New Ways Around Hazardous Reagent Chemistry

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Many transformations that afford important categories of organic building blocks useful for the synthesis of pharmaceutical intermediates and APIs cannot be performed due to hazardous conditions. Reactions that require the use of unstable reagents lead to the formation of highly reactive intermediates, and those that are highly exothermic typically are not suitable for implementation on a large scale because of the hazards they pose.

Research is ongoing in both the industrial and academic setting to develop alternative approaches that will enable these transformations to be performed safely on a commercial scale. Such approaches include the development of new forms of hazardous reagents that are stable and can be readily manipulated in the plant setting; identification of new reaction conditions, such as the use of flow chemistry, to reduce the quantities of hazardous reagents and/or provide highly controlled conditions for energetic reactions; and the identification of entirely new routes that do not have any of these issues.

Examples of recent approaches to overcome hazardous transformations are described in the following sections.

The benefits of flow chemistry
In the Vilsmeier (or Vilsmeier-Hack) reaction, aryl aldehydes and ketones are obtained from substituted amides via their reaction with phosphorous oxychloride and electron-rich aromatic compounds. The substituted chloroiminium ion formed from the reaction of the substituted amide with phosphorous oxychloride is referred to as the Vilsmeier reagent (VR). While this reaction can provide a wide range of interesting carbonyl compounds, its use on a large scale can be difficult, because VRs are often irritants and also hazardous reagents due to their high thermal energies of decomposition.

Researchers at Novartis Pharma employed flow chemistry to address this issue (1). They achieved the in-line formation and immediate consumption of VRs using a combination of batch and flow technologies and applied the new process to the synthesis of the anti-diabetic drug vildagliptin.

Researchers at AMRI also performed a potentially hazardous cyclopropane ring-opening reaction in a continuous-flow reactor to increase the safety of the process (2). Subsequent copper-mediated Diels-Alder and palladium-catalyzed Negishi coupling reactions were also used in the optimized synthesis of taxadienone on a decagram scale.

At Bristol-Myers Squibb, a hazardous analysis of a reaction involving the conversion of a tertiary alcohol to a hydroxypyrrolotriazine intermediate identified the potential for thermal runaway (3). To mitigate this potential, a continuous oxidative rearrangement process was developed that involves the mixing of three different, stable feed streams in a specific order using in-line static mixers. A “plug flow” design achieved using heat exchangers ensures sufficient residence times for completion of the reaction. The continuous process has been employed on the pilot plant and commercial manufacturing scales for the production of the investigational liver cancer drug brivanib alaninate.

Increasing safety with PAT
Advances in process analytical technology (PAT) not only help speed up process development and optimization, they can also facilitate the control, and thus increase the safety, of synthetic organic reactions. Researchers at Merck Sharp & Dohme recently reported the successful application of PAT for determining the appropriate timing of reagent addition and reaction quenching (4). The technologies discussed included process video microscopy (PVM), a new focused-beam reflectance measurement (FBRM) method, miniature process infrared (IR) spectroscopy, and a flow IR sensor. PVM was used as a nondestructive method for analyzing particle morphologies in real time, while the new FBRM technique has improved reliability due to its greater resistance to probe fouling. The miniaturized IR system was found to be easier to use at scale-up and more robust, and the miniature IR flow sensor was a more cost-effective tool with a faster response, and thus useful for continuous flow processes.

The IQ Consortium, an organization of pharmaceutical and biotechnology companies with the mission of advancing science-based and scientifically-driven standards and regulations for pharmaceutical and biotechnology products worldwide, also recently reported on the current state of PAT use in the development of APIs (5). In the paper, the authors point out that PAT can minimize the hazards posed to operators when sampling hazardous materials and also provide more reliable data on processes that involve the use of hazardous materials. Through greater process understanding, increased process control-often through the use of simplified monitoring and control systems-is possible at the commercial production scale.

Surrogates with better safety profiles
One of the most effective methods for eliminating the concerns associated with hazardous reagents is to develop stable derivatives or totally new alternatives that accomplish the desired transformation without the safety concerns of the original compounds. Several examples have appeared in literature recently.

Michael Willis at the University of Oxford developed a method for the synthesis of sulfonamides via in situ formation of intermediate sulfinates from magnesium-, lithium-, and zinc-based reagents and DABSO, a surrogate for sulfur dioxide (6). The sulfinates were reacted with N-chloroamines, which were also generated in situ by reacting amines with aqueous bleach. While sulfonamide groups are present in biologically relevant compounds, they are often accessed through the corresponding sulfonyl chlorides, which can be unstable. The new method provides a route that avoids sulfanyl chlorides. Primary and secondary amines, anilines, and amino acids were all suitable for the reaction, which proceeded most efficiently with Grignard reagents.

Sodium metal is often used effectively for Birch reductions and the reduction of esters (Bouveault-Blanc reduction), but does have associated safety concerns at larger scale given the pyrophoric nature of sodium metal and the volatility of ethanol. Researchers at the University of Manchester and Pentagon Fine Chemicals reported that a dispersion of sodium metal particles with diameters ranging from 5-15 μm in a mineral oil is a nonpyrophoric, free-flowing powder alternative that can be handled in air and provides results similar to sodium metal (7). In particular, the Bouveault-Blanc reduction was found to proceed in high yields at 0 °C in hexane for a wide range of aliphatic ester substrates with 2.5 equivalents of isopropanol rather than ethanol and just 4.5 equivalents of the sodium dispersion. Notably, alkenes, aryl amines and fluorides, acidic protons, and sterically hindered carbon centers were tolerated

Direct aryl C-H chlorination is another desirable reaction for the preparation of aromatic chlorides, but the most reactive methods typically require the use of hazardous reagents such as chlorine (Cl₂) or sulfuryl chloride (SO₂C_l2). Milder reagents are available, including N-chlorosuccinimide (NCS) and 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), but their applicability is limited due to their reduced reactivity.

Other reagents that have been employed also suffer from unattractive features such as toxicity, hydroscopicity, light/heat sensitivity, and explosive properties among others. Phil S. Baran and colleagues at The Scripps Research Institute and Bristol-Myers Squibb have developed the guanidine-based chlorinating reagent 2-chloro-1,3-bis(methoxycarbonyl)guanidine (CBMG), which they refer to as Palau’chlor, as an alternative for the mild and safe direct chlorination of nitrogen-containing heterocycles and certain arenes, conjugated π-systems, sulfonamides, and silyl enol ethers (8). The new reagent is an air-stable solid that is thermally stable below 100 °C, yet achieves transformations that have only been possible in the past with highly reactive, hazardous chlorinating reagents. Importantly, the cost of the reagent and its functional group tolerability are similar to that of NCS.

References
1. L. Pellegatti and J. Sedelmeier, Org. Process Res. Dev, 19 (4), 551-554 (2015).
2. S. G. Krasutsky, et al., Org. Process Res. Dev. 19 (1), 284-289 2015.
3. Thomas L. LaPorte, et al., Org. Process Res. Dev. 18 (11), 1492-1502 (2014).
4. George Zhou, et al., Org. Process Res. Dev. 19 (1), 227-235 (2015).
5. John D. Orr ,et al., Org. Process Res. Dev. 19 (1), 63-83 (2015).
6. M.C. Willis, et al., Angew. Chem., Int. Ed. Engl. 54 (4), 1168-1171 (2015)
7. D.J. Proctor, et al., J. Org. Chem. 79 (14), 6743-6747 (2014).
8. Phil S. Baran, et al., J. Am. Chem. Soc. 136 (19), 6908-6911 (2014).