2-[4-(4-Aminophenyl)piperazin-1-yl]ethan-1-ol

To a solution of 2-(4-(4-nitrophenyl)piperazin-l-yl)ethanol (3.6 g, 14.3 mmol) in MeOH (40 mL) was added Pd/C (700 mg) and the resulting mixture was stirred at r.t.overnight. The mixture was filtered, and the filtrate was concentrated to afford 2-(4-(4- aminophenyl)piperazin-l-yl)ethanol (2.8 g, 88percent yield) as yellow solid.Step: 3A-2Synthesis of 2-[4-(4-Amino-phenyl)-piperazin-l-yl]-ethanol.Procedure:Pd-C (0.3g) was added to a solution of 2-[4-(4-Nitro-phenyl)-piperazin-l-yl]-ethanol (3g, 0.01195mol) in MeOH (20ml) and hydrogenated for 2hrs. The reaction was monitored by the TLC (20percent MeOH: CHC1A stirred solution of 2—(4—(4—nitrophenyl)piperazin—1— yl)ethanol (1.2 g, 4.78 mmol) in ethanol (20 mL) washeated to 50 °C. 10percent palladium on carbon (0.254 g, 0.239 mmol) was added followed by portionwise addition of ammonium formate (1.506 g, 23.88 mmol) and the suspension was stirred for 1 hour. The suspension was filtered through Celite® washing with fresh ethanol (20 mL) . Theethanol was removed in vacuo to give the title compound(1.10 g, 104 percent) . ‘H NMR (400 MHz, CDC13) : 3 6.81 (d, 2H), 6.66 (d, 2H), 3.69 (t, 2H), 3.09 (t, 4H), 3.02 (br s, 3H), 2.74 (t, 4H), 2.66 (t, 2H) . LCMS (Method C): =0.13 mi m/z = 222 [M+H].To a solution of 2-(4-(4-nitrophenyl)piperazin-l-yl)ethanol (3.6 g, 14.3 mmol) in MeOH (40 mL) was added Pd/C (700 mg) and the resulting mixture was stirred at r.t.overnight. The mixture was filtered, and the filtrate was concentrated to afford 2-(4-(4- aminophenyl)piperazin-l-yl)ethanol (2.8 g, 88% yield) as yellow solid.601 2-(4-(4-nitrophenyl)piperazin-1-yl)ethan-1-ol (0.9 g, 3.58 mmol) was dissolved in 10 mL 6 EtOH, further 10 mL 7 water was added under stirring. 203 Iron powder (0.6 g, 10.75 mmol) and 67 NH4Cl (0.383 g, 7.16 mmol) were then added. The resulting mixture was heated at 90 C. for 1-2 h. The reaction was monitored by LCMS. After completion of reaction, mixture was filtered through celite bed, solvent form the filtrate was removed under reduced pressure. Water was added to the residue and extracted using 30 MeOH: 82 CH2Cl2 (10%), dried over Na2SO4. The solvent was removed under reduced pressure to afford 604 2-(4-(4-aminophenyl) piperazin-1-yl) ethan-1-ol (0.550 g, 70%) as a brown solid. (0626) LCMS: 221 [M+1]+Step: 3A-2Synthesis of 2-[4-(4-Amino-phenyl)-piperazin-l-yl]-ethanol.Procedure:Pd-C (0.3g) was added to a solution of 2-[4-(4-Nitro-phenyl)-piperazin-l-yl]-ethanol (3g, 0.01195mol) in MeOH (20ml) and hydrogenated for 2hrs. The reaction was monitored by the TLC (20% MeOH: CHC13). The resultant was filtered, washed with MeOH and concentrated to afford 1.8g (69% yield) of 2-[4-(4-Amino-phenyl)-piperazin-l-yl]-ethanol as a pink solid.REFERENCE EXAMPLE 19b Reference Example 19b A stirred solution of 2-(4-(4-nitrophenyl)piperazin-1- yl)ethanol (1.2 g, 4.78 mmol) in ethanol (20 mL) washeated to 50 C. 10% palladium on carbon (0.254 g, 0.239 mmol) was added followed by portionwise addition of ammonium formate (1.506 g, 23.88 mmol) and the suspension was stirred for 1 hour. The suspension was filtered through Celite washing with fresh ethanol (20 mL) . Theethanol was removed in vacuo to give the title compound(1.10 g, 104 %) . 'H NMR (400 MHz, CDC13) : 3 6.81 (d, 2H), 6.66 (d, 2H), 3.69 (t, 2H), 3.09 (t, 4H), 3.02 (br s, 3H), 2.74 (t, 4H), 2.66 (t, 2H) . LCMS (Method C): =0.13 mi m/z = 222 [M+H].[00214] Step 2: A solution of the above product (2.74 g) in methanol (50 mL) was hydrogenated in the presence of 10% Pd/C (270 mg) by using an H2 balloon. After 16 h, the reaction mixture was filtered through a pad of Celite and rinsed with methanol (3 x 15 mL). The filtrate was concentrated to the desired product (2.70 g) as light yellow solids. The product was used directly in the next step without further purification. ESI-MS: calcd for (C13H21N3) 219, found 220 (MH+).General procedure: The substituted nitro compound 11 (1 equiv in a mixture of EtOH-H2O, 95:5, 20mL) was treated with 10% Pd-carbon (5% w/w). The reaction was subjected to hydrogenation under hydrogen gas at room temperature and the reaction was monitored by TLC. After completion of the reaction, the mixture was filtered through a Celite bed and concentrated in a vacuum to afford product 12.To a stirred solution of 21 3-(2, 6-dichlorophenyl)-7-(methylthio)-2, 3-dihydro-4H-pyrimido[5, 4-e][1, 3]oxazin-4-one (0.2 g, 0.58 mmol, 1.0 eq) in 5 mL 24 toluene 25 m-CPBA (0.251 g, 1.46 mmol, 2.5 eq) was added under stirring and resulting mixture was allowed to stir at rt for 30 min. Further, 604 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.[00215] Step 3 : A flask was charged with intermiediate 2 (50 mg, 0.16 mmol), 2-(4-(4- aminophenyl)piperazin-l-yl)ethanol (30.4 mg, 0.16 mmol), DIPEA (60uL), DMSO (2 mL). The reaction was stirred at room temperature for over. The crude product was purified with flash chromatography (0-10% MeOH-in DCM) to afford the desired product as light yellow solids (42 mg, 54% yield). 1H MR (400 MHz, DMSO-d6) delta 11.83 (br, 1H), 9.86 (br, 1H), 8.23 (s, 1H), 7.30 (d, J=8.4Hz, 2H), 7.00 (dd, J=5.6Hz, J = 10.4 Hz, 1H), 6.90 (d, J=8.8Hz, 2H), 6.34 (s, 1H), 3.51 (m, 2H), 2.84 (m, 2H), 2.41 (s, 3H), 2.11 (m, 2H), 1.03 ( s, 3H), 1.01 (s, 3H); ESI-MS: calcd for (C26H25F2N70) 489, found 490 (MH+).

Molecular Weight:221.30
XLogP3:0.5
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:221.152812238
Monoisotopic Mass:221.152812238
Topological Polar Surface Area:52.7
Heavy Atom Count:16
Complexity:196
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes