1,4-Cyclohexadiene → 3-(6'-Bromo-4-methyl-3'-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3'H-[1,2']bipyrazinyl-4'-yl)-N-cyclopropyl-4-methyl-benzamide

Participants

Reaction Conditions

Reaction Steps

A mixture of 3-(3,5-dibromo-2-oxo-2H-pyrazin-1-yl)-4-methyl-benzoic acid, methyl ester (Example 1b, 115 mg), 1-methyl-3-phenyl-piperazine (77 mg), N,N-diisopropylethylamine (0.1 mL) and tetrahydrofuran (1 mL) was heated within a microwave for 30 minutes at 100° C. before being cooled to room temperature. The mixture was transferred to a mixture of palladium on carbon (10%, 50 mg) and tetrahydrofuran (1 mL) and 1,4-cyclohexadiene (1 mL) was added. The mixture was heated under atmosphere of nitrogen within a microwave for 2.5 h at 120° C. An additional portion of palladium on carbon (50 mg) in tetrahydrofuran (1 mL) was added and the mixture was heated for 1 h at 120° C. After cooling, cyclopropylamine (0.3 mL) was added followed by dropwise addition of a solution of iso-propylmagnesium chloride (2M in tetrahydrofuran, 2.5 mL). The mixture was stirred for 10 min. and quenched with sat. aqueous NH4Cl and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) afforded N-cyclopropyl-4-methyl-3-(4-methyl-3′-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3′H-[1,2′]bipyrazinyl-4′-yl)-benzamide (49 mg) and 3-(6′-Bromo-4-methyl-3′-oxo-2-phenyl-3,4,5,6-tetrahydro-2H,3′H-[1,2′]bipyrazinyl-4′-yl)-N-cyclopropyl-4-methyl-benzamide (8 mg).

Provenance & Evidence