{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T14:27:59Z","timestamp":1762957679776,"version":"build-2065373602"},"reference-count":26,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T00:00:00Z","timestamp":1755129600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["23-90-04000"],"award-info":[{"award-number":["23-90-04000"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Several approaches to the synthesis of risdiplam, a pharmacologically relevant pyridopyrimidinone derivative, have been recently reported. However, most of these routes rely exclusively on palladium-catalyzed, cross-coupling reactions and involve low-yielding intermediates, which limit their scalability and complicate impurity control. In this work, we present a five-step, straightforward route to risdiplam, utilizing ethyl 2,8-dimethylimidazo[1,2-b]pyridazine-3-carboxylate\u2014an accessible and cost-effective building block previously developed by our research group\u2014as a starting material. The key step involves construction of the 4H-pyrido[1,2-a]pyrimidin-4-one scaffold via a copper(I)-catalyzed heterocyclization reaction. This represents a novel and convenient protocol for the synthesis of 2-(2,8-dimethylimidazo[1,2-b]pyridazin-6-yl)-7-fluoro-4H-pyrido[1,2-a]pyrimidin-4-one, which serves as a crucial intermediate in the final stages of risdiplam synthesis. The overall process allows us to obtain the target compound with a 20% total yield (from abovementioned starting material) and high purity (99.86%, by HPLC-UV), with a maximum level of unidentified impurities not exceeding 0.046%. The developed approach eliminates the use of palladium catalysis and chromatographic purification, offering a practical and scalable alternative for risdiplam production.<\/jats:p>","DOI":"10.3390\/molecules30163375","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T15:16:37Z","timestamp":1755184597000},"page":"3375","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Convenient, Pd-Free Approach to the Synthesis of Risdiplam"],"prefix":"10.3390","volume":"30","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8365-6942","authenticated-orcid":false,"given":"Georgiy","family":"Korenev","sequence":"first","affiliation":[{"name":"Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy Ave. 1, 354340 Sirius, Krasnodar Region, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1034-9033","authenticated-orcid":false,"given":"Alexey A.","family":"Gutenev","sequence":"additional","affiliation":[{"name":"Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy Ave. 1, 354340 Sirius, Krasnodar Region, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0843-3742","authenticated-orcid":false,"given":"Fyodor V.","family":"Antipin","sequence":"additional","affiliation":[{"name":"Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy Ave. 1, 354340 Sirius, Krasnodar Region, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1347-4398","authenticated-orcid":false,"given":"Vladimir V.","family":"Chernyshov","sequence":"additional","affiliation":[{"name":"Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy Ave. 1, 354340 Sirius, Krasnodar Region, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1554-1523","authenticated-orcid":false,"given":"Julia A.","family":"Shulgina","sequence":"additional","affiliation":[{"name":"Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy Ave. 1, 354340 Sirius, Krasnodar Region, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9807-7783","authenticated-orcid":false,"given":"Maria P.","family":"Korobkina","sequence":"additional","affiliation":[{"name":"Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy Ave. 1, 354340 Sirius, Krasnodar Region, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5432-1326","authenticated-orcid":false,"given":"Maxim B.","family":"Nawrozkij","sequence":"additional","affiliation":[{"name":"Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy Ave. 1, 354340 Sirius, Krasnodar Region, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9573-4183","authenticated-orcid":false,"given":"Roman A.","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy Ave. 1, 354340 Sirius, Krasnodar Region, Russia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2120","DOI":"10.1016\/S0140-6736(08)60921-6","article-title":"Spinal Muscular Atrophy","volume":"371","author":"Lunn","year":"2008","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1038\/nrn2670","article-title":"Spinal Muscular Atrophy: Why Do Low Levels of Survival Motor Neuron Protein Make Motor Neurons Sick?","volume":"10","author":"Burghes","year":"2009","journal-title":"Nat. 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