Optimization of the intramolecular cyclization to form the clozapine lactam intermediate under continuous-flow conditions and elucidation of the H2SO4-catalyzed mechanism by DFT
5 affiliations
- 1Institute of Chemistry, Vietnam Academy of Science and Technology Vietnam [email protected] [email protected].
- 2Faculty of Chemical Technology, Hanoi University of Industry Hanoi Vietnam.
- 3Faculty of Pharmaceutics and Pharmaceutical Technology, Hanoi University of Pharmacy Hanoi Vietnam.
- 4Laboratory of Biophysics, Institute for Advanced Study in Technology, Ton Duc Thang University Ho Chi Minh City Vietnam.
- 5Faculty of Applied Sciences, Ton Duc Thang University Ho Chi Minh City Vietnam.
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.
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BibTeX
@article{anh2026optimization,
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}},
author = {Nguyen Thi Kim Anh and Tran Thi Yen and Nguyen Ngoc Chien and Ngo Quoc Anh and Nguyen Thi Thuy Hang},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra09280b},
url = {https://europepmc.org/article/PMC/PMC13717509},
note = {CC BY},
}
RIS
TY - JOUR
TI - Optimization of the intramolecular cyclization to form the clozapine lactam intermediate under continuous-flow conditions and elucidation of the H2SO4-catalyzed mechanism by DFT
AU - Nguyen Thi Kim Anh
AU - Tran Thi Yen
AU - Nguyen Ngoc Chien
AU - Ngo Quoc Anh
AU - Nguyen Thi Thuy Hang
PY - 2026
DA - 2026/10/29
JO - RSC advances
DO - 10.1039/d6ra09280b
UR - https://europepmc.org/article/PMC/PMC13717509
AB - 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.
SN - 2046-2069
ER -