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𝗥𝗲𝗽𝗹𝗶𝗰𝗮𝘁𝗶𝗼𝗻 𝗼𝗳 𝘁𝗵𝗲 𝗥𝗲𝗽𝗼𝗿𝘁𝗲𝗱 𝗦𝘆𝗻𝘁𝗵𝗲𝘀𝗶𝘀 𝗥𝗼𝘂𝘁𝗲 𝗼𝗳 𝗢𝗫𝟮𝗥 𝗠𝗼𝗱𝘂𝗹𝗮𝘁𝗼𝗿

ChemAIRS examined the synthesis of an OX2R modulator, specifically focusing on compound 29 from Vertex Pharmaceuticals’ patent. The synthesis involved two key intermediates, 13a and 13b, with 13a being commercially sourced (Scheme 1).

The pathway to 13b closely follows the method described by Vertex Pharmaceuticals, where the precursor cyclohexanol 5b was stereoselectively obtained via ketone 4a reduction. A crucial chirality-inducing step included the reduction of Boc-amino pyridine (9a) to Boc-amino piperidine (10a), producing a racemic mixture subsequently resolved via chiral chromatography.

𝘐𝘯 𝘵𝘩𝘦 𝘧𝘪𝘯𝘢𝘭 𝘴𝘺𝘯𝘵𝘩𝘦𝘵𝘪𝘤 𝘴𝘵𝘦𝘱, 𝘊𝘩𝘦𝘮𝘈𝘐𝘙𝘚 𝘳𝘦𝘤𝘰𝘮𝘮𝘦𝘯𝘥𝘦𝘥 𝘢 𝘥𝘪𝘳𝘦𝘤𝘵 𝘰𝘯𝘦-𝘴𝘵𝘦𝘱 𝘴𝘺𝘯𝘵𝘩𝘦𝘴𝘪𝘴 𝘵𝘰 𝘵𝘩𝘦 𝘧𝘪𝘯𝘢𝘭 𝘤𝘰𝘮𝘱𝘰𝘶𝘯𝘥 𝘶𝘴𝘪𝘯𝘨 𝘵𝘩𝘦 𝘤𝘰𝘮𝘮𝘦𝘳𝘤𝘪𝘢𝘭𝘭𝘺 𝘢𝘷𝘢𝘪𝘭𝘢𝘣𝘭𝘦 3-(𝘣𝘳𝘰𝘮𝘰𝘮𝘦𝘵𝘩𝘺𝘭)𝘰𝘹𝘦𝘵𝘢𝘯𝘦-3-𝘤𝘢𝘳𝘣𝘰𝘯𝘪𝘵𝘳𝘪𝘭𝘦 (13𝘢), 𝘪𝘯 𝘤𝘰𝘯𝘵𝘳𝘢𝘴𝘵 𝘵𝘰 𝘢 𝘱𝘳𝘦𝘷𝘪𝘰𝘶𝘴 𝘵𝘩𝘳𝘦𝘦-𝘴𝘵𝘦𝘱 𝘱𝘳𝘰𝘤𝘦𝘴𝘴 𝘴𝘵𝘢𝘳𝘵𝘪𝘯𝘨 𝘧𝘳𝘰𝘮 3-(𝘩𝘺𝘥𝘳𝘰𝘹𝘺𝘮𝘦𝘵𝘩𝘺𝘭)𝘰𝘹𝘦𝘵𝘢𝘯𝘦-3-𝘤𝘢𝘳𝘣𝘰𝘯𝘪𝘵𝘳𝘪𝘭𝘦. Additionally, to offer a more economical path to obtain 13a, ChemAIRS proposed a cost-effective synthetic route for 13a as depicted in Scheme 2.

𝗣𝗿𝗼𝗽𝗼𝘀𝗶𝗻𝗴 𝗔𝗹𝘁𝗲𝗿𝗻𝗮𝘁𝗶𝘃𝗲 𝗦𝘆𝗻𝘁𝗵𝗲𝘁𝗶𝗰 𝗦𝘁𝗿𝗮𝘁𝗲𝗴𝗶𝗲𝘀 𝗳𝗼𝗿 𝗢𝗫𝟮𝗥 𝗠𝗼𝗱𝘂𝗹𝗮𝘁𝗼𝗿

ChemAIRS not only identified a synthetic route similar to previously reported methods but also proposed alternative strategies for synthesizing the final API, as illustrated in Schemes 3 and 4. Scheme 3 outlines the synthesis of two chiral molecules, 9a and 9b, from commercially available precursors, which are then condensed to form 10a and further processed to yield the key intermediate 12b. Scheme 4 describes the synthesis of chiral 4-phenylcyclohexanol 2a in a single step, followed by its reaction with bromo-pyridine 2b and subsequent reduction of an additional aromatic ring, leading to the formation of chiral piperidinyl carbamate 5a.
𝘊𝘩𝘦𝘮𝘈𝘐𝘙𝘚 𝘢𝘭𝘴𝘰 𝘴𝘶𝘨𝘨𝘦𝘴𝘵𝘦𝘥 𝘷𝘢𝘳𝘪𝘰𝘶𝘴 𝘴𝘵𝘳𝘢𝘵𝘦𝘨𝘪𝘦𝘴 𝘧𝘰𝘳 𝘴𝘺𝘯𝘵𝘩𝘦𝘴𝘪𝘻𝘪𝘯𝘨 𝘢 𝘮𝘢𝘤𝘳𝘰𝘤𝘺𝘤𝘭𝘪𝘤 𝘮𝘰𝘭𝘦𝘤𝘶𝘭𝘦, such as the condensation of 11a to produce 12b (Scheme 3) or the intramolecular etherification of 7a to yield 8a (Scheme 4).

In summary, #ChemAIRS excels in providing synthetic pathways consistent with established methodologies and proposing innovative, practical alternatives. This versatility enables chemists to explore new synthetic avenues, facilitating accelerated innovation in the lab and positioning ChemAIRS as a valuable resource for advancing chemical research and development.