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CAS No. : | 302800-13-1 | MDL No. : | MFCD09862513 |
Formula : | C7H7BrN2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FTVGSRGPTYFWRQ-UHFFFAOYSA-N |
M.W : | 231.05 g/mol | Pubchem ID : | 10609530 |
Synonyms : |
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Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P261-P264-P270-P271-P280-P302+P352-P304+P340-P310-P330-P361-P403+P233-P405-P501 | UN#: | 2811 |
Hazard Statements: | H301-H311-H331 | Packing Group: | Ⅲ |
GHS Pictogram: |
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* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With zinc In methanol; water at 20℃; for 1 h; | A solution of 12a (350 mg, 1.51 mmol), zinc (495 mg, 7.57 mmol), and NH4Cl (810 mg, 15.15 mmol) in MeOH (4 mL)/water (2 mL) was stirred at rt for 1 h. The insoluble material was removed by filtration and neutralized satd NaHCO3 solution. The mixture was concentrated and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give the title compound as a brown solid (282 mg, 93percent). 1H NMR (400 MHz, DMSO-d6) δ 2.68 (3H, d, J = 4.9 Hz), 4.60 (2H, s), 4.87 (1H, d, J = 4.9 Hz), 6.32-6.58 (3H, m). MS (ESI/APCI) m/z = 202.09 [M+H]+. |
78% | With iron; ammonium chloride In methanol; water at 75℃; for 12 h; | The NH4Cl (18.01g,336 . 7 mmol) of H2O (80 ml) solution is added to 5 - bromo - N - methyl -2 - nitroaniline (10.00 g, 43 . 28 mmol) in MeOH (85 ml) solution, and then the iron powder (9.65 g, 172.8 mmol) added new staff in the mixed solution, 75 °C oil bath is heated under reflux reaction 12 h. The reaction cooling to room temperature, filtered to remove insoluble matter, concentrated under reduced pressure, to the residue add saturated NaCl in aqueous solution (50 ml), then DCM (100 ml × 3) extraction, the combined organic phase, and anhydrous Na2SO4Drying, concentrated under reduced pressure, the crude product separation and purification with silica gel column chromatography (eluent: PE/EtOAc (v/v)=6/1), to obtain the product as a brown solid (6.80 g, 78percent). |
73.4% | With sodium dithionite In ethanol; water | Step B(2-amino-5-bromophenyl)methylamine [00303] To a bright yellow solution of 5-bromo-N-methyl-2-nitroaniline (1.56 g, 6.75 mmol) in EtOH (100 mL) was added dropwise a solution of sodium dithionate (8.35 g, 40.5 mmol) in H20 (80 mL). The resulting pale yellow slurry was filtered and the solid was washed with EtOH. The filtrate was concentrated. The residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with a sat. NaCI solution (100 mL) and concentrated to obtain (2-amino-5-bromophenyl)methylamine (996 mg, 4.95 mmol, 73.4 percent yield) as a brown oil: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.68 (s, 3 H) 4.62 (br. s., 2 H) 4.89 (br. s., 1 H) 6.40 (d, J=2.15 Hz, 1 H) 6.42 - 6.46 (m, 1 H) 6.49 - 6.54 (m, 1 H); ES LC-MS m/z =201.5 (Br79, M+H)+; ES LC-MS m/z =203.4 (Br81, M+H)+. |
53% | With tin(ll) chloride In ethanol at 70℃; for 3 h; | Part B:To compound 229 (5.40 g, 23.4 mmol) in ethanol (200 ml_) was added tin (II) chloride (22.2 g, 117 mmol). The resulting solution was stirred at 7O0C for 3 hours at which time LC-MS indicated that the reaction was complete. The reaction mixture was <n="113"/>concentrated under vacuum. Ice-water was added to the residue, the pH adjusted to 10 with aqueous sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anh sodium sulfate and concentrated under vacuum. Purification by column chromatography (SiO2, 5percent EtOAc/DCM) afforded compound 230 as a yellow oil 2.50 g (53percent). 1H NMR (400 MHz, DMSO-d6) δ 6.50 (dd, 1 H), 6.43 (d, 1 H), 6.38 (d, 1 H)1 4.6 (bs, 2H), 2.68 (d, 3H). |
8.36 g | With hydrogenchloride; ammonium chloride; zinc In methanol; water at 50℃; | Example 47 4- (Benzyloxy) -1- (2-ethyl-l-methyl-lH-benzimidazol-6- yl) pyridin-2 (1H) -one A) 6-Bromo-2-ethyl-l-methy1-lH-benzimidazole A mixture of 5-bromo-N-methyl-2-nitroaniline (10 g) , zinc (14.15 g), NH4C1 (23.15 g) , MeOH (70 ml), 1 M HC1 (10 ml) and water (35 ml) was stirred at 50°C overnight. The mixture was neutralized with saturated NaHCC>3 solution and passed through celite pad to remove the precipitate. After evaporation of the solvent, the mixture was extracted with EtOAc three times. The organic layer was separated, washed with water and brine, dried over MgS04, passed through NH silica pad, and concentrated in vacuo to give an intermediate diamine (8.36 g) as a dark brown oil. The intermediate diamine was dissolved in DMF (160 ml) , and N, N-diisopropylethylamine (15.12 ml), propanoic acid (3.53 ml) and HATU (18.1 g) were added. The mixture was stirred at room temperature for 2 h. The mixture was quenched with brine and extracted with EtOAc five times. The organic layer was separated, dried over MgS04 and concentrated in vacuo. The resulting residue was dissolved in AcOH (70.0 ml), and stirred at 80°C for 1 h. After evaporation of the solvent, the residue was passed through NH silica pad and purified by NH silica gel column chromatography (hexane/EtOAc) . The resulting, solid was washed with IPE/hexane to give the title compound (5.92 g) as a red solid. MS (ESI+) : [M+H]+ 239.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Stage #1: With tin(ll) chloride In ethanol at 80℃; for 4 h; Stage #2: With toluene-4-sulfonic acid In toluene at 110℃; for 15 h; |
Step 3: 6-Bromo-l-methyl-117-benzoimidazole; [0311] To a suspension of (5-bromo-2-nitro-phenyl)-methyl-amine (1.2 g, 5.19 mmol) in ethanol (25 mL) was added tin(II) chloride (1.97 g, 10.39 mmol). The reaction mixture was stirred at 8O0C for 4h, then it was concentrated in vacuo. To the residue was added toluene (12 mL), trimethyl orthoformate (0.625 mL, 5.71 mmol), and para-toluenesulfonic acid (49 mg, 0.26 mmol). The reaction mixture was stirred at HO0C for 15h, then it was concentrated in vacuo and the residue was adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-8percent methanol/dichloromethane afforded 482 mg of 6- bromo-1 -methyl- l//-benzoimidazole as a dark orange solid (44percent yield): 1H NMR (DMSO- EPO <DP n="84"/>d6) δ 3.83 (s, 3H), 7.33 (dd, IH), 7.59 (d, IH), 7.86 (d, IH), 8.21 (s, IH); MS (m/z) 211, 213 [M+H+]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With iron; ammonium chloride In isopropyl alcohol for 24 h; Reflux | [0444j Step B: Preparation of 6-bromo-1-methyl-benzimidazole: A mixture of 5- bromo-N-methyl-2-nitro-aniline (6.0 g, 26 mmol), iron powder (14.5 g, 260 mmol), ammonium chloride (13.9 g, 260 mmol) and formic acid (49.0 mL, 1298 mmol) in 2- propanol (75 mL) was stirred under reflux for 24 hours. After cooling to ambient temperature, ethyl acetate (50 mL) was added. The solid was removed by filtering through a pad of celite. The filtrate was concentrated. Saturated sodium bicarbonate (20 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by flash chromatography on silica gel 10:1 ethyl acetate/MeOH to give 6-bromo-1-methyl-benzimidazole (5.35 g, 98percent) as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | In ethanol; water; for 2h;Heating / reflux; | To a solution of intermediate 1 (8g, 28.5 mmol) in EtOH (200ml) was added a solution of methylamine 40% in water (200ml) and the mixture was heated under reflux for 2 hours and then cooled. The resulting precipitate was filtered and dried. The title compound was obtained as an orange solid (5g, 76%); m.p. 130-132C. |
76% | In ethanol; water; at 80℃; for 3h; | Step 2: (5-Bromo-2-nitro-phenyl)-methyl-amine; [0310] To a solution of 2,4-dibromo-l-nitro-benzene (2.0 g, 7.14 mmol) in ethanol (50 mL) was added a 40% aqueous solution of methylamine (50 mL). The reaction mixture was stirred at 8O0C in a closed vessel for 3 h, then cooled to O0C. Water was added and the precipitate was filtered, washed with water, and dried in vacuo to give 1.26 g of (5-bromo- 2-nitro-phenyl)-methyl-amine as an orange solid (76% yield): 1H NMR (CDCl3) delta 3.04 (s, 3H), 6.79 (dd, IH), 7.03 (d, IH), 8.05 (d, IH), 8.0-8.1 (broad s, IH); MS (m/z) 231, 233 [M+H+]+. |
76% | In ethanol; water; for 2h;Heating / reflux; | To a solution of intermediate 1 (8g, 28.5 mmol) in EtOH (200ml) was added asolution of methylamine 40% in water (200ml) and the mixture was heated under reflux for 2 hours and then cooled. The resulting precipitate was filtered and dried.The title compound was obtained as an orange solid (5g, 76%); m.p. 130-132C |
68% | In ethanol; water; for 2h;Heating / reflux; | Example 14; 224 229 230 231232Part A:Compound 224 was prepared via the synthetic method described in Example 13 (Part A). A solution of compound 1 (10.0 g, 35.8 mmol) and 40% aqueous methylamine (270 ml_) in ethanol (270 ml_) was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature, resulting in the formation of a precipitate, which was filtered and dried to afford compound 229 as a yellow solid 5.6 g (68%). 1H NMR (400 MHz, DMSO-d6) delta 7.95 (d, 1 H), 7.14 (d, 1 H), 6.79 (dd, 1 H), 2.94 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | In ethanol; water monomer; at 20℃; for 48h; | [0443j Step A: Preparation of 5 -bromo-N-methyl-2-nitro-aniline: A suspension of 4- bromo-2-fluoro-1-nitro-benzene (5.0 g, 22.7 mmol) in 95% ethanol (20 mL) was treated with 40% methylamine in water (5.9 mL, 68 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 2 days. Water (200 mL) was added. The resulting mixture was stirred at ambient temperature for 10 minutes. Ethyl acetate (100 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure to give 5-bromo-N-methyl-2-nitro-aniline (5.2 g, 99%) as solid. |
98% | In tetrahydrofuran; methanol; at 45℃; for 12h; | To the mixture of 4-bromo-2-fluoro-l -nitrobenzene (25.0 g, 113.0 mmol) in MeOH (100.0 mL) and THF (50.0 mL) was added MeNH2 (67.5 mL, 135.0 mmol, 2 M in THF) dropwise. The mixture was stirred at 10 C for 12 hours. Then more MeNH2 (60.0 mL, 2 M in THF) was added to the mixture and the mixture was stirred at 45 C for 12 hours. The mixture was concentrated in vacuo to give residue. Water (200.0 mL) added to the mixture and the mixture was extracted with EtOAc (200.0 mL x 2). The organic layers were washed with brine and dried over anhydrous Na2S04, filtered and the filtrate was concentrated in vacuo to give 5-bromo-A-methyl-2-nitroaniline (25.5 g, 98% yield) as a yellow solid. 1HNMR (400 MHz, CDCl3) 7.95 (d, J= 9.2 Hz, 2H), 6.93 (d, 7= 1.6 Hz, 1H), 6.71-6.68 (m, 1H), 7.48 (s, 1H), 2.94 (d, 7= 5.2 Hz, 3H). |
97% | In tetrahydrofuran; at 20℃; for 0.166667h; | [00328] Step 1. 4-Bromo-2-fluoro- 1 -nitrobenzene 16-A (5.5 g, 25 mmol) was added to a solution of methyl amine in THF (37.5 mL, 2 M). The mixture was stirred at room temperature for 10 min, quenched with a sat. NFLCl aqueous solution (10 mL). The aqueous mixture was extracted with EtOAc (30 mL x 3), and the combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2S04, concentrated to provide the intermediate 16-B as a yellow oil (5.6 g, 97%). LC-MS: m/z = 231.0 [M+H]+. |
95% | In ethanol; at 20℃; for 0.583333h; | 2M Methylamine in ethanol (4.9 ml; 9.73 mmol; 2.00 eqf.) is dropped in over 5 min at rt to the stirred solution of 4-bromo-2-fluoro-1 -nitrobenzene (1.07 g; 4.86 mmol; 1.00 eq.) in ethanol (10.00 ml). RM is stirred at rt for 30 min, then solvent is evaporated and residue is triturated with water to remove methylamine hydrofluoride. The remaining residue is collected by filtration, washed with water and dried at 60 C in an oven to give 5-bromo-N-methyl-2- nitroaniline (1.07 g; 4.62 mmol; yield 95.0%; 100% by UPLC) as orange thin needles. |
95% | In ethanol; | 4-Bromo-2-fluoro-l -nitrobenzene (23 g, 105 mmol) was dissolved in EtOH(20 mL), Με Η2 (250 mL, 33%,in EtOH) was added, the mixture was stirred at R.T overnight, The mixture was detected by LC-MS, the starting material was consumed, evaporated the solvent, the crude was dissolved in EtOAc (300 mL) and washed with water (200 mL x 2) and brine (200 mL),dried with Na2S04, filtered and the organic phase was evaporated the solvent, 23 g of the target compound was obtained as yellow solid (95 % yield). NMR (400 MHz, CDCb) δ 8.03 (d, J= 9.2 Hz, 2H), 7.01(s, 1H), 6.76 (d, J= 9.2 Hz, 1H), 3.02(s, 3H); LC-MS (ESI+): m/z 232.1 (M+H)+ . |
95% | In ethanol; at 20℃; | To a solution of 4-bromo-2-fluoro-1-nitrobenzene (23 g, 105 mmol) in EtOH (50 mL) was added MeNH2 (250 ml, 33% in EtOH). After the addition, the mixture was stirred at rt overnight. The reaction mixture was concentrated under reduce pressure. The residue was dissolved in EtOAc (300 mL), washed with water (200 mL×2) and brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (23 g, 95% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=9.2 Hz, 2H), 7.01 (s, 1H), 6.76 (d, J=9.2 Hz, 1H), 3.02 (s, 3H). LC/MS (ESI, m/z): [M+1]+=231.1 |
95% | With potassium carbonate; In tetrahydrofuran; dichloromethane; at 20℃; for 16h; | To a stirred solution of 4-bromo-2-fluoro-1-nitrobenzene (1, 300 g, 1.36 mol) in DCM (3 L) were added K2CO3 (0.94 Kg, 6.8 mol) and methylamine (2M in THF) (2.04 L, 4.09 mol) at RT and stirred for 16 h. Two batches of the reaction were combined. After completion of reaction, the reaction mixture was diluted with water (3.0 L) and extracted with DCM (2.5 L x 2). The combined organic layer was washed with saturated sodium bicarbonate solution (1.5 L x 2) and brine (1.5 L x 2). The organic layer was dried over sodium sulphate, filtered and solvent removed under reduced pressure to obtain 5-bromo-N-methyl-2-nitroaniline (2, 600 g, 95% yield) as a yellow solid. LCMS (ES+): m/z 231.1 [M+H]+ |
95% | With potassium carbonate; In tetrahydrofuran; dichloromethane; at 20℃; for 16h; | To a stirred solution of 4-bromo-2-fluoro-l -nitrobenzene (300 g, 1.36 mol) in DCM (3 L) were added K2CO3 (0.94 Kg, 6.8 mol) and methylamine (2M in THF) (2.04 L, 4.09 mol) at room temperature and stirred for 16 h. Two batches of the reaction were combined. After completion of reaction, the reaction mixture was diluted with water (3.0 L) and extracted with DCM (2 x 2.5 L). The combined organic layer was washed with saturated sodium bicarbonate solution (2 x 1.5 L) and brine (2 x 1.5 L). The organic layer was dried over sodium sulphate, filtered and solvent removed under reduced pressure to obtain 5-bromo-N-methyl-2-nitroaniline (600 g, 95% yield) as a yellow solid. LCMS (ES+): 231.1 [M+H]+ |
95% | In tetrahydrofuran; dichloromethane; at 20℃; for 18h; | To a 1 L round bottomed flask were added 4-bromo-2-fluoro-l -nitrobenzene (16 g, 73 mmol) and DCM (400 mL). To this mixture was added methylamine (2.0 M solution in THF) (88 mL, 180 mmol). Upon addition of amine, the solution rapidly changed from a pale yellow to a bright orange solution. The reaction mixture was stirred at room temperature under a closed system. After 18 h, the reaction mixture was filtered through a plug of SiCh (250 g), with 2: 1 Hex:EtOAc as eluent. The filtrate was concentrated and dried in vacuo to afford the title compound (16 g, 69 mmol, 95 % yield) as a yellow solid. ’H NMR (500 MHz, METHANOL-d4) 6 8.05 (d, J=9.1 Hz, 1H), 7.18 (d, J=1.9 Hz, 1H), 6.85-6.78 (m, 1H), 3.02 (s, 3H). Analytical LC/MS (Method 3): Observed Mass: 232.9; Retention Time: 0.97 min. |
95% | In tetrahydrofuran; dichloromethane; at 20℃; for 18h; | To a 1 L round bottomed flask were added 4-bromo-2-fluoro-l -nitrobenzene (16 g, 73 mmol) and DCM (400 mL). To this mixture was added methylamine (2.0 M solution in THF) (88 mL, 180 mmol). Upon addition of amine, the solution rapidly changed from a pale yellow to a bright orange solution. The reaction mixture was stirred at room temperature under a closed system. After 18 h, the reaction mixture was filtered through a plug of SiCh (250 g), with 2: 1 Hex:EtOAc as eluent. The filtrate was concentrated and dried in vacuo to afford the title compound (16 g, 69 mmol, 95 % yield) as a yellow solid. ’H NMR (500 MHz, METHANOL-d4) 6 8.05 (d, J=9.1 Hz, 1H), 7.18 (d, J=1.9 Hz, 1H), 6.85-6.78 (m, 1H), 3.02 (s, 3H). Analytical LC/MS (Method 3): Observed Mass: 232.9; Retention Time: 0.97 min. |
94% | In ethanol; at 20℃; for 1h; | To a solution of 11 (25.0 g, 114 mmol) in EtOH (100 mL) was added methylamine (40% in MeOH, 34.8 mL, 341 mmol) at rt. The mixture was stirred at rt for 1 h and then cooled to 0 C. The precipitate was collected by filtration, and washed with EtOH and IPE successively to give the title compound (24.8 g, 94%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.95 (3H, d, J = 4.9 Hz), 6.83 (1H, dd, J = 9.1, 1.9 Hz), 7.17 (1H, d, J = 1.9 Hz), 7.98 (1H, d, J = 9.1 Hz), 8.23 (1H, br s). |
93% | In dichloromethane; at 13℃; for 10h; | The methylamine aqueous solution (30 ml, 250 mmol, 33 wt %) is added to the 4 - bromo -2 - fluoro -1 - nitrobenzene (10.22 g, 46 . 45 mmol) in DCM (50 ml) solution, room temperature (13 C) reaction under 10 h. The reaction solution concentrated under reduced pressure, to obtain the product as a yellow solid (10 g, 93%). |
93% | In ethanol; at 20℃; for 16h;Sealed tube; | Into a sealed tube were added 4-bromo-2-fluoro-1-nitrobenzene (46 g, 209 mmol) and methylamine (30% in ethanol, 500 mL) at room temperature. After stirring for an additional 16 h, the resulting solution was concentrated under reduced pressure. The residue was triturated with water (1 L) and filtered. The filter cake was collected and dried under vacuum to afford 5-bromo- N-methyl-2-nitroaniline (45 g, 93%) as an orange solid. 1H NMR (400 MHz, DMSO-d6) d 8.25 (br s, 1H), 8.02-7.94 (m, 1H), 7.17 (t, J = 2.9 Hz, 1H), 6.83 (dd, J = 9.1, 2.2 Hz, 1H), 2.95 (d, J = 4.7 Hz, 3H). LC/MS (ESI, m/z): [(M + 1)]+ = 231.15, 233.15 |
92% | In ethanol; at 23℃; for 0.5h;Inert atmosphere; | Methylamine (56.6 mL, 455 mmol, 33% wt in EtOH) was added to a mixture of 4-bromo-2-fluoro-1-nitro-benzene (50.0 g, 227 mmol) in EtOH (455 mL) at 23 C under nitrogen. The mixture was stirred at 23 C for 30 min, filtered and washed with cold EtOH (200 mL) to provide the title compound as a solid (48.2 g, 92%). m/z (ES+) [M+H]+= 231.0, LCMS (A05); tR = 2.51 min; .1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J = 4.3 Hz, 1H), 7.98 (d, J = 9.1 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 6.82 (dd, J = 9.1, 2.1 Hz, 1H), 2.95 (d, J = 5.0 Hz, 3H) |
90.6% | With potassium carbonate; potassium iodide; In dichloromethane; at 80℃; for 18h; | 4-bromo-2-fluoro-1-nitrobenzene (5.000 g, 22.727 mmol), methanamine (0.777 g, 25.000 mmol), potassium carbonate (6.282 g, 45.455 mmol) and potassium iodide (0.377 g, 2.273 mmol) were dissolved in dichloromethane (100 mL) at room temperature, after which the resulting solution was stirred at 80 for 18 hours, and then a reaction was finished bylowering a temperature to room temperature. Hexane was put into the reaction mixture and stirred, after which a precipitated solid was filtered and dried to obtain a title compound (4.760 g, 90.6%) in a yellow solid form. |
83% | In tetrahydrofuran; at 15℃; for 0.166667h; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS321-23-3) was added to a solution of methylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C. for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 7.16 (d, J=1.6 Hz, 1H), 6.82 (dd, J=8.4, 1.6 Hz, 1H), 2.95 (d, J=4.8 Hz, 3H). |
83% | at 15℃; for 0.166667h;Inert atmosphere; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid.1H NMR (400MHz, DMSO-d6) d 8.22 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H). |
83% | at 15℃; for 0.166667h;Inert atmosphere; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) d 8.22 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H). |
83% | In tetrahydrofuran; at 15℃; for 0.166667h; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CAS321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid.1H NMR (400MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 1.6 Hz, 1H), 6.82 (dd, J = 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H). |
83% | In tetrahydrofuran; at 15℃; for 0.166667h; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CASNo.321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (d, J= 9.2 Hz, 1H), 7.16 (d, J= 1.6 Hz, 1H), 6.82 (dd, J= 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H). |
83% | In tetrahydrofuran; at 15℃; for 0.166667h; | 4-bromo-2-fluoro-1-nitro-benzene (230 g, 1.05 mol, CASNo.321-23-3) was added to a solution of mehylamine in tetrahydrofuran (2 M, 1.51 L). The mixture was stirred at 15 C for 10 minutes. On completion, the mixture was diluted with H2O (250 mL) and extracted with EtOAc (3 X 300 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (200 g, 83% yield) as a yellow solid. 1H NMR (400MHz, DMSO-d6) δ 8.22 (s, 1H), 7.98 (d, J= 9.2 Hz, 1H), 7.16 (d, J= 1.6 Hz, 1H), 6.82 (dd, J= 8.4, 1.6 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H). |
77% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 20h; | j00417j To a solution of 4-bromo-2-fluoro-1-nitrobenzene (5.0 g, 22.7 mmol) in N,Ndimethylformamide (80 mL) was added methylamine (2 M in tetrahydrofuran, 22.7 mL) and potassium carbonate (3.93 g, 28.4 mmol). The mixture was stirred at room temperature for 20 hours, then poured into water (50 mL) and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give compound B-73 (4.0 g, 77% yield) as a yellow solid. LCMS (B): tR=0.777 mi, (ES) mlz (M+H) =231.0. ‘H-NMR (CD3C1, 400 MHz): 8.03 (d, J=9.2 Hz, 2H), 7.02 (d, J=1.6 Hz, 1H), 6.78 (dd, J11.2 Hz, J21.2 Hz, 1H), 3.02 (s, 3H). |
74.3% | With potassium carbonate; In tetrahydrofuran; at 90℃; for 6h; | Step A5-bromo-N-methyl-2-nitroaniline[00302] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), a 2 M methylamine solution in THF (5.00 mL, 10.00 mmol) and K2C03 (2.51 g, 18.18 mmol) in DMF (20 mL) was heated at 90 C for 3 h. More methylamine solution in THF (10.00 mL, 20.00 mmol) was added and the reaction mixture was heated at 90 C for 3 h. The resulting mixture was allowed to cool to room temperature, diluted with EtOAc (100 mL) and washed with a 5% aq. LiCI solution (3x100 mL). The organic layer was concentrated onto Celite and purified by column chromatography (silica gel, 0-40% EtOAc/hexane) to obtain 5-bromo-N-methyl-2- nitroaniline (1.56 g, 6.75 mmol, 74.3 % yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 2.94 (d, 3 H) 6.82 (dd, J=9.07, 2.05 Hz, 1 H) 7.16 (d, =1.95 Hz, 1 H) 7.98 (d, J=9.07 Hz, 1 H) 8.24 (d, .7=4.19 Hz, 1 H). |
In ethanol; at 0 - 20℃; for 0.416667h; | To a solution of 4-bromo-2-fluoro-1 -nitrobenzene (10 g, 45.45 mmol) in 20 ml of ethanol under 00C, 30 ml methylamine (33 wt% in ethanol) was added dropwise. After addition, reaction mixture was gradually warmed up to room temperature and stirred for 25 minutes. The mixture was concentrated under reduced pressure to yield N-methyl-(5-bromo- 2-nitrophenyl)amine (9.13 g). 400 MHz 1H NMR (CDCI3) δ 8.0 (d, 1H), 7.0 (d, 1H), 6.7 (dd, 1 H); MS+ 230, 232. | |
In ethanol; acetonitrile; at 20℃; for 4h; | To a stirred partial solution of 4-bromo-2-fluoronitrobenzene (9.2 g; Aldrich) in acetonitrile (140 ml) was added a solution of 8M methylamine in ethanol (86 ml). The reaction was stirred at room temperature for 4 hr and then evaporated to dryness. The residue was partitioned between EtOAc (500 ml) and water (500 ml). The aqueous phase was separated off and extracted with EtOAc (500 ml). The organic phases were combined, washed with water (500 ml) and brine, dried (magnesium sulphate) and evaporated to give the title compound (9.47 g) as an orange-brown solid. | |
In 1,4-dioxane; methanol; at 90℃; for 3.5h;Inert atmosphere; | To a round bottom flask was added added 4-bromo-2-fluoro- 1 -nitrobenzene (11.8 g, 53.7 mmol), anhydrous 1,4 Dioxane (100 mL), and a 2.0 M solution of methyl amine in methanol (56.4 mL, 113 mmol). The reaction mixture was then heated to 90C while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 3.5 hours. The crude reaction mixture was then allowed to cool to room temperature, and concentrated to give 5-bromo-N-methyl-2-nitroaniline (1-1). MS (M)+: observed = 230.9, calculated = 231.05. | |
In methanol; ethanol; at 23℃; for 13h; | S-bromo-N-methyl-2-nitroaniiine (1-2)A solution of 4-Bromo-2-ftuoronitrobenzene (1-1, 10.5 g, 47.7 mmol) in EtOH(100 ml) was treated with Methylamine (2M in MeOH, 28.6 ml, 573 mmol, 1.2 eq) and the resulting dark maroon solution was stirred at 23 deg C for 13 h. The reaction was then concentrated in vacuo, and the residual yellow-orange solid was partitioned between EtOAc (2x250 ml) and water (300 ml). The combined organic layers were dried over Na2S04 and concentrated, leaving the title compound, 5-bromo-N-methyl-2-nitroaniline (1-2), as a bright orange solid. 1HNM (300 MHz, CDC13) δ 8.03 (d, IH, J=9.15 Hz), 7.01 (sd, IH, J=l,83 Hz), 6.77 (dd, IH, J=7.02 Hz), 3.02 (d, 3H, J=4.88 Hz). LRMS m/z: Calc'd for C7H7BrN202 (M+H) 232.1, found 232.8. | |
With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; | Intermediate IX(5-Bromo-2-nitro-phenyl)-methyl-amine Methylamine (2 M in tetrahydrofuran, 11.4 mL) was added to a mixture of 4-bromo-2-fluoro-1-nitro-benzene (2.50 g) and K2CO3 (1.90 g) in N,N-dimethylformamide (40 mL). The resulting mixture was stirred at ambient temperature overnight. Then, the mixture was concentrated under reduced pressure and dichloromethane was added. The resulting mixture was washed with 0.5 M aqueous HCl solution and brine and dried (MgSO4). The solvent was removed to give the product as a solid.Yield: 2.60 g (99% of theory); Mass spectrum (ESI+): m/z=231/233 (Br) [M+H]+. | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 85℃;Sealed vial; | [000202] 4-Bromo-2-fluoronitrobenzene (Aldrich, 1 eqvt), methylamine (2 eqvt), and hunig's base (3 eqvt) in DMF (1 Molar in substrate) were placed in a sealed vial and heated to 85 C overnight. The crude mixture was diluted with water, and the product collected by filtration. Purification by chromatography (gradient: 92:8 hexanes:ethyl acetate to 68:32 hexanes:ethyl acetate) provided the title compound. 1HNMR (DMSO-d6, 400 MHz) δ 8.22 (bd, J = 4.4 Hz, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 2 Hz, 1H), 6.80 (dd, J = 9.2, 2.4 Hz, 1H), 2.92 (d, J = 4.8 Hz). | |
24.8 g | In methanol; ethanol; at 20℃; for 1h; | Example 2 1- (2-Cyclopropyl-l-methyl-lH-benzimidazol-6-yl) -4- ( (4- fluorobenzyl ) oxy) pyridin-2 ( 1H) -one A) 5-Bromo-N-methyl-2-nitroaniline To a solution of 4-bromo-2-fluoro-l-nitrobenzene (25 g) in EtOH (100 ml) was added methylamine (40% in MeOH, 34.8 ml) at room temperature. The mixture was stirred at room temperature for 1 h. After being stirred, the reaction mixture was cooled to 0C, and the precipitate was collected by filtration and washed with EtOH (0C) and IPE. The solid was dried to give the title compound (24.8 g) as a yellow solid. XH NMR (300 MHz, DMSO-d6) : δ 2.95 (3H, d, . J = 4.9 Hz), 6.83 (1H, dd, J = 1.9, 9.1 Hz), 7.17 (1H, d, J = 1.9 Hz), 7.98 (1H, d, J = 9.1 Hz) , 8.23 (1H, brs) . |
24.8 g | In methanol; ethanol; at 20℃; for 1h; | A) 5-Bromo-N-methyl-2-nitroaniline [0294] To a solution of 4-bromo-2-fluoro-1-nitrobenzene (25 g) in ethanol (100 mL) was added methylamine (40% in methanol, 34.8 mL) at room temperature, and the mixture was stirred for 1 hr. The obtained mixture was cooled to 0C, and the resulting precipitate was collected by filtration and washed with ice-cooled ethanol and diisopropyl ether. The obtained solid was dried to give the title compound (24.8 g) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 2.95 (3H, d, J = 4.9 Hz), 6.83 (1H, dd, J = 9.1, 1.9 Hz), 7.17 (1H, d, J = 1.9 Hz), 7.98 (1H, d, J = 9.1 Hz), 8.23 (1H, brs). |
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 2h; | [0007991 To a stirred solution of the compound 1 (2 g, 1 eq)) in DMF (20 mL), methyl amine 2 M solution in THF (9.19 mL, 2 eq) and DIPEA (3.53 g, 3 eq) were added and stirred at room temperature for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3 X 25 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude product 2 (2 g) and used as such for the next step without further purification. | |
In methanol; at 80℃; for 15h; | A mixture of 4-bromo-2-fluoro-1-nitrobenzene (4.0 g, 18.26 mmol) in 30 mLMeNH2/MeOH was stirred at 80 C for 15 h, and poured into H20 (100 mL). The mixture wasextracted with EA (30 mL x 3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to afford 5-bromo-N-methyl-2-nitroaniline (3.8 g, 90 %) as a yellow solid. LC-MS m/z: 232.9 [M+H]+. Purity (214 nm): 88.0%; tR = 1.89 min | |
In ethanol; at 0 - 20℃; for 0.416667h; | To a solution of bromo-2-fluoro-1- nitrobenzene (10 g, 45.45 mmol) in 20 ml of ethanol under O0C, 30 ml methylamine (33 wt% <n="67"/>in ethanol) was added dropwise. After addition, reaction mixture was gradually warmed up to room temperature and stirred for 25 minutes. The mixture was concentrated under reduced pressure to yield N-methyl-(5-bromo-2-nitrophenyl)amine (9.13 g). 400 MHz 1H NMR (CDCI3) δ 8.0 (d, 1 H), 7.0 (d, 1 H), 6.7 (dd, 1 H); MS+ 230, 232. | |
In ethanol; | 4-Bromo-2-fluoro-1-nitrobenzene (23 g, 105 mmol) was dissolved in EtOH (20 mL), Me Eh (250 mL, 33% in EtOH) was added, the mixture was stirred at R.T overnight. When LC- MS showed the starting material was consumed, the solvent was evaporated and the resulting crude was dissolved in EtOAc (300 mL) and washed with water (200 mL x 2) and brine (200 mL), dried over anhydrous Na2S04. The solid was filtered and the filtrate was concentrated to give the crude product 5-bromo-N-methyl-2-nitroaniline as yellow solid (23 g, 95 % yield). 1H NMR (400 MHz, CDCb) δ 8.03 (d, J= 9.2 Hz, 2H), 7.01 (s, 1H), 6.76 (d, J= 9.2 Hz, 1H), 3.02 (s, 3H). LC-MS (ESI+): m/z 232.1 (M+H)+. | |
In methanol; ethanol; at 20℃; for 1h; | To a solution of 4-bromo-2-fluoro-1 -nitrobenzene (0.50 g, 2.28 mmol), in EtOH (10 ml_), methylamine (40% wt/v in methanol, 1 .0 ml.) was added and stirred at room temperature for 1 hour. The precipitated material was filtered under vacuum, washed with hexanes and dried to obtain 5-bromo-N-methyl-2-nitroaniline. 1 H NMR (400 MHz, DMSO-d6) d: 8.24 (brs,1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.16 (d, J = 2 Hz 1 H), 6.82 (dd, J = 2 Hz and 9.2 Hz, 1 H), 2.94 (d, J = 4.8 Hz, 3H). | |
With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 25℃; for 18h;Inert atmosphere; | Step A: 5-Bromo-N-methyl-2-nitroaniline Under a protection of nitrogen, to a solution of 4-bromo-2-fluoro-1-nitroaniline (15.0g, 68.18mmol) and potassium carbonate (11.31g, 81.82mmol) in DMF (250mL) was added dropwise methylamine in tetrahydrofuran (2M, 68.18mL) at 25C, and it was stirred at 25C for 18 hours. The reaction solution was poured into 500mL water, and it was stirred for 10 minutes. The precipitated solid was filtered and dried to give the title compound. 1H NMR (400MHz, CHLOROFORM-d) δ=8.03 (d, J=9.4 Hz, 2H), 7.01 (s, 1H), 6.77 (dd, J=1.8, 9.2 Hz, 1H), 3.02 (d, J=5.1 Hz, 3H). | |
In tetrahydrofuran; at 20℃; | To a solution of 4-bromo-2-fluoro-1-nitro-benzene (1 g, 4.55 mmol) in THF (15 mL) was added methanamine (6.82 mL, 13.64 mmol) (2 M solution in THF), and the mixture was stirred at 20 C. for 2 hours. (0305) The mixture was concentrated to give the crude product (1200 mg, 4.97 mmol) as a solid. LCMS Rt=0.815 min in 1.5 min chromatography, MS ESI calcd. for C7H8BrN2O2 [M+H]+ 231.0, found 230.7. | |
In tetrahydrofuran; at 20℃; | To a solution of 4-bromo-2-fluoro-1-nitro-benzene (1 g, 4.55 mmol) in THF (15 mL) was added methanamine (6.82 mL, 13.64 mmol) (2 M solution in THF), and the mixture was stirred at 20 C. for 2 hours. (0305) The mixture was concentrated to give the crude product (1200 mg, 4.97 mmol) as a solid. LCMS Rt=0.815 min in 1.5 min chromatography, MS ESI calcd. for C7H8BrN2O2 [M+H]+ 231.0, found 230.7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With iron; acetic acid; In water; ethyl acetate; at 50 - 80℃; for 4h;Inert atmosphere; | To a solution of 5-bromo-N-methyl-2-nitroaniline (45 g, 195 mmol) in EtOAc (600 mL) were added AcOH (200 mL), H2O (20 mL) and Fe (45 g, 806 mmol) in portions at 50 oC under nitrogen atmosphere. The resulting mixture was stirred for 4 h at 80 oC. After cooling to room temperature, the resulting mixture was filtered and the filtrate was diluted with water (1 L). The organic phase was separated and the aqueous phase was extracted with EtOAc (2 x 500 mL). The combined organic layers was washed with brine (2 x 400 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 5-bromo- N1-methylbenzene-1,2-diamine (38 g, 97%) as a reddish brown oil. 1H NMR (400 MHz, DMSO- d6) d 6.53 (dd, J = 8.1, 2.2 Hz, 1H), 6.45 (d, J = 8.1 Hz, 1H), 6.41 (d, J = 2.2 Hz, 1H), 4.89 (q, J = 5.1 Hz, 1H), 4.61 (s, 2H), 2.69 (d, J = 4.2 Hz, 3H). LC/MS (ESI, m/z): [(M + 1)]+ = 200.90, 202.90 |
93% | With zinc; In methanol; water; at 20℃; for 1h; | A solution of 12a (350 mg, 1.51 mmol), zinc (495 mg, 7.57 mmol), and NH4Cl (810 mg, 15.15 mmol) in MeOH (4 mL)/water (2 mL) was stirred at rt for 1 h. The insoluble material was removed by filtration and neutralized satd NaHCO3 solution. The mixture was concentrated and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give the title compound as a brown solid (282 mg, 93%). 1H NMR (400 MHz, DMSO-d6) delta 2.68 (3H, d, J = 4.9 Hz), 4.60 (2H, s), 4.87 (1H, d, J = 4.9 Hz), 6.32-6.58 (3H, m). MS (ESI/APCI) m/z = 202.09 [M+H]+. |
78% | With iron; ammonium chloride; In methanol; water; at 75℃; for 12h; | The NH4Cl (18.01g,336 . 7 mmol) of H2O (80 ml) solution is added to 5 - bromo - N - methyl -2 - nitroaniline (10.00 g, 43 . 28 mmol) in MeOH (85 ml) solution, and then the iron powder (9.65 g, 172.8 mmol) added new staff in the mixed solution, 75 C oil bath is heated under reflux reaction 12 h. The reaction cooling to room temperature, filtered to remove insoluble matter, concentrated under reduced pressure, to the residue add saturated NaCl in aqueous solution (50 ml), then DCM (100 ml × 3) extraction, the combined organic phase, and anhydrous Na2SO4Drying, concentrated under reduced pressure, the crude product separation and purification with silica gel column chromatography (eluent: PE/EtOAc (v/v)=6/1), to obtain the product as a brown solid (6.80 g, 78%). |
75% | With iron; acetic acid; In water; ethyl acetate; at 50 - 80℃; for 6h; | To a mixture of 5-bromo-N-methyl-2-nitro-aniline (200 g, 865 mmol) in EtOAc (1 L) and H2O (500 mL) was added AcOH (1.00 L). The mixture was warmed to 50 C., and then Fe (174 g, 3.11 mol) was added to the reaction mixture. After that, the reaction mixture was stirred at 80 C. for 6 hours. On completion, the mixture was filtered through celite. The filtrate was concentrated in vacuo and the residue was diluted with H2O (250 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with aq.NaHCO3 and brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography to give the title compound (130 g, 75% yield) as black oil. 1H NMR (400 MHz, DMSO-d6) delta 6.55-6.52 (m, 1H), 6.48-6.45 (m, 1H), 6.43-6.42 (m, 1H), 4.89-4.88 (m, 1H), 4.61 (s, 2H), 2.70 (d, J=4.0 Hz, 3H). |
73.4% | With sodium dithionite; In ethanol; water; | Step B(2-amino-5-bromophenyl)methylamine [00303] To a bright yellow solution of 5-bromo-N-methyl-2-nitroaniline (1.56 g, 6.75 mmol) in EtOH (100 mL) was added dropwise a solution of sodium dithionate (8.35 g, 40.5 mmol) in H20 (80 mL). The resulting pale yellow slurry was filtered and the solid was washed with EtOH. The filtrate was concentrated. The residue was partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with a sat. NaCI solution (100 mL) and concentrated to obtain (2-amino-5-bromophenyl)methylamine (996 mg, 4.95 mmol, 73.4 % yield) as a brown oil: 1H NMR (400 MHz, DMSO-d6) delta ppm 2.68 (s, 3 H) 4.62 (br. s., 2 H) 4.89 (br. s., 1 H) 6.40 (d, J=2.15 Hz, 1 H) 6.42 - 6.46 (m, 1 H) 6.49 - 6.54 (m, 1 H); ES LC-MS m/z =201.5 (Br79, M+H)+; ES LC-MS m/z =203.4 (Br81, M+H)+. |
70% | With iron; acetic acid; In water; ethyl acetate; at 50 - 80℃; | 5-Bromo-N-methyl-2-nitroaniline (23.0 g, 0.10 mol) was dissolved in AcOH (230 mL), then EtOAc (230 mL) and H20 (50 mL) were added, the mixture was warmed to 50C, Fe (20 g, 0.36 mol) was added, the mixture was heated to 80C about 30 min, the starting material was consumed, the mixture was cooled to R.T, EtOAc (300 mL) and H20 (300 mL) were added, the organic phase was washed with H20 (500 mL x 2), evaporated the solvent, the crude was purified with column (EA: PE = 1 :2), 14 g of product was obtained (70 % yield). LC-MS (ESI+): m/z 202.1 (M+H)+ . |
70% | With iron; acetic acid; In ethyl acetate; at 50 - 80℃; for 1h; | To a solution of 5-bromo-N-methyl-2-nitroaniline (23.0 g, 0.10 mol) in AcOH (230 mL)/EtOAc (230 mL)/(50 mL) was added Fe (20 g, 0.36 mol) at 50 C. After the addition, the reaction mixture was heated to 80 C. and stirred for 1 h. Then the mixture was cooled to rt and filtered. The filtrate was concentrated under reduce pressure. The residue was diluted with EtOAc (300 mL) and H2O (300 mL). The organic layer was washed with H2O (500 mL×2) and brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified with column (EA:PE=1:2) to afford the title compound (14 g, 70% yield) as a yellow solid. LC/MS (ESI, m/z): [M+1]+=201.1 |
53% | With tin(ll) chloride; In ethanol; at 70℃; for 3h; | Part B:To compound 229 (5.40 g, 23.4 mmol) in ethanol (200 ml_) was added tin (II) chloride (22.2 g, 117 mmol). The resulting solution was stirred at 7O0C for 3 hours at which time LC-MS indicated that the reaction was complete. The reaction mixture was <n="113"/>concentrated under vacuum. Ice-water was added to the residue, the pH adjusted to 10 with aqueous sodium carbonate and extracted with ethyl acetate. The organic layer was dried over anh sodium sulfate and concentrated under vacuum. Purification by column chromatography (SiO2, 5% EtOAc/DCM) afforded compound 230 as a yellow oil 2.50 g (53%). 1H NMR (400 MHz, DMSO-d6) delta 6.50 (dd, 1 H), 6.43 (d, 1 H), 6.38 (d, 1 H)1 4.6 (bs, 2H), 2.68 (d, 3H). |
To a solution of intermediate 2 (5g, 21.6mmol) in EtOH (200ml) was added portionwise SnCI2.2H2O (9.8g, 43mmol) and the mixture was heated under reflux for 4 hours and then concentrated under reduced pressure. The residue was treated with water (200ml) and 1N NaOH (100ml). After extraction with CH2CI2, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in toluene (50ml) and trimethylorthoformate (2.6ml, 24 mmol) and ARTS (0.2g) were added and the mixture was heated under reflux for 2 hours and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH2CI2/MeOH (95/5). The title compound was obtained as a cream powder (2.5g, 54.74%); m.p. 126-128C. | ||
With tin(ll) chloride; In ethanol; for 4h;Heating / reflux; | To a solution of intermediate 2 (5g, 21.6mmol) in EtOH (200ml) was added portionwise SnCl2.2H2O (9.8g, 43mmol) and the mixture was heated under reflux for 4 hours and then concentrated under reduced pressure. The residue was treated with water (200ml) and NaOH 1N (100ml). After extraction with CH2CI2, the organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in toluene (50ml) and trimethylorthoformate (2.6ml, 24 mmol) and ARTS (0.2g) were added and the mixture was heated under reflux for 2 hours and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with CH2CI2/MeOH (95/5). The title compoundwas obtained as a cream powder (2.5g, 54.74%); m.p. 126-128C | |
With hydrazine hydrate;Raney nickel; In methanol; water; for 1h;Reflux; | 5-bromo-N-methyl-2-nitroaniline (1.5 g) was dissolved in methanol (60 mL) by heating to 80 C. Hydrazine hydrate was added (3.2 mL) followed by Raney Nickel (50% slurry in water, 6 drops) and the reaction mixture was heated to reflux for 1 hour. The reaction mixture was filtered through Celite and concentrated under reduced pressure, providing 5-bromo-N1-methylbenzene-1,2-diamine as an amber oil. This product was used in the next step without further purification. | |
With water; iron; calcium chloride; In ethanol; for 2h;Heating / reflux; | To a solution of 120 ml ethanol and 30 ml water, N-methyl-(5-bromo-2- nitrobenzene)amine (10.5 g, 45.4 mmol), iron powder (11.4 g, 204.5 mmol) and calcium chloride (4.54 g, 40.9 mmol) was added sequentially. The mixture was heated to reflux for 2 hours. After cooling down to room temperature, the mixture was filtered over celite and <n="63"/>concentrated under reduced pressure to yield 5-bromo-N1-methylbenzene-1 ,2-diamine (9.13 g). MS (M+1 ) 201 , 203. | |
To a stirred solution of (5-bromo-2-nitrophenyl)methylamine (9.46 g, may be prepared as described in intermediate 45) in ethanol (300 ml) was added tin (II) chloride (47.35 g) and the resulting mixture was heated at reflux for 2.5 hr. More tin (II) chloride (30.05 g) was added and reflux was continued for 1 hr. The mixture was allowed to cool then poured into stirred ice / water (2I). The mixture was basified to pH 8 using saturated aqueous sodium bicarbonate and then EtOAc was added. The resultant thick white suspension was filtered through Celite. The aqueous phase was separated off and extracted with EtOAc. The organic phases were combined, washed with brine and dried (sodium sulfate) and evaporated to give the target compound as a dark brown oil (9.50 g). | ||
With acetic acid; zinc; In 1,4-dioxane; at 0 - 90℃; | To a stirred solution of 5-bromo-N-methyl-2-nitroaniline (1-1) (12.4 g, 53.7 mmol) in 1,4 Dioxane (100 mL) at 0C was added powdered zinc (17.6 g, 269 mmol), followed by dropwise addition of glacial acetic acid (15.0 mL, 262 mmol). The reaction mixture was then permitted to warm to room temperature, sonicated for a few minutes, then permitted to stir at room temperature overnight, then heated to 90C in a hot oil bath for four hours. The crude reaction mixture was then cooled to room temperature, then suspended in ethyl acetate, cooled to 0C and neutralized with 6N NaOH while stirring until slightly basic. Crude mixture was then filtered. Filtrate organics were separated, then washed with a saturated solution of sodium bicarbonate, followed by water, then brine, dried over sodium sulfate, filtered, and concentrated to give 4-bromo-N2-methylbenzene-1,2-diamine (1-2) as a black oil. MS (M)+: observed = 200.9, calculated = 201.06. | |
4-bromo-N -methylbenzene-l,2~diamme (1-3)An orange solution consisting of 5-bromo-N-methyl-2-nitroaniline (1-2, 10.5 g, 45.4 mmol) in Acetic acid (200 ml) was treated with Zinc dust (8.92 g, 136 mmol, 3.0 eq), generating a mild exotherm. The cloudy maroon reaction mixture was capped and stirred for 20 mi . The reaction was >80% complete, so an additional amount of Zinc dust (1.0 g, 16 mmol, 0.35 eq) was added and the reaction was stirred for 15 min. LC/MS showed complete reduction, so the reaction mixture was filtered through Celite and washed with MeOH. The residual filtrate was concentrated in vacuo, then partitioned between EtOAc (2x300 ml) and saturated aqueous NaHC03 (350 ml). The combined organic layers were dried over Na2S04 and concentrated, affording the title compound, 4-bromo-N2-methylbenzene-l,2-diamine (1-3), as a brown solid with >90% purity. LRMS m/z: Calc'd for C7¾BrN2 (M+H) 202.1, found 202.8. | ||
With hydrogen; In tetrahydrofuran; at 20℃; under 2585.81 Torr; | Intermediate X4-Bromo-2-methylamino-aniline A mixture of (5-bromo-2-nitro-phenyl)-methyl-amine (2.60 g) and Raney nickel (0.25 g) in tetrahydrofuran (100 mL) was shaken under hydrogen atmosphere (50 psi) at room temperature overnight. Then, the catalyst was separated by filtration and the filtrate was concentrated under reduced pressure to give the crude title compound as a brown oil that was used without further purification.Yield: 2.20 g (97% of theory); Mass spectrum (ESI+): m/z=201/203 (Br) [M+H]+. | |
8.36 g | With hydrogenchloride; ammonium chloride; zinc; In methanol; water; at 50℃; | Example 47 4- (Benzyloxy) -1- (2-ethyl-l-methyl-lH-benzimidazol-6- yl) pyridin-2 (1H) -one A) 6-Bromo-2-ethyl-l-methy1-lH-benzimidazole A mixture of 5-bromo-N-methyl-2-nitroaniline (10 g) , zinc (14.15 g), NH4C1 (23.15 g) , MeOH (70 ml), 1 M HC1 (10 ml) and water (35 ml) was stirred at 50C overnight. The mixture was neutralized with saturated NaHCC>3 solution and passed through celite pad to remove the precipitate. After evaporation of the solvent, the mixture was extracted with EtOAc three times. The organic layer was separated, washed with water and brine, dried over MgS04, passed through NH silica pad, and concentrated in vacuo to give an intermediate diamine (8.36 g) as a dark brown oil. The intermediate diamine was dissolved in DMF (160 ml) , and N, N-diisopropylethylamine (15.12 ml), propanoic acid (3.53 ml) and HATU (18.1 g) were added. The mixture was stirred at room temperature for 2 h. The mixture was quenched with brine and extracted with EtOAc five times. The organic layer was separated, dried over MgS04 and concentrated in vacuo. The resulting residue was dissolved in AcOH (70.0 ml), and stirred at 80C for 1 h. After evaporation of the solvent, the residue was passed through NH silica pad and purified by NH silica gel column chromatography (hexane/EtOAc) . The resulting, solid was washed with IPE/hexane to give the title compound (5.92 g) as a red solid. MS (ESI+) : [M+H]+ 239.0. |
With water; iron; ammonium chloride; In ethanol; at 60℃; for 4h; | [00319] To a solution of 5-bromo-N-methyl-2-nitroaniline (10 g, 43.5 mmol) in EtOH/H20 (700 mL) was added Fe (14.6 g, 261 mmol), ammonium chloride (14 g, 261 mmol) and the reaction mixture was heated at 60 C for 4 h. The crude reaction mixture was filtered, concentrated, dissolved in ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was used in next reaction without further purification. (7.9 g, yield 90%) MS (ESI+) e/z: 202.1. | |
With iron; ammonium chloride; In ethanol; water; at 60℃; for 4h;Inert atmosphere; | To a solution of 5-bromo-N-methyl-2-nitroaniline (10 g, 43.5 mmol) in ethanol/water (700 mL) were added Fe (14.6 g, 261 mmol) and ammonium chloride (14 g, 261 mmol). The reaction mixture was heated at 60 C under the atmosphere of nitrogen for 4h. The solid was removed by filtration. The filtrate was concentrated in vacuo then dissolved in ethyl acetate (300 mL), washed with brine, dried over Na2SO4, and concentrated in vacuo to give the crude product which was used in next step without further purification (7.9 g, 9 1%). LCMS (mlz): 202.1 (M+1). | |
With iron; ammonium chloride; In ethanol; water; for 2h;Reflux; | [000800j To a stirred solution of compound 2 (6 g, 1 eq), in ethanol: water (2:1; 60 mL), iron powder (6 g) and ammonium chloride (5.53 g, 4 eq) were added and heated to reflux for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with ethyl acetate (3 X 50 mL). Combined organic extracts were washed with brine and dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 3. LCMS (mlz): 201.00 (M +1). | |
With water; iron; ammonium chloride; In ethanol; at 60℃; for 13h; | j00419j To a solution of compound B-73 (2.5 g, 10.8 mmol) in ethanol (100 mL) and water (75 mL) was added iron powder (3.6 g, 65 mmol) and ammonium chloride (3.5 g, 65 mmol). The mixture was stirred at 60 C for 13 hours, then concentrated in vacuo to remove ethanol, diluted with water (30 mL) and extracted with ethyl acetate (3 x 90 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give compound B-74 (2.1 g, crude) as a brown oil. LCMS (B): tR=0.468 mi, (ES) m/z (M+H)=201.0. | |
With iron; ammonium chloride; In methanol; at 20 - 75℃; for 15h; | To a mixture of 5-bromo-N-methyl-2-nitroaniline (3.6 g, 16 mmol) in 100 mL ofMeOH were added Fe powder (4.38 g, 78 mmol) and NH4C1 (16.53 g, 311.8 mmol) at RT andthe mixture was stirred at 75 C for 15 h, cooled and filtered. The filtrate was concentrated in vacuo, and the residue was washed with H20 (50 mL). The aqueous phase was extracted with EA (30 ml. x 3), and the organic phases were dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo to afford 5-bromo-N?-methylbenzene-1,2-diamine as a blacksolid (3.1 g, 90 %). LC-MS m/z: 201.1 [M+H]. Purity (214 nm): 73%; tR = 1.66 min | |
With calcium chloride;iron; In ethanol; water; for 2h;Heating / reflux; | To a solution of 120 ml ethanol and 30 ml water, 5-bromo-N-methyI-2-nitrobenzenamine (10.5 g, 45.4 mmol), iron powder (11.4 g, 204.5 mmol) and calcium chloride (4.54 g, 40.9 mmol) was added sequentially. The mixture was heated to reflux for 2 hours. After cooling down to room temperature, the mixture was filtered over celite and concentrated under reduced pressure to yield 5-bromo-N1-methylbenzene- 1 ,2-diamine (9.13 g). MS (M+1) 201 , 203. | |
14 g | With iron; acetic acid; In water; ethyl acetate; at 50 - 80℃; | 5-Bromo-N-methyl-2-nitroaniline (23.0 g, 0.100 mol) was dissolved in AcOH (230 mL), then EtOAc (230 mL) and H20 (50 mL) were added. The mixture was warmed to 50 C, then Fe powder (20 g, 0.36 mol) was added and the mixture was heated to 80 C about 30 min. TLC the starting material was consumed, the mixture was cooled to R.T. EtOAc (300 mL) and H20 (300 mL) were added, the organic phase was washed with H20 (500 mL x 2) and brine (300 mL), the organic phase was dried over anhydrous Na2S04. The solid was filtered and the filtrate was concentrated, the residue was purified by column chromatography on silica gel (EA: PE = 1 :2) to give the product 5-bromo-Nl-methylbenzene-l,2-diamine (14 g, yield 70 %). LC-MS (ESI+): m/z 202.1 (M+H)+ |
With ammonium chloride; zinc; In methanol; water; at 20℃; for 2.25h; | To a solution of 5-bromo-N-methyl-2-nitroaniline (0.40 g, 1 .73 mmol) in a mixture of methanol: water (2:1 , 15.0 ml_), zinc dust (1 .12 g, 17.3 mmol) was added followed by portion wise addition of ammonium chloride (0.91 g, 17.3 mmol) over a period of 15 minutes. After complete addition, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered on celite pad and washed with EtOAc (100 ml_). The organic layer was washed with saturated aqueous sodium bicarbonate solution (50 ml_), water (50 ml_), brine (50 ml_), dried over anhydrous sodium sulfate and concentrated under vacuum to obtain 5- bromo-N1 -methylbenzene-1 ,2-diamine. 1 H NMR (400 MHz, DMSO-d6) d: 6.51 (dd, J = 2.4 Hz and 8 Hz, 1 H), 6.44 (d, J = 8.4 Hz, 1 H), 6.39 (d, J = 2 Hz, 1 H), 4.88 (d, J = 5.2 Hz, 1 H), 4.60 (s, 2H), 2.68 (d, J = 4.8 Hz, 3H). | |
With sodium dithionite; In methanol; water; at 60℃; for 12h; | To the mixture of 5-brorno-Af-rnethyl-2-nitroaniline (10.0 g, 43.2 mmol) in MeOH (150.0 mL) was added sodium dithionite (67.5 g, 388.0 mmol) in H20 (60.0 mL) dropwise. The mixture was stirred at 60 C for 12 hours. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was extracted with EtOAc (200.0 mL x 3), the organic layers were washed with H20 (100.0 mL) and brine (100.0 mL), then dried over anhydrous Na2S04. The mixture was filtered and the filtrate was concentrated in vacuo to give the product of 5-bromo-M-m ethylbenzene- 1, 2-diamine (8.60 g, crude) as a brown oil. |
Yield | Reaction Conditions | Operation in experiment |
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With triethylamine; In DMF (N,N-dimethyl-formamide); at 0 - 70℃; | Step 2:; A mixture of compound 33-2 (6.3 g, 22.4 mmol) and methylamine hydrochloride (3.0 g, 44.8 mmol) in DMF (50 mL) and cooled to 0C. Triethylamine (9.4 mL, 67 mmol) was added and the mixture was allowed to stir at RT for 3.5 h, then heated at 70C overnight. The mixture was poured into water and the resulting precipitate was filtered. The filtrate was extracted with EtOAc (3X) and the extract was washed with water (3X) and saturated NaCI, dried (MgS04), filtered and concentrated to give a mixture of compounds 33-3 and 33-4 as an orange solid (4.8 g), which was used as is in the next step. |
Yield | Reaction Conditions | Operation in experiment |
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44% | Step 3: 6-Bromo-l-methyl-117-benzoimidazole; [0311] To a suspension of (5-bromo-2-nitro-phenyl)-methyl-amine (1.2 g, 5.19 mmol) in ethanol (25 mL) was added tin(II) chloride (1.97 g, 10.39 mmol). The reaction mixture was stirred at 8O0C for 4h, then it was concentrated in vacuo. To the residue was added toluene (12 mL), trimethyl orthoformate (0.625 mL, 5.71 mmol), and para-toluenesulfonic acid (49 mg, 0.26 mmol). The reaction mixture was stirred at HO0C for 15h, then it was concentrated in vacuo and the residue was adsorbed on silica gel. Purification by flash chromatography on silica gel using a gradient of 0-8percent methanol/dichloromethane afforded 482 mg of 6- bromo-1 -methyl- l//-benzoimidazole as a dark orange solid (44percent yield): 1H NMR (DMSO- EPO <DP n="84"/>d6) delta 3.83 (s, 3H), 7.33 (dd, IH), 7.59 (d, IH), 7.86 (d, IH), 8.21 (s, IH); MS (m/z) 211, 213 [M+H+]+. |
Yield | Reaction Conditions | Operation in experiment |
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With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 60℃; for 16h; | To a suspension of 4-bromo-2-fluoro-1-nitrobenzene (3.0 g) in acetonitrile (100 mL) was added 3.7 g of methylamine hydrochloride followed by 12 mL of N,N-diisopropylethylamine. The mixture was stirred at 60 C. for 16 hours. After cooling down to room temperature, the reaction mixture was concentrated, dissolved in ethyl acetate (100 mL) and washed 3 times with water, then brine, and dried over sodium sulfate. The solvent was removed under reduced pressure, providing 5-bromo-N-methyl-2-nitroaniline as an orange solid. The product was used in the next step without further purification. | |
With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h;Microwave irradiation; | [00318] To a solution of 4-bromo-2-fluoro-l -nitrobenzene (10 g, 45.7 mmol) in DMSO (50 mL) was added TEA (18.47 g, 183 mmol), methylamine hydrochloride (6.1 g, 91.4 mmol) and the reaction mixture was heated under microwave conditions at 120 C for 3 h. The mixture was cooled, extracted with ethyl acetate; the combined organic extracts were washed with brine, dried over sodium sulfate and concentrated. The crude product was used in next step without further purification. (10.5 g, yield 98%) MS (ESf) e/z: 231.1. | |
With triethylamine; In dimethyl sulfoxide; at 120℃; for 3h; | To a solution of 4-bromo-2-fluoro-1-nitrobenzene (10 g, 45.7 mmol) in DMSO (50 mL) were added triethylamine (18.47 g, 183 mmol) and methylamine hydrochloride (6.1 g, 91.4 mmol). The reaction mixture was heated at 120 C for 3 hours. After cooling, the mixture was extracted with ethyl acetate (100 mL x 3), the combined organic layers washed with brine, dried over Na2SO4, and concentrated in vacuo to yield a crude product which was used in next step without further purification (10.5 g, 98%). LCMS (mlz): 231.1 (M+1). |
With N-ethyl-N,N-diisopropylamine; at 50℃; for 1h; | To a solution of 4-bromo-2- fluoro-1-nitrobenzene (1 g, 4.55 mmol) in CH3CN (25 mL) was added DIEA (2.94 g, 22.7 mmol, 3.96 mL) and methanamine (1.23 g, 18.3 mmol, HCl). The mixture was stirred at 50 C for 1 hour. TLC indicated the starting material was consumed completely and one new spot was formed. The reaction mixture was partitioned between Ethyl acetate (25 mL) and H2O (25 mL). The organic phase was separated, washed with sat. NaCl (25 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give 29a. 1H NMR (400 MHz, CD3Cl) d 11.25 - 11.44 (m, 1H), 8.04 (br d, J = 9.0 Hz, 1H), 8.01 - 8.08 (m, 1H), 7.02 (s, 1H), 6.78 (br d, J = 8.6 Hz, 1H), 3.63 - 3.71 (m, 1H), 3.07 - 3.13 (m, 1H), 3.01 - 3.05 (m, 3H), 1.46 (d, J = 6.6 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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With potassium acetate;Pd(dppf); In 1,4-dioxane; at 80℃; for 3h;Inert atmosphere; | [000203] 5-Bromo-N-methyl-2-nitroaniline (1 eqvt), bis(pinacolatodiboron) (1.2 eqvt), and potassium acetate (2 eqvt) were combined in dioxane (0.15 M) and degassed 3x replacing the air with nitrogen gas. Pd(dppf) (0.1 eqvt) was added and degassing was done once more. The reaction mixture was heated to 80 C for three hours. The mixture was then cooled to room temperature and partitioned between water and ethyl acetate. The organic fraction was washed with brine, then concentrated onto silica gel and purified by chromatography to provide the title compound. MS (m/z): 317.2 (M + K)+. 1HNMR (DMSO-d6, 400 MHz) δ 8.1 1 (bd, J = 4.8 Hz, 1H), 8.01 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 0.8 Hz, 1H), 6.87 (dd, J = 8.4, 0.8 Hz, 1H), 2.93 (d, J = 4.8, 3H), 1.28 (s, 12 H). |
Yield | Reaction Conditions | Operation in experiment |
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478 mg | Example 29 4- ( (4-Chlorobenzyl) oxy) -1- (2- (methoxymethyl) -1-methyl-lH- benzimidazol-6-yl ) pyridin-2 (1H) -one A) N- (5-Bromo-2-nitrophenyl) -2-methoxy-N-methylacetamide To a solution of <strong>[302800-13-1]5-bromo-N-methyl-2-nitroaniline</strong> (500 mg) in THF(10 ml) was added NaH (40% oil dispersion, 104 mg) at 0C. The mixture was stirred at 0C under a dry atmosphere (CaCl2 tube) for 30 min. After being stirred, methoxyacetyl chloride (0.237 ml) was added to the reaction mixture. The mixture was stirred at 60C under a dry atmosphere (CaCl2 tube) for 3 h and then at room temperature overnight. The mixture was quenched with water and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSC>4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc) . The resulting solid was washed with Et20 to give the title compound (478 mg) as a pale yellow solid. MS (ESI+) : [M+H] + 305.0. |
Yield | Reaction Conditions | Operation in experiment |
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44% | With copper(l) iodide; potassium carbonate; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane; In dimethyl sulfoxide; at 120℃; for 1h;Sealed tube; Microwave irradiation; | General procedure: To a stirred degassed mixture of 8a (502 mg, 2.0 mmol), 4a (470 mg, 2.0 mmol), and K2CO3 (552 mg, 4.0 mmol) in dioxane (15 mL) were added CuI (76 mg, 0.4 mmol) and trans-N,N'-dimethyl-cyclohexane-1,2-diamine (56 mg, 0.4 mmol). The reaction vessel was sealed and heated at 110 C for 16 h. The reaction mixture was cooled to rt and concentrated. The resulting residue was diluted with DCM (250 mL), washed with brine (100 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, DCM/MeOH = 97/3 to 96/4) to give the title compound (150 mg, 18%) as a white solid. |
2.63 g | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 150℃; for 2h; | Example 13 4- ( (4-Fluorobenzyl) oxy) -1- (l-methyl-2- (tetrahydrofuran-3-yl) - lH-benzimidazol-6-yl ) pyridin-2 (1H) -one A) 4- ( (4-Fluorobenzyl) oxy) -1- (3- (methylamino) -4- nitrophenyl) pyridin-2 ( 1H) -one A mixture of 4- ( (4-fluorobenzyl) oxy) pyridin-2 (1H) -one (2.06 g) , <strong>[302800-13-1]5-bromo-N-methyl-2-nitroaniline</strong> (2.17 g) , Ν,Ν'- dimethylethylenediamine (1.00 ml), copper iodide (1.79 g) , potassium carbonate (3.90 g) and DMSO (30 ml) was stirred at 150C for 2 h. The mixture was added to 28% NH3 solution. The precipitate was collected and washed with water to give the title compound (2.63 g) as a yellow solid. MS (ESI+) : [M+H] + 370.1. |
Yield | Reaction Conditions | Operation in experiment |
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0.78 g | Example 14 4- ( ( 4-Fluorobenzyl ) oxy) -1- ( l-methyl-lH-benzimidazol-6- yl ) pyridin-2 ( 1H) -one A) 6-Bromo-l-methyl-2- (trichloromethyl ) -lH-benzimidazole A mixture of 5-bromo-N-methyl-2-nitroaniline (0.65 g) , iron (0.63 g) , CaCl2 (0.62 g) , EtOH (14 ml) and water (14 ml) was heated at 70C for 3h. The inorganic material was removed by filtration, and the filtrate was concentrated. The residue was basified with saturated NaHCC>3, and extracted with EtOAc. The extract was washed with brine, dried over MgS04, and concentrated to give the title compound (0.51 g) as a brown oil. To the oil in AcOH (3 ml), methyl 2,2,2- trichloroacetimidate (0.42 ml) was added dropwise at 0C. The mixture was stirred at room temperature for 2 h. After addition of water, the precipitate was collected by filtration and washed with water to give the title compound (0.78 g) as a gray solid. XH NMR (300 MHz, CDCI3) : delta 4.09 (3H, s) , 7.46 (1H, dd, J = 1.7, 8.5 Hz), 7.58 (1H, d, J = 1.5 Hz), 7.74 (1H, d, J = 8.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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5.92 g | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 2h; | Example 47 4- (Benzyloxy) -1- (2-ethyl-l-methyl-lH-benzimidazol-6- yl) pyridin-2 (1H) -one A) 6-Bromo-2-ethyl-l-methy1-lH-benzimidazole A mixture of <strong>[302800-13-1]5-bromo-N-methyl-2-nitroaniline</strong> (10 g) , zinc (14.15 g), NH4C1 (23.15 g) , MeOH (70 ml), 1 M HC1 (10 ml) and water (35 ml) was stirred at 50C overnight. The mixture was neutralized with saturated NaHCC>3 solution and passed through celite pad to remove the precipitate. After evaporation of the solvent, the mixture was extracted with EtOAc three times. The organic layer was separated, washed with water and brine, dried over MgS04, passed through NH silica pad, and concentrated in vacuo to give an intermediate diamine (8.36 g) as a dark brown oil. The intermediate diamine was dissolved in DMF (160 ml) , and N, N-diisopropylethylamine (15.12 ml), propanoic acid (3.53 ml) and HATU (18.1 g) were added. The mixture was stirred at room temperature for 2 h. The mixture was quenched with brine and extracted with EtOAc five times. The organic layer was separated, dried over MgS04 and concentrated in vacuo. The resulting residue was dissolved in AcOH (70.0 ml), and stirred at 80C for 1 h. After evaporation of the solvent, the residue was passed through NH silica pad and purified by NH silica gel column chromatography (hexane/EtOAc) . The resulting, solid was washed with IPE/hexane to give the title compound (5.92 g) as a red solid. MS (ESI+) : [M+H]+ 239.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.3 g | B) 6-Bromo-2-cyclopropy1-1-methyl-lH-benzimidazole A mixture of <strong>[302800-13-1]5-bromo-N-methyl-2-nitroaniline</strong> (4.2 g) , zinc (5.9 g) , NH4C1 (9.7 g) , MeOH (50 ml) and water (25 ml) was stirred at room temperature for 3 h. After removing MeOH, the mixture was neutralized- with saturated NaHC03 solution and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgS04 and concentrated in vacuo. To a solution of the residue in P0C13 (1.68 ml) was added cyclopropanecarboxylic acid (2.86 ml) at room temperature. The mixture was stirred at 120C for 3 h. After cooling to 0C, ice water and saturated NaHCC>3 solution were carefully added, and the mixture was extracted with EtOAc. The extract was washed with brine, dried over MgS0 , concentrated to give a brown solid. This solid was dissolved in 1 M HC1 and washed with EtOAc. The aqueous layer was basified with 4 M. NaOH, and extracted with EtOAc. The organic layer was washed with brine, dried over MgS04, and concentrated to give the title compound (3.3 g) as a brown solid. XH NMR (300 MHz, DMSO-d6) : δ 0.95-1.14 (4H, m) , 2.23 (1H, tt, J = 5.1, 7.9 Hz), 3.83 (3H, s) , 7.24 (1H, dd, J = 2.1, 8.5 Hz), 7.41 (1H, d, J = 8.7 Hz), 7.75 (1H, d, J = 1.9 Hz). | |
3.3 g | B) 6-Bromo-2-cyclopropyl-1-methyl-1H-benzimidazole [0295] A mixture of <strong>[302800-13-1]5-bromo-N-methyl-2-nitroaniline</strong> (4.2 g), zinc (5.9 g), ammonium chloride (9.7 g) and methanol (50 mL) was stirred at room temperature for 3 hr. After removing the methanol, the obtained mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The obtained organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The obtained residue was dissolved in phosphorus oxychloride (1.68 mL), and cyclopropanecarboxylic acid (2.86 mL) was added to the solution at room temperature. The obtained mixture was stirred at 120C for 3 hr. After cooling the reaction mixture to 0C, ice water and saturated aqueous sodium hydrogen carbonate solution were carefully added dropwise, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The obtained residue was dissolved in 1 N hydrochloric acid and washed with ethyl acetate. The aqueous layer was basified with 4 N sodium hydroxide and extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give the title compound (3.3 g) as a brown solid. 1H NMR (300 MHz, DMSO-d6): δ 0.95-1.14 (4H, m), 2.23 (1H, tt, J = 7.9, 5.1 Hz), 3.83 (3H, s), 7.24 (1H, dd, J = 8.5, 2.1 Hz), 7.41 (1H, d, J = 8.7 Hz), 7.75 (1H, d, J = 1.9 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.1 g | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 150℃; for 1h;Inert atmosphere; | Example 150 Methyl (IRS, 2SR) -2- (6- (4- (benzyloxy) -2-oxopyridin-l (2H) -yl) -1- methyl-lH-benzimidazol-2-yl) cyclopropanecarboxylate A) 4- (Benzyloxy) -1- (3- (methylamino) -4-nitrophenyl ) pyridin- 2(lH)-one The mixture of 4- (benzyloxy) pyridin-2 ( 1H) -one (5.0 g), 5- bromo-N-methyl-2-nitroaniline (5.74 g) , copper iodide (4.73 g) , N, N' -dimethylethylenediamine (2.8 ml) and potassium carbonate (10.30 g) in DMSO (250 ml) was stirred at 150C under N2 for 1 h. After cooling to room temperature, 28% NH3 solution was added to the resulting mixture. The resulting suspension was filtered. The precipitate was washed with water and IPA and dried to give the title compound (5.1 g) as a yellow solid. MS (ESI+) : [M+HJ+ 352.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12 g | With copper(l) iodide; potassium carbonate; N,N`-dimethylethylenediamine; In dimethyl sulfoxide; at 150℃; for 2h; | Example 74 Methyl (IRS, 2RS) -2- (6- (4- ( ( 4-chlorobenzyl ) oxy) -2-oxopyridin- 1 (2H) -yl) -l-methyl-lH-benzimidazol-2- yl) cyclopropanecarboxylate A) 4- ( (4-Chlorobenzyl) oxy) -1- (3- (methylamino) -4- nitrophenyl) pyridin-2 (1H) -one A mixture of 4- ( (4-chlorobenzyl) oxy) pyridin-2 (1H) -one (10 g) , <strong>[302800-13-1]5-bromo-N-methyl-2-nitroaniline</strong> (9.80 g) , Ν,Ν'- dimethylethylenediamine (4.76 ml), copper iodide (8.08 g) , potassium carbonate (17.59 g) and DMSO (200 ml) was heated at 150C for 2 h. The mixture was poured into 28% NH3 solution. The resulting precipitate was collected and washed with IPA. The solid was dissolved in DMSO (100 ml) at 80C, and allowed to cool to room temperature to give a precipitate. After filtration, the precipitate was washed with IPA and dried to give the title compound (12 g) as a yellow solid. MS (ESI+) : [M+H] + 386.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
165 mg | Example 15 1- (2- (Cyclopropylmethyl) -l-methyl-lH-benzimidazol-6-yl) -4- ( (4- fluorobenzyl) oxy) pyridin-2 ( 1H) -one A) 6-Bromo-2- (cyclopropylmethyl) -1-methyl-lH-benzimidazole Zinc (212 mg) was added to a mixture of 5-bromo-N-methyl- 2-nitroanilin.e (150 mg) , NH4C1 (347 mg) , eOH (2 ml) and water (1 ml) at room temperature. The mixture was stirred at room temperature for 1 h. After filtration and addition of saturated NaHC03 solution, the mixture was concentrated and extracted with AcOEt . The organic layer was separated, washed with brine, dried over MgS04 and concentrated in vacuo. To the resulting residue, DMF (2.0 ml), cyclopropylacetic acid (0.060 ml), N,N-diisopropylethylamine (0.339 ml) and HATU (259 mg) were added, and the mixture was stirred at room temperature for 1 h. The mixture was. quenched with brine and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgS04, passed through NH silica pad and concentrated in vacuo. The resulting residue was dissolved in AcOH (2.0 ml), and stirred at 80C for i h. After evaporation of the solvent, the residue was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (165 mg). as a purple gum. MS (ESI+) : [M+H] + 265.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With iron; ammonium chloride; In isopropyl alcohol; for 24h;Reflux; | [0444j Step B: Preparation of 6-bromo-1-methyl-benzimidazole: A mixture of 5- bromo-N-methyl-2-nitro-aniline (6.0 g, 26 mmol), iron powder (14.5 g, 260 mmol), ammonium chloride (13.9 g, 260 mmol) and formic acid (49.0 mL, 1298 mmol) in 2- propanol (75 mL) was stirred under reflux for 24 hours. After cooling to ambient temperature, ethyl acetate (50 mL) was added. The solid was removed by filtering through a pad of celite. The filtrate was concentrated. Saturated sodium bicarbonate (20 mL) and ethyl acetate (50 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by flash chromatography on silica gel 10:1 ethyl acetate/MeOH to give 6-bromo-1-methyl-benzimidazole (5.35 g, 98percent) as solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h; | Dissolve raw material 2 (i.e. <strong>[5228-61-5]5-bromo-2-nitroaniline</strong>) (4.34g, 20mmol) in 50mLTo N,N-dimethylformamide, potassium carbonate (5.53g, 40mmol) was added in sequence,Methyl iodide (2.84g, 20mmol), react at room temperature for 12 hours,Intermediate 3(3.74g, 81% yield). |
Tags: 302800-13-1 synthesis path| 302800-13-1 SDS| 302800-13-1 COA| 302800-13-1 purity| 302800-13-1 application| 302800-13-1 NMR| 302800-13-1 COA| 302800-13-1 structure
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