Cyanide synthesis (via bromide group): 

 

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%). 

 

Patent reference: WO2010032200 (Pfizer)

 

 

 

 

 

Cyanide synthesis (via bromide group):  

 

 

Pottasium Ferrocyanide trihydrate (3.70 g, 17.5 mmol) was added to a solution of 4-bromo-3-methyl-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 120°C 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%).

 

Patent reference: WO2010032200 (Pfizer)

 

 

 

 

 

Cyanide synthesis (via bromide group): 

 

Bromine coumpound (2.0 g, 5.83 mmol), zinc cyanide (1.03 mg, 8.77 mmol) and tetrakis-(triphenylphosphine)-palladium (673mg, 0.58 mmol) in N,N-dimethylformamide (20 ml) was heated at 1600C for 15 min in a microwave reactor. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 70 ml). The combined organic layers were washed with brine (2 x 40 ml), dried (magnesium sulfate) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/ heptane) on silica gel to yield the title compound as light yellow foam (693 mg, 41%). 

 

Patent reference: WO2010026110 (Roche)

 

 

 

 

 

 

 

Cyanide synthesis (via tosyl group): 

 

Sodium cyanide (1.91 g, 38.9 mmol) was added to a solution of the compound described in Tosyl compound (4.30 g, 15.56 mmol) in dimethyl sulphoxide (20 ml). This mixture was stirred at room temperature for 3 hours, after this time it was heated to 80°C for 2 hours. It was then cooled to room temperature and partitioned between brine (50 ml) and diethyl ether (2 x 50 ml). The combined organic extracts were washed with brine (50 ml), dried over magnesium sulphate, filtered and evaporated under reduced pressure to an oil (1.72 g, 84%). 

 

Patent reference: WO2010026110 (Roche)

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