1-BOC-4-(4-BROMO-2-CYANOPHENYL)PIPERAZINE

In a pressure tube, 5-bromo-2-fluorobenzonitrile (2500 mg, 12.5 mmol), tert-butyl piperazine-1-carboxylate (2444.45 mg, 13.12 mmol), triethylamine (5.23 ml, 37.5 mmol) in dimethylsulfoxide (10 ml) were combined and refluxed at 100 C for ovn. The mixture was cooled, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried using sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel 5-60percent ethyl acetate/hexane to provide a light brown oil, tert-butyl 4-(4-bromo-2-cyanophenyl)piperazine-1-carboxylate (3660 mg, 80percent).A mixture of 1—15 (3.0 g, 14.99 mmcl), 1-Boc-piperizine(3.33 g, 17.99 mmcl) and Cs2003 (9.68 g, 29.98 mci) in DMSO(60 ml) was stirred at 12000 for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (100 ml x 3) . The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give thedesired product 1—16 (2.5 g, 44percent) as yellow solid which wasused in the next step without purification; LCMS: m/z 312 [MtBu+1]In a pressure tube, 5-bromo-2-fluorobenzonitrile (2500 mg, 12.5 mmol), tert-butyl piperazine-1-carboxylate (2444.45 mg, 13.12 mmol), triethylamine (5.23 ml, 37.5 mmol) in dimethylsulfoxide (10 ml) were combined and refluxed at 100 C for ovn. The mixture was cooled, and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried using sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel 5-60% ethyl acetate/hexane to provide a light brown oil, A mixture of 1-15 (3.0 g, 14.99 mmcl), 1-Boc-piperizine(3.33 g, 17.99 mmcl) and Cs2003 (9.68 g, 29.98 mci) in DMSO(60 ml) was stirred at 12000 for 1 hour. The reaction mixture was diluted with water (100 mL) and extracted with diethyl ether (100 ml x 3) . The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give thedesired product 1-16 (2.5 g, 44%) as yellow solid which wasused in the next step without purification; LCMS: m/z 312 [MtBu+1]STEP A: 4-(4-Bromo-2-cvano-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. A mixture of 5-bromo-2-fluoro-benzonitrile (1.05g), piperazine-1 -carboxylic acid tert-butyl ester (1.08g) and Na2CO3 (1.03g) in DMF was heated to 1000C for 24h. The resulting mixture was cooled, diluted with water (50 ml_) and extracted with diethyl ether. The resulting mixture was dried over MgSO4, the solvent was removed and the resulting residue purified on SiO2 (hexanes/ EtOAc 0 to 25%) to yield the title compound.To a solution of 1-16 (2.5 g, 6.83 mmcl) in DMSO (6 mL) were added aqueous 30% H202 (0.15 ml, 8.88 mmcl) and K2003 at 0CC, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reactionmixture was poured into ice cold water (100 ml) and extracted with diethyl ether (100 mL x 3) . The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product so obtained was purified by silica gel column chromatography (60-120 mesh) using 30% EtOAc in hexanesas eluent to give the desired product 1-17 (1.3 g, 50%) as a white solid; LOMS: m/z 384.0 [M+1]General procedure: Dissolved (3i?, 55)-tert-butyl 3, 5-dimethyl-4-(4-(pyrazolo[l, 5-a]pyrimidin-6- yl)phenyl)piperazine-l-carboxylate (0.24 g, 0.589 mmol) in DCM (8 mL). Cooled in ice bath then added N-Bromosuccinimide (0.105 g, 0.589 mmol) in DCM (3 mL). Warmed to RT. Added 10 mg x 2 until SM gone. 2 h at RT. Removed solvent in vacuo. Suspended between EA and 2 M Na2C03. Washed org. with water, brine, dried (Na2S04), filtered and concentrated. Triturated in EtOH and filtered. Obtained (3i?, 55)-tert-butyl 4-(4-(3- bromopyrazolo [ 1 , 5 -a]pyrimidin-6-y l)phenyl)-3 , 5 -dimethylpiperazine- 1 -carboxylate (0.159 g, 0.327 mmol, 55.5 % yield) as a yellow solid.General procedure: Under an argon atmosphere, 2-fluoro-5-nitrotoluene(7.93 g, 51.13 mmol), 1- (tert-butoxycarbonyl) piperazine (10 g, 53.69 mmol) in N, N- dimethylformamide(100 mL), potassium carbonate (17.66 g, 127.8 mmol) was added and the mixture was stirred at 120 C. for 24 hours. Ethyl acetate was added to the reaction solution and washed with water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure.The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (8.13 g, 49%). Yellow oilSTEP B: 2-[4-(4-Bromo-2-cvano-phenyl)-piperazin-1-yl)-N.N-diethyl-2-phenyl-acetamide. A solution of 4-(4-Bromo-2-cyano-phenyl)-piperazine-1 -carboxylic acid tert- butyl ester (151.6mg) prepared as in STEP A above was dissolved in CH2CI2 (3 ml_) and the resulting mixture treated with TFA (1 ml_). The resulting mixture was stirred for 6h, then the solvent was removed to yield a residue. To the residue was added 2-bromo-N, N-diethyl-2-phenyl-acetamide (0.14g), Na2CO3 (0.2Og) and DMF (3 ml_). The resulting mixture was stirred for 16h, then diluted with water (50 ml_) and extracted with diethyl ether. The resulting mixture was dried over MgSO4, the solvent was removed and the resulting residue purified on SiO2 (hexanes/ EtOAc O to 50%) to yield the title compound.

Molecular Weight:366.25
XLogP3:3.1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:365.07389
Monoisotopic Mass:365.07389
Topological Polar Surface Area:56.6
Heavy Atom Count:22
Complexity:446
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes