4-Methylanisole → 7-Cyano-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2,8-dicarboxylic acid 2-tert-butyl ester

Participants

Reaction Conditions

Reaction Steps

A mechanically stirred mixture of bis(triphenylphosphine)palladium (II) chloride (425 mg), triphenylphosphine (425 mg), 4-methylanisole (125 mL) and poly(ethylene glycol) (Average Mn ca 4600, 850 g) was treated with 7-cyano-8-iodo-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid 2-tert-butyl ester (7.5 g, Reference Example 20), then placed under a blanket of carbon monoxide. The reaction mixture was heated to 80° C. and then treated with a solution of sodium hydroxide (10.6 g) in water (125 mL) dropwise over 30 minutes whilst maintaining the temperature at 80° C. After vigorously stirring at 80° C. for a further 6 hours the reaction mixture was allowed to cool to room temperature and then left to stand overnight. The reaction mixture was treated with diethyl ether, the layers separated and the basic aqueous fraction filtered through celite. The filtrate was acidified to pH 1 with concentrated hydrochloric acid and then extracted with ethyl acetate. The organic extract was dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether to give the title compound (4.40 g) as an off white solid, m.p. 212–215° C. 1H NMR [(CD3)2SO]: δ 7.62–7.50 (m, 5H), 4.83 (s, 2H), 3.95 (t, 2H), 3.68 (t, 2H) and 1.45 (s, 9H).

Provenance & Evidence