2-CHLOROPYRIMIDINE-5-BORONIC ACID

Step 1: 34). Synthesis of 2-chloro-5-(4, 4, 5, 5-tetramethyl-[1, 3, 2]dioxaborolan-2-yl)-pyrimidine; To a solution of 5-bromo-2-chloro-pyrimidine (10 mmol, 1.93 g) and triisopropyl borate (12 mmol, 2.8 ml.) in toluene (16 ml) and THF (4 mi_) is added n-buty. lithium \r, hexane (1.58 M, 12 mmol, 7.6 mL) dropwise at -78 1) In a sealed vial, 2-chloropyrimidin-5-yl)boronic acid (1 eq) and 4-(2-fluoroethyl)piperidine HCI (1 eq) were dissolved, with an excess of trimethylamine (TEA), in absolute methanol (2.5 ml). The reaction was run in a preheated oil bath at 80 C for 45 min. (0637) The solution was cooled, diluted with dioxane (2.7 ml), and 2-bromo-6-methoxyimidazo[l, 2- a]pyridine (203 mg, 1 eq) was added followed by bubbling of N2 for 2 min. Then 2 M K2CO3 (1.34 ml, 3 eq) was added, followed by Pd(dppf)CI2 DCM complex 1:1 (37 mg, 5 mol%). The solution was again bubbled with N2 for 5 min then the vial was capped. The reaction was run in a preheated oil bath at 90 C for 1 h. (0638) The reaction mixture was cooled, diluted with ethyl acetate, washed with water, dried with MgS04, filtered and the solvent removed in vacuo to give the crude product. The crude product was purified on the ISCO (24 g silica, applied with DCM, eluted with 40- 80% ethyl acetate/hexane) to give 2-[4-(2-fluoroethyl)piperidin-l-yl]-5-{6- methoxyimidazo[l, 2-a]pyridin-2-yl}pyrimidine (32 mg solid, 11% yield, HPLC Rf 3.05, MS m/z (M+l) 356.3). TLC: ethyl acetate Rf 0.26.In a sealed vial, 2-chloropyrimidin-5-yl)boronic acid (1 eq) and 4-(2-fluoroethyl)piperidine HCI (1 eq) were dissolved, with an excess of trimethylamine (TEA), in absolute methanol (2.5 ml). The reaction was run in a preheated oil bath at 80 C for 45 min. (0634) The solution was cooled, diluted with dioxane (3 ml), and 2-bromoimidazo[l, 2-a]pyridine (197 mg, 1 eq) was added followed by bubbling of N2 for 2 min. Then 2 M K2C03 (1.5 ml, 3 eq) was added, followed by Pd(dppf)CI2 DCM complex 1:1 (41 mg, 5 mol%). The solution was again bubbled with N2 for 5 min then the vial was capped. The reaction was run in a preheated oil bath at 90 C for 1 h. The reaction mixture was cooled then diluted with ethyl acetate, washed with water, dried with MgS04, filtered and the solvent removed in vacuo to give the crude product. (0635) The crude product was purified on the ISCO (24 g silica, applied with DCM, eluted with 15- 80% ethyl acetate/hexane) to give 2-[4-(2-fluoroethyl)piperidin-l-yl]-5-{imidazo[l, 2- a]pyridin-2-yl}pyrimidine (25 mg solid, 8% yield, HPLC Rf 2.99, MS m/z (M+l) 326.3). TLC: ethyl acetate Rf 0.26.In a sealed vial, 2-chloropyrimidin-5-yl)boronic acid (1 eq) and 4-(2-fluoroethyl)piperidine HCI (1 eq) were dissolved, with an excess of trimethylamine (TEA), in absolute methanol (2.5 ml). The reaction was run on a preheated oil bath at 80 C for 45 min. The solution was cooled and diluted with dioxane (3 ml) and ethyl 2-bromo-6-benzothiazolecarboxylate (286 mg, 1 eq) was added, followed by bubbling of N2 through the solution for 3 min. Then 2 M K2CO3 (1.5 ml, 3 eq) was added followed by Pd(dppf)CI2 DCM complex 1:1 (41 mg, 5 mol%). The solution was again bubbled with N2 for 5 min then the vial was capped. The reaction was run in a preheated oil bath at 90 C for 1 h. (0584) The solution was cooled, diluted with ethyl acetate, and the solid filtered. The solid was then refluxed with ethyl acetate, and the insoluble portion was filtered off. A small volume of hexane was added to the solution, the solid was filtered, and washed with hexane to give ethyl 2-{2-[4-(2-fluoroethyl)piperidin-l-yl]pyrimidin-5-yl}-l, 3-benzothiazole-6-carboxylate (50 mg solid, 12% yield, HPLC Rf 4.10 min, MS m/z (M+l) 415.3). TLC: 30% ethyl (0585) acetate/hexane Rf 0.40.In a 20 ml microwave vial, In a sealed vial, 2-chloropyrimidin-5-yl)boronic acid (1 eq) and 2-(piperidin-4-yl)ethan-l-ol (1 eq) were dissolved with triethylamine (TEA) (1.4 eq) in anhydrous methanol or absolute ethanol (2.5 ml/ mmol boronic acid). The reaction was run in a preheated oil bath at 80 C for 45 min. The progression of the reaction was monitored by the formation of the product mass (MS m/z (M+l) 252, (M-l): 250). No purification was carried out, and the reaction mixture solution containing the crude {2- [4-(2-hydroxyethyl)piperidin-l-yl]pyrimidin-5-yl}boronic acid was used directly in the Suzuki reactionsTo a solution of 3-bromo-4-nitrobenzamide (Matrix Scientific, cat No.184225: 600.0 mg, 2.449 mmol), To a degassed solution of tert-butyl (3S)-3-[(5-bromo-3-pyridyl)amino]pyrrolidine-1-carboxylate (5.0 g, 14.6 mmol), Nitrogen is bubbled subsurface through a 2 M solution of aqueous NaHCO3(50 mL) and 1, 4-dioxane (126 mL) for 20 min in a round-bottom flask, and tert-butyl 3-[(6- bromopyrazin-2-yl)amino]azetidine-l-carboxylate (8.9 g, 27.2 mmol), (2-chloropyrimidin-5- yl)boronic acid (4.0 g, 25.3 mmol) and [l, l'-bis(di-t- butylphosphino)ferrocene]dichloropalladium(II) (0.5 g, 0.7 mmol) are added under a nitrogen atmosphere. The flask is fitted with a reflux condenser and heated in an aluminum heat block at 70 C overnight. The reaction mixture is diluted with 800 mL EtOAc and heated to boiling with stirring for ~ 15 min. The mixture is hot filtered over a bed of diatomaceous earth. The filtrate is partially concentrated under reduced pressure to ~ 300 mL, and hexanes (~ 200 mL) are added dropwise to the stirred suspension. The resulting light yellow precipitate is isolated by filtration and dried under reduced pressure to obtain the title compound (5.6 g, 61% yield). ES/MS m/z (35C1/37C1) 385.0/387.0 [M+Na].