| 92% |
With sulfuric acid; nitric acid; for 2.5h; |
2, 3,4-Trifluoro-5-nitro-benzoic acid 2A 3 liter three neck round bottom flask is charged with 125 ml H2504. Fuming nitricacid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1(25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solutionis stirred for 60 mm at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3 x 600 ml). The combinedorganic extracts are dried (Mg504) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 mm after which time it is filtered togive 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (-) nilz 220 (M-1) detected. |
| 88% |
With sulfuric acid; nitric acid; at 90℃; for 5h; |
Compound 1 (5 g, 28.41 mmol) was added to a solution of concentrated sulfuric acid (15 ml) and heated to 90 C.Then, a mixed acid of concentrated H2SO4 (3.2 g, 98%) and HNO3 (3 g, 68%) was added dropwise, and reacted for 5 hours.After cooling to room temperature, the mixture was poured into EtOAc (EtOAc)EtOAc.An oil of 5.5 g was obtained in a yield of 88%. |
| 78% |
With sulfuric acid; nitric acid; In water; |
Step a Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78% yield; m.p.; 1H-NMR (400 MHz; DMSO)delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95,1 23.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m). |
| 78% |
With sulfuric acid; nitric acid; In water; |
Step a Preparation of 5-Nitro-2,3,4-trifluorobenzoic Acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78% yield; m.p.; 1H-NMR (400 MHz; DMSO) delta14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m). |
| 78% |
With sulfuric acid; nitric acid; In water; |
Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 % yield; m.p.;1H-NMR (400 MHz; DMSO) delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m). |
| 78% |
With sulfuric acid; nitric acid; In water; |
Step a: Preparation of 5-nitro-2,3,4-trifluorobenzoic acid To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3 x 200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78 % yield; m.p.;1H-NMR (400 MHz; DMSO) delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0. 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta-120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m). |
| 78% |
With sulfuric acid; nitric acid; for 0.75h; |
To gently stirring concentrated sulfuric acid (50 ml) was added fuming nitric acid (3.4 ml, 0.076 mol). Solid 2,3,4-trifluorobenzoic acid (10.00 g, 0.05565 mol) was added directly in increments. After stirring 45 minutes, the reaction mixture had become an orange homogeneous solution which was then poured over chilled water (400 ml). The resulting aqueous suspension was extracted with diethyl ether (3*200 ml). The combined extracts were dried with anhydrous magnesium sulfate and concentrated in vacuo to yield 12.30 g of a dull, light-yellow solid. Recrystallization from chloroform (50 ml) afforded 9.54 g of the pale yellow microcrystalline product; 78% yield; m.p.; 1H-NMR (400 MHz; DMSO) delta 14.29 (broad s, 1H), 8.43-8.38 (m, 1H); 13C-NMR (100 MHz; DMSO) delta 162.41, 154.24 (dd, JC-F=270.1, 10.7 Hz), 148.35 (dd, JC-F=267.0, 9.2 Hz), 141.23 (dt, JC-F=253.4 Hz), 133.95, 123.30 (d, JC-F=2.2 Hz), 116.92 (dd, JC-F=18.2, 3.8 Hz); 19F-NMR (376 MHz; DMSO) delta -120.50 to -120.63 (m), -131.133 to -131.27 (m), -153.63 to -153.74 (m). |
| 75% |
With sulfuric acid; nitric acid; at 0 - 20℃; for 6h; |
Example 1; Preparation of 6-(4-bromo-2-chlorophenylamino)-7-fluoro-3-methyl-3H- benzoimidazole-5-carboxylic acid; [00238] Step A; 2,3,4-Trifluoro-5-mtrobenzoic acid; Fuming HNO3 90% (549.0 g,7.84 mol corrected for 90% wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H2SO4 over 18 minutes with stirring. The solution OfHNO3 was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H2SO4 in a second flask with ice- water bath cooling over an hour. When addition was complete, the reaction solution was allowed to warm to room temperature. After 5 hours, the reaction was complete as determined by HPLC and the reaction mixture (brown solution) was poured into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice over 10 minutes. The yellow slurry was cooled to 14 C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven-dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 0C under high vacuum overnight to yield 1035.9 g (75%) of 2,3,4-trifluoro-5-nitrobenzoic acid as a yellowish solid. HPLC was 98 a% (220 nm) and 100% (254 nm). 1H NMR (400 MHz, DMSO-d6) delta 8.44 (IH, apparent dt, J 1.9, 7, Ar-H); 19F NMR (376 EPO <DP n="51"/>MHz, DMSOd6) delta -153.9, -131.5, -120.9. 13C NMR (100 MHz, DMSO-d6) delta 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F, dd, J 265, 13), 154 (C-F, dd, J 265, 10), 163 (COOH). IR v^/cnf1 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected. |
| 75% |
With sulfuric acid; nitric acid; at 0 - 20℃; for 6.3h;Product distribution / selectivity; |
Fuming HNO3 90% (549.0 g,7.84 mol corrected for 90% wt, 1.26 equiv.) was added to 2.0 L (3.35 kg) of concentrated H2SO4 over 18 minutes with stirring. The solution Of HNO3 was then added to a mixture of 2,3,4-trifluorobenzoic acid (1094 g, 6.21 mol, 1 equiv.) in 3.3 L (5.85 kg) of concentrated H2SO4 in a second flask with ice-water bath cooling over an hour. Upon complete addition, the reaction mixture was allowed to warm to room temperature. After 5 hours, the reaction was complete by HPLC and the reaction mixture (brown solution) was poured over 10 minutes into a mechanically stirred mixture of 10.6 kg of distilled water and 11.8 kg of ice. The yellow slurry was cooled to 14 C, stirred for 2 hours and then filtered. The cake was rinsed with 4.0 L of distilled water and then with 5 L of heptane. The wet cake was oven- dried overnight. The crude solids (1.791 kg) were then stirred in 16 L of distilled water (9 vol.), filtered and oven-dried at 55 0C under high vacuum overnight to yield 1035.9 g (75%) of compound 2 as a yellowish solid. HPLC was 98 a% (220 nm) and 100% (254 nm). 1H NMR (400 MHz, d6 DMSO) delta 8.44 (IH, apparent dt, J 1.9, 7, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.9, -131.5, -120.9. 13C NMR (100 MHz, d6 DMSO) delta 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, 7251, 10), 148 (C-F5 dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR vmJcmA 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected. |
| 74.3% |
With Hexamethyldisiloxane; sulfuric acid; nitric acid; at 15 - 25℃; for 6.25h;Product distribution / selectivity; |
Trifluorobenzoic acid (70 Kg5 398 MoI) in sulphuric acid (96 wt%; 194 L) and hexamethyldisiloxane (6,5 Kg5 40 MoI)5 at 23 0C, was added a 1:1 mixture of sulphuric acid (96 wt%) and nitric acid (98 wt%) (total 70.1 Kg)5 over 75 min. The temperature of the reaction mixture was maintained between 15 and 25 0C during the addition. The mixture was stirred for a further 5 hours and then run onto ice (700 Kg)5 keeping the temperature of the ice micture below 0 C. Water (35 L) was used to rinse the nitration reactor into the quench reactor and the obtained mixture was stirred for 2 hours at 0 0C5 then isolated on a centrifuge. The resultant wet cake was washed with cold water (350 L)5 and the solid was then suspended in water (280 L) and stirred for 2 hours at 0 C. This suspension was then centrifuged and the cake was washed with cold water (210 L), then dried in a vacuum oven at 45 0C for 2 days, to provide 2,354-Trifluoro-5-nitro benzoic acid (69.4 Kg5 74.3% yiled). 1H NMR (400 MHz5 d6 DMSO) delta 8.44 (IH, apparent dt, J 2, 7, Ar-H). 19F NMR (376 MHz, d6 DMSO) delta -153.9, -131.5, -120.9. 13C NMR (100 MHz5 d6 DMSO) delta 117 (C, m), 124 (CH, b s), 134 (C, s), 141 (C-F, dt, J251, 10), 148 (C-F5 dd, J265, 13), 154 (C-F, dd, J265, 10), 163 (COOH). IR vmjcm l 3108 (br), 1712, 1555, 1345, 1082. MS APCI (-) m/z 220 (M-I) detected. |
| 50% |
With sulfuric acid; nitric acid; In sulfuric acid; at 5 - 20℃; for 2h; |
Example 1 5-FLUORO-6-(2-FLUORO-4-IODO-DHENYLAMINO)-3-METHYL-3H-BENZOIMIDAZOLE-5-CARBOXYLIC ACID (2-- OH-ETHOXY)-AMIDE Step A: Preparation of 2. 3. 4-trifluoro-5-nitrobenzoic acid Fuming HNO3 was added dropwise to the cold (5 TO-10 C) conc. H2SO4 (5L) and stirred in a three-necked round bottom flask (20L), maintaining the temperature between 5 to- 10 C. Then was added 2, 3, E-TRIFTUOROBENZOIC acid (1 kg, 5.6 mol) in portions, maintaining the temperature at 5O C and after completion of the addition the reaction mixture was allowed to warm to room temperature, stirred for 2h and (the suspension becomes light yellow solution) then poured into 30 kg of crushed ice. The mixture was extracted with ether (3 X 4.0 L) and the organic extracts were washed with water (2 X 2L), brine (2.0 L), dried over anhydrous MGS04, filtered and evaporated under vacuum. The residue (cream colored solid) obtained is re-crystallized from hot chloroform provided the title compound as a solid (yellow). Yield : 880G (50%), mp. 128-129 OC |
|
With sulfuric acid; nitric acid; for 2.5h; |
Example 1; Step A: 2,3,4-Trifluoro-5-nitro-benzoic acid 2 . A 3 liter three neck round bottom flask is charged with 125 mL H2SO4. Fuming nitric acid is added (8.4 mL, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid 1 (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 minutes at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3×600 mL). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 minutes after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid: MS APCI (-) m/z 220 (M-1) detected. |
| 29 g (92%) |
With sulfuric acid; nitric acid; |
Step A 2,3,4-Trifluoro-5-nitro-benzoic acid A 3 liter three neck round bottom flask is charged with 125 ml H2SO4. Fuming nitric acid is added (8.4 ml, 199 mmol) and the mixture gently stirred. 2,3,4-Trifluorobenzoic acid (25 g, 142 mmol) is added in 5 g portions over 90 minutes. The dark brownish yellow solution is stirred for 60 min at which time the reaction is complete. The reaction mixture is poured into 1 liter of an ice:water mixture and extracted with diethyl ether (3*600 ml). The combined organic extracts are dried (MgSO4) and concentrated under reduced pressure to give a yellow solid. The solid is suspended in hexanes and stirred for 30 min after which time it is filtered to give 29 g (92%) of clean desired product as an off-yellow solid. |
|
With sulfuric acid; potassium nitrate; In hexane; |
(1) 2,3,4-Trifluoro-5-nitrobenzoic acid: 2,3,4-Trifluorobenzoic acid (1 g) was added to sulfuric acid (5 ml), and potassium nitrate (630 mg) was gradually added to the mixture under cooling on ice. The resultant mixture was stirred overnight at room temperature, and the reaction mixture was poured onto crushed ice. The mixture was extracted with diethyl ether, and the organic phase was dried over magnesium sulfate. The solvent was removed through distillation, and n-hexane was added to the residue, to thereby collect the solid of the title compound (1 g) by filtration. Form: colorless powder Melting point: 127-135 C. 1 H--NMR(CDC kappa3)delta; 8.67-8.71(m, 1H) |
|
With potassium nitrate; In hexane; sulfuric acid; |
Referential Example 5 Synthesis of 2,3,4-Trifluoro-5-nitrobenzoic Acid 2,3,4-Trifluorobenzoic acid (2.5 g) was dissolved in concentrated sulfuric acid (15 ml). Potassium nitrate (1.62 g) was added to the solution under ice cooling. The temperature of the reaction mixture was (given back to room temperature to conduct stirring for 2 days. The reaction mixture was poured into ice water (300 ml) and extracted with ether (200 ml). An organic layer was dried and concentrated. Hexane was added to the residue to conduct filtration, thereby obtaining the title compound (3.06 g) as a pale yellow powder. 1 H-NMR (d6 -DMSO) delta: 8.40-8.47(m,1H). |
|
With sulfuric acid; nitric acid; at 5 - 20℃; for 2h; |
00128] Step A: 2,3,4-Trifluoro-5-nitrobenzoic acid:[00129] Fuming nitric acid (1.7 ml) is added dropwise to concentrated sulfuric acid (25 ml) while maintaining the temperature at 5 - 10 C. 2,3,4-Trifluorobenzoic acid (5 g, 28 mmoles) is added in small portion to this solution while keeping the reaction temperature at 5 C. After completion the reaction mixture is stirred at room temperature for an additional 2 hours and poured into ice. The mixture is extracted with ether (3 x 75 ml). The organic layers are combined, washed with brine, dried (MgSO4). The solvent is removed, and the crude product is recrystallized from hot chloroform to obtain the title compound. |
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