Fentanyl is a synthetic opioid drug first synthesized by Dr. Paul Jannsen in Belgium, 1960. It, like many other opiod drugs, binds to the μ receptor (Stanley, 2014, 1215). The μ receptor is best known for its role in how opioids work in the brain, being the primary receptor for the body's opioid system (“Mu Opioid Receptor: A Gateway to Drug Addiction,” 2004, 370).
Jannsen’s team looked at the commonly used analgesic drugs of the time, like morphine, and suggested one of the most important reasons they work is their shared piperidine ring (Fig. 1). Modifying meperidine as their base, the team continued with their research creating hundreds of different drugs over the course of the mid-to-late fifties. Their goals were to make a more potent and fat soluble drug. They cited meperidine as being too hydrophilic, and therefore couldn’t cross the blood brain barrier easily, which made it much less potent compared to morphine (Stanley, 2008, 454).
Their research culminated first in 1957, when they first made the drug phenoperidine, which was over 50 times more potent than morphine, and the effects quickly set in. This drug was then released across Europe, and is still used in many countries as an analgesic (Stanley, [1] 2014, 1216).
After reducing the distance between the piperidine and benzene rings, along with adding nitrogen between them, and many other small tweaks, the team discovered fentanyl (Stanley, 2008, 453). Fentanyl’s use in pain management cannot be overstated. “Mu opioid receptors are widely distributed throughout brain reward circuits and their role in drug… reward is well established” Hamida et al. write in their paper “Mu opioid receptors in GABAergic neurons of the forebrain promote alcohol reward and drinking.” In short, they make you feel good. Fentanyl patches have been available for decades and transmucosal ‘lollipops’ since the 90’s (Stanley, 2014, 1217, Hanida et al., 2019, 28). All in the aim of treating chronic pain. An efficient and cheap way to produce an important precursor is necessary to make treatments cheaper for the patient, and have a good line of production for all who need it.
This process of making N-Phenylethylpiperidin-4-one (NPEP4) is a long task, though it does produce a pure result that is important to producing safe fentanyl and other analgesics (Valdez et al., 2014, 3).
To start off, production of 4-Piperidone HCL Hydrate is necessary, (Valdez et al., 2014, 1) bring 318.46[2] grams of Piperidine-4-one Hydrochloride into a beaker with 9,553.8 ml of Dichloromethane at 0 degrees celsius (Valdez et al., 2014, 5). Add 820 ml of triethylamine and 253.17 ml of ethyl chloroformate to this solution, (roughly a 32:10 ratio) and stir at ambient temperatures[3] for 2 hours or longer. Dilute the solution with water, and dry the organic layer that separates with anhydrous sodium sulfate. Then remove any volatiles under low pressure to get approximately 500 grams of N-Carbethoxy-4-piperidone at a 98% yield (How to Synthesize N-Carbethoxy-4-Piperidone, n.d.).
Bring the 500 grams of N-Carbethoxy-4-piperidone to a beaker with 2 liters of methanol and 500 grams of trimethyl orthoformate. Lightly stir while charging in a reactor at 30 degrees celsius. Raise the mixture to 30 degrees celsius and slowly add 7.5 grams of P-toluene sulphonic acid over 4 partitions.
Once the full mass of the PTSA is added, cool to 25c for 15 minutes and then raise the temperature to 63 degrees celsius for an hour to obtain a mass. This mass will consist of N-Carbethoxy-4,4-dimethylpiperidine.
Cool down the mass to approximately 50 degrees celsius and in a beaker measure out 1500 grams of 50% KOH solution in water (or alternatively measure 750 grams of KOH and 750 grams of water and stir heavily to dissolve). add this over 90 minutes to get a slurry. Keep this slurry at 60 degrees celsius for 15 minutes and then slowly rise to 75 degrees celsius. Maintain this temperature for >32 hours to obtain a mixture of 4,4-dimethylpiperidine. Using a still, distill out the methanol and trimethyl orthoformate at atmospheric pressure and ambient temperatures.
Once they are completely removed, cool the mixture to 40 degrees celsius and allow to settle for an hour. Separate the organic layer, distill the solvents that remain and the water at a low vacuum. slowly increase the temperature whilst remaining under 80 degrees using a 1 foot column having structure packing. Place under a high vacuum and distill out approximately 350 grams of >99%[4] purity 4,4-dimethylpiperidine.[5]
1050 grams of 30% HCL is to be charged in a reactor at 25 celcius and then cooled to 10 celsius. Add the 350 grams of 4,4-dimethylpiperidine over 2 hours to create a mass. Maintain the mass at 10 degrees celsius for 20 minutes, and then raise it to 75 degrees celsius and held at that temperature for 4 hours to find a mass containing Piperidone HCL hydrate. After the reaction is complete, apply a vacuum to distill out HCL under 80 degrees celsius until the mixture becomes a hazy viscous slurry.
After complete distillation, the mass should be cooled to <40 degrees, add 1750 ml of isopropanol (Isopropyl alcohol) and stir for 20 minutes. This will result in the creation of a mixture which is to be cooled to 5 celsius and maintained at that temperature for 3 hours. Finally, filter the mixture and wash over with 500 ml of isopropanol, to obtain a ‘wet cake’. Dry under a vacuum at 55 degrees celsius for 5 hours to acquire 320 grams of 98% pure 4-Piperidine[6] HCL hydrate (Soni et al., 2022).
Take 22 grams of the 4-Piperidine HCL hydrate that was produced and dissolve it into 400 ml of acetonitrile in a one liter round bottom flask with a stir bar and condenser. Then add 102.6 grams of cesium carbonate and 17.8 ml of 2-bromoethyl benzene at ambient temperature. Stir the solution heavily at 80 degrees celsius for 5 hours while refluxing (continually boiling and then condensing the vapours back into the solution) (Valdez et al., 2014, 5).
Funnel the solution and partition (Dichloromethane and water[7]) and wash the organic phase of the solution in a simple salt brine (NaCl and water) and satd. sodium bicarbonate, to dry over sodium sulfate. Concentrate the mixture in a vacuum and purify via flash column chromatography[8] to obtain an amber looking oil of N-phenylethylpiperidin-4-one that is 88% pure (Valdez et al., 2014, 5).
The main problem with this method as currently described is in the production of 4,4-dimethylpiperidine from slurry, which takes over 24 hours (Soni et al., 2022). It makes the process significantly longer, and in future documentation should be optimized. One way to combat this could be to use flash column chromatography in this step, so that the pressured gases separate it from the other components, like excess water[9] (Moore, 2020. Material Harvest, 2008). You could also use flash column chromatography to further purify the ending NPEP-4-one and get better results. These are my recommendations for the process. [10]
In all, through synthesizing numerous sources an improved discipline in producing N-phenylethylpiperidin-4-one as a precursor to fentanyl is shown, and improvements are still to be made. Scientifically, fentanyl is a vital component to modern pain management, for doctors, patients, and friends and family (Stanley, 2014, 1217). In finding an easier and safer way to produce precursor chemicals we can build a stable foundation for the future of analgesic discovery. “The current field of pain management exists in an incredible era…” Dr. Matthew Slitzky et al. writes in their paper “The Future of Pain Medicine: Emerging Technologies, Treatments, and Education.”, “that may one day bring relief to hundreds of millions across the globe.”
Bode, J., Rochester University, & UC Santa Barbara department of chemistry. (n.d.). How to Run a Flash Column. Not voodoo x.4. https://www.chem.rochester.edu/notvoodoo/pages/how_to.php?page=flash_column
Dunmire, B., & Lehigh university of chemical engineering. (2013, October 12). Extraction — Organic Lab. CHEMICAL AND BIOMOLECULAR ENGINEERING. https://lehighcheme.wordpress.com/2013/10/16/extraction-organic-lab/
Fuesz, J. R. (2025, February 19th). Fuzzsimp. https://fuzzsimp.neocities.org/imag
Hanida, S. B., Boulos, L.-J., McNicholas, M., Charbogne, P., & Kieffer, B. L. (2019, January). Mu opioid receptors in GABAergic neurons of the forebrain promote alcohol reward and drinking. Addiction Biology, 24(1), 28-39.
How to Synthesize N-Carbethoxy-4-piperidone. (n.d.). guidechem. https://www.guidechem.com/question/how-to-synthesize-n-carbethoxy-id130368.html
Jingdong, Y., Bin, Z., Shoukao, D., & Tianming, G. (2014, January 8). Method for preparing high-purity acetonitrile from acetic acid and ammonia by two steps. https://patents.google.com/patent/CN101891648A/en
Material Harvest. (2008). Silica Gels for Column Chromatography. MaterialHarvest. http://www.materialharvest.com/welcome/silica_products/silica_gels_chromatography.html
Moore, S. (2020, October 22). What is Flash Column Chromatography? News-Medical. Retrieved January 29, 2025, from https://www.news-medical.net/life-sciences/What-is-Flash-Column-Chromatography.aspx
Mu opioid receptor: a gateway to drug addiction. (2004, june). Current Opinion in Neurobiology, 14(3), 370-378.
Slitzky, M., Yong, R. J., Bianco, G. L., Emerick, T., Schatman, M. E., & Robinson, C. L. (n.d.). The Future of Pain Medicine: Emerging Technologies, Treatments, and Education. Journal of Pain Research, (2024:17). https://pmc.ncbi.nlm.nih.gov/articles/PMC11370752/pdf/jpr-17-2833.pdf
Soni, P. R., AMI ORGANICS INC., Bhagatwala, H. K., Desai, J. T., Dubey, R. R., & Choubey, A. K. (2022, september). A PROCESS FOR THE PREPARATION OF 4-PIPERIDONE HCL HYDRATE [patent disclosure for the formation of 4-piperidone hydrochlordide hydrate, an important precursor to fentanyl.] [patent]. WIPO PCT. https://patentimages.storage.googleapis.com/c0/0b/7a/1c9c9e7b0b90fd/WO2022195497A1.pdf
Stanley, T. H. (2008, February). A Tribute to Dr. Paul A. J. Janssen: Entrepreneur Extraordinaire, Innovative Scientist, and Significant Contributor to Anesthesiology. Anesthesia & Analgesia, 104(2), 451-456. https://journals.lww.com/anesthesia-analgesia/fulltext/2008/02000/a_tribute_to_dr__paul_a__j__janssen__entrepreneur.16.aspx
Stanley, T. H. (2014, December). The Fentanyl Story. The Journal of Pain, 15(12), 1215-1226.
Stanley, T. H., Hague, B., Mock, D. L., Streisand, J. B., Bubbers, S., Dzelzkalns, R. R., Bailey, P. L., Pace, N. L., East, K. A., & Ashburn, M. A. (n.d.). Oral transmucosal fentanyl citrate (lollipop) premedication in human volunteers. Anesthesia and Analgesia. https://pubmed.ncbi.nlm.nih.gov/2742164/
Valdez, C. A., Leif, R. N., & Mayer, B. P. (2014, September 18). An Efficient, Optimized Synthesis of Fentanyl and Related Analogs. PLOS one. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108250
[1] Figure: Skeletal structures of Fentanyl, morphine, and meperidine. They all share a carbon ring with 1 nitrogen and a hydrogen, also known as a piperidine ring (Fuesz, 2025).
[2] All math here was multiplied at a ~159.23x scale to deliver the 350 grams of 4,4-dimethylpiperidine for the next step(s).
[3] For this purpose, assume ambient temperature(s) are/is ~21 degrees celsius.
[4] Purities from the original paper(s) were determined via gas chromatography (a.k.a. GC analysis) (Soni et al., 2022)
[5] Figure: Van der Waals sphere structure of the compound 4-piperidone HCL hydrate (Fuesz, 2025).
[6] From my research, in these cases there is no clear distinction between a ‘piperidone' and a ‘piperidine’ other than spelling. The paper this is cited from did use the term piperidone here. The term piperidone does seem to be extensively and almost exclusively linked to 4-piperidone.
[7] Liquid/ liquid extraction works by putting a solute in water and then adding an organic liquid with a differing density that the solute diffuses into. Caffeine is an example, if you did a DCM/H2O extraction with tea, caffeine would diffuse over into the DCM that it is more soluble in. This layer is then extracted (Dunmire & Lehigh university of chemical engineering, 2013).
[8] 1:1 → 7:3 EtOAc/hexanes according to “An Efficient, Optimized Synthesis of Fentanyl and Related Analogs” written by Carlos Valdez, Roald Leif, and Brian Mayer.; Flash column chromatography is a way to purify a substance by having it partition through silica while being forced through by either a vacuum or gas. You then take out parts where the desired compounds are present (Bode et al., n.d.) (Moore, 2020).
[9] If there is sufficient water, you could also partition it over dichloromethane to remove the organic layer.
[10] Fig. 3: Van der Waals sphere structure of NPEP-4 (Fuesz, 2025).
