Green and Sustainable Medicinal Chemistry – 25 years later


What is Green Chemistry?

In short, Green Chemistry aims to prevent pollution through waste minimisation and by avoiding toxic and hazardous substances in the production and application of chemical products.  This is achieved by substitution of undesirable chemical products and processes by cleaner, safer and environmentally friendlier alternatives.1

In the 1990s the 12 Principles of Green Chemistry were established (Figure 1).

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Figure 1: 12 Principles of Green Chemistry.  Image taken directly from source.1

 

Green Chemistry Metrics and Tools to assist Medicinal Chemists

Atom economy (AE)

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Environmental factor (E factor)

The E-factor is the amount of waste (kg) produced when 1 kg of desired product is made, taking into account all of the auxiliary components – yield, reagents, waste solvents, waste from chemicals used in work-up and fuel (although difficult to quantify) and can be applied to a multistep process.1

Solvent Selection guides

Solvent selection guides exist that give information about the hazards of particular solvents (Table 1).2  Solvents represent at least half of the material used in the synthesis of pharmaceuticals and a significant amount of the waste per kg of desired compound.2

Recently, solvents have been ranked as follows:2

– Recommended (or preferred): solvents to be tested first in a screening exercise, if of course there is no chemical incompatibility in the process conditions.

– Problematic: these solvents can be used in the lab or in the Kilolab, but their implementation in the pilot plant or at the production scale will require specific measures, or significant energy consumption.

Hazardous: the constraints on scale-up are very strong. The substitution of these solvents during process development is a priority.

Highly hazardous: solvents to be avoided, even in the laboratory.

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Table 1: CHEM21 solvent guides (both taken from directly from source)2

Reagent guides

Members of the ACS GCI Pharmaceutical Roundtable have access to a Reagent guide that’s aim is to encourage chemists to choose ‘greener’ reaction conditions.  At the moment I have not come across a similar guide for non-members.  For the time being it is up to the individual to search in Reaxys or Scifinder, look at reaction conditions and choose greener alternatives.

Green Chemistry and Pharma

Roger Sheldon’s E(fficiency) factor highlighted that Pharma in particular produces vast amounts of waste per kg of desired product (Table 2).3

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Table 2:  The E factor (taken directly from source)3

However, it is important to note that the E factor does not take into account that the implicit molecular complexity of pharmaceuticals is twinned with limited engineering flexibility of reaction set-up.  This puts a significant responsibility for synthetic efficiency directly upon the medicinal chemist compared to those producing Bulk chemicals.  It also does not recognise that some waste is more hazardous than other waste products.4

Over the past two decades the Pharma industry has made great strides in incorporating Green Chemistry and engineering philosophies, especially into process development (read on for highlights).1

Advances in In Silico drug design and increased understanding of physicochemical properties (e.g. Lipinkski’s Rule of 5) has undoubtedly reduced waste through better and more targeted design.4  Many companies and academic institutions (including the SDDC) are documenting experiments in electronic lab notebooks (ELN) rather than using paper lab books thus reducing waste.

The ACS GCI Pharmaceutical Roundtable (12 globally leading pharmaceutical companies and 3 associate members) was established in 2005 specifically to encourage the integration of green chemistry and green engineering in the pharmaceutical industry.

Process Chemistry highlights

MSD and Codexis’ collaboration on the greener synthesis of Sitagliptin increased the overall yield by 50% and reduced the amount of waste by 80%.  This was achieved by discovering that the amino group of a key enamine intermediate did not need to be protected prior to enantioselective hydrogenation (pathway b).5  Codexis then went one step further and through directed evolution and biocatalysis were able to streamline the process.  High-pressure hydrogenation, rhodium catalyst, and the chiral purification steps were eliminated, providing a 13% increase in overall yield to 87% (pathway c).6

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Scheme 1:  Greener synthesis of Sitagliptin (image taken from source)7

The telescoping synthesis of Imatinib (Gleevec) by the Ley group furnished pure product in 32% overall yield and > 95% purity (Scheme 2).  The apparatus engineered employed solid supported scavengers packed into a series of columns to minimise the waste associated with work-ups and purifications between steps.  In-situ reaction monitoring and infrequent handling of potentially hazardous intermediates was also advantageous.8

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Scheme 2:  Ley’s greener synthesis of Gleevec (image taken from source)8

The Boots synthesis of Ibuprofen is a classic in Green Chemistry.  The original synthesis (Scheme 3) devised in the 1960s produced a vast amount of waste as a consequence of poor AE.

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Scheme 3: 1960s Boots synthesis of Ibuprofen

In 1991 a three-step synthesis was devised by Boots-Hoechst-Celanese (BHC) that had high AE thus eliminating most of the waste by products (Scheme 4).  Hydrofluoric acid, Raney nickel and palladium catalysts were recycled, again reducing waste and making the process even more efficient.

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Scheme 4:  1991 BHC greener synthesis of Ibuprofen

Recent ‘Green’ reaction highlights

Looking through the ‘most read’ articles of high impact journals there are an increasing number of Green and Sustainable chemistries reported.  Below I have picked some interesting examples of ‘greener’ reactions that caught my eye and may be attractive to other medicinal chemists.

Li’s photoinduced trifluoromethylation of inactivated arenes avoids the use of expensive metal and toxic metal catalysts (Figure 2)9.  The same group also reported a photoinduced metal-free aromatic Finklestein reaction and Sonogashira coupling.11
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Figure 2:  Li et al Photoinduced trifluoromethylation of inactivated arenes (image taken directly from source)9

The Stahl group showed that a copper(I) salt and TEMPO (2,2,6,6-tetramethylpiperidinyl-N-oxyl) selectively oxidise a range of primary alcohols to aldehydes at room temperature with ambient air as the oxidant (Figure 3).12

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Figure 3:  Stahl’s air oxidation of alcohols (image taken directly from source)12

Mechanistic studies encouraged the same group to develop a new catalyst system that exhibits broader scope and efficiently oxidizes both primary and secondary alcohols (Figure 4).12

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Figure 4:  Stahl’s air oxidation of alcohols (image taken directly from source)12

The main advantages of this reaction are the lack of stoichiometric reagents used (other than oxygen) which greatly simplifies product isolation and reduces waste. Also chlorinated solvents, which are commonly needed with other classes of oxidation reactions, are not required.12

During my project I have had some experience in using T3P® in amide couplings.  In general its use has shortened my reaction times and improved yields over more conventional coupling reagents.  The main advantages reported for T3P® are lower levels of epimerisation, easy work-up as only water-soluble by-products are formed (Scheme 5).13  T3P® is also less hazardous compared to some conventional coupling reagents such as HOBt (now classed as explosive).13

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Scheme 5:  T3P® amide coupling (image taken from source)13

T3P® has also been used in the synthesis of Denagliptin (Scheme 6), initially for amide bond formation and then subsequent dehydration of the primary amide to form the nitrile.13  Thus avoiding the use of hazardous reagents such as phosphorus oxychloride or thionyl chloride.

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Scheme 6:  T3P® amide dehydration (image taken from source)13

Conclusion

Green Chemistry begins with good synthetic route design by the medicinal chemist.  There are now a number of tools and metrics in place to help medicinal chemists to choose the most attractive route both in terms of reaction efficiency and safety.  It is obvious that reducing waste at the source (the lab) will minimise the cost of its treatment and will strengthen economic competitiveness through more efficient use of raw materials.

The increased adoption and publication of ‘greener’ reactions will populate databases such as Reaxys which in turn will encourage chemists to use ‘greener’ reagents and procedures for their own safety.  Ultimately, it is up to the individual chemist to find and use ‘greener’ reactions and it is important that these ‘greener’ reactions are just as good as conventional reactions in terms of reaction efficiency.

It will be interesting to note how future investments and government policy on sustainable and green processes will be shaped by the falling price of fossil fuel derived feedstocks, as a result of lifting sanctions on Iran and the current Shale Gas revolution.

Hopefully, one day we will move towards a greener circular economy rather than the traditional ‘take-make-use-dispose’ economy.  It is promising (at least for the time-being for a Brit!) that Principle 2 (Figure 1) and this green philosophy that encapsulates it, forms the basis of the European Commission’s “Roadmap to a resource efficient Europe”.1

 

Blog written by: Scott Henderson

References

  1. A. Sheldon. Green Chem., 2016, 18, 3180.
  2. Prat et al. Green Chem., 2016, 18, 288.
  3. A. Sheldon. Chem. Ind., 1992, 903.
  4. L. Tucker. Organic Process Research & Development 2006, 10, 315.
  5. B. Hansen et al J. Am. Chem. Soc. 2009, 131, 8798.
  6. https://www.organicdivision.org/ama/orig/Fellowship/2013_2014_Awardees/Essays/Payne.pdf
  7. https://en.wikipedia.org/wiki/Process_chemistry
  8. G. Newman and K.F. Jensen. Green Chem., 2013, 15, 1456.
  9. Li et al J. Am. Chem. Soc. 2016, 138, 5809.
  10. Li et al J. Am. Chem. Soc., 2015, 137, 8328.
  11. Li et al. Nature Communications, 2015, 6, 6526.
  12. S. Stahl and B. L. Ryland. Angew. Chem. Int. Ed. 2014, 53, 8824.
  13. http://www.euticals.com/attachments/article/20/EUTICALS_T3P.pdf

 

 

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