One-pot Synthesis of 4-pyrimidone-2-thioether Through Base/acid-mediated Condensation of -alkylisothiourea and β-ketoester

Overview

Journal RSC Adv

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2024 Feb 14

PMID 38352681

Authors

Zhichao Lu

Tsung-Yun Wong

Yonghong Gan

Guihui Chen

Dinesh J Paymode

Cheng-Yi Chen

Affiliations

Soon will be listed here.

Abstract

4-Pyrimidone-2-thioethers can be useful synthetic precursors to densely functionalized pyrimidines, commonly encountered in bioactive molecules. A convenient one-pot access to 4-pyrimidone-2-thioethers is reported herein, which utilizes a sequential base- and acid-mediated condensation of alkylisothioureas with β-ketoesters. Owing to mild reaction conditions, good to excellent functional group tolerance and yields are achieved. The utility of this approach is demonstrated by the synthesis of the crucial intermediate on a 200 gram scale.

References

Fell J, Fischer J, Baer B, Blake J, Bouhana K, Briere D . Identification of the Clinical Development Candidate , a Covalent KRAS Inhibitor for the Treatment of Cancer. J Med Chem. 2020; 63(13):6679-6693. DOI: 10.1021/acs.jmedchem.9b02052. View

Tintori C, Brai A, Dasso Lang M, Deodato D, Greco A, Bizzarri B . Development and in Vitro Evaluation of a Microbicide Gel Formulation for a Novel Non-Nucleoside Reverse Transcriptase Inhibitor Belonging to the N-Dihydroalkyloxybenzyloxopyrimidines (N-DABOs) Family. J Med Chem. 2016; 59(6):2747-59. DOI: 10.1021/acs.jmedchem.5b01979. View

Yu K, Bae K, Shon J, Cho J, Yi S, Chung J . Pharmacokinetic and pharmacodynamic evaluation of a novel proton pump inhibitor, YH1885, in healthy volunteers. J Clin Pharmacol. 2003; 44(1):73-82. DOI: 10.1177/0091270003261321. View

Alford V, Kamath A, Ren X, Kumar K, Gan Q, Awwa M . Targeting the Hemopexin-like Domain of Latent Matrix Metalloproteinase-9 (proMMP-9) with a Small Molecule Inhibitor Prevents the Formation of Focal Adhesion Junctions. ACS Chem Biol. 2017; 12(11):2788-2803. PMC: 5697452. DOI: 10.1021/acschembio.7b00758. View

Pochampally S, Hartman K, Wang R, Wang J, Yun M, Parmar K . Design, Synthesis, and Biological Evaluation of Pyrimidine Dihydroquinoxalinone Derivatives as Tubulin Colchicine Site-Binding Agents That Displayed Potent Anticancer Activity Both In Vitro and In Vivo. ACS Pharmacol Transl Sci. 2023; 6(4):526-545. PMC: 10111625. DOI: 10.1021/acsptsci.2c00108. View

Shirai F, Tsumura T, Yashiroda Y, Yuki H, Niwa H, Sato S . Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors. J Med Chem. 2019; 62(7):3407-3427. DOI: 10.1021/acs.jmedchem.8b01888. View

Chen C, Lu Z, Scattolin T, Chen C, Gan Y, McLaughlin M . Synthesis of (MRTX849), a Covalent KRAS Inhibitor Drug for the Treatment of Cancer. Org Lett. 2023; 25(6):944-949. PMC: 9942190. DOI: 10.1021/acs.orglett.2c04266. View

Chiacchio M, Iannazzo D, Romeo R, Giofre S, Legnani L . Pyridine and Pyrimidine Derivatives as Privileged Scaffolds in Biologically Active Agents. Curr Med Chem. 2018; 26(40):7166-7195. DOI: 10.2174/0929867325666180904125400. View

Ishikawa C, Senba M, Mori N . Anti-adult T‑cell leukemia/lymphoma activity of cerdulatinib, a dual SYK/JAK kinase inhibitor. Int J Oncol. 2018; 53(4):1681-1690. DOI: 10.3892/ijo.2018.4513. View

10.

Koumarianou A, Kaltsas G . Surufatinib - a novel oral agent for neuroendocrine tumours. Nat Rev Endocrinol. 2020; 17(1):9-10. DOI: 10.1038/s41574-020-00439-0. View

11.

Wang Z, Zalloum W, Wang W, Jiang X, De Clercq E, Pannecouque C . Discovery of Novel Dihydrothiopyrano[4,3-]pyrimidine Derivatives as Potent HIV-1 NNRTIs with Significantly Reduced hERG Inhibitory Activity and Improved Resistance Profiles. J Med Chem. 2021; 64(18):13658-13675. DOI: 10.1021/acs.jmedchem.1c01015. View

12.

Kim H, Park S, Cheung D, Cho Y, Kim J, Kim S . Clinical trial: inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects. J Gastroenterol Hepatol. 2010; 25(10):1618-25. DOI: 10.1111/j.1440-1746.2010.06408.x. View

13.

Rui R, Tang C, Zhang C, Pan W, Gan K, Luo R . C6-structural optimizations of 2-aryl-1H-pyrazole-S-DABOs: From anti-HIV to anti-DENV activity. Bioorg Chem. 2021; 119:105494. DOI: 10.1016/j.bioorg.2021.105494. View

14.

Nadar S, Khan T . Pyrimidine: An elite heterocyclic leitmotif in drug discovery-synthesis and biological activity. Chem Biol Drug Des. 2021; 100(6):818-842. DOI: 10.1111/cbdd.14001. View

15.

Usach I, Melis V, Peris J . Non-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability. J Int AIDS Soc. 2013; 16:1-14. PMC: 3764307. DOI: 10.7448/IAS.16.1.18567. View

16.

Wang J, Ma M, Lu N, Yang Y, Yang J, Li Y . Synthesis and anti-HIV activity of non-nucleoside reverse-transcriptase inhibitor DB02 phosphate derivatives based on water-soluble optimization. Drug Dev Res. 2023; 84(3):423-432. DOI: 10.1002/ddr.22036. View