PDF herunterladen
CC BY 4.0 · Pharmaceutical Fronts 2023; 05(02): e84-e90
DOI: 10.1055/s-0043-1768692
Original Article

Synthesis and Impurity Research of 2-Thioadenosine Monohydrate

Jing-Jing Xiang   #
1   School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People's Republic of China
,
Bi-Bo Jiang   #
2   Engineering Research Center for Improvement and Industrialization of Pharmaceutical Processes, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Wen-Qing Sun
3   Shandong Ruizhi Pharmaceutical Technology Co., Ltd., Heze, People's Republic of China
,
Fu-Li Zhang
1   School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People's Republic of China
2   Engineering Research Center for Improvement and Industrialization of Pharmaceutical Processes, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Jun Yu
2   Engineering Research Center for Improvement and Industrialization of Pharmaceutical Processes, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
› Institutsangaben
› Weitere Informationen
Auch verfügbar auf
   Lizenzen und Reprints


Abstract

2-Thioadenosine monohydrate (1) is a vital intermediate in the synthesis of cangrelor. However, its industrial-scale preparation process and the analysis of the impurities formed during this process remained largely unknown. Herein, cangrelor was synthesized from oxidate adenosine, and the key step involved in the synthesis of compound 1 from intermediate 5. The effects of key synthesis parameters that influenced the reaction, including reaction temperature and time, were discussed. Moreover, four process-related impurities were purified, synthesized, and identified via nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. The process can be utilized to produce 1 on a kilogram scale, with a high-performance liquid chromatography purity of 98.0%. The study sheds light on and helps drug manufacturers further understand the formation process of impurities in the preparation of cangrelor.

Keywords

cangrelor - 2-thioadenosine monohydrate - a kilogram scale - impurities

# These authors contributed equally to this work.


Supplementary Material



Publikationsverlauf

Eingereicht: 21. Dezember 2022

Angenommen: 04. April 2023

Artikel online veröffentlicht:
24. Mai 2023

© 2023. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Fischer B, Boyer JL, Hoyle CH. et al. Identification of potent, selective P2Y-purinoceptor agonists: structure-activity relationships for 2-thioether derivatives of adenosine 5′-triphosphate. J Med Chem 1993; 36 (24) 3937-3946
    CrossrefPubMedGoogle Scholar
  • 2 El-Tayeb A, Michael S, Abdelrahman A. et al. Development of polar adenosine A2A receptor agonists for inflammatory bowel disease: synergism with A2B antagonists. ACS Med Chem Lett 2011; 2 (12) 890-895
    CrossrefPubMedGoogle Scholar
  • 3 Heisig F, Gollos S, Freudenthal SJ, El-Tayeb A, Iqbal J, Müller CE. Synthesis of BODIPY derivatives substituted with various bioconjugatable linker groups: a construction kit for fluorescent labeling of receptor ligands. J Fluoresc 2014; 24 (01) 213-230
    CrossrefPubMedGoogle Scholar
  • 4 Jacopo B, Mattia B, Barbara N. Efficient method for the preparation of Cangrelor. WO Patent 2019092546. May 2019
    PubMed
  • 5 Kikugawa K, Suehiro H, Yanase R, Aoki A. Platelet aggregation inhibitors. IX. Chemical transformation of adenosine into 2-thioadenosine derivatives. Chem Pharm Bull (Tokyo) 1977; 25 (08) 1959-1969
    CrossrefPubMedGoogle Scholar
  • 6 Yanachkov IB, Chang H, Yanachkova MI. et al. New highly active antiplatelet agents with dual specificity for platelet P2Y1 and P2Y12 adenosine diphosphate receptors. Eur J Med Chem 2016; 107: 204-218
    CrossrefPubMedGoogle Scholar
  • 7 Fujii T, Saito T, Kizu K. et al. XLVIII. Syntheses and proton nuclear magnetic resonance study of 2-deuterioadenines substituted or unsubstituted at the 9-position and of their N-oxygenated derivatives. Chem Pharm Bull (Tokyo) 1991; 39 (02) 301-308
    CrossrefGoogle Scholar
  • 8 Marumoto R, Yoshioka Y, Miyashita O, Shima S, Imai K. Synthesis and coronary vasodilating activity of 2-substituted adenosines. Chem Pharm Bull (Tokyo) 1975; 23 (04) 759-774
    CrossrefPubMedGoogle Scholar
  • 9 Nair V, Young DA. Photoinduced alkylthiolation of halogenated purine nucleosides. Synth 1986; 6: 450-453
    Artikel in Thieme ConnectGoogle Scholar
  • 10 Bhattarai S, Pippel J, Scaletti E. et al. 2-Substituted α,β-methylene-ADP derivatives: potent competitive ecto-5′-nucleotidase (CD73) inhibitors with variable binding modes. J Med Chem 2020; 63 (06) 2941-2957
    CrossrefPubMedGoogle Scholar
  • 11 Debiec K, Matuszewski M, Podskoczyj K, Leszczynska G, Sochacka E. Chemical synthesis of oligoribonucleotide (ASL of tRNALys T. brucei) containing a recently discovered cyclic form of 2-methylthio-N6 -threonylcarbamoyladenosine (ms2 ct6 A). Chemistry 2019; 25 (58) 13309-13317
    CrossrefPubMedGoogle Scholar
  • 12 Huang S, Wang M, Jiang X. Ni-catalyzed C-S bond construction and cleavage. Chem Soc Rev 2022; 51 (19) 8351-8377
    CrossrefPubMedGoogle Scholar
  • 13 Feng M, Tang B, Liang SH, Jiang X. Sulfur containing scaffolds in drugs: synthesis and application in medicinal chemistry. Curr Top Med Chem 2016; 16 (11) 1200-1216
    CrossrefPubMedGoogle Scholar
  • 14 Li J, Wang M, Jiang X. Diastereoselective synthesis of thioglycosides via Pd-catalyzed allylic rearrangement. Org Lett 2021; 23 (23) 9053-9057
    CrossrefPubMedGoogle Scholar
  • 15 Cao D, Pan P, Li C. et al. Photo-induced transition-metal and photosensitizer free cross-coupling of aryl halides with disulfides. Green Synthesis and Catalysis 2021; 2: 303-306
    CrossrefGoogle Scholar
  • 16 Xiao X, Huang YQ, Tian HY. et al. Robust, scalable construction of an electrophilic deuterated methylthiolating reagent: facile access to SCD3-containing scaffolds. Chem Commun (Camb) 2022; 58 (18) 3015-3018
    CrossrefPubMedGoogle Scholar
  • 17 Ding H, Zhang X, Wang H. HPLC detection method for cangrelor intermediate impurities. CN Patent 112630349. April 2021
    PubMed
  • 18 Wang Q, Yang J, Ding H. et al. Method for preparing cangrelor intermediate adenosine-2-thioketone. CN Patent 112724181. April 2021
    PubMed