Efonidipine hydrochloride ethanol, NZ-105, Landel
盐酸依福地平 依福地平 Chemical Name: (?-5-(5,5-Dimethyl-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 2-(N-benzyl-N-phenylamino)ethyl ester P-oxide hydrochloride ethanol; (?-5-(2,2-Dimethylpropylenedioxyphosphinyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 2-(N-benzyl-N-phenylamino)ethyl ester hydrochloride,compound with ethyl alcohol (1:1)
CAS No. 111011-76-8, 111011-63-3 (free base, non adduct), 111011-53-1 (monoHCl salt, non-adduct)
项目整合开发状态: Launched-1994
项目研究机构: Nissan Chemical (Originator), Shionogi (Distributor), Zeria (Codevelopment)
合成路线:A new synthesis of efonidipine has been described:The cyclization of 2,2-dimethylbutane-1,4-diol (I) with triethyl phosphite (II) by heating at 100 C gives 2-methoxy-5,5-dimethyl-1,3,2-dioxaphosphorinan (III),which,by treatment with iodoacetone (IV) in refluxing ether,yields 2-acetonyl-5,5-dimethyl-1,3,2-dioxaphosphorinan-2-one (V).The condensation of (V) with 3-nitrobenzaldehyde (VI) by means of piperidine in acetic acid affords 3-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-buten-2-one (VII),which is finally cyclized with 3-amino-2-propenoic acid 2-(N-benzyl-N-phenylamino)ethyl ester (VIII) in refluxing toluene.
📌 参考资料/链接：
参考文献标题:Synthesis of 1,4-dihydropyridine-5-phosphonates and their calcium antagonistic and antihypertensive activities: Novel calcium-antagonist NZ-105 and its crystal structure
文献作者:Sakoda,R.; Kamikawaji,Y.; Seto,K.
参考来源:Chem Pharm Bull 1992,40(9),2362
📄 详细内容
合成路线:A new synthesis for (4S)-efonidipine has been described:The reaction of 5,5-dimethyl-2-(2-oxopropyl)-1,3,2-dioxaphosphorinan-2-one (I) with dimorpholino(3-nitrophenyl)methane (II) by means of trifluoroacetic acid in hot toluene gives 5,5-dimethyl-2-[1-acetyl-2-(3-nitrophenyl)vinyl]-1,3,2-dioxaphosphorina n-2-one (III),which is cyclized with 3-aminocrotonic acid 2(S)-methoxy-2-phenylethyl ester (IV) in refluxing toluene; the recrystallization of the resulting product affords 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4(S)-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid 2(S)-methoxy-2-phenylethyl ester (V).The protection of the NH group of (V) with chloromethyl methyl ether and NaH in THF yields the N-methoxymethyl derivative (VI),which is transesterified with 2-(N-benzyl-N-methylamino)ethanol (VII) and NaH in DMSO,giving the protected final product (VIII).Finally,this compound is deprotected with HCl in ethanol.
参考文献标题:Synthesis and crystal structure of optically active 2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate (NZ-105)
文献作者:Sakoda,R.; Matsumoto,H.; Seto,K.
参考来源:Chem Pharm Bull 1992,40(9),2377
合成路线:An enantioselective synthesis of efonidipine has been described:The enantioselective hydrolysis of 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-n itrophenyl)-1,4-dihydropyridine-3-carboxylic acid propionyloxymethyl ester (I) with lipase AH in 2,5-dimethyltetrahydrofuran saturated with water gives the corresponding free acid of the (S)-isomer (III),while the propionyloxymethyl ester of the (R)-isomer (II) remains undisturbed.After chromatographic separation,the (R)-ester (II) is hydrolyzed with NaOH in methanol to the (R)-acid (IV).Finally,both enantiomerically pure acids (III) and (IV) are separately esterified with 2-(N-benzyl-N-phenylamino)ethanol in the usual way.
参考文献标题:Lipase-catalyzed enantiosynthesis of (R)- and (S)-2-[benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate (NZ 105)
文献作者:Ebiike,H.; Achiwa,K.; Yamazaki,Y.
参考来源:Chem Pharm Bull 1995,43(7),1251
产品链接: CAS No. 111011-76-8›› 产品链接: CAS No.111011-63-3››