4-CYANO-2-FLUOROBENZOIC ACID METHYL ESTER

Step (i) Potassium carbonate (3.70 g, 26.7 mmol ) was added to a solution of 4-cyano-2- fluorobenzoic acid (4 g, 24.3 mmol) in DMF (350 mL). After stirring at RT for 15 minutes, iodomethane (1.66 mL, 26.7 mmol) was added. The flask was stoppered, and the mixture stirred at 40 °C for 2 h. The mixture was concentrated under reduced pressure and the residue partitioned between DCM (50 mL) and brine (50 mL). The organic phase was passed tlirough silica and concentrated to give methyl 4-cyano-2-fluorobenzoate (4.1 g, 94percent). NMR (300 MHz, CDC1Potassium carbonate (3.70 g, 26.7 mmol) was added to a solution of 4-cyano-2-fluorobenzoic acid (4 g, 24.3 mmol) in DMF (350 mL). Example 42 4-fluoromethyl-3-[4-(tetrahydropyran-4-yloxymethyl)phenoxy]benzamide (42a) methyl 4-cyano-2-fluorobenzoate 4-Cyano-2-fluorobenzoic acid (5.15 g, 31.2 mol) was dissolved in dimethylformamide (50 mL), potassium carbonate (6.47 g, 46.8 mmol) and methyl iodide (3.88 mL, 62.4 mmol) were added, and the mixture was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title object compound as a white powder (1.70 g, yield 30percent). EXAMPLE 20A STEP 2: To a solution of methyl 4-bromo-2-fluorobenzoate (9.1 mmol) in DMF (50 mL) was added zinc cyanide (641 mg, 5.5 mmol) followed by tetrakis(triphenyphosphine)palladium(0) (1.05 g, 0.91 mmol). The mixture was heated to 100 °C and stirred for 3 h. At that point, additional tetrakis(triphenyphosphine)- palladium(O) (500 mg, 0.43 mmol) was added. The mixture was stirred a further 30 min and was then cooled to room temperature. Water and ethyl acetate were added, and insoluble solids were removed by filtration through celite. The layers were then separated. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, washed with 10percent aqueous lithium chloride, dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography (10percent ethyl acetate in hexanes) to provide methyl 4-cyano-2-fluorobenzoate (1.36 g, 7.6 mmol, 84percent yield). 1H NMR (400 MHz, CDClEXAMPLE 17A Preparation of methyl 4-(aminomethyl)-2-fluorobenzoate: A solution of 4-cyano-2-fluorobenzoic acid (4.02 g, 24.36 mmol, Aldrich) in methanol (50 mL) was treated with p-toluenesulfonic acid monohydrate (0.46 g, 2.43 mmol) and heated to reflux overnight. The solvent was removed and the reaction residue was extracted with EtOAc, washed with saturated NaExample 33A 4-cyano-2-fluoro-benzoic acid 13.20 g (79.9 mmol) was dissolved in acetone 300 mL. Then, 22.10 g of potassium carbonate A (159.9 mmol) and dimethyl sulfate 9.08 ml (95.9 mmol) were added consecutively. The mixture was refluxed at a temperature of 20 hour Stirred . Then, the reaction mixture was mixed with 300 mL of water, and the acetone on a rotary evaporator It was removed. It can in turn was extracted with dichloromethane. The combined organic phases are washed with a saturated aqueous sodium chloride solution, and sulfuric acid Dried over sodium. Then, the solvent was removed in vacuo. The remaining solid was used without further purification. The title compound was 16.1 g (84percent of theory) as a colorless solid

Molecular Weight:179.15
XLogP3:1.5
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:179.03825660
Monoisotopic Mass:179.03825660
Topological Polar Surface Area:50.1
Heavy Atom Count:13
Complexity:245
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes