LAS-333
Chemical Name: 2(R)-Amino-3-[6,7-dimethyl-3-(phosphonomethyl)quinolin-2-yl]propionic acid; 3-[6,7-dimethyl-3-(phosphonomethyl)quinolin-2-yl]-D-alanine
项目整合开发状态: Biological Testing
项目研究机构: AstraZeneca (Originator)
合成路线:The acylation of 3,4-dimethylaniline (I) with 3-chloropropionyl chloride (II) in toluene gives the expected anilide (III),which is cyclized with DMF by means of POCl3 yielding 2-chloro-3-(chloromethyl)-6,7-dimethylquinoline (IV).The reaction of (IV) with POBr3 at 100 C affords the corresponding dibromo derivative (V),which is condensed with triethyl phosphite in toluene to give the phosphonic ester (VI).The condensation of (VI) with N-(tert-butoxycarbonyl)-3-iodo-D-alanine methyl ester (VII) by means of Zn-Cu,Pd(OAc)2,tri(2-furyl)phosphine and DMA in hot toluene yields the esterified target compound (VIII),which is finally hydrolyzed with 6N HCl.Alternatively,the dichloro derivative (IV) can also be condensed with triethyl phosphite giving the phosphonate (IX),which is treated with NaI and p-toluenesulfonic acid in refluxing 2-butanone to yield the corresponding 2-iodo derivative (X).Finally,this compound is condensed with D-alanine (VII) as before to afford the previously described intermediate (VIII).
📌 参考资料/链接：
参考文献标题:Heterocyclic cpds.
文献作者:Swahn,B.-M.(AstraZeneca plc)
参考来源:EP 0736032; JP 1997506895; US 5710139; WO 9517410
📄 详细内容
合成路线:The acylation of 3,4-dimethylaniline (I) with 3-chloropropionyl chloride (II) in toluene gives the expected anilide (III),which is cyclized with DMF by means of POCl3 yielding 2-chloro-3-(chloromethyl)-6,7-dimethylquinoline (IV).The reaction of (IV) with POBr3 at 100 C affords the corresponding dibromo derivative (V),which is condensed with triethyl phosphite in toluene to give the phosphonic ester (VI).The condensation of (VI) with N-(tert-butoxycarbonyl)-3-iodo-D-alanine methyl ester (VII) by means of Zn-Cu,Pd(OAc)2,tri(2-furyl)phosphine and DMA in hot toluene yields the esterified target compound (VIII),which is finally hydrolyzed with 6N HCl.Alternatively,the dichloro derivative (IV) can also be condensed with triethyl phosphite giving the phosphonate (IX),which is treated with NaI and p-toluenesulfonic acid in refluxing 2-butanone to yield the corresponding 2-iodo derivative (X).Finally,this compound is condensed with D-alanine (VII) as before to afford the previously described intermediate (VIII).
参考文献标题:New heteroaryl-spaced phosphono alpha-amino acids are competitive NMDA antagonists with analgesic activity
文献作者:Molin,H.; Pelcman,B.; Besidski,Y.; Swahn,B.-M.; Berge,O.-G.; Sandberg,M.P.; Claesson,A.
参考来源:Bioorg Med Chem Lett 1996,6(14),1635