Organic Process Research & Development最新文献

Presented here is the design and performance of a coalescing liquid–liquid filter, based on low-cost and readily available meltblown nonwoven substrates for separation of immiscible phases. The performance of the coalescer was determined across three broad classes of fluid mixtures: (i) immiscible organic/aqueous systems, (ii) a surfactant laden organic/aqueous system with modification of the type of emulsion and interfacial surface tension through the addition of sodium chloride, and (iii) a water–acetone/toluene system. The first two classes demonstrated good performance of the equipment in effecting separation, including the separation of a complex emulsion system for which a membrane separator, operating through transport of a preferentially wetting fluid through the membrane, failed entirely. The third system was used to demonstrate the performance of the separator within a multistage liquid–liquid counterflow extraction system. The performance, robust nature, and scalability of coalescing filters should mean that this approach is routinely considered for liquid–liquid separations and extractions within the fine chemical and pharmaceutical industry.

A packed reactor bed incorporating a polymer-supported isothiourea HyperBTM catalyst derivative has been used to promote the enantioselective synthesis of a range of heterocyclic products derived from α-azol-2-ylacetophenones and -acetamides combined with alkyl, aryl, and heterocyclic α,β-unsaturated homoanhydrides in continuous flow via an α,β-unsaturated acyl-ammonium intermediate. The products are generated in good to excellent yields and generally in excellent enantiopurity (up to 97:3 er). Scale-up is demonstrated on a 15 mmol scale, giving the heterocyclic product in 68% overall yield with 98:2 er after recrystallization.

In the production of pharmaceutically active ingredients, the formation of new carbon–carbon bonds is essential. A widespread and frequently employed method is the use of organometallic reagents (e.g., RLi, RMgX, RZnX), which differ greatly in their reactivity and are selected according to the specific reaction pathway desired. Organozinc compounds (RZnX) represent a class of compounds whose reactivity is lower than that of the widely used Grignard reagents and far below that of organolithium compounds, allowing them to tolerate the presence of functional groups incompatible with organomagnesium and organolithium compounds. Organozinc compounds are highly sensitive to oxygen and moisture, which results in difficult handling and problematic storage and limits the use of organozinc compounds in synthetic chemistry. In order to overcome this limitation and make organozinc reagents widely accessible for process chemists of varying industries, a continuous synthetic route to a large number of organozinc reagents was established on a laboratory and pilot scale. Flow rates, solvents, the metal activation mechanism, and the initial concentration of the starting materials were varied. For this purpose, a bed of Zn granules was used, which provides an approximately 250-fold excess of Zn throughout the reaction. The formed zinc organyls were analyzed by manual titration and GC analysis after quenching to determine conversion and yield as well as possible side product formation. For the formation of monozinc organyls, a lab-scale reactor originally designed for the formation of Grignard reagents was used, including a Zn replenishing unit. The main objective of this work was to establish the scalable continuous formation of organozinc reagents, which enables fast and safe process optimization. It was found that complete conversion of the organic halides used could be achieved in a single passage through the reactor with zinc organyl yields of 78–100%. Furthermore, the continuous conversion of highly concentrated 2.0 M starting materials was successfully carried out for the first time. Sufficient process reliability was ensured, and good to very good yields of 84–100% were demonstrated. The synthesis of some selected zinc organyls was then also transferred to a pilot scale, where a maximum liquid throughput of 18 L/h was achieved. With residence times of 1.5–14.0 min, complete conversion of the organic halide was achieved in all syntheses with high zinc organyl yields of up to 98%.

A scalable continuous manufacturing process for the synthesis and crystallization of form III carbamazepine (CBZ) from iminostilbene (ISB) has been established. A high-yielding synthesis was first obtained using a plug flow reactor (PFR) and then scaled up using a continuous oscillatory baffled reactor (COBR). A real-time in-line Raman spectroscopy method was implemented to ensure that the conversion of the starting material ISB to the product CBZ was maintained above 99.0%. The monitored product stream was telescoped into a mixed-suspension mixed-product crystallizer (MSMPR-1) and a filtration unit to isolate the preliminary CBZ form I polymorph. A cooling recrystallization process was designed by using a crystal growth model derived from microscopy measurements. The impurity purging capacities and polymorph attainments were compared for the batch and flow processes. This study outlines the role of process modeling and process analytical technology (PAT) for impurity purging in a telescoped continuous manufacturing process.