A streamlined synthesis of the neurosteroid 3β-methoxypregnenolone assisted by a statistical experimental design and automation

Croci, Federico; Lozza, Anna Maria; Cerra, Bruno; Gioiello, Antimo

doi:10.1039/c9re00353c

Cited by 5 publications

(7 citation statements)

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“…This work was built on in 2020 with a further publication on the synthesis of neurosteroid 3-βmethoxypregnenolone, once again demonstrating the use of in-line UV-vis spectroscopy in the synthesis of this API. 62 In 2019, Kappe and co-workers developed a convenient method for monitoring reagent concentration using in-line UV-vis spectrometry in the generation, purification and Scheme 22 Telescoped continuous flow synthesis of imatinib 58 incorporating in-line UV-vis spectroscopy to monitor product dispersion following step 1 (amide formation). 60 Scheme 23 Telescoped flow synthesis of 16-DPA using in-line UV-vis spectroscopy to monitor reaction completion.…”

Section: Use Of Uv-vis Spectroscopy In Enabling Reaction Telescoping ...mentioning

confidence: 99%

The role of PAT in the development of telescoped continuous flow processes

Kearney,

Collins,

Maguire

2024

React. Chem. Eng.

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Section: Use Of Uv-vis Spectroscopy In Enabling Reaction Telescoping ...mentioning

confidence: 99%

The role of PAT in the development of telescoped continuous flow processes

Kearney,

Collins,

Maguire

2024

React. Chem. Eng.

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“…Other promising in-line technologies that could be used in MCFS have also been briefly mentioned. These examples illustrate how in-line purification technologies have made MCFS more compatible with various reaction conditions, thus making the synthesis of diversified complex molecules more feasible. ,− The advantages, limitations, and potential future developments of these in-line purification technologies are briefly summarized in Table .…”

Section: Perspective and Outlookmentioning

confidence: 99%

Advanced In-Line Purification Technologies in Multistep Continuous Flow Pharmaceutical Synthesis

Lei

Ang

2023

Org. Process Res. Dev.

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Continuous flow synthesis is a widely used method for synthesizing fine chemicals due to its benefits such as process intensification, improved reproducibility, and the ability to perform otherwise impossible transformations. Multistep continuous flow synthesis (MCFS) simplifies the synthesis of complex molecules by telescoping multiple steps into a streamlined and potentially automated process, reducing human efforts and time. Despite these advantages, challenges such as solid formation, solvent and reagent incompatibilities, and intermediate purification difficulties limit the development of MCFS. Overcoming these challenges will accelerate the innovative development of MCFS, thereby leading to enhanced multistep synthesis. This Perspective highlights representative examples of complex molecule production enabled by MCFS, where various in-line purification technologies were utilized during the flow processes.

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“…More recently, a central composite design (CCD) was employed for the synthesis optimization of the neurosteroid 3β-methoxypregnenolone (MAP4343, 22) from pregnenolone (20) (Scheme 6). [24] CCD is a response surface design usually employed for the identification of optimal conditions and to study the impact of small experimental changes on the reaction outcome. [20] Initially, batch screenings led to the initial identification of the Proton Sponge™ (DMAN, 21) and methyl trifluoromethanesulfonate (MeOTf) as appropriate reagents for the flow reaction.…”

Section: Steroid Synthesis Optimization By Computer-assisted Flow Sys...mentioning

confidence: 99%

Merging Continuous Flow Technology, Photochemistry and Biocatalysis to Streamline Steroid Synthesis

et al. 2023

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Since their structural elucidation in 1935, the introduction and substitution of functional groups and the modification of the steroidal scaffolds have been a fertile ground of research for synthetic and medicinal chemists. The discovery of steroids with hormonal and pharmacological activity has stimulated tremendous efforts to the development of highly selective and efficient synthetic procedures. Despite the progress made, steroid chemistry remains challenging and the preparation of steroidal compounds of pharmaceutical interests and in clinical practice, often requires long and elaborated synthesis. In recent years, a new impetus in the field came with the advent of enabling chemical technologies, such as continuous flow chemistry, which are exploited to overcome problems that arise from batch synthesis. Although it is still a niche sector, the use of flow technology in steroid synthesis and functionalization holds the premise to empower methodology development and to provide innovative tactics also for many hitherto uncharted chemistries. In this review, scientific contributions are reported and discussed in terms of flow set‐up and advantages offered concerning process efficiency, optimization, waste minimization, safety improvement, easy scale‐up and costs. We also highlight the main challenges, key improvements and the future trajectory in the application of continuous flow chemistry and its implementation to different disciplines such as photochemistry and biocatalysis with the ultimate goal of streamlining steroid synthesis.magnified image

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A streamlined synthesis of the neurosteroid 3β-methoxypregnenolone assisted by a statistical experimental design and automation

Abstract: The potential of integrating flow synthesizers, statistical design of experiments and automation has been exemplified to realize the streamlined etherification of pregnenolone to the neurosteroid 3β-methoxypregnenolone (MAP4343).

Cited by 5 publications

References 36 publications

The role of PAT in the development of telescoped continuous flow processes

The role of PAT in the development of telescoped continuous flow processes

Advanced In-Line Purification Technologies in Multistep Continuous Flow Pharmaceutical Synthesis

Merging Continuous Flow Technology, Photochemistry and Biocatalysis to Streamline Steroid Synthesis

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