Improvement On The Synthetic Process Of The Antidiabetic Drugs Linagliptin

With the improvement of living standards,the incidence of diabetes is rising,and it is becoming one of the main killers leading to people's death.At present,effective treatment methods mainly depend on oral medicines.Some new hypoglycemic drugs with excellent characteristics are gradually coming into people's vision.Linagliptin plays an important role in the market of hypoglycemic drugs because of its good hypoglycemic effect,less adverse reactions and normal use of patients with liver and kidney dysfunction.The synthetic method of linagliptin has also attracted the attention of chemical workers.Its basic patent will expire in2023.There are some shortcomings in the synthetic methods reported in the literature,so it is necessary to develop a more simple and reasonable synthetic process suitable for industrial production.In this paper,starting from the synthesis of 2-chloromethyl-4-methylquinazoline and 8-bromo-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1H-Purine-2,6-dione is a useful synthetic intermediate,two important intermediates involved in the synthesis of linagliptin.The existing process was improved and a new synthetic route was designed.At the same time,the reaction conditions of each step were optimized.And on this basis,the synthesis process of the target product was explored and the reaction conditions were optimized.Firstly,methyl urea was used as raw material to condensate and cyclize with ethyl cyanoacetate,then 3-methylxanthine was obtained by nitrification,reduction and cyclization.Finally,8-bromo-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1H-Purine-2,6-dione was obtained by bromination and substitution.The total yield of six steps is about 41.2%.Secondly,o-aminoacetophenonewas synthesized from o-nitrobenzoic acid by acyl chlorination,substitution,hydrolysis and reduction.Finally,2-chloromethyl-4-methylquinazoline was synthesized by cyclization.The total yield of five steps is about 42.9%.In addition,the method of preparing o-nitroacetophenone from o-nitrobenzoic acid has been deeply explored.The yield of the improved method has been significantly improved.The method has certain substrate universality and can be used for preparing many acetophenone compounds which are not easy to obtain.Finally,the two intermediates were subjected to a substitution reaction,followed by substitution with(R)-3-Boc-aminopiperidine,and the target product linagliptin was obtained.The total yield of three steps is about 44.2%.The target products and the intermediates involved were confirmed by~1H NMR,IR and MS.The obtained spectra were consistent with the structural characteristics of the related compounds.