摘要
目的:设计阿戈美拉汀二聚体最佳制备工艺,建立反相高效液相色谱法测定阿戈美拉汀二聚体含量。方法:以原料药S与三溴化硼反应制备N-[2-(7-羟基-1-萘基)乙基]乙酰胺,再与1,4-二溴丁烷反应制备得最终产物阿戈美拉汀二聚体。含量测定使用Diamonsil C18色谱柱(250 mm×4.6 mm,5μm),以甲醇(A)-水(B)为流动相,梯度洗脱(0～16 min,78%A;16～25 min,78%A→96%A;25～35 min,96%A;35～40 min,96%A→78%A),流速1.0 mL·min-1,检测波长230 nm,柱温为室温,进样体积20μL。结果:本法合成阿戈美拉汀二聚体的产率达75%,经1H NMR进行了结构确证,纯度达99.2%;阿戈美拉汀二聚体浓度在40～160 mg·mL-1范围内与峰面积呈良好线性关系(r=0.9998,n=7),检测限(S/N=3)为0.4 ng,定量限(S/N=10)为1.2 ng,精密度试验的RSD(n=6)为1.0%,重复性试验的RSD(n=6)为0.96%。结论:本文改进的阿戈美拉汀二聚体合成工艺,操作简单,环保,低成本,适于工业化生产;本文建立的HPLC方法经初步方法学试验证明,基本满足阿戈美拉汀二聚体的含量控制要求。
Objective：To design an optimum preparation technology of agomelatine dimer and establish a RP - HPLC method for its determination. Methods：The bulk drug S was reacted with boron tribromide to prepare N - 12 - （7 - hydroxy - naphthalen - 1 - yl） - ethyl ] - acetamide which was further reacted with 1,4 - dibromo - butane to prepare the final product agomelatine dimer. A Diamonsil C18 column（250 mm× 4.6 mm,5 μm） was adopted for content determination, the mobile phase was methanol（A） -water（ B ） with a gradient elution in a to- tal run time of 40 mins （0 - 16min,78% A;16 - 25min,78% A→96% A;25 - 35min,96% A;35 -40 min, 96% A→78% A） ;the flow rate was 1.0 mL · min-1 ,the detection wavelength was set at 230 nm,and the volume of injection was 20 μL. Results：The yield of this synthetic method was up to 75% , and the structure of synthe- tized agomelatine dimer was identified by 1H NMR, and its purity reached 99.2% ; the calibration curve was in good linearity in the concentrate range of 40 - 160 mg · mL-1 （r = 0. 9998, n = 7 ） for agomelatine dimer, the lim- it of the detection （ S/N = 3 ） was 0.4 ng, the limit of the quantity （ S/N = 10 ） was 1.2 ng, the precision of the e- quipment and the reproducibility were good （RSD was 1.0% and 0.96% , respectively, n = 6）. Conclusion：This optimal synthetic procedure is simple, environment -friendly and suitable for industrial production with low cost. And the methodology test confirmed that the established HPLC method for determination can meet the content con- trol requirement of agomelatine dimer.
出处
《药物分析杂志》
CAS
CSCD
北大核心
2013年第3期474-477,共4页
Chinese Journal of Pharmaceutical Analysis
基金
十二五国家科技重大专项"重大新药创制"综合性新药研究开发技术大平台(2012ZX09301003-001-010)
国家自然科学基金项目(81072613)
关键词
抗抑郁药
褪黑素受体激动剂
二价配体
萘环衍生物
阿戈美拉汀二聚体
优化合成工艺
量效关系
含量控制
反相高效液相色谱
antidepressant
melatonin receptor agonists
bivalent ligand
naphthalenic derivatives
agomelatine di-mer
the optimal synthetic procedure
structure - activity relationship （SAR）
drug content control
RP - HPLC
