* 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.
With caesium carbonate In DMF (N,N-dimethyl-formamide) at 18 - 22℃;
The nitrophenol starting material B2 (3.1 g; 14.2 MMOL) was dissolved in DMF (20 mL) and to the solution was added ground cesium carbonate (5. 58 G ; 17.1 MMOL) followed by Mel (2.6 mL; 42.5 MMOL). The mixture was stirred at room temperature overnight. The DMF was evaporated, the residue taken up in ether (1X 200 mL), washed with water (1X 200 ML), brine (4x 100 mL), dried (MGS04), filtered and evaporated to afford the crude 2-bromo-3-nitroanisole B3 (94percent; 3.1 g) as an orange solid. MS 234 (M+2H) + ; Homogeneity by HPLC (TFA) 220 nm: 98percent.
94%
With caesium carbonate In N,N-dimethyl-formamide at 20℃;
Step B:; The nitrophenol starting material 1b2 (3.1 g; 14.2 mmol) was dissolved inDMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1mmol) followed by Mel (2.6 mL; 42.5 mmol). The mixture was stirred at roomtemperature overnight. The DMF was evaporated, the residue taken up in ether (1 X200 mL), washed with water (1 X 200 mL), brine (4 X 100 mL), dried (MgSO4), filteredand evaporated to afford the crude 2-bromo-3-nitroanisole 1b3 (94percent; 3.1 g) as anorange solid.MS 234 (M+2H)+; Homogeneity by HPLC (TFA) (at) 220nm: 98percent
94%
With caesium carbonate In DMF (N,N-dimethyl-formamide) at 20℃;
The nitrophenol starting material 1b2 (3.1 g; 14.2 mmol) was dissolved in DMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1 mmol) followed by Mel (2.6 mL; 42.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated, the residue taken up in ether (1*200 mL), washed with water (1*200 mL), brine (4*100 mL), dried (MgSO4), filtered and evaporated to afford the crude 2-bromo-3-nitroanisole 1b3 (94percent; 3.1 g) as an orange solid.MS 234 (M+2H)+; Homogeneity by HPLC (TFA)at;220 nm: 98percent
94%
With caesium carbonate In N,N-dimethyl-formamide at 20℃;
The nitrophenol starting material 2b2 (3.1 g; 14.2 mmol) was dissolved inDMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1mmol) followed by Mel (2.6 mL; 42.5 mmol). The mixture was stirred at roomtemperature overnight. The DMF was evaporated, the residue taken up in ether (1 X200 mL), washed with water (1 X 200 mL), brine (4 X 100 mL), dried ( MgSO4),filtered and evaporated to afford the crude 2-bromo-3-nitroanisole 2b3 (94percent; 3.1 g)as an orange solid.MS 234 (M+2H)+; Homogeneity by HPLC (TFA) (at) 220nm: 98percent
94%
With caesium carbonate In N,N-dimethyl-formamide at 18 - 22℃;
Step B; The nitrophenol starting material 2B2 (3.1 g; 14.2 mmol) was dissolved in DMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1 mmol) followed by MeI (2.6 mL; 42.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated, the residue taken up in ether (1 X 200 mL), washed with water (1 X 200 mL), brine (4 X 100 mL), dried (MgSO4), filtered and evaporated to afford the crude 2-bromo-3-nitroanisole 2B3 (94percent; 3.1 g) as an orange solid. MS 234 (M+2H)+; Homogeneity by HPLC (TFA) (at) 220nm: 98percent
Stage #1: With hydrogen bromide; sodium nitrite In water at 0℃; for 0.666667 h; Stage #2: With copper(I) bromide In water at 0 - 60℃; for 2 h; Heating / reflux
A solution of sodium nitrite (1.48 mol) in water (250 mL) was added to a cold (0-5° C.) solution of the nitroaniline (1.08 mol) in hydrobromic acid (4.87 mol) (prepared by heating the reaction mixture at 90° C. for 2 h). The reaction mixture was maintained for 40 min and was filtered. The filtrate was added dropwise to a cold (0-5° C.) solution of copper (I) bromide (1.81 mol) in hydrobromic acid (640 mL) and the reaction mixture was maintained for 30 min. The reaction mixture was warmed to 60° C. and was maintained for 30 min. The reaction mixture was warmed to reflux and was maintained for 1 h. The reaction mixture was diluted with water (2 L) and was extracted with dichloromethane (3*1 L). The combined organic layers were washed with 10percent sodium hydroxide (1.0 L), water (2.0 L), 10percent hydrochloric acid (1.6 L) and water (2.0 L), dried (magnesium sulfate) and concentrated. The residue was recrystallized from ethanol to provide the bromide in 50percent yield as a yellow solid.
Reference：
[1] Patent: US2007/78147, 2007, A1, . Location in patent: Page/Page column 67
[2] Bulletin of the Chemical Society of Japan, 1978, vol. 51, p. 2437 - 2438
[3] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5352 - 5362
3
[ 603-85-0 ]
[ 67853-37-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5352 - 5362
[2] Journal of Organic Chemistry, 1988, vol. 53, # 6, p. 1170 - 1176
4
[ 101935-40-4 ]
[ 77-78-1 ]
[ 67853-37-6 ]
Reference：
[1] Journal of Organic Chemistry, 1988, vol. 53, # 6, p. 1170 - 1176
5
[ 67853-37-6 ]
[ 112970-44-2 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogenchloride; iron In ethanol for 1.5 h; Reflux
Step 1. Synthesis of 2-bromo-3-methoxyaniline (C23) Iron (1.94 g, 34 mmol) was added to a solution of 2-bromo-1-methoxy-3-nitrobenzene (2.50 g, 10.77 mmol) in ethanol (18 mL) and concentrated hydrochloric acid (1 mL), and the reaction was heated at reflux for 1.5 hours. The mixture was cooled to room temperature, filtered through Celite and concentrated in vacuo to afford the title compound as a solid. Yield: 2.57 g, 10.77 mmol, 100percent. LCMS m/z 202.1 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.77 (s, 3H), 6.30 (d, J=8.0 Hz, 1H), 6.43 (d, J=8.0 Hz, 1H), 6.98 (dd, J=8.0, 8.0 Hz, 1H).
96%
With iron; ammonium chloride In ethanol; water for 1 h; Heating / reflux
Iron powder (1.08 mol) and ammonium chloride (862 mmol) were added to a solution of the bromide (216 mmol) in ethanol (200 mL) and water (140 mL) and the reaction mixture was heated at reflux for 1 h. The suspension was filtered and concentrated and the residue was extracted with ethyl acetate (3*200 mL). The combined organic layers were dried (sodium sulfate) and concentrated to give the bromoaniline in 96percent yield as a yellow liquid.
96%
With hydrogenchloride; iron In ethanol; water at 85℃; for 2 h;
To a suspension of 2-bromo-1-methoxy-3-nitrobenzene (3.90 g, 16.81 mmol) and iron powder (2.82 g, 50.4 mmol) in EtOH (50 mL) was added concentrated HC1 (3.08 mL, 37.0 mmol). The mixture was heated at 85 °C for 2.0 h. HPLC indicated a completion of the reaction. After cooled to room temperature, the solvent was removed under vacuum. The residue was suspended in EtOAc and saturated sodium bicarbonate.The insoluble material was removed by filtration through a pad of wet celite. The organic layer of the filtrate was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, Intermediate iSA (3.25 g, 16.09 mmol, 96 percentyield) was obtained as brown oil. It was used for the next step without further purification. ‘H NMR (500MHz, chloroform-d) 7.08 (t, J=8.1 Hz, 1H), 6.45 (dd, J8.0, 1.4 Hz, 1H), 6.34 (dd,J=8.3, 1.1 Hz, 1H), 3.89 (s, 2H); LC-MS: method A, RT = 1.21 mm, MS (ESI) m/z: 202.0 and 204.0 (M+H)
95%
With iron; ammonium chloride In tetrahydrofuran; methanol; water for 1 h; Reflux
2-bromo-1-methoxy-3-nitrobenzene (1 g, 4.31 mmol), Fe (1.68 g, 30.17 mmol) and NH4Cl (1.61 g, 30.17 mmol)were dissolved in THF (4 mL)/MeOH (4 mL)/H2O (2 mL) solution and stirred for 1 hour under reflux. After terminationof the reaction, the reaction solution was cooled to room temperature, diluted with saturated NaHCO3 solution andextracted with EtOAc. The extract solution was concentrated under reduced pressure and purified by column chromatography(eluent, EtOAc/Hex = 1/5) to obtain the title compound (0.83 g, 95 percent yield).1H NMR (500 MHz, CDCl3) δ 7.05(dd, 1H), 6.42(d, 1H), 6.31(d, 1H), 3.86(s, 3H)
91%
With acetic acid In ethanol for 3.5 h; Heating / reflux
2-Bromo-3-nitroanisole B3 (1.00 g; 4.31 MMOL) was dissolved in glacial acetic acid (11.0 mL) and ethanol (11.0 mL). To this solution was added iron powder (0.98 g; 17.5 MMOL). The mixture was stirred at reflux for 3.5 h and worked up. The reaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 and the product extracted with CH2CI2 (3X 50 mL). The extracts were dried (NA2SO4), filtered and CONCENTRATED IN VACUO to afford the crude product, 2-bromo-3 methoxyaniline B4 (91 percent; 0. 79 g) as a pale yellow oil. MS 201.8 (MH) + ; Homogeneity by HPLC (TFA) 220 nm: 95percent.
91%
With iron; acetic acid In ethanol for 3.5 h; Heating / reflux
Step C:; 2-Bromo-3-nitroanisole 1b3 (1.00 g; 4.31 mmol) was dissolved in glacialacetic acid (11.0 mL)/ethanol (11.0 mL) and to the solution was added iron powder(0.98 g; 17.5 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. Thereaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 and theproduct extracted with CH2CI2 (3X 50 mL). The extracts were dried (Na2SO4), filteredand concentrated in vacua to afford the crude product, 2-bromo-3 methoxyaniline 1b4(91percent; 0.79 g) as a pale yellow oil. MS 201.8 (MH)+; Homogeneity by HPLC (TFA) (at)220nm: 95percent
91%
With iron; acetic acid In ethanol for 3.5 h; Heating / reflux
2-Bromo-3-nitroanisole 1b3 (1.00 g; 4.31 mmol) was dissolved in glacial acetic acid (11.0 mL)/ethanol (11.0 mL) and to the solution was added iron powder (0.98 g; 17.5 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 and the product extracted with CH2Cl2(3*50 mL). The extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product, 2-bromo-3 methoxyaniline 1b4 (91percent; 0.79 g) as a pale yellow oil. MS 201.8 (MH)+; Homogeneity by HPLC (TFA)at;220 nm: 95percent
91%
With iron; acetic acid In ethanol for 3.5 h; Heating / reflux
2-Bromo-3-nitroanisole 2b3 (1.00 g; 4.31 mmol) was dissolved in glacialacetic acid (11.0 mL )/ethanol (11.0 mL) and to the solution was added iron powder(0.98 g; 17.5 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. Thereaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 andthe product extracted with CH2CI2( 3X 50 mL). The extracts were dried (Na2SO4),filtered and concentrated in vacuo to afford the crude product, 2-bromo-3methoxyaniline 2b4 (91percent; 0.79 g) as a pale yellow oil. MS 201.8 (MH)+;Homogeneity by HPLC (TFA) (at) 220nm: 95percent
91%
Stage #1: With iron; acetic acid In ethanol for 3.5 h; Heating / reflux Stage #2: With sodium carbonate In ethanol; water
Step C; 2-Bromo-3-nitroanisole 2B3 (1.00 g; 4.31 mmol) was dissolved in glacial acetic acid (11.0 mL)/ethanol (11.0 mL) and to the solution was added iron powder (0.98 g; 17.5 mmol). The mixture was stirred at reflux for 3.5 h and worked up. The reaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 and the product extracted with CH2CI2 (3X 50 mL). The extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product, 2-bromo-3 methoxyaniline 2B4 (91percent; 0.79 g) as a pale yellow oil. MS 201.8 (MH)+; Homogeneity by HPLC (TFA) (at) 220nm: 95percent
89%
With water; iron; ammonium chloride In tetrahydrofuran at 70℃; for 2.5 h;
A solution of 2-bromo-l-methoxy-3 -nitrobenzene (500 mg, 2.16 mmol) in CH3OH (5 mL) and THF (5 mL) was added to a solution OfNH4Cl (572 mg, 10.7 mmol) in water (5 mL). Then, iron (325 mesh, 601 mg, 10.7 mmol) was added and the resulting mixture was heated to 70 °C under nitrogen. After 2.5 h, the reaction mixture was cooled to room temperature, filtered over kieselguhr, diluted with AcOEt, and successively washed with a saturated solution OfNaHCO3 in water and brine. The organic layer was dried (Na2SO4) and evaporated. The residue was triturated in CH2Cl2, the filtered to give 390 mg (89 percent) of the target product 37 as a beige solid.
Reference：
[1] Patent: US2012/252758, 2012, A1, . Location in patent: Page/Page column 27
[2] Journal of Medicinal Chemistry, 2015, vol. 58, # 23, p. 9287 - 9295
[3] Patent: US2007/78147, 2007, A1, . Location in patent: Page/Page column 67
[4] Patent: WO2018/13774, 2018, A1, . Location in patent: Page/Page column 318
[5] Patent: EP3239143, 2017, A2, . Location in patent: Paragraph 0441
[6] Patent: WO2004/103996, 2004, A1, . Location in patent: Page 40-41
[7] Patent: WO2006/7700, 2006, A1, . Location in patent: Page/Page column 62
[8] Patent: US2006/19905, 2006, A1, . Location in patent: Page/Page column 24-25
[9] Patent: WO2006/85, 2006, A1, . Location in patent: Page/Page column 75-76
[10] Patent: WO2007/9227, 2007, A1, . Location in patent: Page/Page column 35
[11] Patent: WO2007/14919, 2007, A1, . Location in patent: Page/Page column 91
[12] Journal of Organic Chemistry, 1988, vol. 53, # 6, p. 1170 - 1176
[13] Synthetic Communications, 2007, vol. 37, # 16, p. 2777 - 2786
[14] Bulletin of the Chemical Society of Japan, 1978, vol. 51, p. 2437 - 2438
[15] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5352 - 5362
6
[ 67853-37-6 ]
[ 101935-40-4 ]
Yield
Reaction Conditions
Operation in experiment
98%
With boron tribromide In dichloromethane at -70 - 20℃; for 26 h; Inert atmosphere
SSynthesis of 2-f2'-Nitro-6'-pyridin-4-yl-biphenyl-4-yloxymethyl)-αuinoline (Example 384)2-Bromo-3-nitrophenol Error. Objects cannot be created from editing field codes.BBr3 (1.0M in CH2Cl2, 88 mL, 88 mmol) was added dropwise over 1 h to a stirred solution of 2-bromo-3-nitroanisole in CH2Cl2 (35 mL) under argon at -70 0C. The resulting deep burgundy-colored reaction mixture was allowed to warm up to RT slowly (over 2 h) and stirred at RT for 23 h. The reaction mixture was poured onto 35O g crushed ice and extracted with EtOAc (300 mL). The organic phase was separated, washed with brine (75 mL), and dried over MgSO4. Concentration and purification by chromatography (5-70percent EtO Ac/heptane) gave the title compound 2-bromo-3-nitrophenol (5.36 g, 98percent) as a yellow solid. 1H NMR (300 MHz, CDCI3/TMS) δ 7.48 (d, J= 8.1 Hz, IH), 7.37 (t, J = 8.1 Hz, IH), 7.27 (d, J= 8.4 Hz, IH), 6.13 (br s, IH); 13C NMR (75 MHz, CDCI3/TMS) δ 153.7, 128.7, 119.8, 117.5, 102.9.
With hydrogenchloride; iron; In ethanol; for 1.5h;Reflux;
Step 1. Synthesis of 2-bromo-3-methoxyaniline (C23) Iron (1.94 g, 34 mmol) was added to a solution of 2-bromo-1-methoxy-3-nitrobenzene (2.50 g, 10.77 mmol) in ethanol (18 mL) and concentrated hydrochloric acid (1 mL), and the reaction was heated at reflux for 1.5 hours. The mixture was cooled to room temperature, filtered through Celite and concentrated in vacuo to afford the title compound as a solid. Yield: 2.57 g, 10.77 mmol, 100%. LCMS m/z 202.1 (M+1). 1H NMR (400 MHz, CD3OD) delta 3.77 (s, 3H), 6.30 (d, J=8.0 Hz, 1H), 6.43 (d, J=8.0 Hz, 1H), 6.98 (dd, J=8.0, 8.0 Hz, 1H).
96%
With iron; ammonium chloride; In ethanol; water; for 1h;Heating / reflux;
Iron powder (1.08 mol) and ammonium chloride (862 mmol) were added to a solution of the bromide (216 mmol) in ethanol (200 mL) and water (140 mL) and the reaction mixture was heated at reflux for 1 h. The suspension was filtered and concentrated and the residue was extracted with ethyl acetate (3*200 mL). The combined organic layers were dried (sodium sulfate) and concentrated to give the bromoaniline in 96% yield as a yellow liquid.
96%
With hydrogenchloride; iron; In ethanol; water; at 85℃; for 2h;
To a suspension of 2-bromo-1-methoxy-3-nitrobenzene (3.90 g, 16.81 mmol) and iron powder (2.82 g, 50.4 mmol) in EtOH (50 mL) was added concentrated HC1 (3.08 mL, 37.0 mmol). The mixture was heated at 85 C for 2.0 h. HPLC indicated a completion of the reaction. After cooled to room temperature, the solvent was removed under vacuum. The residue was suspended in EtOAc and saturated sodium bicarbonate.The insoluble material was removed by filtration through a pad of wet celite. The organic layer of the filtrate was collected, washed with brine, dried over sodium sulfate. After evaporation of solvent, Intermediate iSA (3.25 g, 16.09 mmol, 96 %yield) was obtained as brown oil. It was used for the next step without further purification. ?H NMR (500MHz, chloroform-d) 7.08 (t, J=8.1 Hz, 1H), 6.45 (dd, J8.0, 1.4 Hz, 1H), 6.34 (dd,J=8.3, 1.1 Hz, 1H), 3.89 (s, 2H); LC-MS: method A, RT = 1.21 mm, MS (ESI) m/z: 202.0 and 204.0 (M+H)
95%
With iron; ammonium chloride; In tetrahydrofuran; methanol; water; for 1h;Reflux;
2-bromo-1-methoxy-3-nitrobenzene (1 g, 4.31 mmol), Fe (1.68 g, 30.17 mmol) and NH4Cl (1.61 g, 30.17 mmol)were dissolved in THF (4 mL)/MeOH (4 mL)/H2O (2 mL) solution and stirred for 1 hour under reflux. After terminationof the reaction, the reaction solution was cooled to room temperature, diluted with saturated NaHCO3 solution andextracted with EtOAc. The extract solution was concentrated under reduced pressure and purified by column chromatography(eluent, EtOAc/Hex = 1/5) to obtain the title compound (0.83 g, 95 % yield).1H NMR (500 MHz, CDCl3) delta 7.05(dd, 1H), 6.42(d, 1H), 6.31(d, 1H), 3.86(s, 3H)
91%
With acetic acid;iron; In ethanol; for 3.5h;Heating / reflux;
2-Bromo-3-nitroanisole B3 (1.00 g; 4.31 MMOL) was dissolved in glacial acetic acid (11.0 mL) and ethanol (11.0 mL). To this solution was added iron powder (0.98 g; 17.5 MMOL). The mixture was stirred at reflux for 3.5 h and worked up. The reaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 and the product extracted with CH2CI2 (3X 50 mL). The extracts were dried (NA2SO4), filtered and CONCENTRATED IN VACUO to afford the crude product, 2-bromo-3 methoxyaniline B4 (91 %; 0. 79 g) as a pale yellow oil. MS 201.8 (MH) + ; Homogeneity by HPLC (TFA) 220 nm: 95%.
91%
With iron; acetic acid; In ethanol; for 3.5h;Heating / reflux;
Step C:; 2-Bromo-3-nitroanisole 1b3 (1.00 g; 4.31 mmol) was dissolved in glacialacetic acid (11.0 mL)/ethanol (11.0 mL) and to the solution was added iron powder(0.98 g; 17.5 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. Thereaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 and theproduct extracted with CH2CI2 (3X 50 mL). The extracts were dried (Na2SO4), filteredand concentrated in vacua to afford the crude product, 2-bromo-3 methoxyaniline 1b4(91%; 0.79 g) as a pale yellow oil. MS 201.8 (MH)+; Homogeneity by HPLC (TFA) (at)220nm: 95%
91%
With iron; acetic acid; In ethanol; for 3.5h;Heating / reflux;
2-Bromo-3-nitroanisole 1b3 (1.00 g; 4.31 mmol) was dissolved in glacial acetic acid (11.0 mL)/ethanol (11.0 mL) and to the solution was added iron powder (0.98 g; 17.5 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. The reaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 and the product extracted with CH2Cl2(3*50 mL). The extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product, 2-bromo-3 methoxyaniline 1b4 (91%; 0.79 g) as a pale yellow oil. MS 201.8 (MH)+; Homogeneity by HPLC (TFA)a220 nm: 95%
91%
With iron; acetic acid; In ethanol; for 3.5h;Heating / reflux;
2-Bromo-3-nitroanisole 2b3 (1.00 g; 4.31 mmol) was dissolved in glacialacetic acid (11.0 mL )/ethanol (11.0 mL) and to the solution was added iron powder(0.98 g; 17.5 mmol). The mixture was stirred at reflux for 3.5 hr and worked up. Thereaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 andthe product extracted with CH2CI2( 3X 50 mL). The extracts were dried (Na2SO4),filtered and concentrated in vacuo to afford the crude product, 2-bromo-3methoxyaniline 2b4 (91%; 0.79 g) as a pale yellow oil. MS 201.8 (MH)+;Homogeneity by HPLC (TFA) (at) 220nm: 95%
91%
Step C; 2-Bromo-3-nitroanisole 2B3 (1.00 g; 4.31 mmol) was dissolved in glacial acetic acid (11.0 mL)/ethanol (11.0 mL) and to the solution was added iron powder (0.98 g; 17.5 mmol). The mixture was stirred at reflux for 3.5 h and worked up. The reaction mixture was diluted with water (35 mL), neutralized with solid Na2CO3 and the product extracted with CH2CI2 (3X 50 mL). The extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the crude product, 2-bromo-3 methoxyaniline 2B4 (91%; 0.79 g) as a pale yellow oil. MS 201.8 (MH)+; Homogeneity by HPLC (TFA) (at) 220nm: 95%
89%
With water; iron; ammonium chloride; In tetrahydrofuran; at 70℃; for 2.5h;
A solution of 2-bromo-l-methoxy-3 -nitrobenzene (500 mg, 2.16 mmol) in CH3OH (5 mL) and THF (5 mL) was added to a solution OfNH4Cl (572 mg, 10.7 mmol) in water (5 mL). Then, iron (325 mesh, 601 mg, 10.7 mmol) was added and the resulting mixture was heated to 70 C under nitrogen. After 2.5 h, the reaction mixture was cooled to room temperature, filtered over kieselguhr, diluted with AcOEt, and successively washed with a saturated solution OfNaHCO3 in water and brine. The organic layer was dried (Na2SO4) and evaporated. The residue was triturated in CH2Cl2, the filtered to give 390 mg (89 %) of the target product 37 as a beige solid.
A solution of sodium nitrite (1.48 mol) in water (250 mL) was added to a cold (0-5 C.) solution of the nitroaniline (1.08 mol) in hydrobromic acid (4.87 mol) (prepared by heating the reaction mixture at 90 C. for 2 h). The reaction mixture was maintained for 40 min and was filtered. The filtrate was added dropwise to a cold (0-5 C.) solution of copper (I) bromide (1.81 mol) in hydrobromic acid (640 mL) and the reaction mixture was maintained for 30 min. The reaction mixture was warmed to 60 C. and was maintained for 30 min. The reaction mixture was warmed to reflux and was maintained for 1 h. The reaction mixture was diluted with water (2 L) and was extracted with dichloromethane (3*1 L). The combined organic layers were washed with 10% sodium hydroxide (1.0 L), water (2.0 L), 10% hydrochloric acid (1.6 L) and water (2.0 L), dried (magnesium sulfate) and concentrated. The residue was recrystallized from ethanol to provide the bromide in 50% yield as a yellow solid.
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 18 - 22℃;
The nitrophenol starting material B2 (3.1 g; 14.2 MMOL) was dissolved in DMF (20 mL) and to the solution was added ground cesium carbonate (5. 58 G ; 17.1 MMOL) followed by Mel (2.6 mL; 42.5 MMOL). The mixture was stirred at room temperature overnight. The DMF was evaporated, the residue taken up in ether (1X 200 mL), washed with water (1X 200 ML), brine (4x 100 mL), dried (MGS04), filtered and evaporated to afford the crude 2-bromo-3-nitroanisole B3 (94%; 3.1 g) as an orange solid. MS 234 (M+2H) + ; Homogeneity by HPLC (TFA) 220 nm: 98%.
94%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
Step B:; The nitrophenol starting material 1b2 (3.1 g; 14.2 mmol) was dissolved inDMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1mmol) followed by Mel (2.6 mL; 42.5 mmol). The mixture was stirred at roomtemperature overnight. The DMF was evaporated, the residue taken up in ether (1 X200 mL), washed with water (1 X 200 mL), brine (4 X 100 mL), dried (MgSO4), filteredand evaporated to afford the crude 2-bromo-3-nitroanisole 1b3 (94%; 3.1 g) as anorange solid.MS 234 (M+2H)+; Homogeneity by HPLC (TFA) (at) 220nm: 98%
94%
With caesium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃;
The nitrophenol starting material 1b2 (3.1 g; 14.2 mmol) was dissolved in DMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1 mmol) followed by Mel (2.6 mL; 42.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated, the residue taken up in ether (1*200 mL), washed with water (1*200 mL), brine (4*100 mL), dried (MgSO4), filtered and evaporated to afford the crude 2-bromo-3-nitroanisole 1b3 (94%; 3.1 g) as an orange solid.MS 234 (M+2H)+; Homogeneity by HPLC (TFA)a220 nm: 98%
94%
With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;
The nitrophenol starting material 2b2 (3.1 g; 14.2 mmol) was dissolved inDMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1mmol) followed by Mel (2.6 mL; 42.5 mmol). The mixture was stirred at roomtemperature overnight. The DMF was evaporated, the residue taken up in ether (1 X200 mL), washed with water (1 X 200 mL), brine (4 X 100 mL), dried ( MgSO4),filtered and evaporated to afford the crude 2-bromo-3-nitroanisole 2b3 (94%; 3.1 g)as an orange solid.MS 234 (M+2H)+; Homogeneity by HPLC (TFA) (at) 220nm: 98%
94%
With caesium carbonate; In N,N-dimethyl-formamide; at 18 - 22℃;
Step B; The nitrophenol starting material 2B2 (3.1 g; 14.2 mmol) was dissolved in DMF (20 mL) and to the solution was added ground cesium carbonate (5.58 g; 17.1 mmol) followed by MeI (2.6 mL; 42.5 mmol). The mixture was stirred at room temperature overnight. The DMF was evaporated, the residue taken up in ether (1 X 200 mL), washed with water (1 X 200 mL), brine (4 X 100 mL), dried (MgSO4), filtered and evaporated to afford the crude 2-bromo-3-nitroanisole 2B3 (94%; 3.1 g) as an orange solid. MS 234 (M+2H)+; Homogeneity by HPLC (TFA) (at) 220nm: 98%
a. 2,2'-Dibromo-3,3'-dimethoxyhydrazobenzene Using a procedure similar to that described in example 1a, except using <strong>[67853-37-6]2-bromo-3-methoxynitrobenzene</strong> as starting material, the titled compound was obtained (8.41 g, 97%) and used without further purification. MS(CI): 401(m+1).
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; for 24h;Inert atmosphere; Reflux;
Synthesis of 2-(|2'-Methoxy-6'-(pyridin-4-yl)biphenyl-4- yloxy)methyl)quinoline (Example 385)4'-(Benzyloxy)-2-methoxy-6-nitrobiphenyl Error. Objects cannot be created from editing field codes.2-Bromo-3-nitroanisole (2.50 g), 4-benzyloxyphenyl boronic acid (2.94 g), and 2 M Na2COs solution (16.2 mL) in 150 ml dioxane was degassed four times before Pd(dppf)Cl2 (0.39 g) was added. The mixture was degassed four more times, then heated to reflux for 24 h. The mixture was cooled down to room temperature and the solvent was removed. The residue was washed with dichloromethane, and the filtrate was concentrated and purified by silica gel flash chromatography eluting with 50% ethyl acetate in heptane to give 4'-(benzyloxy)-2-methoxy-6-nitrobiphenyl (3.4 g) as a yellow solid. 1H NMR (300 MHz, CDCI3/TMS) delta 7.47-7.33 (m, 7H), 7.20 (d, J= 8.7 Hz, 2H), 7.13 (d, J= 7.8 Hz, IH), 7.02 (d, J= 8.7 Hz, 2H), 5.05 (s, 2H), 3.75 (s, 3H); 13C NMR (75 MHz, CDCI3/TMS) delta 158.83, 157.84, 151.48, 137.05, 130.63, 128.82, 128.24, 127.82, 124.97, 124.80, 115.56, 114.88, 114.44, 70.29, 56.74.
With boron tribromide; In dichloromethane; at -70 - 20℃; for 26h;Inert atmosphere;Product distribution / selectivity;
SSynthesis of 2-f2'-Nitro-6'-pyridin-4-yl-biphenyl-4-yloxymethyl)-alphauinoline (Example 384)2-Bromo-3-nitrophenol Error. Objects cannot be created from editing field codes.BBr3 (1.0M in CH2Cl2, 88 mL, 88 mmol) was added dropwise over 1 h to a stirred solution of 2-bromo-3-nitroanisole in CH2Cl2 (35 mL) under argon at -70 0C. The resulting deep burgundy-colored reaction mixture was allowed to warm up to RT slowly (over 2 h) and stirred at RT for 23 h. The reaction mixture was poured onto 35O g crushed ice and extracted with EtOAc (300 mL). The organic phase was separated, washed with brine (75 mL), and dried over MgSO4. Concentration and purification by chromatography (5-70% EtO Ac/heptane) gave the title compound 2-bromo-3-nitrophenol (5.36 g, 98%) as a yellow solid. 1H NMR (300 MHz, CDCI3/TMS) delta 7.48 (d, J= 8.1 Hz, IH), 7.37 (t, J = 8.1 Hz, IH), 7.27 (d, J= 8.4 Hz, IH), 6.13 (br s, IH); 13C NMR (75 MHz, CDCI3/TMS) delta 153.7, 128.7, 119.8, 117.5, 102.9.
With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 72h;
Step 1 : Lambda/-(2-Methoxy-6-nitrophenyl)-N'-methyl-Lambda/-propylthane-l,2-diamine hydrochloride[0145] A mixture of BOC-homopiperazine (1.0 g, 5 mmol, 1 equiv), 2-bromo-l-methoxy- 3 -nitrobenzene (1.16 g, 1 equiv), cesium carbonate (1.7 g, 1 equiv) in 10 mL of DMF was heated at 60 0C over 72 hrs. After cooling down to room temperature, ethyl acetate (100 mL) and water (50 mL) were added. The organic layer was subjected to flash chromatography (5 to 40% ethyl acetate in hexane) to give 4-(2-methoxy-6-nitrophenyl)-[l,4]diazepane-l- carboxylic acid tert-butyi ester (0.50 g, 25%), which was then treated with 50 mL of 4N HCl in dioxane at 60 0C for 2 hrs. The mixture was then evaporated to dryness and used in the next step directly. MS (ES) m/z 252.1 (M+H+).
(4-bromo-2-methoxy-6-nitrophenyl)cyclohexylamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
at 100℃;Sealed tube;
In a sealed vial, a solution of <strong>[67853-37-6]2-bromo-3-nitroanisole</strong> (700 mg, 3.02 mmol) in cyclohexylamine (6 mL) was stirred overnight at 100C and then concentrated. The residue was diluted with water and DCM. The organic layer was washed with saturated NaHCO3, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative TLC on silica gel (cyclohexane/EtOAc 7/3) to afford compound (166a) (715 mg, 2.86 mmol, 95%).
Step 1: <strong>[67853-37-6]2-bromo-1-methoxy-3-nitrobenzene</strong> (10.6 g, 45.7 mmol) and cyclopropylamine (16 mL, 230 mmol) were dissolved in 1,4-dioxane (50 mL). The stirred mixture was heated mixture in sealed flask to 115 C. After 66 h, mixture was cooled to r.t. and was diluted with EtOAc (100 mL), water (100 mL) and brine (50 mL). The phases were separated and extracted with EtOAc (100 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The concentrate was purified by silica gel chromatography (0-20% EtOAc in hexanes) to afford N-cyclopropyl-2-methoxy-6-nitroaniline.
(R)-4-((R)-1-((1-cyclopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one[ No CAS ]
tert-butyl 4-(6-(1-cyclopropyl-7-((R)-1-((R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidin-3-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)pyridin-3-yl)piperazine-1-carboxylate[ No CAS ]
(R)-4-((R)-1-((1-cyclopropyl-5-(5-(4-(methylsulfonyl)piperazin-1-yl)pyridin-2-yl)-1H-benzo[d]imidazol-7-yl)oxy)ethyl)pyrrolidin-2-one trifluoroacetate[ No CAS ]
2-(3-(1-cyclopropyl-7-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-1-yl)-2-methylpropanoic acid trifluoroacetic acid salt[ No CAS ]
2-methoxy-N-((1-methyl-1H-pyrazol-3-yl)methyl)-6-nitroaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
288 mg
In 1,4-dioxane; at 120 - 150℃;Sealed tube;
A mixture of (1 -methyl-1 H-pyrazol-3-yl)methanamine (383 mg, 3.45 mmol) and 2-bromo-1 - methoxy-3-nitrobenzene (400mg, 1 .724 mmol) in 1 ,4-dioxane (3.5 mL) was stirred into a sealed vessel at 120 °C overnight. The reaction was then heated at 150 "C for 24 hours followed by 120 over the weekend. The reaction was concentrated in vacuo, and the resulting residue was purified by silica gel chromatography (0-50percent EtOAc/hexanes) to afford the desired product (288 mg) as an orange oil. LC-MS (ES) m/z = 263 [M+H]+.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
Life Science
For Research Only
100K+ Compounds
Competitive Price
1-2 Day Shipping
