| 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). |
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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. |
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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 |
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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. |
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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. |
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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). |
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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. |
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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. |
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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. |
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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. |
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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). |
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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). |
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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. |
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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 |
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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)+ |
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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). |
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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. |
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