Sodium Carbonate → (E)-3-{3-[6-(3-Ethylamino-propylamino)-pyrazin-2-yl]-phenyl}-acrylic acid

Participants

Reaction Steps

2,6-Dichloropyrazine (298 mg, 2.0 mmol) was dissolved in 25 mL dichloromethane. 1,5,7-triazabicyclo[4.4.0]dec-5-ene polystyrene (PS-TBD) (2.0 g, 5.0 mmol) was added followed by N-ethyltrimethylenediamine (194 mg, 1.90 mmol). The resulting mixture was agitated at room temperature overnight. The resin was filtered and the mother liquors were concentrated to a solid H (429 mg, 100%, mixture of isomers), which was used directly. [3-(E-3-methoxy-3-oxo-1-propen-1-yl)phenyl]boronic acid (618 mg, 3.0 mmol) and bistriphenylphosphinepalladium(II)chloride (35 mg, 0.05 mmol) were dispersed in 5 mL DMF in a reaction tube. Subsequently 1.5 mL of 2M Na2CO3 was added followed by intermediate H prepared above (429 mg, 2.0 mmol) as a solution in 5 mL DMF. The tube was sealed and the reaction mixture was heated at 85° C. for 72 hours. The reaction mixture was then filtered through a plug of celite, and the mother liquors were treated with a silica-bound sulfonic acid (Si-tosic acid), (9.5 g, 8.36 mmol). The resulting mixture was agitated for 24 hours, then the silica was isolated by filtration and washed with methanol. Intermediate I (150 mg, 88%, mixture of isomers) was eluted from the silica with 7N ammonia in methanol, and isolated by concentration of the eluant. The mixture was used directly. Intermediate I prepared above (140 mg, 0.41 mmol) was dissolved in 15 mL methanol. Amberlyst A26 (OH form) (1.5 g, 2.16 mmol) was added and the resulting mixture was agitated at room temperature for 72 hours. The resin was isolated by filtration and washed with methanol. The product was eluted from the resin using 20% formic acid in methanol, and isolated by concentration of the eluant (105 mg, 73%, mixture of isomers). The mixture was purified by preparative HPLC to provide the title compound (18.4 mg, 13%); MS analysis electrospray, 327 (M+H).

Provenance & Evidence