1,1-Dimethylethyl 4-(6-nitro-3-pyridinyl)-1-piperazinecarboxylate

Under a nitrogen purge, l-(6-nitro-pyridin-3-yl)-piperazine (Method 48; 15.6g; 0.075mol) was suspended in ca 120ml THF. In single portions, triethylamine (10.5ml; 0.075mol) and the 4-dimethylaminopyridine (0.46g; 5molpercent) were added sequentially. Di-t- butyl dicarbonate (16.6g; 0.075mol) was dissolved in ca 50ml THF and placed in an addition funnel. The solution was added dropwise to the stirring suspension, maintaining the temperature below 27°C throughout by controlling the addition rate. After the addition was complete, the temperature was allowed to drop to ambient temperature, before heating to EPO A mixture of 5-Bromo-2-nitropyridine (203 g, 1.37 mol), piperazine (153 g, 1.77 mol), tetrabutylammonium iodide (25.2 g, 0.068 mol), and potassium carbonate (207 g, 1.50 mol) in dimethyl sulfoxide (2.6 L) was stirred at 80°C overnight. The resultant reaction mixture was cooled to room temperature, and the mixture was poured into water (7 L). The resultant solid was collected by filtration, and the solid was washed with dichloromethane (1 L × 2) and dried. The filtrate was extracted with chloroform (2 L × 7). The resultant organic phase was washed with water (2 L) and then with saturated brine (2 L), and the organic phase was concentrated under reduced pressure to yield solid. The resultant solid products were combined together and used for the subsequent reaction without further purification. (0173) The solid product (490 g) was dissolved in THF (2 L) and water (500 mL), and sodium hydrogen carbonate (119 g, 1.42 mol) was added to the solution. To the resultant suspension was added di-tert-butyl dicarboxylate (262 g, 1.2 mol), and the mixture was stirred at room temperature for three hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (1 L) and extracted with dichloromethane (1 L × 3). The resultant organic phases were combined together and then washed with water (1 L). The aqueous phase was extracted with dichloromethane (300 mL). The resultant organic phases were combined together and dried over anhydrous magnesium sulfate. The solid was separated by filtration, and the filtrate was concentrated under reduced pressure. The resultant solid was suspended in ethyl acetate (2 L) and heated to 60°C, and the solid was separated by filtration at 60°C. The solid was dried under reduced pressure to yield the title compound (191 g, 62percent) APCI-MS (M+H)A nitrogen-flushed, suitably equipped 22 L 4-neck round bottom flask is charged with 589 g (2.41 mol, 1.0 eq.) of 1-(6-nitropyridin-3-yl)piperazine hydrochloride (A2b).To a vessel was added 5-bromo-2-nitropyridine (10.0 g, 1.0 equiv.) along with DMSO (25 ml_, 2.5 vol). N-Boc piperazine (13.8 g, 1.5 equiv.) was added, followed by triethylamine (7.5 g, 1.5 equiv.) and LiCI (2.1 g, 1.0 equiv.). The mixture was warmed to 60-65°C for a minimum of 12 hours.Water (5 ml_, 0.5 vol) was added slowly to the vessel at 60-65°C. The mixture was kept at 60-65 °C for one hour, then cooled to room temperature. The slurry was kept at 20-25 °C for 1 hour and then filtered onto a 2 Whatman™ paper filter. The cake was rinsed with water (50 ml_, 5 vol.). The crude solids were collected and transferred back to a clean vessel. Water (100 mL, 10 vol.) was added to the vessel containing the solids and the mixture was warmed to 35-40°C for 2 hours, then filtered while warm onto a 2 Whatman paper™ filter. The solids were rinsed with water (40 mL, 4 vol.) and allowed to dry overnight in the vacuum oven at 50-55°C. The 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester was isolated as a yellow solid (14.1 g collected; -93percent yield).500 mL of the reaction flask was added to the starting material III20.3 g (0.1 mol) and IV27.9 g (0.15 mol) of starting material, 200mL DMSO, 15.2 g (0.15 mol) of triethylamine and 4.2 g (0.1 mol) of lithium chloride were added with stirring, System temperature to 60-65 incubation reaction 12h.65 ° C to the system slowly adding 200mL of water, Stir for 1 h. The system was cooled to room temperature and stirred for 1 h. The mixture was filtered and washed thoroughly with water at 50-55 ° C overnight to give 27.7 g of pure product as a pale yellow solid. Yield: 90.0percentStep 1 Step a): synthesis of 1-Boc-4-(6-nitro-3-pyridyl)piperazine (formula 3)Step b): A 1 -L RBF, was charged with 50 g of 5-Bromo-2-nitro-pyridine (0.246 mol, 1 .00 eq.), 175 ml DMSO and 35 ml water. To the resulting mixture was added 37.45 g potassium carbonate (0.271 mol, 1 .1 eq.) followed by 59.64 g boc-piperazine (0.320 mol, 1 .3 eq.). The mixture was heated to 70^ and stirred under argon until completion (approx. 28 h). The reaction was diluted with 315 ml of water and allowed to cool down to RT. After 2 h stirring, the solid was collected by filtration, washed with water (2 x 250 ml) and left in air at RT overnight to give crude wet 1 -Boc-4-(6-nitro-3- pyridyl)piperazine as yellow solid. HPLC (Method 1 ): 6.49 min (96.4percent) (230 nm)Crude product was suspended in 250 ml toluene, followed by concentrated under reduced pressure. The residue was dissolved in 200 ml toluene, under reflux. Resulting orange solution was allowed to cool down slowly to RT without stirring. After 3 h, precipitated solid was filtered, washed with toluene (50 ml), TBME (2 x 100 ml) and dried at 50To a solution of 5-bromo-2-nitropyridine (40.0 g, 197 mmol) in DMSO (150 mL) were added 1-Bocpiperazine(47.4 g, 252 mmol) and DIPEA (38 mL, 219 mmol) . The reaction mixture was heated at 80 °C for11 h. The reaction mixture was poured into ice-water andthen extracted with EtOAc. The combined extracts werewashed with water and brine. The organic layer was driedover Na2SO4, filtered, and concentrated under reducedpressure. Purification by column chromatography (1:9methanol/ dichloromethane) gave 1-Boc- 4-(6-nitro-pyridin-3-yl)-piperazine (49.9 g, 82percent) as yellow solid. 1H NMR(400 MHz, CDCl3): δ 8.11 (d, J = 9.1 Hz, 1H), 8.08 (d, J =2.7 Hz, 1H), 7.18 (dd, J = 9.1, 2.8 Hz, 1H), 3.65–3.56 (m, 4H), 3.48–3.38 (m, 4H), 1.45 (s, 9H).To a stirred solution of 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol) and piperazine-1-carboxylic acid tert-bλxtyl ester (4.97 g, 26.7 mmol) in CHA solution of 1-Boc-piperazine (15.0 mmol) and 5-bromo-2-nitropyridine (5.00 mmol) in N-methyl pyrrolidone (15 mL) was stirred at 120 °C for 3 h. The reaction mixture was diluted with water and the precipitate was collected by filtration to give 2 (80percent) as a colorless powder. Nitrile analogues can be made by the following. To a stirred solution of 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol) and piperazine-1-carboxylic acid tert-butyl ester (4.97 g, 26.7 mmol) in CHPreparation of 4-(6-Nitro-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester; B Exampl e 2A: Preparation of 4-(6-Nitro-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester To 1.0 kg (5 mol) 5-bromo-2-nitropyridine was added 1.2 kg {6.4 mol) boc piperazine (tert-Butyl piperazine-1-carboxylate) in 2.6L DMSO and 0.5 kg triethylamine under nitrogen. The mixture was heated to 65-70Synthesis of compound 107.1 To a solution of 78.4(1. Og, 4.92mmol, 1.0 eq) in DMSO (10 ml) was added BuPreparation XX To the reaction flask was added 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol), Piperazine-1-carboxylic acid tert-butyl ester (4.97 g, 26.7 mmol)Diisopropylethylamine (4.65 mL, 26.7 mmol) and acetonitrile (60 mL)The mixture was stirred at 110 ° C for 72 hours.Cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (DCM / MeOH = 10/1)The resulting residue was purified to give the title compound (4.5 g, white solid) in 60percent yield.Compound 11a (13.7 g, 73.9 mmol), compound 11b (10 g, 49.3 mmol), potassium iodide (81.8 mg, 0.493 mmol)and potassium carbonate (13.6 g, 98.6 mmol) were added into DMSO (100 mL). The reaction solution was stirred at120 °C overnight and then cooled to room temperature, adjusted to pH 7 with hydrochloric acid (1 mol) and then extractedwith dichloromethane. The aqueous phase was alkalize by saturated solution of sodium carbonate, and then extractedwith dichloromethane again. The organic phase was combined and dried over anhydrous Na2SO4, concentrated andthen slurried by water to give compound 11c (9.2 g, 60percent). LCMS:309(M+H)+, RT=1.710min.N, N-Diisopropylethylamine (4.77g, 36.94mmol) was added to a solution of 82 5-bromo-2-nitropyridine (5.00g, 24.63mmol) and 100 tert-butyl piperazine-1-carboxylate (5.10g, 27.09mol) in 101 acetonitrile ([ACN] 30mL). The mixture was refluxed for 2h, cooled to RT, concentrated under a vacuum, and purified by silica gel column chromatography (from 102 PE/86 EA=1:1 to 103 DCM/87 MeOH=20:1) to obtain 104 tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (3.80g; yield, 50percent) as a yellow solid. Pd/C (100.0mg) was added to a solution of tert-butyl 4-(6-nitropyridin-3-yl) piperazine-1-carboxylate (925.0mg, 3.0mmol) in EA/MeOH (10 mL/10mL). The mixture was degassed by flushing with H4.1.39 Compound 38 (10.2 g, 49.52 mmol) was added to the reaction flask, respectively, Compound 36 (10.40 g, 54.47 mmol)Dissolved in DMF, DIPEA (7.78 g, 59.42 mmol) was added.50 ° C under the conditions of reaction, TLC tracking, to be completely complete, The reaction system is poured into ice water, There is a yellow solid precipitation, Filter solids, beat with EA, Dried to obtain 6.20 g of compound 39, Yield: 40.63percent.Into a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L) were added K2COTo a solution of 5-bromo-2-nitropyridine (30 g, 148 mmol) in DMSO (1 L) was added KExample 101g 4-(6-nitro-3-pyridinyl)-1-piperazinecarboxylic acid, 1, 1-dimethylethyl ester Dissolved 5-bromo-2-nitropyridine (1.0 g, 4.92 mmol) and tert-butyl piperazine-1- carboxylate (1.1 g, 5.91 mmol) in N-methylpyrrolidine and stirred at 120 C for 18 h. Thereafter the reaction mixture was cooled to 30 C and diluted with water and extracted with ethyl acetate (2 x 200 mL). The combined organic extract was washed with brine (50 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to give crude product. The crude product was purified by column chromatography to give 400 mg of the desired product. LC-MS: m/z calcd for C14H2A microwave vial was charged with 5-chloro-2-nitropyridine (1 g, 6.31 mmol), 1 -boc-piperazine (1 .29g, 6.94mmol) and potassium carbonate (3.3ml_, 18.92mmol), which was suspended in DMSO (15ml_). The resulting mixture was irradiated for 1 hour at 100°C. After this time, the mixture had solidified. LC-MS showed the reaction had not gone to completion. The solid mixture was then transferred to a flask along with DMSO (5ml_) and heated to 1 10°C, at which point the solid mixture had melted. This was left heating overnight, after which LC-MS showed product formation and no starting material. Reaction was allowed to cool. The reaction mixture was then added to water and extracted with EtOAc (x3). The organics were then combined, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness, affording an orange solid. Purification by flash column chromatography was then performed, (40g S1O2, eluting with 0-50percent EtOAc in heptane). The fractions containing product were combined and concentrated to dryness, affording tert-butyl 4-(6- nitro-3-pyridyl)piperazine-1 -carboxylate (1 .24g, 4.02mmol, 63.81 percent yield) as a bright orange/yellow solid. MS Method 2: RT: 1 .61 min, ES