Synthesis of valproic acid for medicinal chemistry practical classes

Oldřich Farsa

doi:10.1515/cti-2025-0028

Article Open Access

Synthesis of valproic acid for medicinal chemistry practical classes

Oldřich Farsa

Published/Copyright: May 28, 2025

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From the journal Chemistry Teacher International Volume 7 Issue 3

Abstract

Medicinal (or also Pharmaceutical) Chemistry practical classes are intended to familiarize students who have already passed Inorganic and Organic Chemistry Courses in the first or the second year of a Faculty of Pharmacy with real syntheses of medicines that are used in the practice. The selection of practical tasks is limited by the time reserved for each practical lesson in which at least one step of a multi-step synthesis must be done. This fact pushes us to optimize individual synthesis steps to shorten them as much as possible, but with acceptable yields. Valproic acid, 2-propylpentanoic acid, is a drug approved originally as an antiepileptic but is now used as a co-analgesic and in various neurology indications. Our synthesis comes from the classical malonate synthesis but is newly optimized to be managed during three practical lessons.

Keywords: medicinal chemistry; practical classes; active pharmaceutical ingredient (API) synthesis; valproic acid

1 Introduction

Medicinal Chemistry (MC), or, in some mainly central or western European Universities called Pharmaceutical Chemistry (e.g. Pharmazeutische Chemie in German), is one of the key disciplines of the master’s degree in pharmaceutical study. This type of study does not prepare experts only for work in pharmacies and other positions within the health care system but also for the pharmaceutical research and industry. MC also presents a structure base for pharmacology, a science dealing with mechanisms of drug activity and the fate of a drug in a body, that is considered the top discipline of whole pharmaceutical study.

The situation on the drug market in Europe during and after the COVID-19 pandemic uncovered a desperate dependence of European countries on the import of drug substances (APIs) mainly from China and India. That was why the EU as well as national political representatives appealed, in addition to other measures, for the renewal of the APIs production in Europe. ¹ Pharmaceutical faculties (=colleges of pharmacy) in the Czech Republic have also been invited to take part in this process. This is why we at the Department of Chemical Drugs decided to improve practical classes in Medicinal Chemistry to enable the students to familiarize more realistically with syntheses of drugs that are used in therapy. The other reason for this is a simple need to innovate and modernize practical tasks and replace those, which were remaining in the syllabus for long years. The criteria for the selection of suitable practical tasks included financially available raw materials and the acceptable length of an individual synthetic step not exceeding 6 h 40 min which is a planned time allocation for one practical lesson in our innovative Pharmacy master study program currently prepared for a new accreditation by the Czech National Accreditation Authority (NAÚ) in a near future. As the first candidate, we have chosen a synthesis of valproic acid, 2-propylpentanoic acid. This drug, initially approved in France in 1967 as an antiepileptic, is now used in a variety of indications from epileptic seizures to bipolar disorders, and migraine. It was also recently reported to have an effect against hepatic and renal fibrosis, which can be mediated by the inhibition of different isoenzymes of histone deacetylases. ²

We had previously tried to prepare valproic acid by “upcycling” allobarbital and 5,5-dipropyl barbituric acid, old barbiturate drugs, which were being prepared at our practical classes in the 1990s, and which remained in our chemical storage as hard-to-use stock. ³ Such a synthesis would meet some criteria for green chemistry. Unfortunately, its yields were due to the high stability of the ureide bond too low to be possible to adapt it for practical classes.

Similarly to the traditional synthesis of the symmetrical barbiturates mentioned above, our finally selected synthesis of valproic acid is based on the classical malonester synthesis, with some improvements made due to necessarily shortening one of the synthetic steps and using a less expensive solvent. Other synthetic ways, such as acetonitrile dipropylation under sonochemical conditions ⁴ followed by a nitrile group alkaline hydrolysis, or ethyl cyanoacetate dipropylation, followed by deacetylation and decarboxylation of the intermediate, and also nitrile hydrolysis, ⁵ were also being considered, but they did not comply with the required length of a synthetic step. Mainly nitrile group hydrolysis was always too long.

Our valproic acid synthesis procedure, described further, is intended for students in the second or the third year of university pharmaceutical study, in other words, sophomores or juniors at a university or a college, who have already passed practical classes and exams in general, inorganic and organic chemistry.

2 Materials and methods

2.1 Materials

The chemicals and materials used in the experiment are as follow: 1-bromopropane for synthesis, diethyl-malonate for synthesis, propan-1-ol for synthesis, sodium (metal), sodium iodide for synthesis, potassium hydroxide for synthesis, copper(I) iodide for synthesis, activated charcoal for synthesis, sodium sulfate anhydrous for synthesis, water (purified), silicone oil for heating bathes, deuterated chloroform for NMR, deuterated dimethyl sulfoxide for NMR, sample tubes for NMR, Eppendorf tubes for NMR and IR samples, pH indicator papers, beakers, stirring and heating plate, heating mantle, stainless steel bowls for heating bathes, condenser, drying tube, separatory funnel, thermometers, stir bars, rounded bottom flasks, NMR tubes, vacuum rotary evaporator, distillation head, distillation receiver with a distributor, ⁶ “collar apparatus”(made by Kavalierglass, Sázava, Czech Republic; discontinued), Hickman still head ⁷ ^, ⁸ or micro distillation head, ⁸ ball-to-ball distillation ⁹ or Kugelrohr apparatus, ¹⁰ pressure gauge, membrane vacuum pump, water or other vacuum pump suitable for suction filtration, microwave reactor (StartSynth, Milestone, Italy) or a heating mantle for a 50 ml Apollo flask, NMR spectrometer, IR spectrometer.

Figure 1:

A four-step synthetic procedure for the preparation of valproic acid at practical classes in medicinal chemistry was proposed by the author. The procedure is for organizational reasons separated into three parts. Metallic sodium is first dissolved in propanol to form sodium propoxide, and diethyl malonate is then deprotonated and alkylated with bromopropane, the product is then hydrolyzed to 2,2-dipropyl malonic acid, which is finally decarboxylated to valproic acid.

2.2 Experimental procedure

Groups of two or, at the maximum, three students carry out the procedures conducted in this laboratory experiment. Each group performs the synthesis steps as they follow each other. A single synthesis step is performed at each exercise (Figure 1).

Step 1: Dipropyl 2,2-dipropylmalonate

In a dry 100 ml flask equipped with a condenser with a drying tube filled with potassium hydroxide beads, 1.84 g (0.08 mol, 2 eq) sodium is dissolved in 30 ml anhydrous propanol by boiling. After dissolving all the sodium, the reaction mixture is cooled down to approx. 80 °C and then, 6.4 g (0.04 mol, 1 eq) diethyl malonate is added in parts. The reaction mixture is then stirred for 10 min at the same temperature, then sodium iodide (0.7 g, 0.005 mol, 0.12 eq) is added and then, slowly and in parts, bromopropane (13.5 g, 0.11 mol, 2.7 eq) is added. The reaction mixture is then heated to the temperature at which it slightly boils and kept refluxing at the same temperature for 2 h. The reaction mixture is then cooled down and the excess of propanol is distilled off at a rotary evaporator. 13 ml water is then added to the residuum. The mixture is moved to a separatory funnel and the (upper) oily layer is separated. The aqueous layer is extracted 3 times with 15 ml diethyl ether, the ether extract is mixed with the separated oily layer, and the organic mixture is dried with anhydrous sodium sulfate. The drying agent is then removed by filtration through a piece of the cotton wool in the neck of a funnel, and the residue on the wool is then washed with a small volume of ether, also to the organic mixture. Diethyl ether is then distilled off at a rotary evaporator. Optionally, the residue can be distilled at a reduced pressure. The fraction of the boiling point corresponding with 150–155 °C/1.6 kPa is then collected and used for further reaction. Alternatively, the residue after the evaporation of ether can be directly used for further reaction A confirmation of identity and purity of the product by ¹H-NMR is recommended. ¹H-NMR (400 MHz, CDCl3, J[Hz]): 4.06 t 4H J = 6 (2 CH₂COO), 1.85 4H t J = 8 (2 CH₂C), 1.65 m 4H (2 CH₂), 1.20 m 4H (2 CH₂), 0.94 t 6H J = 7.6 (CH₃ ester alkyl), 0.92 t 6H J = 7.4 (CH₃ C-alkyl) The molar ratio between diethyl- and dipropyl 2,2-dipropylmalonates is approximately 0.66/3.61 ÷ 1:5.5 (from the ratio of integral areas of ester CH₂ groups of both compounds). ¹H-NMR as an image together with mentioning of impurities signals which are visible in the spectrum are included in the Supplementary Material NMR spectra. The amounts of chemicals used in further synthetic steps should be calculated so that all the amount of a previous step is used for the next reaction.

Step 2: 2,2-Dipropyl malonic acid

Dipropyl 2,2-dipropyl malonate (typically 7.6 ml, approx. 8 g, 0.03 mol, 1 eq) from the previous step is mixed with 10 times greater volume of 50 % potassium hydroxide solution (ρ(KOH) = 1.502 g/ml, typically 76 ml, containing 57 g (1.02 mol, 34 eq) potassium hydroxide and 57 ml water) in a flask of a suitable size equipped with a condenser. Then, the mixture is heated under stirring to a reflux for 5 h. After cooling down, the reaction mixture is carefully neutralized with concentrated hydrochloric acid in the molar amount equivalent to potassium hydroxide used (students should calculate its volume in advance, a teacher checks it), under stirring and cooling with an ice bath. The pH is checked and should be ≤1. The cooling (water/ice) and stirring are continued until crystallization. The resulting solid is then separated by a suction at a Büchner funnel, washed with a small amount of water, and let to be streamed with the air at the filter for several minutes. Then it is dried, and its identity is confirmed by the melting point, and optionally by NMR/IR spectra. M.p. 157–158 °C. ¹¹ ¹H-NMR (400 MHz, DMSO-D₆, J[Hz]): 12.58 2H bs (2 COOH), 1.69 4H m (2 CH₂), 1.12 4H m (2 CH₂), 0.87 6H t J = 7.4 (2 CH₃) ¹H-NMR as an image together with mentioning of water signal visible in the spectrum are included in the Supplementary Material NMR spectra.

Step 3: Valproic acid (2-propylpentanoic acid)

2,2-Dipropyl malonic acid (typically 2 g, 0.011 mol, 1 eq) from the previous step is placed into a suitable rounded bottom flask (GL 14), and inserted into a system, which enables heating of the flask to a high temperature with simultaneous distilling of the liquid phase formed. Copper(I) iodide (0.05 eq, typically 0.105 g, 0.00055 mol) is added and the flask is then heated to approx. 160 °C in the bath, or to the temperature, at which a liquid phase starts to distill, when made at a heating mantle. ¹² ^, ¹³ If a box-type microwave reactor is used, activated charcoal (0.05 eq, typically 0.007 g, 0.00055 mol) is used instead of copper(I) iodide. The liquid phase is collected as long as it is formed (approx. 2 h). This procedure enables us to directly get a virtually pure valproic acid as a colorless liquid. The procedure can be made e.g. at a “collar” apparatus, or at a Hickman still head, which enables a boiling temperature observation. Alternatively, a ball-to-ball distillation or a Kugelrohr apparatus can be used for this reaction stage, without the usage of a vacuum. The product can be optionally redistilled by a ball-to-ball distillation under reduced pressure, b.p. (118–120 °C/1.33 kPa) The structure should be confirmed by NMR. ¹H-NMR (400 MHz, CDCl₃, J[Hz]): 11.34 1H bs (COOH), 2.38 1H m (CH), 1.62 2H m, 1.45 2H m, 1.36 4H m, 0.92 6H t J = 7.2 (2 CH₃).

The identity of the product can be also simply confirmed by a refractive index measurement, the value ranges around 1.42 (1.4239 at 20 °C, ¹⁴ 1.425 at 24.5 °C ¹⁵ ). The specific design of the experiment can be adapted to the conditions of a specific workplace.

2.3 Assessment of the student’s work

This laboratory activity is separated into three sections that can be completed over three standard 6 h 40 min sessions: synthesis of dipropyl 2,2-dipropylmalonate, synthesis of 2,2-dipropylmalonic acid, and final decarboxylation to valproic acid. All the above steps should be finished with a structure confirmation by ¹H-NMR and, in 2,2-dipropylmalonic acid, also by melting point. Students who have already passed practical classes in general inorganic, and organic chemistry, are experienced enough to do most synthetic and separation procedures by themselves. The assistance of the instructor or laboratory assistant is needed in the arrangement of apparatuses for vacuum distillation and decarboxylation. NMR measurement is performed by the instructor best in the presence of students. They then interpret their spectra and write standardized listings of them. Their results, together with reaction schemes, descriptions of procedures exactly as they were done, yields, melting and boiling points, and interpreted spectra listings are then summarized in reports. One written report per group is required.

2.4 Hazards

Students are instructed concerning occupational and fire safety at the beginning of the whole series of practical classes following the valid legislation. ¹⁶ They are informed about specific hazards of chemicals used in this synthesis during the practical lesson when the first step is performed, and the main safety warnings are also reminded during every practical lesson. Sodium as the risky material is given to students already cut into small pieces directly into a flask with prepared alcohol by a laboratory assistant or a teacher. All the operations can be done at laboratory desks with the appropriate personal protective equipment including safety glasses, lab coats, and disposable gloves. The work in a fume hood is preferred in case of optional vacuum distillations and is always performed with the direct participation of a teacher or a laboratory assistant.

3 Results

This modified synthesis of valproic acid has been successfully tested with a group of 20 students in the fall semester of 2023, and fully implemented in six groups of up to 24 students in the fall semester of 2024. The results of the student group of 2023 are shown in Table 1.

Table 1:

Results of the first run of the project.

Reaction step	Group 1	Group 2	Group 3	Group 4	Group 5	Group 6	Group 7	Group 8	Group 9	Group 10	Average yield [%]
Dipropyl 2,2-dipropyl malonate (yield [%])	54.7	50.6	72.7	67.0	45.9	48.7 b.p. 128–132 °C/2.4–2.5 kPa	64.8	84.5	68.8	61.7	54.7
2,2-Dipropyl malonic acid (m.p. [C], yield [%])	135–140^a, 50.6	138–143^a, 40.3	130–135, 58.0	135–140^a, 51.3	135–140^a, 78.6	135–139, 69.1	150–154^a, 46.2	135–200^a, >100^b,c	132–137^a, 59.9	135–139^a, 44.5	55.4
Valproic acid (yield [%])	62.6	55.1	45.8	39.5	38.6	61.8	42.6	43.5	60.5	62.2	51.2

^aMeasured after two weeks of drying in a Petri dish at room temperature. ^bExcluded from the average yield calculation. ^cImpurities: K⁺ salts.

The identity of all the intermediate and product samples has been confirmed by ¹H-NMR. The composition of the samples of dipropyl 2,2-dipropyl malonate was determined by this method as a mixture of dipropyl- and diethyl 2,2-dipropyl malonates, with the first one predominating (see also further under Discussion). Both esters were then hydrolyzed to the same 2,2-dipropylmalonic acid. The average yields of the individual reaction steps were 54.7 % for dipropyl 2,2-dipropylmalonate, 55.4 % for 2,2-dipropylmalonic acid, and 51.2 % for valproic acid. The use of either conventional or microwave heating for the decarboxylation did not show any significant difference.

4 Discussion

Bromopropane was used for dipropylation of diethyl malonate. Potassium iodide was added in a catalytic amout to the reaction mixture. It served for increasing of bromopropane reactivity using Finkelstein reaction. ¹⁷ ^, ¹⁸ This reaction is an S_N2 exchange of one halogen for another one by alkylation of halogenide anion. Here, alkyl bromide is changed for alkyl iodide. After dialkyl malonate alkylation with iodopropan, the iodide anion is released and serves for the next run of Finkelstein. Propan-1-ol was chosen as a solvent for the first step, the dipropylation of diethyl malonate, instead of absolute ethanol typically used in this synthesis. ¹² Two reasons lead to this solvent change: first, propane-1-ol boils 23 °C higher than ethanol. This enabled us to shorten the reaction time to a well-acceptable length of 2 h. Second: propan-1-ol is enough dry and markedly cheaper than absolute ethanol. This seemingly paradoxical situation is due to the special tax on ethanol levied by most countries. This change led to the formation of dipropyl 2,2-dipropylmalonate instead of a common diethyl 2,2-dipropylmalonate, due to an alkaline transesterification. More accurately, a mixture of both dialkyl 2,2-dipropyl malonates was prepared, in which the dipropyl ester predominated with the ratio roughly 5.5:1 (from ¹H-NMR), with some admixture of analogous 2-(mono) propyl malonates. This was clear from the ¹H- and ¹³C-NMR spectra. The alkaline or base-catalyzed transesterification, of alcoholysis of esters, has been known for a long time. ¹⁹ Currently, it is often used for biodiesel production ²⁰ (see Figure 2).

Figure 2:

The base-catalyzed transesterification mechanism. (Redrawn by the author based on the reference ²⁰ ).

Here, propanol is in an equilibrium with propanolate. Di- or mono-deprotonated diethyl malonate plays the role of a base. Propanolate attacks the carbonyl carbon with its negatively charged oxygen and a tetrahedral intermediate is formed. This stands in an equilibrium with newly formed propyl ester and ethanolate. Ethanolate turns to ethanol by reaction with non-deprotonated malonate. This reaction runs on one or both ester groups. ²⁰ There was concern that hydrolysis of the dipropyl ester would be more difficult than that of the diethyl ester. Fortunately, this was not confirmed. The optional simple vacuum fraction distillation led to a more homogenous product with a greater predominance of dipropyl 2,2-dipropylmalonate. However, the following alkaline hydrolysis gave virtually the same result in both distilled and non-distilled intermediate. The neutralization of the alkaline reaction mixture after dipropyl 2,2-dipropyl malonate hydrolysis must be done carefully and under vigorous stirring and cooling in a water-ice bath. An inappropriate performance of this step can result in the crystallization of 2,2-dipropylmalonic acid potassium salt, or potassium chloride together with 2,2-dipropylmalonic acid, which can be recognized by the melting range over 160 °C (see column “Group 8” in Table 1). The final step, the decarboxylation of 2,2-dipropylmalonic acid to 2-propylpentanoic acid, was performed either by conventional heating to about 160 °C with copper(I) iodide as a catalyst, or with an admixture of charcoal in a microwave reactor. The first attempts with microwave decarboxylation were also made with copper(I) salts, but there was no liquid product there, and the composition of the solid residual was difficult to determine. The activated charcoal was then selected exclusively as a finely powdered, chemically relatively inert electric conductor, capable of simply transforming the microwave energy to heat. No specific catalytic effect is assumed here. The addition of charcoal led to the formation of valproic acid, which was distilled from the molten reaction mixture as a relatively pure substance. The usage of charcoal as a reagent for decarboxylation has not been reported in the literature yet. The copper(I) salts mono decarboxylation of substituted malonic acids has been, on the contrary, well reported in the literature. The cyclic catalytic mechanism requires both carboxyls (see Figure 3).

Figure 3:

The copper(I) salt catalyzed mechanism of mono-decarboxylation of substituted malonic acids (adapted from reference ¹³ ).

First, copper(I) hydrogen malonate is formed. This compound decomposes under releasing of carbon dioxide, H^+, and a mono-carboxylic acid with Cu(I) bound to α-carbon. The latter one rearranges into copper(I) carboxylate, which then changes by reaction with H⁺, released in the previous step, to a monocarboxylic acid. Copper(I) salt is renewed and ready for the next run of the catalytic cycle. ¹³

As far as non-catalyzed mono decarboxylation is concerned, the mechanism is analogous to that of β-keto acids. It is an example of 1,3-elimination. When a carboxyl carbon is β to a π-bond (as in a carbonyl, alkene, or aryl) intramolecular transfer of a proton to the oxygen of the carbonyl (or to the sp² carbon of alkenes) is possible. Proton transfer requires a syn orientation of the carbonyl oxygen and hydrogen. This thermal process results in cleavage of the bond connecting the carboxyl carbon, loss of carbon dioxide, and renewal of a π-bond. If there is a possibility of keto-enol tautomerism the keto form is preferred. Decarboxylation begins with an internal acid-base reaction, where the acid is the O–H unit of the carboxylic acid, and the base is the oxygen of the carbonyl β to the acid moiety, i.e. of the second carboxyl. Decarboxylation is then possible because of the facile loss of a neutral leaving group of carbon dioxide ²¹ (Figure 4). If there is no β sp² carbon available the decarboxylation runs much harder. This is the case of the theoretic second decarboxylation, i.e. valproic acid to heptan.

Figure 4:

Reaction mechanism of non-catalyzed mono-decarboxylation of substituted malonic acids. ²¹

Such a decarboxylation requires special conditions. It typically runs in a gaseous phase and requires high temperature combined with lowered pressure ²² or a special catalyst like tetracarbonyldiiodoruthenium dihydrogenhexachloroiridate. ²³ Phenylacetic acid has been, for example, found to decompose by pyrolysis occurring in a concerted manner, yielding toluene and carbon dioxide, probably via a four-centre transition state (see Figure 5). ²²

Figure 5:

Thermal decomposition of phenylacetic acid going through a four-centre transition state. ²²

Our modified synthesis has been successfully tested with one model group of 20 students in the fall semester of 2023 and, based on the results, fully implemented in six groups of up to 24 students in the fall semester of 2024. Our practical classes in MC are organized as a series of six consecutive exercises in the fall semester, forming the round. Students work in pairs. While the other tasks are always for only one practical class, the three-step synthesis of valproic acid takes up three consecutive practical classes. That was why not all the students could do this synthesis. After the end of practical classes, both students and teachers involved in this task were asked for their opinions on this synthesis using a questionnaire arranged as a shared Excel sheet. 46 addressed students were asked if

the teaching support was of enough quality
the educational material was of sufficient quality
they were satisfied with the equipment used
the task was difficult for them
the task was interesting to them
it was worth attending
it contributed to an improvement in their knowledge of Medicinal Chemistry
it contributed to an improvement in their knowledge of pharmacy in general
it was adequate to their knowledge of chemistry

The results are summarized in the plot in Figure 6.

Figure 6:

Students’ final feedback after finishing practical classes expressed as a percentage of defined answers to the individual questions.

Briefly, the quality of the teaching support was rated by all students positively, or rather positively. The clarity of the educational material was evaluated most positively or moderately positively. The vast majority of students were satisfied with the laboratory equipment. The task was not difficult, or rather not difficult, for all students, and it was also interesting, or rather interesting for all of them. It was worth attending for the vast majority, and at least rather worth attending for the rest. Most students stated that the task improved, or rather improved their knowledge of MC. All students were also convinced that the task contributed, or rather contributed, to improving their knowledge of pharmacy in general. Finally, all students believed that the task was adequate to their knowledge of Chemistry.

All seven teachers involved in tutoring practical classes in MC, including the author, were asked if:

the teacher’s contribution was important
the educational material was clear
they were satisfied with the equipment
collaboration between teachers (two at every practical class), and between them and the laboratory assistant, was beneficial
the task contributed to the improvement of student’s knowledge of MC
the task contributed to the improvement of student’s knowledge in chemistry in general
the task was stimulating for students
the task was adequate to the chemical knowledge of students
the task contributed the an improvement of the overall practical classes set

The results are summarized in the plot in Figure 7.

Figure 7:

Teachers’ final feedback after finishing practical classes expressed as a percentage of defined answers to the individual questions.

Briefly, teachers convinced that the teacher’s care of students was important or rather important, they found the educational materials clear or almost clear. The equipment was satisfactory in the opinion of the teachers. Teachers were also convinced that the task contributed to the improvement of student’s knowledge in MC, and rather contributed to the improvement of their knowledge in chemistry in general. Teachers also judged that students took a rather positive or positive attitude toward the task. Teachers were divided on whether the activity was stimulating for students. Most of them stated that it was rather stimulating, a larger minority that it was rather not stimulating (around 29 %), and the rest (about 14 %) that it was unambiguously stimulating. In the opinion of the teacher, the task was adequate, or rather adequate to the knowledge of students in chemistry. Teachers also stated that the task rather, or unambiguously contributed to the improvement of the overall practical classes set in MC.

5 Conclusions

This project aimed to develop a simple synthetic procedure for the preparation of valproic acid, separable into blocks of a maximum length of 6 h and 40 min, which could be successfully performed by university students with experience in general, inorganic, and organic chemistry practical classes. The chosen modified malonester synthesis followed by a thermal decarboxylation of 2,2-dipropylmalonic acid met the desired results. The presented procedure was proven as a safe and reliable way to the desired product, which is well-performable in practical classes in MC, or a similar discipline typically at a pharmaceutical faculty. It can be also potentially usable at other faculties with at least partial chemical orientation. It must be only mentioned that undergraduate students performing this three-step synthesis must have previous experience with a synthetic practice from practical classes at least in organic chemistry. The task was also positively rated by both students and teachers involved in it.

Supplementary information

Laboratory instruction for students.

Photos of apparatuses used for the decarboxylation.

NMR spectra of the intermediates and final product.

Corresponding author: Oldřich Farsa, Faculty of Pharmacy, Department of Chemical Drugs, Masaryk University, Brno, Czech republic, E-mail: farsao@pharm.muni.cz

Acknowledgments

The author is grateful to Ms. Anna Sedláčková for her assistance in performing many experiments during the development of this synthetic protocol, and to the group of students of 3rd year of Pharmacy of the autumn semester 2023 for testing this procedure during their practical laboratory classes.

Research ethics: Not applicable.
Informed consent: Not applicable.
Author contributions: The author has accepted responsibility for the entire content of this manuscript and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The author states no conflict of interest.
Research funding: None declared.
Data availability: Not applicable.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/cti-2025-0028).

Received: 2024-12-03

Accepted: 2025-05-14

Published Online: 2025-05-28

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Articles in the same Issue

https://doi.org/10.1515/cti-2025-0028

Keywords for this article

medicinal chemistry; practical classes; active pharmaceutical ingredient (API) synthesis; valproic acid

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