Improved synthesis process for the diabetes drug troglitazone succinate: minimizing impurity generation

Troglitazone succinate, a new oral DPP-4 inhibitor developed by Takeda Pharmaceuticals, has been approved for the treatment of type II diabetes in Japan on March 26, 2015.
　　The activity data showed that troglitazone succinate inhibited DPP-4 more effectively than Alogliptin, another type II diabetes drug developed by Takeda Pharmaceuticals, and Sitagliptin (trade name: Genovel), a heavyweight hypoglycemic drug owned by Merck Sharp & Dohme, and, moreover, the selectivity of the drug was excellent.
　　It is because of the unique therapeutic effect and good market prospect of troglitazone succinate that pharmaceutical researchers have been improving its preparation process and developing new preparation processes.

Figure 1 Synthesis process of troglitazone succinate




　　Takeda Pharmaceutical's synthetic process for troglitazone succinate is shown in Figure 1. The route is based on 4-fluoro-2-methylbenzonitrile as the starting material, and compound 3 is obtained after bromination; compound 3 can be condensed with intermediate 6 to obtain compound 4, and further condensed with compound 7 to obtain troglitazone, which can be successfully prepared by further acidification and recrystallization of troglitazone succinate.

Figure 2 Synthesis of compounds 8-11
　　Researchers noted that the nucleophilic substitution step is key to obtain high regioselectivity for the reaction. For the condensation of compound 4 with compound 7, in order to avoid the formation of the regional isomer 8 (Figure 2), some researchers had reported in 2016 an optimization improvement study of this step using N-protected compound 7 condensed with compound 4, but it was difficult to avoid the formation of by-products such as cyanohydrolysis products during deprotection. In the new study, the researchers optimized the conditions of several steps, including this step.
　　In previous reports, the initial raw material 2 was reacted with 1 equivalent of 1,3-dibromo-5,5-dimethylethanoylurea in DCE solvent to give mainly product 3', which was then stripped of one molecule of HBr under diethyl phosphite, DIPEA conditions to give compound 3. In the improved process, the researchers successfully replaced a class of toxic solvents, DCE, with a benign solvent, DCM, and by adjusting the equivalents, etc., to achieve the one-pot preparation of compound 3. Subsequently, the researchers studied the nucleophilic substitution more systematically, and the impurities formed in this step are mainly compound 8, compound 9 and compound 10 shown in Figure 2; when the protonic solvent (MeOH, EtOH, i-PrOH or DMF) is used for this reaction, impurities 11a-11d are formed. to better study these impurities, the researchers also synthesized them specifically (Figure 2).