How was the Small Molecule Apixaban with Annual Sales of Nearly USD10 Billion “Tempered”?

As an oral, direct coagulation factor Xa inhibitor developed by BMS and Pfizer, Eliquis (apixaban) was first approved for marketing in May 2011 in the EU and mainly used for the prophylaxis of venous thromboembolism in patients who have undergone hip or knee replacement. From the perspective of function characteristic, Eliquis is highly selective for coagulation factor Xa, with the binding reversible, and can produce the antithrombotic effect without antithrombin III; and no dose adjustment of Eliquis is required in patients with mild or moderate hepatic impairment owing to its diverse metabolic pathways in bodies. In terms of thromboembolism prevention, the clinical effects of Eliquis are significantly superior to those of enoxaparin and aspirin, and Eliquis has higher safety. Thanks to the huge market demands for anticoagulant, Eliquis reached sales of nearly USD10 billion in 2018, ranking top of sales of the small molecule and macromolecular drugs.

Fig. 1 Structural Formula of Eliquis (Apixaban)

As a star marketed drug molecule with annual sales approaching USD10 billion, the preparation method of Eliquis is certainly chased after by the pharmaceutical enterprises and researchers. Now, let’s see the main synthesis process of Eliquis (apixaban).

Fig. 2 Analysis of Synthesis of Eliquis (Apixaban)

As shown in Fig. 2, the synthetic strategy of Eliquis is generally: condense the intermediates 3 and 4 to obtain the intermediate 2, then convert the ester in 2 into amide to obtain the target product 1. In these routes, the condensation condition of the intermediates 3 and 4, the selection of the intermediate 4, and the sequence of each reaction on the reaction route are keys for route optimization.

Fig. 3 Original Process of BMS

Fig. 3 shows the original process reported by BMS. The route took p-iodoaniline and 5-bromovaleryl chloride as the raw materials to react to obtain the intermediate 5a, then used phosphorus pentachloride for chlorination to obtain the intermediate 6a, which was then coupled with morpholine to obtain the intermediate 7a, which was then condensed with the compound 3 to obtain the intermediate 8a, which was then condensed with piperidone to obtain the key precursor 2, and finally, converted the ester in 2 into amide to obtain the target product 1.

According to researchers, the defects of this original process route were that: A. An excess of morpholine should be used in the process of converting 6a to 7a; B. The yield in the condensation of 8a and piperidone was only 21%. Those shortcomings restricted the mass preparation of Eliquis.

Fig. 4 Early Process Improvement

As a result, many process developers including researchers of BMS had been exploring an efficient synthetic process of Eliquis, including realizing route shortening through Approach B process, to adjust the reaction sequence (Approach C) to increase the yield. The method shown in Approach D used p-nitroaniline as the starting material, involving two reactions with 5-Chlorovaleryl chloride. However, those processes had some problems difficult to avoid, such as the introduction of caprolactam bringing challenges to impurity control; the formation step of caprolactam possibly producing the genotoxic impurity: 5-chloro-N-phenyl pentanamides.

Fig. 5 First-Generation Eliquis Synthetic Process without Caprolactam Formation

To avoid the above problems, researchers developed the Eliquis synthetic process without caprolactam formation. As shown in Fig. 5, researchers directly used caprolactam as a raw material; they first used phosphorus pentachloride for halogenation to obtain the intermediate 10; then obtained the intermediate 11 under the action of lithium carbonate; condensed the intermediate 11 and morpholine to obtain the compound 12; then condensed it with the intermediate 3 to obtain the intermediate 13; then removed morpholine from it to obtain the intermediate 14, condensed the intermediate 14 and 5a to obtain the key precursor compound 2, and finally converted ester in compound 2 to amide bond to obtain the target product.

However, we can see from the route in Fig. 5 that the yields of the first steps of the route were not high (separately 66%, 62%, 43%, and 65% in the first four steps), and the introduction and removal of morpholine made the reaction route become lengthy. Therefore, based on the above, researchers further developed the second-generation Eliquis synthetic process without caprolactam formation.

Fig. 6 Second-generation Eliquis Synthetic Process without Caprolactam Formation

The second-generation Eliquis synthetic process without caprolactam formation is as shown in Fig. 6, where researchers optimized the synthesis of the intermediate 11, to greatly increase the yield of each step. Furthermore, researchers explored the direct condensation of the intermediate 11 and intermediate 3 to obtain 14, to avoid the connection and removal of morpholine, which successfully simplified the reaction steps and increased the yields. Healthcare supply companies also made a great contribution to it.

Fig. 7 Other Xa Inhibitors Marketed

With the annual sales of USD10 billion, Eliquis (apixaban) is a well-deserved star molecule. Others marketed in the coagulation factor Xa inhibitor market include fondaparinux, rivaroxaban, edoxaban tosilate, and the newly marketed betrixaban (Fig. 7). Eliquis (apixaban) is a strong performer among the coagulation factor Xa inhibitors; the further successful development of its preparation process will bring cost and efficiency benefits to enterprises and indirectly benefit the patients.

References:

1. A morpholine-free process amenable convergent synthesis of apixaban: a potent factor Xa inhibitor，Monatsh Chem；

2. Thomson数据库；

3. Thomson Database;

4. FDA：https://www.fda.gov/media/84943/download

About  the Author:    

Yuntian, Ph.D. in medicinal chemistry, is mainly engaged in small molecule drug research, especially good at small molecule drug synthesis process and later stage drug development research. He has completed the synthesis and activity evaluation of multiple anti-cancer drug molecules. 

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