Editorial pubs.acs.org/OPRD
Sustainable Chemistry
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EMEND and further expanded via synthesis of several chiral alcohols from ketones. The third article describing the application and power of biocatalysis is from Ferrero et al. in Spain. The quest for largescale synthesis of protected nucleosides useful as buildingblocks for therapeutic oligonucleotides led to the development of an enzyme-based regioselective acylation protocol. This is first report on the impact and influence of hydrophobic group during biocatalytic transformation. The use of 4-tert-butylphenoxyacetyl group (Tac) appears to be ideal as a protecting group for nucleobases to accelerate the rate of acylation reaction for all four natural nucleosides. The process was successfully transferred from batch mode to continuous mode on a 25 g scale. Langanke and Wolf from Bayer in Germany report on the development of continuous co-oligomerization of propylene oxide and carbon dioxide to yield high-quality [narrow and molecular weight distributions (MWDs) and strict hydroxyl end group] polyether carbonate polyols. This feat was accomplished on 75 kg scale where some of the polyether carbonate polyols described herein have potential applications in the manufacturing of sustainable materials. On a similar theme of polyols, Pagliaro (Italy), Dumeignil (France), and coauthors reviewed the synthesis, market potential, and regulatory aspects of glycerol-derived polyglycerols as useful as biocompatible green additives. It is expected that cosmetic and food industry will continue to use nontoxic ingredients preferably of natural origin. The authors conclude that polyglycerols (PGs) and their esters are good candidates to replace polyethylene glycols (PEGs). Acrylic acid and acrylates are essential chemicals for various industries currently obtained from fossil resources such as oil, coal, and natural gas. Unfortunately, these sources are not renewable within a human time scale. In order to overcome this limitation, the article by Schweitzer and Snell report the conversion of various biobased crotonates to acrylates utilizing a cross-metathesis reaction. The authors screened several catalysts and found that the Hoveyda−Blechert catalyst performed best for their system. The optimized reaction conditions for cross-metathesis resulted in an increase of catalyst turnover numbers by 2 orders of magnitude compared to the literature report. The article from Exelixis by Naganathan et al. describes a perfect example of sustainable process development efforts leading to kilo-scale production of highly pure API containing benzoxazepine core. The authors have carefully orchestrated the assembly of three distinct fragments needed for final assembly of the API in eight synthetic steps. One of these fragments was obtained via borane reduction. Given the hazardous nature of this reaction and need for safe containment of hydrogen generated during this step was crucial to the success of this step. The calorimetric evaluation showed that
he importance of Sustainable Chemistry has been clearly recognized during past decade by exceptional growth in the number of publications, books, and dedicated journals. In 2011, OPR&D published a special issue on “Sustainable Process Chemistry” highlighting the central role of this topic in a cluster of articles. The past success and continued interest in this subject matter encouraged us to develop another special issue covering the evolution of this topic. The conventional definition of Sustainable Chemistry has not changed significantly since 2011, where safe scientific strategies are developed and practiced, while human health and environmental harmony are preserved. However, more recently a host of chemometric parameters have been used to quantify the sustainability and greenness of a chemical process. Among these, three new metrics are worthy of consideration to measure the sustainability. These are (i) renewable percentage (RP); (ii) optimum efficiency (OE), and (iii) waste percentage (WP), as summarized in a recent article by Clark et al.1 In addition, the European Union initiated CHEM21 (Chemical Manufacturing Methods for the 21st Century Pharmaceutical Industries) is established by members of academia and industry for development of manufacturing sustainable pharmaceuticals.2 With the implementation these new metrics and consortium such as CHEM21, it is expected that more sustainable protocols will continue to emerge and be published. In this vein, we are pleased to offer yet another cluster of articles utilizing various attributes of Sustainable Chemistry in this issue of OPR&D. Biocatalysis continues to be a cornerstone of sustainable processes offering highly regio-, stereo-, and chemoselective transformations that are not accessible via conventional chemical transformations. Particularly when enzymes are immobilized, recovery, recycling, and reuse are very efficient, making the entire process economical and environmentally friendly. The article by Hernaiz et al. describes for the first time immobilization of lipase from Pseudomonas stutzeri (Lipase TL) via covalent bonding onto a porous polymer. The Lipase TL was successfully used for kinetic resolution of symmetrical and unsymmetrical benzoins. Also, the dynamic kinetic resolution of benzoin was accomplished by combination of Lipase TL and Shvo’s catalyst while maintaining excellent enantioselectivity during six catalytic cycles. The authors also discussed various metrics to quantify the greenness of their protocol reporting a reaction mass efficiency (RME) value of ≥0.618 and a favorable benign index (BI) for their studies. The next article on use of immobilized enzyme is contributed by Li et al., a group of scientists from Merck. This article constitutes the first example of an immobilized ketoreductases P1B2, capable of operating in organic solvent, that has been developed and demonstrated. The immobilized enzyme exhibited excellent selectivity, reaction conversion, and reuse both in batch mode and in a continuous plug flow reactor. The utility of the immobilized enzyme was demonstrated via synthesis of an intermediate needed for the synthesis of © 2015 American Chemical Society
Special Issue: Sustainable Chemistry Published: July 17, 2015 685
DOI: 10.1021/acs.oprd.5b00200 Org. Process Res. Dev. 2015, 19, 685−686
Organic Process Research & Development
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the heat evolution and gas evolution could be controlled by the rate of borane addition. Another article in this set is truly international contributed by Ilharco (Portugal), Béland (Canada), Pagliaro (Italy), and their coauthors. These authors have done an excellent job in reviewing the industrial applications of SilicaCat summarizing examples of cross-coupling, hydrogenation, and hydrosilylation reactions. This review clearly demonstrates that use of heterogeneous catalysts has the power to eliminate the waste at its source enabling Sustainable Chemistry. The highly open mesoporous silica framework of SilicaCat is ideal for both fixedbed and continuous applications. The article by Mullen et al. describes a protocol for production of n-butanol from poly-3-hydroxybutyrate (P3HB) in two steps. First, thermolysis of P3HB furnished crotonic acid, and second, hydrogenation of crotonic acid provided nbutanol. The authors have carefully studied various parameters to optimize the hydrogenation step where n-butanol was produced in >80% yield. Given the use of n-butanol as an industrial chemical required for variety of applications, including usage as liquid fuel, this article offers a bio-based alternative. Wells and coauthors have contributed an excellent survey of solvent usage in 388 articles published in OPR&D during 1997−2012. A critical analysis of (i) solvents of concern; (ii) dipolar aprotic solvents; and (iii) neoteric solvents for a variety of scale-up reactions is presented. Although authors conclude that there is an encouraging trend when reactions were carried out over 100 kg scale, there remains room for improvement in how solvents are used for Sustainable Chemistry. We hope that these articles will further strengthen our desire to excel and develop Sustainable Chemistry and products. Furthermore, the access to new tools such as process mass intensity tool (PMI) may permit measurement of process efficiency for new and improved processes. The PMI for a product can be calculated by the following protocol or the tool available on the ACS Web site.3 process mass intensity (PMI) =
Editorial
AUTHOR INFORMATION
Corresponding Author
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[email protected]. Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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REFERENCES
(1) McElroy, C. R.; Constantinou, A.; Jones, L. C.; Summerton, L.; Clark, J. H. Green Chem. 2015, 17, 3111−3132. (2) http://www.chem21.eu/. (3) http://www.acs.org/content/acs/en/greenchemistry/industrybusiness/pharmaceutical.html. (4) Bandichhor, R.; Bhattacharya, A.; Diorazio, L.; Dunn, P.; Fraunhoffer, K.; Gallou, F.; Hayler, J.; Hickey, M.; Hinkley, B.; Hughes, D.; Humphreys, L.; Kaptein, B.; Mathew, S.; Oh, L.; Richardson, P.; White, T.; Wuyts, S. Org. Process Res. Dev. 2014, 18, 863−874.
quantity of raw materials input (kg) quantity of bulk API out (kg)
where process is all steps of a synthetic path from commonly available materials to the final bulk active pharmaceutical ingredient (“API”); raw materials input is all materials, including water, that are used directly in the process of synthesizing, isolating, and purifying the API final form; and bulk API out is the final form of the active ingredient that was produced in the synthesis, dried to the expected specification. We encourage the broader use of PMI as a metric to demonstrate route improvement through development and to gauge how sustainable a particular process has become. In 2014, OPR&D published a summary of selected articles describing Green and Sustainable Chemistry protocols useful for pharmaceutical industry.4 This further confirms our commitment in publishing Sustainable Chemistry related work in OPR&D, and we welcome your next manuscript on this topic describing your accomplishments.
Beth Lorsbach Yogesh S. Sanghvi,* Guest Editors and Members of the Editorial Advisory Board
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DOI: 10.1021/acs.oprd.5b00200 Org. Process Res. Dev. 2015, 19, 685−686
