MN-221, KUR-1246
(-)-2-[7(S)-[2(R)-羟基-2-[4-羟基-3-(2-羟基)苯基]乙基胺]-5,6,7,8-四氢萘-2-亚氧]-N,N-二甲基乙酰胺硫酸盐(2:1) 贝多拉君 Chemical Name: (-)-2-[7(S)-[2(R)-Hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)phenyl]ethylamino]-5,6,7,8-tetrahydronaphthalen-2-yloxy]-N,N-dimethylacetamide sulfate (2:1)
CAS No. 194785-31-4, 194785-19-8 (free base)
项目整合开发状态: Phase II
项目研究机构: Kissei (Originator), MediciNova (Licensee), Teikoku Hormone (Codevelopment)
合成路线:The benzyl-protected 2-(2-hydroxyethyl)phenol (I) was brominated in HOAc to give (II).Lithiation of aryl bromide (II) followed by in situ condensation of the resulting organolithium derivative (III) with diethyl oxalate under -95 C furnished the keto ester (IV).Subsequent ketone reduction by NaBH4 afforded hydroxy ester (V),which was further hydrolyzed to the mandelic acid derivative (VI).The condensation of racemic acid (VI) with (S)-2-amino-7-hydroxytetraline (VII) gave rise to a diastereomeric mixture of hydroxy amides from which the desired (S,R)-diastereoisomer (VIII) was isolated by column chromatography.Reduction of the amide function of (VIII) using borane-dimethyl sulfide complex yielded the amino alcohol (IX).Alkylation of the phenolic hydroxyl group of (IX) with 2-bromo-N,N-dimethylacetamide (X) provided the corresponding (aryloxy)acetamide (XI).Then,hydrogenolysis of the benzyl protecting groups over Pd/C furnished the target compound,which was finally isolated as the corresponding sulfate salt.
📌 参考资料/链接：
参考文献标题:3,4-Disubstd.phenylethanolaminotetralincarboxamide derivs.
文献作者:Kitazawa,M.; Okazaki,K.; Tamai,T.; Saito,M.; Muranaka,H.; Tanaka,N.; Kobayahi,H.; Kikuchi,K.(Kissei Pharmaceutical Co.,Ltd.)
参考来源:EP 0882704; US 6133266; WO 9730023
📄 详细内容
合成路线:An alternative method,suitable for large-scale synthesis,has been described: The chloromethylation of 4'-hydroxyacetophenone (XII) using formaldehyde and HCl gave (XIII).Displacement of the chloride group with NaCN provided nitrile (XIV),which was further hydrolyzed to the carboxylic acid (XV).Esterification of (XV) with methanol and sulfuric acid yields (XVI),whose phenolic hydroxyl group was protected as the benzyl ether (XVII) by alkylation with benzyl chloride.Subsequent bromination of ketone (XVII) yielded the phenacyl bromide (XVIII).The chiral amino alcohol (XX) was prepared from (-)-camphor (XIX) by ketone oxidation in position alpha with SeO2,followed by condensation with hydroxylamine and reduction with LiAlH4.Asymmetric reduction of the bromo ketone (XVIII) with borane in the presence of aluminum triethoxide and the chiral auxiliary (XX) provided the desired (R)-bromohydrin (XXI).The hydroxyl groups of (XXI) were then protected by silylation with tert-butyldimethylsilyl chloride,yielding (XXII).Condensation of the silyl-protected bromide (XXII) with (S)-2[(2-amino-1,2,3,4-tetrahydronaphthalen-7-yl)oxy]-N,N-dimethylacetamide (XXIII) furnished adduct (XXIV).
合成路线:The silyl protecting groups of (XXIV) were cleaved by acidic treatment yielding diol (XXV).Then,O-benzyl group hydrogenolysis in (XXV) using Pd/C,followed by salification with H2SO4,provided the title compound.
合成路线:The optically pure (S)-amine (XXIII) was prepared as follows: Demethylation of the previously described (S)-7-methoxy-1,2,3,4-tetrahydronaphth-2-ylamine (XXVI) in concentrated HBr under reflux gave the amino naphthol (VII).After protection of the amino group of (VII) as the N-Boc derivative (XXVII),the phenolic hydroxyl was alkylated with 2-chloro-N,N-dimethylacetamide (XXVIII) to give (XXIX).Then,Boc group cleavage in (XXIX) by means of HCl in isopropanol furnished the intermediate amine (XXIII).
参考文献标题:The practical synthesis of a uterine relaxant,bis (2-{[2S)-2-({(2R)-2-hydroxy-2-[4-hydroxy-3-(2-hydroxyethyl)-phenyl]ethyl}amino)-1,2,3,4-tetrahydronaphthalen-7-yl]oxy}-N,N-dimethylacetamide)sulfate (KUR-1246)
文献作者:Yanagi,T.; Kikuchi,K.; Takeuchi,H.; Ishikawa,T.; Nishimura,T.; Yamamoto,I.
参考来源:Chem Pharm Bull 2001,49(8),1018
产品链接: CAS No. 194785-31-4›› 产品链接: CAS No.194785-19-8››