5-BROMO-2-(4-BOC-PIPERAZIN-1-YL)PYRIMIDINE

To 1, 4-dioxane (30 mL) were added tert-butyl piperazine-1-carboxylate (2.89 g, 15.51 mmol), 5-bromo-2-chloropyrimidine (2.00 g, 10.34 mmol) and potassium carbonate (2.86 g, 20.68 mmol) sequentially. The mixture was heated to 110 °C, after stirring for 12 hours, the reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a pale yellow solid (3.15 g, 88.7percent).MS (ESI, pos. ion)m/z: 343.1 [M+H] and‘HNMR(400IVIHz, CDC13): (ppm) 8.29 (s, 2H), 3.83-3.66 (m, 4H), 3.56-3.41 (m, 4H), 1.48 (s, 9H).To a solution of commercially available S-bromo-2-chloropyrimidin (9.75 g, 50 mmol) in CH3CN (100 mL) was added compound i-Boc-piperazine (9.25 g, 50 mmol) and K2003 (13.8 g, 100 mmol). The reaction mixture was stirred at 80 00 overnight. Then, the reaction mixture was concentrated under vacuo andextracted with EA and washed with water, dried by Na2SO4 and concentrated under vacuo to give the KR-7 (15 g 87.7percent yield). ESI-MS (Mi-i): 343, 345calc. for C13H19BrN4O2: 342.1.Preparation of reagents Preparation of reagent KR-1 : 1 - e/t-Butoxycarbonyl-4-(5-bromopyrimidin-2- vQpiperazine To a solution of commercially available 5-bromo-2-chloropyrimidin (9.75 g, 50 mmol) in CHTo a stirred solution of 1-boc piperazine (10.42 g, 56.86 mmol, Symax fine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g, 51.69 mmol, Oakwood chemicals) were added at rt and the reaction mixture was stirred at80 °C for 14 h. The reaction mixture was cooled to rt and poured into water (100 mL). Theformed precipitate was filtered and washed with diethyl ether (50 mL) to afford the titleproduct. Yield: 84.5percent (15 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 68.49(s, 2H), 3.69 (t, J = 5.2 Hz, 4H), 3.40 (t, J = 5.1 Hz, 4H), 1.42 (5, 9H). LCMS: (Method A) 345.23 (M+2), Rt. 4.92 mm, 99.6percent (Max).To a stirred solution of 1-boc piperazine (10.42 g, 56.86 mmol, Symax fine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g, 51.69 mmol, Oakwood chemicals) were added at rt and the reaction mixture was stirred at 80 °C for 14 h. The reaction mixture was cooled to rt and poured into water (100 mL). The formed precipitate was filtered and washed with diethyl ether (50 mL) to afford the title product. Yield: 84.5percent (15 g, off white solid). To a solution of 5-bromo-2-chloropyrimidine (50.0 g, 258 mmol) and 1-tert-butoxycarbonylpiperazine (72.2 g, 387 mmol) in 1, 4-dioxane (500 mL) was added potassium carbonate (67.8 g, 491 mmol), and the mixture was stirred under reflux for 1.5 h. The reaction was cooled to RT, quenched by water (500 mL) and extracted with diethyl ether (1000 mL*2). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography (petroleum ether:ethyl acetate=8:1-4:1) to give the title compound (70.5 g, 80percent) as a white solid. MS (ES+) CStep 4: To a solution of 5-bromo-2-chloro-pyrimidine (0.5 g, 2.58 mmol) in 1, 4-dioxane (20 mL), tert-butyl piperazine-1-carboxylate (0.722 g, 3.88 mmol) and K2C03 (0.713 g, 5.17 mmol)were added at RT. The reaction mixture was refluxed for 4 h (TLC indicated complete consumption of starting material). The reaction mixture was brought toRT, diluted withwater (20 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts werewashed with water (2 x 40 mL), brine (1 x 40 mL), dried over Na2S04 and concentratedunder reduced pressure to give the residue. The residue was further purified by columnchromatography (100-200 silica gel, 15 g, 10percent EtOAc-Hexane) to afford tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-l-carboxylate (0.7 g, 78percent) as a white solid.1H NMR [400 MHz, CDCh]: J 8.29 (s, 2H), 3.75 (t, J = 4.8 Hz, 4H), 3.47 (t, J = 5.2 Hz, 4H), 1.47 (s, 9H).LCMS: m/z: 287.44 [M-tBut.To a stirred solution of 1-boc-piperazine (6.0 g, 31.5 mmol) in DMF (50 mL), triethyl amine (7 mL, 46.00 mmol) and 5-bromo-2-chloropyrimidine (6.3 g, 37.00 mmol) were added and the reaction mixture was stirred at 90 °C for 8 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added and the desired product was extracted with DCM (150 mL). The organic layer was dried over NaTo a stirred solution of 1-boc-piperazine (6.0 g, 31.5 mmol) in DMF (50 mL), triethyl amine (7 mL, 46.00 mmol) and 5-bromo-2-chloropyrimidine (6.3 g, 37.00 mmol) were added and the reaction mixture was stirred at 90 °C for 8 h. The reaction mixture was concentrated under reduced pressure. Water (50 mL) was added and the desired product was extracted with DCM (150 mL). The organic layer was dried over Na2SO4and concentrated under reduced pressure. The crude product was purified by flash chromatography (10percent EtOAc in pet ether) to afford the title compound. Yield: 76percent (7 g, white). 1H NMR (400 MHz, DMSO-d6): 6 8.46 (s, 2H), 3.68-3.67 (m, 4H), 3.39-3, 37 (m, 4H), 1.40 (s, 9H). LCMS: (Method A) 289.0 (M+H), Rt. 5.19 mm, 99.05percent (Max).

Molecular Weight:343.22
XLogP3:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:342.06914
Monoisotopic Mass:342.06914
Topological Polar Surface Area:58.6
Heavy Atom Count:20
Complexity:332
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes