Organometallics in Flow: Scalable synthesis of Mg- and Zn-organometallics

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Introduction
For more than a century, organometallic reagents, initially based on direct insertion of zinc as a metal (1) and later complemented and expanded by magnesium-based compounds (Grignard reagents) (2), have been a very valuable and intricate tool for process chemists in the formation of novel carbon-carbon bonds. Particularly in the synthesis of Active Pharmaceutical Ingredients (API), Grignard reagents and zinc reactive intermediates are regularly employed and 50 % of the Grignard reagent market is taken up by the use in the pharmaceutical sector (3, 4).
However, organometallic reagent handling is flawed by a sensitivity to water and oxygen and their formation is challenging because of variable length incubation periods due to metal surface passivation, in many cases high exothermicities in the formation that have to be appropriately managed, and a tendency for side product formation. Since the overall market for Grignard reagents is expected to grow over the next years, production capacities and product variety will increase (3). A modular continuous production process allows for tight process control, reduced storage times, and provides the necessary flexibility to adapt to varying processes.

Continuous processing of Mg- and Zn-based reactive intermediates
Conventional synthesis and conversion of Mg- and Zn-based reactive intermediates is performed in a dosing-controlled manner in big reaction vessels. A number of studies have continuously synthesized organometallic reagents to be used in carbon-carbon bond formation describing the application of continuous stirred tank reactors (5, 6) or flow tubes equipped with metal packings (7–10) and even using ball milling (11, 12). However, metal replenishment is pivotal to render the process truly continuous in liquid and solid feed and the very important question of scalability is essential for the transfer to production scale. Since the trend in the pharmaceutical industry goes to more potent and therefore lower dosage API (13), throughputs in the range of up to twenty litres per hour already are industrially relevant for multiple stages of development of new drugs.

 

Figure 1 shows a simplified schematic description of the decision process for the implementation of a continuous Mg- or Zn-based organometallic reagent formation. Modified flow tube reactors providing a large excess of either magnesium or zinc metal turnings can be used to produce organometallic reagents with throughputs of up to about 20 L/h (accessible throughput is always dependent on reagent’s concentration and reactivity). Metal replenishing either portion wise (Lab scale) or alternatively also truly continuous (Pilot scale) is incorporated to address concerns of true continuous processing in both feeds and a modular scale-up concept allows industrially relevant production capacities.

 

Relatively small reactor volumes even on a larger pilot scale also render the continuous synthesis inherently safer for the operator and the environment. Finally, the sustainability of using organometallic reagents can be improved by minimizing waste (such as undesired side products), increasing accessible concentration ranges, and producing tailor-made on-demand amounts freshly whenever needed. Magnesium- and zinc-based organometallic reagents are notoriously sensitive to oxygen and moisture, but due to the nature of a continuous manufacturing process and on-demand production, contamination can be prevented, and high quality ensured.

Given the foundation of being able to process either class of reagents, process chemists are then enabled to choose freely between reagents of either class depending on follow-up reaction(s), solubility issues, and downstream processing needs.

 

Interchangeable equipment ensures maximum flexibility
It has already been demonstrated that the process window of employing a modified flow tube reactor with a large metal excess yields higher selectivities and therewith better product quality compared to conventional batch-type synthesis in a glass flask (14).
Syntheses of magnesium- and zinc-based organometallic reagents mainly differ based on their respective reactivity and the commercially available metal turning size. A multi-purpose plant, interchangeable between the two metals magnesium and zinc, allows for maximum flexibility in research and production, since optimal process conditions for a specific reagent are only dependent on the reagents’ reactivity and concentration and magnesium and zinc can both be investigated for a specific organic moiety attached. For an optimization of conditions for either metal, flow rate and temperature employed in the synthesis must be adjusted accordingly but modifications of the set-up itself are not necessarily needed.
Tight process control is maintainable and especially essential for syntheses that are demanding in process conditions. Table 1 shows an exemplary comparison for benzyl magnesium bromide and benzyl zinc bromide in comparable concentrations on the laboratory as well as the pilot scale to elucidate how either one is accessible within the same equipment with only slight modifications in process conditions.

Completely converting halide starting materials to reactive organometallic intermediates within a single reactor passage in a few minutes residence time is achievable on either throughput scale. Immediately joining this with a follow-up step (Grignard reaction, Negishi coupling, etc.) or even performing reagent formation and conversion in a single step (Barbier reaction) is also facilitated using flow chemistry. This minimizes some of the handling issues of the organometallic reactive intermediates by the immediate use never having to hold available large quantities of these reagents.

Being able to produce magnesium- and zinc-based organometallic reagents via direct metal insertion in comparable yields allows for a decision depending on the specific follow-up route and the necessary process conditions. The enablement to choose between magnesium and zinc reagents opens a wide range of choices for process chemists in the pharmaceutical as well as the fine chemical industry. Figure 2 shows a schematic description of how the two steps of continuous organometallic reagent formation and exemplary conversion of the organometallic reagent by e.g. reaction with an aldehyde can be consecutively performed in flow reactors.

The choice is obviously influenced by the characteristics of the corresponding reagents. Grignard reagents often seem to be first choice as they are known to be more reactive than their zinc counterparts. In contrast to Grignard reagents, the formation of organozinc reagents via direct metal insertion usually requires highly reactive Rieke zinc or initial chemical activation of the zinc metal due to the reduced reactivity (15). Using continuous processing, chemical activation can be performed prior to synthesis without the chemicals ending up in the collected product. The lower reactivity renders zinc reagents more tolerable to the presence of functional groups, leading to potential process step reduction by already including a functional group in the starting materials or by performing the formation and consumption reaction simultaneously (Barbier reaction). However, due to their reduced reactivity their consumption reaction is often supported by catalysts. Therefore, providing process chemists with a quick and easy way to either zinc or magnesium reagents enables a profound decision on which metal to employ.

 

Conclusions
By now, it is widely known that continuous processing is very beneficial for fast exothermic reactions such as reactive intermediate formation. In the formation of organometallic reagents for carbon-carbon bond formation it particularly enables working in an unconventional process window compared to the batch. Set-ups are designed to be interchangeable for whole reagents classes namely Mg- as well as Zn-based organometallic reagent formation and interrelated reaction classes for their consumption. Continuous manufacturing technology allows process chemists to assess their options in a fast and simple approach on the laboratory as well as the pilot scale with a broadened scope for reactive intermediates. Since it also allows to either include a follow-up step all-in-one (Barbier reaction) in the same equipment depending on the reaction needs of simultaneous formation and consumption or to immediately follow the formation in a second continuous step with a catalysed or non-catalysed consumption reaction, the accessibility and the exploitation of organometallic reagents based on magnesium and zinc via continuous processing can be vastly improved.

 

Figure 1. Simplified schematic description of decision process for the implementation of a continuous Mg- or Zn-based organometallic reagent formation.

 

Figure 2. Simplified schematic description of a 2-step process for organometallic reagent formation and an example for an uncatalyzed follow-up step namely the reaction with an aldehyde in flow.

 

Table 1. Comparison of reaction conditions and results for benzylic Grignard and zinc reagent.

 

References and notes

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