Structure of 321-23-3
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CAS No. : | 321-23-3 |
Formula : | C6H3BrFNO2 |
M.W : | 220.00 |
SMILES Code : | BrC1=CC(=C(C=C1)[N+](=O)[O-])F |
MDL No. : | MFCD01930221 |
InChI Key : | VQCWSOYHHXXWSP-UHFFFAOYSA-N |
Pubchem ID : | 2783362 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 11 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 42.92 |
TPSA ? Topological Polar Surface Area: Calculated from |
45.82 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.57 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.45 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.92 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.06 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.81 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.96 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.09 |
Solubility | 0.181 mg/ml ; 0.000822 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.06 |
Solubility | 0.193 mg/ml ; 0.000879 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.92 |
Solubility | 0.266 mg/ml ; 0.00121 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.9 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.85 |
* 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 |
---|---|---|
25% | In tetrahydrofuran; at -40℃; for 1h; | To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1.0 g, 4.54 mmol) in THF (20 mL) was added vinyl magnesium bromide (1M in THF, 13.62 mL, 13.62 mmol) slowly at -40 C. The reaction mixture was maintained at this temperature for 60 min. After completion of the reaction saturated aqueous NH4Cl solution was added and the mixture was extracted with EtOAc (2*20 mL). The combined organic layers were dried over Na2SO4 and evaporated to dryness. Flash chromatography (silica, EtOAc:petroleum ether 9:1) gave 5-bromo-7-fluoro-1H-indole as a gummy solid (0.24 g, 25%). |
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 |
---|---|---|
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 |
---|---|---|
53% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 26h; | Step A5-bromo-2-ni henyl]aniline[00447] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (1.353 g, 6.15 mmol), 3-(1 ,3-oxazol-5-yl)aniline (0.985g, 6.15 mmol) and K2C03 (1.7 g, 12.3 mmol) in DMF (13.5 mL) was heated at 90 C for 26 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with a 5% LiCI solution (3x100 mL). The organic layer was concentrated and the residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to obtain 5-bromo-2- nitro-N-[3-(1 ,3-oxazol-5-yl)phenyl]aniline as bright red - orange solid (1.18g, 53%). 1H NMR (400 MHz, DMSO-c/s) δ ppm 9.54 (s, 1 H) 8.48 (s, 1 H) 8.07 (d, .7=9.2 Hz, 1 H) 7.75 (s, 1 H) 7.71 (s, 1 H) 7.59 - 7.64 (m, 1 H) 7.53 - 7.58 (m, 1 H) 7.36 (d, J=8.0 Hz, 1 H) 7.23 (d, J=2.0 Hz, 1 H) 7.07 (dd, J=9.0, 2.0 Hz, 1 H). ES-LCMS: 360.0 (M+1 ). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; | Step A(R)-5-bromo-N- -2-nitroaniline[00224] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (2 g, 9.09 mmol), (R)-2- methyl-1-phenylpropan-l-amine, Hydrochloride (1.357 g, 9.09 mmol) and K2CO3 (2.51 g,18.18 mmol) in DMF (20 mL) (1.51 g) The mixture was heated overnight at 90°C. The mixture was allowed to cool to room temperature then diluted with EtOAc. The mixture was then washed with 5percent LiCI solution 3 x 100 mL then brine. The organic layer was dried with Na2S04, filtered and purified by silica gel chromatography (0-20 percent EtOAc in hexanes). Fractions containing the product were combined and concentrated to obtain 3.48 g of a yellow oil. The sample was dissolved in DMF (20mL) and (R)-2-methyl-1-phenylpropan-1 -amine, Hydrochloride (543 mg) was added followed by K2C03 (1.51 g). The mixture was heated overnight at 90°C.The mixture was allowed to cool to room temperature then diluted with EtOAc. The mixture was then washed with 5percent LiCI solution 3 x 100 mL then brine. The organic layer was dried with Na2S04, filtered and purified by silica gel chromatography (0-20 percent EtOAc in hexanes) to obtain (R)-5-bromo-N-(2-methyl-1-phenylpropyl)-2-nitroaniline as a yellow oil, (3.11 g, 8.11 mmol as 0.3 ethyl acetate, 89 percent yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.55 (d, J=7.2 Hz, 1 H) 7.99 (d, J=9.0 Hz, 1 H) 7.30 - 7.44 (m, 4 H) 7.22 - 7.30 (m, 1 H) 7.04 (d, J=2.0 Hz, 1 H) 6.81 (dd, J=9.1 , 2.0 Hz, 1 H) 4.65 (t, J=7.0 Hz, 1 H) 2.07 - 2.24 (m, 1 H) 0.68 - 1.07 (m, 6 H). LCMS: m/z 349.1 (M+H+).Step B |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 1h; | a) To a solution of 4-bromo-2-fluoro-nitrobenzene (5.8 g, 25.6 mmol) and (lR)-l- (2,4-dichlorophenyl)ethanamine (prepared from Example 1, 5.1 g, 26.8 mmol) in anhydrous dimethyl sulfoxide (DMSO, 55 mL) was added potassium carbonate (K2CO3, 7.4 g, 53.1 mmol). The reaction mixture was heated at 120 C for 1 h. After cooling to room temperature, the mixture was diluted with deionized water (750 mL) and the flask was rinsed with z'PrOH (25 mL). The mixture was stirred for 30 min, and a bright yellow solid was obtained. The solid was collected by filtration, and dried in vacuo to give the desired product (9.7 g, 25.0 mmol, 94%). MS: (ES) m/z calculated for Ci4H12BrCl2 202 [M + H]+ 388.9, found 390. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 25℃; for 12h; | To a solution of 4-bromo-2-fluoro-1-nitrobenzene (1, 2.19g, 10mmol) in DMF (50ml) and DIPEA (10ml) at 25C was added <strong>[28466-26-4]1H-pyrazol-4-amine</strong> (1.25g, 15mmol). Then the mixture was stirred at room temperature 12h. DMF and DIPEA were removed at reduced pressure and add water (100ml), and the residue was purified through a column chromatography on silica with chloroform/methanol (V:V 20:1) as a red solid. (2.68g, 95.0% yield). mp 94-96C.1H NMR (400MHz, DMSO-d6) delta 13.03 (s, 1H, NH), 9.19 (s, 1H, NH), 8.03 (d, J=9.1Hz, 1H, Ar-H), 7.96-7.58 (m, 2H, Ar-H), 7.06 (d, J=2.0Hz, 1H, Ar-H), 6.93 (dd, J=9.1, 2.0Hz, 1H, Ar-H). 13C NMR (100MHz, DMSO-d6) delta 145.63, 136.48, 131.50, 130.93, 128.51, 125.80, 120.00, 119.94, 118.08. ESI-MS: m/z 281.1 [M-H]+. |
Tags: 321-23-3 synthesis path| 321-23-3 SDS| 321-23-3 COA| 321-23-3 purity| 321-23-3 application| 321-23-3 NMR| 321-23-3 COA| 321-23-3 structure
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P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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