* 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.
p-Brombenzoic acid (8, 5.00 g, 24.9 mmol) was slowly added in portions to a cold mixture (0 °C) of conc. nitric acid (6.2 mL, 0.15 mmol) and conc. sulfuric acid (15.2 mL, 300 mmol). The addition was performed in such a way that the temperature did not exceed 5 °C. After stirring for 3 h at 0 °C and 2 h at room temp., the mixture was poured on ice-containing water. The resulting colourless solid was filtered off and washed extensively with water. Yield: 6.00 g (24.4 mmol, 98percent) (ref.[2]: 96percent), m. p. 202 °C. 1H NMR (200 MHz, DMSO-d6): δ = 8.46 – 8.42 (m, 1H, Ar-H-2), 8.09–8.05 (m, 2H, Ar-H-5,6) ppm. 13C NMR (50 MHz, DMSO-d6): δ = 165.0 (s, CO2H), 149.7 (s, Ar-C-3), 135.4 (d, Ar-C-6), 132.4 (d, Ar-C-5), 131.7 (s, ArC-1), 125.9 (d, Ar-C-2), 118.0 (Ar-C-4) ppm. MS (EI, 70 eV): m/z = 245/247 (95/100) [M]+·. MS (CI, isobutane): m/z = 246/248 (100/99) [M + H]+. IR (ATR): ν = 3082 (arylH), 2820 (br., OH), 1684 (C=O), 1595 (arom. C=C), 1530, 1303 (NO2), 1034 (aryl-Br), 907, 809 (1,2,4-trisubst. aryl) cm-1
96%
at 0 - 20℃; for 2 h;
Example 65; 4-Bromo-3-nitrobenzoic acid (43) (Scheme 9); Fuming nitric acid (12.4 mL, 0.3 mol) was slowly added to conc. sulfuric acid (30.1 mL, 0.6 mol) at 0-5° C. The cooled nitrating mixture was taken in a beaker equipped with a mechanical stirrer and addition funnel. 4-Bromotoluic acid 42 (40 g, 0.2 mol) was added to this mixture in small portions over 5 hours at such a rate to maintain the temperature at 0-5° C. The reaction mixture was stirred further for additional 2 h at room temperature and then poured over ice. The solid that separated was filtered, washed with water till it was free of acid and then air dried to constant weight to give the pure compound 43. White solid (47.2 g, 96percent). 1H NMR (300 MHz, CDCl3): δ 7.85 (d, J=12.0 Hz, 1H); 8.09 (d, J=12.0 Hz, 1H); 8.48 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 124.2, 132.1, 135.2, 138.0, 139.8, 159.8, 171.0.
90%
Reflux
A 200 mL flask was charged with 4-bromobenzoic acid (9.84 g, 49.0 mmol), nitric acid (70percent, 90 mL) and fuming nitric acid (90percent, 70 mL), fitted with a reflux condenser and the resulting suspension was stirred under reflux overnight. The homogeneous yellow solution obtained was cooled to 0 °C, filtered and the solid washed with cold water (100 mL) to yield a white powder. Recrystallization from methanol/water afforded the product (10.82 g, 44.0 mmol, 90percent) as a microcrystalline white powder. ‘H NMR (400 MHz, DMSO-d6) 13.74 (bs, 1H), 8.39 (s, 1H), 8.09—7.94 (m, 2H). ‘3C NMR (100 MHz, DMSO-d6) 165.0,149.6, 135.4, 133.8, 131.7, 126.0, 118.2.
88%
With nitric acid In water for 24 h; Heating / reflux
4-bromo-3-nitrobenzoic acid (1): IN AS 1 L flask, 4-bromobenzoic acid (50.0 g, 0.25 mol, Aldrich Co. ), nitric acid (450 mL) and fuming nitric acid (100 mL) were mixed and refluxed for 24 h. The mixture was cooled at 0°C and the white precipitate filtered through a Buecher funnel, washed thoroughly with water and dried under reduced pressure to provide 53.9 g of the title product as a white solid. M. P.: 202-204°C (Yield : 88percent). 1H NMR (300 MHz, Acetone-d6, ppm): 11.37 (s, 1H) ; 8.47 (d, 1H, J= 1. 9 HZ) ; 8.16 (dd, 1H, J= 6.6 and 1.6 Hz); 8.04 (d, 1H, J= 8.3 Hz). 13C NMR (75 MHz, Acetone-d6, ppm): 206.35 ; 165.07 ; 136.29 ; 134.55 ; 132.26 ; 126.90 ; 119.08.
Reference：
[1] Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 2267 - 2273
[2] Patent: US2008/293736, 2008, A1, . Location in patent: Page/Page column 32
[3] Patent: WO2017/7634, 2017, A1, . Location in patent: Paragraph 0730; 0731; 0732
[4] Patent: WO2005/16882, 2005, A1, . Location in patent: Page/Page column 13
[5] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 178 Anm. 1
[6] Justus Liebigs Annalen der Chemie, 1867, vol. 143, p. 241
[7] Patent: WO2015/143653, 2015, A1, . Location in patent: Page/Page column 56
[8] Patent: WO2015/148344, 2015, A2, . Location in patent: Page/Page column 104
[9] Patent: WO2015/143652, 2015, A1, . Location in patent: Page/Page column 46
[10] Patent: WO2016/161572, 2016, A1, . Location in patent: Page/Page column 74
[11] ACS Medicinal Chemistry Letters, 2017, vol. 8, # 11, p. 1148 - 1152
2
[ 5326-34-1 ]
[ 6319-40-0 ]
Yield
Reaction Conditions
Operation in experiment
48.6%
With pyridine; hydrogenchloride; potassium permanganate In water
Reference Example 34 4-Bromo-3-nitrotoluene (25.3 g, 0.117 mol) was added to a mixed solution of pyridine and water (1:1, 300 mL), and potassium permanganate (36.9 g, 0.234 mol) was added thereto over 5 hours while the solution was stirred under heat at 50°C. Then, excess potassium permanganate was quenched with methanol. The reaction mixture was concentrated under reduced pressure; the residue obtained was washed with ether and dissolved in water; and aqueous 4 N hydrochloric acid solution was added thereto until the solution becomes acidic, allowing precipitation of solid. The crude product was recrystallized from methanol and water, to obtain 4-bromo-3-nitrobenzoic acid (14.0 g, 48.6percent) as pale yellow needle crystals. 1H-NMR(CDCl3) δ:7.89(1H,d,J=8.3Hz),B.12(1H,dd,J=8.3,2.0Hz), 8.53(1H,d,J=1.95Hz)ppm FABMS:247(M+1)
Reference：
[1] Patent: EP1820799, 2007, A1,
[2] Patent: WO2006/51851, 2006, A1, . Location in patent: Page/Page column 59
[3] Chemistry - A European Journal, 2012, vol. 18, # 3, p. 880 - 886
[4] Justus Liebigs Annalen der Chemie, 1867, vol. 143, p. 241
3
[ 163596-75-6 ]
[ 6319-40-0 ]
Reference：
[1] Journal of the Chemical Society, 1927, p. 25
[2] Chem. Zentralbl., 1912, vol. 83, # II, p. 1965
4
[ 1122-91-4 ]
[ 6319-40-0 ]
Reference：
[1] Journal of the Chemical Society, 1927, p. 25
5
[ 7664-93-9 ]
[ 163596-75-6 ]
[ 7697-37-2 ]
[ 577-52-6 ]
[ 6319-40-0 ]
[ 860725-17-3 ]
Reference：
[1] Yakugaku Zasshi, 1937, vol. 57, p. 298,305; dtsch. Ref. S. 124, 125[2] Chem. Zentralbl., 1937, vol. 108, # II, p. 3311
Reference Example 35 The compound in Reference Example 34 (4.94 g, 20.1 mmol) and nickel chloride-hexahydrate (9.56 g, 40.2 mmol) were mixed in methanol (100 mL) and the solution was stirred. Then, sodium borohydride (3.8 g, 0.1 mol) was added gradually, while the solution was cooled on an ice bath to keep the reaction temperature low. Then, the mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure; the residue was dissolved in ethyl acetate; the solution was filtered through Celite; and the filtrate was washed with saturated aqueous citric acid solution and then saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the precipitated crystals were washed with hexane, to obtain 3-amino-4-bromobenzoic acid (2.95 g, 68percent) as a colorless solid. 1H-NMR(DYSO-d6),δ:7.01(1H,dd,J=8.3,2.5Hz),7.39 (1H, d, J = 2.5Hz), 7.45 (1H, d, J = 8.3Hz) ppm FABMS:215(M+1)
Reference：
[1] Patent: EP1820799, 2007, A1,
9
[ 6319-40-0 ]
[ 2840-29-1 ]
Reference：
[1] Chemistry - A European Journal, 2012, vol. 18, # 3, p. 880 - 886
[2] Patent: WO2006/51851, 2006, A1, . Location in patent: Page/Page column 59
[3] Justus Liebigs Annalen der Chemie, 1884, vol. 222, p. 183
With sulfuric acid; at 0℃; for 4h;Reflux; Inert atmosphere;
4-Bromo-3-nitrobenzoic acid (42 g; 170 mmol.) is dissolved in MeOH (100 ml). Con.H2SO4 (10 mL) is added dropwise at 0C. The solution is stirred at reflux for 4.0 h before cooled to room temperature. Then cooled water (100 mL) was added, and the precipitate was filtrated, washed with water to afford a white solid (48 g), which was used to the next step without further purification. Then the crude product (48 g) and Na2S2O4 (88 g) were dissolved in MeOH/water (565 mL/170 mL), and the mixture was stirred at reflux until the starting material was consumed (about 4 h). After cooling to room temperature, the solvent was evaporated and the crude reaction mixture was treated with aqueous of Na2CO3 (10%, 200 mL) and EtOAc (3x100 mL), and the two layers were separated in a separation funnel. The organic layer was washed with water (100 mL), brine (100 mL), dried, evaporated to get the crude product (13 g) which was used without further purified.
With sulfuric acid; In water; at 0℃; for 4h;Reflux;
4-Bromo-3-nitrobenzoic acid (42 g; 170 mmol.) is dissolved in MeOH (100 ml). Con.H2SO4 (10 mL) is added dropwise at 0 C. The solution is stirred at reflux for 4.0 h before cooled to room temperature. Then cooled water (100 mL) was added, and the precipitate was filtrated, washed with water to afford a white solid (48 g), which was used to the next step without further purification. Then the crude product (48 g) and Na2S2O4 (88 g) were dissolved in MeOH/water (565 mL/170 mL), and the mixture was stirred at reflux until the starting material was consumed (about 4 h).
With sulfuric acid; In water; at 20℃; for 2h;Reflux;
To a solution of 4-bromo-3-nitrobenzoic acid (1 15 g, 47.0 mmol) in MeOH (600 mL) was added aqueous H2SO4 solution (18 M, 200 mL) at ambient temperature. The mixture was heated at reflux for 2 h, and then cooled and filtered. The filtered solid was washed with water and dried to give the title compound. MS: m/z = 260, 262 (M + 1). lH NMR (400 MHz, DMSO) delta 8.48 (s, 3H), 8.09 (s, 2H), 3.91 (s, 3H)
With sulfuric acid; at 20℃; for 2h;Reflux;
Step B: Methyl 4-bromo-3-nitrobenzoateTo a solution of 4-bromo-3-nitrobenzoic acid (1 15 g, 47.0 mmol) in MeOH (600 mL) was added aqueous H2S04 solution (18 M, 200 mL) at ambient temperature. The mixture was heated at reflux for 2 h, and then cooled and filtered. The filtered solid was washed with water and dried to give the title compound. MS: m/z = 260, 262 (M + 1). XH NMR (400 MHz, DMSO-d6) delta 8.48 (s, 3H), 8.09 (s, 2H), 3.91 (s, 3H).
With sulfuric acid; In water; at 20℃; for 2h;Reflux;
Step B: Methyl 4-bromo-3-nitrobenzoateTo a solution of 4-bromo-3-nitrobenzoic acid (115 g, 47.0 mmol) in MeOH (600 mL) was added aqueous H2S04 solution (18 M, 200 mL) at ambient temperature. The mixture was heated at reflux for 2 h, and then cooled and filtered. The filtered solid was washed with water and dried to give the title compound. MS: m/z = 260, 262 (M + 1). 1H NMR (400 MHz, DMSO) delta 8.48 (s, 3H), 8.09 (s, 2H), 3.91 (s, 3H).
With sulfuric acid; In water; for 2h;Reflux;
To a solution of 4-bromo-3-nitrobenzoic acid (115 g, 47.0 mmol) in MeOH (600 mL) was added aqueous H2504 solution (18 M, 200 mL) at ambient temperature. The mixture was heated at reflux for 2 h, and then cooled and filtered. The filtered solid was washed with water and dried to give the title compound. MS: m/z = 260, 262 (M + 1). ?H NMR (400 MHz, DMSO-d6)oe 8.48 (s, 3H), 8.09 (s, 2H), 3.91 (s, 3H).
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In pyridine at 20℃; for 16h;
4
Example 4 4-Bromo-N-(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-3-nitro-benzamide 3. To a solution of 1 (1.65 g, 10 mmol) and 2 (2.46 g, 10 mmol) in pyridine (80 mL) was added and EDC (2.87 g, 15 mmol), and mixture was stirred at room temperature for 16 h. Pyridine was removed in vacuo and the residue was dissolved in EtOAc, washed sequentially with 3M HCl, satd. NaHCO3, and satd. NaCl, and then dried over Na2SO4. The solvent was removed in vacuo to give compound 3 (3.19 g, 81%) as a yellow solid: MS: m/z 393.03 (M+H)+.
With sodium borohydrid; In methanol; ethyl acetate;
Reference Example 35 The compound in Reference Example 34 (4.94 g, 20.1 mmol) and nickel chloride-hexahydrate (9.56 g, 40.2 mmol) were mixed in methanol (100 mL) and the solution was stirred. Then, sodium borohydride (3.8 g, 0.1 mol) was added gradually, while the solution was cooled on an ice bath to keep the reaction temperature low. Then, the mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure; the residue was dissolved in ethyl acetate; the solution was filtered through Celite; and the filtrate was washed with saturated aqueous citric acid solution and then saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the precipitated crystals were washed with hexane, to obtain 3-amino-4-bromobenzoic acid (2.95 g, 68%) as a colorless solid. 1H-NMR(DYSO-d6),delta:7.01(1H,dd,J=8.3,2.5Hz),7.39 (1H, d, J = 2.5Hz), 7.45 (1H, d, J = 8.3Hz) ppm FABMS:215(M+1)
To a solution of the selected benzoic acid I or G (1.2 equiv.) in pyridine under argon atmosphere and cooled at -20°C / 0°C, the selected amine (5.0 equiv.) and phosphorus oxychloride (1.5 equiv) were successively added. After 30-40 min at 0°C, the reaction was hydrolyzed with HC1 1M and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. Purification by flash-chromatography afforded the expected benzamide.; Compound 25 was obtained according to general procedure II, method B, starting from 4-bromo-3-nitrobenzoic acid and cyclohexylethylamine. The reaction was cooled at -20°C for 10 min, then allowed to reach 0°C and hydrolysed after 30 min at 0°C. Purification by flash-chromatography (10percent to 20percent AcOEt in cyclohexane) afforded the product in 91percent yield. M/Z (M[79Br]+H)+ = 355.
Multi-step reaction with 2 steps
1.1: sulfuric acid / water / 2 h / 20 °C / Reflux
2.1: copper(l) iodide / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere
2.2: 3 h / 110 °C
Multi-step reaction with 2 steps
1.1: sulfuric acid / 2 h / 20 °C / Reflux
2.1: copper(l) iodide / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere
2.2: 3 h / 110 °C
Multi-step reaction with 2 steps
1.1: sulfuric acid / water / 2 h / 20 °C / Reflux
2.1: copper(l) iodide / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere
2.2: 3 h / 110 °C
Multi-step reaction with 2 steps
1.1: sulfuric acid / water / 2 h / Reflux
2.1: copper(l) iodide / N,N-dimethyl-formamide / 0.17 h / 20 °C / Inert atmosphere
2.2: 3 h / 110 °C / Inert atmosphere
4-bromo-3-nitrobenzoic acid (42 g, 170 mmol) was added to methanol (100 mL) and concentrated sulfuric acid (10 mL) was added dropwise at 0 C.The mixture was heated to reflux, stirred for 4 hours and cooled to room temperature. Cold water (100 mL) was added and the precipitate was filtered and washed with water to give a white solid (48 g) which was used directly in the next reaction without further purification. The crude product obtained above (48 g) and sodium hydrosulfite (88 g)Dissolved in methanol (565 mL) and water (170 mL). The mixture was heated to reflux for about 4 hours until TLC showed the starting material was complete. The reaction mixture was cooled to room temperature and the solvent was evaporated to dryness. Aqueous sodium carbonate (10%, 200 mL) was added to the residue and extracted three times with ethyl acetate (100 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried and evaporated to dryness to give the crude product (13 g) which was used directly in the next reaction without further purification.
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