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Ibuprofen has a long history and has become one of the most popular non-steroidal anti-inflammatory drugs in clinical use since it was introduced in the UK in 1966. In addition, Ibuprofen is also one of the essential medicines in people's daily life, with antipyretic, analgesic and anti-inflammatory effects. Due to its precise effect and small adverse reactions, it is one of the three pillars of antipyretic and analgesic medicines, together with Aspirin and Acetaminophen (Paracetamol). In daily life, when people feel headache, toothache, joint pain, or fever caused by the common cold, or women's physiological period pain, most people will choose ibuprofen for treatment.

Brief history and mechanism of action of ibuprofen

In the 1960s, when researching certain plant growth hormones, it was found that compounds such as naphthalene acetic acid, indole acetic acid and 2,4-disubstituted phenoxyacetic acid have certain anti-inflammatory effects, and the anti-inflammatory effect can be increased by adding a hydrophobic group to the benzene ring. Among them, 4-isobutylphenylacetic acid has a very good anti-inflammatory and analgesic effect and is less irritating to the gastrointestinal tract, but it has been found to have a certain degree of hepatotoxicity after clinical application. In order to solve this limitation, it was found that if a methyl group was introduced into the α-carbon atom of the acetic acid group, 4-isobutyl-α-methylphenylacetic acid (ibuprofen) was obtained, which not only enhanced the anti-inflammatory and analgesic effects, but also reduced the toxicity. The mechanism of action of ibuprofen varies according to its symptoms. Generally speaking, it produces analgesic and anti-inflammatory effects by inhibiting the enzyme cyclooxygenase and reducing the synthesis of prostaglandins; it also exerts antipyretic effects through the thermoregulatory center of hypothalamus.

Chemical Synthesis of Ibuprofen

The structure of ibuprofen is not very complex, and thus the chemical synthesis is not very difficult. The molecule contains only one chiral center, and theoretically has two optical isomers, and it is important to point out that the main one used in the clinic at present is the racemate. In fact, only the enantiomer of the (S)-configuration is pharmacologically active, and there is evidence that (S)-ibuprofen alone is more potent than the racemate and has significantly fewer toxic side effects.

The synthesis of the racemate ibuprofen is based on isobutylbenzene as a starting material, the introduction of acetyl group into the benzene ring using Friedel-Crafts acylation reaction, Darzens condensation with ethyl chloroacetate under the action of sodium alcohol, hydrolysis, decarboxylation and then further oxidized to obtain the aldehyde intermediates under alkaline conditions, and oxidation of the aldehyde to carboxylic acid by strong oxidizing agent AgNO3 to obtain the target product, ibuprofen.

Similar to the traditional method of obtaining chiral pure compounds, the synthesis of (S)-ibuprofen can be realized by splitting method and asymmetric catalysis. The currently reported splitting methods mainly include chemical splitting and biological splitting, both of which have been applied to some extent, but this ancient and conventional method is characterized by cumbersome process, low productivity, high cost, and pollution of the environment which need to be solved urgently.

In 1996, Zhao Jun et al. used 90% optically pure natural (S)-lactic acid as the raw material, dehydrated with methanol to form an ester, and then further prepared it into a Ts-activated lactic acid ester, in which the chiral center could be maintained unchanged during the whole process. Subsequently, a Friedel-Crafts alkylation reaction with isobutylbenzene was carried out, and (S)-ibuprofen could be directly synthesized after hydrolysis. It is worth mentioning that the alkylation process does not result in the formation of a true positive carbon ion, and thus the "racemization" effect due to its planar structure is not significant.

Adverse effects of ibuprofen

Although ibuprofen has few adverse effects, it can cause discomfort if not taken properly. The most common adverse reactions are nausea and vomiting, and the most common skin reactions are itching and the development of maculopapular rash, drug rash, and photosensitive dermatitis. In addition, it should be pointed out that, after taking ibuprofen try not to drink alcohol, alcohol is easy to aggravate the adverse effects of the drug, increase the stimulation of the gastrointestinal tract, causing nausea and vomiting, in severe cases, can lead to gastric ulcers, gastric hemorrhage, increase the drug's liver and kidney toxicity, and will also affect the action of the drug.

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