Large-Scale Amidations in Process Chemistry: Practical Considerations for Reagent Selection and Reaction Execution

Abstract

This review describes the practical aspects involved in the implementation of large-scale amidations in process chemistry. Coupling reagent, base, additive, and solvent selections are critically analyzed to highlight their pros and cons. Other important factors to be considered on large scale, such as atom economy, cost, safety, and toxicity, are also examined. These concepts are then showcased through selected examples from the literature for the synthesis of active pharmaceutical ingredients.

Cefonicid Benzathine Salt: A Convenient, Lean, and High-Performance Protocol to Make an Old Cephalosporin Shine

“…As amidation is one of the most commonly used chemical reactions in the synthesis of these semi-synthetic compounds, and as a broad class of coupling reagents exists, we focused our selection of activators on the practical aspects of standard chemistry processes: costs, yields, safety, and waste. As indicated in Table 1 , activation via O -acylisoureic ester, boron-derived mixed anhydride, and sulfonate-based mixed anhydride are the techniques used in our work [ 56 , 57 , 58 , 59 , 60 , 61 , 62 ].…”

A 1-pot synthesis of the SARS-CoV-2 Mpro Inhibitor Nirmatrelvir, the key ingredient in Paxlovid

“…Because of its low cost, availability, and extended use on scale as an activating agent for carboxylic acids, 11 thionyl chloride was originally screened in anticipation that the resulting acid chloride would facilitate coupling of 1 with the bicyclic proline (as its lithium salt) to arrive at intermediate acid 3 following an acidic aqueous work up and precipitation by heptane (Scheme 1). However, it is important to note that even after several efforts at optimization, the yields of 3 were consistently low (see the SI, Table S1) and several impurities could be detected by 1 H NMR.…”

“…Aside from the difficulty associated with handling this highly activated acid chloride due to its sensitivity to moisture, especially on a smaller academic scale, the potential for the acid chloride to cyclize to form an oxazolone type intermediate was also appreciated. 11,12 The possibility that residual LiOH was present from hydrolysis of the precursor methyl ester en route to the bicyclic proline lithium salt further encouraged investigation into an alternative strategy. Consideration of the numerous peptide coupling reagents in terms of both cost and "greenness" turned our focus to alkyl chloroformates, which have been widely used on scale for this purpose.…”

“…They are known for minimizing racemization, while imparting far greater stability to the resulting intermediates, especially to adventitious moisture. 11,13,14 The use of ethyl chloroformate (ECF), along with equimolar quantities of base (NMM or DIPEA), did not provide the desired high yields (Table 1, entries 1 and 2), although the overall cleanliness of the reaction and isolated product did improve relative to the acid chloride approach. The lower yields obtained were not due to incomplete conversion; rather, the issue stemmed from the regioselectivity of attack by the proline nitrogen on this unhindered alkyl chloroformate.…”

2-Azaaryl-1-methylpyridinium Halides: Aqueous-Soluble Activating Reagents for Efficient Amide Coupling in Water

“…Amide bonds are covalent C­(O)–N linkages prevalent in a wide range of natural (e.g., proteins, alkaloids, and cofactors) and synthetic compounds and polymers (e.g., agrochemicals, household chemicals, food additives, and pharmaceuticals). − Approximately 25% of drugs on the market have at least one amide bond, and over 80 therapeutic peptides have been approved for clinical use …”