| 97% |
With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 16h; |
A 500-mL bottle was purged with nitrogen and charged with 115a (3.1 g, 10 mmol), 10% palladium on carbon (50% 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 115b (2.7 g, 97%). MS: [M+H]+279 |
| 97% |
With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 16h; |
Example 101h tert-Butyl 4-(6-Aminopyridin-3-yl)piperazine-1-carboxylate 101h A 500-mL bottle was purged with nitrogen and charged with tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 101g (3.1 g, 10 mmol), 10% palladium on carbon (50% 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 101h (2.7 g, 97%). MS: [M+H]+ 279 |
| 97.4% |
|
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 97.4%, purity 98.8%. |
| Ca. 96% |
With 5%-palladium/activated carbon; hydrogen; In ethyl acetate; at 42 - 47℃; under 2585.81 Torr;Inert atmosphere; |
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 50% water wet 5% Pd/C (480 mg, 4% 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 42-47C 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 20-25C 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 50-55C. 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; -96% yield).1H NMR (500 MHz, DMSO-de): delta 7.62 (dd, J = 2.99, 0.60 Hz, 1 H), 7.17 (dd, J = 8.85, 2.99 Hz, 1 H), 6.40 (dd, J = 8.85, 0.60 Hz, 1 H), 5.45 (bs, 2H), 3.43 (m, 2H), 2.85 (m, 2H), 1.41 (s, 9H);13C NMR (125 MHz, DMSO-de): delta 154.8, 153.8, 138.7, 136.8, 125.9, 108.3, 78.9, 50.5, 43.8, 43.0, 28.0; HRMS: Calcd for C14H23N4O2 (M+H)+: 279.18155, Found: 279.18173. |
| 96.2% |
With methanol; sodium sulfide; ammonium chloride; In water; at 70 - 80℃; for 2h; |
Based on compound III, 50.0 g of compound III synthesized in Example 1 was added to the reactor, and 150 g of purified water and 180 g of methanol were added. After stirring, 100.0 g of sodium sulfide nonahydrate was added, and 15.6 g of ammonium chloride was added. 70 ~ 80 , holding reaction for 2h. After the reaction was detected to be complete, the temperature was lowered to 20-30 C. 330 g of dichloromethane was added to the reaction solution, and the mixture was extracted by stirring. The layers were allowed to stand and the organic phase was taken. The organic phase was washed twice with purified water, each time the amount of purified water was 150 g, and the washed organic phase was dried over anhydrous sodium sulfate. The dried organic phase was filtered, and the filtrate was distilled under reduced pressure at 40 to 50 C. When the remaining volume of the reaction solution was about 100 ml, 170 g of n-heptane was added, and the distillation was continued under reduced pressure at 40 to 50 C. When the volume is about 100ml, the temperature is lowered to 5-10 C, the crystallization is stirred for 1.5h, filtered, and the wet product is dried at 50-55 C to obtain 43.4 g of product IV, yield: 96.2%. |
| 95.0% |
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; |
A suspension of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (15.4 g, 50 mmol) in CH3OH (200 mL) with the 1.54 g 10% palladium carbon was stirred for 5 h at room temperature under an atmosphere of hydrogen gas. The reaction mixture was filtered and concentrated in vacuo to offord 11a (13.2 g, 95.0%) as a brown solid. MS (ESI) m/z 279.2 [M+H]+; 1H NMR (400MHz, CDCl3): delta 7.77 (d, J=2.50Hz, 1H), 7.17 (dd, J=2.50Hz, 8.90Hz, 1H), 6.49 (d, J=8.80Hz, 1H), 4.20 (s, 2H), 3.57 (t, J=4.80Hz, 4H), 2.96 (t, J=4.90Hz, 4H), 1.48 (s, 9H). |
| 95% |
With palladium on activated charcoal; hydrogen; In methanol; ethanol; at 20℃; for 2h; |
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, 50%) 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 H2, stirred at RT under a H2 atmosphere for 2h, and filtered and concentrated under a vacuum to obtain INT-3 (792.0mg; yield, 95%) as an off-white solid. ESI-MS: m/z 279.2 [M+H]+. |
| 95.46% |
With 5% Pd/C; hydrogen; In methanol; at 50℃; under 2585.81 Torr; for 18h; |
Step 2 tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate In a nitrogen atmosphere, to a solution of tert-butyl 4-(6-nitro-3-pyridine) piperazine-1-carboxylate (28.00 g, 90.81 mmol, 1.00 equivalent) in methanol (600 mL) was added palladium on carbon (6%, 1.7 g). The suspension was evacuated and filled with hydrogen several times. The solution was stirred at 50C in a hydrogen atmosphere (50psi) for 18 hours. TLC (dichloromethane: methanol = 10: 1) showed that the starting material reacted completely. The suspension was filtered, and the filtrate was dried using a rotary vacuum dryer to give the title compound (24.13 g, 86.69 mmol. 95.46% yield) as a purple solid. 1H NMR (400 MHz, CDCl3) delta 7.78 (d, J = 2.64 Hz, 1H) 7.18 (dd, J = 8.78, 2.89 Hz, 1H) 6.50 (d, J = 8.78 Hz, 1H) 4.21 (brs, 2H) 3.60-3.54 (m, 4H) 3.00-2.92 (m, 4H) 1.48 (s, 9H). |
| 95% |
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 2250.23 Torr; for 12h; |
Add 100 ml of methanol, 0.10 g of 10% 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 0.5%. 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 95%, purity over 99%. |
| 95.46% |
With 5% Pd/C; hydrogen; In methanol; at 50℃; under 2585.81 Torr; for 18h; |
Under the protection of nitrogen gas, to a solution of compound (3) (28.00 g, 90.81 mmol, 1.00 eq) in methanol (600 mL), palladium on carbon (6%, 1.7 g) was added. The suspension was evacuated and charged with hydrogen gas for several times. The solution was stirred for 18 hours at 50 C. under an atmosphere of hydrogen gas (50 psi). TLC (dichloromethane:methanol=10:1) showed that the starting materials were completely reacted. The suspension was filtered, and the filtrate was dried by rotary evaporation to obtain compound (4) (24.13 g, 86.69 mmol, yield: 95.46%). 1H NMR (400 MHz, CDCl3) delta 7.78 (d, J=2.64 Hz, 1H) 7.18 (dd, J=8.78, 2.89 Hz, 1H) 6.50 (d, J=8.78 Hz, 1H) 4.21 (br s, 2H) 3.60-3.54 (m, 4H) 3.00-2.92 (m, 4H) 1.48 (s, 9H). |
| 94% |
With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate; under 760.051 Torr; |
A mixture of 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.40 g, 11.0 mmol) and 10% 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, 94% yield). MS(ESI) m/z 278 (M+H)+ |
| 93% |
With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate; for 24h; |
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 10% 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, 93%). (LCMS: Rt 2.41, [M+H]+ 279). |
| 93.4% |
With hydrogen;palladium 10% on activated carbon; In methanol; water; at 19 - 54℃; under 1551.49 - 2327.23 Torr; for 0.25h;Inert atmosphere; |
A 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 10% palladium on carbon, 50% water wet catalyst and 807 g (1020 mL) of methanol. The reaction vessel is inerted three times with nitrogen (ca. 30 psi), evacuating the atmosphere above the reaction mixture each time. The vessel is pressurized twice with hydrogen (ca. 30 psi), evacuating the atmosphere above the reaction mixture each time. The reaction vessel is pressurized to 45 psi with hydrogen. The shaker motor is started. The reaction is exothermic. A temperature rise from 19 to 54 C. over 15 min is observed after which time the hydrogen uptake stops. The mixture is allowed to cool to 30 C. over 1 h at which point the shaker is stopped. The hydrogen atmosphere is replaced with nitrogen as described above (Inert the reaction vessel). The catalyst is removed by filtration through a 10 g pad of filter cel. This entire process is repeated once more, both filtrates are combined and charged to a clean 3 L 4-neck round bottom flask.; The filtrates from Step 2.3 is stirred and concentrated under reduced pressure (50 mbar, 40 C. internal MAXIMUM.) to a thick paste. 190 g (250 mL) of tert-butyl methyl ether is charged to the residue. The sample is again stirred and concentrated under reduced pressure (50 mbar, 30 C. internal MAXIMUM.) to a thick paste. 342 g (500 mL) of heptane is charged to the residue and the resulting suspension is stirred for 15 min at 22+/-3 C. The solids are filtered and the filter cake is washed with 68 g (100 mL) of heptane. Dry the solids at 50 C. for 16 h, to afford 112.3 g (93.4%) of Compound A2 as tan plates, mp 124-126 C. |
| 93% |
With palladium 10% on activated carbon; hydrogen; In ethanol; ethyl acetate; at 20℃; for 12h; |
Add to the reaction flask4- (6-nitropyridin-3-yl) piperazine-1-tert-butylcarboxylate (3.4 g, 11 mmol,First step), and palladium on carbon (10%, 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 93% yield. |
| 93.1% |
With palladium on activated charcoal; hydrogen; In methanol; at 20℃; |
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: 93.1%. |
| 92% |
With palladium 10% on activated carbon; hydrogen; In ethanol; ethyl acetate; at 20℃; |
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 10% 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,92%) as yellow solid. 1H NMR (400MHz, CDCl3): delta 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). |
| 92.03% |
With palladium 10% on activated carbon; hydrogen; In ethanol; at 100℃; under 11251.1 Torr; for 0.00833333h; |
300g of tert-butyl 4-(6-nitro-3-pyridyl)-1-piperazinecarboxylate was weighed into 6LAnhydrous ethanol, stir well and add 20g of 10% 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 100C, 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 010C, heat and stir for 1 small test.The filter cake was rinsed with 300 ml of n-hexane.Evaporation under vacuum at 40C for 12 hours gave 249.24 g of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate, yield 92.03%, purity 99.59%. |
| 90.88% |
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 4h; |
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. % 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, 90.88% yield). MS Method 2: RT: 1 .22min, ES+ m/z 279.2 [M+H]+ H NMR (400MHz, CDCb) delta/ppm: 7.70-7.71 (d, J=3.1 Hz, 1 H), 7.08-7.1 1 (d, J=8.0Hz, 1 H), 6.40-6.43 (dd, J=8.0, 3.1 Hz, 1 H), 4.1 1 -4.15 (bs, 2H), 3.50-3.54 (m, 4H), 2.86-2.89 (m, 4H), 1 .42 (s, 9H). |
| 89% |
With acetic acid; zinc; In water; at 10 - 20℃; for 2h; |
To the mixture of tert-butyl 4-(6-nitropyridin-3-yl) piperazine- 1-carboxylate (100 g) and zinc dust (100 g) in 500 ml of DM water was added acetic acid (300 ml) at 10-20C. The reaction mixture was stirred over 2 hrs at 10-20C. Dichloromethane was added to reaction mixture followed by celite bed filtration to remove excess zinc. Layer was separated out followed by washing of organic layer with 15 % Potassium Carbonate solution. The organic layer was concentrated under vacuum and added n-heptane (1000 mL). Reaction mixture was stirred for 2-3 hrs at 20-30C. The solid was collected by filtration to give tan solid (80 g).Yield: 89.0 %; HPLC Purity: 100.0% 1H MR (400 MHz CDC13) delta ppm 7.77 (d, J=2.8, 1H), 7.17-7.14 (dd Jl=9.2, J2=3.2, 1H), 6.49-6.47(d, J=8.0, 1H), 4.24 (br, 2H), 3.56 (t, 4H), 2.97 (t, 4H), 1.48 (s, 9H). |
| 89% |
With palladium 10% on activated carbon; In methanol; at 20℃; for 10h; |
Compound 15 (6.2 g, 20 mmol), was dissolved in 150 mL of methanol was added 10% Pd / C (0.4g, 4 mmol), at room temperature for 10 hours, the reaction was stopped, and filtered. The filtrate by rotary evaporation, purified by silica gel column (petroleum ether: dichloromethane = 10: 1-5: 1) to give a yellow solid 16 (5.0 g, 89%). |
| 85% |
With 10% Pd/C; hydrogen; In methanol; at 20℃; |
Compound 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, 85%). LCMS:279M+H)+, RT=1.120min |
| ~ 84% |
With hydrogen;palladium(II) hydroxide/carbon; In isopropyl alcohol; |
Example 2: Preparation of 4-(6-Nitro-pyridin-3yl)-piperazine-1-carboxylic acid tert-butyl ester (2); 60.0 g of 20% Pd(OH)2/C, 1213.1 g (3.9 moles) of intermediate 2a, and isopropanol were charged and stirred in a Parr reactor, then purged under gas, followed by removal of the catalyst under pressure. The filtrates were concentrated in vacuo at -20 0C leaving 917 g of dry brown powder (crude yield -84%). |
| 83% |
With hydrogen; In methanol; water; under 2585.81 Torr; for 5h; |
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, 50% 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 0C for 45 minutes. The resultant solid was separated by filtration and dried under reduced pressure to yield the title compound (62.5 g, 83%). ESI-MS (M+H)+ 279, C14H22N4O2=278.17 |
| 83% |
With hydrogen; In methanol; water; under 2585.81 Torr; |
tert-Butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (83 g, 269 mmol) prepared in Referential Example 4 was dissolved in methanol (1.3 L) in a Parr Shaker and Raney nickel (15 g, 50% aqueous suspension) was added to the solution. The reaction mixture was stirred under a hydrogen atmosphere (50 psi) for five hours. The reaction mixture was passed through Celite pad to filter out a solid. The filtrate was concentrated under reduced pressure. The resulting solid was suspended in diethyl ether (120 mL), and the suspension was stirred for four hours. Heptane was added, and the suspension was cooled at 0C for 45 minutes. The solid was collected by filtration, and dried under reduced pressure to give the title compound (62.5 g, yield: 83%). ESI-MS (M+H)+ 279, C14H22N4O2 = 278.17 |
| 82.5% |
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 760.051 Torr; for 24h; |
Step 2: Synthesis of tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate 10% palladium/carbon catalyst (0.50 g) was added to a solution of tert-butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (2.85 g, 9.24 mmoL) in methanol (150 mL). The mixed solution was stirred under a hydrogen atmosphere (1 atm) at room temperature for 24 h, and filtered through Celite. The filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (2.12 g, yield: 82.5%). |
| 80% |
With palladium 10% on activated carbon; hydrogen; In ethanol; ethyl acetate; at 20℃; under 750.075 Torr; for 5h; |
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 10% 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 (69%) of the title compound. The mother liquor was purified by column chromatography on silica gel (eluent: gradient 100% ethyl acetate to ethyl acetate / methanol 5: 1 ) to yield further 4.2 g (1 1 %). 1H-NMR (400MHz, DMSO-d6): delta [ppm]= 1 .41 (s, 9H), 2.83 - 2.87 (m, 4H), 3.40 - 3.44 (m, 4H), 5.45 (s, 2H), 6.39 (d, 1 H), 7.17 (dd, 1 H), 7.61 (d, 1 H). |
|
With cyclohexane;palladium 10% on activated carbon; In ethanol; at 85℃; for 60h; |
Under a nitrogen purge, 4-(6-nitro-pyridin-3-yl)-piperazine-l-carboxylic acid tert- butyl ester (Method 50; 15.4g; 0.05mol) was suspended in ca 250ml EtOH. In single portions, cyclohexane (78ml; 0.75mol) and then 10% palladium-on-carbon (7.8g; 7.5mol %) were added, washing in with some more EtOH. The suspension was heated in an oil bath maintained at 85C for 60 h. The reaction mixture was filtered hot through pad of diatoniaceous earth. The filter cake was washed with portions of hot EtOH until filtrate came through nearly clear. Volatiles were removed under reduced pressure to obtain 13g of a beige solid which was further purified by recrystallization from hot methylcyclohexane. NMR: 1.50 (s, 9H), 2.98 (m, 4H), 3.58 (m, 4H), 4.7 (br s, 2H), 6.58 (d, IH), 7.28 ( d, IH), 7.68 (s, IH); m/z 279. |
|
With hydrogen;palladium 10% on activated carbon; In ethanol; ethyl acetate; at 20℃; |
The title compound was prepared by the method described in J Med. Chem. 2005, 48 (7), 2388-2406. Thus, a mixture of 5-bromo-2-nitropyridine (5.03g; 24.8 mmol), potassium carbonate (3.8 g; 1.1 eqiuv.), piperazine (2.8 g; 1.3 equiv.) and tetra-n-butylammoniurn iodide (0.46 g; 0.05 equiv.) in 60 ml of DMSO was heated at 80 C overnight, then cooled and poured into 300 ml of water. The solid was collected by filtration washed with water (50 ml) and DCM (50 ml) and sucked dry to give 650 mg of yellow solid. The aqueous filtrate was extracted with CHCl3 (4 x 150 ml), the combined organics were washed with brine (100 ml), dried (MgSO4), filtered and evaporated to give 5.5g of yellow solid.The 2 batches of product were dissolved in THF / water (40 ml : 10 ml), treated with sodium hydrogen carbonate (3.1 g; 1.5 equiv.) and di-tert-butyl dicarbonate (6.5g; 1.2 equiv.), stirred at room temperature overnight and then evaporated. The residue was partitioned between DCM and brine (100 ml : 100 ml), and the DCM layer separated, dried (MgSO4), filtered and evaporated. The crude material was purified by flash column chromatography (eluting with 1 :2 to 2: 1 EtOAc / P.E.). Product-containing fractions were combined and evaporated to give 4.5 g of 4-(6- nitro-pyridin-3-yl)-piperazine-l-carboxylic acid tert-butyl ester.A mixture of 4-(6-nitro-pyridin-3-yl)-piperazine-l-carboxylic acid tert-butyl ester and 10% palladium on carbon in ethanol / ethyl acetate (100 ml / 100 ml) was hydrogenated at room temperature and pressure overnight, then filtered and the filtrate evaporated to give to give 4 g of 4-(6-amino-pyridin-3-yl)-piperazine-l- carboxylic acid tert-butyl ester as a brown solid. 1H NMR (d6-DMSO) 7.63 (IH, d), 7.18 (IH, dd), 6.40 (IH, d), 5.45 (2H, s), 3.45 (4H, m) 2.85 (4H, m), 1.43 (9H, s). |
|
With hydrogen;palladium on carbon; In methanol; for 4h; |
To a round-bottom flask was added tert-butyl 4-(6-nitropyridin-3- yl)piperazine-l-carboxylate 125-3 (3.4 g, 11 mmol), Pd/C (0.5 g) and methanol (100 mL). The reaction was stirred for 4 hours under hydrogen atmosphere by attaching a hydrogen balloon. The reaction was flushed with nitrogen and the solid was removed by filtration. The solvent was removed by rotary evaporation to give tert-butyl 4-(6-aminopyridin-3-yl)piperazine-l- carboxylate 125-4 as purple solid. MS m/z 279.2 (M + 1). |
|
With hydrogen;Raney-Nickel; In methanol; at 20℃; for 4h; |
EXAMPLE 103C ierf-butyl 4-(6-aminopyridin-3-yl)piperazine-l -carboxy late To a suspension of EXAMPLE 103B (4.5 g, 14.6 mmol) in methanol (100 mL) was added Raney -Nickel (450 mg) and the mixture was stirred at ambient temperature under hydrogen for 4 hours. The catalyst was filtered off and the filtrate was concentrated to give the title compound, which was used in the next step without further purification. |
|
With palladium 10% on activated carbon; hydrogen; In ethanol; for 2h; |
A suspension of 2 and 10% palladium on carbon in ethanol was hydrogenated for 2 h. The reaction mixture was filtered through celite and concentrated in vacuo to give 3 as brown oil. 1H NMR (400 MHz, DMSO-d6): delta 7.77-7.76 (d, J = 2.1 Hz, 1H, ArH), 7.27-7.14 (dd, J = 3.0 Hz, 1H, ArH), 6.51 (d, J = 9.0 Hz, 1H, ArH), 3.61-3.59 (m, 4H, piperazine-CH2), 3.39-3.36 (m, 4H, piperazine-CH2), 1.48 (s, 9H. t-butyl-CH3). |
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With palladium 10% on activated carbon; hydrogen; In methanol; for 3h;Inert atmosphere; |
Synthesis of compound 107.2. A solution of 107.1 (1.2g, 3.89 mmol, 1.0 eq) in methanol (20 mL) was added with 10% Pd/C (120g) under nitrogen atmosphere. Mixture was purged with H2 gas for 3 hours. Reaction mixture was filtered through celite and obtained filtrate was concentrated under reduced pressure to get crude 107.2 (0.8g, 73%) which was used as such for the next step, MS (ES): m/z 204.3 [M+H]+. |
| 26 g |
With ammonium chloride; zinc; In methanol; at 20℃; for 1h; |
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 80C, 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: 90%). |
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With hydrogen; In methanol; at 40℃; |
(2) 20 g of the compound of formula (3) was dissolved in 300 ml of methanol,After nitrogen protection,Through6L hydrogen,Set the temperature to 40 ,Reaction is completed,After filtration,The organic solvent was removed by distillation under reduced pressure,Adding water and extractant to extract compound of formula (4) |
| 7.68 g |
With hydrogen; In methanol; at 20℃; for 4h; |
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 95% yield |
| 792 mg |
With palladium on activated charcoal; hydrogen; In methanol; ethyl acetate; at 20℃; for 2h; |
A 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. The reaction was carried out at room temperature for 2 h. The reaction product was filtered, and concentrated to obtain the titled compound (792 mg, off-white solid). MS (ESI): mass calcd. for C14H22N4O2 278.2, m/z found 279.2 [M+H]+. |
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With palladium on activated charcoal; hydrogen; In ethanol; at 25℃; for 3h; |
To 4-(6-nitro-pyridin-3-yl)-piperazine-1 -carboxylic acid tert- butyl ester (2.0 g, 6.43 mmol) in EtOH (15 ml.) is added Pd/C (200 mg) under a hydrogen atmosphere maintained by a H2 balloon for 3h. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure to afford the crude title compound. (0489) Yield: 1.90 g (quantitative) |
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