新产品编号:1275601
Chemical Name: N-[2-[1-Aminoethyl(hydroxy)phosphorylmethyl]-3-(4-biphenylyl)propionyl]-L-alanine hydrobromide
项目整合开发状态: Biological Testing
项目研究机构: INSERM (Originator)
合成路线:Treatment of triethyl phosphoacetate (I) with NaH and 4-bromobenzyl bromide (II) in DMF provides the 2-substituted triethyl phosphoacetate (III),which then undergoes reaction with formaldehyde and K2CO3 to afford acrylate derivative (IV).Michael condensation of (IV) with phosphinic acid (V) in N,O-bistrimethylsilylacetamide (BSA) yields intermediate (VI),which then undergoes Suzuki condensation in toluene with phenylboronic acid (VII) and NaHCO3 in MeOH catalyzed by Pd(PPh3)4 to give (VIII).Hydrolysis of ethyl ester (VIII) by means of NaOH in EtOH furnishes carboxylic acid (IX),which is then coupled to L-alanine (X) by means of BOP and DIEA or Et3N in DMF to yield methyl ester (XI).Compound (XI) is then hydrolyzed by treatment with NaOH or LiOH in EtOH and,finally,the Z-protecting group is removed with BBr3 in dichloromethane.
📌 参考资料/链接：
参考文献标题:Novel (alpha-aminophosphino) peptide derivs.,method for making same and therapeutic applications thereof
文献作者:Fournie-Zaluski,M.-C.; Chen,H.; Roques,B.P.(INSERM (Institut National de la Sante et de la Recherche Medicale))
参考来源:EP 1009750; WO 9818803
📄 详细内容
合成路线:Treatment of triethyl phosphoacetate (I) with NaH and 4-bromobenzyl bromide (II) in DMF provides the 2-substituted triethyl phosphoacetate (III),which then undergoes reaction with formaldehyde and K2CO3 to afford acrylate derivative (IV).Michael condensation of (IV) with phosphinic acid (V) in N,O-bistrimethylsilylacetamide (BSA) yields intermediate (VI),which then undergoes Suzuki condensation in toluene with phenylboronic acid (VII) and NaHCO3 in MeOH catalyzed by Pd(PPh3)4 to give (VIII).Hydrolysis of ethyl ester (VIII) by means of NaOH in EtOH furnishes carboxylic acid (IX),which is then coupled to L-alanine (X) by means of BOP and DIEA or Et3N in DMF to yield methyl ester (XI).Compound (XI) is then hydrolyzed by treatment with NaOH or LiOH in EtOH and,finally,the Z-protecting group is removed with BBr3 in dichloromethane.
参考文献标题:Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: A class of central analgesics
文献作者:Chen,H.; Noble,F.; Coric,P.; Fournie-Zaluski,M.-C.; Roques,B.P.
参考来源:Proceedings of the National Academy of Sciences of the United States of America 1998,95(20),12028
合成路线:Treatment of triethyl phosphoacetate (I) with NaH and 4-bromobenzyl bromide (II) in DMF provides the 2-substituted triethyl phosphoacetate (III),which then undergoes reaction with formaldehyde and K2CO3 to afford acrylate derivative (IV).Michael condensation of (IV) with phosphinic acid (V) in N,O-bistrimethylsilylacetamide (BSA) yields intermediate (VI),which then undergoes Suzuki condensation in toluene with phenylboronic acid (VII) and NaHCO3 in MeOH catalyzed by Pd(PPh3)4 to give (VIII).Hydrolysis of ethyl ester (VIII) by means of NaOH in EtOH furnishes carboxylic acid (IX),which is then coupled to L-alanine (X) by means of BOP and DIEA or Et3N in DMF to yield methyl ester (XI).Compound (XI) is then hydrolyzed by treatment with NaOH or LiOH in EtOH and,finally,the Z-protecting group is removed with BBr3 in dichloromethane.
参考文献标题:Phosphinic derivatives as new dual enkephalin-degrading enzyme inhibitors: Synthesis,biological properties,and antinociceptive activities
文献作者:Chen,H.; Noble,F.; Morth? A.; Meudal,H.; Coric,P.; DaNascimento,S.; Roques,B.P.; George,P.; Fournie-Zaluski,M.C.
参考来源:J Med Chem 2000,43(7),1398