TAK-475
拉帕司他Chemical Name: 2-[1-[2-[1-(3-Acetoxy-2,2-dimethylpropyl)-7-chloro-5(S)-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3(R)-yl]acetyl]piperidin-4-yl]acetic acid
CAS No. 189060-13-7
项目整合开发状态: Phase II
项目研究机构: Takeda (Originator)
合成路线:The optically active amino benzhydrol (I) is acylated with dimethylmalonyl chloride monoethyl ester (II) to yield amide (III).Subsequent reduction of the amide-ester (III) by means of LiAlH4 furnishes amino alcohol (IV).Alternatively,the intermediate amino alcohol (IV) is prepared by reductive alkylation of (I) with 3-hydroxy-2,2-dimethylpropionaldehyde (V) in the presence of NaBH3CN.Condensation of (IV) with fumaryl chloride monoethyl ester (VI) provides amide (VII).Intramolecular cyclization of the conjugated carboxamide (VII) in the presence of K2CO3 leads to the benzoxazepine derivative (VIII).The ethyl ester group of (VIII) is then hydrolyzed under alkaline conditions to furnish acid (IX).
合成路线:Acid (IX) is coupled to ethyl 4-piperidineacetate (X) by means of diethylphosphoryl cyanide to give amide (XI).The ethyl ester group of (XI) is then hydrolyzed to the corresponding carboxylic acid (XII) employing NaOH in ethanol.Finally,esterification of the alcohol function of (XII) with acetic anhydride in pyridine gives rise to the target acetate ester.
📌 参考资料/链接：
参考文献标题:Benzoxazepine cpds.,their production and use as lipid lowering agents
文献作者:Yukimasa,H.; Sugiyama,Y.; Tozawa,R.(Takeda Chemical Industries,Ltd.)
参考来源:EP 0862562; EP 1097928; JP 1997136880; JP 2001097963; US 6110909; US 6613761; WO 9710224
📄 详细内容
合成路线:The optically active amino benzhydrol (I) is acylated with dimethylmalonyl chloride monoethyl ester (II) to yield amide (III).Subsequent reduction of the amide-ester (III) by means of LiAlH4 furnishes amino alcohol (IV).Alternatively,the intermediate amino alcohol (IV) is prepared by reductive alkylation of (I) with 3-hydroxy-2,2-dimethylpropionaldehyde (V) in the presence of NaBH3CN.Condensation of (IV) with fumaryl chloride monoethyl ester (VI) provides amide (VII).Intramolecular cyclization of the conjugated carboxamide (VII) in the presence of K2CO3 leads to the benzoxazepine derivative (VIII).The ethyl ester group of (VIII) is then hydrolyzed under alkaline conditions to furnish acid (IX).
合成路线:Acid (IX) is coupled to ethyl 4-piperidineacetate (X) by means of diethylphosphoryl cyanide to give amide (XI).The ethyl ester group of (XI) is then hydrolyzed to the corresponding carboxylic acid (XII) employing NaOH in ethanol.Finally,esterification of the alcohol function of (XII) with acetic anhydride in pyridine gives rise to the target acetate ester.
参考文献标题:Synthesis of novel 4,1-benzoxazepine derivatives as squalene synthase inhibitors and their inhibition of cholesterol synthesis
文献作者:Miki,T.; Kori,M.; Mabuchi,H.; Tozawa,R.; Nishimoto,T.; Sugiyama,Y.; Teshima,K.; Yukimasa,H.
参考来源:J Med Chem 2002,45(20),4571
产品链接: CAS No. 189060-13-7››