* 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.
4-Methyl-3-nitrobenzoic acid (5.43 g, 30 mmol) and concentrated sulfuric acid (45 mL, 98percent) were added to a 250 mL two-neck flask, then 1,3-dibromo-5,5-dimethylhydantoin (4.29 g, 15 mmol) was added in portions. The reaction mixture was stirred for 16 h at rt. The resulting mixture was poured into ice-water (1000 mL). The mixture was extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, then the residue was purified by silica gel chromatography (methanol/dichloromethane (v/v) = 1/30) to give the title compound as a white solid (7.1 g, 91percent).MS (ES-API, pos. ion) m/z: 260.9 [M + 2]t
85%
With DBDMH In sulfuric acid at 20℃; for 16 h;
DBDMH(14.3g, 0.05mol) was added to the solution of compound 1(18. lg, O.lmol) in concentrated H2SO4(100ml) in portions. The reaction mixture was stirred at rt for 16h., and then poured into the ice (400g) while stirring for another 20min. Product 2 was collected by filtration and drying (22.1 g, 85percent) as solid.
Stage #1: With hydrogenchloride; sodium nitrite In water at 0 - 5℃; Stage #2: With copper(I) bromide In water at 0 - 35℃;
Step 3:; To a suspension of 3-amino-4-methyl-5-nitrobenzoic acid (50 g, 254 mmole) in a mixture of cone, hydrochloric acid (350 ml) and water (350 ml) was added at between 0-50C a solution of sodium nitrite (18.6 g, 270 mmole) in water (30 ml) over a period of 15 to 20 minutes. After stirring at 0-50C for another 30 minutes, the reaction mixture was then slowly added to a cold cuprous bromide (73.21 g, 516 mmole) solution in cone, hydrochloric acid (220 ml) with stirring. The reaction mixture was stirred at 0-50C for 30 minutes and then at room temperature for another 30 minutes. Finally, after stirring at 30-350C for 30 minutes, precipitated solid was filtered, washed with water (50 ml) and dried under vacuum to yield 58 g of 3-bromo-4-methyl-5- nitrobenzoic acid as pink solid (88percent). 1H-NMR in CD3OD-d4 δ ppm : 2.6 (3H, s, CH3), 8.21 (IH, d, J = 1.4 Hz, Ar-H), 8.27 (IH, d, J = 1.2 Hz, Ar-H).
Reference：
[1] Patent: WO2010/59549, 2010, A1, . Location in patent: Page/Page column 16-17
[2] Justus Liebigs Annalen der Chemie, 1891, vol. 266, p. 223,227
3
[ 16533-71-4 ]
[ 34545-20-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1891, vol. 266, p. 223,227
3-Bromo-4-methyl-5-nitrobenzoic acid (7.10 g, 27.3 mmol) and methanol (100 mL) were added to a 250 mL single-neck flask, then dichloro sulfoxide (2.96 mL, 41.0 mmol) was added dropwise at 0°C. The reaction mixture was stirred for 12 h at 90°C. The resulting mixture was concentrated in vacuo to remove the solvent. To the residue was added saturated sodium bicarbonate (200 mL) and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, then the residue was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) = 1/30) to give the title compound as a pale yellow solid (6.36 g, 85percent).
82%
at -5℃; Reflux
Thiolyl chloride (7.2g, 0.06mol) was added into methanol(50ml) drop-wisely at -5°C, and then followed by the addition of 3-bromo-4-methyl-5-nitrobenzoic acid(13g, 0.05mol). The reaction mixture was stirred for 30min at rt, and then refluxed for 2h. The mixtuer was evaporated at reduced pressure and the residue was purified by column chromatograph to give the product 3 (1 1.2g, 82percent).
Step 3:; To a suspension of 3-amino-4-methyl-5-nitrobenzoic acid (50 g, 254 mmole) in a mixture of cone, hydrochloric acid (350 ml) and water (350 ml) was added at between 0-50C a solution of sodium nitrite (18.6 g, 270 mmole) in water (30 ml) over a period of 15 to 20 minutes. After stirring at 0-50C for another 30 minutes, the reaction mixture was then slowly added to a cold cuprous bromide (73.21 g, 516 mmole) solution in cone, hydrochloric acid (220 ml) with stirring. The reaction mixture was stirred at 0-50C for 30 minutes and then at room temperature for another 30 minutes. Finally, after stirring at 30-350C for 30 minutes, precipitated solid was filtered, washed with water (50 ml) and dried under vacuum to yield 58 g of 3-bromo-4-methyl-5- nitrobenzoic acid as pink solid (88%). 1H-NMR in CD3OD-d4 delta ppm : 2.6 (3H, s, CH3), 8.21 (IH, d, J = 1.4 Hz, Ar-H), 8.27 (IH, d, J = 1.2 Hz, Ar-H).
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃; for 16.0h;
4-Methyl-3-nitrobenzoic acid (5.43 g, 30 mmol) and concentrated sulfuric acid (45 mL, 98%) were added to a 250 mL two-neck flask, then 1,3-dibromo-5,5-dimethylhydantoin (4.29 g, 15 mmol) was added in portions. The reaction mixture was stirred for 16 h at rt. The resulting mixture was poured into ice-water (1000 mL). The mixture was extracted with ethyl acetate (150 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, then the residue was purified by silica gel chromatography (methanol/dichloromethane (v/v) = 1/30) to give the title compound as a white solid (7.1 g, 91%).MS (ES-API, pos. ion) m/z: 260.9 [M + 2]t
89%
With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; sulfuric acid; at 20℃;
To a mixture of 4-methyl-3 -nitrobenzoic acid (25.0 g, 138 mmol, 1.0 eq) in cone. H2SO4 (100 mL) was added l,3-dibromo-5,5- dimethylimidazolidine-2,4-dione (39.4 g, 152 mmol, 1.1 eq) portion wise at room temperature. When the addition was completed, the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice-water (500 g) with stirring, the white solid was formed, filtered and dried in vacuo to give 3 -bromo-4-methyl-5 -nitrobenzoic acid (32 g, 89%). 1HNMR (300 MHz, DMSO-de): delta 8.33-8.31 (m, 2H), 2.72 (s, 3H). ESI-MS (m/z): 257.7 (M-H)-.
85%
With DBDMH; In sulfuric acid; at 20℃; for 16.0h;
DBDMH(14.3g, 0.05mol) was added to the solution of compound 1(18. lg, O.lmol) in concentrated H2SO4(100ml) in portions. The reaction mixture was stirred at rt for 16h., and then poured into the ice (400g) while stirring for another 20min. Product 2 was collected by filtration and drying (22.1 g, 85%) as solid.
Step 4:; To a solution Of KMnO4 (176.85 g, 1.12 mole) in water (2650 ml) was added at ambient temperature <strong>[34545-20-5]3-bromo-4-methyl-5-nitrobenzoic acid</strong> (97 g, 373 mmole) and the mixture was then heated to reflux. After every 3 h, additional lots Of KMnO4 (58.95g, 373 mmole; 117.9g, 746 mmole; 58.95g, 373 mmole) were added and thereafter refluxing continued for a further 5 h. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated to approximately 400 ml on a rotavap. The concentrated aqueous mixture was cooled to 0-50C and acidified to pH 2 with cone. HCl. The precipitated solid was filtered and washed with water (50 ml) to yield 85 g of 2-bromo-6-nitroterephthalic acid as an off- white solid after drying (79%). 1H-NMR in DMSO- d6 delta ppm : 8.12 (IH, s, Ar-H) 8.31 (IH, s, Ar-H).
To a solution of 3 -bromo-4-methyl-5 - nitrobenzoic acid (40.0 g, 153 mmol, 1.0 eq) in MeOH (1.2 L) at room temperature was addedconc. H2S04 (10 mL), the mixture was heated to reflux and stirred for 8 h. LCMS showed no starting materials left. The mixture was concentrated under reduced pressure to remove most of MeOH, diluted with EtOAc (200 mL), washed with sat. NaHCO3 (100 mL x 2), the organic layer was dried over Na2SO4, concentrated in vacuo to give the desired product methyl 3-bromo- 4-methyl-5-nitrobenzoate (40 g, 93%) as a white solid, which was used in the next step without further purification. ?H NMR (300 MHz, DMSO-d6): 5 8.35 (s, 2H), 3.90 (s, 3H), 2.50 (s, 3H).
85%
With thionyl chloride; at 0 - 90℃; for 12.0h;
3-Bromo-4-methyl-5-nitrobenzoic acid (7.10 g, 27.3 mmol) and methanol (100 mL) were added to a 250 mL single-neck flask, then dichloro sulfoxide (2.96 mL, 41.0 mmol) was added dropwise at 0C. The reaction mixture was stirred for 12 h at 90C. The resulting mixture was concentrated in vacuo to remove the solvent. To the residue was added saturated sodium bicarbonate (200 mL) and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo, then the residue was purified by silica gel chromatography (ethyl acetate/petroleum ether (v/v) = 1/30) to give the title compound as a pale yellow solid (6.36 g, 85%).
82%
With thionyl chloride; at -5℃;Reflux;
Thiolyl chloride (7.2g, 0.06mol) was added into methanol(50ml) drop-wisely at -5C, and then followed by the addition of <strong>[34545-20-5]3-bromo-4-methyl-5-nitrobenzoic acid</strong>(13g, 0.05mol). The reaction mixture was stirred for 30min at rt, and then refluxed for 2h. The mixtuer was evaporated at reduced pressure and the residue was purified by column chromatograph to give the product 3 (1 1.2g, 82%).
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
