Synthesis of a dipeptide by integrating a continuous flow reaction and continuous crystallization

Tanaka, Masashi; Hosoya, Masahiro; Manaka, Atsushi; Tsuno, Naoki

doi:10.1016/j.cherd.2021.09.013

Cited by 6 publications

(8 citation statements)

References 49 publications

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“…17 In our previous work, we successfully integrated flow reaction and continuous crystallization to directly subject an unstable reaction solution to continuous crystallization. 18 The flow reaction was conducted using standard tube reactors, and continuous crystallization was done in continuous stirred tank reactors (CSTRs). However, to move to the industrial scale, each configuration must be individually introduced and maintained.…”

Section: ■ Introductioncontrasting

confidence: 83%

“…An integrated system of a flow reaction and downstream operations is limited by the need for custom-optimized equipment for these processes, and also because integrated continuous operations pose technical difficulties . In our previous work, we successfully integrated flow reaction and continuous crystallization to directly subject an unstable reaction solution to continuous crystallization . The flow reaction was conducted using standard tube reactors, and continuous crystallization was done in continuous stirred tank reactors (CSTRs).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Integration of Liquid–Liquid Biphasic Flow Alkylation and Continuous Crystallization Using Taylor Vortex Flow Reactors

Hosoya

Tanaka

Manaka

et al. 2022

Org. Process Res. Dev.

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This work established the integration of a continuous flow reaction and continuous crystallization using Taylor vortex flow reactors. We previously developed liquid–liquid biphasic flow alkylation using a Taylor vortex flow reactor, which is a scalable flow reactor with high mixing efficiency. To maximize the efficiency of this methodology, we evaluated process parameters and instrumental parameters, such as the rotating speed and tilt of the reactor, and optimized the reaction conditions. As a result, the throughput increased more than 20-fold compared to our previous work, and a long-run experiment verified its robustness. Liquid–liquid biphasic flow alkylation, quenching, phase separation, continuous crystallization, and filtration were integrated by using Taylor vortex flow reactors for both the flow reaction and continuous crystallization. The integrated system using two Taylor vortex flow reactors provided the alkylated product continuously from the solution of the starting material.

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Section: ■ Introductioncontrasting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Integration of Liquid–Liquid Biphasic Flow Alkylation and Continuous Crystallization Using Taylor Vortex Flow Reactors

Hosoya

Tanaka

Manaka

et al. 2022

Org. Process Res. Dev.

Self Cite

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“…Recent literature has developed innovative methods of continuous crystallization. [23][24][25] Typically, crystallization is achieved by changing the temperature of the solution or by adding an antisolvent to precipitate (i. e., crash out) the product for manual separation. However, in continuous flow, it is not desired to rapidly precipitate an API without additional separation strategies, as this can entrap impurities.…”

Section: Process Intensified Separationsmentioning

confidence: 99%

Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

Hyer,

Gregory,

Kay

et al. 2024

Adv Synth Catal

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The pharmaceutical industry has traditionally employed batch processing as a means of synthesizing active pharmaceutical ingredients (APIs) on a commercial scale. Batch manufacturing enables API synthesis in large quantities in order to meet regulations. Yet, this strategy remains cumbersome, is labor‐intensive, and creates complex logistical networks. In recent decades, batch API processing has gradually eroded American economic competitiveness and has led to the off‐shoring of API manufacturing from the United States. Today it is estimated that +80% of APIs are manufactured overseas. Meanwhile, disruptions from the Coronavirus Disease (SARS‐CoV‐2) have exacerbated weaknesses in the global supply chain, culminating with widespread shortages of critical life‐saving drugs. These shortages have emphasized the importance of reshoring drug manufacturing to the U.S. and fostered a regulatory landscape that seeks advanced methods of API manufacturing in order to bolster America’s supply chain resiliency. Recently, increased attention has been directed towards continuous drug manufacturing to enable nonstop API production within modular stand‐alone flow systems. Continuous manufacturing (CM) facilitates modular automation, offers new avenues towards process intensification, and even enables in‐line analytical monitoring from raw materials to packaged products. This strategy offers better conversion, increased safety, reduced waste, and overall cost savings versus traditional batch‐style processing. The rise of advanced API manufacturing, coupled with the current regulatory landscape, offers a rare window of opportunity to convert traditional batch pharmaceutical processes into continuous, streamlined production systems to on‐shore API manufacturing and eliminate drug shortages. This review will outline the current state‐of‐the‐art in the CM of APIs and will highlight the translation of chemistry and unit operations from batch processes to modular CM systems.

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“…The peptide coupling reaction was performed continuously aided by a MSMPR crystallizer system. This system ultimately shortened the holding time for the quenched solution, leading to a robust crystallization procedure regardless of the manufacturing scale [117].…”

Section: Inline Precipitation and Crystallizationmentioning

confidence: 99%

Inline purification in continuous flow synthesis – opportunities and challenges

García-Lacuna¹,

Baumann²

2022

Beilstein J. Org. Chem.

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Continuous flow technology has become the method of choice for many academic and industrial researchers when developing new routes to chemical compounds of interest. With this technology maturing over the last decades, robust and oftentimes automated processes are now commonly exploited to generate fine chemical building blocks. The integration of effective inline analysis and purification tools is thereby frequently exploited to achieve effective and reliable flow processes. This perspective article summarizes recent applications of different inline purification techniques such as chromatography, extractions, and crystallization from academic and industrial laboratories. A discussion of the advantages and drawbacks of these tools is provided as a guide to aid researchers in selecting the most appropriate approach for future applications. It is hoped that this perspective contributes to new developments in this field in the context of process and cost efficiency, sustainability and industrial uptake of new flow chemistry tools developed in academia.

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Synthesis of a dipeptide by integrating a continuous flow reaction and continuous crystallization

Cited by 6 publications

References 49 publications

Integration of Liquid–Liquid Biphasic Flow Alkylation and Continuous Crystallization Using Taylor Vortex Flow Reactors

Integration of Liquid–Liquid Biphasic Flow Alkylation and Continuous Crystallization Using Taylor Vortex Flow Reactors

Continuous Manufacturing of Active Pharmaceutical Ingredients: Current Trends and Perspectives

Inline purification in continuous flow synthesis – opportunities and challenges

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