Original articleSynthesis of the major isomers of Aprepitant and Fosaprepitant
Graphical abstract
The synthesis of two isomers of Aprepitant and three isomers of Fosaprepitant is described. The detailed information reported herein can provide a good reference for quality control in manufacturing.
Introduction
Aprepitant (APT) and its prodrug, Fosaprepitant (FPT), are both potent antiemetic drugs and are well-known in the class of non-peptide antagonists to the tachykinin neurokinin NK1 receptor [1]. They also exhibit other widespread therapeutic activities. Aprepitant has been approved by the U.S. FDA in 2003, under the name “Emend”, for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) [2]. In 2008, Fosaprepitant dimeglumine was developed as a prodrug for injection [3].
The molecular structures of Aprepitant, chemically 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]-3-(4-fluoroprenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one, and Fosaprepitant are shown in Fig. 1. Three chiral centers in their structures lead to eight isomers. Therefore, it is essential to synthesize these diastereomers involved in synthetic routes for further research.
To the best of our knowledge [4], [5], [6], the most efficient and environmental route to synthesize Aprepitant and Fosaprepitant is shown in Scheme 1.
This route involves two typical classical steps: converting the chiral center of compound 3 under strong base to get 4, and then adding the 4-fluorobenzyl group to the amide bond to afford 5 via Grignard addition. Utilizing HPLC analysis, it is not difficult to determine that there are three major diastereomers in the final product of Aprepitant as shown in Fig. 2.
The formation of these three isomers was investigated. When the optical purity of the key starting material 2 is not high enough, the enantiomer SSR-APT in the final product begins to appear and is very difficult to remove. As shown in Scheme 2, the RSR-APT results from the impurity 6, which is an incompletely converted product when the chiral center is changed to yield 4. The last RRR-APT isomer results mainly from the Grignard reaction, in which hydrogenation occurred followed by the formation of the imine at room temperature in high stereo selectivity. However, we found that an increase in temperature leads to the increased RRR-APT during the reaction.
Section snippets
Experimental
Those impurities in Fig. 2 are minor byproducts in the reaction, and difficult to purify by column chromatography. Gangula et al. have reported the synthesis of RRR-APT [7]. Herein, we design an efficient route to synthesize the other two impurities. As shown in Scheme 3, the coupling of 7 and 9 in acetic acid gives a mixture of 10 and its enantiomer. Upon heating this mixture in an isopropyl acetate solution of hydrogen chloride, the isomer is successfully transformed into 10 as its
Results and discussion
Gangula et al. reported a route to synthesize SSR-APT and RSR-APT using 1-(3,5-bis(trifluoromethyl)phenyl)ethanone as the starting material [7]. Apparently, this achiral material resulted in a complex mixture of four optical isomers, which was then directly employed to synthesize RRR-APT in five steps. The minor byproduct in the preparation of RRR-APT was purified by preparative HPLC and then used to synthesize the key intermediates 13 and 14 which were the starting materials to yield SSR-APT
Conclusion
In summary, we report two major isomers of Aprepitant describing their formation and the method of synthesis in high yield and the first report involving the study of the isomers of Fosaprepitant. All the target compounds were confirmed by elemental analyses, IR, NMR and MS data analysis [12]. All of the investigations are essential and important for quality control in manufacturing.
Acknowledgment
We would like to express our gratitude for financial support from Sichuan provincial science and technology support program (No. 2011SZ0014).
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