Organic Process Research & Development最新文献

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.

Emprumapimod was a p38α MAPK inhibitor developed for LMNA-related dilated cardiomyopathy. One key modification from the discovery synthesis to the manufacturing synthesis involved moving the biaryl ether formation toward the end of the synthetic sequence. Herein, we discuss the redesigned route to suit large-scale manufacture. The development of a copper-catalyzed biaryl etherification reaction is detailed, including high-throughput experiments, process development and optimization, and purification. Subsequent amide formation afforded desired emprumapimod, delivering 82 kg of API across three batches. We anticipate this report will further support the utilization of nonprecious metal catalysis in pharmaceutical manufacture processes.

DS55980254 (1) is a potent and selective phosphatidylserine synthase 1 (PTDSS1) inhibitor discovered by Daiichi Sankyo. We have developed a practical and unique optical resolution method using a chiral amine for 2,3-pyrrolidinedione, enabling the large-scale synthesis of the active pharmaceutical ingredient with high enantiomeric excess. Through optimization of the entire synthesis method from the perspective of process chemistry, enhancement in yields, complete elimination of chromatographic purification, and reduction in the number of unit operations were achieved. The productivity was dramatically improved compared to the original synthesis route, and the overall yield was increased by approximately 3-fold. This newly developed process consistently provided high-quality and high-yield products in each step, resulting in the efficient and robust synthesis of the PTDSS1 inhibitor on a multikilogram scale.

The quality-by-design (QbD) approach is widely utilized for developing and validating manufacturing processes for drug substances as well as drug products. This paper discusses the application of the risk-based QbD approach used at F. Hoffmann-La Roche Ltd. for development, optimization, and characterization of drug substance manufacturing processes for small molecules. It presents the evolution of the QbD concept into statistical thinking and development of a quantitative tool, namely, the impact ratio concept, for its successful implementation. The utilization of this approach is illustrated with a case study from the taselisib drug substance manufacturing process.

Thiophene-2-carbonyl chloride (TCC) is the key raw material in the preparation of tioxazafen, a proprietary seed treatment that was being developed by Bayer AG as a broad-spectrum nematicide. Current manufacturing routes to TCC suffer from side product formation and significant waste generation, which lead to high manufacturing costs. A new and potentially more cost-effective process to prepare TCC from thiophene has been developed. The key step in the process utilizes homogeneous liquid-phase aerobic oxidation of 2-acetylthiophene (AcT). This article describes development details for each of the three steps involved in the new process.

Epilepsy is a chronic disorder characterized by recurrent unpredictable seizures. Levetiracetam (Keppra) was introduced by UCB for the treatment of partial onset seizures in patients above 16 years of age diagnosed with epilepsy. This review reports synthetic strategies available for the synthesis of (S)-levetiracetam and will certainly aid the quest for the development of new routes for its synthesis.

This manuscript provides a comprehensive summary of 12 process impurities in baloxavir marboxil, including four previously unreported impurities. Through identification, synthesis, and characterization using MS and NMR techniques, the formation pathways of each impurity were proposed to enhance the understanding of the process. Corresponding control strategies were established. Three batches of kilogram-scale demonstrations were conducted, resulting in baloxavir marboxil with a yield of 51%, purity exceeding 99.8%, and a single impurity detected at <0.10%, all achieved from chiral starting material A-1. Notably, the two genotoxic impurities were effectively purged to levels below detection limits, meeting the criteria specified by the Threshold of Toxicological Concern (TTC).

Separation and purification in organic solvents are indispensable procedures in pharmaceutical manufacturing. However, they still heavily rely on the conventional separation technologies of distillation and chromatography, resulting in high energy and massive solvent consumption. As an alternative, organic solvent nanofiltration (OSN) offers the benefits of low energy consumption, low solid waste generation, and easy scale-up and incorporation into continuous processes. Thus, there is a growing interest in employing membrane technology in the pharmaceutical area to improve process sustainability and energy efficiency. This Review comprehensively summarizes the recent progress (especially the last 10 years) of organic solvent nanofiltration and its applications in the pharmaceutical industry, including the concentration and purification of active pharmaceutical ingredients, homogeneous catalyst recovery, solvent exchange and recovery, and OSN-assisted peptide/oligonucleotide synthesis. Furthermore, the challenges and future perspectives of membrane technology in pharmaceutical applications are discussed in detail.

Acylation of 5-amino-1H-1,2,4-triazoles is selective for the nitrogen atom at the ring 1-position of the heterocycle to give 1-acyl-5-amino-1H-1,2,4-triazoles. Thermal rearrangement of 1-acyl-5-amino-1H-1,2,4-triazoles has required high temperatures and concentrated to neat conditions to produce 5-acylamino-1H-1,2,4-triazoles. The mechanism of this rearrangement was thought to be intramolecular and later proposed to be intermolecular based on concentration effects. This work demonstrates that base can promote this rearrangement under mild conditions, and crossover experiments support an intermolecular trans-aminoacylation mechanism.

Significant emphasis has been placed on the development of nonprecious metal alternatives to precious-metal-catalyzed reactions due to the lower cost and greater sustainability they can achieve. This review is part of a series describing advances in nonprecious-metal-catalyzed transformations published between March and June 2023 that are relevant to pharmaceutical process chemistry.