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Synthesis 2022; 54(05): 1365-1374
DOI: 10.1055/a-1664-2282
paper

Rapid Multigram-Scale End-to-End Continuous-Flow Synthesis of Sulfonylurea Antidiabetes Drugs: Gliclazide, Chlorpropamide, and Tolbutamide

Cloudius R. Sagandira
,
Paul Watts  ∗
We thank the National Research Fund (NRF SARChI Grant) and Technology Innovation Agency (TIA) for financial support.
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Abstract

A multigram-scale robust, efficient, and safe end-to-end continuous-flow process for the diabetes sulfonylurea drugs gliclazide, chlorpropamide, and tolbutamide is reported. The drugs were prepared by the treatment of an amine with a haloformate affording carbamate, which was subsequently treated with a sulfonamide to afford sulfonylurea. Gliclazide was obtained in 87% yield within 2.5 minutes total residence time with 26 g/h throughput; 0.2 kg of the drug was produced in 8 hours of running the system continuously. Chlorpropamide and tolbutamide were both obtained in 94% yield within 1 minute residence time with 184–188 g/h throughput; 1.4–1.5 kg of the drugs was produced in 8 hours of running the system continuously. N-Substituted carbamates were used as safe alternatives to the hazardous isocyanates in constructing the sulfonyl urea moiety.

Key words

chlorpropamide - gliclazide - diabetes - end-to-end continuous flow - sulfonylurea - and tolbutamide

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1664-2282.
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Publication History

Received: 16 September 2021

Accepted after revision: 07 October 2021

Accepted Manuscript online:
07 October 2021

Article published online:
22 November 2021

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  • References

  • 1 International Diabetes Federation - Facts & Figures (accessed Dec 14, 2020): https://www.idf.org/aboutdiabetes/what-is-diabetes­/facts-figures.html
  • 2 Apicella M, Campopiano MC, Mantuano M, Mazoni L, Coppelli A, Del Prato S. Lancet Diabetes Endocrinol. 2020; 8: 782
    CrossrefPubMed
  • 3 Lim S, Bae JH, Kwon HS, Nauck MA. Nat. Rev. Endocrinol. 2020; 17: 11
    CrossrefPubMed
  • 4 Sardu C, Gargiulo G, Esposito G, Paolisso G, Marfella R. Cardiovasc. Diabetol. 2020; 19: 4
    CrossrefPubMed
  • 5 Pugliese G, Vitale M, Resi V, Orsi E. Acta Diabetol. 2020; 57: 1275
    CrossrefPubMed
  • 6 Sola D, Rossi L, Schianca GP. C, Maffioli P, Bigliocca M, Mella R, Corlianò F, Paolo Fra G, Bartoli E, Derosa G. Arch. Med. Sci. 2015; 11: 840
    CrossrefPubMed
  • 7 Kharbanda C, Alam MS. Chem. Biol. Interface 2013; 3: 230
  • 8 Ambulgekar GV, Dhake V, Kumar P, Reddy MR, Hattali J. Lett. Org. Chem. 2018; 15: 760
    Crossref
  • 9 Xiaohua D, Che D. Patent CN102993080A, 2013
    PubMed
  • 10 Che D, Du X. Patent WO 2011/054312 Al, 2011
    PubMed
  • 11 Hunter R, Msutu A, Dwyer CL, Emslie ND, Hunt RC, Bezuidenhoudt BC. B. Synlett 2011; 2335
    Article in Thieme Connect
  • 12 Hron R, Jursic BS. Tetrahedron Lett. 2014; 55: 1540
    Crossref
  • 13 Mizuno T, Kino T, Ito T, Miyata T. Synth. Commun. 2000; 30: 3081
    Crossref
  • 14 Tanwar DK, Ratan A, Gill MS. Org. Biomol. Chem. 2017; 15: 4992
    CrossrefPubMed
  • 15 Tan D, Vjekoslav Š, Cristina M, Friščić T. Chem. Commun. 2013; 50: 1
  • 16 Hernández JG, Friščić T. Tetrahedron Lett. 2015; 56: 4253
    Crossref
  • 17 Juárez R, Corma A, García H. Top. Catal. 2009; 52: 1688
    Crossref
  • 18 Gong N. Patent CN106588746A, 2017
    PubMed
  • 19 Lijun L, Xiaoliang R, Guanghong W, Yuxi C, Xilu Y, Xuan L. Patent CN106831536A, 2017
    PubMed
  • 20 Xiaoliang R, Lijun L, Yuxi C, Yuliang W, Haijian X. Patent CN106892856A, 2017
    PubMed
  • 21 Cai H. Patent CN103508934A, 2014
    PubMed
  • 22 Sang-yeon K, Lee J, Jae LM, Il-sung P, Yoo G. Patent KR100310936B1, 2001
    PubMed
  • 23 Yoshiaki I, Haruo K. Patent JPH0641073A, 1994
    PubMed
  • 24 Hilmer H, Korger G, Weyer R, Aumuller W. Patent US3607935A, 1971
    PubMed
  • 25 Juárez R, Corma A, García H. Top. Catal. 2009; 52: 1688
    Crossref
  • 26 Tanwar DK, Surendrabhai VR, Gill MS. Synlett 2017; 28: 2495
    Article in Thieme Connect
  • 27 Kreye O, Mutlu H, Meier MA. R. Green Chem. 2013; 15: 1431
    Crossref
  • 28 Bogdan AR, Dombrowski AW. J. Med. Chem. 2019; 62: 6422
    CrossrefPubMed
  • 29 Aguiar RM, Leão RA. C, Mata A, Cantillo D, Kappe CO, Miranda LS. M, De Souza RO. M. A. Org. Biomol. Chem. 2019; 17: 1552
    CrossrefPubMed
  • 30 Badman C, Cooney CL, Florence A, Konstantinov K, Krumme M, Mascia S, Nasr M, Trout BL. J. Pharm. Sci. 2019; 108: 3521
    CrossrefPubMed
  • 31 Sagandira CR, Moyo M, Watts P. ARKIVOC 2020; (iii): 24
    Crossref
  • 32 de Souza JM, Galaverna R, de Souza AA. N, Brocksom TJ, Pastre JC, de Souza RO. M. A, de Oliveira KT. An. Acad. Bras. Cienc. 2018; 90: 1131
    CrossrefPubMed
  • 33 Porta R, Benaglia M, Puglisi A. Org. Process Res. Dev. 2016; 20: 2
    Crossref
  • 34 Diab S, McQuade DT, Gupton BF, Gerogiorgis DI. Org. Process Res. Dev. 2019; 23: 320
    Crossref
  • 35 Baumann M, Moody TS, Smyth M, Wharry S. Org. Process Res. Dev. 2020; 24: 1802
    Crossref
  • 36 Sagandira CR, Watts P. Synlett 2020; 31: 1925
    Article in Thieme Connect
  • 37 Advanced Manufacturing | FDA (accessed Dec 11, 2020): https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/advanced-manufacturing
  • 38 Chatterjee, S. FDA Perspective on Continuous Manufacturing, IFPAC Annual Meeting, Baltimore; January 2012.
  • 39 Riley DL, Strydom I, Chikwamba R, Panayides JL. React. Chem. Eng. 2019; 4: 457
    Crossref
  • 40 Sagandira CR, Siyawamwaya M, Watts P. Arab. J. Chem. 2020; 13: 7886
    CrossrefPubMed
  • 41 Hayashi Y. J. Org. Chem. 2021; 86: 1
    CrossrefPubMed
  • 42 Fülöp Z, Szemesi P, Bana P, Éles J, Greiner I. React. Chem. Eng. 2020; 5: 1527
    Crossref
  • 43 Akwi FM, Watts P. Chem. Commun. 2018; 54: 13894
    CrossrefPubMed