NOVEL PROCESS FOR PREPARING CHIRAL (5-AMINO-1,2-DIHYDRO-2-METHYL-3-PHENYLPYRIDO3,4-BPYRAZIN-7-YLCARBAMICACID-ETHYL-ESTERS AND ITS NEW INTERMEDIATES

摘要

The present invention relates to a new process for (-) - (S) - (5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamic acid Ethyl ester and (+) - (R) - (5-amino-1,2-dihydro-2-methyl-3-phenylpyrido [3,4-b] pyrazin-7-yl) carbamic acid ethyl ester and pharmaceutically acceptable salts thereof. According to the invention, N-protected S - (-) - L-alanine or N-protected R - (+) - L-alanine is treated with a tertiary aliphatic amine and a chloroformic (lower alkyl) ester. N, O-di (lower alkyl) hydroxylamine hydrochloride in a suitable solvent at a temperature between -25 ° C and 25 ° C under a nitrogen atmosphere and then the resulting compound of formula (2a) 'or (2a). the amide is deprotected and reacted with ethyl 2-amino-3-nitro-4-chloropyridine-6-carbamic acid in the presence of a tertiary alkylamine in a lower alcohol solvent and the resulting new (Ia) or ( The intermediate carbamate of formula IIa) is treated with a phenyl-Grignard reagent in a suitable solvent and the resulting (S) - [6-amino-4 - [(1-methyl-2-oxo-2-phenylethyl) amino] 5-Nitro-2-pyridinyl] -carbamic acid ethyl ester or (R) - [6-amino-4 - [(1-methyl-2-oxo-2-phenyl-ethyl) -amino] -5-nitro- 2-pyridyl dinyl] carbamic acid ethyl ester is subjected to Raney nickel reductive cyclization in a known manner and, if desired, the product obtained is reacted with a pharmaceutically acceptable acid or a pharmaceutically acceptable salt thereof in a known manner. ŕ