Survey of Solvent Usage in Papers Published in Organic Process

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Review

Survey of Solvent Usage in Papers Published in Organic Process Research and Development 1997-2012. christopher paul ashcroft, Peter Dunn, John Hayler, and andy s wells Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/op500276u • Publication Date (Web): 22 Sep 2014 Downloaded from http://pubs.acs.org on October 1, 2014

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Organic Process Research & Development

Survey of Solvent Usage in Papers Published in Organic Process Research and Development 1997-2012. Christopher P. Ashcroft1, Peter J. Dunn2, John D. Hayler3, Andrew S. Wells*4 1

Chemical Research and Development, World Wide Research and Development, Pfizer, Discovery Park, Ramsgate Road, Sandwich, Kent, United Kingdom, CT13 9NJ 2 Pfizer Global Supply, Discovery Park, Ramsgate Road, Sandwich, Kent, United Kingdom, CT13 9NJ 3 Global API Chemistry, GSK Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, United Kingdom, SG12NY 4 Charnwood Technical Consulting, Parklands, Northage Close, Quorn, Leics., United Kingdom, LE12 8AT

Abstract A survey of solvent usage for papers published in Organic Process Research and Development has been carried out for the years 1997-2012. Three solvent categories were studied: (i) solvents of concern (ii) dipolar aprotic solvents (iii) neoteric solvents. In the analysis of dipolar aprotic solvent use it was found that nearly 50 % of DMF/DMAc/NMP/DMSO usage is attributed to nucleophilic substitution reactions (mostly SNAr and SN2 reactions). Ideas on how to minimise the use of these four solvents in nucleophilic substitution reactions are presented and it is hoped that these ideas will be adopted by chemists looking at SN type reactions at all stages of development. The only neoteric solvent showing any significant use is 2-methyltetrahydrofuran, usage of this solvent grew rapidly during the survey period. Introduction From an environmental perspective, solvent usage remains the most critical aspect of pharmaceutical manufacturing. A survey by the ACS Green Chemical Institute (GCI) Pharmaceutical Roundtable showed that 56 % of materials used in pharmaceutical manufacturing were solvents, with water contributing a further 32 %.1 In addition, it has been estimated that solvents contribute 50 % of the post treatment green-house gas emissions of pharmaceutical manufacturing.2 Several companies or organisations have published solvent selections guides to encourage greener solvent selection, for example, GSK,3 Pfizer,4 Sanofi5 and the ACS GCI Pharmaceutical Roundtable6 have all published guides. Organic Process Research and Development has been a journal at the forefront of efforts to persuade scientists to select greener and safer methodology and solvents with editorials to discourage the use of diisopropyl ether7 and to encourage greener solvent selection.8 This survey, conducted as part of the CHEM21 project,9 looks at trends in solvent usage over the first 16 years of the journal’s life (1997-2012). Methodology The survey was conducted by experienced process chemists at Charnwood Technical Consulting, GSK and Pfizer. The review was designed to look at trends in the adoption of greener processing technology and solvents over the past 16 years and to complement

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a similar internal survey of the six EFPIA members of CHEM21. First a list of 388 publications was selected using key word searching of publication titles using key words such as Development, Manufacture/Manufacturing, New Route, Process, Route Change, Supply and Scale up. Scientists then filled out the review template, which is given in the supplementary information, for each publication. Details were collected on a wide variety of topics such as, the reason to change route, types of chemical methodology used, and solvent usage. Other outputs will also be published, but this publication just focuses on solvent use. If a publication described the historical development of a chemical process with several synthetic routes presented, only the last synthesis was reviewed. On closer examination of the nominated publications, 53 papers were rejected as the chemistry was described at an insignificant scale (e.g. milligrams or grams only) with no indication of the chemistry being scaled up. Details of the 388 publications are given in Table 1. It can be seen that there are a larger number of papers from the mid2000s onwards reflecting the growth of the journal (moving from 6 to 12 issues per year in 2012), a greater willingness to publish in the process chemistry community and the globalisation of the process chemistry community. Obviously due to the high attrition rate in the industry, most of the chemistry published will be for molecules that have never reached the market. In addition, a review of this type does not reflect the state of the art at the current time. Most publications will be 2-7 years “in arrears” and processing that is kept an industrial secret is of course, not visible.

Year of Publication 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012

Number of Publications Selected 12 17 11 9 14 20 14 21 15 29 28 33 25 37 49 54

Total Journal Pages 438 434 494 614 670 994 1085 1087 1024 1314 1151 1316 1432 1552 1470 1876

Table 1: Information on the 388 Publications Selected for Analysis The variation in the scale of manufacture is presented in Figure 1. and reflects a significant scale of operation, with the majority of publications in the 1-100 kg category.


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In the context of full manufacturing scale, it is worth bearing in mind that for very potent compounds (inhalation, oncology etc) a few kg could represent a significant scale.

250 200 150 Number of papers 100 50 0 100's grms

1-100 Kg

100Kg+

Figure 1 Scale of Operation in the Survey Analysis The papers were reviewed for solvent use in three areas: solvents of concern, dipolar aprotic solvents and neoteric “green” solvents. It was deemed too big a task to categorise every solvent employed, and solvent efficiency for each paper. If a synthesis used one of these three types of solvent in several process steps, the use of the solvent was only counted once per paper. So for example a synthesis may have contained several steps run in dichloromethane but for this paper, dichloromethane usage was only captured once. Solvents of Concern Solvents of concern captured in the survey along with the reason for concern are listed in Table 2. Solvents of Concern Dichloromethane Chloroform Carbon tetrachloride 1,2-Dichloroethane Diisopropyl ether Benzene

Reason(s) for Concern Suspect Carcinogen, Listed under water framework directive Suspect Carcinogen Suspect Carcinogen, Ozone depleting chemical Suspect Carcinogen Explosion hazard through peroxide formation Carcinogen



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n-Hexane Chlorobenzene Trifluorotoluene 1,2-Dimethoxyethane 1,4-Dioxane Diethyl ether Trichloroethylene Diglyme 2,2,2-Trifluoroethanol Pyridine Nitromethane

Neurotoxin Toxic to the aqueous environment Toxic to the aqueous environment Male reprotoxin Suspect Carcinogen Fire and explosion hazard Suspect Carcinogen Male reprotoxin High environmental impact High environmental impact Explosion hazard

Table 2 : Solvents of Concern A bar chart showing the usage of these solvents of concern is shown in Figure 2. The eight most commonly used solvents of concern are dichloromethane, n-hexane, diisopropyl ether, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, 1,2-dichloroethane and chloroform and the usage of these materials over time is shown in Figure 3. From other reports, some companies are clearly making good progress in reducing their usage of materials of concern, for example in the period 1990-2000 dichloromethane was the third most commonly used solvent in the GSK Pilot plant, by 2005 it was the eighth.10 Pfizer has not transferred a commercial process which used a chlorinated solvent to its manufacturing division in the last eight years and has reduced chloroform usage in its medicinal chemistry group by 99 % (usage by the process chemistry group was stopped decades ago).11 In spite of these successes it is clear from Figure 3 that the global industry as a whole is not making any significant progress and that materials such as chloroform, diethyl ether, n-hexane, diisopropyl ether and 1,2-dichloroethane are still being selected for use when alternatives are readily available.4,8 In the publication data set, we only found one paper which used benzene as solvent, but this process was run on more than 400 kg scale.12 We also found a batch process using chloroform reported in OPRD at more than 1500 kg scale.13 Full details of the survey with usage on each individual year can be found in the supplementary materials. One encouraging trend is that it appears that since 2001, the usage of chloroform and n-hexane is falling. The usage of many solvents (e.g. dichloromethane) is consistent over time but one solvent which seems to be on the increase is dioxane. Closer examination of the data base revealed the main uses of this solvent. One application is its use in Suzuki or Buchwald reactions and the other is the use of commercially available HCl/dioxane solution in BOC deprotection reactions and it is likely that both of these uses are inherited from medicinal chemistry activities. Much greener options are now available to process chemists for these transformations. Suzuki reactions can be run using heterogeneous palladium on carbon using an aqueous alcohol as solvent, a combination which also allows easy recycling of the palladium.14 Process chemists often perform BOC deprotections with tosic acid in an ester solvent which can have the additional advantage that the unmasked amine crystallises directly as the tosic acid salt.15


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CH2Cl2 IPE Dioxane Et2O Diglyme CCl4 MeNO2 Benzene C2H2Cl4 0

20

40

60

80

100

120

Number of papers

Figure 2: Usage of Solvent of Concern in OPRD (1997-2012)


140

160

180


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Figure 3: Percentage of papers using the eight most commonly used solvents of concern over time

Dipolar Aprotic Solvents Dipolar aprotic solvents are a class of solvents which are currently indispensable to the pharmaceutical industry. They are typically employed as they promote widely used reactions such as nucleophilic substitution reactions (mostly SNAr and SN2). It has been known for more than 50 years that SNAr reactions are up to 105 times faster in a dipolar aprotic solvent than they are in protic solvent16 and that dipolar aprotic solvents also massively accelerate nucleophilic substitution reactions, particularly for small, negatively charged nucleophiles.17 In addition they are widely used for their solubilising power particularly for polar heterocyclic molecules, inorganic reagents and salts. The usage of twelve dipolar aprotic solvents was captured in the survey: dimethylformamide (DMF), dimethylacetamide (DMAc), dimethyl sulphoxide (DMSO), N-methyl-2-pyrrolidinone (NMP), N-ethyl-2-pyrrolidinone (NEP), acetonitrile, sulpholane, 1,3-dimethyl-2imidazolidinone (DMI), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), formamide, propionitrile and butyronitrile. Full results of the survey can be found in the supplementary materials but a summary of the usage is presented in Figure 4. Perhaps not surprisingly, the five most commonly used solvents in this class are acetonitrile, DMF, DMSO, NMP and DMAc. There are significant issues with each of these five commonly used solvents. DMF, DMAc and NMP are female reprotoxins; DMSO has some significant process safety issues.18 Acetonitrile has fewer issues than the other four solvents but also lacks the solubilising power of DMF, DMAc, NMP or DMSO. In 2007 the ACS GCI Pharmaceutical Roundtable identified finding “greener” alternatives for DMF, DMAc, NMP and DMSO as one of twelve key Green Chemistry Research Areas19 and in 2013 awarded one of its



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annual research grants to a research proposal in this area.20 More recently the need to find greener alternatives in this area became even more urgent when DMF, DMAc and NMP were named on the REACh substances of very high concern (SVHC) list21 and are being subjected to detailed discussion in the REACh process. Although related materials such as NEP are not listed, testing has shown that they will have similar reprotoxicity issues.22

MeCN DMF DMSO NMP DMAc DMI C2H5CN C3H7CN Sulpholane DMPU Formamide NEP 0

20

40

60

80

100

120

140

160

Number of papers

Figure 4: Usage of Dipolar Aprotic Solvents in OPRD (1997-2012) The usage of DMF, DMAc, NMP and DMSO over time is shown in Figure 5. DMF is the most commonly used of these four solvents and its usage is fairly consistent over time. There is also a smaller but persistent use of DMAc. When the toxicity issues with DMF became apparent, the general consensus was to replace with NMP, which has now itself been identified as a reprotoxin. Hence there has been a significant increase in the use of NMP during the lifetime of OPRD as can be seen in Figure 4 but this does not seem to have reduced DMF or DMAc use which may reflect a move to less soluble compounds over the time period. Over the first 16 years of the journal, DMSO use is similar to NMP and perhaps has a slight upward trend.


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Dimethyl Sulphoxide (DMSO) 15.0%

10.0%

5.0%

0.0% 1997 2000

2001 2004

2005 2008

2009 2012

Publication Year

Figure 5: Percentage of papers using DMF, DMAc, NMP and DMSO over time A more detailed analysis was then carried out on the five most commonly used dipolar aprotic solvents. The experimental procedures were interrogated and the use was defined as either (i) use in work-up (ii) use in nucleophilic substitution type reactions (SN RXN) (iii) use in amide formation (iv) other, largely solubility related. The results of this analysis for the five solvents are shown in Figure 6.


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70

Dipolar aprotic vs. use

60 50 Work up

40

SN RXN

Number of papers

30

Amide Other

20 10 0 MeCN

DMSO

NMP

DMF

DMAc

Figure 6: Reasons for Dipolar Aprotic Solvent use in OPRD 90 80 70 60 Number of 50 papers 40 30 20 10 0 work-up

SN RXN

Amide

Other

Figure 7: Combined analysis for DMF, DMAc, NMP and DMSO. The combined results for DMF, DMAc, NMP and DMSO are shown in Figure 7 which reveals that nearly 50 % of the usage can be attributed to their use in nucleophilic substitution reactions. In the view of the authors, these reactions present the greatest opportunity to reduce the usage of dipolar aprotic solvents in the manufacture of pharmaceuticals and several examples of successful scale up of nucleophilic substitution reactions following successful replacement of a dipolar aprotic solvent are now presented.



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The SN2 alkylation of the amine 1 by the mesylate 2 in DMF as solvent gives an excellent yield (95 %) of the tertiary amine 3 (Scheme 1) however the reaction is also accompanied by extensive epimerisation of the chiral centre with the chiral purity falling from 99.1 % ee to 7.6 % ee. Under the same reaction conditions but replacing DMF with acetone as solvent the desired product is also obtained in excellent yield (94 %) but this time with much improved chiral purity (97.8 % ee). The chiral purity could then be upgraded to 99.8 % ee by forming the fumarate salt of 3 which was the desired API. Many SN2 reactions tend to work very well in aprotic solvents that are not too polar,24 so exploring the use of acetone or other ketones with this type of reaction is an important strategy in minimising the use of dipolar aprotic solvents.

O

O

HO N

HN Me

+ OMs

2

K2CO3 (3 equiv) NaI (5 equiv) Solvent, 24 h, rt

O

O 1

O HO N N Me

O

O O

3

Scheme 1: Successful replacement of DMF by acetone in the alkylation of amine 1 Another example of successful replacement of DMF by a much greener solvent (EtOH) in a nucleophilic substitution reaction was reported by Rhone-Poulenc Rorer as part of the synthesis of a PDE IV inhibitor (Scheme 2).25 In the initial medicinal chemistry synthesis, phenol 4 was alkylated with cyclopentyl bromide 5 using sodium hydride as base and DMF as solvent. The authors initially switched the base to potassium carbonate which improved the yield from 57 % to 84 % as well as removing the significant process safety hazard.26 Finally Rhone-Poulenc Rorer switched to a protic solvent (EtOH) which gave an excellent 95 % yield of the desired product 6 reproducibly on a 10 Kg scale.

Medicinal Chemistry Method: DMF, NaH, 50 °C, 22h, 57 %


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1st Process Chemistry Method: DMF, K2CO3, 65 °C, 8h, 84 % 2nd Process Chemistry Method: EtOH, K2CO3, reflux, 8h, 95 %

Scheme 2: Successful replacement of DMF by ethanol in the alkylation of phenol 4 An example of replacing DMF with 2-MeTHF in an SNAr reaction has been published by Pfizer.27 In the original medicinal chemistry synthesis, aryl fluoride 7 underwent reaction with phenol 9 using potassium carbonate as base and DMF as solvent at 100 °C. The reaction produced a 4:1 mixture of the desired bis aryl ether 10 and its regioisomer 12 (Scheme 3). In order to minimise formation of the regioisomer, Pfizer modified the route so that aryl fluoride 8 was reacted with phenol 9 and this strategy was successful in minimising the regioisomer 13. Initially potassium carbonate (2.2 equiv) and DMF were selected for the reaction, but this time the reaction was conducted at 120 °C to give a 63 % yield of the desired product. The authors then conducted a solvent/base screen on the reaction and some results from this screen are shown in Table 3. As can be seen in the table, a dipolar aprotic solvent is not required for this reaction and the reaction can even be successfully conducted in toluene (entry 5). The reaction with potassium t-butoxide in 2-MeTHF gives essentially the same yield as the DMF reaction albeit in a somewhat slower reaction. Pfizer successfully scaled up both the DMF and the 2-MeTHF reactions and reported the 2-MeTHF reaction (entry 4) on a 333 g scale.

Scheme 3: Replacement of dipolar aprotic solvents for the alkylation of phenol 9 entry

Base (equiv)

1

K2CO3 (2.2)

2

K2CO3 (2.2)

Solvent, temp DMF 120 °C NMP 120 °C

Reaction time 12 h

Conversion by HPLC 96 %

Isolated yield of 11 63 %

18 h

88 %

NA



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3

KOBut (1.1)

4

KOBut (1.1)

5

KOBut (1.1)

THF 65 °C 2-MeTHF 78 °C Toluene 110 °C

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6 days

82 %

NA

5 days

92 %

62 %

4 days

93 %

NA

Table 3: Results of the solvent/base screen for the SNAr reaction of phenol 9 with aryl fluoride 8.27 Another useful strategy for replacing dipolar aprotic solvents is the use of phase transfer catalysis. The SNAr reaction of chloropyridine 14 with aminophenol 15 can be carried out using potassium t-butoxide as base in DMSO to give the desired bisaryl ether 16 (Scheme 4).28 However, successful reaction could also be achieved using tetrabutylammonium bisulphate as a phase transfer catalyst in aqueous THF in slightly higher yield.28 Some caution needs to be exercised with phase transfer catalysis, since some materials used as catalysts are ecotoxic and should not be discharged in aqueous waste streams.

(i)

KOBut, DMSO 80 °C, 78% or NaOH, H2O/THF, Bu4NHSO4, 67 °C, 82%

Scheme 4: Replacement of DMSO with phase transfer conditions In conclusion, although the kinetics of nucleophilic substitution reactions are often faster in dipolar aprotic solvents16,17 these reactions can work very successfully in alternative solvents and process chemists should be screening a wide range of alternative solvents in order to minimise the use of dipolar aprotic solvents. As the kinetics are slower, chemists may have to resort to reactions in sealed systems under a small positive pressure in order to get reasonable reaction times. For example in the Pfizer chemistry given in Scheme 3 and Table 3, an examination of entries 3-5 at a temperature 20 or 30 °C above boiling point was probably warranted. It is worth noting that the SNAr reaction in Scheme 3 is a fairly challenging substrate with the nucleophilic attack taking place at a relatively hindered, tetrasubstituted benzene ring, in many cases dipolar aprotic solvents can be replaced by greener solvents without pushing the reaction temperature above the solvent boiling point as in the examples given in Schemes 1 and 2. In the OPRD survey, nearly 10 % of the DMF/DMAc/DMSO/NMP use is associated with amide formation reactions. Watson et al. report that in a broader, Sci-Finder based


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survey of 680,000 amidation reactions, that 47 % of amidations use DMF as the reaction medium.29 The same paper also shows that for pharmaceutically relevant molecules, greener alternatives to DMF can nearly always be found so this is an additional opportunity for the industry to reduce its reliance on dipolar aprotic solvents. In order to find alternatives to dipolar aprotic solvents (and some solvents of concern) process chemists may need to look at a broader range of possible solvents and to use principal component analysis to identify similar solvents to screen.30 Aubry et al. studied a group of 220 solvents and came up with 40 solvents which they consider green (based on CMR rating and toxicity).31 The authors then demonstrated using the Hansen solubility parameters [dispersive (δd), polar (δp), hydrogen (δh)]32 that this group of 40 solvents was well dispersed in chemical space.31 The Hansen solubility parameters of DMF are also reported in this paper (along with those of the other 219 solvents) but DMF does not feature in the “green group” of solvents because of its CMR potential. Scale of Operation For some key solvents of concern and dipolar aprotic solvents, another more detailed analysis was conducted to see if there were any differences in scale of operation. The survey data was split into two sections: processes above 100 kg and processes below 100 kg. The results can be found in Table 4.

Chlorinated* n-Hexane 1,2-Dimethoxyethane 1,4-Dioxane Diethyl ether Diisopropyl ether Dimethylformamide Dimethylacetamide Dimethyl sulphoxide N-Methyl-2-pyrrolidinone

Less than 100 Kg Scale 56 % 14 % 5% 6% 3% 7% 31 % 12% 12 % 9%

Greater than 100 Kg scale 40 % 5% 5% 0 0 2% 12% 5% 5% 7%

*includes dichloromethane, chloroform, 1,2-dichloroethane and chlorobenzene

Table 4: Usage of some key solvents of concern and dipolar aprotic solvents at different scales of operation. The results show a general improvement on scale. Particularly pleasing are the large reductions in DMF, n-hexane, diisopropyl ether, DMAc, DMSO and the complete elimination of diethyl ether and dioxane. Neoteric Solvents



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In the last 15-20 years many ideas have been put forward for greener processing liquids for example ionic liquids as non-volatile materials avoiding flammability issues or 2methyltetrahydrofuran (2-MeTHF) as a solvent derived from renewable C5-sugars. Although champions or manufacturers propose these materials as green, it is important that they are assessed against a broad range of criteria for example as proposed by Henderson et al.3 The survey examined the usage of eight solvents or solvent types namely ionic liquids, supercritical fluids, 2-MeTHF, cyclopentyl methyl ether, fluorous phases, methyl or ethyl lactate (derived from corn starch), ethylene/propylene glycol (non-volatile alcohols) or water (specifically reactions “on water”33). Full results of the survey are given in the supplementary information but between 1997 and 2012 only 2MeTHF grew rapidly in that period as shown in Table 5. It is interesting to note that ionic liquids, fluorous phases, supercritical fluids and “on water” reactions are completely absent from the data set.

Publication Year 1997–2000 2001–2004 2005–2008 2009–2012

Number of publications in the survey using 2-MeTHF 0% 0% 4.4 % 14.3 %

Table 5: The usage of 2-MeTHF over time There are a number of reasons why the industry appears to be slow or reluctant to adopt new solvents, despite a genuine desire to move away from certain solvents of concern. Some of these are discussed below. Cost and availability of new solvents No new solvents are developed for pharmaceutical synthesis; new solvents tend to be developed for other large volume sectors (e.g. fuels) and are adopted by synthetic chemists. Specialist solvents like fluorous-phase materials are too expensive to be used in manufacture. In addition, many companies are reluctant to lock into a solvent that has a single supplier as surety of supply is extremely important in pharmaceutical manufacture. Purity Many industrial materials may not have the correct purity or consistency of purity to be used in cGMP manufacture and the relatively low volumes required for pharmaceutical manufacture are unlikely to warrant additional purification to a higher specification. Regulation


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Lack of regulatory guidance for permitted solvent levels has detracted from the introduction of new solvents where no mammalian toxicology data exists.34 Sustainability Many suggested “greener” replacement solvents have been selected on the basis of single issue sustainability, and greater consideration of environmental and life cycle analysis (LCA) does not support initial claims.35,36 However in some sectors, design for the environment is now being actively considered.37 Recycle/disposal Many neoteric solvents based upon natural products tend to be more viscous and have higher degrees of oxygenation, increasing boiling points and the energy burden for recovery by distillation. However, recovery and reuse will probably be required to make use of the solvent economically viable. The energy cost burden in recycling solvent-water mixtures could be alleviated to some extent by replacing water miscible solvents such as THF and MeCN with 2-MeTHF, although both THF and MeCN can be immiscible with water at high solute concentrations. Given the factors above, it is perhaps not surprising that solvent selection is very conservative, and the introduction of new solvents is proceeding very slowly. However older undesirable solvents are being phased out or their use restricted, hence the industry will need to accelerate its introduction of new solvents.

Conclusions The results of the survey show that there is much room for improvement across the global pharmaceutical industry. Solvent selection guidance is widely available3-6 and should be used in process development. Chemists need to avoid falling into the trap of associating certain solvents with certain reactions. There are some encouraging trends, for example the reduction in chloroform and n-hexane use since 2001 and it would be interesting to repeat the survey in 2016 and see if these trends are continued. Another encouraging trend is the improvement seen in solvent utilisation in processes run at above the 100 kg scale. In the area of dipolar aprotic solvents, the authors feel that they have been able to identify some key areas to reduce the use of these solvents though dipolar aprotics will remain essential for pharmaceutical manufacture for some years to come.

Acknowledgements



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The authors would like to thank Matthew Badland, David Henderson, Roger Howard, Craig Knight, Daniel Laity, Ian Moses, Christopher Seaman, Robert Walton and Katherine Wheelhouse for their help in completing the survey. This work has been funded by the Innovative Medicines Initiative (www.imi.europa.eu) joint undertaking under grant agreement number 115360, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.38 References 1. Jimenez-Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Org. Process Res. Dev. 2011, 15, 912-917. 2. Jimenez-Gonzalez, C.; Curzons, A. D.; Constable, D. J. C.; Cunningham, V. L. Clean Tech. Environ. Policy 2005, 7, 42-50. 3. Henderson, R. K.; Jimenez-Gonzalez, C.; Constable, D. J. C.; Alston, S. R.; Inglis, G. G. A.; Fisher, G.; Sherwood, J.; Binks, S. P.; Curzons, A. D. Green Chem. 2011, 13, 854-862. 4. Alfonsi, K.; Colberg, J.; Dunn, P. J.; Fervig, T.; Jennings, S; Johnson, T. A.; Kleine, H. P.; Nagy, M. A.; Perry, D. A.; Stefaniak, M. Green Chem. 2008, 10, 31-36. 5. Prat, D.; Pardigon, O.; Flemming, H.-W.; Letestu, S.; Ducandas, V.; Isnard, P.; Guntrum, E; Senac, T.; Ruisseau, S.; Cruciani, P.; Hosek, P. Org. Process Res. Dev. 2013, 17, 1517-1525. 6. “A Collaboration to Deliver a Solvent Selection Guide for the Pharmaceutical Industry” a presentation by C. R. Hargreaves at the American Institute of Chemical Engineers Annual Meeting, Philadelphia, 17th November, 2008. 7. Laird, T. Org. Process Res. Dev. 2004, 8, 815. 8. Laird, T. Org. Process Res. Dev. 2012, 16, 1-2. 9. CHEM21 is Europe’s largest public-private partnership dedicated to sustainable manufacturing of pharmaceuticals. It brings together 6 EFPIA companies (Bayer, GSK, Janssen, Sanofi, Orion and Pfizer), 9 Universities (Austrian Centre of Industrial Biotechnology, Leibniz Institute for Catalysis, University of Antwerp, University of Durham, University of Leeds, University of Manchester, University of Stuttgart, University of York and VU Amsterdam) and four small to medium enterprises (Cat Sci Ltc, Charnwood Technical Consulting, Evolva Biotec and Reaxa Ltd). 10. Constable, D. J. C.; Jimenez-Gonzalez, C.; Henderson, R. K. Org. Process Res. Dev. 2007, 11, 133-137. 11. Dunn, P. J.; Wells, A. S. and Williams, M. T. “Future Trends for Green Chemistry in the Pharmaceutical Industry” in Green Chemistry in the Pharmaceutical Industry, Wiley-VCH, 2010, p 333-355. 12. Fujimoto, M.; Maeda, T.; Okumura, K.; Uda, M.; Makoto, N.; Teruka, K.; Takashi, T. Org. Process Res. Dev. 2004, 8, 915-919. 13. Kompella, A.; Adibhatla, B. R. K.; Muddasani, P. R.; Rachakonda, S.; Gampa, V. K.; Dubey, P. K. Org. Process Res. Dev. 2012, 16, 1794-1804.


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14. Yates, M. H.; Koenig, T. M.; Kallman, N. J.; Ley, C. P.; Mitchell, D. Org. Process Res. Dev. 2009, 13, 268-275 see also Ennis, D. S.; McManus, J.; WoodKaczmar, W.; Richardson, J.; Smith, G. E.; Carstairs, A. Org. Process Res. Dev. 1999, 3, 248-252. 15. Patterson, D. E.; Powers, J. D.; LeBlanc, M.; Sharkey, T.; Boehler, E.; Irdam, E.; Osterhout, M. H. Org. Process Res. Dev. 2009, 13, 900-906. 16. Miller, J.; Parker, A. J. J. Am. Chem. Soc. 1961, 83, 117-123. 17. Parker, A. J. J. Chem. Soc. 1961, 1328-1337. The advantages of using polar aprotic solvents in nucleophilic substitution reactions (particularly for enhanced kinetics) have been taught to organic chemistry students for decades for example see McMurry, J., Organic Chemistry, 3rd edition, Wadsworth, 1992, pp 372-373 and Roberts, J. D. and Caserio, M. C., Basic Principles of Organic Chemistry, 2nd edition, W. A. Benjamin Inc., 1979, pp 237-240. March, J., Advanced Organic Chemistry 4th edition, John Wiley and Sons, 1992, pp 348-350. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd edition, Oxford University Press, 2012 pp 344.346 (see also reference 24). 18. Lam, T. T.; Vickery, T.; Tuma, L. J. Thermal Analysis and Calorimetry 2006, 85, 25-30. 19. Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.; Leazer, Jr., J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411-420. 20. ACS GCI Pharmaceutical Roundtable Research Grant 2013 awarded to Dr Janet L. Scott in collaboration with CatScI and Charnwood Technical Consulting “Intelligent Selection of Greener Solvents” http://www.catsci.com/green-solventsproject.html (last accessed 9th May, 2014). 21. The candidate list for Substances of Very High Concern (SVHC) is updated twice a year and can be found at http://echa.europa.eu/candidate-list-table (last accessed 12th June, 2014). 22. A summary of the toxicity information for N-ethyl-2-pyrrolidinone can be found at http://echa.europa.eu/documents/10162/13626/opinion_for_nep_adopted_final_en .pdf (last accessed 12th June, 2014). 23. Kato, T.; Ozaki, T.; Tsuzuki, K.; Ohi, N. Org. Process Res. Dev. 2001, 5, 122126. 24. Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd edition, Oxford University Press, 2012 pp 344.346. ISBN 978-0-19-927029-3. 25. Cook, D. C.; Jones, R. H.; Kabir, H.; Lythgoe, D. J.; McFarlane, I. M.; Pemberton, C.; Thatcher, A. A.; Thompson, D. M.; Walton, J. B. Org. Process Res. Dev. 1998, 2, 157-168. 26. Bretherick's handbook of reactive chemical hazards edited by P. G. Urben, 7th Edition, Academic Press, Oxford. ISBN-13: 978-0-12-373945-2. See also http://www.crhf.org.uk/incident101.html (last accessed 10th May, 2014). 27. Tao, Y; Widlicka, D. W.; Hill, P. D.; Couturier, M.; Young, G. R. Org. Process Res. Dev. 2012, 16, 1805-1810. 28. Feng, W.; Gao, X.; Dai, X. (Suzhou Zelgen Biopharmaceutical) US Patent 8, 669, 369; 11th March, 2014.



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29. MacMillan, D. S.; Murray, J.; Sneddon, H. F.; Jamieson, C.; Watson, A. J. B. Green Chem. 2013, 15, 596-600. 30. Moseley, J. D.; Murray, P. M. J. Chem. Technol. Biotechnol. 2014, 89, 623-632. 31. Benazzouz, A.; Moity, L.; Pierlot, C.; Sergent, M., Molinier, V.; Aubry, J.-M. Industrial and Engineering Chemistry Research 2013, 52, 16585-16597. 32. Hansen, C. M. J. Paint Technol. 1967, 39, 104. See also Hansen, C. M. Hansen Solubility Parameters, A User’s Handbook; CRC Press; Boca Raton, FL, 2007. 33. Narayan, S.; Muldoon, J.; Finn, M. G.; Fokin, V. V.; Kolb, H. C.; Sharpless, K. B. Angew. Chem. Int. Ed. 2005, 44, 3275-3279. 34. Antonucci, V.; Coleman, J.; Ferry, J. B.; Johnson, N.; Mathe, M.; Scott, J. P.; Xu, J. Org. Process Res. Dev. 2011, 15, 939-941. 35. Cho, C.-W.; Pham, T. P. T.; Jeon, Y.-C.; Yun, Y.-S. Green Chem. 2008, 10, 6772. 36. Wells, A. S.; Coombe, V. T. Org Process Res. Dev., 2006, 10, 794-798. See also Pretti, C.; Chiappe, C.; Pieraccini, D.; Gregori, M.; Abramon, M.; Monni, G.; In Torre, L. Green Chem. 2006, 8, 238-240. 37. Myles, L.: Gore, R.; Spulak, M.; Gathergood, N.; Connon, S. J. Green Chem. 2010, 12, 1157-1162. 38. http://www.chem21.eu (last accessed 26th May, 2014). Insert Table of Contents Graphic and Synopsis Here


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Survey of Solvent Usage in Papers Published in Organic Process

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