4-(2-BROMOETHYL)-1-PIPERAZINECARBOXYLIC ACID, 1,1-DIMETHYLETHYL ESTER

Carbon tetrabromide (1.681 g, 5.07 mmol) was dissolved in dichloromethane (17 ml), cooled with ice.thereTertiary butyl 4- (2-hydroxyMethyl) piperazine-1-carboxylate (1.062 g, 4.61 mmol), triphenylphosphine (1.329 g, 5.07 mmol), and stirred overnight at room temperature was added dichloromethane (11 ml). After the reaction, the solvent was evaporated. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (1.131 g, 83.7percent) as a yellow solid.STEP A: A solution of tetrabromomethane (1.58 g, 4.7 mmol) in DCM (10 mL) is added dropwise (30 min) to the solution of N-Boc-piperazin-4-ethanol (1 g, 4.34 mmol) and triphenylphosphine (1.23 g, 4.7 mmol) in DCM (10 mL) at 0°C. The reaction is left at RT for 20 h. The organic solvent is removed under reduced pressure and the crude is purified by flash column chromatography (eluent petroleum ether/EtOAc) to give the expected compound (1 g, 3.38 mmol, Yield 78percent) as colourless oil. HExample 24 Carbon tetrabromide (1.681 g, 5.07 mmol) was dissolved in dichloromethane (17 ml), cooled with ice.thereTertiary butyl 4- (2-hydroxyMethyl) piperazine-1-carboxylate (1.062 g, 4.61 mmol), triphenylphosphine (1.329 g, 5.07 mmol), and stirred overnight at room temperature was added dichloromethane (11 ml). After the reaction, the solvent was evaporated. The residue was purified by silica gel column chromatography (SNAP ULTRA 25 g, hexane / ethyl acetate) to give the title compound (1.131 g, 83.7percent) as a yellow solid.STEP A: A solution of tetrabromomethane (1.58 g, 4.7 mmol) in DCM (10 mL) is added dropwise (30 min) to the solution of N-Boc-piperazin-4-ethanol (1 g, 4.34 mmol) and triphenylphosphine (1.23 g, 4.7 mmol) in DCM (10 mL) at 0°C. The reaction is left at RT for 20 h. The organic solvent is removed under reduced pressure and the crude is purified by flash column chromatography (eluent petroleum ether/EtOAc) to give the expected compound (1 g, 3.38 mmol, Yield 78percent) as colourless oil. H1-NMR (CDCI3) delta (ppm): 3.41-3.47 (m, 6H); 2.81 (t, J=6.00 Hz, 2H); 2.48 (t, J=6.00 Hz, 4H); 1.46 (s, 9H)Example 63; l-{2-[4-(3, 5-dimethoxybenzyl)piperazin-l-yl]ethyl}-3, 3-bis(4-fluorophenyl)pyrrolidin-2- one; Example 63A; tert-butyl 4-(2-bromoethyl)piperazine-l-carboxylate; tert-Butyl 4-(2-hydroxyethyl)piperazine-l-carboxylate (5.76 g, 25.0 mmol) was dissolved in dry tetrahydrofuran (100 mL) and carbon tetrabromide (9.12 g, 27.5 mmol). A solution of triphenyl phosphine (6.62 g, 25.3 mmol) in dry tetrahydrofuran (25 mL) was added dropwise, and the mixture was stirred for 20 hours. The reaction was diluted with n- hexane (100 mL) and washed with a saturated NaHCO3 solution, water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes 1 :4 gave the title compound. MS (DCI) m/z 295(M+H)+.General procedure: 2, 5-Dihydroxybenzaldehyde (1.0 eq.) and cesium carbonate (1.0 eq.) were suspended in DMF and the suspension, warmed to 60 °C for 15 min. After cooling down to rt, the corresponding bromide (1.1 eq.) was added in DMF (0.5 M concentration of 2, 5-dihydroxybenzaldehyde) and the reaction was stirred at rt for 2h for benzylic haloalkanes or at 60 °C overnight for aliphatic haloalkanes. The solvents were evaporated and the crude dissolved in water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (3x) and the combined organic layers were dried over magnesium sulfate, filtered and the solvent evaporated. The crude product was purified by flash chromatography.ethyl (7R, 21S)-17-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethyl}-19-chloro-1-(4-fluorophenyl)-20-methyl-16-oxo-10-{[2-(3, 3, 3-trifluoropropoxy)pyrimidin-4-yl]methoxy}-7, 8, 16, 17-tetrahydro-15H-18, 21-etheno-13, 9-(metheno)-6, 14-dioxa-2-thia-3, 5, 17-triazacyclononadeca[1, 2, 3-cd]indene-7-carboxylate Example 16L (67.1 mg) was dissolved in N, N-dimethylformamide (0.8 mL). tert-Butyl 4-(2-bromoethyl)piperazine-1-carboxylate (35.2 mg) and cesium carbonate (78.0 mg) were added. The reaction mixture was stirred at ambient temperature for 40 minutes. The mixture was diluted with ethyl acetate and water. The organics were separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography on an AnaLogix IntelliFlash280 system (50-100percent ethyl acetate/heptanes, linear gradient) to provide the title compound. LC/MS (APCI) m/z 1050.3 (M+H)+.

Molecular Weight:293.20
XLogP3:1.7
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:4
Exact Mass:292.07864
Monoisotopic Mass:292.07864
Topological Polar Surface Area:32.8
Heavy Atom Count:16
Complexity:233
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes