In 1832, German chemist Justus von Liebig used dry chlorine gas to treat anhydrous ethanol and synthesized one of the first active pharmaceutical ingredients (APIs ) — chloral hydrate, which revolutionized the pharmaceutical manufacturing industry with the introduction of halogenation. There now existed an efficient method of synthesizing and altering organic compounds.
There are two primary reasons a bromine atom might be incorporated into an API. Firstly, for its desired pharmacological effect on the API. Secondly for its effect on the chemical reactivity and selectivity during the synthesis of an API. UV bromination is a rare, efficient halogenation technique that uses ultraviolet light — a single oxidant — as a catalyst to introduce a bromine atom into a specific position in a molecule and change its chemical properties. As one of the least reactive and most selective halogens, bromine in conjunction with UV light as a catalyst negates the use of solvents or other, more volatile reagents.
Application of UV Bromination
UV bromination enables the selective substitution of bromine atoms with hydrogen atoms in aliphatic or aromatic compounds. For example, UV bromination of methylbenzene creates bromine free radicals, which displace hydrogen atoms on the methyl group. The reaction results in either bromomethyl benzene or dibromomethyl benzene, depending on the amount of bromine used. Once complete, it's possible to convert dibromomethyl benzene into 4-Bromo-2-chlorobenzaldehyde — a molecule with API potential.
Bromination can have the following effects on the building block of API:
- Altering reactivity, affinity, stability, or solubility
- Enhancing lipophilicity
- Changing molecular structure to improve potency, selectivity, receptor interactions, or pharmacokinetic properties
Ultraviolet bromination has specific advantages over other types of bromination, such as the H2O2/HBr or Lewatit LK2621/Br2 methods. Primarily, it doesn't require the use of solvents or other reagents, resulting in the overall method being environmentally friendly, as there is less waste. UV light activated brominations can also be operated in mild conditions, such as ambient or moderate temperatures. This is more cost-effective for lab operators, as it eliminates excessive spend on heating and cooling solutions.
UV light enables the streamlined, rapid activation of bromine without requiring extreme temperatures or harsh chemicals. Overall, UV bromination facilitates efficient reactions compared to other methods, improving productivity and operational efficiency for pharmaceutical manufacturers.
The following are examples of intermediates that may undergo bromination, which is specific to particular products and rarely publicly disclosed:
- Zolpidem contains a bromine atom
- A bromine atom is introduced to Bromfenac's API
- Bromocriptine undergoes bromination during synthesis
UV Bromination Is the Most Efficient Way to Create Advanced Intermediate Building Blocks
Having a bromine group on the intermediate allow you to synthesize complex chemical compounds. These chemical compounds are base materials for APIs and are composed of several organic molecules. In some cases, adding a bromine atom can bring about a desired reaction or set of reactions.
Brominated intermediates are especially useful in the manufacturing of certain pharmaceuticals:
- 4-Bromobenzyl bromide: Anticancer and antiviral agents
- 2-Bromopropiophenone: Anticonvulsant and pain relief drugs
- Bromoindoles: Anticancer and antimicrobial
- 3-Bromopyruvic acid: Cancer therapy
Using UV bromination makes intermediates production more efficient and cost-effective because it eliminates heat and chemical processing. UV bromination is practical for producing intermediates at scale, not just because of the increased speed afforded by the UV catalyst — but also because of regioselectivity and stereoselectivity:
- Regioselectivity: Permits selective introduction of a bromine atom to enable the required biological activity
- Stereoselectivity: Able to achieve control over the spatial arrangement of the bromine atom for accurate stereochemistry where necessary
Why Ascensus Uses UV Bromination
Ascensus Specialties: Cambridge creates chemistries to simplify, advance, and optimize life. Our team uses a mixture of classical organic synthesis techniques in addition to specialized reaction capabilities using halogenation. UV bromination is an under-utilized, highly effective form of halogenation. It's one of the techniques the company uses to create its comprehensive range of more than 2,000 aromatic starting materials and multistep intermediates.
Smaller, Controlled Volumes for Improved Quality
Perhaps the most pertinent benefit of UV bromination for pharmaceutical companies is its potential to improve quality throughout the manufacturing process, regardless of volume. It enables precise control of the duration and intensity of UV light exposure, which results in more stable and consistent reactions — and fewer missteps. Since UV bromination negates the unwanted variations and side reactions caused by traditional bromination methods, manufacturers can reliably maintain a higher level of quality. Furthermore, due to the fact fewer steps are required for chemical synthesis, there’s more time to design and implement stringent quality control measures.
The Future of UV Bromination in Pharmaceuticals Manufacturing
As scientists look to find better, more environmentally friendly methods, UV bromination will gain more attention. In addition to the above benefits, it can potentially be used in continuous flow reactions, making pharmaceutical production more sustainable, efficient, and streamlined. Its relative lack of reactivity and high selectivity make it a cost-effective and safe alternative to traditional bromination methods.