降糖新药三肽Diapin的化学法合成

目的:化学法合成三肽Diapin(甘氨酰-甘氨酰-亮氨酸,glycyl-glycyl-leucine,GGL),同时适用于通式(glycyl) n-leucine的多肽,包括其L-和D-构型。固相法和液相法要进行基团的保护和脱保护,然后裂解,再进行液相HPLC制备,成本高,操作繁琐。方法:以亮氨酸和氯乙酰氯为起始原料进行酰化反应,生成甘氨酰-亮氨酸氯代二肽,然后用氨水氨解得到甘氨酰-亮氨酸二肽;二肽再和氯乙酰氯进行酰化反应生成甘氨酰-甘氨酰-亮氨酸氯代三肽,然后再用乌洛托品氨解得到甘氨酰-甘氨酰-亮氨酸三肽。结果:总收率为56%(以亮氨酸计),HPLC纯度为99. 8%。结论:用化学法合成三肽Diapin或(glycyl) n-leucine的多肽,包括其L-和D-构型,比固相和液相法步骤简单,原料易得,收率高,易于工业化生产。产物经元素分析、¹H-NMR、¹³C-NMR、MS结构确证。

Chemical synthesis of a new antidiabetic drug tripeptide Diapin

Objective: Using the chemical method to synthesize tripeptide Diapin (glycyl-glycyl-leucine,GGL) and those applicable for the formula (glycyl) n-leucine polypeptide including their L-and D-configurations.Solid and liquid phase methods need group protection and deprotection,as well as followed lysis and liquid phase HPLC preparation,which are high cost and complicated in operation. Methods: Leucine and chloroacetyl chloride were used as the starting materials for acylation. The glycyl leucine chlorinated dipeptide was formed,and then was aminolyzed using ammonia water solution to form glycyl leucine dipeptide. The dipeptide was reacted with chloroacetyl chloride by acylation reaction to generate glycyl-glycyl-leucine chlorinated tripeptide,which was then further aminolyzed using Urotropine ammonia solution to obtain glycyl-glycyl-Leu tripeptide. Results: The total yield was 56% calculated by leucine and purity by HPLC was 99. 8%. Conclusion: The D-and L-configurations of the tripeptides were synthesized by the developed chemical method,including Diapin and those applicable for the structure (glycyl) n-leucine. The chemical method is easier than solid-phase and liquid-phase methods,of which the raw materials are easy to obtain,the yield is high,and the industrial production is operatable. The structure of the product was confirmed by elemental analysis,1H-NMR,13C-NMR and MS.