| 90% |
With sulfuric acid; at 0 - 25℃; for 16.0h; |
To a mixture of 3-nitro-5-(trifluoromethyl)benzoic acid (20 g, 85 mmol) in MeOH (200 mL) was added H2SO4 (12 mL, 225 mmol) at 0 °C dropwise, then the mixture was stirred for 16 h at 25 °C. Then the solvent was concentrated and was adjusted pH = 9 with NaHC03 solution. The solvent was concentrated to give the residue which was extracted with DCM (200 mL x 2), dried over NaaSOzi, filtered, and concentrated to yield an oil of methyl 3-nitro-5-(trifluoromethyl)benzoate (20 g, 76 mmol, 90percent yield): lH NMR (400 MHz, CD3OD) delta 8.99 (s, 1H), 8.74 (s, 1H), 8.62 (s, 1H), 4.01 (s, 3H); ES-LCMS m/z 250 (M+l). |
| 88% |
hydrogenchloride; at 20℃; |
Methyl 3-nitro-5-(trifluoromethyl)benzoate. 3-Nitro-5-(trifluoromethyl) benzoic acid (25.0 g, 106.3 mmol) was dissolved in methanol (60 mL) which was bubbled with hydrochloric acid gas for 1 h. The reaction was allowed to stir at room temperature overnight and concentrated. The crude product was dissolved in ethyl acetate, washed with water (2.x.), brine (2.x.) dried over sodium sulfate and concentrated. Flash chromatography on silica gel afforded 23.4 g (88percent) of the desired compound. 1H-NMR (CDCl3, 500 MHz) delta 9.02 (s, H), 8.66 (s, 1H), 8.61 (s, 1H), 4.03 (s, 3H). |
| 87% |
With sulfuric acid; for 48.0h;Reflux; |
3-Nitro-5-trifluoromethylbenzoic acid (32a) (1 g, 4.25 mmol)was dissolved in methanol (15 mL), and 5 drops of concentratedsulfuric acid were added. The mixture was refluxed for 48 h. Thesolvents were then evaporated under reduced pressure, and theresidue was dissolved in EtOAc (20 mL) and washed with 5percentNa2CO3 (3 x 20 mL) and brine (1 x 20 mL). The organic layer wasdried over anhydrous Na2SO4 and evaporated under reducedpressure. Methyl 3-nitro-5-trifluoromethylbenzoate was usedwithout further purification. Yield: 87percent as a colorless oil. 1H NMR(500 MHz, CDCl3) delta 9.05 (t, J = 1.8 Hz, 1H), 8.68 (t, J = 1.8 Hz, 1H),8.63 (s, 1H), 4.05 (s, 3H). 13C NMR (126 MHz, CDCl3) delta 163.62,148.47,133.16, 132.83 (q, J = 34.7 Hz), 131.87 (q, J = 3.5 Hz), 127.50, 124.42(q, J = 3.8 Hz), 122.37 (q, J = 273.2 Hz), 53.26. |
| 86% |
With sulfuric acid; for 20.0h;Heating / reflux; |
14). Synthesis of (3-chloromethyl-5-trifluoromethyl-phenyl)-dimethylamine; A solution of 5-nitro-3-(trifluoromethyl)benzoic acid (2.35 g, 10 mmol) and H2SO4 (53 mul_, 1 mmol) in methanol (30 mL) is allowed to warm to reflux and stir for 20 hours. The mixture is cooled to room temperature, then the mixture is concentrated under reduced pressure. The obtained residue is neutralized with saturated aq. NaHCO3. The mixture is extracted with CH2CI2. The combined organic layer is washed with brine, dried over <n="162"/>Na2SO4, filtrated, and concentrated under reduced pressure to give 3-nitro-5-trifluoromethyl- benzoic acid methyl ester (2.15 g, 86percent), which is used in the next step without further purification. |
| 70% |
With sulfuric acid; for 3.0h;Inert atmosphere; Reflux; |
To a flame dried pressure tube under argon was added 3-nitro-5-(trifluoromethyl)benzoic acid (450 mg, 1.91 mmol) and 20 mL of anhydrous MeOH. Sulfuric acid (0.176 mL) was added and the reaction was heated to reflux and stirred for 3 h. The reaction was cooled to room temperature and slowly poured onto solid NaHCO3, filtered, diluted with 20 mL of deionized H2O, and extracted with EtOAc (x 2). The pooled organic layers were dried with MgSO4, filtered, and concentrated under reduced pressure to give crude material that was purified with column chromatography (75/25 hexanes/EtOAc) to give 11 (332 mg, 1.33 mmol) in 70percent yield as a colorless oil that slowly solidified at 0°C into a white solid. |
|
With sulfuric acid;Heating / reflux; |
Trifluoromethyl-3-nitrobenzoic acid (0.7g, 3.0 mmol) was dissolved in methanol and 10 drops of sulphuric acid (cone.) were added, and the reaction was stirred over night at reflux temperature. Methanol was removed and the residue re-dissolved in dichloromethane and washed with water. The solvent was dried (magnesium sulphate) and removed under vacuum to give 0.71 g of 5- trifluoromethyl-3-nitrobenzoate methyl ester. |
|
With sulfuric acid;Heating / reflux; |
5-Trifluoromethyl-3-nitrobenzoic acid (0.7g, 3.0 mmol) was dissolved in methanol and 10 drops of sulphuric acid (conc.) were added, and the reaction was stirred over night at reflux temperature. Methanol was removed and the residue re-dissolved in dichloromethane and washed with water. The solvent was dried (magnesium sulphate) and removed under vacuum to give 0. 71 g of 5- trifluoromethyl-3-nitrobenzoate methyl ester. |
|
With thionyl chloride; for 5.0h;Reflux; |
Add thionyl chloride (2 mL) dropwise to the solution of 3-nitro-5-(trifluoromethyl) benzoic acid (1.5 g, 6.4 mmol) in methanol (20 mL), reflux for 5 hrs. TLC (PE:EtOAc=l:l) shows the reaction is complete. Concentrate under reduced pressure to give the crude product (1.8 g, 100percent) which is used in next step without further purification. |
|
With thionyl chloride; for 5.0h;Reflux; |
Add thionyl chloride (2 mL) dropwise to the solution of 3-nitro-5-(trifluoromethyl)benzoic acid (1.5 g, 6.4 mmol) in methanol (20 mL), reflux for 5 hrs. TLC (PE:EtOAc=1:1) shows the reaction is complete. Concentrate under reduced pressure to give the crude product (1.8 g, 100percent) which is used in next step without further purification. |
|
With toluene-4-sulfonic acid; for 8.0h;Reflux; |
(Reference Example 28) Synthesis of methyl 3-amino-5-(trifluoromethyl)benzoate: A solution of 3-nitro-5-(trifluoromethyl)benzoic acid (1.0 g, 4.2 mmol) and p-toluenesulfonic acid (0.05 g) in methanol was stirred while heating under reflux for eight hours. The obtained solution was returned to room temperature and then concentrated under vacuum. The obtained residue was dissolved in methanol, palladium (5.0percent by weight) on carbon (containing 50percent water by weight, 0.2 g) was added thereto, and the obtained solution was stirred at room temperature for three hours under hydrogen atmosphere. The reaction mixture was filtered through Celite? and the filtrate was concentrated under vacuum. The obtained crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 2:1, Rf = 0.47) to obtain the title compound (0.85 g, 91percent) (hereinafter referred to as the compound of Reference Example 28) as an oily substance. MS(ESI) [M + H]+: 220. |
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