L-375378

Chemical Name: N-(6-Amino-2-methylpyridin-3-ylmethyl)-2-[6-methyl-2-oxo-3-(2-phenylethylamino)-1,2-dihydropyrazin-1-yl]acetamide dihydrochloride
项目整合开发状态: Preclinical
项目研究机构: Merck & Co. (Originator)
合成路线:Condensation of glycine benzyl ester (I) and acetaldehyde (II) in the presence of trimethylsilyl cyanide produced the aminonitrile (III),which was isolated as the hydrochloride salt.Further reaction of (III) with oxalyl chloride in o-dichlorobenzene at 100 C afforded the pyrazinone (IV).Subsequent,displacement of the 3-chloro group of (IV) by phenethylamine (V) in refluxing EtOAc gave the aminopyrazinone (VI).The benzyl ester group of (VI) was then hydrolyzed with LiOH in a mixture of H2O/MeOH/THF to yield acid (VII).Dechlorination of (VIII) by Raney-Ni alloy in the presence of NaOH provided pyrazinone (VIII).Reaction of 6-amino-3-bromo-2-methylpyridine (IX) with CuCN in boiling DMF gave nitrile (X),which was reduced to the primary amine (XI) by catalytic hydrogenation over Pd/C.Finally,acid (VIII) was coupled with amine (XI) using EDC and HOBt to furnish the corresponding amide,which was converted to the dihydrochloride salt.