Green Chemistry Articles of Interest to The Pharmaceutical Industry

Green Chemistry Highlights pubs.acs.org/OPRD

Green Chemistry Articles of Interest to The Pharmaceutical Industry 1. INTRODUCTION The American Chemical Society’s (ACS) Green Chemistry Institute (GCI) Pharmaceutical Roundtable (PR) was developed in 2005 to encourage the integration of green chemistry and green engineering into the pharmaceutical industry. The Roundtable currently has 16 member companies as compared to three in 2005. The membership scope has also broadened to include contract research/manufacturing organizations, generic pharmaceuticals, and related companies. Members currently include ACS GCI, Amgen, AstraZeneca, Asymchem, Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Codexis, Eli Lilly and Company, F-Hoffmann-La Roche Ltd., GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Novartis, Pfizer, Inc., Sanofi, and WuXi AppTec, Co., Ltd. One of the strategic priorities of the Roundtable is to inform and influence the research agenda. Two of the first steps to achieve this objective were to publish a paper outlining key green chemistry research areas from a pharmaceutical perspective (Green Chem. 2007, 9, 411−420) and to establish annual ACS GCIPR research grants. This document follows on from the Green Chemistry paper and is largely based on the key research areas though new sections have been added. The review period covers April to September 2016. These articles of interest represent the opinions of the authors and do not necessarily represent the views of the member companies. Some articles are included because, while not currently being regarded as green, the chemistry has the potential to improve the current state of the art if developed further. The inclusion of an article in this document does not give any indication of safety or operability. Anyone wishing to use any reaction or reagent must consult and follow their internal chemical safety and hazard procedures.

understanding of the effect that not only the composition but also the method of preparation has on the physical properties and in particular the stability of such emulsions. TrujilloCayado et al. have carried out a comprehensive study evaluating a series of O/W emulsions prepared using a mixture of a fatty acid dimethylamide (AMD-10) and α-pinene as the organic component (30%) with a nonionic surfactant, Levenol C-201, as an emulsifying agent. Initial studies showed that the ratio of the two solvents had a significant effect on both the droplet size distribution as well as the stability of the emulsions with a ratio of 75/25 AMD-10/α-pinene deemed to be optimal. Further studies on the two potential methods of preparation with a particular focus on the mechanism of emulsion decomposition indicated that, when rotor-stator devices were used in the material preparation, submicrometer emulsions with lower mean diameters and higher apparent viscosity and stabilities were obtained as the homogenization rate increased. When high pressure homogenizers were utilized, higher viscosities and smaller sizes were generally observed compared to the rotorstator devices, as well as an increase in stability observed with an increase in homogenization pressure (the most stable emulsion was obtained from a single pass through a M110P high pressure homogenizer with micro fluidizer technology at 15 000 psi) provided the emulsion was only subjected to one pass through the system (Ind. Eng. Chem. Res. 2016, 55, 7259−7266). There is still a significant discussion regarding the potential of ionic liquids (ILs) as green solvents, though despite their negligible vapor pressure, concerns continue to emerge regarding their biodegradability, corrosivity and toxicity. Kunz and Häckl have provided a critical commentary debating whether the use of ILs as bulk solvents replacing conventional solvents is achievable given both their price and in many cases difficult syntheses, and therefore considering these materials as high-performance chemicals is a more realistic goal. The article initially summarizes the continued exponential growth in the number of publications regarding ILs and the disconnection between their positions as materials and solvents on a typical “hype-cycle”. Explicit aspects of ILs are then considered drawing particular attention to properties which are often overlooked when their use as a solvent is considered, and in particular the low vapor pressure, which although viewed as an advantage will cause large amounts of energy to be expended in typical distillative work-ups. Finally, the authors provide suggested guidelines for the scientific community for future publications on ILs and stress that, in cases in which they are being proposed as solvents, they should enable new products or processes currently not possible with conventional solvents or be both cost-competitive and less toxic than the currently utilized solvent for a transformation. Finally, the advantages of

2. SOLVENTS Lipshutz et al. have published a perspective contrasting the manner in which nature performs chemistry as opposed to the laboratory chemist drawing the conclusion that the fact that “modern” synthetic chemistry embraced conventional solvents from the outset has caused the current dilemma with regard to sustainable reaction media. After consideration of several potential alternative reaction media, the authors provide an overview of chemistry performed in water enabled by micellar catalysis invoking examples from Suzuki−Miyaura reactions (using Pd-nanoparticles and water-soluble ligands), nitro group reductions as well as amide bond formations (see also Section 3). Finally, a reaction sequence consisting of all three transformations as well as a SNAr reaction is performed wholly in aqueous media with the advantages of each step highlighted to generate an API of significant complexity (ACS Sustainable Chem. Eng. 2016, 4, 5838−5849). Oil-in-water (O/W) emulsions prepared using “green” solvents present a potential opportunity to investigate as alternative media for both reactions and formulation purposes. However, the key to success in this area requires deep © XXXX American Chemical Society

Received: September 6, 2017 Revised: September 10, 2017 Accepted: September 14, 2017

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DOI: 10.1021/acs.oprd.7b00292 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Green Chemistry Highlights

3. AMIDE FORMATION The relatively inert nature of amides compared to other acyl donors often necessitates harsh reaction conditions for transamidation to occur, and as such it is not often a viable pathway for amide bond formation. However, in the period under review, two reports of transamidation utilizing heterogeneous catalysis were published. Chevella et al. have reported on nanosized zeolite beta as an efficient catalyst to mediate this transformation highlighting that the reduction in particle size of standard zeolites from micrometres to nanometers leads to a significant change in the physical characteristics with a large external surface area and shortened diffusion path lengths. In model studies on the reaction between benzamide and benzylamine, the nanosized zeolite beta outperformed regular zeolite beta (92% vs 72% yield) with both temperature (135 °C) and molar ratio (1:2 amide− amine) shown to be crucial parameters for optimization. Aromatic, heteroaromatic, and aliphatic primary amides were all successful substrates while benzylic amines were the optimal amines; aliphatic amines provided the desired amides in moderate yields. The catalyst could be easily recovered and recycled through four reactions with minimal loss of activity (Catal. Commun. 2016, 81, 29−32).

both deep eutectic solvents (DES) and low melting mixtures (LMMS) in terms of cost, toxicity, and ease of preparation is proposed as a viable alternative to investigate, though herein their inherent hydrophilicity and the fact they are mixtures may cause concerns (Chem. Phys. Lett. 2016, 661, 6−12). The exploitation of readily available biomass feedstocks to deliver commercial biofuels and multiple high value chemicals provides a sustainable alternative to the petrochemical industry. However, for this endeavor to be economically viable, and environmentally sustainable, one must consider the solvents utilized in many of the steps involved in the processing of Biomass including extractions, reactions, and formulations. Two groups have provided perspectives evaluating contrasting approaches to solve this problem. Hulsbosch et al. have proposed a “closed-loop” type of approach suggesting the use of ILs derived from products originally obtained from the processing of biomass, such as amino acids, sugars, or terpenes. The report then considers the common feedstocks (proteins, polysaccharides, lignin) and provides an overview of ILs derived from each describing not only the utility but also the potential cost and sustainability of each synthesis. The report then looks at the applications of the ILs described with the key focus being on the physical properties desired within the specific IL to successfully fulfill the proposed purpose (ACS Sustainable Chem. Eng. 2016, 4, 2917−2931). Soh and Eckelman have provided a more conventional approach to the solvents utilized in biomass processing with the initial discussion looking at the solvents currently utilized for this task. An overview of the various physical properties of solvents enables the authors to identify those that are key for the successful processing of biomass. In addition to identifying the greener solvent options that are already utilized, the report evaluates the viability of several other approaches (biobased solvents, CO2, switchable solvents) with a keen focus on the economic considerations required to implement each of these (ACS Sustainable Chem. Eng. 2016, 4, 5821−5837). Harrell et al. have reported on the use of hydrocarbon oligomers as alternatives to alkanes such as heptane in biphasic thermomorphic reaction systems using soluble polymer-bound catalysts that can easily be separated after reaction through their high affinity for the nonpolar hydrocarbon phase. In previous studies, heptane is not only disadvantageous due to its low volatility but also due to the fact that losses always occur due to it partitioning into the polar phase. A series of poly-α-olefins (PAOs), poly(propylene hexene) (PP), and polyisobutylene (PIB) polymers of varying MW, density, and viscosity were evaluated with cost, toxicity and availability key parameters in the selection process. Through a series of NMR studies on each system’s leaching into a series of polar solvents (DMF, MeOH, and MeCN), insignificant leaching was demonstrated for each of the polymers evaluated. In addition, a model system with a polymer-bound azo-dye was utilized to simulate a catalyst, and again this showed minimal leaching of the azo-dye into the polar phase after a heat cycle. Comparison experiments of both a light-induced and acid-catalyzed isomerization of an azo-dye in the various media studied as well as heptane demonstrated identical reaction kinetics for each system, though in the cases of the acid-mediated experiments the higher MW PAOs required prewashing with triethylamine to remove residual acid from the preparation process. Recycling of the PAOs was also successfully demonstrated over a series of five cycles with no deterioration in terms of performance (J. Am. Chem. Soc. 2016, 138, 14650−14657).

Thale et al. have reported on an Fe3O4 nanocatalyst also used under neat conditions. The same model reaction was employed, which showed that again temperature was a key parameter to optimize (140 °C). The scope focused on benzamide, formamide, acetamide and phthalimide reacting with benzylic and aliphatic amines as well as anilines. The same system is then applied to the N-formylation of amines using DMF as both the solvent and the formylation agent. The catalyst can be easily separated using an external magnet, and successfully reused without deterioration in yield over six cycles (RSC Adv. 2016, 6, 52724−52728).

The synthesis of amides through dehydrogenative methods under ruthenium catalysis has recently been reviewed by Chen et al. This concise article not only features sections on the couplings of amines with alcohols, aldehydes and esters, but also provides an overview of some of the challenges still existing in this research domain. In particular, the need for more active catalysts with a broader substrate scope is highlighted to enable protocols which are applicable to the synthesis of higher value compounds such as complex bioactive materials (RSC Adv. 2016, 6, 55599−55607). In an intriguing study, Chen et al. have described a dehydrogenative coupling focusing on volatile alcohols using a Pd−Ag membrane reactor, which facilitates the selective B




removal of hydrogen from the system. Despite the potential disadvantage of high costs associated with the synthesis of the ceramic Pd−Ag membrane reactor, the ability to reuse and apply the technology to the synthesis of high value products significantly offsets this concern. Model studies on the reaction of ethanol and 1-butylamine indicated that utilizing the Milstein catalyst (with KOtBu as base added to generate the active catalytic species), the optimal solvent was toluene with the reaction being conducted at 140 °C (70%, cf. 98%) and enantiomeric excess (up to >98% ee) (ACS Catal. 2016, 6, 3753−3759).

Wu et al. have successfully developed several biocatalytic cascades to prepare chiral intermediates such as α-hydroxy acids, 1,2-amino alcohols, and α-amino acids. For the proof of concept, modules using different enzymes have been optimized: epoxidases and epoxide hydrolases (module 1), alcohol dehydrogenases and aldehyde dehydrogenases (module 2), alcohol dehydrogenases, ω-transaminases and alanine dehydrogenases (module 3), and hydroxy acid oxidases, ω-transaminase, catalase, and glutamate dehydrogenase (module 4). Engineering of these enzyme modules in E. coli afforded biocatalysts able to convert styrenes in one pot reaction to several chiral relevant intermediates (R = p-MeC6H4, p-ClC6H4, o-FC6H4, m-BrC6H4) (Nat. Commun. 2016, 7, 11917).

Transaminases are enzymes that are frequently used to access chiral amines and are hence of great importance to the pharmaceutical industry. To expand their substrate scope Pavlidis et al. have applied extensive enzyme engineering to an (S)-selective transaminase to access a range of products with bulky substituents (1,2-dihydroacenaphthylen-1-amine, aryl− aryl, aryl-alkyl). The engineered enzyme showed excellent enantioselectivity (up to >99% ee) and vastly improved activity (up to 8900 fold). Based on an identified sequence motif six additional (S)-selective transaminases with activity on bulky substrates could be identified. This work complements previous evolution work on (R)-selective transaminases (Nat. Chem. 2016, 8, 1076−1082).

Imine reductases are enzymes that have the potential for broad application in the pharmaceutical industry due to their ability to both stereoselectively reduce CN double bonds as well as to conduct reductive aminations. Maugeri and Rother have shown that these type of enzymes could be used in “micro-aqueous reaction systems” (5−15% aqueous v/v), which were first been studied for lipases (Ann. N. Y. Acad. Sci. 1988, 542, 282−293). Compared to predominantly aqueous reaction systems, the solubility of hydrophobic substrates is significantly increased, which is a key advantage when targeting bulky substrates that are normally found in the later stages of API synthesis routes. Conversions of up to 96% and stereoselectivities >99% ee were shown in the CN bond reduction of β-carboline harmane and 1-methyl-3,4-dihydroisoquinoline to their respective amines. The application of

9. REDUCTIONS Iron presents an attractive alternative to PGM catalysts, but harnessing its different redox profile can be frustrating. Identifying the activity of trace PGMs can also be a disappointment in some cases but can provide access to PGM chemistry without the associated intensive extraction processes. Feng et al. have reported that iron nanoparticles containing palladium at ppm levels can deliver reduction of nitro groups using NaBH4 in the presence of aqueous surfactants. In this case it was necessary to dope Pd at levels H




group where dimerization side reactions also seen in related B(C6F5)3 studies were observed. Other more sterically demanding 1,1-dialkyl alkenes were not subject to this issue. A single trisubstituted alkene was also reduced (Org. Lett. 2016, 18, 2463−2466).

of 80 ppm to deliver reactivity, but nanoparticle preparation was straightforward and conducted at room temperature unlike some previous studies. The presence of iron was critical to successful reaction; this was presumed to be through acting as a dispersant preventing agglomeration. Chemoselectivity was good with tolerance of groups such as aryl halide, vinyl, propargyl alcohol, ester, and heteroaromatic rings. This was demonstrated through a range of substrates of a typical complexity to those used in pharmaceutical programmes. The approach is an extension of earlier studies showing how water/ surfactant mixes can replace traditional organic solvents in many transformations (Angew. Chem., Int. Ed. 2016, 55, 8979−8983).

10. ALCOHOL ACTIVATION FOR NUCLEOPHILIC DISPLACEMENT Marichev and Takacs conducted a systematic screen of ruthenium complexes for the amination of secondary alcohols by primary amines. Model reactions between 1-phenylethanol and 2-octanol and aniline and n-hexylamine were used to evaluate the influence of ligand steric and electronic factors, neutral or cationic catalyst precursors, and coordinating vs noncoordinating counterions. A number of chiral ligands were tested but did not give significant asymmetric induction. Catalyst system 1 gave the most consistent results across the four reactions and was studied further. Reactions were run in toluene at 110 °C for 24 h using 2% catalyst and 0.5 equiv of potassium tert-butoxide affording secondary amines in good to high yield. These conditions are thought to be the most efficient reported for ruthenium catalyzed amination of secondary alcohols. The catalyst is also very effective for the reaction of primary alcohols at 1% loading, allowing selective, sequential, amination of mixed primary and secondary diols (e.g., 1,2-propanediol). Reaction with diols gives five or sixmembered ring cyclic heterocycles via inter- or intramolecular cyclization (ACS Catal. 2016, 6, 2205−2210).

Borane-catalyzed reduction of amides is generally demonstrated with strong Lewis acids such as tris(pentafluorophenyl)borane. Mukherjee et al. have shown that the much weaker Lewis acid triphenylborane promotes the reduction of tertiary amides by hydrosilanes. This showed a complementary reactivity profile to the stronger Lewis acid species in that carbonyl activation was more dominant in determining reactivity. The system demonstrated strong chemoselectivity for amides over less Lewis basic species such as ketones and esters. Aldehydes were also found to react, while imines did not. A number of solvents of varying dielectric constant were investigated; those forming adducts with BPh3 were compromised. Pyridine gave no conversion, while acetonitrile led to extended reaction times although still with high yields suggesting that loadings could be further reduced. Despite this observation, the Lewis base THF was one of the best solvents alongside DCM and propylene carbonate. It is disappointing that subsequent examples were all run using DCM as the solvent rather than propylene carbonate. Although there are some differences in reactivity patterns, this study shows that there is still scope to consider the use of BPh3 as a catalyst in reduction systems rather than the more commonly promoted catalyst B(C6F5)3 (Angew. Chem., Int. Ed. 2016, 55, 13326−13329).

Another alternative to B(C6F5)3 was reported by Chatterjee and Oestreich who used Brønsted acids and cyclohexa-1,4dienes to reduce imines and alkenes. In general imines were reduced more slowly and in lower yield than with B(C6F5)3. This was rationalized on the basis of reduced kinetic and thermodynamic reactivity mandating the need for higher reaction temperatures. Conversely, aldimines were successfully reduced using Brønsted acids which was attributed to the reduced steric footprint in the cyclohexa-1,4-diene hydride donor. Alkene reduction proved to be more successful. Various cyclohexadienes were effective as reductants, whereas the related Hantsch ester hydrogen donors were not. A range of 1,1-disubstituted alkenes were reduced in yields ranging from 41% to 99% using 5 mol % Tf2NH. The weaker (but much cheaper and accessible) acid TsOH was also shown to be effective, while other acids such as C6F5CO2H or Ph2P(O)OH gave no conversion. This option was not exemplified further. Lower yields were associated with alkenes bearing a methyl

Schlepphorst et al. relay a “borrowing hydrogen” approach utilizing a ruthenium-N-heterocyclic carbene (NHC) catalyst for the α-alkylation of α-substituted ketones. This work focuses on the alkylation of methylene ketones with primary alcohols and builds on earlier work in the field using methanol to achieve alkylation. Using an optimized Ru(NHC)2 complex with lithium tert-butoxide as base in a mixture of tert-amyl alcohol and n-hexane under thermal conditions, the authors were able to achieve moderate to high conversion to a number of branched ketones. The reaction proceeds with only a slight excess of alcohol, which enables sequential double alkylation of α-methyl ketones, the first step being a selective monoalkylation. The alkylation of cyclic ketones was demonstrated with the preparation of donepezil (ACS Catal. 2016, 6, 4184−4188). I




Stålsmeden et al. have extended the chemistry of glycerol, a readily available byproduct of biofuel manufacture, through the amination of solketal with 1.2 equiv of secondary amines and sterically hindered primary amines. Reactions were run neat, or in toluene or tert-amyl alcohol, with a ruthenium catalyst system using dppf of DPEPhos ligands at 130 °C for 48 h. Deprotection of the resulting acetonide with HCl in acetone, followed by neutralization with polymer bound carbonate afforded the amino diol. The methodology was demonstrated by the preparation of dropropizine, a cough suppressant in 86% overall yield from solketal (ACS Sustainable Chem. Eng. 2016, 4, 5730−5736).

In contrast Wu et al. use alumina supported heterogeneous bimetallic platinum−tin as a catalyst for the alkylation of secondary alcohols by primary alcohols. 1-Phenylethanol and substituted 1-phenylethanols are alkylated by benzyl alcohol, substituted benzyl alcohols, and arylmethanols, the reactions being run neat in the presence of a 1:3 mol ratio of Pt:Sn, supported on γ-alumina, with 0.075 mol % Pt loading, and potassium phosphate (0.5 equiv) at 155 °C for 48 h. Products are typically obtained in >80% yield, with a few exceptions: reaction of 1-phenylethanol with o-tolylmethanol (25%), furan2-ylmethanol (20%), and 1-(p-tolyl)ethanol with benzyl alcohol (40%). The catalyst is removed by filtration and can be regenerated by washing with water and calcination in air at 450 °C for 4 h; it could be reused 4 times without appreciable loss of activity. The authors propose a sequence of hydrogen transfer reactions with an aldol condensation of the intermediate acetophenone and benzaldehyde (Tetrahedron Lett. 2016, 57, 4017−4020).

11. CHEMISTRY IN WATER Gallou et al. report their use of the nonionic surfactant TPGS750-M in water to carry out three common chemical transformations used in the pharmaceutical industry on multikilogram scale for the synthesis of an API. While other groups have published work demonstrating these techniques and transformations, this particular article demonstrates the technology at a significant scale and includes a quantitative analysis of the surfactant’s impact on key metrics of the synthetic route. The comparison is based on performing the three consecutive steps (SNAr, Suzuki-Miyaura coupling, amide bond formation) in organic solvents, as their originally developed procedure, against a redesign of the steps using TPGS-750-M in water, using organic solvents only for extraction and isolation. Key improvements discussed include the reduction of PMI by 30%, reduced stoichiometry of costly materials, improved yields and selectivity, reduced reaction times, and elimination of undesirable dipolar aprotic solvents. Overall reduction in the cost of the synthesis is also discussed as a driver for investing in the development of more sustainable practices in the pharmaceutical industry (Green Chem. 2016, 18, 14−19).

Bartolucci et al. have prepared substituted tryptamine derivatives by reacting indoles with aminoalcohols in the presence of 2.5 mol % iridium catalyst and 1.1 equiv of cesium carbonate. Reactions were performed neat in a sealed vial at 150 °C for 48 h; the addition of solvent resulted in lower conversion and increased byproducts. Building on previously reported work (J. Org. Chem. 2015, 80, 3217−3222), N-acetyl protected tryptamine and homotryptamine were prepared in 54% and 76% yield, respectively. Substituted amino alcohols gave mixed results with N-acetyl L-alaninol and N-acetyl Lserine methyl ester giving low yields accompanied by racemisation of the chiral center. N-Methylpiperidine-4-ol afforded 3-(N-methylpiperidyl)indole in 72% yield. N,NDimethylethanolamine and N-benzylethanolamine react with 4- and 5-benzyloxyindoles to give pharmacologically active molecules, including serotonin, after deprotection by catalytic transfer hydrogenation (Tetrahedron 2016, 72, 2233−2328). J




transformation in DCM and other solvents are reported; however, water proved to be a superior solvent with respect to reaction rate and yield. While other copper(I) salts performed well on the model substrates, the coordinated tetrakis(acetonitrile)Cu(I) perchlorate catalyst was used in experiments demonstrating the scope of the reaction. Derivatives of both the aniline and the α-phenyl diazo phosphate were explored and 73−97% yields achieved for a broad range of functional groups and substitution position, with the exceptions of benzyl (95% HPLC purity and >90% yield for most substrates. This processing approach was demonstrated to prepare boronic acid, aldehydes, and alcohols, often in rates of 1 g/min (Org. Lett. 2016, 18, 3630−3633).

aerobic oxidation of more complex molecules. However, advancing these technologies to a meaningful scale comes with challenges, such as poor mass transfer due to low solubility of oxygen in organic solvents and flammability of organic vapor/oxygen mixtures. Gavriilidis et al. have compiled a review which describes the chemical and engineering hurdles that complicate the utilization of aerobic oxidation in the fine chemical and pharmaceutical industries and the flow technologies that can be used to overcome them. A number of case studies are presented which highlight strategies to scaling up aerobic oxidation including using continuous flow (React. Chem. Eng. 2016, 1, 595−612). Gutmann et al. provide a good example of how continuous flow can be leveraged to scale O2 oxidation in a pair of publications describing the N-demethylation of opiates, an important transformation for the synthesis of opiate antagonists. Traditional approaches use strong electrophiles such as cyanogen bromide and chloroformates to activate the tertiary amine through quaternization producing considerable waste. Alternatively, N-demethylation is accomplished through oxidation to an iminium cation intermediate using palladium acetate and oxygen. The active catalyst is a finely dispersed Pd(0) suspension that is formed upon heating palladium acetate in DMA and stabilized with AcOH to prevent precipitation on the reactor surfaces. Continuous flow offered improved process safety (The flash point of DMA is 63 °C; however, DMA is a potential reproductive toxicant and is on the substances of very high concern list of candidates under EU REACH legislation. Some alternative solvents were screened during the development of the reaction) and improved O2 mass transfer giving low residence times and permitting the production on the 10 L scale (ACS Sustainable Chem. Eng. 2016, 4, 6048−6061 and Chem.Eur. J. 2016, 22, 10393− 10398).

13. GENERAL GREEN CHEMISTRY Various tools (iSUSTAIN, Cognis’s Four Leaf, etc.) exist enabling the assessment of so-called “greenness” of a reagent throughout the four major life-cycle stages. However, issues often exist in terms of the complexity, ease-of-use and acceptability of these tools given that they emphasize different elements of sustainability, and as such are not universally applicable across all fields of chemistry. In addition, often the desired information to utilize the existing tools are not readily available in the public domain thus providing an inaccurate and incomplete analysis. Shen et al. have reported on the development of a “Greenness Index”, which attempts to utilize easy to access information (from the suppliers MSDS), is simple to use, and delivers an easy to understand evaluation particularly when comparing potential reagents for a particular purpose. The “Greenness Index” consists of five criteria: (i) health impact (6 categories), (ii) general properties (12 categories), (iii) odor (1 category), (iv) fire safety (3 categories), and (v) stability (5 categories), with several of these being further broken down into subcategories to look at particular properties provided by the MSDS. Each criterion (or subcategory) is scored on a scale of −5 to +5 where −5 is the least green and +5 is the greenest. The various categories are

Hernandez-Perez and Collins have published a follow-up report on a continuous photoredox synthesis of carbazoles through C−C bond formation using Fe(Phen)3 (NTf2 ) 2 photocatalyst and O2. Earlier related work was previously highlighted in Issue 14. Improvements in this report include a second-generation catalytic system allowing for the use of O2 as the terminal oxidant and improvements to the continuous flow reactor (tube-in-tube setup) and a “numbering-up” strategy which improved throughput. With that said, throughput remains in the g/day scale (Org. Lett. 2016, 18, 4994−4997).

One concern about the use of precious metal catalysts is the removal and recycling of the metals once processing is complete. Ormerod et al. have published on the use of ceramic membranes to recycle and reuse the Pd catalysts by three strategic approaches: Online processing, at-line processing and off-line processing. Online processing involves the addition of the reagents into the filration loop, containing the catalyst, where the reaction occurs. A diafiltration step is required for L




reductive elimination, and transmetalation) of transition-metal catalyzed cross-coupling reactions. With the long established understanding that the chemistry of 17- and 19-electron transition state complexes react at dramatically faster rates compared to the even-electron congeners, the authors provide evidence from the literature of stoichiometric examples of oxidative addition and reductive elimination facilitated by one electron reductions and oxidations, respectively. These have been subsequently reproduced in a catalytic manner with the reduction/oxidation process mediated by a photoredox catalyst. Although transmetalation lacked the same degree of precedence, powerful examples of C−C bond formation under mild conditions are provided featuring a one-electron oxidation of a nucleophile and subsequent one-electron reduction of a metalcomplex leading to recombination and subsequent product generation. Future areas for reaction development based on previously reported stoichiometric single electron processes, as well as the challenges of selectivity control are also highlighted (Chem. Sci. 2016, 2, 293−301). Finally, Horn et al. have provided an overview on synthetic organic electrochemistry highlighting its unique ability to be able to “dial-in” a specific voltage to perform either anodic oxidation or cathodic reduction permitting highly selective transformations on highly complex molecules. The authors note that despite electrochemistry having been performed on multiton scale to produce commodity chemicals since the late 19th century, uptake in the field has been inhibited by the perceived complex reaction setup. Many of the current reports feature simple homemade reaction set-ups, which although effective lead to concerns regarding reproducibility, though the development of standardized “out of the box” instrumentation will undoubtedly continue to fuel the renaissance of this technique (Chem. Sci. 2016, 2, 302−308). Interest continues to develop in the area of Green Analytical Chemistry (GAC) with the E-factor of activities in current analytical laboratories being 25−100, matching that of fine chemical industries. In addition, it is estimated that for every analytical data point, HPLC generates 50 mL of chemical waste with a corresponding slow return of data given that this is an off-line sampling technique. El-Rahman et al. have provided a comparison using both HPLC and a potentiometric ionselective electrode (ISE) to monitor the alkaline hydrolysis at a range of temperatures and pHs of ipratropium bromide (IP), which is used for the treatment of asthma and bronchitis. The authors note that research into ISEs is in a revival phase and that the electrode is easy to assemble with a coated ionophore (CX6) present to enhance selectivity. For the study, both ISE and HPLC gave similar results in terms of kinetics of decomposition of IP, though from a GAC perspective ISE out-performed HPLC across all 12 principles, in particular being an in situ based technique as well as utilizing a minimal amount of energy. Although daily calibration of the electrode was required, it is envisioned that this “just-dip-it” approach will have further applications in simplifying analytical development (ACS Sustainable Chem. Eng. 2016, 4, 3122−3132). Eldin et al. have provided a review of the current state of analytical chemistry within pharmaceutical quality control and highlighted a number of areas where improvements can be made from a GAC perspective. In particular, modified methods of sample preparation, greener chromatographic techniques, miniaturization as well as opportunities for switching to more benign solvents/modifiers are highlighted (J. Anal. Chem. 2016, 71, 861−871).

scored based either on a sliding scale based on the values provided by the MSDS, or on a binary logic scale based on the severity of the outcome. The data is initially viewed in tabular format featuring averages for each criterion as well as the percentage of information available thus allowing an indication in the overall confidence of prediction. The output can then be expanded into a series of primary and secondary spider plots enabling a visual display of where the particular areas of concern for a specific reagent exist. The report provides an example using potassium amyl xanthate as the test reagent (Miner. Eng. 2016, 94, 1−9). Heterocyclic chemistry is the cornerstone of many branches of chemistry with particular emphasis within drug discovery and development, and as such numerous “name” reactions for the synthesis of heterocycles are consistently highlighted in organic chemistry text books. Cabrele and Reiser have published a fascinating perspective on the status of modern synthetic heterocyclic chemistry with a focus on sustainable strategies being brought to bear in this field. The initial section discusses 11 recent total syntheses with (i) atom/step economy, (ii) convergent/cascade strategies, (iii) C−H activation, (iv) avoidance of protecting groups, and (v) catalysis with economical and environmentally benign reagents highlighted. The second section addresses a series of heterocycles (containing only a single heteroatom) for which classical syntheses exist, providing a brief synopsis of new mainly catalytic strategies to access these common motifs. In addition, gaps in the new methodologies are highlighted. β-Lactams, quinolones, indoles, pyridines, pyrroles, furans, pyrrolidines, and piperidines are all discussed in this section. Finally, the use of renewable resources to provide chemical feedstocks in the future is addressed with focus on carbohydrates derived from lignocellulosic biomass. Although significant difficulties in processing this material still exist, 6-hydroxymethylfurfural (HMF) and furfural are highlighted as platform chemicals, and the development of several key transformations (cycloaddition, Piancatelli rearrangement, Achmatowicz rearrangement) of furans are highlighted to further generate complex molecules (J. Org. Chem. 2016, 81, 10109−10125). Chemical Science has published three outlook articles focusing on emerging technologies, which will have a significant impact not only on the future of sustainable synthesis, but also on the ability to access more complex chemical space in a more facile manner. Hartwig and Larsen discuss the area of undirected C−H bond functionalization with its potential utility to transform abundantly available chemical feedstocks (alkanes) into higher-value materials. The overview initially discusses the selectivity differences between various alkyl and aryl C−H bonds, and the factors affecting hydrogen atom abstraction depending on the reactivity paradigm involved (radical vs metal−carbon bond formation). The authors also highlight the synthetic utility of the borylation and silylation of heteroarenes, and the principles dictating the regioselectivity of these transformations. Challenges still exist in this area, and it is envisioned that the development of catalysts capable not only of mediating the desired transformation, but also chelating the substrate in a particular orientation, as well as hybrids of enzyme/organometallic systems, will represent key research areas for breakthroughs in undirected C−H functionalization (Chem. Sci. 2016, 2, 281−292). Levin et al. have provided an overview on how the emergence of photoredox catalysis has facilitated each of the three fundamental mechanistic steps (oxidative addition, M




Green Chemistry Articles of Interest are produced on behalf of The ACS GCI Pharmaceutical Roundtable.

Marian C. Bryan Genentech, Inc., 1 DNA Way, MS 18B, South San Francisco, California 94080, United States

Andrew Cosbie Amgen, Thousand Oaks, California 91320, United States

Louis Diorazio AstraZeneca, Macclesfield, SK10 2NA, U.K.

Zhongbo Fei Novartis Pharmaceuticals (China) Suzhou Operations, #18 Tonglian Road, Changshu, Jiangsu 215537, China

Kenneth Fraunhoffer Bristol-Myers Squibb, Co., One Squibb Drive, New Brunswick, New Jersey 08903, United States

John Hayler* GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K.

Matthew Hickey* Bristol-Myers Squibb, Co., One Squibb Drive, New Brunswick, New Jersey 08903, United States

Shaun Hughes AstraZeneca, Macclesfield, SK10 2NA, U.K.

Mark McLaws Asymchem Inc., 600 Airport Boulevard, Suite 1000, Morrisville, North Carolina 27560, United States

Paul Richardson Pfizer Global Research and Development, 10578 Science Center Drive, La Jolla, California 92121, United States

Gheorghe-Doru Roiban GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K.

Markus Schober GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, U.K.

Alan Steven AstraZeneca, Macclesfield, SK10 2NA, U.K.

Timothy White Eli Lilly, Indianapolis, Indiana, United States

Jingjun Yin

■

Merck and Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Marian C. Bryan: 0000-0002-3138-6888 John Hayler: 0000-0003-3685-3139 Gheorghe-Doru Roiban: 0000-0002-5006-3240 Alan Steven: 0000-0002-0134-0918

N


Green Chemistry Articles of Interest to The Pharmaceutical Industry

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