阿戈美拉汀二聚体的合成和分析

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- 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,5 μm),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20 μL。 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- -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 total 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 synthetized 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 limit 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 equipment 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 control requirement of agomelatine dimer.