Organic Process Research & Development最新文献

Levonorgestrel, a representative 13β-ethyl progestin, poses a synthetic challenge due to the construction of its 13β-ethyl precursor. Herein, we report the chemical synthesis of the common 13β-ethyl precursor, (13S,14S)-13-ethyl-3-methoxy-6,7,11,12,13,14,15,16-octahydro-17H-cyclopenta[a]phenanthren-17-one, in seven or eight steps from inexpensive 3-bromoanisole or 3-methoxybenzaldehyde. Key transformations include a Hajos–Wiechert-type reaction to introduce the chiral ethyl group, a Friedel–Crafts cyclization to form the B ring, and regio- and stereoselective hydrogenation. Starting from this 13β-ethyl precursor, levonorgestrel was subsequently obtained in four steps, including an ethylenediamine-mediated Birch reduction.

A seven-step enantioselective route for the synthesis of benzyl (R)-10-oxo-2-oxa-7-azaspiro[4.5]decane-7-carboxylate (1) with >99% ee is reported on a multi-hundred-gram scale in 42% overall yield. The synthesis features an asymmetric allylic alkylation to establish the quaternary stereocenter on a piperidine ring, followed by an oxidation/reduction and Mitsunobu conditions sequence to construct the tetrahydrofuran ring within the chiral oxa-azaspirocycle.

Carpino’s invention of fluorenylmethoxycarbonyl (Fmoc) as a base-labile amino protecting group (PG) (J. Am. Chem. Soc. 1970, 92, 5748) has transformed peptide chemistry in a manner so profound that only Merrifield’s solid-phase peptide synthesis (J. Am. Chem. Soc. 1963, 85, 2149) does not pale in its comparison. In fact, Fmoc is the most important PG in peptide chemistry with no viable alternatives in sight, enabling the assembly of a staggering variety of peptides including blockbuster therapeutics. Here, we report that α-Fmoc amino acids (Fmoc-AA-OHs) are susceptible to undergo formation of impurities differing from parent compounds by −2 and +14 Da, respectively. Based on tandem mass spectrometry (MSMS) analyses, we propose that these byproducts are ene and epoxide alterations of the Fmoc group, situated adjacent to the fluorene core of Fmoc. The generality of these Fmoc-ene/-epoxide byproducts was exemplified by detecting them in five Fmoc-AA-OHs by liquid chromatography high-resolution mass spectrometry (LC-HRMS), while based on the dependence of the rate of Fmoc-ene/-epoxide formation on temperature, air, and iron, we propose storage and handling protocols aimed at keeping the content of ene/epoxide Fmoc alterations to a minimum. Finally, we report that Fmoc-ene/-epoxide alterations are stable toward the coupling additive ethyl cyanohydroxyiminoacetate (Oxyma) and the Fmoc removal base piperidine, whereas exposure to the standard cleavage reagent trifluoroacetic acid (TFA) results in a breakdown of the Fmoc-ene/-epoxide moieties. Notably, exposure to TFA in the presence of triisopropylsilane (TIS)/H₂O/dithiothreitol (DTT) as scavengers leaves the Fmoc-ene alteration unscathed, whereas Fmoc-epoxide is ring-opened to the corresponding alcohol, suggesting that whether Fmoc-ene/-epoxide peptide truncations will remain unaltered will depend on synthesis and cleavage protocols used. As peptide drugs are subject to stringent quality requirements, varying the content of Fmoc-ene/-epoxide impurities coupled with synthesis/cleavage protocols impacting Fmoc alterations in a varying manner may pose challenges during downstream processing, warranting that due care is paid to the formation and reactivity of Fmoc-ene/-epoxide alterations.

Plastic waste, especially from packaging, poses major recycling challenges due to the presence of mixed polymers, which often result in inconsistent blends that are unsuitable for reuse in food-grade applications. Chemical recycling, particularly alkaline hydrolysis, offers a promising solution in the case of chemically reactive polymers, such as polyesters, with poly(ethylene terephthalate) (PET) being one of the dominant plastics suitable for both mechanical and chemical recycling. Mechanical recycling is currently used for the largest part of PET recycling, due to the fact that turning the polymer back into its monomeric building blocks requires catalysts, elevated temperatures, or prolonged reaction times. This study presents a recently developed Heated High-Ethanol Alkaline Aqueous (HHeAA) process that enables efficient, catalyst-free PET hydrolysis under milder conditions. Nearly complete hydrolysis was achieved within just 20 min at 90 °C using a loading of 0.624 g of NaOH/g of PET. The process was successfully scaled up with commercial PET bottles, achieving full hydrolysis while significantly reducing the liquid-to-solid ratio from 20 to just 5 L/kg. These results highlight the industrial potential of the HHeAA method as a more sustainable and energy-efficient alternative for PET recycling and chemical reuse and in turn reduced environmental impact.

A robust and scalable continuous-flow hydrogenation process was developed for the synthesis of 1,2,3,4-tetrahydroisoquinoline (THIQ) scaffold using a commercially available heterogeneous Pt/Al₂O₃ catalyst in a trickle-bed reactor. This study outlines the systematic selection of catalysts and solvents as well as process optimization using the Design of Experiments (DoE). A scale-up run was successfully demonstrated at a 13 kg scale of THIQ with a 99% isolated yield in pilot equipment. This work demonstrates a practical strategy for the continuous-flow synthesis of THIQ, highlighting its potential for industrial.

An efficient, scalable, and chromatography-free six-step synthesis of the laxative drug bisacodyl (1) has been developed, starting from inexpensive 2-picolinic acid. This practical route achieves an overall yield of 46% and delivers the active pharmaceutical ingredient (API) in 99.88% HPLC purity. Key innovations include a crystallization-based workup for the key acid chloride intermediate, a highly selective Friedel–Crafts acylation/alkylation sequence, and a final acetylation employing a solvent-free system to suppress impurity formation. The process is distinguished by its operational simplicity, featuring direct filtration for the isolation of intermediates in five of the six steps and has been successfully demonstrated on a 500 g scale. This approach offers a robust, cost-effective, and environmentally friendly alternative to existing literature methods for the industrial manufacturing of bisacodyl.

In this work, design of experiments (DoE) methodologies were applied to optimize the continuous-flow synthesis of various meso-aryl-substituted porphyrins. Starting from the synthesis of meso-tetraphenylporphyrin (TPP), a response surface model was established correlating yield with temperature and residence time. The study was then extended to structurally and electronically diverse aldehydes, leading to the classification of substrates into four electronic families (groups A–D), based on Mulliken charge calculations at the carbonyl carbon. For each group, optimized quadratic models were developed, enabling the prediction of specific experimental conditions for maximum yield. These predictions were validated through the synthesis of over 10 porphyrin derivatives under continuous-flow conditions. Notably, yields as high as 50% were achieved, and significant productivities were recorded. This modular approach demonstrates the power of combining DoE modeling with electronic structure calculations for scalable, efficient, and generalizable synthesis of functional porphyrins, paving the way for their broader application in catalysis, photomedicine, and materials science.

The generation and application of kinetic models are of significant interest to process chemists, as they can enable rationale-driven process development, model-based optimization, and bolster and codify process understanding. However, there is a current critical gap in laboratory automation technologies in the gathering of representative, data-rich kinetic data at reasonable throughput to support the early and broad deployment of kinetic models. The novel ReactAll workstation seeks to close this gap. Herein, an evaluation of this workstation was carried out to investigate its suitability within the context of kinetic modeling activities. As a result, a kinetic model for an acid-catalyzed diethyl acetal deprotection process was developed that unexpectedly supported quinolinium species to be catalytically active.