RPR-118723
Chemical Name: (-)-2-(6-Chloro-9-methyl-2,3-dioxo-2,3,4,9-tetrahydro-1H-indeno[1,2-b]pyrazin-9-yl)acetic acid
CAS No. 173187-06-9, 173187-05-8 ((+)-enantiomer), 173186-99-7 (undefined isomer)
项目整合开发状态: Preclinical
项目研究机构: Aventis Pharma (Originator)
合成路线:Knoevenagel condensation of ketone (I) with ethyl cyanoacetate followed by Michael addition of cyanoacetamide to the resulting alpha-cyanocinnamate (IIa-b) yields cyclic imide (III).Hydrolysis and decarboxylation of (III) with H2SO4 gives diacid (IV),which is cyclized by means of hot H2SO4 to provide indanone (V).Treatment of (V) with oxalyl chloride in CH2Cl2 and catalytic DMF followed by addition of EtOH affords ethyl ester (VI),which is then converted into oxime (VII) by means of t-BuONO in Et2O and HCl.Hydrogenolysis of (VII) with H2 over Pd/C in HOAc/HCl provides alpha-amino derivative (VIII).By reacting (VIII) with ethyl oxalyl chloride (A),in CH2Cl2 in presence of Et3N,(IX) was obtained and then cyclized in presence of NH4OAc in refluxing HOAc to yield pyrazino derivative (X).Finally (X) is hydrolyzed with HCl in dioxane.
📌 参考资料/链接：
参考文献标题:5H-Indeno[1,2-b]pyrazine-2,3-dione derivs.,their preparation and medicinal products containing them
文献作者:Jimonet,P.; Ribeill,Y.; Audiau,F.; Aloup,J.-C.; Barreau,M.; Mignani,S.; Genevois-Borella,A.; Damour,D.(Aventis Pharma SA)
参考来源:US 5922716; WO 9526342
📄 详细内容
合成路线:Knoevenagel condensation of ketone (I) with ethyl cyanoacetate followed by Michael addition of cyanoacetamide to the resulting alpha-cyanocinnamate (IIa-b) yields cyclic imide (III).Hydrolysis and decarboxylation of (III) with H2SO4 gives diacid (IV),which is cyclized by means of hot H2SO4 to provide indanone (V).Treatment of (V) with oxalyl chloride in CH2Cl2 and catalytic DMF followed by addition of EtOH affords ethyl ester (VI),which is then converted into oxime (VII) by means of t-BuONO in Et2O and HCl.Hydrogenolysis of (VII) with H2 over Pd/C in HOAc/HCl provides alpha-amino derivative (VIII).By reacting (VIII) with ethyl oxalyl chloride (A),in CH2Cl2 in presence of Et3N,(IX) was obtained and then cyclized in presence of NH4OAc in refluxing HOAc to yield pyrazino derivative (X).Finally (X) is hydrolyzed with HCl in dioxane.
参考文献标题:Indeno[1,2-b]pyrazin-2,3-diones: A new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity
文献作者:Jimonet,P.; Ribeill,Y.; Bohme,A.; Boireau,A.; Cheve,M.; Damour,D.; Doble,A.; Genevois-Borella,A.; Herman,F.; Imperato,A.; Le Guern,S.; Manfre,F.; Pratt,J.; Randle,J.C.; Stutzmann,J.M.; Mignani,S.
参考来源:J Med Chem 2000,43(12),2371