4-BOC-1-(5-BROMO-2-PYRIDYL)PIPERAZINE

To a stirred solution of 2, 5-dibromopyridine (2 g, 10.7 mmol), sodium tert-butoxide (1.6 g, 16.6 mmol), xantphos (400 mg, 0.7 mmol) and toluene (100 mL) in sealed tube argon waspurged for 5 min. To the reaction mixture tert-butyl piperazine-1-carboxylate (3 .4 g, 14.30mmol) followed by Pd2(dba)3 (200 mg, 0.21 mmol) was added and heated at 80 °C for 4 h(TLC indicated complete consumption of starting material). The reaction mixture was dilutedwith EtOAc (200 mL), water (100 mL), filtered through Celite bed and washed with EtOAc(2 x 30 mL). The combined organic extracts were washed with brine (50 mL), dried overNa2S04 and concentrated under reduced pressure to give the crude product which waspurified by column chromatography (100-200 silica gel, 50 g, 10-20percent EtOAc-hexanes) toafford tert-butyl4-(5-bromo-2-pyridyl)piperazine-1-carboxylate (3 g, 82percent) as a yellow solid.LCMS (ESI+ ): m/z: 342.57 [M+Ht.General procedure: 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).; The title compound was prepared using tert-butyl piperazine-1-carboxylate (1.45 g, 7.79 mmol), 5-bromo-2-chloropyridine (1.00 g, 5.20 mmol) and potassium carbonate (1.44 g, 10.39 mmol) in acetonitrile (30 mL) according to the process described in Step 4 of Example 1, and the crude product was purified by silica gel chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a pale yellow solid (1.45 g, 8 1.5percent).MS (ESI, pos. ion) m/z: 342.1 [M+H] and‘H NMR (600 MHz, CDC13): (ppm) 8.17 (d, J 2.4 Hz, 1H), 7.52 (dd, J 9.0, 2.5 Hz, 1H), 6.52 (d, J 9.0 Hz, 1H), 3.55 - 3.49 (m, 4H), 3.49 - 3.45 (m, 4H), 1.46 (s, 9H).To a stirred solution of 1-Boc piperazine (10.6 g, 57.29 mmol, Symax fine chemicals) in dryDMF (lOOmL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyrimidine (10 g, 52.08mmol, Oakwood chemicals) were added and the reaction mixture was stirred at 80°C for 14h. It was cooled down to rt and poured on iced water (100 mL). The resulting precipitatewas filtered and washed with hexane (50 mL) to afford the title compound. Yield: 58.8percent(10 g, off white solid). 1H NMR (400 MHz, DMSO-d6): 68.60(s, IH), 8.13 (dd, J= 8.6, 2.4Hz, IH), 7.54 (dd, J = 8.4, 0.4 Hz, IH), 3.22-3.20 (m, 4H), 2.61-2.59 (m, 4H), 1.42 (5, 9H).LCMS: (Method A) 343.9 (M +2H), Rt. 5.58 mm, 98.9percent (Max).To a stirred solution of 1-Boc piperazine (10.6 g, 57.29 mmol, Symax fine chemicals) in dry DMF (100mL), TEA (14.43 mL, 103.39 mmol) and 5-bromo-2-chloropyridine (10 g, 52.08 mmol, Oakwood chemicals) were added and the reaction mixture was stirred at 80°C for 14 h. It was cooled down to rt and poured on iced water (100 mL). The resulting precipitate was filtered and washed with hexane (50 mL) to afford the title compound. Yield: 58.8percent (10 g, off white solid). Step 1: K[0949] To a solution ofcompound 90a (125 g, 516 mmol) inDCM (300mL), TEA (104 g, 1.03 mol) was added, followedby (BOC) 2 0 (135 g, 619 mmol) in portions with stirring at ooC. The resulting mixture was stirred overnight at room temperature. The reaction was then quenched with water (1 00mL), and the product was extracted with DCM (3x150 mL).The combined organic layers were concentrated underreduced pressure to obtain compound 90b as a white solid(125 g, 71percent yield). Mass Spectrum (LCMS, ESI pos.): Calcd.for C14H20BrN3 0 2 : 342.1 (M+H). found 342.1.

Molecular Weight:342.23
XLogP3:2.7
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:341.07389
Monoisotopic Mass:341.07389
Topological Polar Surface Area:45.7
Heavy Atom Count:20
Complexity:338
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes