1-propan-2-ylpiperazine;dihydrochloride

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A solution of NaOH (24.0 g, 0.600 mol) in de-ionized H2O (240 mL) and toluene (60 mL) at 0° C. was treated with isopropyl piperazine dihydrochloride salt (39.0 g, 194 mmol). The resulting biphasic solution was stirred at 0° C. for 30 min. A solution of 4-formyl-benzoyl chloride in toluene was added in a slow stream via an addition funnel over 1 h, with vigorous mechanical agitation. The mixture was allowed to warm to room temperature over 16 h, then cooled to 0° C., and the pH adjusted to 10 with 1 N NaOH. The phases were separated and the aqueous layer was extracted with toluene (2×200 mL). The organic layers were combined, washed with brine (200 mL), and concentrated to yield 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (52.5 g, mass balance 101%) as a pale, yellow-brown oil. The oil was dissolved in EtOH (600 mL) and, with vigorous mechanical agitation, was treated with a solution of NaHSO3 (23.1 g, 222 mmol) in de-ionized H2O (50 mL) which was added via an addition funnel over 30 min. The resulting mixture was stirred at room tempertaure for 48 h, and then cooled to 0° C. Methyl-tert-butyl ether (500 mL) was added and the resulting the slurry was stirred for 30 min. The precipitate was collected by suction filtration through a medium porosity glass frit, washed with cold EtOH/EtOAc (5:1, 3×60 mL). The solids were dried under vacuum for 2 h, then at 40° C. in a vacuum oven for 16 h to yield the title compound as a white solid. to warm to room temperature over 16 h cooled to 0° C. The phases were separated the aqueous layer was extracted with toluene (2×200 mL) washed with brine (200 mL) concentrated

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

実験手順: To a solution of tert-butyl piperazine-1-carboxylate (100 g) and acetone (48 mL) in CH2Cl2 (1 L) was added acetic acid (31 mL) and NaBH(OAc)3 (170 g). The reaction mixture was stirred for 18 h, then was diluted with 1 N NaOH (500 mL), and extracted with CH2Cl2 (500 mL×2). The combined organic layers were dried (Na2SO4) and concentrated to a residue. The residue was dissolved in MeOH (200 mL) and 4 M HCl in 1,4-dioxane (700 mL) was added to the reaction mixture over a period of several hours. After 18 h, the reaction mixture was concentrated to yield a solid, which was washed with Et2O (500 mL×2) and dried overnight to yield the title compound as a white solid. extracted with CH2Cl2 (500 mL×2) The combined organic layers were dried (Na2SO4) concentrated to a residue The residue was dissolved in MeOH (200 mL) 4 M HCl in 1,4-dioxane (700 mL) was added to the reaction mixture over a period of several hours After 18 h the reaction mixture was concentrated to yield a solid, which was washed with Et2O (500 mL×2) dried overnight

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

実験手順: To a solution of tert-butyl piperazine-1-carboxylate (100 g) and acetone (48 mL) in CH2Cl2 (1 L) was added acetic acid (31 mL) and NaBH(OAc)3 (170 g). The reaction mixture was stirred for 18 h, then was diluted with 1 N NaOH (500 mL), and extracted with CH2Cl2 (500 mL×2). The combined organic layers were dried (Na2SO4) and concentrated to a residue. The residue was dissolved in MeOH (200 mL) and 4 M HCl in 1,4-dioxane (700 mL) was added to the reaction mixture over a period of several hours. After 18 h, the reaction mixture was concentrated to yield a solid, which was washed with Et2O (500 mL×2) and dried overnight to yield the title compound as a white solid. extracted with CH2Cl2 (500 mL×2) The combined organic layers were dried (Na2SO4) concentrated to a residue The residue was dissolved in MeOH (200 mL) 4 M HCl in 1,4-dioxane (700 mL) was added to the reaction mixture over a period of several hours After 18 h the reaction mixture was concentrated to yield a solid, which was washed with Et2O (500 mL×2) dried overnight

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

実験手順: 6-(4-Isopropyl-piperazine-1-carbonyl)-nicotinic acid methyl ester. To a solution of pyridine-2,5-dicarboxylic acid 5-methyl ester (1.00 g, 5.50 mmol) and 1-isopropyl-piperazine dihydrochloride (1.20 g, 6.10 mmol) in DCM (100 mL) was added 1-hydroxybenzotriazole hydrate (HOBt, 1.10 g, 8.30 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 1.60 g, 8.30 mmol), and N-methyl morpholine (2.9 mL, 27.0 mmol). After 18 h, the reaction mixture was quenched with 1 N aq. NaHCO3 (50 mL) and extracted with DCM (3×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2; 2-5% 2 M NH3 in MeOH/DCM) gave the title compound (1.20 g, 74%). the reaction mixture was quenched with 1 N aq. NaHCO3 (50 mL) extracted with DCM (3×50 mL) dried (Na2SO4) concentrated

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

実験手順: 6-(4-Isopropyl-piperazine-1-carbonyl)-nicotinic acid methyl ester. To a solution of pyridine-2,5-dicarboxylic acid 5-methyl ester (1.00 g, 5.50 mmol) and 1-isopropyl-piperazine dihydrochloride (1.20 g, 6.10 mmol) in DCM (100 mL) was added 1-hydroxybenzotriazole hydrate (HOBt, 1.10 g, 8.30 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 1.60 g, 8.30 mmol), and N-methyl morpholine (2.9 mL, 27.0 mmol). After 18 h, the reaction mixture was quenched with 1 N aq. NaHCO3 (50 mL) and extracted with DCM (3×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2; 2-5% 2 M NH3 in MeOH/DCM) gave the title compound (1.20 g, 74%). the reaction mixture was quenched with 1 N aq. NaHCO3 (50 mL) extracted with DCM (3×50 mL) dried (Na2SO4) concentrated

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

実験手順: [4-(4-Isopropyl-piperazine-1-carbonyl)-oxazol-2-ylmethyl]-(2-methoxy-ethyl)-carbamic acid tert-butyl ester. A mixture of the crude material from Step C (1.10 g, 3.67 mmol), 1-isopropyl-piperazine dihydrochloride (0.810 g, 4.03 mmol), 1-hydroxybenzotriazole (0.595 g, 4.40 mmol), and N-methylmorpholine (2.42 mL, 22.0 mmol) in DMF (20 mL) was stirred for 1 h. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.845 g, 4.40 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with H2O (500 mL) and extracted with DCM (3×60 mL). The combined organic extracts were washed with H2O (3×300 mL), dried over Na2SO4, filtered and concentrated to yield the crude title compound (1.30 g). MS (ESI): exact mass calcd. for C20H34N4O5, 410.25; m/z found, 411.5 [M+H]+. the mixture was stirred overnight extracted with DCM (3×60 mL) The combined organic extracts were washed with H2O (3×300 mL) dried over Na2SO4 filtered concentrated

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

実験手順: 2,2-Dimethyl-Propionic acid 4-(4-isopropyl-piperazine-1-carbonyl)-thiazol-2-ylmethyl ester. The crude product from Step A (6.42 g, 24.2 mmol), 1-isopropyl-piperazine dihydrochloride (5.36 g., 26.68 mmol) and 1-hydroxybenzotriazole (4.915 g., 36.38 mmol) were dissolved into a mixture of N-methylmorpholine (14.72 g., 101.20 mmol) and DCM (120 mL). The mixture was stirred for 30 min under nitrogen. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.97 g, 36.4 mmol) was added, and the reaction mixture was stirred for 18 h at rt. The reaction was quenched by the addition of 1 M NaOH (25 mL), and was stirred for 1 h. The mixture was diluted with water and extracted with DCM (3×60 mL). The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated to yield dark brown crude oil (6.2 g). The crude product was purified on silica gel column using 30-50% acetone-DCM to give the title compound as a brown oil (3.9 g, 46%). 1H NMR (500 MHz, CDCl3): 7.89 (s, 1H), 5.38 (s, 2H), 3.90-3.84 (m, 2H), 3.81-3.75 (m, 2H), 2.75-2.69 (m, 1H), 2.62-2.50 (m, 4H), 1.27-1.23 (s, 9H), 1.05 (d, J=6.3, 6H). the reaction mixture was stirred for 18 h at rt The reaction was quenched by the addition of 1 M NaOH (25 mL) was stirred for 1 h The mixture was diluted with water extracted with DCM (3×60 mL) The combined organic extracts were washed with H2O dried over Na2SO4 filtered concentrated to yield dark brown crude oil (6.2 g) The crude product was purified on silica gel column

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

実験手順: 5-(4-Isopropyl-piperazine-1-carbonyl)-1-methyl-1H-pyrrole-3-carbaldehyde. 4-Formyl-1-methyl-1H-pyrrole-2-carboxylic acid, lithium salt, (1.08 g.) was diluted with thionyl chloride (20 mL) and heated at reflux under nitrogen for 1.5 h. The reaction mixture was carefully concentrated. The residue was co-evaporated with toluene (3×) to remove residual HCl, and then was kept under vacuum for 2 h. Separately, a solution of 1-isopropyl-piperazine dihydrochloride (1.21 g, 6.00 mmol) in DCM (50 mL) was cooled to 0-5° C. TEA (2.23 mL, 24.0 mmol) was added slowly, followed by the above acid chloride solution in DCM (50 mL). The resulting mixture was allowed to stir overnight at rt. The mixture was concentrated to yield the crude product (3.78 g), which was purified on silica gel column using 2-6% 2 M NH3 in MeOH/DCM to yield the title compound (0.20 g). heated at reflux under nitrogen for 1.5 h The reaction mixture was carefully concentrated to remove residual HCl The mixture was concentrated to yield the crude product (3.78 g), which was purified on silica gel column

反応条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 5-(4-Isopropyl-piperazine-1-carbonyl)-furan-2-carbaldehyde. Vilsmeier reagent [(chloromethylene)dimethylammonium chloride, 0.820 g, 6.43 mmol] was suspended in DCM (30 mL) under nitrogen with stirring and cooled to 0° C. To this suspension was added 5-formyl-2-furancarboxylic acid (0.900 g, 6.43 mmol) and the combined mixture was stirred at 0° C. for 30 min. The mixture was warmed to rt, stirred for another 1.5 h, and filtered. The filtrate (containing 5-formyl-furan-2-carbonyl chloride) was set aside and maintained at 0° C. In a second flask, 1-isopropyl-piperizine dihydrochloride (1.28 g, 6.37 mmol) in DCM (15 mL) was cooled to 0° C. The solution was treated with TEA (2.250 g, 22.30 mmol) slowly and then was warmed to rt and stirred for 30 min. The reaction mixture was filtered and the filtrate was cooled to 0° C. This second filtrate was then treated dropwise with the previously prepared solution of 5-formyl-furan-2-carbonyl chloride at 0° C. The combined mixture was stirred at 0° C. for 30 min and then at rt for 1 h. The reaction mixture was cooled to 0° C. and filtered, and the filtrate was washed with H2O (2×15 mL), 0.5 N NaOH (1×15 mL), and satd. aq. NaCl (1×15 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to yield the desired product (1.40 g, 87%). the combined mixture was stirred at 0° C. for 30 min The mixture was warmed to rt stirred for another 1.5 h filtered The filtrate (containing 5-formyl-furan-2-carbonyl chloride) maintained at 0° C was warmed to rt stirred for 30 min The reaction mixture was filtered the filtrate was cooled to 0° C This second filtrate was then treated dropwise with the previously prepared solution of 5-formyl-furan-2-carbonyl chloride at 0° C The combined mixture was stirred at 0° C. for 30 min The reaction mixture was cooled to 0° C. filtered the filtrate was washed with H2O (2×15 mL), 0.5 N NaOH (1×15 mL) The organic layer was separated dried over anhydrous Na2SO4 filtered concentrated

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

実験手順: Using coupling method A, 4-hydroximino-4-phenylbutyric acid (500 mg, 2.6 mmol) and 1-isopropylpiperazine dihydrochloride (521 mg, 2.6 mmol) afforded, after purification (SiO2: 10% isopropylamine in EtOAc), 730 mg (89%) of the title compound. afforded after purification (SiO2: 10% isopropylamine in EtOAc), 730 mg (89%) of the title compound

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

実験手順: A mixture of 5-piperidin-1-ylmethyl-pyrazine-2-carboxylic acid (0.125 g, 0.53 mmol),1-isopropyl-piperazine dihydrochloride (0.117 g, 0.58 mmol), HOBt (0.086 g, 0.64 mmol) and N-methylmorpholine (0.323 g, 3.19 mmol) in DCM (7 mL) was stirred for 1 h. The mixture was then treated with EDC (0.122 g, 0.64 mmol) and stirring was continued for 18 h. The reaction was quenched by the addition of 1 N NaOH (10 mL), and was stirred for 30 min. The mixture was diluted with H2O (10 mL) and extracted with DCM (3×15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to yield the crude product (0.145 g). The crude was purified on SiO2 using 0-5% 2 M NH3 in MeOH/DCM to provide the title compound (0.05 g, 26%). MS (ESI): exact mass calcd. for C18H29N5O, 331.46; m/z found 332.5 [M+H]+. 1HNMR (500 MHz, CDCl3): 8.85 (d, J=1.4,1H), 8.64 (d, J=1.4, 1H), 3.82 (t, J=4.9, 2H), 3.68 (s, 2H), 3.63 (t, J=4.9, 2H), 2.77-2.70 (m, 1H), 2.62 (t, J=4.9, 2H), 2.53 (t, J=4.9, 2H), 2.48-2.42 (m, 4H), 1.63-1.57 (m, 4H), 1.49-1.42 (m, 2H), 1.05 (d, J=6.6, 6H). stirring was continued for 18 h The reaction was quenched by the addition of 1 N NaOH (10 mL) was stirred for 30 min The mixture was diluted with H2O (10 mL) extracted with DCM (3×15 mL) The combined organic layers were dried over Na2SO4 filtered concentrated to yield the crude product (0.145 g) The crude was purified on SiO2 using 0-5% 2 M NH3 in MeOH/DCM

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

実験手順: To a solution of pyridine-2,5-dicarboxylic acid 5-methyl ester (1.00 g, 5.50 mmol) and 1-isopropyl-piperazine dihydrochloride (1.20 g, 6.10 mmol) in DCM (100 mL) was added 1-hydroxybenzotriazole hydrate (HOBt, 1.10 g, 8.30 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 1.60 g, 8.30 mmol), and N-methyl morpholine (2.9 mL, 27.0 mmol). After 18 h, the reaction mixture was quenched with 1 N aq. NaHCO3 (50 mL) and extracted with DCM (3×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated. Chromatography of the residue (SiO2; 2-5% 2 M NH3 in MeOH/DCM) gave the title compound (1.20 g, 74%). the reaction mixture was quenched with 1 N aq. NaHCO3 (50 mL) extracted with DCM (3×50 mL) dried (Na2SO4) concentrated