Synthesis, Table of Contents Synthesis 2023; 55(13): 2061-2069DOI: 10.1055/a-2016-4337 paper New, Scalable Process for the Preparation of 5-Acetyl-1H-pyrazole-3-carboxylic Acid, a Key Intermediate of Darolutamide Authors László Poszávácz Tamás Nagy Katalin Kátai-Fadgyas Balázs Volk ∗ Recommend Article Abstract Buy Article(opens in new window) All articles of this category(opens in new window) Dedicated to the memory of late Professor Ferenc Fülöp (1952–2021) Abstract A new, efficient process for the synthesis of 5-acetyl-1H-pyrazole-3-carboxylic acid, a versatile building block and the key intermediate of darolutamide, using diethyl pyrazole-3,5-dicarboxylate as the starting material is described. Contrary to the synthetic routes known from the literature, this procedure does not employ explosive diazo reagents, moreover it is simple and safe, thereby suitable for scale-up. Keywords Keywordsester hydrolysis - regioselectivity - drug substance - key intermediate - safety - scalability Full Text References References 1 Moilanen A.-M, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ. Sci. Rep. 2015; 5: 12007 2 Fizazi K, Albiges L, Loriot Y, Massard C. Expert Rev. Anticancer Ther. 2015; 15: 1007 3 Fizazi K, Shore N, Tammela TL, Ulys A, Vjaters E, Polyakov S, Jievaltas M, Luz M, Alekseev B, Kuss I, Kappeler C, Snapir A, Sarapohja T, Smith MR. N. Eng. J. Med. 2019; 380: 1235 4 Sugawara T, Baumgart SJ, Nevedomskaya E, Reichert K, Steuber H, Lejeune P, Mumberg D, Haendler B. Int. J. Cancer 2019; 145: 1382 5 U.S. Food and Drug Administration (FDA) approves darolutamide, 31 July 2019 (accessed February 20, 2023): https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer. 6 Matsubara N, Mukai H, Hosono A, Onomura M, Sasaki M, Yajima Y, Hashizume K, Yasuda M, Uemura M, Zurth C. Cancer Chemother. Pharmacol. 2017; 80: 1063 7 Wohlfahrt G, Törmäkangas O, Salo H, Hölung L, Karjalainen A, Knuuttila P, Holm P, Rasku S, Vesalainen A. PCT Intern. Pat. Appl. WO 2011051540, 2011 ; Chem. Abstr. 2011, 154, 540477. 8 U.S. Food and Drug Administration (FDA), 9 August 2019 (accessed February 20, 2023): https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-nubeqa 9 FDA Approved Drug Products: NUBEQA (darolutamide) tablets, for oral use 2019 (accessed February 20, 2023): https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/ 212099Orig1s000lbl.pdf 10 Törmäkangas O, Heikkinen T. PCT Intern. Pat. Appl. WO 2016120530, 2016 ; Chem. Abstr. 2016, 165, 247292. 11 Törmäkangas O, Wohlfahrt G, Salo H, Ramasubramanian RD, Patra PK, Martin AE, Heikkinen T, Vesalain A, Moilanen A, Karjalainen A. PCT Intern. Pat. Appl. WO 2012143599, 2012 ; Chem. Abstr. 2012, 157, 634352. 12 Laitinen I, Karjalainen O. PCT Intern. Pat. Appl. WO 2016162604, 2016 ; Chem. Abstr. 2016, 165, 487647. 13 Yu J, Zhou P, Hu M, Yang L, Yan G, Xu R, Deng Y, Li X, Chen Y. Eur. J. Med. Chem. 2019; 182: 111608 14 Semple G, Averbuj C, Skinner P, Gharbaoui T, Shin Y.-J. PCT Intern. Pat. Appl. WO 2004032928, 2004 ; Chem. Abstr. 2004, 140, 357332. 15 Casuscelli F, Brasca MG, Caldarelli M, Cervi G, Disingrini T, Quartieri F. PCT Intern. Pat. Appl. WO 2012139930, 2012 ; Chem. Abstr. 2012, 157, 634390. 16 Lai KW, Liang J, Zhang B, Labadie S, Ortwine D, Gehling VS, Harmange J.-C. PCT Intern. Pat. Appl. WO 2016057924, 2016 ; Chem. Abstr. 2016, 164, 507513. 17 Fang J, Li Y, Guo W, Wu Y. Chinese Pat. Appl. CN 111138289, 2020 ; Chem. Abstr. 2020, 173, 293895. 18 Nan J, Chao-Jun L. Chem. Commun. 2004; 394 19 Liu C, Weng Y, Zeng X, Zeng W, Wang X, Hu Y. Tetrahedron Lett. 2019; 60: 493 20 Cvetovich RJ, Pipik B, Hartner FW, Grabowski EJ. J. Tetrahedron Lett. 2003; 44: 5867 21 Barge M, Kamble S, Kumbhar A, Rasinkar G, Salunkhe R. Monatsh. Chem. 2013; 144: 1213 22 Kidwai M, Jain A, Poddar R. J. Organomet. Chem. 2011; 696: 1939 23 Fu P, Li Z, Wang Y, Yu P. Asian J. Chem. 2015; 27: 2545 24 Hartner FW, Cvetovich RJ, Tsay F.-R, Amato JS, Pipik B, Grabowski EJ. J, Reider PJ. J. Org. Chem. 1999; 64: 7751 25 Wiles Ch, Watts P, Haswell SJ. Org. Process Res. Dev. 2004; 8: 28 26 Nesmejanow AN, Kotschetkow NK. Izv. Akad. Nauk SSSR, Ser. Khim. 1951; 686 ; Chem. Abstr. 1952, 46, 7565 Supplementary Material Supplementary Material Supporting Information (PDF)
