Organic Process Research & Development最新文献

A convenient, green method to synthesize 4′-(bromomethyl)-2-cyanobiphenyl was developed, where visible light is used to initiate the radical chain reaction and the H₂O₂/HBr system as the bromine source. A range of solvents was tested, and a final multigram protocol was developed to give a good yield of 71% of product with 97% purity and no other purification than simple filtration and wash. Diethyl carbonate was found to be an efficient greener solvent alternative to classical solvents such as carbon tetrachloride and chlorobenzene, and 2-propanol, also considered a green solvent, was suitable for precipitation and washing in the purification step.

Radical reactions have emerged as indispensable tools in the synthesis of complex molecules. In this perspective, we will discuss selected total syntheses that make use of radical processes in a scale of at least one gram as the essential transformation, to showcase their potential applicability in the industry related to pharmaceuticals and fine chemicals. The discussion is divided into three main sections: metal-catalyzed hydrogen atom transfer (HAT) cyclization, nonmetal-mediated radical cyclization, and metal-catalyzed reductive cross-coupling reactions. Finally, a summary and outlook of this area are highlighted.

tert-Butyl carbamates, carbonates, and carbonothioates are useful as bioactive compounds, functional polymers, and synthetic intermediates for a variety of valuable organic compounds. The most conventional approach for the preparation of these tert-butoxycarbonyl (Boc)-containing compounds includes a nucleophilic acyl substitution reaction using commercially available and stable di-tert-butyl dicarbonate (Boc₂O). However, this method usually requires a long reaction time and high-temperature conditions because of the mild electrophilicity of Boc₂O. The use of highly electrophilic BocCl and its equivalent (BocX) allows the rapid and mild preparation of Boc-containing compounds. However, BocX is unstable, which has hampered its use. Herein, we report a rapid, mild, and facile preparation of BocX from triphosgene, t-BuOH, and two different types of bases, N-methylmorpholine and N-methylimidazole in a microflow reactor. The in situ-generated BocX was immediately used for the formation of carbamates, carbonates, and a carbonothioate. The role of the two different bases was also investigated. The developed approach showed a significantly better performance than that using Boc₂O.

A large-scale enantioselective manufacturing route to an unusual piperazine-substituted amino acid is described. Previous synthetic routes to this amino acid relied on the resolution of racemic mixtures using l-tartaric acid that was demonstrated on a 6 kg scale, but this resulted in a reduced overall yield and efficiency. The new enantioselective route to this amino acid uses the S_N2 displacement of a chiral triflate with N-methylpiperazine that proceeds with very high levels of stereocontrol. The key chiral triflate is prepared in five synthetic steps in 38% overall yield and >99% enantiomeric purity (e.p.), starting from cheap and readily available d-serine. Subsequent reaction with N-methylpiperazine was initially demonstrated in batch, providing the benzyl-protected amino acid in 83% e.p. on a 3 kg scale. This transformation was further improved by the application of continuous manufacture to provide the benzyl-protected ester in >99% e.p. on an 80 kg scale. Simple deprotection of the benzyl ester group by hydrogenolysis, followed by isolation of the amino acid as the corresponding dihydrochloride salt, provided a scalable and efficient synthesis of (R)-3-methoxy-2-(4-methylpiperazin-1-yl)propanoic acid in good overall yield (33%) and very high optical purity (>99.5% e.p.).

P-Chiral phosphorus ligands received little attention in organic chemistry until Knowles made his landmark contribution in asymmetric hydrogenation by developing the P-chiral ligands CAMP and DIPAMP. The development of P-chiral phosphorus ligands accelerated in the end of the last century with the advent of some highly efficient and renowned ligands for asymmetric hydrogenation, including BisP*, TangPhos, QuinoxP*, DuanPhos, et al. However, most reported ligands were air-sensitive, difficult to make, or lacked structural modularity, hampering their availability and applicability. The development of sterically and electronically tunable P-chiral phosphorus ligands is particularly desirable. Over the past decade, a family of sterically hindered, electron-rich, structurally tunable, and air-stable P-chiral dihydrobenzooxaphosphole ligands emerged that proved to be efficient and versatile for various asymmetric transformations. The last 5 years witnessed an increasing number of studies related to these ligands with the discovery of their unprecedented catalytic properties in various transformations. This review highlights the unique properties of P-chiral dihydrobenzooxaphosphole ligands in catalysis and their applications in the synthesis of natural products and therapeutic agents.

A kinetic study and model-based design space determination for drug substance flow synthesis using an amination reaction are presented. A flow experiment was conducted to synthesize 3-fluoro-4-morpholinobenzonitrile from 3,4-difluorobenzonitrile, morpholine, and diazabicycloundecene. Concentrations, residence time, temperature, and reactor inner diameter were varied to gather the kinetic data. A set of equations was defined to describe the mass and energy balances, and the developed model could reproduce the experimental profiles with high accuracy. By incorporating the Reynolds number into the pre-exponential factor, the developed one-dimensional model could account for performance variations in different inner diameter conditions. The model was then used to identify the design space, considering yield, temperature, productivity, and environment. The study also evaluated the process robustness given pulse disturbances, which could help identify the required sensor monitoring. Finally, a method for facilitating regulatory processes was proposed. The presented model-based approach can aid in producing high-quality pharmaceuticals in an efficient, sustainable, and cost-effective way by utilizing digital power.

Manual crystallization trials have historically posed significant challenges, demanding substantial expertise for process development and often offering unpredictable outcomes. This study addresses these difficulties by introducing an automated system that alleviates the need for manual iterations and intuitive deductions. The system leverages machine learning algorithms capable of learning from high-quality data to discern patterns and recommend optimal actions for subsequent runs. The automation process commences with a direct chord length (DCL) control system, generating system-specific training data via universal crystallization rules. After that, the automation process will progress into a machine learning iteration loop using adaptive neuro-fuzzy inference system (ANFIS) models. In this iteration loop, multiple models will be built (with accumulative historical data) and deployed to the crystallization process until predefined exit criteria are met or a maximum of five iterative cycles are reached. Results from the two campaigns are presented. It is evident that the automated crystallization platform with machine learning’s ability can confidently explore the operational space, proposing credible processing conditions that yield desirable process outcomes.

Baloxavir marboxil (BXM) is an influenza antiviral drug that exploits a cap-dependent endonuclease (CEN) inhibitor. The synthesis route used in the initial CMC development study had several problems hampering scale-up, such as poor stereochemical outcome which decreased the yield, usage of a corrosive reagent, and a cumbersome protocol for the key step. We addressed these problems to enable practical and operation-friendly manufacture of BXM at a larger production scale for early and successive CMC development. The new route includes the following steps: (1) a magnesium-mediated alkoxy displacement reaction to prepare an intermediate without loss of optical purity and (2) diastereoselective preparation of an intermediate via a dehydration condensation reaction with a crystallization-induced diastereomer transformation (CIDT) process. This facile route enabled scalable manufacturing to supply BXM.

Baloxavir marboxil, a cap-dependent endonuclease inhibitor, is an antiviral drug for influenza. This paper presents the development of two alternative routes for the industry-oriented preparation of a key tricyclic triazinanone intermediate, 7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, in order to overcome the drawbacks of the initial scaled-up synthetic route used in the kilo lab. The first candidate route is based on a late-stage reductive approach to the target starting with raw materials used in the previous route, namely, morpholin-3-one and a pyridone carboxylic acid derivative. The highlight of this approach is the tandem condensation of the morpholine and pyridone units to construct the tricyclic core of the substrate for the final reduction step. The other candidate route engages less expensive raw materials, combination of a protected 2-aminoethanol and 2-bromo-1,1-dimethoxyethane instead of morpholin-3-one, and six chemical steps in total. The efficient transformation was accomplished by a single-step conversion consisting of four elementary steps, including tandem cyclizations accompanied by deprotections. The latter process proved to be robust for production of more than tens of kilograms for practical large-scale manufacturing, providing >27 kg of the targeted triazinanone intermediate per batch in 56% overall yield with satisfactory purity.

Described herein is the discovery and development of a process to prepare chiral triazinanone R-3 and diastereomeric intermediate 5, the key intermediates in the synthesis of the cap-dependent endonuclease inhibitor baloxavir marboxil (1), which can suppress the replication of influenza virus. Chiral triazinanone R-3 was obtained via optical resolution of its racemic form rac-3. Diastereomeric intermediate 5 was obtained by the condensation reaction of triazinanone R-3 and thiepin alcohol 4 using a combination of T3P and MsOH. These reactions were performed successfully on kilogram scale and were critical to the establishment of the baloxavir marboxil manufacturing process.