Expanding the scope of available reactions

The benefits chemists most often discuss in continuous flow methods involve: handling reactive or dangerous reagents, how more efficient the mass to heat transfer is, the ability to use in-line column to scavenge or quench a reaction, but something that has opened my eyes is the reaction space that is opened and how under-utilized it has been for a great number of years outside of some need to add a step in a total synthesis or specific methodology development……that’s right, I am talking about photochemical processes, reactive gas additions, ozonolysis, electrochemical methods and in terms of mixing — how to handle a higher percentage of solids in a flow reactor. An all important topic and it amazes me that in 20+ years in pharma, that I ran very few of these outside of a ozonolysis and some reactive gas addition chemistry (NH3/CO2/CO/H2) so it gives me an opportunity to pull off some of my dusty books off the shelf and have a look at things that are fresh and current again. For a start I thought I would highlight a couple of applications: a photochemical [2+2] cycloaddition (I see the handwaving now) and a reactive aromatic substitution with NH3 under high temperature and pressure as a starting point and then add some uncommon reaction methodologies and see if it gains some traction in the literature (enabling).

For the aromatic substitution with NH3, an application note provided by ThalesNano with a substitution of 3,5-difluorobenzonitrile with ammonia (as well as a series of amines, single and double subsitution) illustrates the ability to use NH3 and operate at very high temperatures and pressures under a continuous flow stream (X-cube). Just for perspective, without the aid of pressure or transition-metal catalyst, substitutions of F with an amine or ammonia on an aromatic ring with EWGs is a pretty sluggish reaction to say the least, with reactions in the neighborhood of 2-4 days in many reports. Microwave enhancements certainly offered a pretty good alternative technology for making this acceptable for a medicinal chemist to generate advanced substrates, but usually avoided the use of ammonia. Although the target compound can be made in different ways, the first proof-of-concept run entailed the flowing pre-absorbed NH3 in NMP and the 3,5-difluorobenzonitrile at 0.5ml/min into a 8 ml loop (16 min residence time at a temperature and pressure of 275C and 200 bar, respectively to provide the desired mono-substituted compound in >99% yield. The high temperature and pressure capability made this a tremendous opportunity to implement reactions that were otherwise unavailable in traditional set-ups.

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Following the success of the the initial run, the group extended to method to include additional amines. One noteworthy observation made had to do with solubility and in order to provide a way to continuously flow all substrate products and amines, a 6% MeOH solution in NMP was found to be the optimal solvent conditions used.

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And as you can imagine, why not add a second substitution to the additional F and round out a series of diamino-substituted benzonitriles, but one can imagine using other substrates to generate mixed substitution patterns as well. Several examples and a fully detailed account of the conditions are available in the note.

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Turning our attention to photochemistry – and I can count the number of these I have performed on both hands so bare with me, lol! Well that’s not entirely true, I dabbled a bit on the microwave side and the results were variable — in the microwave you generally apply and electrodeless lamp that is capable of discharge, and the power has to be just right. It does work but it takes some time….so to see the ease at which a lamp can be placed in the flow of reactants wets my appetite.

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In an application note #36 by Vapourtec, they set the stage by immediately talking about the chemical space that is now available by applying a UV-lamp (take a look at the set-up on their website) in line with the flow of reactants — no doubt this will get used extensively. They chose in this particular example a [2+2] photochemical cycloaddition of maleimide and 1-hexyne to show how a reaction can be set up effectively — because the flow of reactants and the photons/min are both important factors for a successful application. In fact they go on to point out that the photo cell UV-150 can be thought of a reactant that is simply not in-line with the reagents. Man this brings me back to a book every organic chemist should own (Organic Chemistry: The Name Game: the fun part is in the nearly all carbon nature of the chemistry discussed – and photochemistry comes to mind). So back to the reaction: Since the UV-lamp is emitting photons in a specific range, the amount needs to match the transformation and the flow or residence time in front of the lamp.

The flow reactor schematic in the E-Series is shown below — the coil tubing is placed around the photoreactor. And I should point out that photochemical reactions are not thermally driven so in their case they cooled the reactants coming through to 30C (but studied and optimized for higher temperature to make sure). In addition, different filters were used to keep the range of photons at the right frequency for the reaction.

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With an initial reactant concentration of 0.1 M , the flow rate was studied at 1-8ml/min with a constant UV at a constant 120W. The result indicated that 4 ml/min provided >95 yield of the desired. By increasing concentration to 0.4 M and slowing the flow rate to 1 ml/min they could achieve the same conversion, and thus the same output/day. The scheme is shown below but I encourage you to take a look at the application note; it is extensively studied, with a number of details that will help ease you into this new area of continuous flow chemistry and unexplored territory. Happy Reading!

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In-line quenching and scavenging under continuous flow conditions

While there are a number of publications illustrating these techniques in action, I am going to talk about two of them: 1) handing the formation of organic azides and their transformations and 2) the total synthesis of oxomaritidine using in-line techniques.

For the first topic, there are different approaches to handling organic azides formed in flow reactor. For example, an aniline starting material can be diazotized in the presence of a stream of tert-butyl nitrate. Substitution using an azide nucleophile (generated in situ from TMS-N3 provides the requisite azide with loss of N2. However, improvements to the sequence can be made by using an in-line packed bed of sulfonic acid resin, followed by a trialkylamine base resin before the azide leaves the reactor (same bed flow reactor). The SO3H resin will sequester any unreacted aniline – and also functions to degrade and deprotonate any TMS-N3 forming hydrazoic acid. Although dangerous in its’ own right, the hydrazoic acid is scavenged by the presence of the amine resin in the same cartridge, leaving a purified stream of organic azide flowing through the reactor for the next transformation (an example of this utility in the formation of a series of triazoles, (Org Biomol Chem 2011). As illustrated below:

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An alternate strategy, making use of azide ion-exhange polymers to displace more reactive alkyl halides under continuous flow, shows an in-line azide resin with a stream of substrate flowing through in the formation of an organic azide under the appropriate flow and heating conditions. In an illustration below, you see this is the initial step in a synthesis (followed by a key aza-Staudinger-Wittig reaction, Org Biomol Chem 2011), where nearly all of the steps contain an in-line trapping technique or reactive resin in the total synthesis of oxomaritidine (Chem Comm 2006). Happy Reading!

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HEL Group: Modular Tubular Reactors expanding flow capability

So no doubt that I was familiar with HEL and their automated chemistry systems, but I am happy to see that not only are they involved in reactor development, but have added tubular reactor designs for a wide range of temp and pressure, different reactor material options — extending the range of heterogenous and homogeneous catalysis and gas additions (hydrogenations and carbonylations). Take a look through their site for a better idea of what the group is doing in flow chemistry.

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Divergent flow synthesis by stream splitting (Changing the Game)

So there are several aspects to cover from a recent review article from Green Processing and Synthesis (Green Process Synth 2013: Flow chemistry approaches directed at improving chemical synthesis), but one thing that caught my attention (there were several) had to do with the formation of a substrate which was then split into several streams and reacted with additional components to produce products in separate lines. Man talk about a way to produce analogs or even several advanced intermediates to be used again.

Following a prior sequence to form specific ynone products, the Durham group added additional cools and streams to have this substrate react with several other reactants at different temperatures and flow rates independently to form products in separate in-line receiving flasks. Take a look at the set-up and the scheme below to see the innovative approach in using this technology — this would be the model in my lab wet chem set-up moving forward for a number of transformations. Love it. Happy Reading!

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Facile [3+2] cycloaddition continuous flow strategies to triazolopyrimidines

A recent example of reaction route scouting was published by a group at Northeastern University ( J Flow Chem 2014, Graham Jones et al) showing several critical factors going into the [3+2] azide cycloaddition chemistry in forming a desired triazole.

First thing – as they highlight, the triazole pharmacophore is a privileged structure indeed with a final portion of the paper indicating a successful Brilinta analog library. Depending on who you ask — metathesis or click chemistry with the most citations in recent memory, but one thing we call all agree, click chemistry utilization has made the triazole hot again, and this group chose a robust [3+2] cycloaddition of an azide with cyanoacetamide to place the amino-amide functionalities in place to form the requites triazolopyrimidone.

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The group points out several details when using a methodology like this: dealing with hazardous organic azides, temperature for effective transformation and the number of equivalents compared with a traditional batch process. For a proof-of-concept and trial determination, the group utilized a Labtrix S1 system (Chemtrix) for the displacement of benzyl bromide with NaN3 in NMP to form smaller quantities of the small alkyl azide in a flow format while varying the temperature with flow rates of 0.5 to 25 microliters/min — so after a few minutes and less than 100C the final product is produced in high yield.

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From here they were able to utilize the benzyl azide in a second flow reaction and cycloaddition with cyanoacetamide under mixing aq NaOH/NMP, followed by a study varying the amount of cyanoacetamide needed for full conversion (b, below). Lastly a combined 2-step one flow set of conditions were determined using benzyl bromide, NaN3 at 80C and 1 microliters/min followed by injection of NaOH/cyanoacetamide for a one-pot approach over the sequential process.  A schematic of the flow is presented below, but because they wanted to make libraries, this 2-step one pot (a) approach allowed a library of triazoles to be made with commercial starting materials.

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For purposes of the project, they reported the continued synthesis of Brilinta analogs following the triazole ring construction with a cyclocondensation to produce the requisite triazolopyrimidone, chlorination, and 2-independent heteroaromatic substitutions.

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Although it can be imagined that the entire sequence could have been done in flow sequence, the group showed us that this technology can be used in a number of orders in a drug discovery approach — rather than simply thinking of this as a tool, I think this will help medicinal groups and process chemists have real discussions where these strategies can be optimally used for their work — not only can it be used in an analog campaign, but also for the larger production of a best compound intermediate (lets say compound 25 so that divergent analog approaches to high-speed analoging by independent team members take a chunk of the intermediate, thereby yielding more final, testable analogs…….thanks Northeastern (thanks Sara!). 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.