An efficient and practical synthetic process for Daprodustat was developed.Starting with N,N'-dicyclohexylcarbodiimide(DCC)and malonic acid,the key intermediate 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione wa...An efficient and practical synthetic process for Daprodustat was developed.Starting with N,N'-dicyclohexylcarbodiimide(DCC)and malonic acid,the key intermediate 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione was synthesized via condensation reaction with 91%yield.Subsequent activation of this intermediate by 1,1'-carbonyldiimidazole(CDI),followed by a one-pot reaction with glycine ethyl ester hydrochloride,directly afforded Daprodustat in 92%yield with>99.8%HPLC purity.The process achieved an overall yield of 84%upon validation at 62-gram scale.Structural confirmation of the key intermediate was accomplished through nuclear magnetic resonance(NMR)spectroscopy and high-resolution mass spectrometry(HRMS).Compared with existing methods,this streamlined protocol demonstrates advantages including simplified operation,reduced reaction time,and lower production costs,offering significant potential for industrial-scale synthesis of Daprodustat.展开更多
文摘An efficient and practical synthetic process for Daprodustat was developed.Starting with N,N'-dicyclohexylcarbodiimide(DCC)and malonic acid,the key intermediate 1,3-dicyclohexylpyrimidine-2,4,6(1H,3H,5H)-trione was synthesized via condensation reaction with 91%yield.Subsequent activation of this intermediate by 1,1'-carbonyldiimidazole(CDI),followed by a one-pot reaction with glycine ethyl ester hydrochloride,directly afforded Daprodustat in 92%yield with>99.8%HPLC purity.The process achieved an overall yield of 84%upon validation at 62-gram scale.Structural confirmation of the key intermediate was accomplished through nuclear magnetic resonance(NMR)spectroscopy and high-resolution mass spectrometry(HRMS).Compared with existing methods,this streamlined protocol demonstrates advantages including simplified operation,reduced reaction time,and lower production costs,offering significant potential for industrial-scale synthesis of Daprodustat.
