A Tandem Ring Closure and Nitrobenzene Reduction with Sulfide Provides an Improved Route to an Important Intermediate for the Anti-Tuberculosis Drug Candidate Sutezolid.

Sutezolid is an in-development thiomorpholine derivative of the FDA-approved tuberculosis (TB) treatment linezolid. Current synthetic routes for preparing sutezolid start with thiomorpholine as a key structural building block; unfortunately, this material was identified as a major cost driver for the API, which will limit the potential uptake of this treatment in lower income regions. In this work, an alternative, lower-cost synthetic strategy to a known p-phenylenediamine intermediate to sutezolid has been demonstrated. The key step in this process is the construction of the thiomorpholine ring by a nucleophilic sulfide ring closure on an activated bis(2-hydroxyethyl)-functionalized aniline, which was in turn made by reaction of 3,4-difluoronitrobenzene and diethanolamine. This sulfide treatment has the added benefit of affecting a Zinin reduction of the nitro functional group, which alleviates the need for the transition metal reduction used in previous routes. After optimization, this key reaction was able to provide the desired aniline intermediate in yields between 65 and 80% and, after a standard charcoal treatment, purity of >94%. Initial demonstrations of the full 3-step strategy were successfully conducted on scales up to 100 g with overall yields of 53-68%. This preliminary work will serve as the foundation for a broader low-cost redesign of the sutezolid synthetic process.

One-pot synthesis of 4-pyrimidone-2-thioether through base/acid-mediated condensation of S-alkylisothiourea and ß-ketoester.

4-Pyrimidone-2-thioethers can be useful synthetic precursors to densely functionalized pyrimidines, commonly encountered in bioactive molecules. A convenient one-pot access to 4-pyrimidone-2-thioethers is reported herein, which utilizes a sequential base- and acid-mediated condensation of alkylisothioureas with ß-ketoesters. Owing to mild reaction conditions, good to excellent functional group tolerance and yields are achieved. The utility of this approach is demonstrated by the synthesis of the crucial adagrasib intermediate on a 200 gram scale.

Application of Vinamidinium Salt Chemistry for a Palladium Free Synthesis of Anti-Malarial MMV048: A "Bottom-Up" Approach.

MMV390048 (1) is a clinical compound under investigation for antimalarial activity. A new synthetic route was developed which couples two aromatic fragments while forming the central pyridine ring over two steps. This sequence takes advantage of raw materials used in the existing etoricoxib supply chain and eliminates the need for palladium catalysts, which were projected to be major cost-drivers.

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.

Expanding Access to Remdesivir via an Improved Pyrrolotriazine Synthesis: Supply Centered Synthesis.

Pyrrolotriazine 1 is an important precursor to remdesivir. Initial results toward an efficient synthesis are disclosed consisting of sequential cyanation, amination, and triazine formation beginning from pyrrole. This route makes 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. These efforts help to secure the remdesivir supply chain.

Studies toward the Total Synthesis of Parvifolals A/B: An Intramolecular o-Quinone Methide [4 + 2]-Cycloaddition To Construct the Central Tetracyclic Core.

Two different approaches funded upon the intramolecular [4 + 2]-cycloaddition of in situ generated o-quinone methides have been explored to construct the central tetracyclic core of parvifolals A/B. At the outset, a cross-pinacol coupling of 2-formyl tri-O-methyl resveratrol with 4-methoxysalicylaldehyde followed by acid treatment was found to provide the desired tetracyclic core with an internal olefin. The requisite pendant aryl group has been introduced by a Pd-catalyzed direct coupling of corresponding diazonium salt.

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 in situ generated Ru(0) to Ru(II), to continue the catalytic cycle, has been extended.