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With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 110℃; for 6h;
Intermediate 4 (2.2 mmol) and tert-butyl (35)-3-isopropylpiperazine-l-carboxylate (0.5 g, 2.2 mmol) in DMF (10 mL) and DIPEA (0.34 g, 2.63 mmol) were heated at 110C for 6 h. The reaction mixture was allowed to cool, then stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, then partitioned between EtOAc and water. The organic layers were dried over sodium sulfate and concentrated in vacuo, then the crude material was purified by column chromatography (silica gel: 100- 200 mesh, isohexanes:EtOAc, gradient 50% to 100% EtOAc) to give an off- white foam. This was taken up in 4N HC1 in 1 ,4-dioxane (5 mL) and methanol (1 mL), and stirred for 1 h. The reaction mixture was concentrated in vacuo and triturated with diethyl ether to give the title compound (0.08 g, 12%).
4-[(2S)-2-isopropylpiperazin-1-yl]-1-methylpyrazolo[3,4-d]pyrimidin-6-amine dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
2-Amino-4,6-dichloropyrimidine-5-carbaldehyde (2.4 g, 13 mmol) and tert-butyl (35)-3-isopropylpiperazine-l -carboxylate (2.9 g, 13 mmol) in 1,4-dioxane (50 mL) were treated with DIPEA (3.3 g, 5 mL, 25 mmol) and heated at 90C for 6 h. The reaction mixture was cooled and concentrated in vacuo, then partitioned between DCM and water. The organic layers were phase separated and concentrated. The resulting golden foam was taken up in THF (100 mL) with triethylamine (2.7 g, 4 mL, 27 mmol) and methylhydrazine (0.64 g, 0.73 mL, 14 mmol), then stirred for 72 h at room temperature. The reaction mixture was concentrated in vacuo and partitioned between DCM and water, then phase separated. The organic layers were further concentrated in vacuo. The residual foam was taken up in DCM (100 mL), then 4N HC1 in 1,4-dioxane (20 mL) was added and the mixture was stirred overnight. The resultant solution was concentrated in vacuo and triturated with diethyl ether to give the title compound (3.8 g, 95%) as a sticky foam that was >95% pure by LCMS. LCMS (ES+) [M+H]+ 276.2, RT 0.72 minutes (method 2).
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20 - 110℃;
Intermediate 8 7-[(2S)-2-Isopropylpiperazin-1-yl]thiazolo[5,4-d]pyrimidin-5-amine hydrochloride [0228] Intermediate 4 (2.2 mmol) and <strong>[475272-54-9]tert-butyl (3S)-3-isopropylpiperazine-1-carboxylate</strong> (0.5 g, 2.2 mmol) in DMF (10 mL) and DIPEA (0.34 g, 2.63 mmol) were heated at 110 C. for 6 h. The reaction mixture was allowed to cool, then stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, then partitioned between EtOAc and water. The organic layers were dried over sodium sulfate and concentrated in vacuo, then the crude material was purified by column chromatography (silica gel: 100-200 mesh, isohexanes:EtOAc, gradient 50% to 100% EtOAc) to give an off-white foam. This was taken up in 4N HCl in 1,4-dioxane (5 mL) and methanol (1 mL), and stirred for 1 h. The reaction mixture was concentrated in vacuo and triturated with diethyl ether to give the title compound (0.08 g, 12%). LCMS (ES+) 279 (M+H)+, RT 0.91 minutes (method 3).
(S)-methyl 4-(5-((S)-1-((tert-butoxycarbonyl)amino)ethyl)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-1,3-oxazole-4-carbonyl)-2-isopropylpiperazine-1-carboxylate[ No CAS ]
methyl (S)-4-tert-butoxycarbonyl-2-isopropylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
27%
To a solution of 1, 1'-carbonyldiimidazole (1.10 g, 6.57 mmol) in anhydrous DMF (2 mL) were added triethylamine (1.10 mL, 7.88 mmol) and a solution of (S) -tert-butyl 3-isopropylpiperazine-1-carboxylate (1.00 g, 4.38 mmol) in anhydrous DMF (2 mL) dropwise. The mixture was stirred in a sealing tube at rt for 50 min, and anhydrous methanol (12 mL) was added. The resulting mixture was further stirred at 80 for 48 h and concentrated. The residue was diluted with saturated aqueous NaCl (10 mL × 3) , and extracted with EtOAc (15 mL × 2) . The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with Petroleum ether/EtOAc (v/v) 4/1 to give (S) -4-tert-butyl 1-methyl 2-isopropylpiperazine-1, 4-dicarboxylate as colorless liquid (339 mg, 27) .1H NMR (400 MHz, CDCl3) : delta ppm 3.75-4.16 (m, 4H) , 3.70 (s, 3H) , 2.77-2.95 (m, 3H) , 1.91-2.00 (m, 1H) , 1.46 (s, 9H) , 1.02 (d, J 6.5 Hz, 3H) , 0.82 (d, J 6.6 Hz, 3H) and MS-ESI: m/z 187.1 [M+H-100] + .
27%
N'N- to carbonyl diimidazole (1.10g, 6.57mmol) in anhydrous DMF (2mL) was added dropwise a solution oftriethylamine (1.10mL, 7.88 mmol) and (S) -1-BOC-3- isopropyl-piperazine (1.00g, 4.38mmol) in anhydrousDMF (2mL) solution at room temperature in a sealed tube 50 min, adding anhydrous methanol (12mL), 80 Cthe reaction 48h, the solvent was removed, a saturated sodium chloride solution (10mL × 3), dried B Acetate(15mL × 2) and the combined organic phases, Na 2 SO 4 dried over anhydrous solvent removed concentratewas separated by column chromatography (leaching Lotion: Petroleumether / EtOAc (v / v) = 4/1), to give339mg of colorless liquid: 4-tert-butoxycarbonyl -2- (S) - isopropyl-piperazin-1-A Methyl, yield: 27%.
tert-butyl (S)-4-(bis(4-fluorophenyl)methyl)-3-isopropylpiperazine-1-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45.1%
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 85℃;
To a solution of 4,4'-(chloromethylene)bis(fluorobenzene) (0.784 g, 3.28 mmol) in acetonitrile (10 mL) was added <strong>[475272-54-9]tert-butyl (S)-3-isopropylpiperazine-1-carboxylate</strong> (0.5 g, 2.19 mmol), followed by DIPEA (1.147 mL, 6.57 mmol). The reaction mixture was stirred at 85 C overnight. The reaction mixture was concentrated under reduced pressure to remove volatiles and the residue was dissolved in ethyl acetate and washed with water. The aqueous layer was back-extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography on ISCO (5-10 % EtOAc/petroleum ether; 24g column) to afford the tert-butyl (S)-4-(bis(4- fluorophenyl)methyl)-3-isopropylpiperazine-1-carboxylate (425 mg,, 45.1 % yield); LCMS: m/z = 431.2 (M+H); rt 2.215 min (LCMS Method: Column: Kinetex XB-C18 (3 x 75 mm) 2.6 mm; Mobile phase A: 10 mM ammonium formate:acetonitrile (98:2), Mobile phase B: 10 mM ammonium formate:acetonitrile (2:98), Gradient = 20-100 % B over 4 minutes, then a 0.6 minute hold at 100 % B; Temperature: 27 C; Flow rate: 1.0 mL/min; Detection: UV at 220 nm).
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