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With sodium carbonate In ISOPROPYLAMIDE at 120℃; for 15 h;
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, 83percent). 1H NMR (400 MHz, CDCI3): δ 2.60 (s, 3H), 3.95 (s, 3H), 7.65 (d, 1 H), 7.95 (m, 1 H), 8.00 (d, 1 H).
11A: 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 (Na2SO4), filtered and concentrated in vacuo. Purification by flash chromatography (silica, 1:3 EtOAc:hexanes) provided the title compound (12.3 g, 39.8percent yield) as a solid. 1H NMR (400 MHz, CDCl3) 2.59 (s, 3H), 3.93 (s, 3H), 7.66 (d, 1H), 7.90 (d, 1H), 7.97 (d, 1H).
Reference：
[1] Patent: US2007/270438, 2007, A1, . Location in patent: Page/Page column 42
[2] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 14, p. 3679 - 3683
[3] Patent: WO2007/79186, 2007, A2, . Location in patent: Page/Page column 59
3
[ 557-21-1 ]
[ 148547-19-7 ]
[ 25978-68-1 ]
Yield
Reaction Conditions
Operation in experiment
88%
for 16 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 5percent ethyl acetate in pentane to give the title compound as a solid (13.7 g, 88percent). 1H NMR (400 MHz, CDCI3): δ 2.60 (s, 3H), 3.95 (s, 3H), 7.65 (d, 1 H), 7.95 (m, 1 H), 8.00 (d, 1 H).
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