Organic Process Research & Development最新文献

Drug resistance to tuberculosis is still one of the major challenges worldwide. Clofazimine, which belongs to the riminophenazine (antibiotic) class, is still one of the active drugs that are efficient against drug-resistant Mycobacterium tuberculosis. Apart from this, it is also a WHO-approved drug for the treatment of leprosy and, at present, is under phase 2 clinical trial for its activity against the SARS-CoV-2 virus. Owing to its vast importance in clinical research, we have developed a semicontinuous flow-mediated synthesis of Clofazimine using readily available p-chloroaniline and 1-fluoro-2-nitrobenzene. The target drug molecule was obtained from four consecutive chemical transformations with nominal residence time, improved purity, and yields when compared to the batch process. Moreover, the first two steps were also successfully telescoped under the optimized reaction conditions.

Sodium 5,5′-azotetrazolate (Na₂AzT) is a starting material for various azotetrazole salts that find applications as lead-free primary explosives or high-nitrogen compounds for inflating safety systems (in particular, guanidinium azotetrazolate, GZT). Sodium azotetrazolate, after preparation, is commonly isolated as the pentahydrate, which is relatively safe for handling. But it readily loses hydrate water molecules at higher temperatures or by treatment with organic solvents. In such cases, sensitivity to mechanical stimuli increases considerably and explosion accidents may occur. In this work, the thermal conditions and the role of solvents in water loss from sodium 5,5′-azotetrazolate pentahydrate are presented. Impact and friction sensitivity parameters of the products are described. In the case of guanidinium azotetrazolate, the process for its preparation without producing sodium 5,5′-azotetrazolate is introduced, thus avoiding manipulation of hazardous material and increasing the safety of the procedure.

A novel visible-light-induced hydrodesulfurization of a thioacetal was developed. The reaction operates under mild conditions using user-friendly tris(trimethylsilyl)silane as the reductant and a low catalyst loading of photoactive 4CzIPN. The expansion of the reaction scope was thwarted by the operationally hazardous nature of the process, occasionally producing fire. Careful examination of reaction mixtures allowed to identify silane (SiH₄) as the likely culprit causing the pyrophoricity.

This work details the removal of an azine-dimer (AD) impurity from 7-dehydrocholesterol (DHC), a precursor of vitamin D₃, using a newly developed, sustainable hybrid membrane process, from the idea to implementation. Developed by an international team collaborating under tight time frame and COVID restrictions, this innovative method exemplifies a versatile, energy-saving, and cost-effective separation technology by organic solvent nanofiltration (OSN). Traditional purification methods proved to be unsuccessful, costly, or unsustainable, but this process achieved DHC purification with a minimal yield loss of 0.1%. This separation challenge goes beyond typical OSN applications (solute concentration or solvent exchange) by separating two similar solutes in a solvent mixture. In a three-stage OSN process, the impurity level was reduced from approximately 2600 ppm to below 50 ppm in the final permeate. After developing and scaling up the process, the OSN, precipitation, and filtration units were engineered and constructed. These units were installed in the dsm-firmenich vitamin D₃ plant, and the purification process was successfully commissioned.

A catalyst-in-bag system facilitates the recovery and recycling of chiral dirhodium carboxylate catalysts used for enantioselective, intermolecular cyclopropanation. The catalyst-in-bag system incorporates a soluble enantioselective dirhodium complex catalyst within a reusable, commercial dialysis membrane. Dirhodium catalysts of different sizes are examined, and two catalysts with molecular weights above 2400 Da are well-retained by the membrane. The catalyst Rh₂(S-TPPTTL)₄ [TPPTTL = (1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate] is explored in enantioselective cyclopropanation reactions under a variety of conditions. The Rh₂(S-TPPTTL)₄ catalyst, when contained in the catalyst-in-bag system, provides high yields and enantioselectivities, akin to the homogeneous catalyst in solution, with negligible rhodium permeation out of the bag over five catalytic cycles. The catalyst-in-bag approach facilitates recovery of the expensive rhodium metal and ligand, with only ppm level Rh detected in the reaction products. The flexible and expandable catalyst-in-bag system can be accommodated in vessels of different shapes and dimensions.