Study On Synthetic Processes Of Vildagliptin

Vildagliptin is the first in a new class of anti diabetic agents known as dipeptidyl peptidase IV inhibitors(DPP-IV). It leads to a reduction in elevated blood glucose levels that is a characteristic feature of type 2 diabetes. This work is aimed at optimizing and improving the synthesis route of vildagliptin. The intermediate products and target compounds were characterized by MS,1H NMR, IR. In this paper, the reaction mechanism was discussed partly.In the first step, (S)-1-(2-Chloroacetyl)pyrrolidine-2-carbon acid was synthesized from L-proline via reaction with chloro-acetyl chloride. The optimum synthesis condition: n(L-proline):n(chloroacetyl chloride)=1:1.35, the reaction time was 4 h without acid scavenger, at 65℃, with 88.7% yield. This step saved the cost of the reaction and improved the yield.In the second step, (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonacid was ammoniated by 11,’-carbonyldiimidazole with ammonium bicarbonate to (S)-1-(2-chloroacetyl)pyrroli dine-2-carbon amide. The optimum synthesis conditions:n((S)-1-(2-chloroacetyl)pyrroli dine-2-carbonacid):n(CDI)=1:1, n((S)-1-(2-chloroacetyl)pyrrolidine-2-carbonacid):n(am monium bicarbonate)=1:10, the condensation reaction time was 2 h, amination reactio n time was 3h, under room temperature, with 79.0% yield. In this step, CDI as a con densing agent, post-processing is simplified and reaction time was reduced.In the third step, (S)-1-(2-chloroacetyl)pyrrolidine-2-carbon amide was respectively dehydrated by phosphorus oxychloride,trifluoroacetic anhydride or cyanuric chloride to (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. The optimum synthesis conditions:n((S)-1-(2-chloroacetyl)pyrrolidine-2-carbonamide):n(phosphorus oxychloride)=1:3.5,the reac tion time was 3h under ice temperature, with 76.0% yield. In L-proline terms,the yield of (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile was 53.3%. other dehydrating agent was substitute by phosphorus oxychloride, the reaction time was reduced,with a purity of more than 99%.In the fourth step,3-aminoadamantanol was synthesized from 1-adamantanamine hydrochloride by mixed acids, and then was replaced by alkali. The optimum synthesis conditions:n(1-adamantanamine hydrochloride):n(concentrated nitric acid)’ n(concentrated sulfuric acid)=1:2:4, the reaction time was 20h under room temperature. After the completion of nitrification, adjust pH=12, the hydrolysis reaction time was 3 h, at 50℃, with 73.8% yield. This step reduced the amount of mixed acid and the consumption of raw materials, less environmental pollution.The step five was the reaction between 3-aminoadamantanol and (S)-1-(2-chloroac etyl)pyrrolidine-2-carbonitrile to target product vildagliptin. The optimum synthesis con ditions:n((S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile):n(3-aminoadamantanol)=1:1.15, n((S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile):n(K2CO3)=1:3, the reaction time was 5h, at 55℃.the catalyst was KI and acid scavenger was K2CO3.This step,as a catalys t,KI reduced reaction time, the single yield was increased from 70% to 79%. In L-pro line terms, the yield of Vildagliptin was increased from 32% to 42%.