1-(4-aminophenyl)piperidin-4-ol

Reference Example 6 Synthesis of Compound 13 [Show Image] Compound 12 (1.50 g, 6.75 mmol) was dissolved in methanol (25 ml), 10percent palladium-carbon (150 mg) was added, and the interior of the system was replaced with a hydrogen gas. After stirred at room temperature for 2 hours, the reaction solution was filtered using Celite, and washed with methanol. The filtrate, and the washing solution were combined, and the solvent was distilled off under reduced pressure to obtain Compound 13 (1.28 g, yield 99percent). Step: 3A-2Synthesis of l-(4-Amino-phProcedure:Pd-C (150mg) was added to a stirred solution of l-(4-Nitro-phenyl)-piperidin-4-ol (1.4g, 0.00630mol) in MeOH (5ml) under nitrogen atmosphere and then hydrogen gas was passed. The reaction was monitored by the TLC (10percent MeOH: CHC1The 4-hydroxy-N-(4-nitrophenyl)piperidine (11.1 g, 50 mmol) obtained in Example 1(1) was dissolved in methanol (100 ml) and tetrahydrofuran (50 ml), and 10percent palladium-carbon (8.0 g) was added thereto, followed by stirring at room temperature in an atmosphere of hydrogen gas for 7 hours. After the insoluble material was filtered with Celite, the filtrate was concentrated under reduced pressure, diethyl ether was added to the obtained residue, and the precipitate was collected by filtration, thereby obtaining 4-hydroxy-N-(4-aminophenyl)piperidine (9.25 g, 94percent) as a reddish-purple solid.1H-NMR (CDCl3): δ (ppm) 1.65-1.77 (m, 2H), 1.94-2.11 (m, 2H), 2.71-2.85 (m, 2H), 3.23-3.92 (m, 5H), 6.64 (d, J=8.9 Hz, 2H), 6.83 (d, J=8.9 Hz, 2H)To a solution of 17.09g (76.95mmol) of the compound obtained in the Manufacturing Example 94 in 300mL of methanol was added 2.0g of 5percent-palladium-carbon, and the atmosphere was exchanged to hydrogen atmosphere. The mixture was stirred for over night at room temperature and the mixture was filtrated. The filtrate was removed under reduced pressure to give 13.04g (88percent) of the title compound.Step 2: 1-(4-Amino-phenyl)-piperidin-4-ol.; A 50 mL round bottom flask was charged with [3-(4-Methyl-piperazin-1-yl)-propyl]-(4-nitro-phenyl)-amine (0.742 g, 3.34 mmol) and dissolved into EtOH (20 mL). Hydrazine Hydrate (0.642 mL, 20.04 mmol) was then added. Excess RaNi was then added in dropwise until the solution stopped bubbling. The suspension was then allowed to stir for an additional 15 minutes at 65° C. The suspension was cooled to rt and then filtered over celite. The celite was washed with MeOH (20 mL) and the combined organic solutions were then concentrated in vacuo. The crude oil was then purified over silica (3percent Chloroform/Hexanes to 10percent Chloroform/Hexanes) affording pure 1-(4-amino-phenyl)-piperidin-4-ol as a light brown oil in 51percent yield (0.327 g, 1.71 mmol).To a mixture of 1-fluoro-4-nitrobenzene (2.82 g, 20 mmol) and KA suspension of 1-(4-nitro-phenyl)-piperidin-4-ol (1.020 g, 4.59 mmol) and 10percent Pd- C (0.130 g) in ethanol (25 mL) was hydrogenated (balloon) overnight at rt. The catalyst was removed by filtration and washed with ethanol. The combined filtrate was concentrated in vacuo and the residue dried further in vacuo to give 0.706 g 1-(4-amino- phenyl)-piperidin-4-ol. MS (MHTo a stirred solution of 3-(2, 6-dichlorophenyl)-7-(methylthio)-2, 3-dihydro-4H-pyrimido[5, 4-e][1, 3]oxazin-4-one (250 mg, 0.730 mmol, 1.0 eq) in 5 mL of toluene was added mCPBA (314.3 mg, 1.827 mmol, 2.5 eq) and allowed to stir at rt for 30 min. General procedure: To a stirred solution of compound 7, 8, or 9 (1 equiv) in 1-butanol was added compounds 12(1.1 equiv) and p-toluenesulfonic acid (1 equiv). The mixture was placed in a pressure flask, and heated to 100C for 15h. The reaction mixture was quenched by saturated Na2CO3 aqueous solution, and then was extracted with DCM and the organic phase was washed with water, dried over anhydrous Na2SO4. The combined organic layer was concentrated under reduced pressure and was further purified by flash column chromatography using dichloromethane/methanol as eluent to afford product H1-H14, Y1-Y14, or L1-L14 as a pale yellow solid.General procedure: To a stirred solution of compound 7, 8, or 9 (1 equiv) in 1-butanol was added compounds 12(1.1 equiv) and p-toluenesulfonic acid (1 equiv). The mixture was placed in a pressure flask, and heated to 100C for 15h. The reaction mixture was quenched by saturated Na2CO3 aqueous solution, and then was extracted with DCM and the organic phase was washed with water, dried over anhydrous Na2SO4. The combined organic layer was concentrated under reduced pressure and was further purified by flash column chromatography using dichloromethane/methanol as eluent to afford product H1-H14, Y1-Y14, or L1-L14 as a pale yellow solid.General procedure: To a stirred solution of compound 7, 8, or 9 (1 equiv) in 1-butanol was added compounds 12(1.1 equiv) and p-toluenesulfonic acid (1 equiv). The mixture was placed in a pressure flask, and heated to 100C for 15h. The reaction mixture was quenched by saturated Na2CO3 aqueous solution, and then was extracted with DCM and the organic phase was washed with water, dried over anhydrous Na2SO4. The combined organic layer was concentrated under reduced pressure and was further purified by flash column chromatography using dichloromethane/methanol as eluent to afford product H1-H14, Y1-Y14, or L1-L14 as a pale yellow solid.General procedure: Compound 13 (20 mg, 0.06 mmol), aniline (0.05 mmol) were dissolved in 2 mL tert-butanol. To the solutionwas added 2-dicyclohexylphosphino-2?, 4?, 6?-triisopropylbiphenyl (9.6 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium(5.1 mg, 0.01 mmol), potassium carbonate (24.8 mg, 0.18 mmol). In nitrogen atmosphere, the resulting reactionliquid was heated in 120C oil bath with stirring until compound 13 was reacted completely (LC-MS tracking). The reactionwas stopped. The reaction liquid was filtered by one-section silica gel column, concentrated and purified by reversedphasepreparative HPLC (with 0.35% trifluoroacetic acid aqueous solution and methanol as mobile phase), and concentratedin vaccum to yield compound III.General procedure: Compound 3 (18.3 mg, 0.063 mmol), aniline (0.044 mmol) were dissolved in 1 mL tert-butanol. To the solutionwas added trifluoroacetic acid (23.4 mL, 0.32 mmol). The resulting reaction liquid was heated in 110C oil bath with stirring until aniline was reacted completely (LC-MS and TLC tracking). The reaction was stopped. To the reaction liquidwas added saturated sodium bicarbonate solution, and the liquid was separated. The organic phase was washed twicewith saturated sodium chloride solution, dried over anhydride sodium sulfate, concentrated and purified by silica-gel column chromatography (dichloromethane/methanol) to yield compound IA.A mixture of starting material (12 mg, 0.05 mmol),

Molecular Weight:192.26
XLogP3:1.2
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:192.126263138
Monoisotopic Mass:192.126263138
Topological Polar Surface Area:49.5
Heavy Atom Count:14
Complexity:170
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes