Synthetic Research On The Intermediate Of Trelagliptin Succinate

Trelagliptin succinate, discovered by Takeda California. Inc, is a novel two peptide base IV (DPP-4) inhibitor drug and is used in the treatment of type II diabetes, which was approved by the Ministry of health and welfare of Japan (MHLW) in March 26,2015. The drug can be administered once a week to the drug delivery of small molecule diabetes drugs, through selective, sustained suppression of DPP-4, near and control blood glucose levels.In this paper, we mainly study the reaction route and process optimization of Trelagliptin succinate’s important intermediates Q-2. In order to avoid the side effects, increase the yield and lay the foundation for the future process, we analyzed the side reaction in the reaction process and the structure of the by-product.In this paper, I use malonic acid and N-methyl urea as starting materials for the synthesis of 3-methyl-6-chloro-uracil (Q-5), though the intramolecular condensation reaction and chlorinated reaction,72.1%of the two-step molar yield obtained Q-5; use 2-bromo-5-fluorine toluene as starting materials for the synthesis of 2-cyano-5-fluorine benzyl bromide (Q-7), after the cyanide reaction and bromination reaction,54.7%of the two-step molar yield obtained Q-7; use D-ornithine dihydrochloride as starting materials for the synthesis of 3-aminopyridine dihydrochloride (Q-9), via intramolecular condensation reaction, reduction reaction and acid-base neutralization salt forming reaction, to get Q-951.1%of the third molar yield. Then the three intermediates were three steps of alkylation reaction, substitution reaction and acid base neutralization, and the total molar yield of 50%was obtained Trelagliptin succinate.Two synthetic routes were carried out in the synthesis of Q-2, an important intermediate in the synthesis of Trelagliptin succinate. Line 1:1 put the intermediate Q-4 which is used as a raw material and (R)-3-Boc-aminopiperidine reaction, first get intermediate Q-3 and then get intermediate Q-2 to 71.9%two-step molar yield by deprotection method. Line 2:I put the intermediate Q-4 which is used as a raw material and amino piperidine hydrochloride reaction, get intermediate Q-2 to 86.1%two-step molar yield through a series of screening reaction conditions. Comparing the two lines can be obtained the intermediate Q-2, but amino piperidine dihydrochloride ratio (R)-3-Boc-aminopiperidine price of cheaper and reaction process more simple, the line two is more suitable for the synthesis of Trelagliptin succinate from a technical point of view.