4-(4-Amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide

In a magnetic stirring device, In a 250mL three-necked bottle of thermometer and reflux condenser, Add 100 mmol of 4-amino-3-fluorophenol, 100 mmol of anhydrous potassium carbonate, and 85 mmol of 4-chloro-N-methylpyridine-2-carboxamide.2.5 mmol of PEG-400 and 100 mL of dichloroethane, Electromagnetic stirring, The mixture was heated to reflux for 4 hours.Cooling, filtering, The water pump distilled off the dichloroethane under reduced pressure, and the kettle liquid was extracted with 240 mL of diethyl ether.Dry and concentrate to give a light yellow liquid as an intermediateI21.39g, The yield is 96.3percent.The purity is 99.90percentEXAMPLE 6 (0036) Under the protection of nitrogen, 363 g of 4-amino-3-fluorophenol, 374 g of 4-chloro-N-methylpyridine-2-formamide, and 3740 ml of N, N-dimethyl acetamide are successively added to a reaction vessel, which are stirred to dissolve, and then 115 g of sodium hydroxide is added, the temperature is then raised to 105° C. for 1 hour; 5600 ml of water is added, then cool the mixture to a temperature of 10° C., and stir at the foregoing temperature overnight for crystallization, and then filter and dry to obtain 509 g of a brown colored solid of 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide. HPLC content is 99.3percent, mp: 141.5 to 142.5° C., yield 88.9percentTo a solution of 4-amino-3-fluorophenol (18) (100.0 mg, 0.79 mmol) in anhydrous DMF (3 mL) was added To a second reaction flask equipped with a stirrer, 26.7 g of 4-amino-3-fluorophenol and 100 g of 4-methyl-2-pentanone were added. After heating to reflux and stirring for an additional hour, The water was removed by azeotropic distillation. The excess 4-methyl-2-pentanone was then removed by vacuum distillation and replaced with 1-methyl-2-pyrrolidone (70 g) to prepare a solution containing the imine compound according to formula (III). To the resulting reaction mixture was added a solution of 4-chloro-N-methyl-pyridine-2-carboxamide in 1-methyl-2-pyrrolidone. The reaction mixture was heated to about 100 deg C. Dropwise (in about 70 minutes) 123.2 g potassium tert-butoxide in tetrahydrofuran (20percent w / w), While tetrahydrofuran was removed by distillation. Thereafter, The reaction mixture was stirred at 100 deg C an additional 3 hours to complete the reaction. After adjusting to 80 deg C, Add 350 ml of toluene, 392 ml of water and 8 g of acetic acid. The mixture was stirred at 80 deg C 10 minutes. Cooled to 50 ° C and seeded with crystals of 4- (4-amino-3-fluorophenoxy) -N-methylpyridine-2-carboxamide. After cooling to 0 ° C, The suspension was stirred for about 30 minutes. The product was filtered off, Washed with methanol / water (1: 3 v / v, 144 ml) and dried under reduced pressure (30 ° C, 80 mbar). In this way, To give 40.4 g (78percent of theory) of 4-(4-amino-3-fluorophenoxy)-N-methylpyridino-2-carboxamide, As a brown crystals.Example A2 A solution of 4-amino-3-fluorophenol (2.00 g, 15.7 mmol) in anhydrous DMA (32 mL) was degassed by evacuation of the head space and backfilling with argon (repeated 3x). The solution was treated with potassium tert-butoxide (2.12 g, 18.9 mmol) and the resultant mixture was sonicated briefly to bring all solids into the solvent volume and was stirred at RT for 30 min. Example A22 (2.68 g, 15.7 mmol) was added. The reaction mixture was degassed a second time and the reaction mixture was heated to 100 °C overnight under argon. The reaction mixture was poured into ethyl acetate (400 mL) and washed with water (3 x 100 mL) and saturated brine (2 x 100 mL). The combined aqueous was extracted with EtOAc (100 mL). The combined organics were dried (MgSC^), concentrated in vacuo to a brown oil and purified by silica gel chromatography to provide 4-(4-amino-3-fluorophenoxy)-N-methylpicolinamide (3.18 g, 77percent yield). An oven-dried two-necked 100 mL flask (equipped with an inlet adapter and septum) under Ar, was charged with 4-amino-3-fluorophenol (1.12 g, 8.81 mmol) and DMF (18 mL). To the stirred solution was added potassium tert-butoxide (978 mg, 8.72 mmol) in portions over 2 mm. The resulting dark-purple mixture was stirred for 3 hours, then 4-chloro-N- methylpicolinamide (1.06 g, 6.21 mmol) was added in one portion, and the reaction was heated at 90°C for 10 hours under a balloon of Ar. The reaction was allowed to cool to roomtemperature and then was poured into stirred ice-water (50 mL). Stirring was continued for 15 mm and then the mixture was extracted with EtOAc (3 x 50 mL). The organic extracts were pooled, washed with 1 M KOH (3 x 50 mL), water (50 mL) and brine (2 x 50 mL), dried (Na2SO4), and filtered. Concentration under vacuum gave a brown solid, which was purified by silica gel chromatography (40 g cartridge), eluting at 30 mL/min and using a linear gradient ofhexanes/EtOAc: 100:0—*0: 100 over 38 column volumes. Obtained 882 mg (54percent) of the title compound as a light-brown solid: ‘H NIVIR (400 IVIHz, DMSO-d6) ö 8.74 (br q, J=4.6 Hz, 1H), 8.47(d, J=5.6Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 7.09 (dd, J=5.6, 2.7 Hz, 1H), 7.01 (dd, J11.9, 2.6 Hz, 1H), 6.81-6.89 (m, 1H), 6.76-6.80 (m, 1H), 5.22 (br s, 2H), 2.78 (d, J=4.9 Hz, 3H); ‘9F NIVIR (376 IVIFIz, DMSO-d6) ö -130.7 (s, iF); LC-MS (ESI+) m/z: [M+H] Calcd forC, 3H, 3FN302 262.1; Found 262.1.4-amino-3-fluorophenol (18.62 g), potassium tert.butoxide (20.6 g), potassiumcarbonate (10.2 g) & tetrabutylammonium bromide (9.5 g) were added to a pre-cooled acetonitrile (100 ml) at -10°C to -15°C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 0°C to 5°C and stirred for 15 minutes. 4-chloro-N- methylpicolinamide (25 g) was added to the reaction mixture at the same temperature. Heated the reaction mixture to 80°C-85°C and stirred for 6 hours at the same temperature.Distilled off the 60percent volume of the solvent under reduced pressure and cooled the reaction mixture to 25°C-30°C. Pre-cooled water (150 ml) followed by dichioromethane (375 ml) were added to the reaction mixture and stirred for 15 minutes. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Separated both the aqueous and organic layers and extracted aqueous layer with dichloromethane. Combined the organiclayers and washed with water. Distilled off the solvent completely and co-distilled the reaction mixture with acetonitrile. Added acetonitrile to the obtained compound at 25°C- 30°C and cooled the reaction mixture to 0°C to 5°C and stirred for 60 minutes at the same temperature. Filtered the reaction mixture and washed the obtained compound with chilled acetonitrile. Water was added to the obtained compound and stirred the reaction mixture for 2hours at 25°C-30°C. Filtered the solid, washed with water and dried the compound to get the title compound. Yield: 25.25 g; M.R: 136-142°C.4-Amino-3-fiuorophenol (l lg, 0.08 moles) and of 4-Chloro-N-methyl-2- pyridinecarboxamide (8.85 g, 0.05 moles) was added to a reaction flask containing N, N- dimethylacetamide (55 ml) at 25-30°C and stirred for 15 minutes. The reaction mixture was heated to 110-115°C and then potassium tert-butoxide in tetrahydrofuran (60 ml, 0.06 moles) was added slowly over a period of 3 to 4hours. Distill off solvent at same temperature, cooled the reaction mass to 25-30°Cand water(110 ml) was added slowly over a period of 15min. and cooled the reaction mass to 0-5°C . Adjust the pH of the reaction mass in between 7 and 7.5 by using 10percent aqueous hydrochloric acid (~7 ml). Stir the reaction mass for 30min at the same temperature. Filter the product, washed with water (22 mL) and Dried at 50-55 °C for 12hrs. The obtained crude material was added to the flask containing Ethyl acetate (55 mL).The reaction mass was heated to reflux to get a clear solution and stirred for 15min at reflux. Cooled to 0-5°C, stir for 2hrs at the same temperature. Filter the product, washed with Toluene (9 mL) and dried at 50-55°C for 3-5hrs. Above recrystallized material was added to the reaction flask containing methylene dichloride (270 mL) at 25-30°C and stirred for 10-15 min. Activated carbon (1 g) and silica gel (4.4 g) was added to the reaction mass and stir for lh at the same temperature. Filter the reaction mass through hyflow bed and wash with methylene dichloride (18 mL).Distill off solvent still~l-2 volumes of methylene dichloride remains in the flask and then cooled to 25- 30°C. Toluene (20 mL) was added and stirred for 30min at the same temperature. Filtered the product, washed with Toluene (9 mL) and dried at 50-55°C for 12h. (0102) Yield: 9 gm (0103) Chromatographic Purity (By HPLC): 98percentPotassium tert-butoxide (90 g) was added to the solution of 4-amino-3-fluorophenol (90 g) in N, N-dimethylacetamide (400 ml) at 0°C and heated to 60°C. 4-Chloro-N-methylpyridine-2- carboxamide (100 g) was dissolved in N, N-dimethylacetamide (100 ml) and added to the reaction mass at 60°C. The reaction mass was heated to 90°C and stirred for 90 mm. Aftercompletion of reaction, reaction mass was cooled to 30°C. The reaction mass was slowly added into DM water (2500 ml), stirred for 60 mm, filtered the solid product and dried. The dry product was dissolved in ethyl acetate (1200 ml) at 70°C, treated with activated carbon (12 g) for 30 mm and filtered through hyflo bed. The filtrate was partially concentrated, cooled to 0- 5°C and filtered the solid and dried (92.9 g, theory yield: 50.2percent).HPLC purity: 98.893percentAdd 4.71g of 4-amino-3-fluorophenol, 4.13g of sodium hydroxide, 32.11g of potassium iodide, 22.78g of triethylbenzylammonium chloride, 500ml of water to the reaction flask, and heat to 30 ° C to stir and dissolve. When the temperature reaches At 70 ° C, 21.61 g of compound III was added dropwise, and the reaction was stirred for 2 h. After completion of the reaction, the mixture was cooled, washed with a 2percent aqueous sodium hydroxide solution, and the mixture was separated. The organic layer was recrystallized from ethanol to give compound IV 25.48 g, product yield 97.5percent, purity 99.96percent.In a 250mL three-necked bottle with a magnetic stirrer, thermometer and reflux condenser, 0.09 mol of 3-fluoro-4-nitrophenol, 0.10 mol of anhydrous potassium carbonate, 0.10 mol of 4-chloro-N-methylpyridine-2-carboxamide, 0.003 mol of PEG-400 and 100 mL of acetonitrile were stirred under electromagnetic stirring for 4 hours in a water bath.Cool, filter, and pump to dilute acetonitrile under reduced pressure.The obtained residue, 1 g of sugar with activated carbon, 0.1 mmol of ferric chloride, 50 mL of methanol were mixed in a 250 mL four-necked flask.85percent of hydrazine hydrate was added dropwise at reflux temperature, and the addition time was 1 h. After the completion of the dropwise addition, the mixture was refluxed for 2 h.After the reaction was stopped, the mixture was filtered, and the activated carbon was washed with 40 mL of diethyl ether, and the filtrate was distilled to remove methanol. After the distillation, the solution was extracted with 240 mL of diethyl ether.The ether layers were combined, dried and concentrated to give a pale yellow liquid, ie, 21.75 g of Intermediate I, yield 92.5percent, purity 99.92percent.A magnetic stirring device in the vicinity of, a thermometer and a reflux condenser 100 ml three-neck bottle in, adding 0.09 µM of 3 - fluoro -4 - nitro phenol, after heating by adding 0.10 µM of KOH, the reaction under stirring 10 min, then added to the reaction system in the 0.10 µM of 4 - chloro - N - methyl pyridine -2 - carboxamide, temperature control reaction; to TLC endpoint is detected, 1.5 h reaction end; and adding heat to the reaction system of 5percent NaOH solution, heat preservation in 80 °C -85 °C washing 3 times, at the same temperature with water washing 3 times, the reaction mixture is hot and cold water in pouring, cooling, filtering, drying to obtain the solid. The resulting solid, 1 g of the active carbon for sugar, 0.12 mmol of iron trichloride, 50 ml methanol mixed 250 ml four-mouth bottle in, at the reflux temperature next adds by drops 85percent hydrazine hydrate 0.33 µM, dropping time 1 h, after dropping, reflux 2 h. After stopping the reaction, filtration, for 40 ml ethyl ether washing activated carbon, distillation of the filtrate from methanol, after [...], for 240 ml ethyl ether extract the residue, the merger [...], drying, concentration, a pale yellow liquid that shall 21.72 g intermediate I, yield 92.4percent, purity 99.92percent.In a three-necked flask, 12.7 g of 3-fluoro-4-aminophenol and 0.95 g of cuprous iodide were added, 63.7 g of potassium phosphate, heated with stirring to 85 ° C, Then, 18.6 g of 4-chloro-2-pyridinecarboxamide hydrochloride was added to the reaction system in three batches, The reaction was continued for 6 hours by keeping the temperature in contact with N, N-dimethylformamide to give a reconstitution of a regroupene intermediate21.4 g of 4- (4-amino-3-trifluoromethyl) -N-methylpyridine-2-carboxamide was obtained in a yield of 91.1percent

Molecular Weight:261.25
XLogP3:1.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:261.09135480
Monoisotopic Mass:261.09135480
Topological Polar Surface Area:77.2
Heavy Atom Count:19
Complexity:316
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes