Towards cleaner PolarClean: efficient synthesis and extended applications of the polar aprotic solvent methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate

green chemistry Comments Off

Jul 302019

Graphical abstract: Towards cleaner PolarClean: efficient synthesis and extended applications of the polar aprotic solvent methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate

Abstract

As a result of recent efforts in green solvent selection, methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate, sold under the brand name Rhodiasolv PolarClean, has received considerable scientific and industrial attention as a possible non-toxic replacement for common polar aprotic solvents. However, the multicomponent nature and multi-step synthesis of this solvent remains an obstacle for its more widespread use and niche applications. In this work, a retrosynthetic approach was taken to identify novel shorter synthetic routes in alignment with green chemistry principles. High purity methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate was obtained in novel single-step reactions via two different base-catalysed Michael additions from readily available building blocks. The more advanced synthetic route shows great potential owing to the swift (30 min), solvent-free reaction and catalytic amounts of base (<6.5 mol%). Green metrics analysis, including Atom Economy, Complete E factor, Carbon Intensity and hazard analysis found the new synthesis to be more sustainable than the patented routes. Application of this green solvent was demonstrated for the first time for O– and N-arylation in S_NAr reaction with solvent recovery with similar or superior yields compared to other green solvents. Moreover, broad opportunities for this green solvent in membrane science were identified, where the use of conventional, toxic polar aprotic solvents in large quantities is unavoidable. Important practical solvent properties and parameters such as dielectric constant, solubility parameters, solvent miscibility and NMR residual shifts have been determined to facilitate the uptake of methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate as a green solvent.

Towards cleaner PolarClean: efficient synthesis and extended applications of the polar aprotic solvent methyl 5-(dimethylamino)-2-methyl-5-oxopentanoate

Levente Cseri*^a and Gyorgy Szekely*^a^b

Author affiliations

*Corresponding authors

^aSchool of Chemical Engineering and Analytical Science, University of Manchester, The Mill, Sackville Street, Manchester, UK
E-mail: levente.cseri@manchester.ac.uk, gyorgy.szekely@manchester.ac.uk
Tel: +44 (0)1613062662

^bAdvanced Membranes & Porous Materials Center, Physical Science Engineering Division (PSE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
E-mail: gyorgy.szekely@kaust.edu.sa
Tel: +966128082769

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https://pubs.rsc.org/en/Content/ArticleLanding/2019/GC/C9GC01958H?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Pressurized CO2 as a carboxylating agent for the biocatalytic ortho-carboxylation of resorcinol

green chemistry Comments Off

Apr 242018

Green Chem., 2018, 20,1754-1759
DOI: 10.1039/C8GC00008E, Communication

Open Access

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.

Katharina Plasch, Gerhard Hofer, Walter Keller, Sam Hay, Derren J. Heyes, Alexander Dennig, Silvia M. Glueck, Kurt Faber
Utilization of gaseous carbon dioxide as a C₁-building block in the biocatalytic ortho-carboxylation of a phenol.
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http://pubs.rsc.org/en/content/articlehtml/2018/gc/c8gc00008e

Pressurized CO2 as a carboxylating agent for the biocatalytic ortho-carboxylation of resorcinol

Pressurized CO₂ as a carboxylating agent for the biocatalytic ortho-carboxylation of resorcinol

Katharina Plasch,^a Gerhard Hofer,^b Walter Keller,^b Sam Hay,^c Derren J. Heyes,^c Alexander Dennig,^d Silvia M. Glueck*^a^e and Kurt Faber*^a

Author affiliations

* Corresponding authors

^a Department of Chemistry, Organic & Bioorganic Chemistry, University of Graz, Heinrichstrasse 28, 8010 Graz, Austria
E-mail:Si.Glueck@Uni-Graz.at, Kurt.Faber@Uni-Graz.at

^b Institute of Molecular Biosciences, University of Graz, Humboldstrasse 50, 8010 Graz, Austria

^c Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK

^d Institute of Biotechnology and Biochemical Engineering, Graz University of Technology, Petersgasse 12, 8010 Graz, Austria

^e Austrian Centre of Industrial Biotechnology (ACIB), Petersgasse 14, 8010 Graz, Austria

Abstract

The utilization of gaseous carbon dioxide instead of bicarbonate would greatly facilitate process development for enzyme catalyzed carboxylations on a large scale. As a proof-of-concept, 1,3-dihydroxybenzene (resorcinol) was carboxylated in the ortho-position using pressurized CO₂ (∼30–40 bar) catalyzed by ortho-benzoic acid decarboxylases with up to 68% conversion. Optimization studies revealed tight pH-control and enzyme stability as the most important determinants.


Fig. 1 (a) Enzyme-catalyzed de/carboxylation of resorcinol (1). Carboxylated product 2 is a mixture of regio-isomeric 2,6- (2,6-dhba, 2a) and 2,4-dihydroxybenzoic acid (2,4-dhba, 2b) with a ratio of 3:4;^10b (b) CO₂ pressure dependence of the carboxylation of 1 using 2,3-DHBD_Ao; (c) carboxylation activity of decarboxylases with CO₂ (30 bar) using 1 as a substrate; (d) stopped-flow measurements of the decarboxylation of 2,6-dhba (2a) with pressure-pretreated (≤1.5 kbar) 2,3-DHBD_Ao and 2,6-DHBD_Rs.

Conclusion

In summary, we have demonstrated that pressurized carbon dioxide can be used directly as a carboxylating agent in the enzyme catalyzed o-carboxylation of a phenol as an alternative to the high concentration of bicarbonate. Two enzyme candidates (2,3-DHBD_Ao and SAD_Tm) readily accepted the alternative CO₂ source for the carboxylation of the model substrate resorcinol. In contrast, 2,6-DHBD_Rs was inapplicable under CO₂ pressure due to irreversible inactivation, which was correlated to a decrease in pH caused by the dissociation of H₂CO₃.

Overall, the use of pressurized CO₂ gas significantly improves the efficiency of biocatalytic carboxylations and facilitates downstream-processing of this benign and sustainable approach in using CO₂ as a carbon feedstock for the synthesis of organic acids.

Katharina Plasch

DOCTORAL STUDENT,

Katharina Plasch

tel: +43-316-380-8646
e-mail:katharina.plasch(at)uni-graz.at

Katharina Plasch

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Kurt Faber
Institute of Chemistry – Organic & Bioorganic Chemistry
Karl Franzens Universität Graz
Heinrichstrasse 28
8010 Graz

e-Mail: kurt.faber@uni-graz.at
phone: +43 316 380 5332
fax: +43 316 380 9840
web: http://biocatalysis.uni-graz.at

Kurt Faber, born 1953 in Klagenfurt (Carinthia/Austria), studied chemistry at the University of Graz, where he received his PhD in 1982. After a post-doctoral fellowship from 1982 to 1983 in St. John’s (Canada) he continued his career at the University of Technology in Graz, where he became associate professor in 1997. The following year he was appointed full professor at the University of Graz, where he since heads a research group devoted to the use of biocatalysts for the transformation of non-natural compounds. He was a visiting scientist at University of Tokyo (1987/1988), Exeter University (1990), University of Trondheim (1994), Stockholm University (2001) and University of Minnesota (2005).

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Silvia M. Glueck

Silvia M. Glueck, born 1973 in Bruck/Mur (Austria), studied Chemistry at the University of Graz, where she received her PhD under the supervision of Prof. K. Faber in 2004. From 2005 to 2006 she worked as a post-doctoral fellow with Prof. N. J. Turner at the University of Edinburgh and the University of Manchester (MIB). In 2007 she returned to the University of Graz to join Prof. W. Kroutil, and in 2008 she became Research Scientist at the Research Centre Applied Biocatalysis in the group of Prof. K. Faber. Her research interests are focusing on biocatalysis, molecular biology and organic synthesis.

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Pressurized CO₂ as a carboxylating agent for the biocatalytic ortho-carboxylation of resorcinol

K. Plasch, G. Hofer, W. Keller, S. Hay, D. J. Heyes, A. Dennig, S. M. Glueck and K. Faber, Green Chem., 2018, 20, 1754

DOI: 10.1039/C8GC00008E

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Sustainable chemistry: how to produce better and more from less?

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Oct 072017

Sustainable chemistry: how to produce better and more from less?

Green Chem., 2017, Advance Article
DOI: 10.1039/C7GC02006F, Perspective

P. Marion, B. Bernela, A. Piccirilli, B. Estrine, N. Patouillard, J. Guilbot, F. Jerome
This review describes the rapid evolution of chemistry in the context of a sustainable development of our society. Written in collaboration between scientists from different horizons, either from public organizations or chemical companies, we aim here at providing recommendations to accelerate the emergence of eco-designed products on the market.

Sustainable chemistry: how to produce better and more from less?

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C7GC02006F?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

P. Marion,^a B. Bernela,^b A. Piccirilli,^c B. Estrine,^d N. Patouillard,^e J. Guilbot^f and F. Jérôme*^g

Author affiliations

*Corresponding authors

^aSOLVAY, 85 rue des frères Perret, BP 62, F-69192 Saint Fons Cedex, France

^bINCREASE FR CNRS 3707/Centre de Recherche sur l’Intégration Economique et Financière, Université de Poitiers, 2 rue Jean Carbonnier, Bât A1, 86073 Poitiers Cedex 9, France

^cBIOSYNTHIS, 6 Chemin de la Pierre Percée, 91410 Saint-Cyr-sous-Dourdan, France

^dARD-Agro-industrie Recherches et Développements, Green Chemistry Department, Route de Bazancourt, F-51110 Pomacle, France

^ePENNAKEM LLC, 3324 Chelsea avenue, Memphis, USA

^fSEPPIC-AIR LIQUIDE, 127 chemin Poudrerie, 81105 Castres, France

^gINCREASE FR CNRS 3707/Institut de Chimie des Milieux et Matériaux de Poitiers, Université de Poitiers, ENSIP, 1 rue Marcel Doré, 86073 Poitiers, France
E-mail: francois.jerome@univ-poitiers.fr

Abstract

The International Symposium on Green Chemistry (ISGC) organized in 2013, 2015 and 2017 has gathered many senior and young talented scientists from all around the world (2200 attendees in three editions), either from academia or industry. Through outstanding conferences, communications, debates, and round tables, ISGC has been the witness of the rapid evolution of chemistry in the context of a sustainable development of our societies, not only at the scientific and industrial levels but also on education, networking and societal aspects. This critical review synthesizes the different points of view and the discussions having taken place at ISGC and gives a general picture of chemistry, including few scientific disciplines such as catalysis, processes, resource management, and environmental impact, among others, within the framework of sustainable development. This critical review, co-authored by researchers from public organizations and chemical companies (small, medium and large industrial groups) provides criteria and recommendations which, in our view, should be considered from the outset of research to accelerate the emergence of eco-designed products on the market.

Conclusions

Sustainable chemistry is the only mean to generate performant products and long lasting solutions able to generate business and profit for chemical industry. Performance is the best systemic answer for customer needs and our societies. Defining sustainable chemistry is, however, far to be an easy task because chemistry is a highly dynamic system. The sustainability of a value chain is for instance directly depending on the access to energy (and above all to its origin – coal, gas, biomass…) and on the supply of raw materials. In the current economic context, it could be not so easy to predict what will be the best source of energy or raw materials for a desired product in the future. The development of predictive tools is now essential and will represent probably one of the next scientific challenges in the coming years. During the last 20 years, utilization of renewable feedstocks in chemical processes has become a strategy of growing interest but it definitely does not guarantee the establishment of a sustainable chemistry. Indeed, in some cases, it is more sustainable to produce a chemical from a fossil carbon source using decarbonized energy than the reverse. It is very important to distinguish the carbon found in the final product from the carbon content corresponding to the energy which is required the product production (going from raw materials to manufacturing, end of life, etc.). In this area, the concept of biorefinery can help to secure developments and to minimize investments in production plant by mutualizing facilities and R&D initiatives. Cooperation with local producers can also be a valuable way to implement new bio‐based products while favouring sustainable agricultural practices. Whatever the raw materials (renewable or fossil), a complete and systemic life cycle analysis of the whole chain value (from resources to manufacturing, use and end of life) must be performed because it gives us an accurate picture of the overall economic, environmental and societal performances of a product in an application for a defined market. In general, one should never forget that sustainable chemistry should help the society to produce more and better (products). Emergence of sustainable innovations on the market takes a lot of time because chemists have to reinvent chemistry. To achieve our transition to a sustainable society, we must think differently and bring together the worlds of finance, manufacturers, researchers and public authorities. The current method of funding of research and innovation is not satisfying yet because too often based on short‐term projects and with high Technology Readiness Level. Governments have to realize that this funding method slows down, and sometime also hampers, the emergence of future sustainable innovations. Evolution of regulations with the aim of banning toxic, eco‐toxic or poor biodegradable products is an important driver for sustainable innovation. It is now seen and shared as a positive sign providing opportunities to develop systemically better solutions and allowing chemical companies advocating sustainable development and products as a must to stay in the competition. As examples, ban of CFC, replacement of chlorinated or other toxic solvents, substitution of endocrine disruptors lead to better solutions for the global benefit of our societies. Improving public perception and awareness on sustainable chemistry is on the way but more efforts will be needed in the future to definitely contribute to the emergence of eco‐ designed chemicals on the market.

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Below we provide a bulleted list to summarize the main recommendations that are, in our views, essential for designing sustainable products. (1) Products design & Manufacture: For the intended application, sustainable chemicals must imperatively bring a global benefit, created by a scientific or technological breakthrough, while minimizing risks. They should also generate profit to emerge on the market. Products should be produced according to the 12 principles of green chemistry. In addition, their end of life should be integrated at the outset of research, (2) Resources: They should be available for future generations and should have low environmental impact (protecting endangered species, deforestation, erosion of biodiversity, contamination of natural resources, global warming, etc.), it should make progress the societal development of concerned area (sharing any benefits with local producer, no child labour, help developing countries, etc.) and their utilization should not destabilise other supply chains. Non edible raw material, a return to the idea of ‘localness’ and the need for closeness should be preferred, (3) Process: The ideal process would be a low Capex or a progressive Capex process and should be energy‐efficient, not use solvents, be without effluents, should limit the number of reactional and purification steps and should be developed rapidly to limit the associated risks and costs. Efforts are still needed for miniaturisation of equipment, intensification and development of continuous reactors, (4) Energy: The chemical industry is also energy intensive. Although less than 10% of fossil carbon is used for the manufacture of chemicals, finding decarbonized sources of energy is mandatory to avoid the depletion of carbon reserves and price increase and to ensure that future generations will have access to the same resource in the same amount, (5) Life cycle assessment: it should be assessed in all cases, the earlier the better, by preferring a ‘cradle to grave’ approach. It should give an accurate picture of the overall economic, environmental and societal performances of a product in an application for a defined market, (6) Education: we should improve public awareness and perception on sustainable chemistry to facilitate the acceptation of sustainable products by the consumer. More education programs should be launched in the future not only to reassure the consumer but also to create a pool of students better armed to tackle the future challenges of (sustainable) chemistry. The rapid development of digital tools should be helpful to address this issue, (7) Network: we should prefer working in an open innovation mode by bringing together the worlds of finance, manufacturers, researchers and public authorities to accelerate the emergence of eco‐designed chemicals on the market. Networks should enable local players to adapt to changes in their environment while optimising their economic and environmental efficiency, (8) Funding: A good balance between funding to applied research and basic research must be addressed in order to continuously generate scientific innovation. However, public authorities must realise that societal challenges are more important than the short term financial challenges faced by businesses. The current model of our economy based on rapid profitability is unfortunately not well adapted for these advances since long‐term investments will be needed for a more sustainable development of our society, (9) Legislation & Regulation: it should facilitate the emergence of sustainable chemicals by banning harmful chemicals for the human health and the environment, even those nowadays generating substantial profits. The registration process of improved sustainable chemicals by the concerned agencies should be quicker than now to speed up their integrations on the market, (10) Predictive methods: the development of tools to accurately predict the technical and application performances, the economic efficiency, the environmental and societal performance of a targeted product should be developed to limit the risks and costs associated with potential failure and to reassure the investors. It is also urgent to develop these tools for chemicals that are intended to be dispersed in nature.

Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

SYNTHESIS, Uncategorized Comments Off

Jan 062017

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Scheme 1. Pfizer’s Commercial Synthesis of sildenafil citrate (Viagra™)

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“Green chemistry” refers to the promotion of safe, sustainable, and waste-minimizing chemical processes. The proliferation of green chemistry metrics without any clear consensus on industry standards is a significant barrier to the adoption of green chemistry within the pharmaceutical industry. We propose the Green Aspiration Level™ (GAL) concept as a novel process performance metric that quantifies the environmental impact of producing a specific pharmaceutical agent while taking into account the complexity of the ideal synthetic process for producing the target molecule. Application of the GAL metric will make possible for the first time an assessment of relative greenness of a process, in terms of waste, versus industry standards for the production process of any pharmaceutical. Our recommendations also include a simple methodology for defining process starting points, which is an important aspect of standardizing measurement to ensure that Relative Process Greenness (RPG) comparisons are meaningful. We demonstrate our methodology using Pfizer’s Viagra™ process as an example, and outline aspiration level opportunities for industry and government to dismantle green chemistry barriers.

Overcoming barriers to green chemistry in the pharmaceutical industry – the Green Aspiration Level™ concept

F. Roschangar,*^a R. A. Sheldon^b and C. H. Senanayake^a

*Corresponding authors

^aChemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, USA
E-mail: frank.roschangar@boehringer-ingelheim.com

^bDelft University of Technology, Julianalaan 136, 2628 BL Delft, The Netherlands

Green Chem., 2015,17, 752-768

DOI: 10.1039/C4GC01563K, http://pubs.rsc.org/en/content/articlelanding/2015/gc/c4gc01563k#!divAbstract

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

///////////green chemistry, pharmaceutical industry

A deeper shade of green: inspiring sustainable drug manufacturing

drugs Comments Off

Jan 062017

Graphical abstract: A deeper shade of green: inspiring sustainable drug manufacturing

Green and sustainable drug manufacturing go hand in hand with forward-looking visions seeking to balance the long-term sustainability of business, society, and the environment. However, a lack of harmonization among available metrics has inhibited opportunities for green chemistry in industry. Moreover, inconsistent starting points for analysis and neglected complexities for diverse manufacturing processes have made developing objective goals a challenge. Herein we put forward a practical strategy to overcome these barriers using data from in-depth analysis of 46 drug manufacturing processes from nine large pharmaceutical firms, and propose the Green Aspiration Level as metric of choice to enable the critically needed consistency in smart green manufacturing goals. In addition, we quantify the importance of green chemistry in the often overlooked, yet enormously impactful, outsourced portion of the supply chain, and introduce the Green Scorecard as a value added sustainability communication tool.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02901A?utm_medium=email&utm_campaign=pub-GC-vol-19-issue-1&utm_source=toc-alert#!divAbstract

The Green Aspiration Level (GAL) has been constructed on four pillars to ensure consistent application, namely (1) clearly defined synthesis starting points,1 (2) unambiguous complete E factor (cEF)2,3 or Process Mass Intensity (PMI) waste metrics, (3) historical averages of industrial drug manufacturing waste, and (4) complexity of the drug’s ideal manufacturing process (Supplementary Figure 6). cEF or PMI can be used interchangeably in GAL-based analysis enabling organizations using either to calculate their green performance scores. cEF and PMI differ by just one unit (Supplementary Equation 6) and share the same commercial waste goal for an average manufacturing step4 – the transformation-GAL or tGAL – that results in negligible numerical differences from the inclusion of one or the other. The pharmaceutical industry has generally adopted PMI. However, our publication utilizes cEF values due to literature prevalence and potentially broader appeal of E factors.5 It is important to note that all reaction and workup materials are included in the analysis, but excluded are reactor cleaning6 and solvent recycling.7 Standardized process starting points are a critical component of the GAL methodology. A starting material for some may be an intermediate for others. Until recently, the scientific community lacked an unambiguous definition of process starting points in the assessment of process greenness. This has been a bothersome source of inconsistency. Failure to define an appropriate starting material can lead to exclusion of significant amounts of intrinsic raw material waste created during earlier stages of manufacture. We therefore utilize these updated definitions of process analysis starting points to ensuring higher quality of data:8

1) The material is commercially available from a major reputable chemical laboratory catalog company, and its price is listed in the (online) catalog. Materials requiring bulk or custom quotes do not qualify as process starting material. AND 2) The laboratory catalog cost of the material at its largest offered quantity does not exceed US $100/mol. Therefore, published literature must be researched if the material does not qualify as process starting material in order to determine its correct intrinsic cEF. However, we realized that determination of literature cEF values is tedious and involves making assumptions since literature procedures are often incomplete compared to internal or external manufacturing batch records. Thus, standardizing Literature cEF quickly became a desirable goal. In order to facilitate literature analysis we introduced Supplementary Equation 7 that just requires determination of literature step count from ≤$100/mol starting materials without having to retrieve literature waste information.9 The literature step multiplier of 37 kg/kg represents the average literature step cEF across the analyzed projects (Supplementary Table 1), so it equals their average literature cEF (76 kg/kg) divided by average literature step count (2.1). The process cEF and Relative Process Greenness (RPG) derived from the simplified calculated cEF literature values are shown next to their progenitors in Supplementary Table 3. We observe that average calculated and manually determined cEF and RPG values are comparable and within 10% of their means across the three development phases. Thus, we consider the simplified method sound and an importtant element to achieving consistency in green process analysis.

A deeper shade of green: inspiring sustainable drug manufacturing

Frank Roschangar,*^a Juan Colberg,^b Peter J. Dunn,^c Fabrice Gallou,^d John D. Hayler,^e Stefan G. Koenig,^f Michael E. Kopach,^g David K. Leahy,^h Ingrid Mergelsberg,ⁱ John L. Tucker,^j Roger A. Sheldon^k^l and Chris H. Senanayake^a

*Corresponding authors

^aChemical Development, Boehringer Ingelheim Pharmaceuticals, Ridgefield, USA
E-mail: frank.roschangar@boehringer-ingelheim.com

^bPharmaceutical Sciences – Worldwide Research & Development, Pfizer, Groton, USA

^cPfizer, Sandwich, UK

^dChemical & Analytical Development, Novartis Pharma, 4002 Basel, Switzerland

^eAPI Chemistry, GlaxoSmithKline Medicines Research Centre, Stevenage, UK

^fSmall Molecule Process Chemistry, Genentech, a Member of the Roche Group, South San Francisco, USA

^gSmall Molecule Design and Development, Eli Lilly and Company, Indianapolis, USA

^hChemical and Synthetic Development, Bristol-Myers Squibb, New Brunswick, USA

ⁱProcess Chemistry, Merck, Rahway, New Jersey 07065, USA

^jProcess Development, Amgen, Thousand Oaks, USA

^kMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, South Africa

^lDelft University of Technology, 2628 BL Delft, Netherlands

Green Chem., 2017,19, 281-285

DOI: 10.1039/C6GC02901A

Frank Roschangar, PhD MBA

Pharmaceutical process research director, passionate about accelerating drug development and driving green chemistry.

Boehringer Ingelheim

Research and Development Sites

Ingelheim am Rhein, Germany

Research experience

Feb 2002–Sep 2015

Director

Boehringer Ingelheim

Germany · Nieder-Ingelheim
Aug 1996–Feb 1998

Postdoc

The Scripps Research Institute · Skaggs Institute for Chemical Biology · Prof. K.C. Nicolaou

United States · La Jolla
Aug 1992–Aug 1996

PhD Candidate

Rice University · Department of Chemistry

United States · Houston

Supplementary References

1. The $100 per mol laboratory catalog pricing requirement described in Supplementary Discussion 1 does not apply to reagents, catalysts, ligands, and solvents, since they are produced for widespread application and are not specific to the process being evaluated.

2. Since the original E factor has been applied inconsistently, the cEF metric was introduced for the purpose of GAL analysis. cEF accounts for all process reaction and process workup materials, including raw materials, intermediates, reagents, process aids, solvents, and water.

3. All E factors reported herein represent the cEF or sEF contributions of the overall manufacturing process or the sub-process (e.g. external cEF, literature cEF) to produce 1 kg of drug substance.

4. We define a step as a chemical operation involving one or more chemical transformations that form and/or break covalent or ionic bonds and lead to a stable and isolable intermediate, but not necessarily include its isolation. Examples: • Simultaneous removal of two or more protection groups involves multiple transformations, yet it is carried out in one chemical operation  counted as one step • Sequential transformations via a stable and isolable intermediate that are carried out in two operations but without intermediate workup  counted as two steps • Formation of covalent bonds or salts that occur during workup  not counted as an extra step • Separate operation of salt formation from an isolated intermediate  counted as one step • Isolation of a product, following work-up, as a solution that can be stored  counted as one step.

5. A SciFinder search for the terms ‘Process Mass Intensity’, and ‘E factor’ and ‘Environmental impact factor’ on Nov. 14, 2016 revealed that the PMI concept was present in 12, 8, 9, and 12 publications for the years 2013-2016, respectively, while the E factor concept was mentioned 39, 45, 57, and 46 times (76-86%), respectively.

6. The GAL considers only direct process materials, i.e. materials used in the chemical steps and their workups. It does not include solvents and aqueous detergents required for reactor and equipment cleaning between batches or steps, nor the frequency and duration of the equipment and facility specific cleaning operations. These parameters are considered for comprehensive environmental impact in Life Cycle Assessment (LCA) analysis.

7. In US pharmaceutical manufacturing, recycling accounts for 25% of waste handling, while energy recovery burning and treatment constitute 38% and 35%, based on 2012 data from ‘The Right-To-Know Network’ (RTKNET.ORG), Toxic Releases (TRI) Database: http://rtknet.org/db/tri.

8. The $100 per mol commodity pricing criterion was established in ref. 15 of the main article based on the author’s professional experience. The authors of this manuscript consider this figure appropriate and helpful for providing a consistent analysis.

9. If a detailed procedure is available for a particular literature step, its calculated waste can be used in place of the 37 kg/kg default value.

10. J. Li and M. D. Eastgate, Current Complexity: a Tool for Assessing the Complexity of Organic Molecules. Org. Biomol. Chem. 2015,13, 7164–7176.

11. D. P. Kjell, I. A. Watson, C. N. Wolfe and J. T. Spitler, Complexity-Based Metric for Process Mass Intensity in the Pharmaceutical Industry. Org. Process Res. Dev. 2013, 17, 169– 174.

12. R. P. Sheridan, et al., Modeling a Crowdsourcing Definition of Molecular Complexity. J. Chem. Inf. Model. 2014, 54, 1604–1616.

13. M. F. Faul, et al., Part 2: Designation and Justification of API Starting Materials: Current Practices across Member Companies of the IQ Consortium. Org. Process Res. Dev. 2014, 18, 594–600.

14. Besides offering simplicity, the GAL’s process complexity model was selected vs. the alternative structural complexity measures due to its inherent ideality-derived consideration for available synthetic methodology.

15. See main article ref. 16: it defines Construction Reactions (CR) as chemical transformations that form skeletal C-C or C-heteroatom bonds. Strategic Redox Reactions (SRR) are construction reactions that directly establish the correct functionality found in the final product, and include asymmetric reductions or oxidations. All other types of non-strategic reactions are considered as Concession Steps (CS), and include functional group interconversions, non-strategic redox reactions, and protecting group manipulations.

16. M. E. Kopach, et al., Process Development and Pilot-Plant Synthesis of (2-Chlorophenyl)[2-(phenylsulfonyl)pyridin-3- yl]methanone. Org. Process Res. Dev. 2010, 14, 1229–1238.

17. M. E. Kopach, M. M. Murray, T. M. Braden, M. E. Kobierski, O. L. Williams, Improved Synthesis of 1-(Azidomethyl)-3,5-bis- (trifluoromethyl)benzene: Development of Batch and Microflow Azide Processes. Org. Process Res. Dev. 2009, 13, 152–160. 18. RCI (Process B) = 1 − ( ) = 0.25. RCI (Process C) = 1 − ( ) = 0.38

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Green chemistry makes ‘cents’ for cost-focused API firms says expert

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Oct 092014

Green chemistry makes ‘cents’ for cost-focused API firms says expert

By Gareth MacDonald+, 07-Oct-2014

Making drugs generates a huge amount of waste but industry is showing signs of cleaning up its act according to Paul Anastas, the Yale scientist who coined the phrase “green chemistry.”

http://www.in-pharmatechnologist.com/Ingredients/Green-chemistry-makes-cents-for-cost-focused-API-firms-says-expert