公开(公告)号：US06472542B1

公开(公告)日：2002-10-29

申请号：US09996664

申请日：2001-11-29

申请人： Edvige Galeazzi ,  Gustavo A. Garcia ,  Fernando Lara ,  Gema Lopez ,  Orestes Martinez ,  Eugenio Tisselli ,  Alicia Trejo

发明人： Edvige Galeazzi ,  Gustavo A. Garcia ,  Fernando Lara ,  Gema Lopez ,  Orestes Martinez ,  Eugenio Tisselli ,  Alicia Trejo

IPC分类号： C07D30930

CPC分类号： C07D309/30 ,  C07C235/30 ,  C07C2602/28 ,  C07F7/1804 ,  C07F7/1892 ,  Y02P20/55

摘要： Simvastatin is produced from lovastatin in high yield and in pharmaceutical purity by forming an amide of lovastatin and protecting the free hydroxyl groups of the lovastatin amide with hexamethyidisilazane (HMDS) to form a protected lovastatin amide. The &agr;-carbon of the 2-methylbutyrate secondary chain of the protected lovastatin amide may be methylated to form a protected simvastatin amide. The protecting groups may be removed therefrom by quenching the methylation reaction with water. The simvastatin amide which is obtained may be hydrolyzed to form simvastatin acid, followed by forming a simvastatin ammonium salt, lactonizing the salt to form simvastatin, and recrystallizing the thus formed crude Simvastatin to a high degree of purity. The HMDS protecting agent for the lactone hydroxyl groups of Lovastatin is selected so as to result in a reaction that does not produce acid so that a base, such as imidazole, is not required to neutralize the acidity of the reaction medium. Another advantage of using HMDS as a protecting agent is that the removal of the protecting agent after the methylation reaction is carried out simply, for example, by water quenching. The lactonization reaction of the present invention may be carried out using a low boiling point solvent, such as methylene chloride, in the presence of inorganic acids such as sulfuric, hydrochloric, methanesulfonic or phosphoric acid as catalyst.

摘要翻译： 辛伐他汀通过形成洛伐他汀的酰胺并以六水合二硅氮烷（HMDS）保护洛伐他汀酰胺的游离羟基，形成受保护的洛伐他汀酰胺，以高产率和药物纯度从洛伐他汀生产。 被保护的洛伐他汀酰胺的2-甲基丁酸二级链的α-碳可被甲基化以形成受保护的辛伐他汀酰胺。 通过用水淬灭甲基化反应可以将保护基除去。 所获得的辛伐他汀酰胺可以水解形成辛伐他汀酸，然后形成辛伐他汀铵盐，将盐内酯化形成辛伐他汀，并将由此形成的粗制辛伐他汀重结晶至高纯度。 选择洛伐他汀的内酯羟基的HMDS保护剂，以产生不产生酸的反应，从而不需要碱例如咪唑来中和反应介质的酸度。 使用HMDS作为保护剂的另一个优点是在甲基化反应后除去保护剂简单地例如通过水淬。 本发明的内酯化反应可以在无机酸如硫酸，盐酸，甲磺酸或磷酸作为催化剂的存在下，使用低沸点溶剂如二氯甲烷进行。