Rosuvastatin calcium, ZD-4522, S-4522, Crestor
瑞舒伐他汀钙 罗伐他汀 瑞舒伐他汀中间体R-4Chemical Name: (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid calcium salt (2:1)
CAS No. 147098-20-2, 287714-41-4 (free acid), 147098-18-8 (monoNa salt)
项目整合开发状态: Launched-2003
项目研究机构: Shionogi (Originator), AstraZeneca (Licensee)
合成路线:The condensation of 4-fluorobenzaldehyde (I) with 4-methyl-3-oxopentanoic acid ethyl ester (II) by means of piperidine/AcOH in refluxing benzene gives the corresponding benzylidene derivative (III),which is cyclized with S-methylisothiourea (IV) and oxidized with DDQ,affording the pyrimidine derivative (V).The oxidation of (V) with m-chloroperbenzoic acid (m-CPBA) gives the expected methanesulfonyl derivative (VI),which is treated first with methylamine and then with methanesulfonyl chloride to provide the N-methylmethanesulfonamide (VII).The reduction of the ester group of (VII) with DIBAL in toluene,followed by selective oxidation of the resulting alcohol with TPAP,affords the aldehyde (VIII),which is submitted to a Wittig condensation with the phosphorane (IX) in acetonitrile to give the protected heptenoate (X).The deprotection of (X) with FH and the controlled reduction of the resulting keto alcohol with Et2BOMe and NaBH4 affords the chiral dihydroxyheptenoate (XI),which is hydrolyzed with NaOH in ethanol,yielding the corresponding sodium salt (XII).Finally,this compound is treated with calcium chloride.
📌 参考资料/链接：
参考文献标题:Pyrimidine derivs.as HMG-CoA reductase inhibitors
文献作者:Hirai,K.; Ishiba,T.; Koike,H.; Watanabe,M.(Shionogi & Co.Ltd.)
参考来源:EP 0521471; JP 1993178841; US 5260440
📄 详细内容
合成路线:The condensation of 4-fluorobenzaldehyde (I) with 4-methyl-3-oxopentanoic acid ethyl ester (II) by means of piperidine/AcOH in refluxing benzene gives the corresponding benzylidene derivative (III),which is cyclized with S-methylisothiourea (IV) and oxidized with DDQ,affording the pyrimidine derivative (V).The oxidation of (V) with m-chloroperbenzoic acid (m-CPBA) gives the expected methanesulfonyl derivative (VI),which is treated first with methylamine and then with methanesulfonyl chloride to provide the N-methylmethanesulfonamide (VII).The reduction of the ester group of (VII) with DIBAL in toluene,followed by selective oxidation of the resulting alcohol with TPAP,affords the aldehyde (VIII),which is submitted to a Wittig condensation with the phosphorane (IX) in acetonitrile to give the protected heptenoate (X).The deprotection of (X) with FH and the controlled reduction of the resulting keto alcohol with Et2BOMe and NaBH4 affords the chiral dihydroxyheptenoate (XI),which is hydrolyzed with NaOH in ethanol,yielding the corresponding sodium salt (XII).Finally,this compound is treated with calcium chloride.
参考文献标题:Synthesis and biological activity of methanesulfonamide pyrimidine- and N-methanesulfonyl pyrrole-substituted 3,5-dihydroxy-6-heptenoates,a novel series of HMG-CoA reductase inhibitors
文献作者:Watanabe,M.; Koike,H.; Ishiba,T.; Okada,T.; Seo,S.; Hirai,K.
参考来源:Bioorg Med Chem 1997,5(2),437
合成路线:The condensation of 4-fluorobenzaldehyde (I) with 4-methyl-3-oxopentanoic acid ethyl ester (II) by means of piperidine/AcOH in refluxing benzene gives the corresponding benzylidene derivative (III),which is cyclized with S-methylisothiourea (IV) and oxidized with DDQ,affording the pyrimidine derivative (V).The oxidation of (V) with m-chloroperbenzoic acid (m-CPBA) gives the expected methanesulfonyl derivative (VI),which is treated first with methylamine and then with methanesulfonyl chloride to provide the N-methylmethanesulfonamide (VII).The reduction of the ester group of (VII) with DIBAL in toluene,followed by selective oxidation of the resulting alcohol with TPAP,affords the aldehyde (VIII),which is submitted to a Wittig condensation with the phosphorane (IX) in acetonitrile to give the protected heptenoate (X).The deprotection of (X) with FH and the controlled reduction of the resulting keto alcohol with Et2BOMe and NaBH4 affords the chiral dihydroxyheptenoate (XI),which is hydrolyzed with NaOH in ethanol,yielding the corresponding sodium salt (XII).Finally,this compound is treated with calcium chloride.
参考文献标题:ZD-4522
文献作者:Castar,J.; Graul,A.
参考来源:Drugs Fut 1999,24(5),511