RPR-119990
Chemical Name: 2-(4-Oxo-2-phosphono-5,10-dihydro-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-9-yl)acetic acid hydrochloride
CAS No. 183734-91-0, 294841-69-3 (free base)
项目整合开发状态: Preclinical
项目研究机构: Aventis Pharma (Originator)
合成路线:The cyclization of 3-[2-(carboxymethyl)phenyl]propionic acid (I) in the presence of conc.H2SO4 at 100 C gives 2-(1-oxoindan-4-yl)acetic acid (II),which is esterified with (COCl)2 and EtOH to yield the ethyl ester (III).The bromination of (III) with Br2 in HOAc affords 2-(2-bromo-1-oxoindan-4-yl)acetic acid ethyl ester (IV).The condensation of (IV) with 4-(diethoxyphosphoryl)-1H-imidazole-2-carboxylic acid ethyl ester (V) (obtained by cyclization of hydroxyamidinocarboxylic acid ethyl ester (VI) with ethynylphosphonic acid diethyl ester (VII) in the presence of TEA) provides the adduct (VIII).The cyclization of (VIII) with ammonium acetate in refluxing acetic acid gives the tetracyclic phosphonate (IX),which is finally hydrolyzed with refluxing aqueous HCl to yield the target phosphonic acid.
📌 参考资料/链接：
参考文献标题:5H-10H-Imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one derivs.,preparation thereof,and drugs containing said derivs.
文献作者:Aloup,J.-C.; Hardy,J.-C.; Mignani,S.; Jimonet,P.; Audiau,F.; Barreau,M.; Manfre,F.; Damour,D.; Ribeill,Y.; Genevois-Borella,A.; Nemecek,P.(Aventis Pharma SA)
参考来源:WO 9631511
📄 详细内容
合成路线:The cyclization of 3-[2-(carboxymethyl)phenyl]propionic acid (I) in the presence of conc.H2SO4 at 100 C gives 2-(1-oxoindan-4-yl)acetic acid (II),which is esterified with (COCl)2 and EtOH to yield the ethyl ester (III).The bromination of (III) with Br2 in HOAc affords 2-(2-bromo-1-oxoindan-4-yl)acetic acid ethyl ester (IV).The condensation of (IV) with 4-(diethoxyphosphoryl)-1H-imidazole-2-carboxylic acid ethyl ester (V) (obtained by cyclization of hydroxyamidinocarboxylic acid ethyl ester (VI) with ethynylphosphonic acid diethyl ester (VII) in the presence of TEA) provides the adduct (VIII).The cyclization of (VIII) with ammonium acetate in refluxing acetic acid gives the tetracyclic phosphonate (IX),which is finally hydrolyzed with refluxing aqueous HCl to yield the target phosphonic acid.
参考文献标题:Bioisosteres of 9-carboxymethyl-4-oxo-imidazo[1,2-a]indeno-[1,2-e]pyrazin-2-carboxylic acid derivatives.Progress towards selective,potent in vivo AMPA antagonists wit longer durations of action
文献作者:Jimonet,P.; Bohme,G.A.; Bouquerel,J.; Boireau,A.; Damour,D.; Debono,M.W.; Genevois-Borella,A.; Hardy,J.C.; Hubert,P.; Manfre,F.; Nemecek,P.; Pratt,J.; Randle,J.C.; Ribeill,Y.; Stutzmann,J.M.; Vuilhorgne,M.; Mignani,S.
参考来源:Bioorg Med Chem Lett 2001,11(2),127
合成路线:The cyclization of 3-[2-(carboxymethyl)phenyl]propionic acid (I) in the presence of conc.H2SO4 at 100 C gives 2-(1-oxoindan-4-yl)acetic acid (II),which is esterified with (COCl)2 and EtOH to yield the ethyl ester (III).The bromination of (III) with Br2 in HOAc affords 2-(2-bromo-1-oxoindan-4-yl)acetic acid ethyl ester (IV).The condensation of (IV) with 4-(diethoxyphosphoryl)-1H-imidazole-2-carboxylic acid ethyl ester (V) (obtained by cyclization of hydroxyamidinocarboxylic acid ethyl ester (VI) with ethynylphosphonic acid diethyl ester (VII) in the presence of TEA) provides the adduct (VIII).The cyclization of (VIII) with ammonium acetate in refluxing acetic acid gives the tetracyclic phosphonate (IX),which is finally hydrolyzed with refluxing aqueous HCl to yield the target phosphonic acid.
参考文献标题:RPR 119990,a novel alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist: Synthesis,pharmacological properties,and activity in an animal model of amyotrophic lateral sclerosis
文献作者:Canton,T.; B鰄me,G.A.; Boireau,A.; Bordier,F.; Mignani,S.; Jimonet,P.; Jahn,G.; Alavijeh,M.; Stygall,J.; Roberts,S.M.; Brealey,C.; Vuilhorgne,M.; Debono,M.W.; Le Guern,S.; Laville,M.; Briet,D.; Roux,M.; Stutzmann,J.M.; Pratt,J.
参考来源:J Pharmacol Exp Ther 2001,299(1),314