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methyl 2-bromo-5-[ethyl(4-oxocyclohexyl)amino]-4-methylthiophene-3-carboxylate[ No CAS ]
methyl 2-bromo-5-[trans-4-(3-ethoxyazetidin-1-yl)cyclohexyl](ethyl)amino}-4-methylthiophene-3-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.25 g
To a crude sample of methyl 2-bromo-5- [ethyl(4-oxocyclohexyl)amino] -4-methylthiophene-3-carboxylate (2.17 g, 5.80 mmol) in DCM (20 mL), add titanium(W) isopropoxide (6.79 g, 23.2 nimol) and <strong>[535924-73-3]3-ethoxyazetidine hydrochloride</strong> (1.60 g, 11.6 mmol). Stir the reaction at RT for about 18 hr. Add THF (20 mL), then concentrate the mixture in vacuo to about 20 mL. Cool the resulting mixture to -78 C, then add MeOH (25 mL) followed by the drop wise addition of 2M LiBH4 in THF (4.34 mL, 8.70 mmol),Stir the resulting mixture for about 3 hr, then remove the cold bath and allow the mixture to warm slowly to RT, Dilute the reaction mixture with EtOAc (200 mL) and saturated aqueous NaHCO3 solution (50 mL), filter away the solids, concentrate the filtrate in vacuo, dilute the residue with EtOAc (50 mL), and filter the solids again. Concentrate the organic layer in vacuo to afford the title compound (2.25 g, 78 % yield) as yellow gum,suitable for use without separation of the isomers or further chromatography. ES/MS (mlz): (79Br/81Br) 459/461 (M+H),
5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-3-methyl-2-[methyl(4-oxocyclohexyl)amino]-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one[ No CAS ]
5-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-2-[trans-4-(3-ethoxyazetidin-1-yl)cyclohexyl](methyl)amino}-3-methyl-5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepin-4-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
To 5- [(4,6-dimethyl-2-oxo- 1 ,2-dihydropyridin-3-yl)methyl] -3 -methyl-2-[methyl(4-oxocyclohexyl)amino] -5,6,7,8-tetrahydro-4H-thieno [3,2-c]azepin-4-one (0.320 g, 0.616 mmol) in THF (10 mL), add <strong>[535924-73-3]3-ethoxyazetidine hydrochloride</strong> (0.424 g, 3.08mmol) in MeOH (5 mL) and DIPEA (0.55 mL, 3.15 mmol). Stir at RT for 30 mm. Cool the mixture to -78 C and slowly add a solution of 2MLiBH4 in THF (0.650 mL, 1.3 mmol), stir the resulting mixture for 1 hr at -78C, warm to RT, and stir for 1 hr. Pour the reaction mixture into ice-cold saturated NaHCO3 solution, extract with DCM, separate the layers, dry the organic extract over Na2504, filter, and concentrate the filtrate in vacuo.Subject the resulting residue to chromatography on silica, eluting with a gradient of 0-70% of a 10% solution 7Nmethanolic NH3 in DCM to DCM. Collect thechromatography fractions containing the trans- and cis- isomers and concentrate in vacuo.Separate the trans- and cis- isomers by reverse phase chromatography on C- 18 silica(Phenomenex Luna), eluting with a gradient of 40-75% ACN in 10 mM aqueous NH4CO3containing 5% MeOH, to afford the title compound (0.099 g, 37% yield) as a white solidafter solvent evaporation. ES/MS (mlz): 527(M+H).
5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one[ No CAS ]
5-(3-ethoxyazetidin-1-yl)-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With potassium carbonate; In dimethyl sulfoxide; acetonitrile; at 70℃; for 18h;
General procedure: To a stirred suspension of 5-chloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4- yl]methyl]pyridazin-3-one (building block A, 300 mg, 0.947 mmol) and (R)-3- hydroxypyrrolidine (0.14 mL, 1.73 mmol) in DMSO (0.5 mL) and acetonitrile (3 mL) was added potassium carbonate (393 mg, 2.84 mmol) Then the reaction mixture was stirred at 70 C for 18 h. After cooling to room temperature the reaction mixture was diluted with EtOAc (80 mL) was washed three times with water (10 mL) and brine (10 mL). The aqueous layers were back extracted twice with EtOAc (80 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 10% MeOH in CH2CI2) afforded the title compound (341 mg, 93 %) as an off-white foam. MS (ESI): 368.2 ([M+H]+).
4,5-dichloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3-one[ No CAS ]
4-chloro-5-(3-ethoxyazetidin-1-yl)-2-((5-methyl-3-(6-methylpyridin-3-yl)isoxazol-4-yl)methyl)pyridazin-3(2H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
39%
With potassium carbonate; In N,N-dimethyl acetamide; at 70℃; for 4h;
A mixture of 4,5-dichloro-2-[[5-methyl-3-(6-methyl-3-pyridyl)isoxazol-4-yl]methyl]pyridazin-3- one (50 mg, 0.142 mmol), <strong>[535924-73-3]3-ethoxyazetidine hydrochloride</strong> (21.6 mg, 0.157 mmol) and potassium carbonate (59 mg, 0.427 mmol) in /V./V-di mcth yl acctam i de (1 mL) was heated to 70 C for 4 h. The mixture was cooled to room temperature, diluted with water and extracted 3 times with ethyl acetate. The combined organic extracts were dried (Na?S04), filtered and concentrated in vacuo. Purification by flash chromatography (silica, gradient: 0% to 100% (2472) EtOAc in heptane) afforded the title compound (23 mg, 39 %) as a colorless gum. MS (ESI): 416.1 ([M+H]+).
4-(3-ethoxyazetidin-1-yl)-1H-pyridazin-6-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
36%
With potassium carbonate; In N,N-dimethyl acetamide; at 60℃; for 2h;
To a solution of 5-chloropyridazin-3(2H)-one (130 mg, 0.946 mmol) in N,N-d i mcth yl acctam idc (2.5 mL) were added potassium carbonate (654 mg, 4.73 mmol) and <strong>[535924-73-3]3-ethoxyazetidine hydrochloride</strong> (174 mg, 1.23 mmol). The mixture was heated to 60 C for 2 h before being cooled to room temperature. The reaction mixture was purified directly by preparative HPLC to provide the title compound (66 mg, 36 %) as a light brown solid. MS (ESI): 196.1 ([M+H]+).
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