A publication in Reaction Chemistry and Engineering

The CiTOS laboratory of the ULiège and Mithra pharmaceuticals are intensifying their collaboration for the production of biosourced estetrol.

Computational chemistry as an accelerator for the intensification of continuous flow processes (copyright: Michaël Schmitz, CiTOS)

Researchers at CiTOS - Center for Integrated Technology and Organic Synthesis led by Jean-Christophe Monbaliu and the R&D team of Mithra Pharmaceuticals have devised a continuous process for the preparation of a key intermediate of estetrol. The process is based on a thermolysis reaction feeding upon an estrone sulfoxide derivative. Estrone is a bio-based steroid compound sourced from the soybean industry. This successful collaboration relies on a pioneering approach developed at CiTOS, which features synergy between computational chemistry and intensified continuous flow processes. The results of this study are published in the journal Reaction Chemistry and Engineering.


stetrol is a natural biogenic estrogen derivative with breakthrough potential in hormone-dependent treatments and, in particular, for the oral contraceptive market. Estetrol was approved in 2021 by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) in combination with drospirenone as an active pharmaceutical ingredient for fifth-generation oral contraceptives. Estetrol is one of the flagship products of Mithra Pharmaceuticals, a pharmaceutical and biotechnology company based in Liège focused on women's health. In view of estetrol’s market expansion, research efforts toward cost-effective and intensified large-scale synthesis were engaged.

Mithra Pharmaceuticals R&D team has teamed up with CiTOS (MolSys Research Unit, Faculty of Science) to develop a process towards a key enone intermediate. “Our R&D team has been collaborating for almost three years with Prof. Jean-Christophe Monbaliu under the umbrella of his technology flow platform,” says Amaury Dubart, Industrial Synthesis Associate at Mithra. "We present an applied study relying on a unique methodology, where quantum chemical calculations give an experimental design framework. It allows a priori assessment of the feasibility of a reaction in micro-/ and mesofluidic reactors”, comments Pauline Bianchi, F.R.S- FNRS PhD at CiTOS and lead author of the study. Such a priori benchmarking assessment affords a preselection of reaction conditions and suitable combinations of reagents. It positively impacts the reduction of waste generated upon optimization phases. "This last point is a significant improvement to accelerate the development of innovative conditions while minimizing the overall environmental footprint, particularly when compounds with high hormonal activity are at stake", indicates Jean-Christophe Monbaliu.

The collaboration focused on a the thermolysis of a key sulfoxide derivative of estrone, which was carefully tailored to minimize by-products and to improve its robustness and productivity. “After optimization, the thermolysis process was transposed into a production pilot, leading to an unprecedented productivity of ~1 kg every three hours. With these metrics transposed to the entire estetrol production scheme, a forecast of several million doses (15 mg formulation) is therefore achievable with a minimal global footprint,” concludes Jean-Christophe Monbaliu.

JC Monbaliu Estetrol biosource 2

Figure. Intensified preparation of a key enone intermediate toward estetrol.

The successful outcome of this project, funded by the FRS-F.N.R.S. as part of Pauline Bianchi's PhD fellowship, relies on a multidisciplinary approach at the interface between organic chemistry, new process technologies and computational chemistry. This program belongs to one of the priority areas of research at CiTOS, with the ambition of using chemical and technological innovations to accelerate the development of processes with a minimal environmental footprint.

Scientific reference

Bianchi, A. Dubart, M. Moors, D. Cornut, G. Duhirwe, J. Ampurdanés Vilanova, J.-C. M. Monbaliu, Metal-free synthesis of an estetrol key intermediate under intensified continuous flow conditions, React. Chem. Eng. 2023, Advance Article https://doi.org/10.1039/D3RE00051F


F.R.S.-FNRS (Mandat d’aspirant, 1.A.054.21F, PB).


Pauline Bianchi

Jean-Christophe Monbaliu

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