{
  "abstract": "8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (lactam) is a key intermediate in clozapine synthesis. Its formation by cyclization is limited by a long reaction time, and the acid-catalyzed mechanism has not been fully elucidated. This study develops and optimizes the intramolecular cyclization to form the lactam in a continuous-flow system and uses DFT calculations to establish the reaction pathway and examine the cyclization mechanism in the presence of H₂SO₄ at the molecular level. Batch screening identified DMF/H₂SO₄ as a suitable reaction system, giving an 80% yield after 16 h. After transfer to a Vapourtec E-Series system and optimization using a Box-Behnken design, the reaction time was reduced 16-fold to a residence time of 60 min, while the HPLC yield increased to 90.87 ± 1.22% (n = 3) at 130 °C with 3% H₂SO₄. DFT analysis identified a reaction pathway comprising three main stages: proton transfer and carbonyl activation, intramolecular C-N bond formation, and concerted proton transfer-water elimination, and confirmed two reaction pathways originating from intermediate INT3: one via TS3 and an alternative via TS3' and TS3″. Thus, continuous-flow optimization substantially improved the efficiency of the cyclization, while the DFT study elucidated the acid-catalyzed mechanism involving H₂SO₄ at the molecular level.",
  "abstract_shown": true,
  "affiliations": [
    "Institute of Chemistry, Vietnam Academy of Science and Technology Vietnam nguyenthithuyhang1@tdtu.edu.vn nguyenthuyhang@ich.vast.vn.",
    "Faculty of Chemical Technology, Hanoi University of Industry Hanoi Vietnam.",
    "Faculty of Pharmaceutics and Pharmaceutical Technology, Hanoi University of Pharmacy Hanoi Vietnam.",
    "Laboratory of Biophysics, Institute for Advanced Study in Technology, Ton Duc Thang University Ho Chi Minh City Vietnam.",
    "Faculty of Applied Sciences, Ton Duc Thang University Ho Chi Minh City Vietnam."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Nguyen Thi Kim Anh"
    },
    {
      "affs": [
        0
      ],
      "name": "Tran Thi Yen"
    },
    {
      "affs": [
        2
      ],
      "name": "Nguyen Ngoc Chien"
    },
    {
      "affs": [
        0
      ],
      "name": "Ngo Quoc Anh"
    },
    {
      "affs": [
        0,
        3,
        4
      ],
      "name": "Nguyen Thi Thuy Hang",
      "orcid": "0009-0009-2271-1624"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ay2fk53xjeyrz.bib",
  "cited_by": 0,
  "doi": "10.1039/d6ra09280b",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13717509/?tool=EBI",
  "id": "ay2fk53xjeyrz",
  "issns": [
    "2046-2069"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13717509",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Chemistry"
    ],
    [
      "openalex",
      "2204|Innovative Microfluidic and Catalytic Techniques Innovation"
    ]
  ],
  "openalex": "W7224167697",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13717509/pdf/?tool=EBI",
  "pmcid": "PMC13717509",
  "pmid": "42959539",
  "published": "2026-10-29",
  "publisher": "Royal Society of Chemistry",
  "ris": "https://research.draconitic.com/paper/ay2fk53xjeyrz.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T00:20:37Z",
      "native_id": "PMC:PMC13717509",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13717509"
    },
    {
      "first_seen": "2026-11-01T00:20:50Z",
      "native_id": "MED:42959539",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42959539"
    },
    {
      "first_seen": "2026-11-02T12:21:49Z",
      "native_id": "PMC13717509",
      "source": "pmc",
      "url": "https://doi.org/10.1039/d6ra09280b"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "heading:Chemistry",
      "subfield": "general"
    }
  ],
  "title": "Optimization of the intramolecular cyclization to form the clozapine lactam intermediate under continuous-flow conditions and elucidation of the H2SO4-catalyzed mechanism by DFT",
  "title_text": "Optimization of the intramolecular cyclization to form the clozapine lactam intermediate under continuous-flow conditions and elucidation of the H2SO4-catalyzed mechanism by DFT",
  "type": "peer-reviewed",
  "updated_at": "2026-11-02T12:21:49Z",
  "url": "https://research.draconitic.com/paper/ay2fk53xjeyrz",
  "venue": "RSC advances",
  "versions": []
}