Organic Process Research & Development最新文献

In this study, we developed an enhanced and efficient kilogram-scale synthesis method for ketamine hydrochloride. We discovered that using N-bromosuccinimide (NBS) instead of HBr/H₂O₂ improved the conversion rate of the bromination reaction from 88% to 99% and led to a milder and steadier reaction. Besides, CH₃NH₂/K₂CO₃ was used in the methylamination reaction to shorten the reaction time from 80 to 15 h, with an 80% yield of 1-((2-chlorophenyl) (methylimino) methyl) cyclopentanol hydrochloride (6) and 99.5% purity. Furthermore, the residue on ignition of ketamine hydrochloride decreased from 3.00% to below 0.10% with extra aqueous base washing. Several related impurities of ketamine hydrochloride were also assessed, and the clarity and color of the ketamine hydrochloride solution were investigated. In summary, the optimized process was industrially scalable and able to control the final quality of ketamine hydrochloride.

The finding that the widely used peptide coupling reagents DIC and Oxyma form the toxic H-CN (McFarland, A. D. Org. Process Res. Dev. 2019, 23, 2099) has prompted studies aimed at H-CN minimization, attained, for example, by solvent engineering (Erny, M. Org. Process Res. Dev. 2020, 24, 1341) and by substituting DIC with TBEC (Manne, S. R. Org. Process Res. Dev. 2022, 26, 2894). Here, an integrated study of TBEC/Oxyma as peptide couplers is reported, focusing not only on the performance of TBEC in the couplings but also on its cost, hazards associated with its use, sustainability of the route of synthesis, the end of life strategies, as well as the potential impact of impurities in the reagent on the synthesis. TBEC/Oxyma-mediated peptide couplings in NBP/EtOAc (1:4) proceeded with minimal racemization, free of precipitation, and radical side reactions irrespective of TBEC quality. These results hold great promise for broad adoption of TBEC/Oxyma in suitable green media as a coupling strategy for sustainable peptide synthesis from an R&D lab to a manufacturing plant.

5-Methyl-2-pyridinesulfonamide is a regulatory starting material of endothelin receptor antagonist clazosentan. The original route to the key sulfonamide relied on the textbook conversion of the corresponding thiophenol to the intermediate sulfonyl chloride followed by its quenching with aqueous ammonia. However, this route suffered from a wide range of issues such as a low overall yield (29%), challenging aqueous workups and isolations, and the formation of a genotoxic benzyl chloride impurity. Therefore, we developed a conceptually novel production route for 5-methyl-2-pyridinesulfonamide. The new process relied on selectively oxidizing the thiophenol to the intermediate sulfinate salt followed by an electrophilic amination of the nucleophilic sulfinate sulfur-atom with hydroxylamine-O-sulfonic acid (HOSA). This oxidation/electrophilic amination sequence worked as a “one-pot” procedure by simply adding HOSA to the reaction mixture after complete oxidation of the thiophenol with 70% aq. t-BuOOH. The process was extensively optimized with regard to the oxidation step, increasing the stability of HOSA in the reaction mixture, and the final isolation of 5-methyl-2-pyridinesulfonamide. The new process was performed on a 22 kg scale, delivering the desired product as a white solid in 69% overall yield and excellent purity (>99.9% a/a).

The ability to quickly generate and identify crystalline solids for organic compounds in a parallel fashion requires a rapid, adaptable crystallization screening strategy that delivers reliable, valuable, and consistent results. The key to the system is a standard platform small-scale (0.5–2 mg) crystallizer screening array that reproducibly crystallizes compounds and facilitates the presentation of crystallization samples to both an automated polarized light microscope and an instrument capable of PXRD analysis. Data science technologies were leveraged to streamline the workflow of data visualization and processing. The fully developed workflow successfully used both single-crystal and PXRD analyses to identify multiple polymorphs of a test compound in a single screening experiment on 200 mg of input material with commercially available crystallizers and instruments to perform a highly detailed crystallization screening study. The methods and techniques described herein are fully transferrable to those working in the synthetic organic chemistry field.

We report the development of a novel method for the synthesis of Azoxystrobin, which employs trimethylamine as a catalyst. This appealing catalytic system offers several advantages, including low cost, excellent reactivity, easy recovery, and the ability to be used repeatedly with minimal environmental impact. Mechanistic studies and density functional theory (DFT) calculations suggest that the involvement of a highly active quaternary ammonium salt intermediate is likely responsible for the efficient catalysis. This can be attributed to the low steric hindrance, flexible bare nature of the lone pair of electrons on the nitrogen atom, and low activation energy barrier of trimethylamine. These findings hold great promise for the mass production of Azoxystrobin.

The development of a scalable process for the manufacture of a potent and selective JAK1 inhibitor intended for the inhaled treatment of asthma is described. The initial milligram-scale synthetic protocols were unsuitable for larger-scale synthesis, which led to a systematic evaluation of the reaction conditions to identify the optimized reaction conditions for the Suzuki/Buchwald–Hartwig coupling, deprotection of the tosyl group, chemoselective nitro-reduction, and developing mild conditions for the amide coupling of a sensitive amino acid. This work also highlights mitigating critical issues associated with the synthesis of poorly soluble compounds, slurry-to-slurry metal-catalyzed coupling protocols. The optimized amide coupling conditions using chiral amino acid produced the desired active pharmaceutical ingredient (API) in high overall yield and good high-performance liquid chromatography (HPLC) purity.

In this work, two anhydrates (form A and form B) and one dihydrate (form C) of aztreonam were found and were characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis, differential thermal analysis, and Fourier transform infrared spectroscopy. Dynamic vapor adsorption and variable-temperature PXRD experiments were carried out to study their thermal stability and moisture absorption stability. Furthermore, the critical water activity of aztreonam at 10–45 °C was determined, and it was found that the water activity determines the dehydration process of form C. The solubility of form A and form B in methanol solvent was measured at 10–45 °C to decide the thermodynamic stability of the polymorphs, and it was found that form B is thermodynamically stable below 28 °C, while form A is thermodynamically stable above 28 °C. The competitive suspension experiments further proved that form A and form B are enantiotropic polymorphs. In addition, the solution-mediated phase transition (SMPT) process of aztreonam form C was in situ monitored using Raman spectroscopy. The results show that the SMPT process is jointly controlled by the dissolution of the dihydrate and the nucleation of anhydrates, in which temperature plays a very important role. Finally, the SMPT mechanism of the dihydrate form is proposed.

A simple and efficient pilot-scale process was developed for the synthesis and purification of α-asaronol ((E)-3′-hydroxyasarone). 4.29 kg of α-asaronol 4 (purity 99.92%) was produced in one batch, starting with 2,4,5-trimethoxybenzaldehyde 1 and ethyl hydrogen malonate 2 as raw materials to form intermediate ethyl (E)-3-(2,4,5-trimethoxyphenyl)acrylate 3 (yield 93.3%) by the Knoevenagel condensation reaction, which was then reduced by diisobutylaluminum hydride to produce α-asaronol 4 with a yield of 89.2%. Liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) spectroscopy analysis revealed four major impurities in the synthesis process, namely, (2,4,5-trimethoxyphenyl)methanol, 3-(2,4,5-trimethoxyphenyl)propan-1-ol, 5,5′-((1E,1′E)-oxybis(prop-1-ene-3,1-diyl)) bis(1,2,4-trimethoxybenzene), and diethyl 2-(2,4,5-trimethoxybenzyl)malonate. By adapting a commonly used recrystallization process through optimization, a large-scale purification method was developed for the purification of α-asaronol, achieving a purity of 99.92% by recrystallization. The pilot study lays the groundwork for the large-scale, high-yield, and high-purity preparation of the candidate drug.

Mol-scale oxyfunctionalization of cyclohexane to cyclohexanol/cyclohexanone (KA-oil) using an unspecific peroxygenase is reported. Using AaeUPO from Agrocybe aegerita and simple H₂O₂ as an oxidant, cyclohexanol concentrations of more than 300 mM (>60% yield) at attractive productivities (157 mM h^–1, approx. 15 g L^–1 h^–1) were achieved. Current limitations of the proposed biooxidation system have been identified paving the way for future improvements and implementation.