西司他丁钠3个有关物质的合成

Synthesis of Three Related Substances of Cilastatin Sodium

为了对西司他丁钠(1)进行质量控制,合成了EP 11.0中收载的有关物质B、C和G,即(Z)-7-[[(2R)-2-羧基-2-[[(1RS)-1-甲基-3-氧代丁基]氨基]乙基]硫烷基]-2-[[[(1S)-2,2-二甲基环丙基]羰基]氨基]庚-2-烯酸、(Z)-7-[[(2R)-2-羧基-2-[(1,1-二甲基-3-氧代丁基)氨基]乙基]硫烷基]-2-[[[(1S)-2,2-二甲基环丙基]羰基]氨基]庚-2-烯酸和(E)-(2RS)-7-[[(2R)-2-氨基-2-羧基乙基]硫烷基]-2-[[[(1S)-2,2-二甲基环丙基]羰基]氨基]庚-3-烯酸。以1为起始原料,分别与(E)-3-戊烯-2-酮(2)或4-甲基-3-烯-2-戊酮(3)经Michael加成反应,再经制备色谱分离、纯化得有关物质B和C。用7-氯-2-氧代庚酸乙酯(4)和氨基甲酸苄酯经缩合反应,得到(Z)-7-氯-2-[[(苄氧基)羰基]氨基]庚-2-烯酸乙酯(5);5在2,2,6,6-四甲基哌啶锂条件下双键迁移得(E)-7-氯-2-[[(苄氧基)羰基]氨基]庚-3-烯酸乙酯(6);6经三甲基碘硅烷(TMSI)脱除苄氧基羰基(Cbz),随后与(S)-2,2-二甲基环丙基甲酸(8)反应得(E)-7-氯-2-[[(S)-2,2-二甲基环丙烷]-甲酰胺基]庚-3-烯酸乙酯(9);9再与L-半胱氨酸(10)反应,经制备色谱分离、纯化得有关物质G。3个有关物质均经MS、^(1)H NMR和^(13)C NMR确证。

In order to control the quality of cilastatin sodium(1),the synthesis of the related substances B,C and G involved in the EP 11.0,named(Z)-7-[[(2R)-2-carboxy-2-[[(1RS)-1-methyl-3-oxobutyl]amino]ethyl]-sulfanyl]-2-[[[(1S)-2,2-dimethylcyclopropyl]carbonyl]amino]hept-2-enoic acid,(Z)-7-[[(2R)-2-carboxy-2-[(1,1-dimethyl-3-oxobutyl)amino]ethyl]sulfanyl]-2-[[[(1S)-2,2-dimethylcyclopropyl]carbonyl]amino]hept-2-enoic acid and(E)-(2RS)-7-[[(2R)-2-amino-2-carboxyethyl]sulfanyl]-2-[[[(1S)-2,2-dimethylcyclopropyl]carbonyl]amino]hept-3-enoic acid,were reported in this study.Compound 1 was reacted with(E)-3-penten-2-one(2)or 4-methyl-pent-3-ene-2-one(3)via Michael addition,respectively,and purified by preparative chromatography to obtain related substances B and C.Ethyl(Z)-7-chloro-2-[[(benzyloxy)carbonyl]amino]hept-2-enoate(5)was synthesized through condensation of ethyl-7-chloro-2-oxohept-2-enoate(4)and benzyl carbamate.The double bond of 5 was migrated by 2,2,6,6-tetramethylpiperidine lithium(LiTMP)to generate ethyl(E)-7-chloro-2-[[(benzyloxy)carbonyl]amino]hept-3-enoate(6).After deprotection of 6,followed by reaction with(S)-2,2-dimethylcyclopropane carboxylic acid(8)to obtain ethyl(E)-7-chloro-2-(S)-2,2-dimethylcyclopropane carboxamido hept-3-enoate(9).Related substance G was obtained via the reaction of 9 and Lcysteine(10)and the preparative chromatography.The structures of the three target products were confirmed by MS,^(1)H NMR and^(13)C NMR.