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Pharmaceutical Roots – Almonds and Enantiomers

Pharmaceutical roots is a new series from LGC Mikromol, investigating and outlining the natural origins of pharmaceutical substances, and offering a deeper dive into their uses, risks, and mechanisms of action.

Mandelic acid

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Mandelic acid is a small, aromatic compound with many different uses. Although these days it is usually prepared in the lab, mandelic acid was originally extracted from bitter almonds in 1831, by a German pharmacist named Ferdinand Winckler.

The bitter almond, or Prunus dulcis var. amara, is a broader, shorter, and of course more bitter-tasting version of the sweet almond. Native to Iran, ‘almond’ is actually the name given to the tree – the edible part is in fact a seed of the almond fruit.

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Mandelic acid derives its name from the German word mandel, meaning almond. The compound has antibacterial properties, lending it some utility in the treatment of urinary tract infections. It is also a common anti-ageing ingredient in skincare products. As a chiral compound, mandelic acid comes in two forms – (R)-mandelic acid, which is used as a key intermediate for production of semisynthetic cephalosporin antibiotics, and (S)-mandelic acid. Both (R)- and (S)-mandelic acid enantiomers are used as chiral resolving agents, and serve as useful precursors to various drugs, including pregabalin, sertraline, and homatropine.

Enantiomers

Between 1957 and 1962, tens of thousands of babies were born with severe birth abnormalities. These defects were due to a drug called thalidomide. Marketed as an over-the-counter ‘wonder drug’ to treat insomnia, depression, and morning sickness, it wasn’t until 1961 that a correlation was noticed between the use of thalidomide by pregnant women and an increase in birth defects.

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The reason thalidomide caused such tragic problems lies in the chemistry of the drug. Thalidomide is chiral, which means that it comes in two forms which are mirror images of each other. They are labelled as (R)- or (S)-enantiomers. This slight difference in structure can have drastic effects on the way the drug binds to receptors. In the case of thalidomide, the (R)-enantiomer is effective against morning sickness, but the (S)-enantiomer causes birth defects.

The majority of pharmaceuticals are enantiomeric, so it is incredibly important to be able to monitor the stereochemistry of pharmaceuticals. Small enantiomeric compounds, like mandelic acid, can be used to resolve the chirality of drugs and ensure mistakes like thalidomide never happen again.

Uses of Mandelic Acid

Pregabalin is an anticonvulsant used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, and generalised anxiety disorder.

It is a chiral molecule, and the desired enantiomer is (S)-pregabalin. It is often synthesised to give a racemate (mixture of (R)- and (S)- enantiomers) and resolved using (S)-mandelic acid.

Pregabalin molecules feature a carboxylic acid group (highlighted in green), and this group is prone to degradation to form various ester groups. Esters are a class of compounds that typically smell very sweet – they give fruits such as strawberries and apples their smell and are often used in perfumes.  Some examples of ester impurities of pregabalin include pregabalin methyl ester, pregabalin ethyl ester, pregabalin isopropyl ester, and pregabalin isobutyl ester. It is extremely important to monitor impurities, especially degradation products as these can be formed in the final drug product, even under ambient conditions.

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Sertraline is a popular SSRI (selective serotonin reuptake inhibitor) antidepressant particularly effective at treating panic disorder and obsessive-compulsive disorder (OCD).

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Sertraline has an interesting, and slightly more complicated structure than pregabalin, as it is a diastereomer, with two chiral centres and up to four configurations. There are several synthetic routes to sertraline, but generally, it is resolved by (R)-mandelic acid in the final synthesis step, giving rise to 1, the more potent (S,S)-configuration.

Of course, it is not always possible to fully resolve a racemic mixture, and it is important to make sure the levels of the remaining three diastereomers with 2 (S,R), 3 (R,S) and 4 (R,R) configuration are below the minimum threshold.

In the case of sertraline, the main types of impurities that can arise are synthesis related impurities. Several steps in the typical synthesis of sertraline involve hydrogen and a palladium catalyst. During these steps, a common side reaction is the dehalogenation (removal of chlorine) of aromatic groups. A good example of this is the final synthetic step before resolution with mandelic acid. This step begins with compound 5. This ketone reacts with methylamine to give sertraline, but in the process, dehalogenation can occur, giving rise to compounds such as 6 and 7  which are each missing one chlorine atom, or 8 which has had both chlorine atoms removed. It should be noted that compound 5 is a key intermediate impurity.

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Homatropine methylbromide is an anticholinergic medication used to treat various issues including stomach ulcers, intestine problems, nausea, vomiting and motion sickness.

Homatropine methylbromide contains a tropane ring in its structure, which is actually a type of alkaloid that occurs in many members of the Solanceae family (such as the tobacco and tomato plant). To synthesise homatropine, tropine, 9, is reacted with mandelic acid under acidic conditions. This further reacts with methyl bromide to give 10 homatropine methylbromide.

Because of the conditons under which this step is carried out, it is very likely that the ester methyl mandelate 12 will form, as the result of a side reaction between mandelic acid and methylbromide. Homatropine methylbromide can also undergo further oxidation to give epoxide 11.

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Outlook

Recent research has uncovered promising environmentally friendly pathways for the synthesis of mandelic acid, including the use of Escherichia coli (E. coli) bacteria clones. One team of researchers from the Institute for Microbiology at Stuttgart University constructed strains of E. coli which simultaneously expressed a (R)-specific oxynitrilase (hydroxynitrile lyase) from the plant Arabidopsis thaliana together with the arylacetonitrilase from the bacterium Pseudomonas fluorescens. The researchers concluded they had generated “efficiency systems” for the biocatalytic production of (R)-2-hydroxycarboxylic acids and (R)-2-hydroxycarboxamides.

Another team from the Max Planck Institute for Terrestrial Microbiology utilised a newly identified activity of the enzyme oxalyl-CoA decarboxylase (OXC). The researchers found that, alongside degrading oxalate, OXC can create a new bond between two carbon atoms. During this reaction, OXC produces a highly active form of formic acid – the main constituent of ant venom. Via surgical mutations and combinations with other enzymes, the researchers created a three-step cascade that converts oxalic acid and benzaldehyde – both cheap and safe starting materials – into mandelic acid, under mild conditions.

About the author

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Dulcie Phipps is an Assistant Global Product Manager at LGC.

A chemist with a passion for nature, she grew up in the glens of Perthshire, Scotland. Phipps’ academic background includes a Marine Science HNC, an MSc in Chemistry from the University of Glasgow, and a European work placement focusing on lanthanide chemistry at Uppsala University, Sweden. After completing her degree she moved to Luckenwalde, Germany, to work for LGC.

 

 

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