Diastereoselectivity is in the Details: Minor Changes Yield Major Improvements to the Synthesis of Bedaquiline

Bedaquiline is a crucial medicine in the global fight against tuberculosis, yet its high price places it out of reach for many patients. Herein, we describe improvements to the key industrial lithiation-addition sequence that enable a higher yielding and therefore more economical synthesis of bedaquiline. Prioritization of mechanistic understanding and multi-lab reproducibility led to optimized reaction conditions that feature an unusual base-salt pairing and afford a doubling of the yield of racemic bedaquiline. We anticipate that implementation of these improvements on manufacturing scale will be facile, thereby substantially increasing the accessibility of this essential medication.

Toward a Practical, Nonenzymatic Process for Investigational COVID-19 Antiviral Molnupiravir from Cytidine: Supply-Centered Synthesis

A scalable four step synthesis of molnupiravir from cytidine is described herein. The attractiveness of this approach is its fully chemical nature involving inexpensive reagents and more environmentally friendly solvents such as water, isopropanol, acetonitrile and acetone. Isolation and purification procedures are improved in comparison to our earlier report, as all intermediates can be isolated via aqueous acid treatment and recrystallization. The key steps in the synthesis, namely ester formation, hydroxamination and deprotection were done on multigram scale to afford molnupiravir in 36-41% yield with average purity of 98 wt% by q-NMR and 99 area % by HPLC.

Ready, Set, Flow! Automated Continuous Synthesis and Optimization

Synthetic chemistry provides access to advanced materials that facilitate innovation in key industries such as medicine, energy, and agriculture. Automation is poised to challenge the traditional process of chemical synthesis and development. Continuous flow chemistry has recently come into maturity and provides a flexible platform amenable to automation. The merger of synthesis and automation promises to democratize access to custom complex small molecules for non-experts as well as accelerate the development of new synthetic protocols by relieving expert chemists of routine tasks. In this contribution, we discuss recent case studies that present strategies towards realizing automated synthesis with a further focus on works that leverage continuous flow chemistry as an enabling technology.

Continuous flow strategies for using fluorinated greenhouse gases in fluoroalkylations,

Large quantities of fluorinated gases are generated as intermediates or byproducts from fluorinated polymer production annually, and they are effective ozone depleting substances or greenhouse gases. On the other hand, the incorporation of fluoroalkyl groups into drug molecules or bioactive compounds has been shown to enhance biological properties such as the bioavailability, binding selectivity, and metabolic stability. Extraction of fluoroalkyl sources, including trifluoromethyl and difluoromethyl groups, from the fluorinated gases is highly desirable, yet challenging under regular batch reaction conditions. Flow chemistry is an emerging and promising technique to address long-standing challenges in gas–liquid batch reactions such as insufficient interfacial contact and scalability issues. In this review, we highlight recent advances in continuous flow strategies toward enabling the use of fluorinated greenhouse gases in organic synthesis.

Progress Toward a Large-Scale Synthesis of Molnupiravir (MK-4482, EIDD-2801) from Cytidine

Molnupiravir (MK-4482, EIDD-2801) is a promising orally bioavailable drug candidate for the treatment of COVID-19. Herein, we describe a supply-centered and chromatography-free synthesis of molnupiravir from cytidine, consisting of two steps: a selective enzymatic acylation followed by transamination to yield the final drug product. Both steps have been successfully performed on a decagram scale: the first step at 200 g and the second step at 80 g. Overall, molnupiravir has been obtained in a 41% overall isolated yield compared to a maximum 17% isolated yield in the patented route. This route provides many advantages to the initial route described in the patent literature and would decrease the cost of this pharmaceutical should it prove safe and efficacious in ongoing clinical trials.

Di-tert-butyl Phosphonate Route to the Antiviral Drug Tenofovir

Di-tert-butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di-tert-butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent. For the synthesis of tenofovir, a two-step sequence was developed using Mg(OtBu)2 as the base for the alkylation of (R)-9-(2-hydroxypropyl)adenine. Subsequent deprotection could be achieved with aqueous acids. (Di-tert-butoxyphosphoryl)methyl methanesulfonate showed to be the most efficient electrophile tested, affording PMPA in 72% yield on a 5 g scale. The developed protocol could also be applied for the preparation of the hepatitis B drug adefovir (64% yield/1 g scale)

On-Demand Generation and Use in Continuous Synthesis of the Ambiphilic Nitrogen Source Chloramine

Herein, we demonstrate the on-demand synthesis of chloramine from aqueous ammonia and sodium hypochlorite solutions, and its subsequent utilization as an ambiphilic nitrogen source in continuous-flow synthesis. Despite its advantages in cost and atom economy, chloramine has not seen widespread use in batch synthesis due to its unstable and hazardous nature. Continuous-flow chemistry, however, provides an excellent platform for generating and handling chloramine in a safe, reliable, and inexpensive manner. Unsaturated aldehydes are converted to valuable aziridines and nitriles, and thioethers are converted to sulfoxides, in moderate to good yields and exceedingly short reaction times. In this telescoped process, chloramine is generated in situ and immediately used, providing safe and efficient conditions for reaction scale-up while mitigating the issue of its decomposition over time.

A concise route to MK-4482 (EIDD-2801) from cytidine

A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The selective acylation and direct amination eliminate the need for protecting and activating groups and proceed in overall yield of 75%, a significant advancement over the reported yield of 17%. The step count is reduced from five transformations to two, and expensive uridine is replaced with the more available cytidine.

A Concise Route to MK-4482 (EIDD-2801) from Cytidine: Part 2

A new route to MK-4482 was developed. The route replaces uridine with the more available and less expensive cytidine. Low-cost, simple reagents are used for the chemical transformations, and the yield is improved from 17% to 44%. A step is removed from the longest linear sequence, and these advancements are expected to expand access to MK-4482 should it become a viable drug substance.

Deuteriodifluoromethylation and gem-Difluoroalkenylation of Aldehydes Using ClCF2H in Continuous Flow

The deuteriodifluoromethyl group (CF2D) represents a challenging functional group due to difficult deuterium incorporation and unavailability of precursor reagents. Herein, we report the use of chlorodifluoromethane (ClCF2H) gas in the continuous flow deuteriodifluoromethylation and gem-difluoroalkenylation of aldehydes. Mechanistic studies revealed that the difluorinated oxaphosphetane (OPA) intermediate can proceed via alkaline hydrolysis in the presence of D2O to provide α-deuteriodifluoromethylated benzyl alcohols or undergo a retro [2+2] cycloaddition under thermal conditions to provide the gem-difluoroalkenylated product.