| 93% |
With sulfuric acid; nitric acid In dichloromethane for 3h; Cooling with ice; |
1 Compound (3): Synthesis of 4-Fluoro-2-methoxy-5-nitroaniline (3)
Compound (2) (551 mg, 3.90 mmol) is dissolved in dichloromethane (39.0 mL), concentrated sulfuric acid (1.85 mL) is added dropwise with stirring under ice-cooling, and then concentrated nitric acid (267 μL, 5.85 mmol) is added dropwise. did. After stirring for 3 hours under ice-cooling, saturated aqueous sodium bicarbonate was added until pH 8 was reached. After washing with saturated aqueous sodium bicarbonate solution, washing with saturated brine, the organic layer was dried over sodium sulfate and evaporated under reduced pressure to obtain 675 mg of compound (3) (yield 93%). |
| 90% |
Stage #1: 4-fluoro-2-methoxyaniline With sulfuric acid; nitric acid In dichloromethane; water at 0℃; for 4h;
Stage #2: With sodium hydrogencarbonate In water |
|
| 83.7% |
With sulfuric acid; potassium nitrate at -15℃; for 2h; |
1 Step 1: Intermediate 1: 4-Fluoro-2-methoxy-5-nitroaniline
4-Fluoro-2-methoxyaniline (20g) was dissolved in concentrated sulfuric acid at -15 ° C to dissolve all the solids in the mixture.A potassium nitrate solution (5.91 g) dissolved in concentrated sulfuric acid was slowly added.Stirring was continued for 2 h at this temperature.The reaction solution was poured into ice water and NaOH was added.Adjust pH 8.0-9.0, stir vigorously to precipitate solids,Filtration with suction gave 4-fluoro-2-methoxy-5-nitroaniline (22.0 g).The yield was 83.7%. |
| 82% |
With sulfuric acid; potassium nitrate at 0 - 25℃; for 16h; |
4-Fluoro-2-methoxy-5-nitroaniline. 4-Fluoro-2-methoxyaniline (50.0 g, 354 mmol) was added to stirred sulfuric acid (300 mL) at 0 C in portions, ensuring that the temperature did not rise above 10 C. When all of the solid had dissolved up, potassium nitrate (36 g 354 mmol) was added in portions keeping the temperature below 10 C. The reaction mixture allowed to warm to 25 C, and stirred for 16 hr. It was then poured onto was poured onto ice- water (1 L) with vigorous stirring, and the solid was collected by vacuum filtration, rinsed with water (2 x250 mL), and dried to give 4-fluoro-2-methoxy-5-nitroaniline (54 g, 82%) as a light yellow solid. 1H NMR: (CDCl3) 7.35, (1H, d, J = 8 Hz), 7.03 (1H, d, J = 11 Hz), 5.21, (2H, brs), 3.91 (3H, s). |
| 80% |
With sulfuric acid; nitric acid at -20℃; for 0.0833333h; |
2-a.b Step b:
The compound 2-a-2 (8.0g, 43mmol) in 500mL reaction flask, under stirring concentrated sulfuric acid was added (100 mL) to dissolve the substrate. At -20 deg. C condition, to the stirred reaction flask was slowly added dropwise concentrated nitric acid (6.15 mL, 48mmol), and held at that temperature for 5 minutes. The progress of the reaction by TLC, until complete reaction of the substrate, poured into ice water. -20 deg. C kept ice bath, was slowly added to the reaction system sodium hydroxide / water solution (150mL / 300 mL), adjusted to pH 8-9. After completion of the reaction solution with ethyl acetate / water system was extracted three times, the organic layer was separated, washed with water, saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-fluoro-2-methoxy -5-nitroaniline compound 2-a-3 (8.7g), was used directly in the next reaction. Yield: 80%; purity: 100%; |
| 80% |
Stage #1: 4-fluoro-2-methoxyaniline With sulfuric acid for 0.5h; Cooling with ice;
Stage #2: With potassium nitrate at 20℃; for 12h; |
7 Preparation Example 7 Fluoro-2-methoxy-5-nitroaniline preparation
Ice bath,4-Fluoro-2-methoxyaniline (6.5 g, 46 mmol) was dissolved in concentrated sulfuric acid (50 mL)After stirring for 30 minutes in an ice bath,Potassium nitrate (5.2 g, 51 mmol) was added portionwise,After the addition, the reaction was allowed to proceed to room temperature and the reaction was stirred for 12 hours.After completion of the reaction,The reaction was poured into ice and the pH was adjusted to 8 with the addition of ammonia, Ethyl acetate (200 mL × 3), dried over anhydrous sodium sulfate,Concentrated, and purified by column chromatography (petroleum ether: ethyl acetate = 3: 1) to give the title compound (6.9 g, yield 80%). |
| 80% |
With sulfuric acid; nitric acid at -20℃; for 0.0833333h; |
Step b: Compound 1a2 (8.0 g, 43 mmol) was added into a 500 ml reaction flask, and concentrated sulfuric acid (100 ml) was added to dissolve the substrate under constant agitation. At -20° C., concentrated nitric acid (6.15 ml, 48 mmol) was slowly added dropwise with stirring, and the reaction mixture was stirred for 5 mins at this temperature. The reaction progress was monitored by TLC. After completion of the reaction, the mixture was poured into ice water. Sodium hydroxide/water solution (150 ml/300 ml) were added slowly to the reaction system at -20° C. in an ice-water bath, and the mixture was adjusted to pH 8-9. The reaction solution was extracted with EA/water system for three times, the organic layer was separated, washed with water, saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give compound 1a (8.7 g) which was used directly in the next reaction. Yield: 80%; purity: 100%; MS m/z (ESI): 187.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 7.34 (d, J=7.8 Hz, 1H), 7.04 (d, J=13.4 Hz, 1H), 5.25 (brs, 2H), 3.90 (s, 3H). |
| 77% |
With sulfuric acid; potassium nitrate at 15℃; Cooling with ice; |
23 Intermediate 23: 4-Fluoro-2-methoxy-5-nitroaniline
4-Fluoro-2-methoxyaniline (2.4 g, 17.00 mmol) was added portionwise to concentrated H2SO4 (15 mL) which was cooled in a ice/water bath, and where the temperature was kept below 15°C during the addition. The mixture was stirred until all the solid that formed had dissolved. KNO3 (0.815 mL, 17.00 mmol) was added portionwise such that the temperature was maintained below 10°C. The mixture was stirred overnight and then poured onto ice/water. The mixture was basified with concentrated NH4OH. The resulting solid was filtered off and then dissolved in CH2Cl2, washed with water, dried (Na2SO4) and concentrated onto silica. Purification by FCC, eluting with 50-0% heptane in CH2Cl2 gave the title compound (2.450 g, 77%) as a yellow crystalline solid; 1H NMR: 3.91 (3H, s), 5.21 (2H, s), 7.03 (1H, d), 7.35 (1H, d); m/z: ES+ MH+ 187.4. |
| 77% |
Stage #1: 4-fluoro-2-methoxyaniline With sulfuric acid at 15℃;
Stage #2: With potassium nitrate at 10℃; |
|
| 77% |
With sulfuric acid; potassium nitrate at 15℃; |
4-fluoro-2-methoxy-5-nitroaniline
4-Fluoro-2-methoxyaniline (2.4 g, 17.00 mmol)Was added portionwise to concentrated H2SO4 (15 mL) cooled in an ice / water bath,The temperature was maintained below 15 & lt; 0 & gt; C during the addition.The mixture was stirred until all of the formed solids had dissolved.KNO3 (0.815 mL, 17.00 mmol) was added in portions,So as to keep the temperature below 10 ° C. The mixture was stirred overnight and then poured onto ice / water.The mixture was basified with concentrated NH4OH. The resulting solid was filtered off,Then dissolved in CH2Cl2, washed with water, dried (Na2SO4),Concentrated on silica gel. Using FCC for purification,Eluting with 50% by weight of heptane in CH2Cl2,The title compound was obtained as a yellow crystalline solid (2.450 g, 77%). |
| 77% |
With sulfuric acid; potassium nitrate at 10 - 15℃; |
4-fluoro-2-methoxy-5-nitroaniline
4-fluoro-2-methoxyaniline (2.4 g, 17.00 mmol) was added portionwise to a concentrated H2SO4(15 mL)cooled in an ice / water bath andthe temperature was maintained below 15 ° C during the addition TheThe mixture was stirred until all of the formed solidshad dissolved.Was added portionwise a KNO. 3(0.815mL, 17.00mmol), so that the temperature was kept below 10 .The mixture was stirredovernight and then poured onto ice / water.The mixture was basified with concentrated NH4OH.The resulting solid was filtered off, then dissolved inCH2CI2, washed with water, dried (of Na2SO. 4), concentrated onto silica gel.Using the FCC, eluting with 50-0% in CH2CI2iseluted heptane to give the title compound as a yellow crystalline solid (2.450g, 77%).m / z: 186 |
| 77% |
With sulfuric acid; potassium nitrate at 0℃; for 1h; |
1.1b Step 1b: Preparation of 4-fluoro-2-methoxy-5-nitroaniline (Intermediate 103):
Under an ice bath condition, 4-fluoro-2-methoxyaniline (Intermediate 102) (15 g, 106.4 mmol, 1.0 eq) was added dropwise to a concentrated sulfuric acid (150 mL) while controlling the temperature around 0°C during the course of addition. After the forming solid was dissolved completely, potassium nitrate (11 g, 106.4 mmol, 1.0 eq) was added portionwise and the reaction was continued for 1 hour under this condition. The reaction was poured into ice water and the pH was adjusted to basic by sodium hydroxide. A vast amount of solid was precipitated out which was filtered and washed with water, petroleum ether, dried in air to give 4-fluoro-2-methoxy-5-nitroaniline as a brown solid (18 g, yield: 77%). LCMS (ESI): m/z 187 [M + H]+. |
| 77% |
With sulfuric acid; potassium nitrate at 10 - 15℃; |
4-fluoro-2-methoxy-5-nitroaniline
4-Fluoro-2-methoxyaniline (2.4 g, 17.00 mmol) was added portionwise to concentrated H2SO4 (15 mL) cooled in an ice / water bath, and the temperature was kept below 15 ° C during the addition.The mixture was stirred until all the solids formed had dissolved.KNO3 (0.815 mL, 17.00 mmol) was added in portions to keep the temperature below 10 ° C.The mixture was stirred overnight and then poured onto ice / water.The mixture was basified with concentrated NH4OH.The resulting solid was filtered off, then dissolved in CH2Cl2, washed with water, dried (Na2SO4), and concentrated on silica gel.Purified by FCC, eluted with 50-0% heptane in CH2Cl2,The title compound was obtained as a yellow crystalline solid (2.450 g, 77%). m / z: 186 |
| 75.2% |
With sulfuric acid; potassium nitrate at 5 - 20℃; for 2h; |
4; 12 Example 4 Preparation of 2-methoxy-4-fluoro-5-nitroaniline (1)
Take 98wt% sulfuric acid (200 mL) was added to a 500mL three-necked flask,Ice bath cooling to 5 ~ 10 ,2-methoxy-4-fluoroaniline (41.0 g, 0.29 mol) was added in portions;Then divided into batches at 15 was added KNO3 (34.4g, 0.34mol),After adding the natural temperature to room temperature reaction 2h.The reaction solution was slowly poured into 1 L of ice water,Filter out the resulting solid,The filtrate was neutralized with 40 wt% NaOH to pH 10.5,Then stir for 1 h,,The resulting solid was filtered off and washed with water until neutral,The solid was dried to give 40.5 g of terephthalic solid 2-methoxy-4-fluoro-5-nitroaniline in a yield of 75.2%. |
| 75.2% |
With sulfuric acid; potassium nitrate at 0 - 25℃; for 2h; |
1 Example 1 Preparation of 2-methoxy-4-fluoro-5-nitroaniline (1)
Taking 200 ml 98 wt % sulfuric acid is added to a 500 ml three-port flask, ice water bath cooled to 5 - 10 °C, then addition of 2 - methoxy -4 - fluoro aniline (41.0g, 0 . 29 µM), control of speed of addition, the reaction solution maintained at a temperature of 0 - 20 °C; then adding KNO batch3(34.4g, 0 . 34 µM), keep the temperature of the reaction solution is 0 - 20 °C, after adding the reaction liquid natural temperature to 25 °C, reaction 2h end after. The reaction liquid slowly poured into the 1L the ice water, stirring after filtering out the solid, the filtrate 40 wt % NaOH to pH=9 and in, dropwise lye process is maintained in the temperature not higher than 40 °C, after adding stirring 1h, separating solid, after the solid is filtered, washed with water solid to neutral, then dried to obtain the brown body solid 2 - methoxy -4 - fluoro -5 - nitroaniline 40.5g, yield is 75.2%. |
| 70% |
With sulfuric acid; nitric acid Cooling with ice; |
4.1.8 Synthesis of 4-fluoro-2-methoxy-5-nitroaniline (20b)
4-Fluoro-2-methoxyaniline (1.4g, 10mmol) was added portion-wise to concentrated H2SO4 (10mL) in ice-water bath. After the solid dissolved, concentrated nitric acid (10 mmol) was added portion-wise, stirred overnight and poured into cooled water. The mixture was basified by NH4OH, the solid was filtered off and dissolved in ethyl acetate, washed with water and purified by silica chromatography to afford 20b (1.3g, 70%) as a yellow crystalline solid. 1H NMR (600MHz, DMSO-d6) δ (ppm): 7.337 (d, J=7.8Hz, 1H, Ar-H), 7.028 (d, J=13.8Hz, 1H, Ar-H), 5.233 (s, 2H, -NH2), 3.902 (s, 3H, -OCH3). ESI-MS m/z: 187.3 (M+H)+, calcd for C7H7FN2O3: 186.04. |
| 60% |
With sulfuric acid; potassium nitrate at 0 - 20℃; Inert atmosphere; |
1.1 1. Synthesis of intermediate 001-2
Under nitrogen, to a 2000mL three necked flask successively add 001-1 (100g, 708.5mmol) and 800mL sulfuric acid (H2SO4),cooled to 0 deg.C, at 0-10 portionwise added potassium nitrate (KNO3)(71.6g, 708.19mmol), used time 1h, and finally react overnight at room temperature (rt). After completion of the reaction, three-necked flask was added 2000mL of ice water to quench the reaction. At a low temperature the reaction mixture was adjusted to pH 10 with aqueous ammonia, washed with 1 liter (L) in dichloromethane (DCM) and extracted 3 times. The organic layers were combined and backwashed with saturated brine 3000mL three times, dried over anhydrous sodium sulfate, and spin dry. The resulting crude product ispurified by silica gel column chromatography (eluent: ethyl acetate (EA):petroleum ether (PE) = 1: 4-1: 1), after the spin dry eluent to give 79g (60%)001-2, as a yellow solid. |
| 60% |
Stage #1: 4-fluoro-2-methoxyaniline With sulfuric acid at 0 - 10℃; Inert atmosphere;
Stage #2: With potassium nitrate at 20℃; Inert atmosphere; |
1.5 5. Synthesis of Intermediate 001-8
5. Synthesis of Intermediate 001-8 The intermediate 001-7 (100 g, 708.5 mmol) and 800 mL of concentrated sulfuric acid (H2SO4) were added sequentially to a 2000 mL three-necked flask under nitrogen protection and cooled to 0°C, and the reaction temperature was maintained at a temperature between 0 and 10°C. Potassium nitrate (KNO3) (71.6 g, 708.19 mmol) was added in batches for 1 hour, and then the reaction was stirred overnight at room temperature. After completion of the reaction, 2 L of ice water was added to the three-necked flask to quench the reaction. The reaction mixture was adjusted to pH = 10 with aqueous ammonia at low temperature and extracted three times with 1 L of dichloromethane (DCM). Then, the organic phases were combined, washed three times with 3 L of saturated brine, dried over anhydrous sodium sulfate and rotovapped. The crude product was purified by silica gel column chromatography (the used eluent, ethyl acetate (EA) : petroleum ether (PE) = 1: 4 - 1:1) and eluent was rotovapped to give 79 g of the intermediate 001-8 (yield: 60%) as a yellow solid. LCMS: 187.0. |
| 60% |
With sulfuric acid; potassium nitrate at 0 - 20℃; Inert atmosphere; |
122.3 3. Synthesis of Intermediate 122-4
Under nitrogen protection, add 122-3 (100 g, 709 mmol) and 800 mL of concentrated sulfuric acid (H2SO4) to a 2000 mL three-necked bottle in sequence, and cool down to 0°C to maintain the temperature at 0-10°C.Potassium nitrate (KNO3) (71.6 g, 708 mmol) was added in portions over 1 hour.Finally, react overnight at room temperature. After the reaction is completed, add 2 liters (L) to three bottlesIce water quenches the reaction. The reaction mixture was adjusted to pH 10 with aqueous ammonia at low temperature.Extract 3 times with 1 L dichloromethane (DCM). After the organic phase is merged, it is saturated with 3LThe saline was backwashed 3 times, dried over anhydrous sodium sulfate, and spin-dried.The resulting crude product was subjected to silica gel column chromatography (eluent ethyl acetate (EA): petroleum ether (PE) = 1:4:1:1).After spin-drying the eluate, 79 g of 122-4 (yield: 60%) was obtained as a yellow solid. |
| 54.81% |
With sulfuric acid; potassium nitrate at 0 - 10℃; for 3h; |
A2 Embodiment A2
4-Fluoro-2-methoxy-5-nitroaniline
Embodiment A1 (83.00g, 558.67mmol) was slowly added dropwise to concentrated H2SO4 (415mL) at 0°C and then KNO3 (56.48g, 558.67mmol) was added in batches. The mixture was stirred at 0 to 10°C for 3 hours. TLC showed the reaction was complete, NH3·H2O was added until the pH of the reaction mixture was 8, and the temperature was controlled below 10°C. The resulting mixture was filtered and the filter cake was washed with water (500mL) and dissolved in DCM (1L). The solution was dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (PE: DCM = 5: 1, 1: 10) to deliver the title compound (yellow solid, 60.00 g, yield 54.81%). 1H NMR (400 MHz, CDCl3): δ 7.40 (d, J=7.2 Hz, 1 H), 6.64 (d, J=12.4 Hz, 1 H), 3.86-3.97 (m, 5 H). |
| 50.2% |
Stage #1: 4-fluoro-2-methoxyaniline With sulfuric acid for 0.666667h; Inert atmosphere; Cooling with ice;
Stage #2: With potassium nitrate at 0 - 5℃; Inert atmosphere; |
1.2 Synthesis of compound 5-b
Put compound 5-a (675mg, 4.78mmoL) in a single-necked reaction flask, evacuated and protected with nitrogen, under ice-water bath conditions,Then add 5mL concentrated sulfuric acid solvent and stir for 40min,Add potassium nitrate (512mg, 4.78mmoL) into the system,At 0-5, continue to stir for 2-3h, TLC detects that the reaction is complete,The reaction solution was added dropwise to 250 mL of ice water with vigorous stirring,Then add an appropriate amount of 25% ammonia to adjust the pH to 8-9,Extract three times with dichloromethane, combine the organic phases,After washing with saturated NaCl solution, the organic phase was dried with anhydrous NaSO4,After concentrating to dryness under reduced pressure, a brown-black crude product was obtained.Separation by silica gel column(Use petroleum ether: ethyl acetate=4:1 to 2:1 for elution),Compound 5-b (447 mg, yield 50.2%) was obtained as a reddish brown solid. |
|
Stage #1: 4-fluoro-2-methoxyaniline With sulfuric acid; guanidine nitrate for 0.5h; Cooling with ice;
Stage #2: With sodium hydrogencarbonate In water Cooling with ice; |
8 4-Fluoro-2-methoxy-5-nitroaniline
To a suspension of 4-fluoro-2-methoxyaniline (0.71 g) in concentrated sulfuric acid (7.5 mL) was added guanidine nitrate (0.61g) under ice-cooling over 15 minutes, and the mixture was stirred at the same temperature for 15 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution cooled in ice, and the precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, and the solution was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.78 g). |
|
With sulfuric acid; guanidine nitrate for 0.5h; Cooling with ice; |
24.2
Step 2: To a suspension of 4-fluoro-2-methoxyaniline (5.1 g, 36.1 mmol) in concentrated sulfuric acid (55mL) was added guanidine nitrate (4.38g, 36.1 mmol) in portion wise under ice cooling over 15 min. The mixture was stirred at the same temperature for additional 15 min. The reaction was then poured into a saturated cold NaHC03 solution and the precipitated solid were collected by filtration. The residue was taken up in EtOAc and dried over anhydrous Na2S04. The solvent was stripped off to afford the B (4.72g). |
| 4.72 g |
With sulfuric acid; guanidine nitrate for 0.5h; Cooling with ice; |
24.2
To a suspension of 4-fluoro-2-methoxyaniline (5.1 g, 36.1 mmol) in concentrated sulfuric acid (55mL) was added guanidine nitrate (4.38g, 36.1 mmol) in portion wise under ice cooling over 15 min. The mixture was stirred at the same temperature for additional 15 min. The reaction was then poured into a saturated cold NaHCC solution and the precipitated solid were collected by filtration. The residue was taken up in EtOAc and dried over anhydrous Na2SC>4. The solvent was stripped off to afford the B (4.72g). |
|
With sulfuric acid; nitric acid at 0 - 5℃; |
4-Fluoro-2-methoxy-5-nitro-phenylamine (5)
4-Fluoro-2-methoxyaniline (12.0g, 85.0 mmol) was added to cooled concentrated H2SO4 (80 mL).14 The mixture was stirred at 0-10oC for 15-30 min. KNO3 (8.6g, 85.0 mmol) was added to the mixture. The resulting mixture was stirred at 0-5oC for 1-2 h and then poured into ice/water. The mixture was neutralised with concentrated NH4OH. The resulting solid was filtered off and dried under vacuum. A suspension of crude product and Pd/C (0.35g, 0.3%) in methanol (200 mL) was stirred under one atm hydrogen at room temperature for 2-3 h. Filtration of the Pd/C was effected through celite and the solid cake washed with methanol. The combined solvents were evaporated under reduced pressure.The corresponding amine was used in the next step without further purification. |
|
With sulfuric acid; guanidine nitrate at -10 - 0℃; for 3h; |
4-fluoro-2-methoxy-5-nitroaniline
[448] To a concentrated sulfuric acid solution (800 mL) was added 4-fluoro-2-methoxyaniline (A3) (79.4 g, 0.562 mol) at -1 0° C, then guanidine nitrate (68.7 g, 0.562 mol) over the course of 1 h. The mixture was stirred at 0° C for 2 h. Subsequently, the reaction mixture was treated with sodium bicarbonate until the pH was 7. The reaction mixture was then filtered and the filtrate was extracted with DCM (5 Lx 2). The isolated organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 4-fluoro-2-methoxy-5-nitroaniline (A4) as a brown solid. |
|
With sulfuric acid; guanidine nitrate at -10 - 0℃; for 3h; |
4-fluoro-2-methoxy-5-nitroaniline
To a concentrated sulfuric acid solution (800 imL) was added 4-fluoro-2-methoxyaniline (A3) (79.4 g, 0.562 mol) at -10° C, then guanidine nitrate (68.7 g, 0.562 mol) over the course of 1 h. The mixture was stirred at 0° C for 2 h. Subsequently, the mixture was treated with sodium bicarbonate until the pH was 7. The mixture was then filtered and the filtrate was extracted with DCM (5 L x 2). The isolated organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 4-fluoro-2-methoxy-5-nitroaniline (A2) as a brown solid. |
|
With sulfuric acid; guanidine nitrate at -10 - 0℃; for 3h; |
Intermediate A24-fluoro-2-methoxy-5-n itroaniline
[00396] To a concentrated sulfuric acid solution (800 mL) was added 4-fluoro-2-methoxyaniline (A3) (79.4 g, 0.562 mol) at -10° C, then guanidine nitrate (68.7 g, 0.562 mol) over the course of 1 h. The mixture was stirred at 00 C for 2 h. Subsequently, the mixture was treated with sodium bicarbonate until the pH was7. The mixture was then filtered and the filtrate was extracted with DCM (5 L x 2). The isolated organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford 4-fluoro2-methoxy-5 nitroaniline (A2) as a brown solid. |
| 8.7 g |
With sulfuric acid; nitric acid at -20℃; |
b Step b:
Compound 2 (8.0 g, 43 mmol) was placed in a 500 ml one-necked reaction flask, and concentrated sulfuric acid (100 ml) was added to dissolve the substrate with constant agitation. At -20° C., concentrated nitric acid (6.15 ml, 48 mmol) was slowly added dropwise with stirring, and the reaction mixture was stirred for 5 mins at this temperature. The reaction progress was monitored by TLC. After the substrate was completely consumed, the mixture was poured into ice water. Sodium hydroxide/water solution (150 ml/300 ml) were added slowly to the reaction system which was kept in an ice-water bath at -20° C., and the pH of the mixture was adjusted to 8-9. After the neutralization, the reaction mixture was extracted with ethyl acetate/water system for three times, and the organic layer was separated, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound a1 (8.7 g) which was used directly in the next reaction. Yield: 80%; purity: 100%; MS m/z(ESI): 187.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 7.34 (d, J=7.8 Hz, 1H), 7.04 (d, J=13.4 Hz, 1H), 5.25 (brs, 2H), 3.90 (s, 3H). |
| 44 g |
With sulfuric acid; potassium nitrate at 10 - 20℃; |
B2.2 2) Synthesis of compound b2-3:
39 g of crude compound b2-2 was added to 500 ml of concentrated sulfuric acid (ice salt bath)Stirring at T less than 10 °C is stirred under the condition completely dissolved, maintained at this temperature by adding 1ep potassium nitrate, stir at room temperature overnight; the next day the reaction liquid is poured into ice water, adjusted with ammonia water PH7, ethyl acetate extraction, drying, column chromatography separation, obtained 44g product, that is, compound b2-3. |
| 8.7 g |
With sulfuric acid; nitric acid at -20℃; for 0.0833333h; |
b Preparation of compound a1
Compound a1-2 (8.0 g, 43 mmol) was placed in a 500 mL single-necked reaction flask and concentrated sulfuricacid (100 mL) was added under stirring at a constant rate to dissolve the substrate. Concentrated nitric acid (6.15 mL,48 mmol) was slowly added dropwise to the stirred reaction flask at -20 °C and stirred at that temperature for 5 minutes.The progress of the reaction was checked by TLC. After the reaction of the substrate was complete, the reaction mixturewas poured into iced water. In -20 °C ice bath, the aqueous solution of hydroxide/water (150 mL/300 mL) was slowly added to the reaction system and pH was adjusted to 8-9. After neutralization, the reaction solution was extracted threetimes with ethyl acetate/water system. The organic layer was separated, washed with water and then saturated brine,dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the compound 4-fluoro-2-methoxy-5-nitroaniline a1 (8.7 g) which was directly used in the next step. Yield: 80%; purity: 100%; MS m/z(ESI): 187.0 [M+H]+;1HNMR (400 MHz, DMSO-d6): δ 7.34 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 13.4 Hz, 1H), 5.25 (brs, 2H), 3.90 (s, 3H). |
|
With sulfuric acid; potassium nitrate Cooling; |
2 5.2. Preparation of 4-Fluoro-2-methoxy-5-nitro-phenylamine (8)
4-Fluoro-2-methoxyaniline (12.0 g, 85.0 mmol) was added to cooled concentrated H2SO4 (80 mL). The mixture was stirred at0-10 C for 15-30 min. KNO3 (8.6 g, 85.0 mmol) was added tothe mixture. The resulting mixture was stirred at 0-5 C for 1-2h and then poured into ice/water. The mixture was neutralised with concentrated K2CO3. The resulting solid was filtered off anddried under vacuum. The corresponding amine was used in thenext step without further purification. 1H NMR (400 MHz, DMSO)d 7.35 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 13.4 Hz, 1H), 5.28 (s, 1H),3.91 (s, 1H). |
| 18.6 g |
With sulfuric acid; potassium nitrate at 10℃; for 2h; Cooling with ice; |
2 4 - Fluoro -2 - methoxy -5 - nitroaniline (intermediate 2)
Under ice bath, will be 4 - fluoro -2 - anisidine (2 A) (17.1 g, 0.1 mmol) is dissolved in concentrated sulfuric acid (100 ml) in, slowly adding potassium nitrate (10.1 g, 0.1 mmol), 10 °C reaction under 2 hours. In the reaction liquid is poured into the ice, regulated by ammonia water to the reaction solution to pH 8, ethyl acetate (400 ml × 2) extraction, the combined organic phase, the organic phase dried with anhydrous sodium sulfate, concentrated, to obtain 4 - fluoro -2 - methoxy -5 - nitroaniline (intermediate 2), a yellow solid (18.6 g, crude product). |
| 44 g |
With sulfuric acid; potassium nitrate at 20℃; Cooling; |
Synthesis of B1-3:
39g material take B1-2, concentrated sulfuric acid was added to 500ml was added under ice-salt bath. Controlling the temperature of the whole solution was stirred below 10°C. was added maintaining the temperature below 10°C, 1ep potassium nitrate, was stirred overnight at room temperature. The next day, poured into ice water, adjusted with ammonia PH>7, extracted with ethyl acetate, dried and purified through column chromatography to give 44g product. |
|
Multi-step reaction with 3 steps
1: acetic acid / 25 - 90 °C
2: nitric acid; sulfuric acid / 0 - 5 °C
3: hydrogenchloride / methanol; water / 25 °C / Reflux |
|
| 44 g |
With sulfuric acid; potassium nitrate at 10 - 20℃; |
Synthesis of B1-3:39g for raw material B1-2,Add to 500ml of concentrated sulfuric acid,Add under ice salt bath.Control the temperature below 10 ° C and stir to dissolve completely.Keep the temperature below 10 and add 1ep potassium nitrate,Stir overnight at room temperature.The next day, pour into ice water,Use ammonia to adjust PH> 7,Extract with ethyl acetate and dry,After passing through the column, 44 g of product was obtained. |
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Multi-step reaction with 3 steps
1: acetic acid / 0.12 h / 20 - 30 °C / Flow reactor
2: nitric acid / water; acetic acid / 0.01 h / 80 °C / Flow reactor
3: hydrogenchloride; water / ethanol / 5 h / 83 °C |
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Multi-step reaction with 3 steps
1: acetic acid / 0.12 h / 20 - 30 °C / Flow reactor
2: nitric acid / water; acetic acid / 0.25 h / 80 °C / Microwave irradiation
3: hydrogenchloride; water / ethanol / 5 h / 83 °C |
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Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
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110K+ Compounds
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