Targeting chemical synthesis through a single ibuprofen

 Today we will talk about the synthesis and mechanism of action of Ibuprofen, an evergreen drug!

As an essential part of the development of the pharmaceutical industry, the chemical synthesis of drugs is the primary source of candidate drugs. It is also a high-input, high-output, and high-efficiency work.

Medicilon is proud of our extensive expertise in synthetic organic chemistry, providing chemical synthesis services. Medicilon's synthetic chemistry team can independently design synthesis pathways and complex compound treatments, which is key to helping accelerate our clients' drug discovery.

The research and development directions of chemically synthesized drugs mainly include the following:

• Research and development of new chemical entity drugs;
• Create "Me-too" new drugs—research and development of imitative new drugs;
• Further research and development of known drugs;
• Pharmaceutical research and development of existing drugs;
• Research on new uses of existing drugs;
• Avoiding patented technology.

Recently, Ibuprofen has been hard to find and has become a hard currency.

1.Ibuprofen

Ibuprofen, molecular formula C13H18O2, chemical name 2-(4-Isobutylphenyl)propanoic acid. Ibuprofen is a commonly used non-steroidal anti-inflammatory drug (NSAID), which produces analgesic and anti-inflammatory effects by inhibiting cyclooxygenase and reducing prostaglandin synthesis; it acts as an antipyretic agent through the hypothalamic thermoregulatory center. Ibuprofen is usually well tolerated and does not usually cause clinically significant severe acute liver injury.

Image1: Ibuprofen chemical structure

2. Ibuprofen indications

Oral administration: For the relief of mild to moderate pain such as arthralgia, neuralgia, muscle pain, migraine, headache, dysmenorrhea, and toothache, and also for the relief of fever due to the common cold or influenza.

Injectable administration: for antipyretic and analgesic treatment: for mild to moderate pain, as an adjunct to opioid analgesics for moderate to severe pain; antipyretic therapy of fever.

3. Ibuprofen mechanism of action

Ibuprofen is a diastereomeric chiral drug containing R- and S-ibuprofen. Pharmacokinetic studies have shown that most of the pharmacologically active form of the drug is contributed by its S-enantiomer, as it inhibits prostaglandin synthesis. In the early to mid-1970s, the first report of the conversion of the inactive R-enantiomer to the active S-enantiomer by unidirectional enzymatic conversion was made. Approximately 40-60% of the R-enantiomer is metabolized in the liver to the S-ibuprofen form. Its anti-inflammatory effect is due to the inhibitory activity of S-ibuprofen on cyclooxygenase (COX), which is responsible for prostaglandin synthesis and plays a vital role in neuronal death mediated by an increased inflammatory response. Ibuprofen inhibits COX, reduces nitric oxide (NO) production, and activates peroxisome proliferator-activated receptor-γ (PPAR-γ).

Image 2: Mechanism of action of Ibuprofen [1]

4. Ibuprofen Chemical Synthesis

Ibuprofen was first patented by Boots Pure Chemical Company in 1961 and approved as an over-the-counter drug in 1984. Since its introduction, Ibuprofen has been marketed under several brands, including Advil® and Motrin®. The synthesis of ibuprofen begins with isobutyl benzene. The synthesis process includes Friedel-Crafts acylation, reduction, chloride substitution, and the Grignard reaction. The products of each step were then analyzed by IR and 1 H NMR spectroscopy, and the final product was confirmed by melting point determination analysis.

In 1992, BHC developed a new sustainable synthesis method that cut the synthesis steps in half. The first step uses anhydrous hydrogen fluoride as the catalyst and solvent, which is then recycled and reused. In addition, the real highlight behind the BHC method was the reduction of unwanted waste and impurities, generating only one water molecule as a by-product. This led to a genuinely green synthesis.

Image 3: Chemical synthesis of Ibuprofen [2]

In 2009, Andrew R. Bogdan et al. of Florida State University used a microreactor to synthesize Ibuprofen. Microreactors are safer, more efficient, and more selective chemical transformations in microchannels or narrow bore tubes. Using isobutyl benzene and propionic acid as feedstock, the total reaction time was approximately 10 minutes, with a crude yield of 68% and a yield of 51% after recrystallization (99% purity by GC and NMR analysis).

Image 4: Continuous Synthesis Process for Ibuprofen [3]

In 2014, David R. Snead, Ph.D., and Professor Timothy F. Jamison of Massachusetts Institute of Technology (MIT) performed a multi-step sequential reaction using isobutylene and propionyl chloride as feedstocks. Ibuprofen was assembled from its basic structural units in three minutes, with an average yield of over 90% at each step from the starting material to the target compound.

Image 5: The continuous synthesis process of Ibuprofen [4]

References

[1] Ashish Singh et al. Neuroinflammatory responses in Parkinson's disease: relevance of Ibuprofen in therapeutics. Inflammopharmacology. 2021 Feb;29(1):5-14. DOI: 10.1007/s10787-020-00764-w.

[2] Mark A. Murphy. Early Industrial Roots of Green Chemistry and the BHC Ibuprofen process invention's history and quality connection. Foundations of Chemistry volume 20, pages 121-165 (2018).

[3] Andrew R Bogdan, et al. The continuous-flow synthesis of Ibuprofen. Angew Chem Int Ed Engl. 2009;48(45):8547-50. doi: 10.1002/anie.200903055.

[4] David R Snead et al. A three-minute synthesis and purification of Ibuprofen: pushing the limits of continuous-flow processing. Angew Chem Int Ed Engl. 2015 Jan 12;54(3):983-7. DOI: