.8 mmol) in a mixture of methanol/H2O (65 mL/28 mL) were added a solution of HCl 1N in methanol (23.8 mL) and Pd/C (10% wet, 0.2% wt., 400 mg). The reaction mixture was degassed 3 times with hydrogen/vacuum prior to its overnight stirring under hydrogen (P=1 atm). The reaction mixture was then filtered on Clarcel® and washed with methanol. The filtrate was finally concentrated to dryness and the residue was precipitated from a mixture of methanol and ether. The title product was obtained as a beige solid (418 mg, 28%). The reaction mixture was degassed 3 times with hydrogen/vacuum The reaction mixture was then filtered on Clarcel® washed with methanol The filtrate was finally concentrated to dryness the residue was precipitated from a mixture of methanol and ether

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N,N-Diisopropylethylamine (0.29 mL, 1.7 mmol), piperazine-2,6-dione hydrochloride (88 mg, 0.58 mmol), EDCI (112 mg, 0.58 mmol) and HOBt (79 mg, 0.58 mmol) were successively added to a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (which may be prepared in accordance with the experimental described in Example 4, step 4; 150 mg, 0.48 mmol) in dichloromethane (1.6 mL). The reaction mixture was stirred at room temperature overnight then diluted by addition of dichloromethane (20 mL) and a saturated solution of ammonium chloride (20 mL). After separation, the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were washed with a saturated solution of sodium hydrogen carbonate (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (95:5 to 90:10) as eluent. The title product was obtained as a beige solid (130 mg, 66%). may be prepared in accordance with the After separation the aqueous layer was extracted with dichloromethane (2×20 mL) The combined organic phases were washed with a saturated solution of sodium hydrogen carbonate (20 mL) dried over sodium sulfate filtered concentrated under vacuum The residue was purified by chromatography on silica gel

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-benzylpiperazine-2,6-dione (which may be prepared in accordance with the experimental described in Example 4, step 1; 2.0 g, 9.8 mmol) in a mixture of methanol/H2O (65 mL/28 mL) were added a solution of HCl 1N in methanol (23.8 mL) and Pd/C (10% wet, 0.2% wt., 400 mg). The reaction mixture was degassed 3 times with hydrogen/vacuum prior to its overnight stirring under hydrogen (P=1 atm). The reaction mixture was then filtered on Clarcel® and washed with methanol. The filtrate was finally concentrated to dryness and the residue was precipitated from a mixture of methanol and ether. The title product was obtained as a beige solid (418 mg, 28%). The reaction mixture was degassed 3 times with hydrogen/vacuum The reaction mixture was then filtered on Clarcel® washed with methanol The filtrate was finally concentrated to dryness the residue was precipitated from a mixture of methanol and ether

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N,N-Diisopropylethylamine (0.29 mL, 1.7 mmol), piperazine-2,6-dione hydrochloride (88 mg, 0.58 mmol), EDCI (112 mg, 0.58 mmol) and HOBt (79 mg, 0.58 mmol) were successively added to a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (which may be prepared in accordance with the experimental described in Example 4, step 4; 150 mg, 0.48 mmol) in dichloromethane (1.6 mL). The reaction mixture was stirred at room temperature overnight then diluted by addition of dichloromethane (20 mL) and a saturated solution of ammonium chloride (20 mL). After separation, the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were washed with a saturated solution of sodium hydrogen carbonate (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (95:5 to 90:10) as eluent. The title product was obtained as a beige solid (130 mg, 66%). may be prepared in accordance with the After separation the aqueous layer was extracted with dichloromethane (2×20 mL) The combined organic phases were washed with a saturated solution of sodium hydrogen carbonate (20 mL) dried over sodium sulfate filtered concentrated under vacuum The residue was purified by chromatography on silica gel

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-benzylpiperazine-2,6-dione (which may be prepared in accordance with the experimental described in Example 4, step 1; 2.0 g, 9.8 mmol) in a mixture of methanol/H2O (65 mL/28 mL) were added a solution of HCl 1N in methanol (23.8 mL) and Pd/C (10% wet, 0.2% wt., 400 mg). The reaction mixture was degassed 3 times with hydrogen/vacuum prior to its overnight stirring under hydrogen (P=1 atm). The reaction mixture was then filtered on Clarcel® and washed with methanol. The filtrate was finally concentrated to dryness and the residue was precipitated from a mixture of methanol and ether. The title product was obtained as a beige solid (418 mg, 28%). The reaction mixture was degassed 3 times with hydrogen/vacuum The reaction mixture was then filtered on Clarcel® washed with methanol The filtrate was finally concentrated to dryness the residue was precipitated from a mixture of methanol and ether

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: N,N-Diisopropylethylamine (0.29 mL, 1.7 mmol), piperazine-2,6-dione hydrochloride (88 mg, 0.58 mmol), EDCI (112 mg, 0.58 mmol) and HOBt (79 mg, 0.58 mmol) were successively added to a solution of 4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoic acid (which may be prepared in accordance with the experimental described in Example 4, step 4; 150 mg, 0.48 mmol) in dichloromethane (1.6 mL). The reaction mixture was stirred at room temperature overnight then diluted by addition of dichloromethane (20 mL) and a saturated solution of ammonium chloride (20 mL). After separation, the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were washed with a saturated solution of sodium hydrogen carbonate (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (95:5 to 90:10) as eluent. The title product was obtained as a beige solid (130 mg, 66%). may be prepared in accordance with the After separation the aqueous layer was extracted with dichloromethane (2×20 mL) The combined organic phases were washed with a saturated solution of sodium hydrogen carbonate (20 mL) dried over sodium sulfate filtered concentrated under vacuum The residue was purified by chromatography on silica gel

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-benzylpiperazine-2,6-dione (which may be prepared in accordance with the experimental described in Example 4, step 1; 2.0 g, 9.8 mmol) in a mixture of methanol/H2O (65 mL/28 mL) were added a solution of HCl 1N in methanol (23.8 mL) and Pd/C (10% wet, 0.2% wt., 400 mg). The reaction mixture was degassed 3 times with hydrogen/vacuum prior to its overnight stirring under hydrogen (P=1 atm). The reaction mixture was then filtered on Clarcel® and washed with methanol. The filtrate was finally concentrated to dryness and the residue was precipitated from a mixture of methanol and ether. The title product was obtained as a beige solid (418 mg, 28%). The reaction mixture was degassed 3 times with hydrogen/vacuum The reaction mixture was then filtered on Clarcel® washed with methanol The filtrate was finally concentrated to dryness the residue was precipitated from a mixture of methanol and ether