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CAS No. : | 337915-79-4 |
Formula : | C7H9BrN2 |
M.W : | 201.06 |
SMILES Code : | NC1=CC=C(Br)C=C1NC |
MDL No. : | MFCD11977373 |
InChI Key : | WQNHSCZQLLEPOM-UHFFFAOYSA-N |
Pubchem ID : | 12198270 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H317-H319 |
Precautionary Statements: | P280-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.14 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 0.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 47.85 |
TPSA ? Topological Polar Surface Area: Calculated from | 38.05 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 1.59 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 1.92 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 1.89 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 1.91 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 1.46 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.76 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.67 |
Solubility | 0.426 mg/ml ; 0.00212 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -2.34 |
Solubility | 0.913 mg/ml ; 0.00454 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -3.33 |
Solubility | 0.0932 mg/ml ; 0.000463 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 | -6.16 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 | 1.0 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) | 1.69 |
* 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 |
---|---|---|
63% | at 80℃; Inert atmosphere | 5-Bromo-N1-methylbenzene-1,2-diamine (14 g, 69.3 mmol) was dissolved in THF (200 mL), CDI (13.4 g, 83.2 mmol) was added. The mixture was reflux about 2 hours under N2. When LCMS showed the staring material was consumed, the solvent was evaporated and the resulting crude was purified by column chromatography on silica gel (EA : PE = 1 : 2) to give the product 6-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (10 g, yield 63 percent). 1H NMR (400 MHz, DMSO -d ) δ 11.0 (s, 1H), 7.33 (s, 1H), 7.13 (t, J= 8.0 Hz, 1H), 6.92 (d, J= 8.0 Hz, 1H), 3.26 (s, 3H). LC-MS (ESI+): m/z 228.1 (M+H)+. |
63% | at 80℃; Inert atmosphere | 5-Bromo-Nl-methylbenzene-l,2-diamine (14 g, 69.3 mmol) was dissolved in THF (200 mL), CDI (13.4 g, 83.2 mmol) was added, the mixture was reflux about 2 hours under N2. The staring material was consumed, evaporated the solvent, the crude was purified with column (EA : PE = 1 : 2), 10 g of target compound was obtained (63 percent yield). NMR (400 MHz, DMSO -d6) δ 11.0 (s, 1H), 7.33 (s, 1H), 7.13(t, J= 8.0 Hz, 1H), 6.92(d, J= 8.0 Hz, 1H), 3.26(s, 3H); LC- MS (ESI+): m/z 228.1 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 42 mL of 6N HCI and 63 mL of water, 5-bromo-N1-methylbenzene- 1 ,2-diamine (9.1 g, 45.4 mmol) and glycolic acid (17.2 g, 227.2 mmol) was added sequentially. The mixture was heated to reflux for 2 hours. After cooling down to room temperature, the mixture was neutralized to PH 9 by ammonium hydroxide. Precipitate formed, filtered, rinsed by water and dried by vacuum to yield (6-bromo-1-methyl-1H- benzo[d]imidazol-2-yl)methanol (8.5 g). 400 MHz 1H NMR (CDCI3) delta 7.5 (d, 1 H), 7.46 (m, 1H), 7.35 (dd, 1 H), 4.92 (s, 2H), 4.74(b, 1 H), 3.8 (s, 3H); MS (M+1) 241 , 243 | ||
To a solution of 42 ml 6N HCI and 63 ml water, 5-bromo-N1-methylbenzene-1 ,2-diamine (9.1 g, 45.4 mmol) and glycolic acid (17.2 g, 227.2 mmol) was added sequentially. The mixture was heated to reflux for 2 hours. After cooling down to room temperature, the mixture was neutralized to PH 9 by ammonium hydroxide. Precipitate formed, filtered, rinsed by water and dried by vacuum to yield (6-bromo-1-methyl-1 H-benzo[d]imidazol-2-yl)methanol (8.5 g). 400 MHz 1H NMR (CDCI3) delta 7.5 (d, 1 H), 7.46 (m, 1 H), 7.35 (dd, 1 H), 4.92 (s, 2H), 4.74(b, 1H), 3.8 (s, 3H); MS (M+1 ) 241 , 243. |
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 |
---|---|---|
54.74% | With toluene-4-sulfonic acid; In toluene; for 2h;Heating / reflux; | 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. |
54.74% | With toluene-4-sulfonic acid; In toluene; for 2h;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 toluene-4-sulfonic acid; at 100℃; for 4h; | [00320] To a solution of 5-bromo-Nl-methylbenzene-l,2-diamine (7.4 g, 37 mmol) in trimethyl orthoformate (100 mL) was added p-toluenesulfonic acid (0.36g, 1.9 mmol). The reaction mixture was heated at 100 C for 4 h, cooled, concentrated, dissolved in ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The crude product was used in next step without further purification. (7.3 g, yield 93%) MS (ESI+) e/z: 212.1. |
With toluene-4-sulfonic acid; at 100℃; for 4h; | To a solution of <strong>[337915-79-4]5-bromo-N1-methylbenzene-1,2-diamine</strong> (7.4 g, 37 mmol) in HC(OMe)3 (100 mL) was added TsOH (0.36 g, 1.9 mmol). The reaction mixture was heated at 100 C for 4 h and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (200 mL), washed with brine, dried over Na2SO4, and concentrated. The crude product was used in next step without further purification (7.3 g, 93%). LCMS (mlz): 212.1 (M+ 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrazine hydrate; In methanol; water; at 50℃; for 2h; | General procedure: To suspension of Example 8A (700 mg, 2.153 mmol) in 10 mL methanol was added hydrazine monohydrate (0.2 mL, 4.08 mmol) followed by 50% Raney nickel in water (100 mg). The mixture was stirred at 50 C. for 2 hours, filtered through diatomaceous earth with dichloromethane, concentrated and purified by flash chromatography eluting with 100% dichloromethane to give the title compound. | |
With hydrogen; In methanol; at 20℃; for 18h; | General procedure: Step 2: General procedure for the synthesis of Intermediate (4): [000661j To a stirred solution of respective compound 3 (1 eq), in methanol, Raney nickel(50% w/w) was added and stirred at room temperature for 18 h under hydrogen atmosphere. Theprogress of the reaction was monitored by TLC. After completion of the reaction, the reactionmixture was filtered and evaporated under reduced pressure to afford the following intermediates4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; HATU;dmap; In N,N-dimethyl-formamide; at 0 - 20℃; for 2.16667h; | Example 15; 238 Part A: Compound 230 was prepared via the synthetic method described in Example14 (Part B). To a solution of nicotinic acid (0.23 g, 1.90 mmol) in DMF (10 ml_) was added compound 230 (0.46 g, 2.28mmol) and diisopropylethylamine (1.00 ml_, 5.70 mmol). The reaction mixture was stirred at room temperature for 10 minutes, cooled to O0C (ice-bath) and then added HATU (0.87 g, 2.28 mmol) and catalytic DMAP. The reaction mixture was allowed to warm to room temperature, stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with 0.1 N NaOH (x1 ), water (x2), 0.1 N HCI (x1 ) and brine, dried over anh sodium sulfate and concentrated. Purification by column chromatography (Sitheta2, 10% MeOH / DCM) afforded compound 236 as a beige solid 0.60 g (100%). 1H NMR (400 MHz, DMSO-de) delta 9.73 (s, 1 H), 9.15 (d, 1 H), 8.73 (m, 1 H), 8.3 )m, 1 H), 7.55 (m, 1 H), 7.03 (d, 1 H), 6.69 (m, 2H), 2.78 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47% | Intermediate XI6-Bromo-1,2-dimethyl-1H-benzoimidazole A solution of 4-bromo-2-methylamino-aniline (1.10 g) in acetic acid (15 mL) was stirred at 130 C. for 2 h. After cooling to ambient temperature, the solution was concentrated under reduced pressure and the residue was taken up in ethyl acetate. The resulting solution was washed with 10% aqueous K2CO3 solution and brine and dried (MgSO4). The solvent was removed and the remainder was purified by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 99:1:0.1->9:1:0.1) to give the title compound as a solid.Yield: 0.58 g (47% of theory); Mass spectrum (ESI+): m/z=225/227 (Br) [M+H]+. | |
for 2h;Heating / reflux; | Part C:A solution of compound 230 (2.50 g, 12.4 mmol) in the corresponding acid (100 ml_) for preparing the compounds in Table 17 was stirred at reflux for 2 hours, at which time LC-MS analysis indicated that the reaction was complete. The reaction mixture was concentrated under vacuum. Purification by column chromatography (SiO2, 5% MeOH / DCM) afforded compounds of general formula 231 as a solid | |
1.6 g | at 118℃; for 3h; | j00421j A solution of compound B-74 (1.8 g, 9.0 mmol) in acetic acid (27 mL) was stirred at 118 C for 3 hours, then diluted with water (20 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were concentrated and purified by silica gel chromatography [petroleum ether: ethyl acetate = 1:0 to 3:11 to give compound B-75 (1.6 g, 77 % yield) as a red solid. LCMS(B): tR=0.291 mm., (ES) mlz (M+H)=225.0.?H-NMR (CD3C1, 400 MHz): 7.54 (d, J=8.4 Hz, 1H), 7.44 (d, J1.2 Hz, 1H), 7.33 (dd, J1=1.6 Hz, J2=2.0 Hz, 1H), 3.71 (s, 3H), 2.60 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogen bromide; sodium nitrite; In water; at 0 - 20℃; for 4.5h; | To a cooled (0 0C) and stirred suspension of (2-amino-5-bromophenyl)methylamine (9.5g, may be prepared as described in intermediate 46) in 2M hydrobromic acid was added dropwise a cooled (5 0C) solution of sodium nitrite (4.02 g) in water (50 ml). The resultant mixture was stirred at 5 0C for 0.5 hr and then at 15-20 0C for 4 hr. The mixture was partitioned between EtOAc (500 ml) and saturated aqueous sodium bicarbonate (500 ml). The aqueous phase was separated off and extracted with EtOAc (500 ml). The organic phases were combined, washed with water and brine, dried (magnesium sulphate) and adsorbed on to silica gel prior to flash chromatography over silica gel, eluting with EtOAc / cyclohexane (1 :3). Fractions containing the target compound were combined and evaporated to give a brown solid (4.48 g). 2.61 g of this was further purified by chromatography over silica gel, eluting with 2% MeOH in chloroform. The appropriate fractions were combined and evaporated to give the target compound as a pale brown solid (1.3O g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In ethanol; at 120℃; for 0.333333h;Microwave irradiation; | To a solution of crude <strong>[337915-79-4]5-bromo-N1-methylbenzene-1,2-diamine</strong> in ethanol (5 mL) 0. 366 mL of ethyl pyruvate was added. To that mixture sufficient acetic acid was added to provide a 1% v/v acetic acod in ethanol solution. The reaction mixture was heated in a microwave reactor at 120 C. for 20 minutes and allowed to cool to room temperature. The yellow precipitate was collected by filtration and washed with two 5 mL portions of ethanol. The yellow solid was dried under vacuum to provide 7-bromo-1,3-dimethylquinoxalin-2(1H)-one.MS (ESI) m/z 254.9 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With SULFAMIDE; In pyridine; at 125℃; for 14h;Inert atmosphere; | To a round bottom flask was added <strong>[337915-79-4]4-bromo-N2-methylbenzene-1,2-diamine</strong> (1-2) (9.07 g, 45.1 mmol), sulfamide (8.84 g, 92 mmol), and finally anhydrous pyridine (75 mL). The reaction mixture was then heated to 125C while stirring in a hot oil bath with a water cooled reflux condenser attached under an atmosphere of nitrogen for 14 hours. The crude reaction mixture was then allowed to cool to room temperature, suspended in ethyl acetate and added 6N HCl until pH <3. Crude mixture was then filtered. Filtrate organics were separated, then washed with 6N HCl twice dried over sodium sulfate, filtered, and concentrated to give 6- bromo-1 -methyl- 1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (1-3). HRMS (M+H)+:observed = 262.9486, calculated = 262.9484. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In tetrahydrofuran; for 16h;Inert atmosphere; Reflux; | To a stirred solution of <strong>[337915-79-4]5-bromo-N1-methylbenzene-1,2-diamine</strong> (38 g, 189 mmol) in THF (800 mL) was added CDI (37 g, 228 mmol) at room temperature under nitrogen atmosphere. The resulting mixture was refluxed for 16 h. The mixture was cooled to room temperature. The mixture was diluted with water (1 L) and stirred at room temperature for 30 min. The precipitated solids were collected by filtration and washed with water (200 mL). The filter cake was dried under vacuum to afford 6-bromo-1-methyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (40 g, 93%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) d 11.02 (br s, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.14 (dd, J = 8.2, 1.9 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 3.27 (s, 3H). LC/MS (ESI, m/z): [(M + 1)]+ = 227.10, 229.10 |
63% | In tetrahydrofuran; at 80℃;Inert atmosphere; | 5-Bromo-N1-methylbenzene-1,2-diamine (14 g, 69.3 mmol) was dissolved in THF (200 mL), CDI (13.4 g, 83.2 mmol) was added. The mixture was reflux about 2 hours under N2. When LCMS showed the staring material was consumed, the solvent was evaporated and the resulting crude was purified by column chromatography on silica gel (EA : PE = 1 : 2) to give the product 6-bromo-1-methyl-1H-benzo[d]imidazol-2(3H)-one (10 g, yield 63 %). 1H NMR (400 MHz, DMSO -d ) delta 11.0 (s, 1H), 7.33 (s, 1H), 7.13 (t, J= 8.0 Hz, 1H), 6.92 (d, J= 8.0 Hz, 1H), 3.26 (s, 3H). LC-MS (ESI+): m/z 228.1 (M+H)+. |
63% | In tetrahydrofuran; at 80℃;Inert atmosphere; | 5-Bromo-Nl-methylbenzene-l,2-diamine (14 g, 69.3 mmol) was dissolved in THF (200 mL), CDI (13.4 g, 83.2 mmol) was added, the mixture was reflux about 2 hours under N2. The staring material was consumed, evaporated the solvent, the crude was purified with column (EA : PE = 1 : 2), 10 g of target compound was obtained (63 % yield). NMR (400 MHz, DMSO -d6) delta 11.0 (s, 1H), 7.33 (s, 1H), 7.13(t, J= 8.0 Hz, 1H), 6.92(d, J= 8.0 Hz, 1H), 3.26(s, 3H); LC- MS (ESI+): m/z 228.1 (M+H)+ |
In tetrahydrofuran; at 23℃; for 17h;Reflux; | 6-bromo-l-methyI-l,3~dihydro-2H~benzimidazol-2-one (1-4)4-bromo-N2-methylbenzene-l52-diamine (1-3, 9.31 g, 46.3 mmol) was dissolved in anhydrous THF (45 ml) and treated with CDI (9.01 g, 55.6 mmol, 1.2 eq). The resulting orange solution was stirred at reflux for 4 h, then cooled to 23 deg C and stirred for 13 h. The cyclized product was partitioned between EtOAc (2 160 ml) and water (185 ml), and the combined organic layers were dried over Na2S04 and concentrated.The crude mixture contained a tan solid which was not readily soluble in EtOAc or Methylene Chloride. The material was collected via filtration and was found to only contain alittle bit of the desired product, mostly impurity. The filtrate was dried over Na2S04, and concentrated.Obtained 6.79 g of the desired product as a brown-orange solid with >90% purity. LRMS m/z: Calc'd for C8H7BrN20 (M+H) 228.1 , found 228.8. | |
In tetrahydrofuran; for 18h;Reflux; | [000821j To a stirred solution of compound 1 (2 g, 1 eq) in THF (40 mL), CDI (2.42 g, 1.5 eq) was added and heated to reflux for 18 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was diluted with ethyl acetate (100 mL) and washed with water. Organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the crude compound 2. LCMS (mlz): 226.90 (M + 1). |
Tags: 337915-79-4 synthesis path| 337915-79-4 SDS| 337915-79-4 COA| 337915-79-4 purity| 337915-79-4 application| 337915-79-4 NMR| 337915-79-4 COA| 337915-79-4 structure
A135762 [69038-76-2]
4-Bromo-N1-methylbenzene-1,2-diamine
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A207266 [1150102-47-8]
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A135762 [69038-76-2]
4-Bromo-N1-methylbenzene-1,2-diamine
Similarity: 1.00
A207266 [1150102-47-8]
6-Bromo-N1-methylbenzene-1,2-diamine
Similarity: 0.90
A135762 [69038-76-2]
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Similarity: 1.00
A207266 [1150102-47-8]
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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 |
Sorry,this product has been discontinued.
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