Dnyanadeo J. Kesarkar, B. Kashid, Sunil S. Sukthankar
Mar 4, 2021
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Organic Preparations and Procedures International
Abstract
Pyrazole and its derivatives continue to be subjects of considerable importance due to their wide spectrum of biological applications. For example, the Type 2 Diabetes (T2D) drug Teneligliptin hydrobromide incorporates a 1,3,5-substituted pyrazole moiety. Teneligliptin (I, Figure 1) was marketed under the trade name of Tenelia and approved in Japan in 2012 for treatment of T2D. Teneligliptin has been wellreceived in the market, so synthetic chemists have focused considerable attention on the designing of new economical routes to produce this drug at scale while still meeting stringent quality requirements. The original synthetic route is certainly suitable for the production of gram quantities of the desired drug with the required quality; however, the need for timely and economical manufacture of this active pharmaceutical ingredient on multi-kilogram scale in the appropriate purity motivated us towards the development of a new route. Crucial to this is the preparation of 5-piperazine pyrazole derivative (6, Scheme 1), an improved method for which is the subject of this report. An examination of the available literature shows that prior preparations of 6 have had such drawbacks as the instability of starting materials, use of expensive catalysts, or the commercial unavailability of reactants. In particular, the use of alkoxycarbonyl protecting groups leads to formation of impurities and decreased yield. In the same vein, there are also serious safety considerations, particularly with scale-up in mind. In our view, an important consideration for the preparation of 6 is the protection of the piperazine moiety with a methyl or benzyl group (Scheme 1). Our synthesis of 6 begins with commercially available 1-methylor 1-benzylpiperazine, 1 or 1’, respectively. In the first stage, a solution of t-butyl acetoacetate in refluxing toluene is prepared. Using a Dean-Stark apparatus for the removal of generated t-butanol, slow addition of N-methylpiperazine produces ketoamide 2 (95%) (or 2’ for the benzylic case). The ketoamide is then treated with phenylhydrazine hydrochloride to obtain compound 3 (or 3’) as its hydrochloride salt. Compound 3 is then cyclized with POCl3 to obtain the protected pyrazole 4 (or 4’). The protected pyrazole is treated with ethyl