Palonidipine hydrochloride, TC-81
帕洛地平帕洛地平盐酸盐Chemical Name: (?-3-(N-Benzyl-N-methylamino)-2,2-dimethylpropyl methyl 2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1,4-di-hydropyridine-3,5-dicarboxylate hydrochloride; (?-3-(N-Benzyl-N-methylamino)-2,2-dimethylpropyl 3-methoxycarbonyl-2,6-dimethyl-4-(2-fluoro-5-nitrophenyl)-1,4-dihydropyridine-5-carboxylate hydrochloride
CAS No. 96515-73-0 (free base, non-specified stereoch.), 96515-74-1 (monoHCl salt, non-specified stereoch.)
项目整合开发状态: Phase III
项目研究机构: Teijin (Originator)
合成路线:1) The reaction of N-methyl-N-benzylamine (I) with isobutyraldehyde (II) and formaldehyde (III) in refluxing isopropanol,followed by hydrogenation with NaBH4 gives 3-(N-benzyl-N-methylamino)-2,2-dimethylpropanol (IV),which is condensed with diketene (V) in refluxing benzene to yield 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate (VI).Finally,this compound is submitted to cyclization with 2-fluoro-5-nitrobenzeldehyde (VII) (prepared by oxidation of 2-fluoro-5-nitrotoluene (VIII) with CrO3 in acetic ahydride-H2SO4) and methyl 3-aminocrotonate (IX) in refluxing isopropanol.
合成路线:2) The condensation of acetoacetic ester (VI) with aldehyde (VII) gives the benzylidene derivative (X),which is then submitted to cyclization with crotonate (IX) as before.3) Finally,the title product can also be obtained by cyclization of benzylidene derivative (X) with methyl acetoacetate (XI) and concentrated aqueous ammonia in refluxing isopropanol.
📌 参考资料/链接：
参考文献标题:1,4-Dihydropyridine derivs.,process for production thereof and pharmaceutical use thereof
文献作者:Yamaguchi,H.; Odamiya,Y.; Kanno,H.; Sunakawa,K.(Teijin Ltd.)
参考来源:EP 0128010; JP 1984222474; JP 1984227859; JP 1985104065; US 4578395
📄 详细内容
合成路线:1) The reaction of N-methyl-N-benzylamine (I) with isobutyraldehyde (II) and formaldehyde (III) in refluxing isopropanol,followed by hydrogenation with NaBH4 gives 3-(N-benzyl-N-methylamino)-2,2-dimethylpropanol (IV),which is condensed with diketene (V) in refluxing benzene to yield 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate (VI).Finally,this compound is submitted to cyclization with 2-fluoro-5-nitrobenzeldehyde (VII) (prepared by oxidation of 2-fluoro-5-nitrotoluene (VIII) with CrO3 in acetic ahydride-H2SO4) and methyl 3-aminocrotonate (IX) in refluxing isopropanol.
合成路线:2) The condensation of acetoacetic ester (VI) with aldehyde (VII) gives the benzylidene derivative (X),which is then submitted to cyclization with crotonate (IX) as before.3) Finally,the title product can also be obtained by cyclization of benzylidene derivative (X) with methyl acetoacetate (XI) and concentrated aqueous ammonia in refluxing isopropanol.
参考文献标题:TC-81
文献作者:Prous,J.; Castar,J.
参考来源:Drugs Fut 1989,14(3),239
合成路线:A new synthesis for TC-81 has been described:By condensation of 2-(2-fluoro-5-nitrobenzylidene)acetoacetic acid methyl ester (I) with 3-aminocrotonic acid 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl ester (II) by means of triethylamine in refluxing isopropanol.The starting products (I) and (II) are prepared as follows: The condensation of 2-fluoro-5-nitrobenzaldehyde (III) with methylacetoacetate (IV) by means of HCl in toluene gives the benzylidene derivative (I).The condensation of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropanol (V) with diketene (VI) in hot benzene gives the acetoacetic ester (VII),which is treated with gaseous ammonia in ethanol,yielding crotonate (III).
参考文献标题:Synthesis and antihypertensive activity of 1,4-dihydropyridine derivatives with a 4-(disubstituted phenyl)ring and an aminoalkyl ester group: Highly potent and long-lasting calcium antagonists
文献作者:Kanno,H.; Yamaguchi,H.; Okamiya,Y.; Sunakawa,K.; Takeshita,T.; Naruchi,T.
参考来源:Chem Pharm Bull 1992,40(8),2049
产品链接: CAS No. 96515-73-0›› 产品链接: CAS No.96515-74-1››