Flow: Chemistry Unatainable by Batch and Dangerous Reactions Made Safe

Two back-to-back articles should be at the top of your list of reading if you are new to continuous flow chemistry or looking into how to generate a method for a selected transformation. These can be found in Specialty Chemicals Magazine May 2014, with Mark Bratt and Ollie Tames of IntensiChem  pp. 42-44– and Gyorgy Dorman and Richard Jones of ThalesNano pp. 45-47.

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The first article is on the fundamental thinking that goes along in flow chemistry and how it is different than the traditional batch model. Mark and Ollie take us through a storyline where chemists tend to use batch process in their strategies in developing flow methods. Their discussion leads into batch reactions that simply aren’t very good and for a number of different reasons….as opportunities were continuous flow methods would have better potential as a process. Examples with fixed bed catalysis and hydrogenations pop out as the examples that one would like to see, but several factors on temperature and pressure expands the capability some batch process simply can’t carry without major equipment by comparison. Read through several of the examples indicating opportunities where batch processes don’t measure up.

The next phase of the article is spent on the mindset — optimized batch processes have been used from optimized chemistry and that had worked very well for things done. For flow, this is a possibility for industries and reactions where the chemistry is not so well worked out — and how the flow process development can be much more streamlined and provide data and feasibility in a more efficient manner. Mark and Ollie walk us through the differences — flow requires different solutions for different schemes — with in-line analytical techniques, these development times could be lowered considerably…..again the comparisons are made with batch processes and industries involved, which gives us a clearer view of where some of the challenges exist. —- Thanks for the perspective Mark and Ollie!

The second article sets the tone by laying out some specs that are present in modern day flow instrumentation to go along with the reproducibility, speed and telescoping capability. But quickly switching gears, Gyorgy and Richard paint a picture of why flow should be used in place of some of our older techniques with dangerous reactions and reagents — just think about all of the news today on safety and explosion examples in our field. If for no other reason than this, the investment pays for itself on the first level in academia and industry. Since Gyorgy and Richard categorized a number of examples: high temperature thermal cyclizations, hydrogenations, diazotizations, low-temperature transformations, gas-liquid reactions, etc., I will leave you with the article to read. The importance of the article is that is helps provide a complete picture of using this technology in fields where small molecule heterocyclic chemistry is used, be it specialty chemicals or bench medicinal chemistry. Each category shows important parameters that can be utilized in flow to keep a clean, safe operation of reactions that have special conditions when used in a batch format. Thanks for the perspective Gyorgy and Richard

Electrochemistry in Flow: Nazlinine and more

Electrochemistry falls into one of those categories of expansion, where the chemists who perform these reactions are more similar to their specialties — as is the case with photochemistry. These simply don’t fall into the area of study, education or applied retrosynthetic strategies. However, flow chemistry allows us to level the playing field a bit, and asks us to include new reaction space which we would otherwise never draw on the chalkboard.

In a recent example (OL 2014), we are treated with a modification on a throwback Shono oxidation of cyclic amines (protected as a carbamate or amide in the generation of an acyl iminium species with a nucleophilic attack of MeOH). I particularly like this since I have used this reactions in the past, but it requires some care into the appropriate choice of anode and salt bridge — in this case electrolyte in flow).

The scheme to Nazlinine is shown below with a flow oxidation reaction followed by a microwave accelerated Pictet-Spangler to several additional non-natural Nazlinine analogs:

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The table below illustrates the use of a microreactor with choice of anode, electrolyte, flow rate and current (Carbon, 20% Et4NBF4, 43mA, flow,100-120 microliters/min).

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Expanding beyond pyrrolidine expands the utility and the chemical space for libraries around Nazlinine, but also into areas of related systems beyond the scope of the paper:

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Although not the focus of my post, the second reaction, which would otherwise take 15 hours to complete, was shortened to 30 min using microwave irradiation as a final step into Nazlinine and related compounds. You will notice a big effect in the acid choice — they found optimized results with CSA in H2O, but with a deprotection, imiminium formation, and more than one amine, screening additional acids will add additional opportunities here (med chemists — you know that I am talking to you).

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Enjoy the rest of the paper in looking at additional substitutions on the indole and extension of the exo-alkylamine. This should help you think of additional electrochemical reactions that are out there to be used — I can think of a few that I would want to incorporate (please note that references 1-2 in the paper include examples of electrochemical and photochemical reviews as excellent starting points when considering flow approaches). Happy Reading!

A perspective on flow photochemistry

The latest addition of Specialty Chemicals Magazine (November 2014 pp 26-28) features a perspective on flow photochemistry today and tomorrow- both, the process and available tools or light sources needed to operate at the gound state, but also at an excited state (single and triplet state). If interested, I have posted my thoughts on expanding capabilities in flow chemistry. Before highlighting a couple of reactions, I wanted to point out the Duncan Guthrie does an excellent job of setting the mindset that one should enter with for thinking about photochemisty. He talks about the fact that 1% of the total reaction availability is accessed through photochemistry over the years, but that a number of these can be utilized and expanded through use of the appropriate light source and the sustainability of flow techniques — I agree. Duncan then goes on to express that these processes should be embraced by the non-photochemical expert and can be easily performed as a skill developed by performing an extension of normal ground state flow methods…..again, I agree with this sentiment. It can be viewed no different from adding hydrogenations to your arsenal having not done one before…as easy as that, not to mention that re-educating the number of chemical transformations that can be added by opening up this capability.

The article is reasonably short and if you are a synthetic organic chemist, you should dig into the article — a few examples are shown from the article to illustrate the point:

Pericyclizations of the benzamide under flow conditions.

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Publication out of the Seeberger group shows  divergent continuous-flow photochemical methods toward Arteminisin-derived targets as an example of broadening application of flow and photochemistry in natural product synthesis:

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One last point, the filtering of light sources is well defined when application and technique is detailed….as well as the utility of the cooling process for the type of flow technology. Enjoy the article, because the implications provide a broadening of several industries and research. Happy Reading!

So you want to make polysubstituted furans: Enolates at Room Temp

As a continuation in theme perhaps made me think of additional reactions where an enolate is used in the formation of a useful or studied heterocycle. Although furans are not at the top of the list as medicinal chemistry frameworks (simply take a look at how CYP enzymes rid themselves of this backbone), they do represent an area of interest on the materials side of things. A recent publication from Mark York (TL 2011) shows an efficient modification of a low temperature batch enolate formation followed the addition of an alpha-bromoketone to form di-/tri-substituted as well as annulated furans in moderate to very good yield without the need for traditional cooling. So in this particular case, a simple solution of a ketone was mixed with LiHMDS at room temp (starting with a flow of 0.76 ml/min and the base at 1.54 ml/min) while flowing through a 10 ml loop…as the enolate is formed it is reacted with an alpha-bromoketone pumped in from a separate line — the mixture is allowed to flow through 2 10 ml loops and quenched at the end of the sequence — so based on the flow the total time for the reaction sequence is about 9 minutes. The scheme (shown: the appropriate substitution which postulated to form from an initial enolate, addition to the haloketone, elimination of LiBr with concurrent epoxide formation and internal attack with the elimination of water) and a section of the table is included to show some of the compounds made (yields were improved moving from low temp to room temperature — indicating that additional work would be of interest in evaluating reactions at higher temperatures than traditionally reported — with flow the kinetics may serve to eliminate a need to cool the reaction as we have done in the past. Happy Reading!

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Let’s take back our asymmetry with flow technology

For all of the work done utilizing stereoselective chemistry, we have certainly struggled with this concept in med chem from the standpoint of building chiral centers in an advanced drug candidate. With all of the synthetic knowledge, we knew that if something wasn’t naturally built in, we were going to be adding steps on the cost end of the development. I was lucky enough to be part of a number of these types of targets, and it made you think….but with continuous flow developments, this process has been streamlined. Part of the effort here is to bring it back on the table in your thought process. A reasonably recent review from Peter Seeberger et al. (Beilstein JOC 2009) provides a nice review of many of the current methods used in flow chemistry — and this particular review is on applications of homogeneous and heterogeneous asymmetric catalysis, as a sustainable cost effective way generating chiral materials from achiral starting materials.

The number of homogeneous enantioselective reactions reported using a continuous flow technique is low – with hydrogenations and silyl-cyanations reported. From the Seeberger group (Angew Chem Int Ed 2009), aldol condensations catalyzed with 5-(pyrrolidine-2-yl)tetrazole was compared with batch and microwave procedures to provide shorter reaction times and lower catalyst loadings as shown below. Clearly the benefit of these microreactor processes is the ability to screen catalysts, flow and temperature quickly.

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Moving over to the use of heterogeneous chiral catalysts, we have to way the expense of using expensive catalysts and leaching the material through the transformation….however, since we discussed the use of supported reagents, the use of a supported catalysts provides an opportunity to recover catalysts and the format is easy to develop. The downside is that these catalysts need to be put on a supported media, so screening has the potential to take longer. Below are several examples of some of the work done using this concept:

The first example (Adv Synth Catal 2008) is using a Meerifield amino-alcohol resin with the addition of Et2Zn to an aromatic aldehyde to provide good conversions with high ee%s with a flow rate of 0.24 ml/min and a residence time of 9.8 min to provide mutligram quantities of the desired compound in 98% conversion with 93%ee within 3 hr. The catalyst activity remained provided identical recoveries with different aldehydes over a 6 hr time period.

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A similar process for an ene reaction of ethyl glyoxylate and alpha-methylstyrene and a stainless steel column packed with a PyBox-Cu complex (and good for over 80 hours – 5 runs) following the load with Cu(OTf)2 to the PyBox resin (Tetrahedron: Asymmetry 2004).

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Cinchona alkaloid derivatives has been utilized in solution and solid supported reactions for a number of years. The scheme below shows a reaction of ketene (generated from an acid chloride) and imino esters for the formation of beta-lactams (JACS 2001)…so we see the ketene generation on passing through a BEMP support (so no isolation) which was then reacted with a flow of the imino ester in the presence of the supported cinchona resin, and a clean up of excess reagent and by-product and a benzyl amine scavenger. While this was elegant, the process was driven through glass columns and gravity driven, so improvements would increase the utility of the concept.

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Macroporous monolithic materials are becoming popular as strategies for a number of transformations, owing their increased surface area, improves mass-transfer between the supported reagent and liquid phase – and the advantage of not clogging or pressure fluctuation often found in gel-type resins. The ability to adjust the porosity, composition and shape provides a broader range of experimentation (we owe a shout out to our inorganic brethren for giving us insights into this strategy).

A nice example of this process can be found in (Angew Chem Int Ed 2001) from Kirschning et al. with a functionalized chiral Co(salen) complex monolith reactor used in the dynamic kinetic resolution of epibromohydrin (continuous circulated over 20 hr). This example shown could be operated continuously over a 6 day period without the loss of activity of the catalyst, and thus the corresponding ee%s.

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Several additional examples are present in the review, and this topic is receiving attention throughout the field – I imagine you have seen several examples of your own. It is pretty wide open – the wild west. Happy Reading!

 

A look at some CROs and CMOs using flow technology

I’m sure that you would agree that anything other than an exhaustive list of CROs/CMOs using flow technology as part of their services and contract work may not sit on your desk as a guide when you need it — but let’s start that list or at least the thinking for when that time is in front, the resource will provide some support. There are a number of US and Global lists of CRO and CMO chemistry organizations that fulfill the role of research and scale up route enhancement, but for the sake of focusing on flow utilization I have highlighted several — I encourage anyone who knows and wishes to contribute, leave me additional links or companies to highlight on the site. Europe and US, as early adopters, are shown below, but this technology is ever present in China and India – and while this was the focus of my thoughts today – many of you will know examples of places providing these services so I am happy to link these to the site for future reference — please let me know.

US:

Asymchem Inc with facilities in China and North Carolina USA, It takes awhile to get there, but they have flow chemistry services to go along with an extensive list of capabilities from med chem, process at the R&D and kilo scale to full manufacturing facilities.

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Sigma-Aldrich offers products and services utilizing flow technology operations.

Accendo Corporation (Tucson AZ) is a company who provides automated segmented-flow chemical platforms for research and discovery, as well as some design for larger scale capability. There are several collaborative papers on their website, showing utility and implementation.

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 The Chemistry Research Solution (TCRS, Bristol PA): Company specializing in custom synthesis, med chem, scale-up and manufacturing…with flow chemistry and microwave capabilities.

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Chembrex: (Global – Several sites) Provides multiple service and API manufacturing. Their continuous flow microwave platform is bring used for full manufacturing purposes to go along with services.

AMPAC Fine Chemicals (California, US): Although specializing in fine chemicals, AFC has implemented continuous flow methods for a number of years. They are also involved in pharmaceutical products manufacturing as well.

Europe:

Chemtrix (Netherlands) offers several options for flow chemical services in addition to their commercial offerings.

EcoSynth (Belgium): Chemical Contract Research Services on Research and Process side with microwave and flow technology capabilities.

Lonza (Visp, Switzerland): Microflow and FlowPlate technology as a service and manufacturing technology drug products.

Chorisis (Italy): CRO with several research and process scale services including flow chemistry.

Hybridcatalysis (Netherlands): Custom packages depending on need – multiple platforms and flow chemical set-ups.

Onyx Scientific (UK): With a number of service and contract capabilities, Onyx has developed continuous flow technologies.

 

And many more — just a start to be organized as a list for reference.