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Astrazeneca and Mitsubishi Tanabe Pharma Corporation have developed AZD5462, a small-molecule mimetic of relaxin H2 signaling at RXFP1, offering promise as a treatment for heart failure.

𝐎𝐩𝐭𝐢𝐦𝐢𝐳𝐢𝐧𝐠 𝐒𝐲𝐧𝐭𝐡𝐞𝐭𝐢𝐜 𝐏𝐚𝐭𝐡𝐰𝐚𝐲𝐬 𝐟𝐨𝐫 𝐀𝐙𝐃𝟓𝟒𝟔𝟐: 𝐂𝐡𝐞𝐦𝐀𝐈𝐑𝐒' 𝐏𝐫𝐞𝐝𝐢𝐜𝐭𝐢𝐯𝐞 𝐚𝐧𝐝 𝐒𝐜𝐚𝐥𝐚𝐛𝐥𝐞 𝐒𝐨𝐥𝐮𝐭𝐢𝐨𝐧𝐬

The 19-step synthetic route generated by ChemAIRS (Scheme 1) 𝑐𝑙𝑜𝑠𝑒𝑙𝑦 𝑝𝑎𝑟𝑎𝑙𝑙𝑒𝑙𝑠 the strategy outlined by Astrazenecain 2022 (WO2022/122773), utilizing four key intermediates. Notably, ChemAIRS proposed efficient synthetic routes for preparing one of the critical building blocks, 𝑒𝑙𝑖𝑚𝑖𝑛𝑎𝑡𝑖𝑛𝑔 𝑡ℎ𝑒 𝑛𝑒𝑒𝑑 𝑓𝑜𝑟 𝑐𝑜𝑚𝑚𝑒𝑟𝑐𝑖𝑎𝑙 𝑝𝑟𝑜𝑐𝑢𝑟𝑒𝑚𝑒𝑛𝑡.

In addition to replicating the reaction conditions specified in the AstraZeneca's patent for the amide coupling to synthesize 19a (DMF, DIPEA, HATU), ChemAIRS identified an alternative "𝑠𝑐𝑎𝑙𝑒-𝑢𝑝 𝑓𝑟𝑖𝑒𝑛𝑑𝑙𝑦" protocol using DIPEA, EDCI, HOBt (Figure 1).

While the literature method does not address potential side reactions, ChemAIRS 𝑑𝑒𝑡𝑒𝑐𝑡𝑒𝑑 𝑎 ℎ𝑖𝑔ℎ-𝑟𝑖𝑠𝑘 𝑠𝑖𝑑𝑒 𝑟𝑒𝑎𝑐𝑡𝑖𝑜𝑛 associated with the synthesis of 19a (Figure 2). This predictive capability 𝑝𝑟𝑜𝑣𝑖𝑑𝑒𝑠 𝑐ℎ𝑒𝑚𝑖𝑠𝑡𝑠 𝑤𝑖𝑡ℎ 𝑎𝑑𝑣𝑎𝑛𝑐𝑒𝑑 𝑤𝑎𝑟𝑛𝑖𝑛𝑔 𝑎𝑛𝑑 𝑠𝑢𝑝𝑝𝑜𝑟𝑡𝑠 𝑡ℎ𝑒 𝑑𝑒𝑣𝑒𝑙𝑜𝑝𝑚𝑒𝑛𝑡 𝑜𝑓 𝑟𝑜𝑏𝑢𝑠𝑡 𝑐𝑜𝑛𝑡𝑖𝑛𝑔𝑒𝑛𝑐𝑦 𝑠𝑡𝑟𝑎𝑡𝑒𝑔𝑖𝑒𝑠.

𝐀𝐥𝐭𝐞𝐫𝐧𝐚𝐭𝐢𝐯𝐞 𝐒𝐲𝐧𝐭𝐡𝐞𝐭𝐢𝐜 𝐀𝐩𝐩𝐫𝐨𝐚𝐜𝐡 𝐭𝐨 𝐀𝐙𝐃𝟓𝟒𝟔𝟐

Scheme 4 illustrates an alternative synthetic strategy for the preparation of AZD5462, in which our system proposes modified approaches for constructing the key intermediates, 7a and 7b. Notably, these routes reduce the overall step count compared to the previously described pathway in Scheme 1. Specifically, the two-step synthesis of 7b begins with an oxidative hydroxylation of arylboronic acid 1a, followed by a coupling reaction with benzyl alcohol. Furthermore, unlike the sequence presented in Scheme 1, ChemAIRS 𝑟𝑒𝑐𝑜𝑚𝑚𝑒𝑛𝑑𝑠 𝑝𝑒𝑟𝑓𝑜𝑟𝑚𝑖𝑛𝑔 𝑡ℎ𝑒 𝑎𝑚𝑖𝑑𝑒 𝑐𝑜𝑢𝑝𝑙𝑖𝑛𝑔 𝑎𝑠 𝑡ℎ𝑒 𝑓𝑖𝑛𝑎𝑙 𝑠𝑡𝑒𝑝. This adjustment aims to mitigate the risk of the side reaction depicted in the first proposed synthetic pathway.

In summary, ChemAIRS empowers chemists to optimize synthesis strategies by 𝑒𝑓𝑓𝑖𝑐𝑖𝑒𝑛𝑡𝑙𝑦 𝑝𝑟𝑜𝑝𝑜𝑠𝑖𝑛𝑔 𝑠𝑦𝑛𝑡ℎ𝑒𝑡𝑖𝑐 𝑟𝑜𝑢𝑡𝑒𝑠, 𝑖𝑑𝑒𝑛𝑡𝑖𝑓𝑦𝑖𝑛𝑔 𝑝𝑜𝑡𝑒𝑛𝑡𝑖𝑎𝑙 𝑠𝑖𝑑𝑒 𝑟𝑒𝑎𝑐𝑡𝑖𝑜𝑛𝑠, 𝑎𝑛𝑑 𝑠𝑢𝑔𝑔𝑒𝑠𝑡𝑖𝑛𝑔 𝑠𝑐𝑎𝑙𝑎𝑏𝑙𝑒 𝑎𝑙𝑡𝑒𝑟𝑛𝑎𝑡𝑖𝑣𝑒 𝑐𝑜𝑛𝑑𝑖𝑡𝑖𝑜𝑛𝑠. Its advanced predictive capabilities, including risk assessment for critical reactions, enable researchers to proactively address challenges in route development while minimizing reliance on external resources.