5-(4-Methylpiperazin-1-yl)-2-nitroaniline

Solid

A mixture of 5-fluoro-2-nitroaniline (1 g), 1-methylpiperazine (0.752ml) and TEA (1.86ml) in NMP (1.5ml) was heated at 100°C in a microwave oven for 20 h. After cooling down, HA mixture of 5-fluoro-2-nitroaniline (1 g), 1-methylpiperazine (0.752 mL) and TEA (1.86 mL) in NMP (1.5 mL) was heated at 100° C. in a microwave oven for 20 h. After cooling down, H: 5-(4'-methylpiperazin-1'yl)-2-nitroaniline : A stirred mixture of 2-nitro-5- chloroaniline (3. 4g, 19. 76MMOL), 1-METHYLPIPERAZINE (4. 4ML 52MMOL), anhydrous K2CO3 and dry DMF (41ML) was protected with a CaClz DRYING tube and heated at 120°C for 20H. Upon cooling the mixture was poured into 300ml ice cold water and filtration of the resulting suspension afforded a yellow solid Recrystallized using CCl4 to give lustrous bright yellow plates to get 4. 237g (100percent yield) of the title compound. m. p.: 152°C IR : 1H NMR : S 7 27(s, 3H, NCH3), 2.47(m, 4H, H 3', 5'), 6 (d, J 3Hz, 1 H6), 6.37 (dd, J10, 3Hz, 1H, H4), 6.89(s, 2H, NH25-Chloro-2-nitroaniline (401 g, 2.32 mol) was added to a 4-neck 12L round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with NProcedure B[0138] 5-Chloro-2-nitroaniline (308.2 g, 1.79 mol) was added to a 4-neck5000 ml_ round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with NProcedure B5-Chloro-2-nitroaniline (308.2 g, 1.79 mol) was added to a 4-neck 5000 mL round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with NProcedure B [0142] 5-Chloro-2-nitroaniline (308. 2 g, 1.79 mol) was added to a 4-neck 5000 mL round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with N2. 1- Methylpiperazine (758.1 g, 840 mL, 7.57 mol) and 200 proof ethanol (508 mL) were added to the reaction flask with stirring. The flask was again purged with N2, and the reaction was maintained under N2. The flask was heated in a heating mantle to an internal temperature of 97°C (+/-5°C) and maintained at that temperature until the reaction was complete (typically about 40 hours) as determined by HPLC. After the reaction was complete, heating was discontinued and the reaction was cooled to an internal temperature of about 20°C to 25°C with stirring, and the reaction was stirred for 2 to 3 hours. Seed crystals (0.20 g, 0. 85 mmol) of 5- (4-methyl-piperazin-1-yl)-2- nitroaniline were added to the reaction mixture unless precipitation had already occurred. Water (2, 450 mL) was added to the stirred reaction mixture over a period of about one hour while the internal temperature was maintained at a temperature ranging from about 20°C to 30°C. After the addition of water was complete, the resulting mixture was stirred for about one hour at a temperature of 20°C to 30°C. The resulting mixture was then filtered, and the flask and filter cake were washed with water (3 x 2.56 L). The golden yellow solid product was dried to a constant weight of 416 g (98. 6percent yield) under vacuum at about 50°C in a vacuum oven.Procedure C [0143] 5-Chloro-2-nitroaniline (401 g, 2.32 mol) was added to a 4-neck 12 L round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with N2.1- Methylpiperazine (977 g, 1.08 L, 9.75 mol) and 100percent ethanol (650 mL) were added to the reaction flask with stirring. The flask was again purged with N2, and the reaction was maintained under N2. The flask was heated in a heating mantle to an internal temperature of 97°C (+/-5°C) and maintained at that temperature until the reaction was complete (typically about 40 hours) as determined by HPLC. After the reaction was complete, heating was discontinued and the reaction was cooled to an internal temperature of about 80°C with stirring, and water (3.15 L) was added to the mixture via an addition funnel over the period of 1 hour while the internal temperature was maintained at 82°C (+/-3°C). After water addition was complete, heating was discontinued and the reaction mixture was allowed to cool over a period of no less than 4 hours to an internal temperature of 20-25°C. The reaction mixture was then stirred for an additional hour at an internal temperature of 20-30°C. The resulting mixture was then filtered, and the flask and filter cake were washed with water (1 x 1 L), 50percent ethanol (1 x 1L), and 95percent ethanol (1 x 1L). The golden yellow solid product was placed in a drying pan and dried to a constant weight of 546 g (99percent yield) under vacuum at about 50°C in a vacuum oven.Compound P42: 5-(Morpholin-4-yl)-2-nitroaniline To the flask 2-amino-3-nitro-6-chloropyridine (1.50 g, 8.47 mmol), potassium carbonate (1.30 g, 9.32 mmol) and morpholine (10.5 ml, 119 mmol) were added. The reaction was carried out under argon flow at 130°C overnight. The progress of the reaction was monitored by TLC (system: heptane/ethyl acetate, 1 /1 ). The mixture was cooled to room temperature and poured into the ice-water. A precipitated yellow solid was filtered and dried. 1.789 g of the title product were obtained (yield 94.2percent). Compound P44: 5-(4-Methylpiperazin-1 -yl)-2-nitroaniline; The compound was obtained by the method analogous to that described for Compound P42. Starting from 5-chloro-2-nitroaniline (1.50 g, 8.69 mmol), potassium carbonate (1.35 g, 9.74 mmol) and 1 -methylpiperazine (2.61 g, 26.1 mmol) in 2 ml of DMF, 2.021 g of the title product in the form of a yellow solid were obtained (yield 98.4percent). MS-ESI: calculated for CnHi5-Chloro-2-nitroaniline (308.2 g, 1.79 mol) was added to a 4-neck5000 mL round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with N5-Chloro-2-nitroaniline (308.2 g, 1.79 mol) was added to a 4-neck 5000 mL round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with NProcedure B [0142] 5-Chloro-2-nitroaniline (308. 2 g, 1.79 mol) was added to a 4-neck 5000 mL round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with N2. 1- Methylpiperazine (758.1 g, 840 mL, 7.57 mol) and 200 proof ethanol (508 mL) were added to the reaction flask with stirring. The flask was again purged with N2, and the reaction was maintained under N2. The flask was heated in a heating mantle to an internal temperature of 97°C (+/-5°C) and maintained at that temperature until the reaction was complete (typically about 40 hours) as determined by HPLC. After the reaction was complete, heating was discontinued and the reaction was cooled to an internal temperature of about 20°C to 25°C with stirring, and the reaction was stirred for 2 to 3 hours. Seed crystals (0.20 g, 0. 85 mmol) of 5- (4-methyl-piperazin-1-yl)-2- nitroaniline were added to the reaction mixture unless precipitation had already occurred. Water (2, 450 mL) was added to the stirred reaction mixture over a period of about one hour while the internal temperature was maintained at a temperature ranging from about 20°C to 30°C. After the addition of water was complete, the resulting mixture was stirred for about one hour at a temperature of 20°C to 30°C. The resulting mixture was then filtered, and the flask and filter cake were washed with water (3 x 2.56 L). The golden yellow solid product was dried to a constant weight of 416 g (98. 6percent yield) under vacuum at about 50°C in a vacuum oven.Procedure C [0143] 5-Chloro-2-nitroaniline (401 g, 2.32 mol) was added to a 4-neck 12 L round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with N2.1- Methylpiperazine (977 g, 1.08 L, 9.75 mol) and 100percent ethanol (650 mL) were added to the reaction flask with stirring. The flask was again purged with N2, and the reaction was maintained under N2. The flask was heated in a heating mantle to an internal temperature of 97°C (+/-5°C) and maintained at that temperature until the reaction was complete (typically about 40 hours) as determined by HPLC. After the reaction was complete, heating was discontinued and the reaction was cooled to an internal temperature of about 80°C with stirring, and water (3.15 L) was added to the mixture via an addition funnel over the period of 1 hour while the internal temperature was maintained at 82°C (+/-3°C). After water addition was complete, heating was discontinued and the reaction mixture was allowed to cool over a period of no less than 4 hours to an internal temperature of 20-25°C. The reaction mixture was then stirred for an additional hour at an internal temperature of 20-30°C. The resulting mixture was then filtered, and the flask and filter cake were washed with water (1 x 1 L), 50percent ethanol (1 x 1L), and 95percent ethanol (1 x 1L). The golden yellow solid product was placed in a drying pan and dried to a constant weight of 546 g (99percent yield) under vacuum at about 50°C in a vacuum oven.[0137] 5-Chloro-2-nitroaniline (500 g, 2.898 mol) and 1 -methyl piperazine(871 g, 8.693 mol) were placed in a 2000 mL flask fitted with a condenser and purged with N[0130] 5-Chloro-2-nitroaniline (50O g, 2.898 mol) and 1 -methyl piperazine(871 g, 8.693 mol) were placed in a 2000 mL flask fitted with a condenser and EPO [0133] 5-Chloro-2-nitroaniline (200.0 g, 1.16 mol) was added to a 3-neck3000 mL round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The round bottom flask was then purged with N5-Chloro-2-nitroaniline (500 g, 2.898 mol) and 1 -methyl piperazine (871 g, 8.693 mol) were placed in a 2000 niL flask fitted with a condenser and purged with N5-Chloro-2-nitroaniline (500 g, 2. 898 mol) and 1-methyl piperazine (871 g, 8.693 mol) were placed in a 2000 mL flask fitted with a condenser and purged with N2. The flask was placed in an oil bath at 100°C and heated until the 5-chloro-2- nitroaniline was completely reacted (typically overnight) as determined by HPLC. After HPLC confirmed the disappearance of the 5-chloro-2-nitroaniline, the reaction mixture was poured directly (still warm) into 2500 mL of room temperature water with mechanical stirring. The resulting mixture was stirred until it reached room temperature and then it was filtered. The yellow solid thus obtained was added to 1000 mL of water and stirred for 30 minutes. The resulting mixture was filtered, and the resulting solid was washed with TBME (500 mL, 2X) and then was dried under vacuum for one hour using a rubber dam. The resulting solid was transferred to a drying tray and dried in a vacuum oven at 50°C to a constant weight to yield 670 g (97.8percent) of the title compound as a yellow powder.Synthesis of 5-(4-Methyl-piperazin-1-yl)-2-nitroaniline Procedure A[0156] 5-Chloro-2-nitroaniline (500 g, 2.898 mol) and 1 -methyl piperazine (871 g, 8.693 mol) were placed in a 2000 ml_ flask fitted with a condenser and purged with N5-Chloro-2-nitroaniline (500 g, 2.898 mol) and 1 -methyl piperazine(871 g, 8.693 mol) were placed in a 2000 ml_ flask fitted with a condenser and purged with N5-Chloro-2-nitroaniline (500 g, 2.898 mol) and 1-methyl piperazine (871 g, 8.693 mol) were placed in a 2000 mL flask fitted with a condenser and purged with N5-Chloro-2-nitroaniline (500 g, 2. 898 mol) and 1-methyl piperazine (871 g, 8.693 mol) were placed in a 2000 mL flask fitted with a condenser and purged with N2. The flask was placed in an oil bath at 100°C and heated until the 5-chloro-2- nitroaniline was completely reacted (typically overnight) as determined by HPLC. After HPLC confirmed the disappearance of the 5-chloro-2-nitroaniline, the reaction mixture was poured directly (still warm) into 2500 mL of room temperature water with mechanical stirring. The resulting mixture was stirred until it reached room temperature and then it was filtered. The yellow solid thus obtained was added to 1000 mL of water and stirred for 30 minutes. The resulting mixture was filtered, and the resulting solid was washed with TBME (500 mL, 2X) and then was dried under vacuum for one hour using a rubber dam. The resulting solid was transferred to a drying tray and dried in a vacuum oven at 50°C to a constant weight to yield 670 g (97.8percent) of the title compound as a yellow powder.[0134] 5-Chloro-2-nitroaniline (150.0 g, 0.87 mol) was added to a 4-neck3000 ml_ round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The round bottom flask was then purged with N[0135] 5-Chloro-2-nitroaniline (100.0 g, 0.58 mol) was added to a 3-neck2000 ml_ round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The round bottom flask was then purged with N[0131] 5-Chloro-2-nitroaniline (308.2 g, 1.79 mol) was added to a 4-neck5000 mL round bottom flask fitted with an overhead stirrer, condenser, gas inlet, addition funnel, and thermometer probe. The flask was then purged with NUnder the protection of nitrogen, the compound a (20 g, 0.12 µM) and N - methyl piperazine (50 g, 0.50 µM) by adding 100 ml in [...], namely 5 - chloro -2 - nitroaniline with N - methyl piperazine in a molar ratio of 1: 4.2, stirring, oil bath is heated to reflux, the reaction 24 h after, for thin layer chromatography [...] tracking whether a complete reaction, if not complete reaction, continue to reaction to a complete reaction. The reaction liquid is hot and poured into the containing 400 ml water of 1 L of in the beaker, with yellow material separated out, the suspension mechanical stirring for half an hour, filtered, the filter cake ice-ethanol washing 2 - 3 times. Remove filtrate, the obtained filter cake is placed into an oven 60 °C drying, to obtain the product compound b, yield 92percent.[0136] A 1-L, 4-neck round bottom flask was equipped with a heating mantle, an overhead stirrer, condenser, nitrogen inlet, and thermocouple. The flask was charged with 5-chIoro-2-nitroaniline (150 g, 869 mmol, 1 equiv), 1-methylpiperazine (348 mL, 386 g, 3.48 mol, 4 equiv) and 4M aqueous NaCI (247 mL). The contents of the flask were stirred and purged with N5-Chloro-2-nitroaniline (2 g, 11.6 mmol), 4-methylpiperazine (1.53 mL, 13.8 mmol) and KTo a mixture of 10 mmol of 5-chloro-2-nitroaniline and 30 mmol (3 mol equiv) of anhydrous KTo a solution of 5-cholro-2-nitroaniline (172 mg, 1 mmol), n-methylpiperazine (100 mg, 1 mmol) and potassium carbonate (552 mg, 4 mmol) in DMF (5 mL) was heated at 100 A solution of 5-chloro-2-nitroaniline (172 mg, 1 mmol), N-methylpiperazine (100 mg, 1 mmol) and potassium carbonate (552 mg, 4 mmol) in DMF (5 mL) was heated at 100°C for 6 h and then cooled to room temperature. After theaddition of water (20 mL), the resulting precipitate was filtered and the obtained solid was suspended in 2N acetic acid (25 mL) and filtered. The filtrate was slightly basified with ammonia solution and the resulting precipitate was filtered off to give the compound 9a as a yellow solid. Yield: 188 mg, 79percent; mp 132-134°C; To a solution of 5-chloro-2-nitroaniline (2 g, 11.6mmol) in dry DMF (10 mL), K2CO3 (2.40 g, 17.4 mmol) and 1-methylpiperazine (46, 1.93 mL, 17.4 mmol) were added. The reaction mixturewas heated to 110 °C for 36 h. Completion of reaction was observed by TLC(1:9/MeOH:CH2Cl2, Rf 0.35). The reaction mixture was diluted with EtOAc (60 mL), washedsuccessively with H2O (2×50 mL) and brine (20 mL), then dried over MgSO4. The organic layer was removed under reduced pressure and the residue was purified by flash chromatography(SiO2, 1:9/MeOH:CH2Cl2) to afford compound 51 as a yellow solid (2.1 g, 78percent)To a solution of 5-chloro-2-nitro-aniline (5.0 gm, 28.9 mmol) in DMF (16.0 mL), N-methyl piperazine 4800 □L, 44.7 mmol) and KA mixture of 2a (3.45 g, 10mmol), 1-methylpiperazine (11 mL, 100 mmol, 10 equiv) and potassium carbonate (13.8 g, 100 mmol, 10 equiv) in DMF (60 mL) was stirred at 100 oC for 24 h. The reaction mixture was poured into water and the precipitated solid was collected by filtration to give 1.29 g (27percent) of 2b as a yellow solid: 1H NMR (CDCl3, 500 MHz, ?; ppm) 8.02 (1H, d, J = 9.5 Hz), 6.29 (1H, dd, J = 9.5 Hz, 2.5 Hz), 6.13 (2H, br s), 5.94 (1H, d, J = 2.5 Hz), 3.37 (4H, t, J = 4.9 Hz), 2.52 (4H, t, J = 4.9 Hz), 2.34 (3H, s).

Molecular Weight:236.27
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:236.12732577
Monoisotopic Mass:236.12732577
Topological Polar Surface Area:78.3
Heavy Atom Count:17
Complexity:273
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes