4-fluoro-2-Methoxy-5-nitroaniline

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, 82percent) 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).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: 80percent; purity: 100percent;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 80percent).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 Na4-Fluoro-2-methoxyaniline (2.4 g, 17.00 mmol) was added portionwise to concentrated H4-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 50percent by weight of heptane in CH2Cl2, The title compound was obtained as a yellow crystalline solid (2.450 g, 77percent).4-fluoro-2-methoxyaniline (2.4 g, 17.00 mmol) was added portionwise to a concentrated HUnder 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: 77percent). LCMS (ESI): m/z 187 [M + H]Take 98wtpercent 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 wtpercent 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 75.2percent.Taking 200 ml 98 wt percent 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 batch4-Fluoro-2-methoxyaniline (1.4g, 10mmol) was added portion-wise to concentrated HUnder 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 (60percent)001-2, as a yellow solid.5. Synthesis of Intermediate 001-8 The intermediate 001-7 (100 g, 708.5 mmol) and 800 mL of concentrated sulfuric acid (HUnder 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: 60percent) was obtained as a yellow solid.Embodiment A1 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).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: 80percent; purity: 100percent; MS m/z(ESI): 187.0 [M+H]+; 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.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: 80percent; purity: 100percent; 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).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).Dissolve 2, 4-difluoro-5-nitroaniline (3.48 g, 20 mmol) in anhydrous methanol (50 mL).Sodium methoxide (1.30 g, 24 mmol) is added at room temperatureAnd stir for 48 hours.After the reaction is over, Add water (100 mL), Extract with dichloromethane (100 mL x 3).Combine the organic phase, The organic phase was washed with saturated brine (100 mL).Drying with anhydrous sodium sulfateConcentrate under reduced pressure, The crude product was isolated and purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 6:1).A red solid (3.26 g, yield: 87.6percent) was obtained.

Molecular Weight:186.14
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:1
Exact Mass:186.04407025
Monoisotopic Mass:186.04407025
Topological Polar Surface Area:81.1
Heavy Atom Count:13
Complexity:197
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes