3-Bromoimidazo[1,2-a]pyrimidine

Compound C-1 (4 g) and sodium acetate (4.3 g) were dissolved in methanol (40 ml) into a 100 ml three-necked round bottom flask and then cooled to -10. Bromine (5.38 g) was slowly added dropwise. 1 M aqueous sodium sulfide solution (40 ml) was added, and the mixture was concentrated under reduced pressure. The by-product was extracted with ethyl acetate and water, and the resulting material was subjected to column separation using dichloromethane and methanol to obtain 3.2 g of the title compoundA mixture of 4-(4, 4, 5, 5-tetramethyl-1 , 3, 2-dioxaborolan-2-yl)pyridin-2-amine (1.0g, 4.54mmol), 3-bromoimidazo[1 , 2-a]pyrimidine (899mg, 4.54mmol) and Na2C03 (963mg, 9.09mmol) in DMF:H20 (3: 1 , 20ml_) was degassed with N2 for 15 min at rt. Pd(PPh3)4 (525mg, 0.45mmol) was added to this degassed mixture at rt. The reaction mixture was again purged with N2 for 5 min. The reaction vessel was sealed and stirred at 90 C for 16h. The TLC showed reaction to be complete. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure. The crude residue was triturated with MeOH (25ml_) and the precipitated solid was filtered through the sintered funnel. The filtrate was concentrated under reduced pressure. The residue was purified by combiflash chromatography using 12g silica column, eluting with 10% MeOH in DCM to afford 4-(imidazo[1 , 2-a]pyrimidin-3- yl)pyridin-2-amine as a brown solid. Yield: 500mg (51 %); MS (ESI+) for CHNOS m/z 212.0[M+H]+; 1 H NMR (400 MHz, DMSO-d6): <5 8.96-9.05 (m, 1 H), 8.55-8.61 (m, 1 H), 8.40 (s, 1 H), 7.94-8.01 (m, 1 H), 6.98-7.15 (m, 3H), 6.05-6.15 (bs, 2H).Compound C-2 (4 g) and anhydrous tetrahydrofuran (120 ml) were added to a 250 ml three-neck round bottom flask, and stirred under an argon atmosphere, and the temperature of the mixture was lowered to -78. 2.9M isopropylmagnesium bromide (7.6 ml) was added slowly and stirred at the same temperature for 1 hour. Tributyltin chloride (7.9 g) was added at the same temperature, the temperature of the mixture was raised to room temperature, and the mixture was stirred for 12 hours. Water was added and the organic layer was separated and concentrated under reduced pressure.The following reaction was carried out without purification for the material produced by concentration.To a mixture of S1 (140 mg, 0.35 mmol) and To a solution of tert-butyl 2-(3-acetyl-5-(4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl)-1H-indazol-1-yl)acetateacetate (1 equiv) in DCMF/H2O (8:2, 10 vol) at room temperature was added The residues from Step A were each added TFA 0.7 mL alone with anilsole (0.3 mL). The vials were sealed and heated at 55C under stirring. The pressure was released periodically by unscrewing the cap. After 5 hr, the reactions were monitored by UPLC. The mixtures were cooled to room temperature and filtered through filters. The filtrates were concentrated in a GeneVac. The residues were dissolved in DMSO. Each crude mixture was filtered into a 96-well tray and purified with HPLC. The crude products were purified by mass triggered reverse phase HPLC using the following conditions: [column: Waters XBridge CI 8, or Waters Sunfire C18, 5muiotaeta , 19x100 mm; solvent: gradient range 3 -28% initial to 60-95% final MeCN (0.1% TFA) in water (0.1% TFA) 50 or 70 mL/min; 8 min run time] to afford EXAMPLES 647 to 652.General procedure: Step C: 5-(2-(Benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole (0291) To a solution of 5-(2-(benzylthio)-6-bromophenyl)-1H-tetrazole in a mixture of chloroform and water (6 mL and 8 mL, respectively) were added potassium carbonate (1.544 g, 11.17 mmol), tetrabutylammonium chloride (0.311 g, 1.12 mmol) followed by a solution of 1-(chloromethyl)-4-methoxybenzene (1.14 mL, 8.38 mmol) in 2 mL of CHCl3 at 15 C. The resulting mixture was slowly warm to rt, and heated at 50 C. for 3 hr. The reaction mixture was cooled to rt, and transferred to a sep. funnel. The organic layer was separated, dried over MgSO4, filtered and purified using 5 to 80% ethyl acetate in hexanes to provide a mixture of 5-(2-(benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole. Step D: 3-Bromo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide (0292) To a solution of the mixture of 5-(2-(benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole in DCM (40 mL) was added water (0.251 mL, 13.9 mmol) followed by acetic acid (0.796 ml, 13.91 mmol). The resulting mixture was cooled to 0 C., then a solution of sulfuryl chloride (1.131 mL, 13.91 mmol) in DCM (2 mL) was slowly added. The reaction mixture was slowly warmed to rt, and stirred for 4 hr, and then evaporated to dryness. To this residue was added THF (5 mL) and then a mixture of aqueous ammonium hydroxide and THF (20 mL each) at 0 C. The reaction mixture was slowly warmed to rt and stirred for 1.5 hr. The resulting solution was diluted with ethyl acetate (100 mL), washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and purified by column chromatography on silica gel eluted with 10 to 90% ethyl acetate in hexanes to provide mixture of 3-bromo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide. Reference Example 8 3-bromo-N, N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-N, N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide (0308) (0309) To a mixture of 3-Bromo-2-(1-(4-methoxybenzyl)(1H-tetrazol-5-yl))benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)(1H-tetrazol-5-yl))benzenesulfonamide isomers (3.00 g, 7.07 mmol), 1-(chloromethyl)-4-methoxybenzene (2.436 g, 15.56 mmol), in butanone at room temperature, was added potassium carbonate (3.91 g, 28.3 mmol) and sodium iodide (2.332 g, 15.56 mmol). The reaction mixture was stirred overnight under N2 at 80 C. LC-MS showed completion of the reaction. The reaction was filtered and the cake was washed with EtOAc. The filtrates were evaporated, and the crude product was purified by column chromatography (EtOAc/hexanes 0-100%) to afford the title compounds. LC/MS [M+H]+: 664, 666. Reference 3-(5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl)-N, N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-(5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl)-N, N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide (0310) (0311) To a reaction vessel was added an isomeric mixture of 3-bromo-N, N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-N, N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide (3.23 g, 4.86 mmol), 5, 5, 5?, 5?-tetramethyl-2, 2?-bi(1, 3, 2-dioxaborinane) (3.29 g, 14.6 mmol), PCy3 Pd G2 (0.287 g, 0.486 mmol), and potassium acetate (1.431 g, 14.58 mmol). Then anhydrous acetonitrile (new bottle, 25 mL) was added to this flask. Nitrogen was bubbled through this mixture for 10 min, then the mixture was heated at 85 C. for 24 hr. The mixture was cooled to room temperature. 1 M NaOH was added to the reaction mixture. The mixture was extracted with EtOAc. The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 0-80% hexane/EtOAc to give the product, which was contaminated by about of de-Br side product. Step A: Palladium Catalyzed C-C Coupling of Arylboronic Ester and Arylbromides (1228) In a glove box under a dry nitrogen atmosphere, arylbromides (0.3 mmol) (commercially available, known from the literature) and Ad2nBuP Biphenyl Pre-Catalyst (6.71 mg, 10.0 mumol) and 200 muL of 1.5 N degassed aq. Cs2CO3 solution were added into 2 drum vials. 1.0 mL of a solution of the mixture of 3-(5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl)-N, N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide and 3-(5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl)-N, N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide from Reference ...Palladium catalyzed C-C coupling of arylboronic ester and arylbromides. In a glove box under a dry nitrogen atomosphere, arylbromides (0.3 mmol) (commercially available, known from the literature) and Ad2nBuP Biphenyl Pre-Catalyst (6.71 mg, 10.0 muiotaetaomicron) and 200 mu, of 1.5 N degassed aq. CS2CO3 solution were added into 2 drum vials. 1.0 mL of a solution of the mixture of 3-(5, 5-dimethyl-l, 3, 2-dioxaborinan-2-yl)-N, N- bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide and 3-(5, 5- dimethyl-l, 3, 2-dioxaborinan-2-yl)-N, N-bis(4-methoxybenzyl)-2-(l-(4-methoxybenzyl)-lH- tetrazol-5-yl)benzenesulfonamide from Reference (70 mg, 0.1 mmol) in Toluene were added into each vial. The vials were capped and heated at 1 10C with stirring for 20 hr. After the vials were cooled to room temperature, the solvent was removed in a GeneVac. Into each residue was added 600 of H20 and 2 mL of EtOAc. The organic layers were transferred into 2 dram vials. The organic solvent was removed in GeneVac to afford the crude intermediates which were deprotected without further purification in the subsequent step.General procedure: Step C: 5-(2-(Benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole (0291) To a solution of 5-(2-(benzylthio)-6-bromophenyl)-1H-tetrazole in a mixture of chloroform and water (6 mL and 8 mL, respectively) were added potassium carbonate (1.544 g, 11.17 mmol), tetrabutylammonium chloride (0.311 g, 1.12 mmol) followed by a solution of 1-(chloromethyl)-4-methoxybenzene (1.14 mL, 8.38 mmol) in 2 mL of CHCl3 at 15 C. The resulting mixture was slowly warm to rt, and heated at 50 C. for 3 hr. The reaction mixture was cooled to rt, and transferred to a sep. funnel. The organic layer was separated, dried over MgSO4, filtered and purified using 5 to 80% ethyl acetate in hexanes to provide a mixture of 5-(2-(benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole. Step D: 3-Bromo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide (0292) To a solution of the mixture of 5-(2-(benzylthio)-6-bromophenyl)-1-(4-methoxybenzyl)-1H-tetrazole and 5-(2-(benzylthio)-6-bromophenyl)-2-(4-methoxybenzyl)-1H-tetrazole in DCM (40 mL) was added water (0.251 mL, 13.9 mmol) followed by acetic acid (0.796 ml, 13.91 mmol). The resulting mixture was cooled to 0 C., then a solution of sulfuryl chloride (1.131 mL, 13.91 mmol) in DCM (2 mL) was slowly added. The reaction mixture was slowly warmed to rt, and stirred for 4 hr, and then evaporated to dryness. To this residue was added THF (5 mL) and then a mixture of aqueous ammonium hydroxide and THF (20 mL each) at 0 C. The reaction mixture was slowly warmed to rt and stirred for 1.5 hr. The resulting solution was diluted with ethyl acetate (100 mL), washed with water (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and purified by column chromatography on silica gel eluted with 10 to 90% ethyl acetate in hexanes to provide mixture of 3-bromo-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide. Reference Example 8 3-bromo-N, N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-N, N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide (0308) (0309) To a mixture of 3-Bromo-2-(1-(4-methoxybenzyl)(1H-tetrazol-5-yl))benzenesulfonamide and 3-bromo-2-(2-(4-methoxybenzyl)(1H-tetrazol-5-yl))benzenesulfonamide isomers (3.00 g, 7.07 mmol), 1-(chloromethyl)-4-methoxybenzene (2.436 g, 15.56 mmol), in butanone at room temperature, was added potassium carbonate (3.91 g, 28.3 mmol) and sodium iodide (2.332 g, 15.56 mmol). The reaction mixture was stirred overnight under N2 at 80 C. LC-MS showed completion of the reaction. The reaction was filtered and the cake was washed with EtOAc. The filtrates were evaporated, and the crude product was purified by column chromatography (EtOAc/hexanes 0-100%) to afford the title compounds. LC/MS [M+H]+: 664, 666. Reference 3-(5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl)-N, N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-(5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl)-N, N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide (0310) (0311) To a reaction vessel was added an isomeric mixture of 3-bromo-N, N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide and 3-bromo-N, N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide (3.23 g, 4.86 mmol), 5, 5, 5?, 5?-tetramethyl-2, 2?-bi(1, 3, 2-dioxaborinane) (3.29 g, 14.6 mmol), PCy3 Pd G2 (0.287 g, 0.486 mmol), and potassium acetate (1.431 g, 14.58 mmol). Then anhydrous acetonitrile (new bottle, 25 mL) was added to this flask. Nitrogen was bubbled through this mixture for 10 min, then the mixture was heated at 85 C. for 24 hr. The mixture was cooled to room temperature. 1 M NaOH was added to the reaction mixture. The mixture was extracted with EtOAc. The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with 0-80% hexane/EtOAc to give the product, which was contaminated by about of de-Br side product. Step A: Palladium Catalyzed C-C Coupling of Arylboronic Ester and Arylbromides (1228) In a glove box under a dry nitrogen atmosphere, arylbromides (0.3 mmol) (commercially available, known from the literature) and Ad2nBuP Biphenyl Pre-Catalyst (6.71 mg, 10.0 mumol) and 200 muL of 1.5 N degassed aq. Cs2CO3 solution were added into 2 drum vials. 1.0 mL of a solution of the mixture of 3-(5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl)-N, N-bis(4-methoxybenzyl)-2-(2-(4-methoxybenzyl)-2H-tetrazol-5-yl)benzenesulfonamide and 3-(5, 5-dimethyl-1, 3, 2-dioxaborinan-2-yl)-N, N-bis(4-methoxybenzyl)-2-(1-(4-methoxybenzyl)-1H-tetrazol-5-yl)benzenesulfonamide from Reference ...A suspension of 5- (4, 4, 5, 5-tetramethyl-l , 3, 2- dioxaborolan-2-yl ) pyridin-2-amine (1.51 mmol, 0.33 g) , 3- bromoimidazo [1, 2-a] pyrimidine (1.51 mmol, 0.30 g) , sodium carbonate (3.0 mmol, 0.32 g) and (1334) tetrakis (triphenylphosphine) palladium (0.076 mmol, 88 mg) in degassed DMF (6 mL) and water (2 mL) was heated under an atmosphere of nitrogen at 95 C for 12 hours. The mixture was concentrated under reduced pressure and the residual solid triturated with methanol. The organic extract was filtered through a pad of silica, eluting with methanol. The solvent was removed from the filtrate under reduced pressure to give the crude title compound which was used without further purification.

Molecular Weight:198.02
XLogP3:2.1
Hydrogen Bond Acceptor Count:2
Exact Mass:196.95886
Monoisotopic Mass:196.95886
Topological Polar Surface Area:30.2
Heavy Atom Count:10
Complexity:130
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes