Studies On The Synthesis Of Vildagiptin And Its Anologues As Dipeptidyl Peptidase Ⅳ Inhibitors

Recently, the prevalence of diabeties has increased dramatically and become to the third death factor inferior to cardiovascular disease and tumor. Some new antidiabetic drugs with high efficiency and low toxicity were developed for clinic application during the past few years. DPP-Ⅳinhibitors as a new kind of antidiabetic drugs have attracted an extensive attention in recent years, and Vildagliptin is the representative drug of DPP-Ⅳinhibitors in clinic.This article summarized the research progresses on the antidiabetic drugs, especially on the synthesis of DPP-Ⅳinhibitors firstly and then a pratical synthesis for Vildagliptin was developed by two synthetic routes. According to the SAR for Vildagliptin analogues, five novel compounds were designed and synthesized. The main contents of this paper are as follws:1.3-amino-l-adamantanol is an important intermediate in this synthetic route. After comparing the routes in literatures, this synthetic route was chosed and improved as:1-adamantylamine-HC1 as starting material, after nitrated, treated by alkali to give the important intermediate 1-Aminoadamantane-3-o1 with 72% yield. It is suitable for large-scale preparation.2. In this paper, 1-(2-chloroacetyl)-2-(S)-cyanopyrrolidine was synthesized by two different routes. Route one involves the reaction of the L-proline was treated by ammonia first, then reacted with a slight molar excess of chloroacetyl chloride to give 1-(2-chloroacetyl)-2-(S)-pyrrolidinamide. And then 1-(2-chloroacetyl)-2-(S)-cyanopyrrolidine was synthesized by dehydration in the presence of trifluoroacetic acid. Route two is to use L-proline as starting material. L-proline was N-acylated with chloroacetyl chloride to afford 1-(2-chloroacetyl) pyrrolidine-2-(S)-carboxylic acid, then treated with dicyclohexylcarbodiimide, to give 1-(2-chloroacetyl)-2-(S)-cyanopyrrolidine. In conclusion, we have demonstrated an alternative and practical route for the systhesis of 1-(2-chloroacetyl)-2-(S)-cyanopyrrolidine, a key intermediate for the synthesis of DPP-Ⅳinhibitor,starting from less expensive and readily available L-proline.3. Vildagliptin was prepared by treating 1-(2-chloroacetyl)-2-(S)-cyanopyrrolidine with 3-amino-1-adamantanol in THF with on the basis of the patent reported procedures. It is suitable for a large scale preparation.4. In the proccess of designing the target compounds, the two molecules of Vildagliptin and N-acylpiperazine applied in clinic were dissected and hybrided. In the end the frame segment 1-(2-chloroacetyl)-2-(S)-cyanopyrrolidine was preserved, piperazine ring and amide bond was introduced. Vildagliptin analogues. The structural modification of compounds included two aspects: changing the substituted groups on the aromatic ring and changing the connecting chain between the aromatic ring and piperazine. The substituted groups on the aromatic ring include methoxy, chloride, methyl, nitro group and so on. Therefore, five target compounds were synthezied, and confirmed by IR,1HNMR and ESI-MS.5. The target compounds were achieved by the reation between N-acylpiperazine and 1-(2-chloroacetyl)-2-(S)-cyanopyrrolidine. N-acylpiperazine were gotten by the treatment of acyl chloride and piperazine in the acetic acid at 0-10℃. By controlling the reaction conditions to ensure that the product of N-acylpiperazine yield and reduce the production of biacylpiperazine. This process was optimized in this article. Further biological evaluation and structural optimizing of Vildagliptin derivatives are currently underway in our laboratories and collaboration group.