Total Synthesis of (±)-Allocolchicine and Its Analogues Using Co-Catalyzed Alkyne [2 + 2 + 2]-Cyclotrimerization

The total synthesis of (±)-allocolchicine has been completed by employing cobalt-catalyzed alkyne [2 + 2 + 2]-cyclotrimerization as the key reaction. The essential diyne has been synthesized from easily available 3,4,5-trimethoxybenzaldehyde following simple chemical transformations. In general, the cycloaddition gave a mixture of C(9) and C(10) isomers thus allowing the synthesis of both allocolchicine and its C(10)-carboxylate. Because this cycloaddition was employed at the penultimate stage, it allowed the synthesis of various analogues having the diverse functionality at C(9) and/or C(10) of ring C

Ruthenium(II)-Catalyzed C3 Arylation of 2‑Aroylbenzofurans with Arylboronic Acids/Aryltrifluoroborates via Carbonyl-Directed C–H Bond Activation

The Ru­(II)-catalyzed carbonyl-directed C–H activation with (hetero)­arylboron reagents has been executed for the synthesis of 2-aroyl-3-(hetero)­arylbenzofurans. A hypothesis founded upon the involvement of an active carbonatoruthenium­(II) complex for a coordinative insertion and the aerobic oxidation of the <i>in situ</i> generated Ru(0) to Ru­(II), to continue the catalytic cycle, has been extended

Toward a Practical, Two-Step Process for Molnupiravir from Cytidine

A two-step synthesis of molnupiravir (1) is presented. This work focuses on the development of practical reaction and purification conditions toward a manufacturing route. The sequence commences from highly available cytidine (2), and molnupiravir is formed through direct hydroxamination of the cytosine ring and esterification of the sugar’s primary alcohol without use of protecting or activating groups. A highly crystalline hydrate of N-hydroxycytidine (3) resulted in an easily purified intermediate, and a practical, off-the-shelf enzyme was selected for the acylation. The yield was increased through a chemically-promoted, selective ester cleavage which converted a by-product, molnupiravir isobutyryl oxime ester (4), into the final API. Both reactions proceed in >90% assay yield and crystallization procedures are used to afford intermediate and active pharmaceutical ingredient in purities above 99% with an overall yield of 60%. Excellent throughput and sustainability is achieved by limiting the total concentration to 7 volumes of solvent in the course of the two reactions with an overall PMI of 41 including work-up and isolation. Environmentally friendly solvents, water and 2-methyl tetrahydrofuran, enhance sustainability of the operation. </p

Toward Secure Supply of Remdesivir via a 2-Pot Triazine Synthesis: Supply Centered Synthesis

Pyrrolotriazine 1 is an important precursor to Remdesivir, and an efficient synthesis is disclosed. This route features atom economy and reduced derivatization of starting materials, by making use of highly abundant, commoditized raw material inputs. The yield of triazine was doubled from 31% to 59%, and the synthetic step count was reduced from 4 to 2. A one-pot cascade sequence was developed for direct cyanation of pyrrole. Amination and cyclization with formamidine acetate complete the synthesis. The problematic nature of typically dilute electrophilic aminations was solved with semi-continuous processing. Moreover, development of a continuous platform afforded access to the ideal yet non-commercial aminating reagent, monochloramine. These efforts help to secure the Remdesivir supply chain

A Concise Route to MK-4482 (EIDD-2801)

A two-step route to MK-4482 (EIDD-2801, 1) was developed consisting of an esterification and hydroxamination of cytidine. The reactions can be conducted in either order with overall yields of 67% (first step—esterification) and 37% (first step—hydroxamination). Selective esterification of the nucleoside’s primary alcohol by enzymatic means eliminated the need for diol protection/deprotection, and direct transamination with hydroxylamine precluded the necessity of activating the nucleobase for amine coupling. This results in a significant advancement over the reported synthesis which is formed in at best 17% yield. The step count is reduced from five transformation to two, and the more expensive uridine is replaced with the more available cytidine

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

© The Royal Society of Chemistry. 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. This journal i

An Efficient Synthesis of Tenofovir (PMPA): A Key Intermediate Leading to Tenofovir-Based HIV Medicines

Abstract: Herein, we report further improvements to the synthesis of tenofovir 1, the precursor to tenofovir disoproxil fumarate and tenofovir alafenamide fumarate. Starting from acyclic precursor diaminomalononitrile 12, a four-step protocol to tenofovir 1 will allow for vertical integration for more manufacturers. The key transformation is a more convergent one step procedure from 6 as compared to the current commercial process, with an improved yield from 59% (two steps) to 70%. Further improvements include eliminating the need for problematic magnesium tert-butoxide (MTB) and significant solvent reduction by eliminating the need for an intermediate workup. With the costs of HIV/AIDS treatments remaining a barrier for those most in need, lowering the raw material/processing costs and increasing the security of supply can increase patient access.</p

Adagrasib’s Second-Generation Synthesis: Transitioning from Route Scouting to Optimization

Process optimization details are disclosed following the completion of process design for a second-generation manufacturing route of adagrasib. Key objectives for development included control of difficult-to-purge impurities in the key starting materials (KSMs), enhanced scalability of the KSM, improved pyrimidone formation of the core, increased robustness of oxidation, enhanced stability of the step 3 intermediate, removal of the halogenated solvent in the fourth step, and implementation of single crystallization of the final API. These improvements led to more efficient production of adagrasib and a further reduction in the cost of goods by approximately 50%