Recent years have witnessed a growing interest in the synthesis of benfotiamine, most likely as a direct consequence of increased market demand. It has a much higher bioavailability than thiamine (vitamin B1) and is therefore more suitable for therapeutic purposes, especially in oral form. BENSYNTH was conducted as an academic-private collaboration in which we investigated all aspects of small- and large-scale benfotiamine synthesis process. The procedure involves two laborious steps, starting with vitamin B1. We used NMR spectroscopy to monitor the purity of TMP as well as its conversion to benfotiamine. The small-scale reaction was optimized to kg scale and the procedure was replicated by the industrial partner, who also designed a pilot plant. An important aspect was the crystalline form of benfotiamine. We used X-ray powder diffraction, IR and RAMAN spectroscopy to evaluate various crystalline forms that we obtained in different batches or recrystallization experiments, establishing clear experimental procedures for the direct realization of the crystalline form required on the market, but also conversion of any other form that could be obtained from synthesis into the required one. The results of BENSYNTH thus constitute a very useful guide in the synthesis of the most important and most common analog of vitamin B1.
Successful implementation of BENSYNTH impacts on different levels: i) fundamental research through use of modern techniques to study old processes. ii) strengthening the relationship between a higher education and research institution and a private company in the field of synthetic chemistry. iii) industrial level through validation a reliable synthetic methodology for large scale synthesis.
Complementary to the successful achievement of the scientific objectives, BENSYNTH contributed to training of young researchers, at master’s and doctorate level, and the dissemination of the obtained results was achieved through participation of the team members in international conferences, allowing exposure to a competitive scientific environment, including researchers from the private sector. An overview of the meetings, training and participation to scientific events is shown bellow.
Meetings of the research team
During 2023, several meetings of the research teams occurred. At the beginning of the year, the project team met at Microsin site. The team members visited the site and discussed about the project progress.
The planned trainings of the young researchers were performed at the University of Bucharest site, as well as in the laboratories of INCD FM.
Training of the young researchers in the laboratory Nuclear Magnetic Resonance (NMR) proceeded at the Faculty of Chemistry, University of Bucharest site. The 300 MHz (Bruker Fourier) and 500 MHz (Advance III UltraShield Plus) spectrometers were presented to the members, as well as the organic synthesis labs. The reunited research team discussed the project progress and future collaboration perspectives.
Visit of the Microsin team in the labs of INCD FM occurred with training for the main advanced techniques for the young researchers, as well as with discussions of the project progress and proposals for future collaborations.
Publications
A. Hanganu, M.V. Maximov, O.-C. Maximov, C.C. Popescu, N. Sandu, M. Florea, A.G. Mirea, C. Gârbea, M. Matache, D.P. Funeriu., Insights into Large-Scale Synthesis of Benfotiamine, Organic Process Research & Development, 2024, accepted manuscript
A.F. Dobre, A. Hanganu, I. Nicolau, C.C. Popescu, A Paun, A.M. Mădălan, C. Tablet, A.G. Mirea, M. Matache, A Synthetic Approach for Oxadiazole-Decorated Azobenzene Photoswitches, ChemPlusChem, 2024, e202300504. https://doi.org/10.1002/cplu.202300504.
I. Nicolau, N.D. Hădade, M. Matache, D.P. Funeriu, Synthetic Approaches of Epoxysuccinate Chemical Probes, ChemBioChem, 2023, 24, 16, e202300157. https://doi.org/10.1002/cbic.202300157
C.C. Anghel, A.G. Mirea, C.C. Popescu, A.M. Madalan, A. Hanganu, A. Bende, N.D. Hadade, M. Matache, M. Andruh, Shifting emission of oxadiazoles via inter- or intramolecular hydrogen bonding, Dyes. Pigm. 2023, 210, 111023. https://doi.org/10.1016/j.dyepig.2022.111023
Dissemination through conferences and congresses
Nicoleta Sandu, Andrei-Gabriel Grecu, George Costache, Mihaela Matache, Challenges In Romanian Chemical Research Publication, poster, ReachSci Conference, 19th – 21st March, 2023, Cambridge, United Kingdom.
George Costache, Nicoleta Sandu, Andrei-Gabriel Grecu, Marius L. Matache, Mihaela Matache, Challenges and Solutions in STEM Research Training faced and discussed in the ReachSci Programme at Cambridge University, oral presentation, 10th – 13rd April, 2023, Timișoara, Romania.
Anamaria Hanganu, Maximov V. Maxim, Maximov Oana Cristina, Codruța Popescu, Nicoleta Sandu, Adela Dobre, Mihaela Florea, Mihaela Matache, Daniel P. Funeriu, NMR spectroscopy – a useful tool for monitoring formation of benfotiamine from thiamine, poster, 8th International Workshop of Materials Physics, 17th – 19th May, 2023, Măgurele, Romania.
Adela F. Dobre, Nicoleta Sandu, Anamaria Hanganu, Ioana Nicolau, Codruța C. Popescu, Anca Păun, Augustin M. Mădălan, Mihaela Matache, Novel perspectives of azo photoswitches: synthesis of oxa/thiadiazole decorated compounds and evaluation as switches, poster, 8th International Workshop of Materials Physics, 17th – 19th May, 2023, Măgurele, Romania.
Nicoleta Sandu, Anca G. Mirea, Anamaria Hanganu, Mihaela Florea, Ioana Nicolau, Anca Păun, Codruța C. Popescu, Mihaela Matache, Synthesis of novel tricarboxylic units for hybrid organic-inorganic materials, poster, 8th International Workshop of Materials Physics, 17th – 19th May, 2023, Măgurele, Romania.
Adela F. Dobre, Anamaria Hanganu, Ioana Nicolau, Codruta C. Popescu, Anca Păun, Petre Ioniță, Mihaela Matache, Synthesis and novel perspectives of oxadiazole-based azobenzenes as exciting molecular photoswitches, poster, XLVII edition of the “Attilio Corbella” International Summer School on Organic Synthesis, 18th – 22nd June, 2023, Gargnano, Italy.
Nicoleta Sandu, Andreea C. Minea, Anca G. Mirea, Anamaria Hanganu, Codruța C. Popescu, Mihaela Matache, Synthesis of novel precursors of aldehyde and hydrazide type for construction of materials based on N-acylhydrazone functionality, poster, XLVII edition of the “Attilio Corbella” International Summer School on Organic Synthesis, 18th – 22nd June, 2023, Gargnano, Italy.
Adela Dobre, Bogdan C. Enache, George Costache, Nicoleta Sandu, Anamaria Hanganu, Codruța C. Popescu, Anca Paun,, Ioana Nicolau, Mihaela Matache, Photo-sensitive azo-based small molecule switches, Invited Lecture, ROCAM 2024, 10th International Conference on Advanced Materials, 15th – 18th July, ,Bucharest, Romania
Mihaela Matache, Synthetic approaches of photo-sensitive azo switches, invited presentation, Symposium „Modern Directions in Materials Chemistry“, Romanian Academy, 7th of June, 2024, Bucharest, Romania