tert-Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate

4-(6-Aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester is a pharmaceutical intermediate, mainly used for the synthesis of pabuxirib raw material medicine. 4-(6-Aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester is an organic synthesis intermediate and pharmaceutical intermediate, mainly used as a laboratory research and development and chemical medicine synthesis process.

Step b): synthesis of 4-(6-Amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert- butyl ester formula 4)Step b): A 10 L autoclave was charged with 328.2 g of nitro 1 -Boc-4-(6-nitro-3- pyridyl)piperazine (formula 3) (1 .064 mol, 1 .00 eq.) and 3.5 L MeOH. The system was purged with NA 500-mL bottle was purged with nitrogen and charged with 188a (3.1 g, 10 mmol), 10percent palladium on carbon (50percent wet, 1.0 g) and ethanol (100 mL). It was evacuated, charged with hydrogen gas, and stirred for 16 h at room temperature. The hydrogen was then evacuated and nitrogen was charged into the bottle. The catalyst was removed by filtration through a pad of Celite and the filtrate concentrated under reduced pressure to afford 188b (2.7 g, 97percent). MS: [M+H]A 500-mL bottle was purged with nitrogen and charged with 115a (3.1 g, 10 mmol), 10percent palladium on carbon (50percent wet, 1.0 g) and ethanol (100 mL). Example 101h 1-tert-Butoxycarbonyl-4-(6-nitro-3-pyridyl)pyridazine (9.8 g, 31.78 mmol), ferric chloride hexahydrate added in a 250 mL three-neck round bottom flask at room temperature (0.6 g, 2.22 mmol) activated carbon (1.77 g) and ethanol(150mL), heat up to 80 °C for 0.5h, cool down to 65 °C, slowly add hydrazine hydrate (4.5mL, 73.9mmol), continue to heat upThe reaction was stirred at 80 ° C for 14 h, filtered while hot, washed three times with ethanol, most of the ethanol was removed under reduced pressure, and a yellow solid was evaporated.Filtration, drying and recrystallization from ethanol gave yellow acicular solid 1-tert-butoxycarbonyl-4-(6-amino-3-pyridyl)pyridazine8.617 g, yield 97.4percent, purity 98.8percent.To a vessel was added 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (12.0 g, 1.0 equiv.) along with ethyl acetate (48 mL, 4.0 vol.). To the slurry was added 50percent water wet 5percent Pd/C (480 mg, 4percent w/w) and the vessel was purged three times with nitrogen. The vessel was purged three times with hydrogen and then pressurized to 50 psi hydrogen. The mixture was heated to 42-47°C and allowed to stir until hydrogen uptake ceased (at least 8 hours).The product mixture was filtered and washed with ethyl acetate (2 x 1.5 mL). The combined filtrate was concentrated under reduced pressure to a volume of 6 mL (2 vol.). To the solution was added n-heptane (54 mL, 4.5 vol.) and the mixture was distilled under reduced pressure to a volume of 6 mL (2 vol.). To the solution was added n-heptane (54 mL, 4.5 vol.). The resulting thick slurry was cooled to 20-25°C and allowed to stir for 2 hours. The slurry was filtered and the filter cake washed with n-heptane (36 mL, 3 vol.). The solids were allowed to dry overnight in a vacuum oven at 50-55°C. The 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester was isolated as a pale orange solid (10.4 g collected; -96percent yield).A suspension of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (15.4 g, 50 mmol) in CHN, 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 HStep 2 Add 100 ml of methanol, 0.10 g of 10percent palladium carbon to 100 ml of the reaction vessel, and add 1.8 g of 4-(6-nitropyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester. The system is closed and nitrogen-filled to 0.3. MPa, replacement twice, pass H2 to the reactor pressure 0.3MPa, replace once, then start the reaction at room temperature, reaction 12h, HPLC analysis of the reaction solution, the raw material content is less than 0.5percent. The reaction solution was filtered under reduced pressure through a 0.45 um organic filter, and then evaporated to dryness to give a white solid 1.71 g, product yield 95percent, purity over 99percent.A mixture of 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.40 g, 11.0 mmol) and 10percent Pd-C (400 mg, 0.376 mmol) in ethanol (100 ml) and ethyl acetate (100 ml) is agitated under 1 atmosphere pressure of hydrogen overnight. The mixture is filtered and concentrated to give of 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.87 g, 94percent yield). MS(ESI) m/z 278 (M+H)Step 2. Synthesis of 4-(6-amino-pyridin-3-vD-piperazine-l-carboxylic acid tert- butvl ester; A mixture of 4-(6-nitro-pyridin-3-yl)-piperazine-l-carboxylic acid tert-butyl ester (3.40 g, 11.0 mmol) and 10percent Pd/C (400 mg) in EtOH/EtOAc 1:1 (200ml) was stirred under an atmosphere of hydrogen for 24 hours. The mixture was filtered through glass microfibre filter, reduced in vacuo and dried to afford the title compound as a tan solid (2.87 g, 93percent). (LCMS: RA nitrogen-flushed, 2.5 L heavy-wall Parr bottle (pressure rated to 60 psi) is charged with 68 g (0.22 mol, ) of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate, (A2a), 6.8 g of 10percent palladium on carbon, 50percent water wet catalyst and 807 g (1020 mL) of methanol.Add to the reaction flask4- (6-nitropyridin-3-yl) piperazine-1-tert-butylcarboxylate (3.4 g, 11 mmol, First step), and palladium on carbon (10percent, 400 mg)Ethyl acetate / ethanol (100 mL, 1: 1).The mixture was stirred at room temperature for 12 hours in a hydrogen atmosphere.Filtered and concentrated under reduced pressure to give the title compound (2.8 g, white solid) in 93percent yield.To the reaction flask was added compound 39 (5.65 g, 18.34 mmol)Soluble in methanol, 0.5 g Pd / C was added, Catalytic hydrogenation at room temperature, TLC tracking, to be completely complete, Diatomaceous earth, the solvent was removed by distillation under reduced pressure, To obtain a crude solid, And then petroleum ether: ether (30: 1) beating to get pink powder, 4.75 g of compound 7-10 was obtained by drying, Yield: 93.1percent.A solution of 1-methyl-4-(6-nitro-pyridin-3-yl)-piperazine(45.3 g, 147 mmol) in ethanol (1.4 L) and ethyl acetate(1.4 L) was hydrogenated in the presence of 10percent Pd/C(4.7 g) using an H2 balloon. After 16 h, the reaction mixturewas filtered through a pad of Celite and rinsed withmethanol (2 × 15 mL). The filtrate was concentrated andpurified by column chromatography (1:9 methanol/dichloromethane) to afford the title compound (37.6 g, 92percent) as yellow solid. 1H NMR (400MHz, CDCl3): δ 7.75(t, J = 2.7 Hz, 1H), 7.14 (dt, J = 8.6, 3.3 Hz, 1H), 6.47 (dd, J = 8.8, 3.4 Hz, 1H), 4.15 (br s, 2H), 3.54 (t, J = 4.7 Hz Hz, 4H), 2.93 (t, J = 4.7 Hz, 4H), 1.45 (s, 9H).300g of tert-butyl 4-(6-nitro-3-pyridyl)-1-piperazinecarboxylate was weighed into 6LAnhydrous ethanol, stir well and add 20g of 10percent Pd/C, Stir and mix thoroughly to form material I; adjust the flow rate of the slurry pump so that the flow rate of material I is 35.0 g/min, and the flow rate of the H2 gas flowmeter is adjusted to 600 ml/min.The reaction temperature was 100°C, the molar ratio of tert-butyl 4-(6-nitro-3-pyridyl)-1-piperazinecarboxylate to H2 was 1:3.2, and the residence time of the reaction was 27 seconds.The reaction pressure is 1.4Mpa; collect the reaction solution from the reactor outlet, The catalyst was recovered by filtration and the solvent was distilled off under reduced pressure.Add 3 L of ethyl acetate to dissolve, add 15 g of activated carbon, decolorize and stir at room temperature for 1 small test, filter, and add 6 L of cyclohexane to crystallize with stirring.After dropping, cool down to 010°C, heat and stir for 1 small test.The filter cake was rinsed with 300 ml of n-hexane.Evaporation under vacuum at 40°C for 12 hours gave 249.24 g of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, yield 92.03percent, purity 99.59percent.A flask was charged with tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1 -carboxylate (1 g, 4mmol) which was dissolved in methanol (100ml_). The resulting solution was then degassed by evacuation and the vessel back-filled with nitrogen (repeated twice). Palladium, 10 wt. percent on carbon powder, dry (42mg, 0.40mmol) was then added in one portion and the system closed and evacuated again, back-filling with hydrogen (repeated twice). This was left to stir at room temp. After 4 hours, LC-MS showed the reaction was mostly complete, so the system was evacuated and back-filled with nitrogen (repeated twice), the solution filtered through celite and the filtrate concentrated to dryness, affording a brown oily solid tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1 -carboxylate(800mg, 3.63mmol, 90.88percent yield). MS Method 2: RT: 1 .22min, ESCompound 11c (9.2 g, 29.9 mmol) and wet palladium carbon (2 g) were added into methanol (100 mL), the airin reaction solution was replaced by hydrogen for four to five times, and then the reaction system was stirred underhydrogen atmosphere at room temperature overnight. The reaction solution was filtered, the filter cake was washed witha little methanol, the filtrate was concentrated to give compound 11 (7.1 g, 85percent). LCMS:279M+H)+, RT=1.120minPreparation of 4-(6-Nitro-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester (2); 60.0 g of 20percent Pd(OH)The tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate synthesized in Reference Example 4 (83 g, 269 mmol) was dissolved in methanol (1.3 L) in Parr Shaker and Raney nickel (15 g, 50percent aqueous suspension) was added thereto. The resultant reaction mixture was stirred under a hydrogen atmosphere (50 psi) for five hours. The reaction mixture was filtered through a Celite pad to separate solid, and the filtrate was concentrated under reduced pressure. The resultant solid was suspended in diethyl ether (120 mL) and stirred for four hours. Heptane was added to the suspension and cooled at 0°C for 45 minutes. The resultant solid was separated by filtration and dried under reduced pressure to yield the title compound (62.5 g, 83percent). ESI-MS (M+H)Tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1 -carboxylate (41 .3 g, 134 mmol) from example Int01.01 was dissolved in a mixture of ethanol (0.5 L) and ethyl acetate (0.5 L), and 10percent palladium on charcoal (4.10 g) was added. The mixture was stirred at rt for 5 h under hydrogen atmosphere (1 bar). Subsequently, the mixture was filtered and the solvent was removed in vacuo. The residue was triturated with tert-butyl methyl ether and the product collected by suction filtration to yield 26.0 g (69percent) of the title compound. The mother liquor was purified by column chromatography on silica gel (eluent: gradient 100percent ethyl acetate to ethyl acetate / methanol 5: 1 ) to yield further 4.2 g (1 1 percent). Mixture of 5-bromo-2-nitropyridine (40g, 197 mmol, 1.0 eq.), tetrabutylammonium iodide (29.95 g, 216.7 mmol, 1.1 eq.), piperazine (20.06 g, 256.1 mmol, 1.3 eq.) and potassium carbonate (29.95 g, 216.7 mmol 1.1 eq) was dissolved in 450 ml of dimethylsulfoxide. After the reaction was stirred overnight at 80°C, the reaction solution was cooled to room temperature and extracted with dichloromethane and water, the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated with a rotary evaporator to dryness. The concentrated product after silica gel column chromatography to give yellow solid 4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester (48.9 g, crude). The compound obtained above (48.9 g, 197 mmol, 1.0 equiv.) and zinc dust (51.52 g, 788 mmol, 4.0 eq) was dissolved in 1000 ml of methanol was added ammonium chloride (42.15 g, 788 mmol, 4.0 eq.). Stirring at room temperature, after 1 hour, filtered through Celite, and the filtrate was concentrated and extracted with methylene chloride and water, the organic phase was was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated with a rotary evaporator to dryness. The concentrated product by silica gel column chromatography to give a brown solid 4-(6-aminopyridin-3-yl)piperazine-1-carboxylic acid tert-butyl ester111 (26.0 g, two -step total yield: 90percent).250 mL of reaction flask was added 9. Og (0.029 mol) of intermediate 5 and 150 mL of methanol, Room temperature by adding 0.9g Raney nickel, hydrogen at room temperature after 4h stirring monitoring, raw material reaction completely.Filter, try cake with 20mL methanol wash, the filtrate under reduced pressure spin to dry brown solid 7.68g, HPLC 95percent yieldA reaction flask was charged with 4-(6-nitropyridin-3-yl)piperazine-1-carboxylic acid t-butyl ester (0.92 g, 3.0 mmol) prepared in Step 1, ethyl acetate/methanol (10 mL/10 mL) and Pd/C (0.1 g), and introduced with hydrogen gas. 2-aminopyridine, piperazine-1-carboxylic acid tert-butyl ester, The acridine salt visible light catalyst, 2, 2, 6, 6-tetramethylpiperidine-nitrogen-oxide is added to anhydrous dichloroethane, and then the reaction environment is replaced with oxygen three times, and irradiated with a blue LED.The reaction time is 10h. After the reaction is completed, the filtrate is spun dry and separated by column chromatography.The title product was obtained as a colorless white solid, yield 95percent.