{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T21:49:10Z","timestamp":1792273750297,"version":"4.4.0"},"reference-count":28,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T00:00:00Z","timestamp":1752796800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Russian Science Foundation","award":["23-90-04000"],"award-info":[{"award-number":["23-90-04000"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>In this study, we report for the first time a brand-new protocol for the multigram-scale synthesis of 5-methyl-6-oxo-1,6-dihydropyridazine-3-carboxylic and 2,8-dimethylimidazo[1,2-b]pyridazine-6-carboxylic acids, without the utilization of metal-complex catalysts. The developed technology for the production of the aforementioned acids is of great importance for two reasons. Firstly, these acids serve as intermediates in the synthesis of risdiplam, the first small-molecule drug approved for the treatment of spinal muscular atrophy. Secondly, they themselves are valuable building blocks right from a broader medicinal chemistry perspective. The synthesis of risdiplam was carried out using a modified synthetic protocol, utilizing the acids indicated above as the key intermediates. The protocols presented in this study enable the production of target compounds with high purity and an acceptable yield.<\/jats:p>","DOI":"10.3390\/molecules30143011","type":"journal-article","created":{"date-parts":[[2025,7,18]],"date-time":"2025-07-18T10:10:38Z","timestamp":1752833438000},"page":"3011","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Brand-New Metal Complex Catalyst-Free Approach to the Synthesis of 2,8-Dimethylimidazo[1,2-b]pyridazine-6-Carboxylic Acid\u2014A Key Intermediate in Risdiplam Manufacturing Process"],"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]},{"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":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nishio, H., Niba, E.T.E., Saito, T., Okamoto, K., Takeshima, Y., and Awano, H. (2023). Spinal Muscular Atrophy: The Past, Present, and Future of Diagnosis and Treatment. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241511939"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S1090-3798(99)80015-4","article-title":"Prenatal Onset Spinal Muscular Atrophy","volume":"3","author":"Macleod","year":"1999","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S1090-3798(99)80012-9","article-title":"Very Severe Spinal Muscular Atrophy (SMA Type 0): An Expanding Clinical Phenotype","volume":"3","author":"Dubowitz","year":"1999","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1177\/088307380201700915","article-title":"Severe Spinal Muscular Atrophy Variant Associated With Congenital Bone Fractures","volume":"17","author":"Grohmann","year":"2002","journal-title":"J. Child Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1002\/(SICI)1096-8628(19991105)87:1<65::AID-AJMG13>3.0.CO;2-5","article-title":"Spinal Muscular Atrophy Variant with Congenital Fractures","volume":"87","author":"Kelly","year":"1999","journal-title":"Am. J. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/1750-1172-6-71","article-title":"Spinal Muscular Atrophy","volume":"6","author":"Mercuri","year":"2011","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3877","DOI":"10.1007\/s00018-018-2849-1","article-title":"The Role of Survival Motor Neuron Protein (SMN) in Protein Homeostasis","volume":"75","author":"Chaytow","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Butchbach, M.E.R. (2021). Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22157896"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1465","DOI":"10.1007\/s00415-017-8549-1","article-title":"A Multi-Source Approach to Determine SMA Incidence and Research Ready Population","volume":"264","author":"Verhaart","year":"2017","journal-title":"J. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1146\/annurev-genom-102319-103602","article-title":"Twenty-Five Years of Spinal Muscular Atrophy Research: From Phenotype to Genotype to Therapy, and What Comes Next","volume":"21","author":"Wirth","year":"2020","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Sarv, S., Kahre, T., Vaidla, E., Pajusalu, S., Muru, K., P\u00f5der, H., Gross-Paju, K., \u00dctt, S., \u017dordania, R., and Talvik, I. (2021). The Birth Prevalence of Spinal Muscular Atrophy: A Population Specific Approach in Estonia. Front. Genet., 12.","DOI":"10.3389\/fgene.2021.796862"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1021\/acsmedchemlett.0c00659","article-title":"Risdiplam, the First Approved Small Molecule Splicing Modifier Drug as a Blueprint for Future Transformative Medicines","volume":"12","author":"Ratni","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6501","DOI":"10.1021\/acs.jmedchem.8b00741","article-title":"Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 (SMN2) Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy (SMA)","volume":"61","author":"Ratni","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1021\/bk-2022-1423.ch008","article-title":"Development and Optimization of the Manufacturing Process for RNA-Splicing Modifier Risdiplam RG7916","volume":"Volume 1423","author":"Moessner","year":"2022","journal-title":"ACS Symposium Series"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wang, Z. (2010). Conrad-Limpach Quinoline Synthesis. Comprehensive Organic Name Reactions and Reagents, Wiley.","DOI":"10.1002\/9780470638859"},{"key":"ref_16","unstructured":"Kothakonda, K.K., Pitta, B.R., Namana, S.B., Rangisetty, J.B., and Pullagurla, M.R. (2023). A Novel Process for the Preparation of 7-(4,7-Diazaspiro[2.5]Octan-7-Yl)-2-(2,8 Dimethylimidazo[1,2-b]Pyridazin-6-Yl)Pyrido-4H-[1,2-a]Pyrimidin-4-One with Novel Intermediates. (WO 2024\/003798 A1)."},{"key":"ref_17","unstructured":"Adam, J.-M., Pfleger, C., and Wuitschik, G. (2022). Novel Process. (WO 2022\/194909 A2)."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15063","DOI":"10.1021\/acsomega.0c00877","article-title":"Pyruvate Aldol Condensation Product: A Metabolite That Escaped Synthetic Preparation for over a Century","volume":"5","author":"Rios","year":"2020","journal-title":"ACS Omega"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1021\/ja01583a043","article-title":"Hydrazides of Some Pyridazonyl Substituted Acids","volume":"78","author":"McMillan","year":"1956","journal-title":"J. Am. Chem. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1021\/jo102262k","article-title":"POCl 3 Chlorination of 4-Quinazolones","volume":"76","author":"Arnott","year":"2011","journal-title":"J. Org. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9503","DOI":"10.1039\/C4RA14560G","article-title":"1H\/2H and Azide\/Tetrazole Isomerizations and Their Effects on the Aromaticity and Stability of Azido Triazoles","volume":"5","author":"Yang","year":"2015","journal-title":"RSC Adv."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5071","DOI":"10.1016\/j.tet.2010.04.119","article-title":"The Azido-Tetrazole Tautomerism in Azoles and Its Relationships with Aromaticity and NMR Properties","volume":"66","author":"Alkorta","year":"2010","journal-title":"Tetrahedron"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1007\/s10593-017-2157-y","article-title":"Synthesis and Azido-Tetrazole Tautomerism of 3-Azido-1,2,4-Triazines","volume":"53","author":"Deev","year":"2017","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1007\/s11172-005-0311-7","article-title":"A New Approach to the Synthesis of Lamotrigine and Other 3,5-Diamino-1,2,4-Triazine Derivatives","volume":"54","author":"Ulomskii","year":"2005","journal-title":"Russ. Chem. Bull."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1002\/hlca.19210040192","article-title":"\u00dcber Neue Organische Phosphorverbindungen IV Phosphinimine","volume":"4","author":"Staudinger","year":"1921","journal-title":"Helv. Chim. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.chroma.2006.06.004","article-title":"Determination of Triphenylphosphine Oxide in Active Pharmaceutical Ingredients by Hollow-Fiber Liquid-Phase Microextraction Followed by Reversed-Phase Liquid Chromatography","volume":"1127","author":"Richoll","year":"2006","journal-title":"J. Chromatogr. A"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Zhukovets, A.A., Chernyshov, V.V., Al\u2019mukhametov, A.Z., Seregina, T.A., Revtovich, S.V., Kasatkina, M.A., Isakova, Y.E., Kulikova, V.V., Morozova, E.A., and Cherkasova, A.I. (2023). Novel Hydroxamic Acids Containing Aryl-Substituted 1,2,4- or 1,3,4-Oxadiazole Backbones and an Investigation of Their Antibiotic Potentiation Activity. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010096"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8815","DOI":"10.1021\/acs.joc.5b01137","article-title":"Synthesis of Vinyl Chlorides via Triphosgene\u2013Pyridine Activation of Ketones","volume":"80","author":"Saputra","year":"2015","journal-title":"J. Org. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/14\/3011\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:11:52Z","timestamp":1760033512000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/14\/3011"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,18]]},"references-count":28,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2025,7]]}},"alternative-id":["molecules30143011"],"URL":"https:\/\/doi.org\/10.3390\/molecules30143011","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,18]]}}}