• Rio de Janeiro Brasil
  • 14-18 Novembro 2022

Development of process for flow synthesis of Dropropizine from Glycidol.




The present study aimed at the synthesis of Dropropizine. It was synthesized through the reaction of Phenylpiperazine with Glycidol, aiming the transposition from the batch process to flow in microreactor.The maximum yield, 92.8%, was obtained for the flow reaction at 80 °C, 12 min mean residence time and 0.8 M total concentration. For the reactions at 100 °C, the reaction medium showed a color change, from yellowish to orange, and reaction yield higher than 100%, suggesting, possibly, parallel/consecutive reactions yielding by-products that could absorb UV for the same wavelength and same retention time of Dropropizine. Continuing this study, experiments will be replicated at 100 °C to confirm the results and it will be tried to identify the by-product formed at that high temperature.

Palavras chaves

Dropropizine; Microreactor; Flow Chemistry


The reduction of effluent generation and the search for higher efficiency in the use of energy and material resources are crucial factors for a sustainable technical-scientific development (JIMÉNEZ-GONZÁLEZ; CONSTABLE; PONDER, 2012). If the materials and energy required for the synthesis of substances are reduced, consequently, the production processes will be less harmful to environment and more sustainable.The flow synthesis using capillary microreactors has been the object of study in recent years due to its wide advantages over batch reactors (SILVA et al.,2019) that lead to increased chemical reaction rate, conversion, yield, selectivity and safety when working with toxic reagents and products, thus reducing waste generation (YOSHIDA; TAKAHASHI; NAGAKI, 2013). Dropropizine is an antitussive that acts by inhibiting the cough reflex through its action on peripheral receptors and their afferent conductors (MACHADO et al,2021). Its chemical name IUPAC is 3-(4-phenyl-1-piperazinil)-1,2-propanediol and has an optical center. The objective of this study was to transpose the synthesis of Dropropizine from the usual batch process to flow with the use of capillary microreactors. The best operation conditions for this synthesis were determined in the batch process (temperature, reaction time and concentration of the reaction medium) and in the flow process in the capillary microreactor (temperature and mean residence time) to maximize the yield of the drug.

Material e métodos

The experimental procedure for batch synthesis of Dropropizine, based on the patent of Van Lersel (1990), consists of the reaction of Phenylpiperazine and Glycidol in aqueous medium. In this process two series of tests were performed. The first series consisted of determining the highest concentration of the reaction medium so that there was no formation of solids in each reaction studied. The concentrations tested were 0.4, 0.2 and 0.1 M. Then, the influence of temperature of 40, 60, 80 and 100 °C on the product yield was verified. In all assays, aliquots of the reaction medium were collected at times of 0.5, 2, 5, 10 and 20 min for analysis by HPLC-UV. Once the tests were performed in the batch process, it was transposed to the flow process in microreactors. The synthesis in the microreactor consisted of preparing two solutions: 1) Phenylpiperazine (24 mmol; 0.8 M) in water; 2) Glycidol (24 mmol; 0.8 M) in water. The 2 solutions were fed separately to the microreactor at adequate flow and temperature. For the flow tests were tested the best experimental condition determined in the batch process at temperatures of 40, 60, 80 and 100 °C and mean residence times, τ, 1, 2, 4, 8, 12, 16 and 20 min. The quantification of the synthesized compounds was performed by high performance liquid chromatography (HPLC) coupled to UV detector (Shimadzu, mod. Prominence 20AD, JP), using an eluent composed of phosphate acid buffer solution pH 3:methanol (88:12, v/v). Flow rate: 0.9 mL/min. The maximum absorbance of Dropropizine occurs for λ=238 nm

Resultado e discussão

In the tests performed in batch at the concentration of 0.1 M there was formation of solids, making it impossible to perform the transposition to the process in flow, since it can compromise the use of this technology through the blockage of micro channels. There was no formation of solids in the experiments with concentrations of 0.2 and 0.4 M, and thus the transposition to the flow process in the microreactors to the concentration of 0.4 M was tested due to the higher yields observed. Figure 1 shows the results of Dropropizine yield in batch and in flow, as a function of temperature and mean residence time. The results presented in Figure 1 show that the yields for the batch tests were 66.8, 68.0 and 90.8% for the mean residence time of 20 min and temperatures of 40, 60 and 80 °C, respectively. In flow and for the same conditions, yields of 78.7, 52.5 and 77.0% were obtained. The yield of 92.8%, the highest observed, was obtained when the reaction was carried out in flow at 80 °C and mean residence time 12 min. For the temperature of 100 °C and concentration of reagents of 0.4 M, the reaction medium presented a different color when compared to the other experimental conditions, presenting an orange color instead of the usual yellowish tone, and yields greater than 100%. This observation occurred both in batch reactions and in those performed in flow. One hypothesis for this is that there were parallel and/or consecutive reactions whose product has the same retention time of Dropropizine and also absorbing at the same wavelength.

Yield Graph

Dropropizine yield (Yp) in batch reactor (__) and in continuous flow (---). Temperature = (•) 40, (■) 60 and (▲) 80 °C; C = 0.4 M of each reagent.


Maximum yield of 92.8% of product was obtained in the flow synthesis of Dropropizine, from Glycidol and Phenylpiperazine, for concentration of 0.4 M of each reagent, at 80 °C and mean residence time 12 min. With the sequence of this study, triplicates will be performed for each of the experimental conditions studied so far. In addition, efforts will be made to characterize the by-products formed at 100 °C.


We thank the School of Pharmaceutical Science, University of São Paulo - FCF/USP, São Paulo Research Foundation – FAPESP for the Scientific Initiation Scholarship n. 2022/01770-3 and my advisor for the all support given.


JIMÉNEZ-GONZÁLEZ, C.; CONSTABLE, D.J.C.; PONDER, C.S. Evaluating the “Greenness” of chemical processes and products in the pharmaceutical industry—a green metrics primer. Chemical Society Reviews, v. 41, n. 4, p. 1485, 2012.
MACHADO, A. K. M. S.; NEMITZ, M. C.; TODESCHINI, V.; SANGOI, M. S. Characteristics, Properties and Analytical Methods for Determination of Dropropizine and Levodropropizine: A Review. Critical Reviews in Analytical Chemistry, v. 51, n. 2, p .174-182, 2021.
SILVA, R. R. O.; CALVO, P. V. C.; SILVA, M. F., SOLISIO, C.; CONVERTI, A.; PALMA, M. S. A. Flow Synthesis of a Thiazolidine Drug Intermediate in Capillary Microreactors. Chemical Engineering Technology, v. 42, n. 2, p. 465-473, 2019. https://www.researchgate.net/publication/327579603_Flow_Synthesis_of_a_Thiazolizine_Drug_Intermediate_in_Capillary_Microreactor
VAN LERSEL, J. T. M. Preparation of enantiomers of dropropizine Depósito: 22 jun. 1989. Concessão: 3 fev. 1990.
YOSHIDA, J.; TAKAHASHI, Y.; NAGAKI, A. Flash chemistry: flow chemistry that cannot be done in batch. Chemical communications, Cambridge, v. 49, n. 85, p. 896–904, 2013.

Patrocinador Ouro

Conselho Federal de Química

Patrocinador Prata

Conselho Nacional de Desenvolvimento Científico e Tecnológico

Patrocinador Bronze

LF Editorial
Royal Society of Chemistry
Elite Rio de Janeiro


Federación Latinoamericana de Asociaciones Químicas Conselho Regional de Química 3ª Região (RJ) Instituto Federal Rio de Janeiro Colégio Pedro II Sociedade Brasileira de Química Olimpíada Nacional de Ciências Olimpíada Brasileira de Química Rio Convention & Visitors Bureau