A General and Practical Alternative to Polar Aprotic Solvents

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A general and practical alternative to polar aprotic solvents exemplified on an amide bond formation Fabrice Gallou, Pengfei Guo, Michael Parmentier, and Jianguang Zhou Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00190 • Publication Date (Web): 22 Jun 2016 Downloaded from http://pubs.acs.org on June 23, 2016

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Organic Process Research & Development

A general and practical alternative to polar aprotic solvents exemplified on an amide bond formation Fabrice Gallou,*,ᵻ Pengfei Guo,‡ Michael Parmentier,ᵻ Jianguang Zhou‡ ᵻ

Chemical & Analytical Development, Novartis Pharma AG, 4056 Basel, Switzerland

‡

Chemical & Analytical Development, Suzhou Novartis Pharma Technology Company Limited, Changshu, Jiangsu, China 215537 *Corresponding Author: [email protected]

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The identification of sustainable and harmless solvents to be used for general synthetic purposes has been an area of focus by a large population within the chemical community in the last few decades. This has become all the more important as not only the well known ozone-depleting chlorinated solvents were flagged many years ago,(1) but also given the reprotoxicity issues associated with such frequently used polar aprotic solvents as Dimethyl formamide (DMF), Dimethyl acetamide (DMAC) or N-Methyl pyrrolidone (NMP) being made visible by the EU, especially with the REACH process.(2) A key benefit the political endeavor triggered was to drive innovation towards new and sustainable products with the hope of ultimately changing the mindset and to set best standards in the industry. To tackle this particular topic, a variety of somewhat general strategies was followed by multiple groups around the world, developing neoteric solvents, for example, which gave rise to new solvents, such as the bio-based cyrene,(3) ethers such as Cyclopentyl methyl ether (CPME) or the more powerful Methyl tetrahydrofuran (MeTHF).(4) Other harmless derivatives of the problematic solvents were developed directly by chemical producers,( 5, 6, 7) such as ionic liquids,(8) or more sophisticated systems utilizing compressed gases, for example,(9) or phase-transfer catalysis,(10) switchable solvents,(11, 12), and fluorous systems.(13) While punctual success stories can be found and have proven to be of tremendous benefits at times, the generality, however, has still been lagging. This, unfortunately, has therefore not yet led to the required dramatic change in mindset. For example, time-critical experimentations continue to rely on the most established and undesirable use of DMF or NMP, for example. This is all the more critical and relevant in the pharmaceutical industry where the physical properties of the target compounds routinely display limited solubility. We became heavily involved in this topic almost a decade ago and triggered numerous projects in the field with two main goals. The first one was to answer acute problems as they arise, working on projectspecific questions where we faced potential regulatory challenges. The second and more ambitious goal was to identify a long-term general approach towards the complete replacement of undesirable polar aprotic solvents. Around that time, Professor Lipshutz started disclosing his group’s early applications of benign-by-design surfactant chemistry.(14) We immediately saw the potential and assessed the chemistry internally on a variety of transformations. Our preliminary successes (15) were combined with the same challenges others had likely encountered, namely emulsion problems, oiling out, or precipitations resulting in mediocre conversions and limited generality. However, we were fortunate to find a practical and general solution to these issues that made the micellar approach amenable to allscales. In this report, through the design of a process on a real-case but single example, we would like to illustrate the thought process. We hope it will allow peers to repeat the intellectual process necessaryfor the successful development and scale-up of such chemistry, enabled by micellar catalysis in water. Specifically, we describe amide bond formation, one of the most frequently encountered transformations within the pharmaceutical community. (16)


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Scheme 1. Amide bond formation of interest. Such an amide bond-forming step is typically conducted in a polar aprotic solvent, such as DMF, where a substantial amount of epimerization may be observed. In our hands for this specific case (see scheme 1), it varied between 5 and 10% under a variety of conditions. It could certainly be decreased to lower levels with fine-tuning of the coupling reagent, and/or the temperature of the reaction and the process itself. However, our purpose relied mostly in finding a general method. We also endeavored to devise a process leading to a lower environmental footprint and much improved safety profile, while rapidly providing a handle to control the selectivity and extent of epimerization. We therefore investigated the use of surfactants in water. The second generation of benign-by-design surfactant developed by Professor Lipshutz, namely TPGS-750-M, (17) was our surfactant of choice as it was the most readily available at the time of our work, with an already wide acceptance and scope of suitable transformations. (18, 19) While these protocols functioned in a very satisfactory way on small to midscale, and for a large variety of substrates, challenges associated with the physical properties of specific substrates were experienced at times. Indeed, it is not uncommon to face emulsions, oiling out, and/or precipitation that dramatically decrease the chances of success and/or reproducibility with increased scale. The foundation of micellar chemistry suggests that the presence of organic additives can be detrimental to the proper in situ supra-molecular organization of the surfactants into micelles, as well as the rates of desired reactions taking place within, and given the presumed mechanism for successful transformations. Nevertheless, we envisioned that an additive could channel the reactive components of the system from one phase to the other; i.e., between water and the lipophilic micellar interior, playing both roles of slightly increasing the solubility, and the rate of dissolution. This concept was inspired by an analogous physico-chemical effect observed in the food industry with absinthe and the Ouzo effect, for example. (20, 21) We were hoping that the presence of an additive would favor a smooth process and over-ride the specificity of any given substrate. Therefore, we evaluated the effect of several co-solvents in various ratios within our reaction mixture. The aim was initially qualitative: to observe a mixture with suitable physical properties, namely a stable emulsion / reaction mixture that would allow for proper mixing and exchange phenomena, key to reactivity, selectivity, and reproducibility (see table 1). The role of increased quantities of liquid amine base was first evaluated, which could serve not only as base, but also as co-solvent. To our delight, we observed that both the properties of the reaction mixture improved, as did the yields. When an inorganic base was used, poorer performances were observed.



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Entry Base

Appearance Conversion from 1 to 3

1

none

oil ball

2

1 eq NMM oil ball

66%

3

3 eq NMM emulsion

80%

4

1 eq K2CO3 oil ball

67%

0

Table 1. Base effect. Reactions were carried out at room temperature (20 to 25 oC), with 1.5 eq DMTMM and run for 16 h; a 10 wt % of aqueous TPGS-750-M solution was used. Encouraged by these results, we investigated a wide variety of commonly used solvents. While nonpolar and non-water miscible solvents showed no positive effect, such water-miscible solvents as alcohols, THF, acetonitrile or PEG of various sizes (from PEG-200 to PEG-1000) greatly improved the physical aspects of the process and increased the extent of conversion and thus, yields (see table 2). It is interesting to note that important differences can be observed with PEG of various sizes or capping, especially when it comes to fine-tuning and optimization to avoid side-reactions. The amount of cosolvent used, as well as the loading of surfactant in the aqueous medium, can also be fine-tuned, but are not discussed herein. We are still in the process of collecting more data to shed additional light on the actual mechanism. Such observations and ongoing development of this chemistry seemed quite surprising at first (see figure 1). It, indeed, challenges to some extent the presumed micellar mechanism. Nevertheless, our pragmatic approach turned out to work very well for all kinds of water/surfactant-mediated transformations.


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Entry

Co-solvent

Base

Appearance

Conversion from 1 to 3

1

none

1 eq NMM

oil ball

66%

2

2 V EtOH

1 eq NMM

oil ball

< 50%

3

2 V THF

1.2 eq NMM

emulsion

78%

4

Tol

1 eq NMM

oil ball

64%

Table 2. Co-solvent effect. Reactions were carried out at rt (20 to 25 oC), with 1.5 eq DMTMM for 16 h; the amount of co-solvent compares to that of the amino acid 1 assuming a density of 1; a 10 wt % equiv of TPGS-750-M solution in water was used.

Pure organic solvent TPGS-750M water only (typically undesirable polar aprotic solvent)

Co-solvent / 750M water

TPGS- Co-solvent only

Figure 1. Qualitative impact of reaction medium.

For our specific transformation, further fine-tuning with the stoichiometry of the reagent and the base via classical optimization rapidly gave rise to an optimum solution in terms of yield, purity profile, and physical properties of the reaction mixture (see table 3, entry 2).



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Entry

Co-solvent

DMTMM

Base

Appearance

Conversion from 1 to 3

1

2 V THF

1.5 eq

1.2 eq

emulsion

81.5%

2

2 V THF

1.5 eq

2.0 eq

emulsion

96%

3

2 V THF

2.0 eq

2.0 eq

emulsion

83%

4

2 V THF

2.0 eq

1.2 eq

emulsion

78%

Table 3. Base effect. The reactions were carried out at rt (20 to 25 oC), with 2 eq V of THF, NMM as a base, and run for 16 h; the amount of co-solvent compares to that of the amino acid 1 assuming a density of 1; a 10 wt % eq of TPGS-750-M solution in water was used. This process scaled in a very robust manner, and resulted in an easily managed emulsion over the course of the reaction. A general extractive work-up approach was used at the start of this project, and is described, thus providing a rapid and general solution to the isolation of the desired product. While it loses the benefits of the chemistry in water, it still offers the advantage of the selectivity associated with the technology, and allowed us to rapidly go through the initial phases of development where speed and quality are key attributes, without suffering from the potential specifity associated with various substrates. Once a candidate target has been selected, a much more streamlined process can be developed. In any case, the solvents used both for additive and for the work-up have much improved footprint and safety liability compared with the polar aprotic solvents used commonly. (22) Moreover, and in particular regarding the work-up, use of organic solvent for product extraction has the mere requirement that it solubilize the compounds, and not to mediate the transformation. In the case discussed, we diluted first with isopropyl acetate, and did an acidic washing, prior to concentration to an almost pure oily residue that could either be used as such or precipitated. A typical process is as follows: to a degassed 2 weight percent solution of TPGS-750-M in water (1080 mL) was added the amino acid 1 (108.0 g, 430mmol, 1.0 eq) in a mechanically stirred reactor (ca. 100 rpm) at rt. The suspension was stirred at rt for 10 min, and N-methylmorpholine (86.9 g, 860mmol, 2 eq) was added over a few min. A clear solution resulted. DMTMM (178.4 g, 645 mmol, 1.5 eq) in THF (216 mL) was added over ca. 15 min so as to control the formation of a nice and well-stirrable emulsion. Amino acid HCl salt 2 (139.8 g, 471 mmol, 1.1 eq) was added as a solid at a rate such that the emulsion remained stable and homogeneous. The reaction mixture was stirred for an additional 18 h until completion of the reaction as determined by HPLC. At completion, isopropyl acetate (1080 mL) and brine (540 mL) were added. The resulting mixture was stirred for 15 min. Stirring was stopped and the


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phases were separated. The aqueous phase can be extracted a second time. The (combined) organic extract(s) was(were) washed with 1M HCl solution (75 mL), and the resulting organic extract concentrated in vacuo to result in a light yellow oil (228.0 g, purity 95.3%, yield 88%). In conclusion, the counter-intuitive observation has been made that addition of an organic solvent to a reaction mixture being used under micellar conditions is the key to success. This empirical approach has since proven to be particularly general in a variety of transformations, ranging from C-C cross-couplings (Heck, Sonogashira, Suzuki), oxidations, and reductions, as will be reported shortly. This has, in collaboration with Professor Lipshutz, allowed us to develop a powerful and sustainable toolbox for tackling the most frequently encountered transformations within our portfolio, and to open up new fields for novel chemistry. Most remarkable, these efforts which were originally intended to solve an environmental question, have brought much improved selectivities and operational simplicity, resulting in significant economic benefits,(21) and thus a much more ambitious program than originally intended. Nonetheless, this leads us back to the fundamental understanding of the process itself. While a micellar mechanism was quite realistic from early reports, our developed processes challenge such a hypothesis. Whether the mechanism really makes the chemistry happen with homogeneous reactants in one of the phases, being inside the micelle or organic phase, or interfacial, where the reactants are located at the interface between the water and the surfactant, or proceeds via solvation of the reaction components that then allow for entry and subsequent reactivity within micelles still remains to be answered.(23) To date, although we have put much emphasis on the growth of the toolbox of chemistry considering the huge scope being discovered, seemingly on a daily basis and with considerable overall success, we have also started some deeper and more fundamental efforts targeting a real understanding of the underlying principles governing such transformations. More light on the generality and understanding of this co-solvent effect will be reported in due course. Acknowledgements. The authors would like to thank Dr. Tetsuo Uno for the starting point and specific insights on the described transformation, Dr. Daniel Kaufmann and Professor Dieter Seebach for their continuing support, and Professor Lipshutz for the inspiration and fruitful collaboration.



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Table of Contents Graphic

From a difficult to process mixture, to a stable emulsion. A simple but counter-intuitive adjustment:


A General and Practical Alternative to Polar Aprotic Solvents

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