Organic Process Research & Development最新文献

Six nucleophilic aromatic substitution (S_NAr) reactions were efficiently scaled to 10–20 g batch sizes in water without the use of organic solvents or surfactants. Each reaction reached completion within 6 h through simple heating above the melting points of the reactants. The workup involved filtration with pure water, eliminating the need for organic extraction. This streamlined, solvent- and surfactant-free protocol consistently delivered high-purity crystalline products in excellent yield, offering a significantly more sustainable alternative to traditional S_NAr methods that rely on polar aprotic solvents or aqueous surfactant additives.

Attenuated total reflection Fourier transform infrared (ATR-FTIR) is a widely used process analysis technique (PAT) in industrial crystallization, which is generally considered to have no response to solids during crystallization. This work, however, discovered an under-reported distortion in ATR-FTIR spectra during the crystallization of L-carnitine (LC). The observed distorted infrared (IR) spectra appear to exhibit an unexpected blue shift and a large intensity increase of the dissolved L-carnitine (LC) characteristic peak at 1595 cm^–1. PXRD validation and probe-wiping experiments attributed such distortion to partial fouling on the probe surface. Traditional spectral quantification based on the external standard method was found to fail when it was applied to distorted IR spectra. To address the quantification challenge, machine learning (ML) models were evaluated for quantifying the solution concentration under fouling conditions. The results revealed that ML approaches, specifically support vector regression (SVR) and shallow neural network (SNN), achieved accurate quantitative analysis of the LC solution concentration. This work not only improves the understanding of ATR-FTIR spectral distortion but also highlights the potential application of ML-integrated PAT in crystallization process monitoring.

Here, we report on the contribution of structural analysis by microcrystal electron diffraction (3D ED/MicroED) to risk assessment of nitrosamine drug substance-related impurities (NDSRIs). Our study mainly consists of three parts. First, we conducted a basic scope and limitations study on the structure analysis of various nitrosamines and natural nitrosamine products by 3D ED/MicroED. There have been no reports on the feasibility of 3D ED/MicroED analysis of various nitroso compounds to date, and our research has demonstrated that it is possible to determine their molecular structures without any problems. Next, we carried out a 3D ED/MicroED structural analysis of a syn/anti mixture of N-nitrosamines derived from asymmetric secondary amines. N-nitrosovonoprazan was used as a target, and a crystal of the syn/anti mixture could be analyzed as a disordered structure. Finally, we investigated the structural analysis of N-nitroso compounds obtained by direct N-nitrosation of compounds containing two or more secondary amine moieties. Two N-nitroso compounds obtained from the direct nitrosation of palbociclib were analyzed. As a result, the structures of both products were successfully determined easily, including the minor component for which the position of nitroso introduction could not be determined by NMR alone.

A series of ruthenium complexes, mainly Grubbs- and Hoveyda–Grubbs-type catalysts, along with a variety of σ-donor additives, were employed in dehydrogenative alcohol coupling (DAC) reactions to selectively convert primary aliphatic alcohols into carboxylic acids and Guerbet alcohols. Additives such as pyridine or tricyclohexylphosphine served as stabilizing ligands, improving catalyst integrity and thereby boosting selectivity and overall activity in dehydrogenative alcohol coupling (DAC) reactions. Notably, high conversions were achieved with Ru loadings as low as 0.25 mol %. The DAC reactions were systematically investigated to control the product distribution, switching the selectivity from Guerbet alcohol formation to carboxylic acid formation by simply changing the reaction conditions. This selectivity shift was achieved by manipulating the reaction mechanism through conducting the reactions under static nitrogen flow, in air, or in the presence of a hydrogen acceptor molecule. Furthermore, the potential of the DAC system was explored in tandem dehydrogenation/hydrogenation processes, enabling efficient hydrogenation of alkenes and alkynes. Remarkably, the system exhibited high selectivity (85%) and nearly quantitative conversion (99%) toward the formation of E-stilbene when benzyl alcohol was employed as the hydrogen source in the tandem dehydrogenation/hydrogenation sequence, even under high 1-octanol/Ru ratios (5500:1, mol/mol). Hydrogen production performance of the catalytic system, Hoveyda–Grubbs second-generation/pyridine, was evaluated using different alcohols such as methanol, ethanol, and 1-octanol, reaching TON values up to 1300.

Ensuring the quality and safety of synthetic oligonucleotide drug substances demands stringent microbial contamination control. While chemical synthesis inherently carries a lower risk compared with biological manufacturing, robust controls remain critical to minimize potential microbial proliferation at specific stages of the process. Given the limited regulatory guidance directly addressing oligonucleotides, effective contamination control strategies must be built upon thorough risk assessments and established best practices. This work, drawing on the collective expertise of the European Pharma Oligonucleotide Consortium, provides comprehensive recommendations for microbiological control in oligonucleotide manufacturing. Key points include facility design, environmental monitoring, equipment cleaning, in-process controls, and analytical methods. A thorough risk assessment and a holistic approach to microbial management are advocated. Detailed methodologies for risk evaluation, mitigation, and acceptance of residual risks are outlined. This strategic framework aims to proactively manage potential microbiological hazards, ensuring the consistent production of high-quality oligonucleotide therapeutics.

In this work, a new chemo-enzymatic synthesis of (R)-perillaldehyde ((R)-1, 98% ee) was developed by progressively improving the sustainability of the reaction steps. The key transformation is the oxidation of (R)-perillyl alcohol ((R)-2), catalyzed by a recombinant alcohol dehydrogenase from Geobacillus stearothermophilus (ADH-hT), used as cell-free extract (CFE), in the presence of acetone as a sacrificial substrate. Alcohol (R)-2 is obtained in a mixture (44% by NMR analysis) with secondary alcohols 4 and 5 in a two-step sequence starting from the rearrangement of (4R)-limonene oxides catalyzed by aluminum isopropylate in toluene and subsequent allylic rearrangement of the intermediates by S_N2′ displacement in aqueous acetone. Perillyl alcohol is recovered by column chromatography and oxidized with ADH-hT as a catalyst to afford (R)-perillaldehyde (98% ee), which is isolated in pure form by distillation under reduced pressure (22% isolated yield from limonene oxides). When the reaction is performed on the crude mixture containing perillyl alcohol together with the secondary alcohols 4 and 5 as side products, complete chemoselectivity toward the oxidation of the primary alcohol is observed. Thus, we also describe the chemoselective oxidation of alcohol 2 in this mixture (44% by NMR analysis) by means of ADH-hT and subsequent isolation of the corresponding aldehyde by formation of the Bertagnini adduct. A comparison between these two routes and those described in the literature is herein discussed.

With massive production, the agrochemical and specialty chemical industries have seen a sharp increase in the transition from batch to continuous production for highly exothermic processes. This is also true for fine chemicals and pharmaceuticals processes, typically conducted in a batch mode. Highly exothermic reactions can lead to runaway situations, resulting in severe and fatal accidents. Converting batch processes into continuous operation with minimum inventory or holdup in the reactor improves process safety and controllability. A continuous process was developed in this work to produce the key intermediate of silicon-based fungicide flusilazole, which consists of a dual column for Grignard reagent preparation followed by a substitution reaction in a two-stage microreactor system. Herein, we disclose the studies performed to explore a continuous flow process, the reaction parameters of which can be altered as per the process requirements for the completion of the reaction. The improved process explores better heat and mass transfer compared to the batch process, leading to maximum conversion with minimum byproduct formation and high selectivity. The developed process increases production capacity compared to that of the batch process. Handling of moisture-sensitive reagents and high exothermicity were overcome using a two-stage continuous flow reactor. Drastic reduction of reaction time and yield improvement were executed by using a two-stage continuous flow reactor system.

Octreotide is a synthetic somatostatin analogue used in the treatment of various endocrine and neuroendocrine disorders. The primary method for producing an octreotide API is through solid-phase peptide synthesis (SPPS). The SPPS commonly uses dimethylformamide (DMF) as a major solvent for synthesis, but it is categorized as a hazardous solvent under REACH regulations. This work presents an optimized and scalable process for the synthesis of “octreotide”, where DMF consumption is reduced and replaced in major operations with a greener alternative, gamma-valerolactone (GVL). However, fully replacing DMF with GVL is not cost-effective due to the limited supply of GVL on the industrial scale. To address this, a mixed solvent approach is proposed, where GVL is used for reactions only, and DMF is retained for washings. The cleavage process is also optimized to reduce the consumption of trifluoroacetic acid (TFA) and ethers. Also, in the purification process, acetonitrile (ACN) is replaced by alcohol. This mixed solvent strategy did not show any adverse impact on the cost, quality, and yield of the octreotide compared with the conventional method. This approach will help peptide manufacturing industries address the environmental concerns associated with DMF usage while maintaining the efficiency and effectiveness of peptide synthesis, all while being compliant with REACH regulations.

Developing radiochemical strategies that enable the simple, rapid, and high-yielding incorporation of radioisotopes into bioactive targeting vectors using sterile, cassette-based kits is critical to sustaining clinical practice and advancing radiopharmaceutical research. ¹⁸F-bearing positron emission tomography (PET) imaging radiopharmaceuticals that use functionally-complex biomolecules as targeting vectors are particularly challenging to synthesize because they are sensitive to the elevated temperatures and basic conditions traditionally used to incorporate [¹⁸F]fluoride, necessitating complex, low-yielding multistep radiolabeling strategies using ¹⁸F-prosthetic groups. Direct ¹⁸F-labeling of bioactive peptides can be achieved through ¹⁹F-for-¹⁸F exchange of di-tert-butylphenylfluorosilane pendant groups (a.k.a. “SiFA” chemistry). However, the translation of such protocols to automated synthesis units, which are required for the clinical production of ¹⁸F-radiopharmaceuticals, has been hampered by the incompatibility of SiFAylated ¹⁹F-peptide precursors with current methods to isolate [¹⁸F]F^– on anion exchange sorbents, including azeotropic distillation of aqueous eluates containing (bi)carbonate base, or the extraction of [¹⁸F]F^– via strongly-basic Kryptofix-222/KOH complex. Nonbasic tetraalkylammonium salts can be used to release [¹⁸F]F^– from anion exchange cartridges in small volumes of water directly into vessels containing radiolabeling precursors in MeCN or DMSO [a.k.a. nonanhydrous, minimally basic (‘NAMB’) ¹⁸F chemistry]; these “damp” reaction mixtures (1–6% water) can be heated to achieve traditional nucleophilic ¹⁸F-fluorinations, or, as we report here, high-yielding SiFA reactions. This merging of SiFA and NAMB is reported here first for the one-step, manual radiosynthesis of [¹⁸F]SiTATE, a clinically-validated neuroendocrine tumor imaging agent, and then later translated to the FASTlab 1 automated synthesis platform. An exceptionally high non-decay-corrected radiochemical yield (NDC-RCY; 50 ± 6%, n = 4) was obtained after admixing of ¹⁹F-precursor (50 nmol) with tetrabutylammonium dihydrogen phosphate/tetrabutylammonium [¹⁸F]fluoride in 44:50:6 MeCN:DMSO:H₂O (1 mL) for 10 min at ambient temperature. Radiochemical purity was 95% after the purification of ¹⁸F-peptide by solid-phase extraction. The highest activity yield produced from a single cyclotron bombardment was 594 mCi (52% NDC-RCY; 440 GBq/μmol), suggesting that this ultrasimple and efficient automated protocol is amenable to the production of multiple patient doses from a single batch of [¹⁸F]fluoride.