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Enantioselective Organophotocatalytic Telescoped Synthesis of a Chiral Privileged Active Pharmaceutical Ingredient.

ABSTRACT: The continuous flow, enantioselective, organophotoredox catalytic asymmetric alkylation of aldehydes was studied, by using a homemade, custom-designed photoreactor for reactions under cryogenic conditions. Going from microfluidic conditions up to a 10 mL mesofluidic reactor, an increase of productivity by almost 18000 % compared to the batch reaction was demonstrated. Finally, for the first time, a stereoselective photoredox organocatalytic continuous flow reaction in a fully telescoped process for an active pharmaceutical ingredient (API)synthesis was successfully achieved. The final process consists of four units of operation: visible light-driven asymmetric catalytic benzylation under continuous flow, inline continuous work-up, neutralisation and a final oxidative amidation step afforded the pharmaceutically active molecule in 95 % e.e.

SUBMITTER: Herbrik F

PROVIDER: S-EPMC9325444 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Enantioselective Organophotocatalytic Telescoped Synthesis of a Chiral Privileged Active Pharmaceutical Ingredient.

Herbrik Fabian F Sanz Miguel M Puglisi Alessandra A Rossi Sergio S Benaglia Maurizio M

Chemistry (Weinheim an der Bergstrasse, Germany) 20220504 33

The continuous flow, enantioselective, organophotoredox catalytic asymmetric alkylation of aldehydes was studied, by using a homemade, custom-designed photoreactor for reactions under cryogenic conditions. Going from microfluidic conditions up to a 10 mL mesofluidic reactor, an increase of productivity by almost 18000 % compared to the batch reaction was demonstrated. Finally, for the first time, a stereoselective photoredox organocatalytic continuous flow reaction in a fully telescoped process ...[more]

PMID: 35239197

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Project description:Washing is a key step in pharmaceutical isolation to remove the unwanted crystallization solvent (mother liquor) from the active pharmaceutical ingredient (API) filter cake. This study looks at strategies for optimal wash solvent selection, which minimizes the dissolution of API product crystals while preventing the precipitation of product or impurities. Selection of wash solvents to avoid both these phenomena can be challenging but is essential to maintain the yield, purity, and particle characteristics throughout the isolation process. An anti-solvent screening methodology has been developed to quantitatively evaluate the propensity for precipitation of APIs and their impurities of synthesis during washing. This is illustrated using paracetamol (PCM) and two typical impurities of synthesis during the washing process. The solubility of PCM in different binary wash solutions was measured to provide a basis for wash solvent selection. A map of wash solution composition boundaries for precipitation for the systems investigated was developed to depict where anti-solvent phenomena will take place. For some crystallization and wash solvent combinations investigated, as much as 90% of the dissolved PCM and over 10% of impurities present in the PCM saturated mother liquor were found to precipitate out. Such levels of uncontrolled crystallization during washing in a pharmaceutical isolation process can have a drastic effect on the final product purity. Precipitation of both the product and impurities from the mother liquor can be avoided by using a solvent in which the API has a solubility similar to that in the mother liquor; for example, the use of acetonitrile as a wash solvent does not result in precipitation of either the PCM API or its impurities. However, the high solubility of PCM in acetonitrile would result in noticeable dissolution of API during washing and would lead to agglomeration during the subsequent drying step. Contrarily, the use of n-heptane as a wash solvent for a PCM crystal slurry resulted in the highest amount of precipitation among the solvent pairs evaluated. This can be mitigated by designing a multi-stage washing strategy where wash solutions of differing wash solvent concentrations are used to minimize step changes in solubility when the mother liquor and the wash solvent come into contact.

Project description:An environmental risk assessment is presented for mycophenolic acid (MPA), an immunosuppressive pharmaceutical used for prevention of organ rejection, and its prodrug mycophenolate mofetil (MPM). Mycophenolic acid will not significantly adsorb to activated sludge. In activated sludge, 14 C-MPA attained >80% degradation, supporting an older environmental fate test with the same compound. Based on n-octanol/water distribution coefficient (log DOW ) values of 2.28, 0.48, and ≤-1.54 at pH 5, 7, and 9, respectively, MPA is not expected to bioaccumulate. Sales amounts of MPA+MPM in Europe were used to derive predicted environmental concentrations (PECs) in surface waters; PECs were refined by including expected biodegradation in sewage treatment, average drinking water use, and average dilution of the effluents in the receiving waters per country. In addition, the exposure to pharmaceuticals in the environment (ePiE) model was run for 4 European catchments. The PECs were complemented with 110 measured environmental concentrations (MECs), ranging from below the limit of quantitation (<0.001 µg/L) to 0.656 µg/L. Predicted no-effect concentrations (PNECs) were derived from chronic tests with cyanobacteria, green algae, daphnids, and fish. The comparison of PECs and MECs with the PNECs resulted in a differentiated environmental risk assessment in which the risk ratio of PEC/PNEC or MEC/PNEC was <1 in most cases (mostly >90%), meaning no significant risk, but a potential risk to aquatic organisms in generally <10% of instances. Because this assessment reveals a partial risk, the following questions must be asked: How much risk is acceptable? and Through which measures can this risk be reduced? These questions are all the more important in view of limited alternatives for MPM and MPA and the serious consequences of not using them. Environ Toxicol Chem 2019;38:2259-2278. © 2019 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Dataset Information

Enantioselective Organophotocatalytic Telescoped Synthesis of a Chiral Privileged Active Pharmaceutical Ingredient.

Publications

Enantioselective Organophotocatalytic Telescoped Synthesis of a Chiral Privileged Active Pharmaceutical Ingredient.

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