5-Fluoro-2-methylphenol

Colorless transparent liquid

7 mL of a hot solution of concentrated sulfuric acid in 21 mL of water was added to 5-fluoro-2- METHYLPHENYLAMINE (5 g, 40 mmol). The mixture was cooled in an ice bath for 30 minutes and treated with a solution of sodium nitrite (3.38 g, 48 mmol) in 10 mL of water over a period of 10 minutes. After stirring at 0 C for 45 minutes, the reaction was diluted with 20 mL of cold water and treated with 0.3 g of urea. The resulting mixture was added to a stirred solution of 11 mL of concentrated sulfuric acid in 10 mL of water containing 15 g of anhydrous sodium sulfate at 130 C over 10 minutes. After an additional 5 minutes at 130 C, the reaction was allowed to cool to room temperature and was extracted with three 100 mL portions of dichloromethane. The combined organic layers were washed with two 50 ML portions of water and concentrated in vacuo. The reddish oil was dissolved in 250 mL of diethyl ether and washed with three 50 mL portions of 10percent aqueous sodium hydroxide. The combined aqueous sodium hydroxide extracts were washed with two 50 mL portions of diethyl ether. The basic layer was acidified with 1 N aqueous HC1 and extracted with three 100 mL portions of dichloromethane. The combined dichloromethane layers were washed with two 50 ML portions of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a light reddish liquid. The crude was purified by chromatography on Si02 (10percent ethyl acetate in hexanes) to give 5 g of 5-fluoro-2-methylphenol as a light brownish oil (99percent yield). A stirred solution of 5-fluoro-2-methylphenol (640 mg, 5 mmol) in 20 mL of anhydrous acetonitrile was cooled to-30 C to-40 C and treated with nitronium tetrafluoroborate (740 mg, 5.5 mmol). After 45 minutes, the reaction mixture was diluted with 100 mL of cold water and extracted with three 50 ML portions of dichloromethane. The combined organic layers were washed with three 25 mL portions of water, dried over sodium sulfate, and concentrated in vacuo to give a reddish crystalline solid. Chromatography over SI02 (5percent ethyl acetate in hexanes) gave 0. 58 g of the title product as bright yellow solid (68percent yield). The title compound was converted to the corresponding trifluoromethane sulfonate according to the procedure described in Example 26.2-dram vial containing a stir bar was charged with triphenylphosphine and polymer-bound (77 mg, 0.230 mmol), and the mixture was transferred into a glove box. THF (1 mL) was added to the vial, and the mixture was swelled for 15 min. Diethyl azodicarboxylate (0.036 mL, 0.230 mmol) was added to the reaction mixture. The mixture was stirred for 15 min before In a single-mouth round bottom flask, 2-Methyl-5-fluoro-phenol (646 mg, 5.13 mmol) was dissolved in 6 ml of dry DMF.Potassium carbonate (1.42 g, 10.3 mmol) was added.Stir at room temperature and add (E)-4-bromomethyl benzoate (1.31 g, 5.13 mmol).Stirring reaction was continued for 3 h, and the reaction was complete by TLC.Quenched with water, extracted with ethyl acetate (3×30 mL).Dry over anhydrous sodium sulfate and remove the solvent under reduced pressure.Petroleum ether / dichloromethane = 1 / 1 elution, A white solid product of 1.46 g (yield 95%) was obtained.General procedure: A mixture of 12 (0.14 g, 0.49 mmol), 2, 6-dimethylphenol (0.12 g, 0.97 mmol) and K2CO3 (0.13 g, 0.97 mmol) in DMF (4 mL) was stirredat 80 C for 12 h. Then the mixture was diluted with H2O and the whiteprecipitate was filtered and washed with water. The solid was thendried under reduced pressure to give the title compound (0.16 g, 84.4 % yield).To a stirred solution of 1-[5-chloro-1-(oxan-2-yl)-6-oxo-1, 6-dihydropyridazin-4- yl]piperidin-4-yl methanesulfonate (400 mg, 1.02 mmol, 1 equiv.) and 5-fluoro-2- methylphenol(193.1 mg, 1.53 mmol, 1.5 equiv.) in ACN(25 mL) was added Cs2CO3(665.2 mg, 2.04 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 75 degrees Celsius under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (10 x mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 5:1) to afford 4-chloro-5-[4-(5-fluoro-2-methylphenoxy)piperidin-1-yl]-2-(oxan-2-yl)-2, 3- dihydropyridazin-3-one (240mg, 55.73%) as a white solid

Molecular Weight:126.13
XLogP3:2.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:126.048093005
Monoisotopic Mass:126.048093005
Topological Polar Surface Area:20.2
Heavy Atom Count:9
Complexity:94.9
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes