title: Regioselective synthesis of 2,8-disubstituted 4-aminopyrido[3,2-d]pyrimidine-6-carboxylic acid methyl ester compounds.
abstract: We report herein the synthesis of 4-amino-2,8-dichloropyrido[3,2-d]pyrimidine derivatives 2 and their regioselective diversification through S(N)Ar and metal-catalyzed cross-coupling reactions. While amination of 2 took place selectively at C-2, the regioselectivity of thiol or thiolate addition depended on the reaction conditions. Selective C-8 addition was obtained in DMF with Hünig's base and C-2 addition in (i)PrOH. These C-2 or C-8 regioselective thiolations provided an opportunistic way to selectively activate either of the two positions toward the metal-catalyzed cross-coupling reaction. The chloride could be efficiently substituted by Suzuki-Miyaura reaction and the sulfanyl group by Liebeskind-Srogl cross-coupling reaction, demonstrating the orthogonality of both reactive centers. The development of regioselective conditions for these different transformations yielded the synthesis of 4-amino-2,6,8-trisubstituted pyrido[3,2-d]pyrimidine derivatives, with various substituents.
authors: Merck Serono S.A., 9, Chemin des Mines, 1202 Geneva, Switzerland.
authors: Gwenaelle
authors: G
authors: Bouscary-Desforges
authors: Agnes
authors: A
authors: Bombrun
authors: John Kallikat
authors: JK
authors: Augustine
authors: Gérald
authors: G
authors: Bernardinelli
authors: Anna
authors: A
authors: Quattropani
mesh_terms: D000586:Amination; D002384:Catalysis; D003432:Cross-Linking Reagents; D004952:Esters; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: C572514:4-amino-2,8-dichloropyrido(3,2-d)pyrimidine; D003432:Cross-Linking Reagents; D004952:Esters; D011743:Pyrimidines