4-Cyano-3-methylBenzoicacidmethylester

Pottasium Ferrocyanide trihydrate (3.70 g, 17.5 mmol) was added to a solution of 4-bromo-3-nnethyl-benzoic acid methyl ester (4.00 g, 17.46 mmol) in dimethylacetamide (10 ml_), followed by sodium carbonate (1 .85 g, 17.5 mmol) and palladium acetate (78 mg, 0.35 mmol). This mixture was heated at 12O11A: 4-Cyano-3-methyl-benzoic acid methyl ester Zinc cyamide (6.2 g, 52 mmol) and tetrakis(triphenylphosphine) palladium (0) (4 g, 3 mmol) was added to a solution of 4-bromo-3-methyl-benzoic acid methyl ester (20 g, 87 mmol) and DMF (100 mL) and stirred for 4 hours at 120° C. The reaction mixture was cooled to room temperature, diluted with EtOAc (700 mL), washed with water and brine, dried (Na1 , 1 'Bis(diphenylphosphino)ferrocene (8 g, 14.43 mmol) and zinc cyanide (5.08 g, 43.3 mmol), followed by tris-(dibenzylideneacetone) dipalladium (6.61 g, 7.22 mmol), were added to a solution of 4-bromo-3-methyl-benzoic acid methyl ester (16.53 g, 72 mmol) in dimethylformamide (20 ml_). This mixture was stirred at reflux for 16 hours, after which time it was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate (1000 ml_) was added to the crude mixture and the resultant suspension was filtered. The filtrate was washed with water (1000 ml_) and the aqueous layer was extracted with ethyl acetate (2 x 1000 ml_). The combined organic extracts were washed brine (1000 ml_), dried over magnesium sulphate, filtered, and evaporated under reduced pressure. The resulting material was purified by column chromatography eluting with 5percent ethyl acetate in pentane to give the title compound as a solid (13.7 g, 88percent). Pottasium Ferrocyanide trihydrate (3.70 g, 17.5 mmol) was added to a solution of 4-bromo-3-nnethyl-benzoic acid methyl ester (4.00 g, 17.46 mmol) in dimethylacetamide (10 ml_), followed by sodium carbonate (1 .85 g, 17.5 mmol) and palladium acetate (78 mg, 0.35 mmol). This mixture was heated at 12O11A: 4-Cyano-3-methyl-benzoic acid methyl ester Zinc cyamide (6.2 g, 52 mmol) and tetrakis(triphenylphosphine) palladium (0) (4 g, 3 mmol) was added to a solution of 4-bromo-3-methyl-benzoic acid methyl ester (20 g, 87 mmol) and DMF (100 mL) and stirred for 4 hours at 120° C. The reaction mixture was cooled to room temperature, diluted with EtOAc (700 mL), washed with water and brine, dried (Na1 , 1 'Bis(diphenylphosphino)ferrocene (8 g, 14.43 mmol) and zinc cyanide (5.08 g, 43.3 mmol), followed by tris-(dibenzylideneacetone) dipalladium (6.61 g, 7.22 mmol), were added to a solution of 4-bromo-3-methyl-benzoic acid methyl ester (16.53 g, 72 mmol) in dimethylformamide (20 ml_). This mixture was stirred at reflux for 16 hours, after which time it was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate (1000 ml_) was added to the crude mixture and the resultant suspension was filtered. The filtrate was washed with water (1000 ml_) and the aqueous layer was extracted with ethyl acetate (2 x 1000 ml_). The combined organic extracts were washed brine (1000 ml_), dried over magnesium sulphate, filtered, and evaporated under reduced pressure. The resulting material was purified by column chromatography eluting with 5percent ethyl acetate in pentane to give the title compound as a solid (13.7 g, 88percent). Production Example 37; To a mixture of methyl 4-cyano-2-methylbenzoate (3.0 g) and methanol (60 mL) was added dichlorocobalt hexahydrate (8.1 g) under ice-cooling, followed by stirring. To a mixture was slowly added sodium borohydride (3.9 g), followed by stirring at room temperature for 2 hours. Under ice-cooling, to the reaction mixture was added saturated aqueous ammonia (20 mL), followed by stirring at room temperature for 30 minutes. This solution was filtered through Celite and washed with methanol. The filtrate was concentrated under reduced pressure, and to the obtained residue was added 1 M hydrochloric acid (50 mL), followed by washing with diethyl ether. The aqueous layer was adjusted to pH 8 by adding saturated aqueous sodium bicarbonate, and further adjusted to pH 10 by adding a 1 M aqueous sodium hydroxide solution. The mixture was extracted by adding chloroform, and the organic layer was dried over anhydrous magnesium sulfate. A 4 M hydrogen chloride dioxane solution (10 mL) was added thereto, followed by concentration under reduced pressure. The solid was washed with diethyl ether, then collected by filtration, and dried at 60C under reduced pressure to obtain methyl 4-(aminomethyl)-3-methylbenzoate hydrochloride (3.0 g).Pottasium Ferrocyanide trihydrate (3.70 g, 17.5 mmol) was added to a solution of 4-bromo-3-nnethyl-benzoic acid methyl ester (4.00 g, 17.46 mmol) in dimethylacetamide (10 ml_), followed by sodium carbonate (1 .85 g, 17.5 mmol) and palladium acetate (78 mg, 0.35 mmol). This mixture was heated at 12O0C for 15 hours, after which time it was quenched onto water (150 ml_) and extracted with tert-butylmethylether (3 x 50 ml_). The combined organic extracts were washed with water (150 ml_), dried over magnesium sulphate, filtered and evaporated under reduced pressure to give a solid (2.53 g, 83%). 1H NMR (400 MHz, CDCI3): delta 2.60 (s, 3H), 3.95 (s, 3H), 7.65 (d, 1 H), 7.95 (m, 1 H), 8.00 (d, 1 H).A solution of propionithle (97 mul_, 1.37 mmol) in tetrahydrofuran (5 ml_) was added to sodium hydride (60% dispersion in mineral oil) (55 mg, 1.37 mmol). This mixture was stirred at 60 0C for 30 minutes, then a solution of the compound described in Preparation 6 (200 mg, 1.10 mmol) in tetrahydrofuran (5 ml_) was added. This mixture was stirred at 60 0C for 16 hours and then concentrated under reduced pressure. The crude residue was quenched onto an aqueous 10% solution (weight/volume) citric acid (10 ml_) and extracted with ethyl acetate (3 x 10 ml_). The combined organic extracts were washed with an aqueous saturated solution of sodium hydrogen carbonate (3 x 10 ml_), dried over magnesium sulphate, filtered, and evaporated under reduced pressure. This crude material was purified by column chromatography eluting with 20% ethyl acetate in heptane to give the title compound as a solid (60 mg, 27%). 1H NMR (400 MHz, CDCI3): delta 1.65 (d, 3H), 2.65 (m, 3H), 4.35 (m, 1 H), 7.75 (d, 1 H), 7.85 (m, 1 H), 7.95 (d, 1 H).1 , 1 'Bis(diphenylphosphino)ferrocene (8 g, 14.43 mmol) and zinc cyanide (5.08 g, 43.3 mmol), followed by tris-(dibenzylideneacetone) dipalladium (6.61 g, 7.22 mmol), were added to a solution of 4-bromo-3-methyl-benzoic acid methyl ester (16.53 g, 72 mmol) in dimethylformamide (20 ml_). This mixture was stirred at reflux for 16 hours, after which time it was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate (1000 ml_) was added to the crude mixture and the resultant suspension was filtered. The filtrate was washed with water (1000 ml_) and the aqueous layer was extracted with ethyl acetate (2 x 1000 ml_). The combined organic extracts were washed brine (1000 ml_), dried over magnesium sulphate, filtered, and evaporated under reduced pressure. The resulting material was purified by column chromatography eluting with 5% ethyl acetate in pentane to give the title compound as a solid (13.7 g, 88%). 1H NMR (400 MHz, CDCI3): delta 2.60 (s, 3H), 3.95 (s, 3H), 7.65 (d, 1 H), 7.95 (m, 1 H), 8.00 (d, 1 H).

Molecular Weight:175.18
XLogP3:1.9
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:175.063328530
Monoisotopic Mass:175.063328530
Topological Polar Surface Area:50.1
Heavy Atom Count:13
Complexity:241
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes