Organic Process Research & Development最新文献

Nicotine is the chief addictive ingredient in cigarettes, cigars, and snuff, and has extensive applications in the agricultural and pharmaceutical industries. The synthesis of nicotine using free enzyme systems has been widely reported in literature; this approach chiefly utilizes the alkaloid myosmine and the enzymes imine reductase (IRED) as well as glucose dehydrogenase (GDH), and generates the intermediate (S)-nornicotine. Free enzymes are not reusable, thereby resulting in higher cost of production. The use of recyclable immobilized enzymes is an efficient approach for lowering the costs and improving the efficiency of production. In the current study, we present an efficient and environment-friendly approach utilizing immobilized enzymes for synthesizing (S)-nornicotine using batch and continuous flow reaction processes. A highly active coimmobilized enzyme system was successfully obtained by coimmobilizing IRED and GDH on the resin LXTE-706. The immobilized enzymes were amenable to repeated usage for at least 40 operation cycles in the batch mode of operation and yielded a product with a high chiral purity of >99.90%, effectively reducing the overall production cost. Furthermore, a space–time yield of 211.47 g/Lh was obtained using a continuous mode of operation, which is 289.7-fold higher than that obtained with batch mode.

Thermal N-Boc deprotection of a range of amines is readily effected in continuous flow, in the absence of an acid catalyst. While the optimum results were obtained in methanol or trifluoroethanol, deprotection can be effected in a range of solvents of different polarities. Sequential selective deprotection of N-Boc groups has been demonstrated through temperature control, as exemplified by effective removal of an aryl N-Boc group in the presence of an alkyl N-Boc group. As a proof of principle, a telescoped sequence involving selective deprotection of an aryl N-Boc group from 9h followed by benzoylation and deprotection of the remaining alkyl N-Boc group to form amide 13 proved successful.

Process development of E7130 Drug Substance, which is a novel anticancer drug candidate, is described. To accomplish rapid delivery of such a large and structurally complex drug substance for first-in-human (FIH) clinical trial, close collaboration among medicinal chemistry, process chemistry, and academia teams was required. The successful establishment of a suitable synthetic route in a concise time frame while negotiating challenging chemical reactions (e.g., asymmetric catalytic Nozaki–Hiyama–Kishi (NHK) reaction and Zr/Ni-mediated ketone coupling reaction) is described herein. Experience with the development of eribulin mesylate was helpful in anticipating and overcoming the chemical and logistical challenges encountered in the E7130 project. Based on this background, more than 10 g of E7130 Drug Substance has been successfully manufactured under Good Manufacturing Practice (GMP) controls within 1.5 years after the medicinal chemistry team succeeded in the first total synthesis.

A first-of-its-kind, fully continuous synthesis of wax esters from biobased precursors (glucose, fatty acids) was developed using metabolically engineered cells and in vitro enzyme catalysis. The cells, overexpressing fatty acyl-CoA reductase and xylose reductase, could be immobilized onto polyesters and packed in a continuous reactor. The immobilized cells were employed in the bioconversion, incorporating in situ extraction using dodecane as the solvent. Such extractive bioconversion was capable of producing fatty alcohols continuously at a productivity of 8.2 mg/(L·h). The immiscible aqueous-dodecane flow stream from the extractive bioconversion was then separated using an in-line membrane-based separator. The dodecane-rich phase was directed into an enzymatic reactor containing Novozyme 435 for the esterification of fatty alchols and fatty acids into the wax esters. A continuous production of wax esters (6.38–23.35 mg/(L·h)) was achieved as a result of the successful streamlining of the cascade biocatalytic process.

Statistical analysis is used to correlate the thermal decomposition temperature of diverse leaving groups of an avibactam prodrug precursor. SMILES strings and Mordred calculated parameters were leveraged to provide a time-efficient workflow for model development. The resulting models were deployed to predict a novel analogue with a higher onset temperature, allowing for an overall safer reagent and proof of concept for the workflow. Interpretation of the descriptors featured in the models and subsequent DFT analysis uncovered univariate trends, providing a deeper understanding of the decomposition pathway. Finally, this workflow enabled the development of a predictive model correlating energy output of the precursor analogs for a more comprehensive assessment.