Catalyst Cascade Reactions in ‘One-Flow’ within a Compartmentalized, Green-Solvent ‘Digital Synthesis Machinery’ – End-to-End Green Process Design for Pharmaceuticals | One-Flow | Projekt | Ergebnisse | H2020 | CORDIS

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Leistungen

Shifting the epimerization equilibrium of cascade 2
Polymersome-based improvement of cascade 1: a) harmonization of catalyst & solvent

Polymersomes will be used for improving the contact of a biphasic reaction system, as given e.g. between water-soluble enzymes and organic substrates. This results in a strongly enhanced reaction rate, mainly as a result of an improved availability of the enzymes at the biphasic interface.

Development of a critical process parameter map

The processes, developed in WP 1 to 4, will be evaluated towards their critical process parameters. These will be compared to different technology characteristics. This will result in function specifications of the modules, which will specified for a group of processes (cascade/multi-purpose) and a wide range of different conditions. Based on this evaluation at least one demonstration process will be selected for realization and a theoretical realization scenario for a second process.

Application of the systemic operation factory in cascade 4

Using the systemic operations factory approach and the data obtained in Task 3.1., cascade 4 will be optimized. A computer-aided method based on the data bases and on the criteria will help to minimize the number of unit operations as well as the operating conditions for a particular target molecule in order to approach “One-Flow” operation. Just to give an example, matrixes may be built to check for orthogonality, the latter being assessed as a binary answer 0 or 1. The criteria for chemical orthogonality will be defined as 0 when, in a two reactions system, the yields of the expected products are > 99% and without degradation of the yield in solution for a time long enough to proceed with further workup. In any other situation, a non-orthogonal notation (1) is given. Minimizing the value of the matrixes will drive to (close to) One-Flow operations.

Application in TUG cascade

TUG will apply some of the MIC tools to check their suitability for the four above-given “Factory Innovations”. TUG will give feedback to MIC to propose alterations to the commercial equipment which shall lead to the development of one or two new tools to fit specifically to the aims of ONE-FLOW. From these tools, a pilot design will be made.

Platform technology performance test and scaling strategy

The TUG Cascade 4 will be tested at MIC site to judge on the ability for universal use for a wide range of catalytic processes. A scaling strategy for small and medium sized industrial applications will be evaluated. TUE-1 will assist MIC in scaling-up proposal, using the DynoChem® software from Scale-up Systems which is the world’s leading process development and scale-up software for scientists and engineers working in the pharmaceutical industry. In a more far-fetching scenario, QbD of API chemistry in the focus of the project can be facilitated using DynoChem to explore the design space and predict process performance on change of scale (for QbD-based NDA submissions).

Stimuli-responsive Pickering Emulsions and dispersing one phase for cascade 3

Stimuli-responsive Pickering emulsions for controlled destabilisation of emulsions will be developed which to facilitate separation. Water-in-water and oil-in-oil Pickering emulsions arising from immiscible phases of two incompatible polymers shall be investigated and stabilized, e.g. by small plate-like particles of aluminium hydroxide.

Polymersome-based improvement of cascade 1: c) solvent reduction & elimination

Polymersomes will be developed to eliminate the consecutive introduction of the respective solvents for some catalysts and accor¬dingly respective solvent removal strategies. Instead of multiple solvents just one will be used. Finally, it will be tested if this can even eliminate the need for organic solvents at all, and open the door to use only water, not only for enzymes, but also for the organo-based chemocatalysts. Yet, then a switching in the choice of reactants is demanded.

Exploiting iterative reactivity of boronic acids via flow generated reactive intermediates

Exploitation of a newly discovered iterative carbon-carbon bond forming process developed at UCAM, which involves repeated metal-free coupling of boronic acids (commonly available) with in-situ flow-generated diazo compounds, as reactive intermediates. This process opens up wider opportunities to create functional materials and in particular, novel architectures for the pharmaceutical industry.

Application of the microcontroller in cascade 1

An optimization of the cascades will be performed under the constraints of systemic interaction. Computer-aided optimization (see BBM approach) or DoE-experimentation seems to be adequate means to address complexity of this task.

Cascaded enzymes in polymersomes for cascade 2

In a more far-fetching scenario, more catalysts (>2) will be placed in a polymersome which demands a higher quality in the insertion and construction of the polymersomes themselves. Methodologies are already in place at TUE-2 to position three en¬zymes at different locations within one carrier. Here, 3 enzymes will be positioned within the polymersome and a two-step cascade will be effectively executed. Such dedicated action will largely profit from the sound knowledge about the right choice of polymers and assembly conditions to construct semipermeable polymersomes.

Cascade 1 - synthesis of cannabinoid derivatives

Readily accessible geranyl halides and derivatives thereof will be coupled, using Pd-catalyzed cross-coupling reactions, to olivetolic acid which contains an additional halide substituent at the aromatic ring. Initially, Suzuki or Negishi type coupling reactions will be used in which the geranyl partner is converted into a borinate ester or organozinc compound. Then differently substituted olivetolic acid derivatives will be prepared and coupled to the geranyl derivatives. The final step in the biosynthesis of THC in Cannabis sativa is the ring-closure and subsequent decarboxylation of canna¬bigerolic acid. This unique oxidative cyclization reaction is catalyzed by Δ1-tetrahydrocannabinolic acid synthase (THCAS). The effectiveness of the coupling procedure will be evaluated in close collaboration with ESR Y (WP1) under three conditions: non-compartmentalized, in polymersomes, and in Pickering emulsions

Cascade 3 - b) synthesis of Sacubitril

Using the approach of cascade 3a, the synthesis of sacubitril will be carried out in continuous manner.

Cascade 3 – a) synthesis of Valsartan

Valsartan is synthesized continuously in a fixed bed reactor with three different segments. The first step is catalyzed by a base, e.g. K2CO3, which is also needed for the Suzuki-Miyaura coupling and thus can be used for both reactions. For the latter self-made heteroge¬neous Pd-catalysts will be used. These catalysts are either Ce-Sn-Pd (CexSn1-xPd0.01O2-δ) catalysts or Pd-immobilized via a bis(oxazoline) ligand on functionalized silica-gel particles or monoliths. Preliminary experiments will show if it is necessary to protect the tetrazole ring at the free amine position. The last step of the synthesis involves the conversion of the methylester to the acid using an immobilized hydrolase.

Application of the microcontroller in cascade 2

Similar as in Task 4.3, an optimization of the cascades will be performed under the constraints of systemic interaction.

Periodic report action check meeting 3

Scientific action check meeting 3 after 48 months Draft agenda and presentations to be delivered during the action check meeting

Continuous crystallization of cascade 4 product

TUG will develop a continuous crystallization step for cascade 4 product which will provide essential experimental data needed for the proposal of a whole orthogonal formulation. This side string of the objective is based on technology currently explored within a collaboration of TUE-1-TUG and the experience of TUG in continuous crystallization.

Cascade 4 - Synthesis of Capecitabine

At first the individual reaction steps will be studied and suitable catalysts will be identified by means of a screening of organo- and biocatalysts, respectively. Subsequently, process development for the desired key steps for the multi-step synthesis of the Capecitabine key intermediate will be done, followed by an experimental and theoretical study rationalizing the compatibility of the organocatalytic with the enzymatic reactions. Finally, the combination of the steps in a batch-process will be carried out to serve as the benchmark for the subsequent combination under flow.

A new generic microcontroller remote command and control device for chemical reactions in flow

The control platform [the Blueberry Muffin (BBM)] will be able to seamlessly manage equipment modules from different vendors and go beyond simple machine to machine communi¬cation (M2M) to a new level whereby the machines evolve and adapt to a changing environment. Advanced innovative software, neural networking of chemical devices and machine learning techniques will be interconnected and networked through a “Chemical Internet of Chemical Things”.

Catalyst slurries in multi-phase micro-flows

Multi-phase micro-flow processing recirculating heterogeneous catalyst slurries will be developed for the first and/or third chemical step in cascade 4. It needs to be exerted in the presence of enzymes which constitutes entirely new kind of processing. Even the normal use of such kind of processing is scarcely reported and CNRS have a leading position here. For example, three-phase gas-liquid-liquid segmented flow has been reported for material synthesis, crystallization, or enhanced LL mixing, yet only two papers deal with reaction. In turn, that has been approached by CNRS and they demonstrated quantitatively the viability and the robustness of a GLS system under reactive conditions and performed several basic engineering studies on hydrodynamic and LS mass transport.

Technical action check meeting 1

Scientific action check meeting 1 after 16 months Draft agenda and presentations to be delivered during the action check meeting

Construction of second generation lab-scale modules

a 3D printed reactor from materials such as stainless steel, nickel-based alloys or PEEK will be built. With having reactors from those different materials available, basically every corrosion, temperature and pressure requirement should be able to be fulfilled.

Spaciant-based solvent dispersion and unification for cascade 4

Smart solvents, such as supercritical CO2, ionic liquids and fluorous solvents (where needed thermomorphic solvents), will be used to allow the operation of two orthogonal catalysts in close proximity (i.e., in one reactor), which however cannot be dissolved in the same solvent. After reaction, by external stimulus such as cooling down or releasing CO2 gas, the catalysts and their respective solvents will be separated. For Cascade 4, a chemo and biocatalyst will be treated this way. The solvents need to be selected in such way, that reactants and products also will remain in different phases. Then, there is no need for product and catalyst separation, but is rather “automatically” achieved. The investigations follow a generic aim beyond the catalysts and reactants of Cascade 4.There is a multitude of spaciants combination possible for a multitude of processing and purification tasks; some of these will be tested. TUE has complete overview over all relevant literature and made two reviews about, see the following non-published table (shown first time here).

Criteria definition and orthogonality decision execution

Criteria defining compatibility are also required. For example, catalyst deactivation per se might kill several options for equipment in flow mode. The chemical functionalities of those cas¬cades will be checked for their orthogonality and proposals will be made for replacement based on an inventory made collecting known orthogonal functionalities.

Cascade 2 - synthesis of ursodeoxycholic acid

The first step of this task comprises a highly selective dihydroxylation at the 12-position of naturally available cholic acid. In nature so-called dehydroxylases were identified that can carry out this transformation. This enzyme will be identified, expressed and characterized. In the second step, an isomerization will be carried out. 7a and 7b-Hydroxysteroid-dehydroge¬nases as immobilized cell-free enzymes carry out this step with high yields and selectivities. Co-immobilisation of these enzymes will be carried out in Pickering emulsions, possibly in combination with cross-linking. In the final stage of the cascade, compatibility of the two steps will be studied, taking into account the

. Sustainability assessment

Life-cycle assessment First, green chemistry indices established in pharmaceutical industry will be applied. The process mass index, e.g., is suited for focused judgement, e.g. on the efficiency in minimizing solvents. For deeper, holistic analysis in a cradle-to-process gate manner and beyond (cradle-to-cradle), life-cycle assessment will be exerted using Umberto and Gabi softwares. Key is here to have robust data sets implemented in the life-cycle inventory. Cost modelling Operational as well as well as capital costs are determined. This allows to calculate life-cycle costs and to plot this versus the life-cycle impact following BASF eco-efficiency approach [Uhlman, Saling, CEP, 2010] Cash-flow analysis will, in addition, reveal the net-present value and let deduce the time need for depreciation of the capital costs.

Polymersome-based improvement of cascade; b) harmonization of synergetic action of several catalysts

Besides that, the co-flow use of several catalysts in one flow will be established to give rise to high throughput and synergetic effects which arise from the proximity. An example of a synergetic effect is that under flow product inhibition is prevented and enzymes can perform at their maximum turnover rate.

Construction of lab-scale modules

Based on the generated function specifications for the selected process, a design specification will be generated for each module for a lab-scale plant. The challenge will be to design multi-purpose modules, which can deal with very different catalyst characteristics and give access to a wide range of different conditions. An optimised engineering design will be designed with integrated workup.

Enable a co-catalyst flow operation for cascade 3

A combined Pickering-anchoring strategy will be developed to allow a co-flow operation of both catalysts in one fixed-bed reactor, i.e. once the C-C coupling product is formed, it is hydrolyzed immediately at its ester function. For this, a Pickering emulsion containing one catalyst in combination with an immobilization of the chemocatalyst to a solid support will be used. The enzyme hydrolase will be either placed within an emulsifier particle or be the stabilizing particle itself, while the Pd catalyst will be chemically anchored to a solid support, such as functionalized silica particles or monoliths using bis(oxazoline) as organic linkers that strongly bind palladium. Such hybrid operation is thought to be superior to a monolithic use of Pickering emulsions and anchored catalysts alone, allowing (i) higher through¬put (lower pressure drop), (ii) operational simplicity (KISS-based process design), (iii) better reaction outcome. Detailed surface analysis of the catalyst/Pickering emulsion particles and reactor walls will be done before and after reaction and ICP/MS measurements of Pd in the solvents and products will be carried out.

Data acquisition

For all cascades under investigation, data acquisition will be perfor¬med from solubility, miscibility, vapor pressure and equipment data bases. Most of these data are available in the open literature and will be collected and used. Part of the equipment data base will be available from the French project PROCIP (2010-2014) funded by the French National Agency for Research (ANR). Other equipment more specific to Flow Chemistry are not yet included in the PROCIP equipment data base and should be worked out (Syrris type, etc…). Other data such as the reaction time and the chemical orthogonality might require inputs from WP1 and some experimental work with flow technics available at CNRS. All available data bases (solvent miscibility, …) will also be collected but other will be created for the purpose of the project.

Periodic report action check meeting 2

Scientific action check meeting 2 after 28 months Draft agenda and presentations to be delivered during the action check meeting

Data Management Plan

Data Management will be provided and updated during the execution of the project

Updated Data Management Plan

The deliverable 'Data Management Plan' given in month 6 needs an updated version of this deliverable at the end of the project in month 48.

Project webpage and logo

Task PMD 1. Creation of a project webpage and a logo (TUE-1, M1-2) Webpage and project logo. Task PMD 2. Project management and dissemination (all partners, M1-M48) This task accompanies the whole project and guarantees a successful accomplishment of the project. This includes to organize meetings on a regularly basis in order to discuss critical issues and the milestones as well as the storage and exchange of the project data. Furthermore, the results will be disseminated according to the dissemination plan (Chapter 2.2)

Veröffentlichungen

A Practical Method for Continuous Production of sp3‐Rich Compounds from (Hetero)Aryl Halides and Redox‐Active Esters

Autoren: Yiding Chen; Oliver May; Steven V. Ley; Eiichi Watanabe
Veröffentlicht in: Chemistry (Weinheim an der Bergstrasse, Germany), Ausgabe 26, 2020, Seite(n) 186-191, ISSN 0947-6539
Herausgeber: John Wiley & Sons Ltd.
DOI: 10.17863/cam.45802

Multiphase alternated slug flows: Conditions to avoid coalescence and characterization of mass transfer between droplets

Autoren: Camille Méhault, Laurent Vanoye, Régis Philippe, Claude de Bellefon
Veröffentlicht in: Chemical Engineering Journal, Ausgabe 407, 2021, Seite(n) 127215, ISSN 1385-8947
Herausgeber: Elsevier BV
DOI: 10.1016/j.cej.2020.127215

Photoredox Generation of Sulfonyl Radicals and Coupling with Electron Deficient Olefins

Autoren: Yiding Chen, Nicole McNamara, Oliver May, Thanigaimalai Pillaiyar, David C. Blakemore, Steven V. Ley
Veröffentlicht in: Organic Letters, Ausgabe 22/15, 2020, Seite(n) 5746-5748, ISSN 1523-7060
Herausgeber: American Chemical Society
DOI: 10.1021/acs.orglett.0c01730

Living with our machines: Towards a more sustainable future

Autoren: Steven V. Ley, Yiding Chen, Daniel E. Fitzpatrick, Oliver S. May
Veröffentlicht in: Current Opinion in Green and Sustainable Chemistry, Ausgabe 25, 2020, Seite(n) 100353, ISSN 2452-2236
Herausgeber: Elsevier
DOI: 10.1016/j.cogsc.2020.100353

Effect of Particle Wettability and Particle Concentration on the Enzymatic Dehydration of n ‐Octanaloxime in Pickering Emulsions

Autoren: Ana Maria Bago Rodriguez, Lukas Schober, Alessa Hinzmann, Harald Gröger, Bernard P. Binks
Veröffentlicht in: Angewandte Chemie International Edition, Ausgabe 60/3, 2021, Seite(n) 1450-1457, ISSN 1433-7851
Herausgeber: John Wiley & Sons Ltd.
DOI: 10.1002/anie.202013171

Engineering chemistry for the future of chemical synthesis

Autoren: D.E. Fitzpatrick, S.V. Ley
Veröffentlicht in: Tetrahedron, Ausgabe 74/25, 2018, Seite(n) 3087-3100, ISSN 0040-4020
Herausgeber: Pergamon Press Ltd.
DOI: 10.1016/j.tet.2017.08.050

Compartmentalized cross-linked enzymatic nano -aggregates ( c -CLE n A) for efficient in-flow biocatalysis

Autoren: M. Teresa De Martino, Fabio Tonin, N. Amy Yewdall, Mona Abdelghani, David S. Williams, Ulf Hanefeld, Floris P. J. T. Rutjes, Loai K. E. A. Abdelmohsen, Jan C. M. van Hest
Veröffentlicht in: Chemical Science, Ausgabe 11/10, 2020, Seite(n) 2765-2769, ISSN 2041-6520
Herausgeber: Royal Society of Chemistry
DOI: 10.1039/c9sc05420k

A Practical Method for Continuous Production of sp3‐Rich Compounds from (Hetero)Aryl Halides and Redox‐Active Esters

Autoren: Eiichi Watanabe, Yiding Chen, Oliver May, Steven V. Ley
Veröffentlicht in: Chemistry – A European Journal, Ausgabe 26/1, 2020, Seite(n) 186-191, ISSN 0947-6539
Herausgeber: John Wiley & Sons Ltd.
DOI: 10.1002/chem.201905048

One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo- and heterogeneous Lewis acids

Autoren: Victor R. L. J. Bloemendal, Bram Spierenburg, Thomas J. Boltje, Jan C. M. van Hest, Floris P. J. T. Rutjes
Veröffentlicht in: Journal of Flow Chemistry, Ausgabe 11/2, 2021, Seite(n) 99-105, ISSN 2062-249X
Herausgeber: Akademiai Kiado
DOI: 10.1007/s41981-020-00133-2

Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry

Autoren: Katharina Hiebler, Georg J Lichtenegger, Manuel C Maier, Eun Sung Park, Renie Gonzales-Groom, Bernard P Binks, Heidrun Gruber-Woelfler
Veröffentlicht in: Beilstein Journal of Organic Chemistry, Ausgabe 14, 2018, Seite(n) 648-658, ISSN 1860-5397
Herausgeber: Beilstein-Institut
DOI: 10.3762/bjoc.14.52

Nanoreactors for green catalysis

Autoren: M Teresa De Martino, Loai K E A Abdelmohsen, Floris P J T Rutjes, Jan C M van Hest
Veröffentlicht in: Beilstein Journal of Organic Chemistry, Ausgabe 14, 2018, Seite(n) 716-733, ISSN 1860-5397
Herausgeber: Beilstein-Institut
DOI: 10.3762/bjoc.14.61

A Versatile Route to Unstable Diazo Compounds via Oxadiazolines and their Use in Aryl-Alkyl Cross-Coupling Reactions

Autoren: Andreas Greb, Jian-Siang Poh, Stephanie Greed, Claudio Battilocchio, Patrick Pasau, David C. Blakemore, Steven V. Ley
Veröffentlicht in: Angewandte Chemie International Edition, Ausgabe 56/52, 2017, Seite(n) 16602-16605, ISSN 1433-7851
Herausgeber: John Wiley & Sons Ltd.
DOI: 10.1002/anie.201710445

Mimicking the surface and prebiotic chemistry of early Earth using flow chemistry

Autoren: Dougal J. Ritson, Claudio Battilocchio, Steven V. Ley, John D. Sutherland
Veröffentlicht in: Nature Communications, Ausgabe 9/1, 2018, ISSN 2041-1723
Herausgeber: Nature Publishing Group
DOI: 10.1038/s41467-018-04147-2

In-line separation of multicomponent reaction mixtures using a new semi-continuous supercritical fluid chromatography system

Autoren: Daniel E. Fitzpatrick, Robbie J. Mutton, Steven V. Ley
Veröffentlicht in: Reaction Chemistry & Engineering, Ausgabe 3/5, 2018, Seite(n) 799-806, ISSN 2058-9883
Herausgeber: Royal Society of Chemistry
DOI: 10.1039/c8re00107c

Photochemical Homologation for the Preparation of Aliphatic Aldehydes in Flow

Autoren: Yiding Chen, Marco Leonardi, Paul Dingwall, Ricardo Labes, Patrick Pasau, David C. Blakemore, Steven V. Ley
Veröffentlicht in: The Journal of Organic Chemistry, Ausgabe 83/24, 2018, Seite(n) 15558-15568, ISSN 0022-3263
Herausgeber: American Chemical Society
DOI: 10.1021/acs.joc.8b02721

Across-the-World Automated Optimization and Continuous-Flow Synthesis of Pharmaceutical Agents Operating Through a Cloud-Based Server

Autoren: Daniel E. Fitzpatrick, Timothé Maujean, Amanda C. Evans, Steven V. Ley
Veröffentlicht in: Angewandte Chemie International Edition, Ausgabe 57/46, 2018, Seite(n) 15128-15132, ISSN 1433-7851
Herausgeber: John Wiley & Sons Ltd.
DOI: 10.1002/anie.201809080

C–H functionalisation of aldehydes using light generated, non-stabilised diazo compounds in flow

Autoren: Paul Dingwall, Andreas Greb, Lorène N. S. Crespin, Ricardo Labes, Biagia Musio, Jian-Siang Poh, Patrick Pasau, David C. Blakemore, Steven V. Ley
Veröffentlicht in: Chemical Communications, Ausgabe 54/83, 2018, Seite(n) 11685-11688, ISSN 1359-7345
Herausgeber: Royal Society of Chemistry
DOI: 10.1039/c8cc06202a

Three-Component Assembly of Multiply Substituted Homoallylic Alcohols and Amines Using a Flow Chemistry Photoreactor

Autoren: Yiding Chen, David C. Blakemore, Patrick Pasau, Steven V. Ley
Veröffentlicht in: Organic Letters, Ausgabe 20/20, 2018, Seite(n) 6569-6572, ISSN 1523-7060
Herausgeber: American Chemical Society
DOI: 10.1021/acs.orglett.8b02907

An Asymmetric Organocatalytic Aldol Reaction of a Hydrophobic Aldehyde in Aqueous Medium Running in Flow Mode

Autoren: Lukas Schober, Shahilan Ratnam, Yasunobu Yamashita, Niklas Adebar, Matthias Pieper, Albrecht Berkessel, Volker Hessel, Harald Gröger
Veröffentlicht in: Synthesis, Ausgabe 51/05, 2019, Seite(n) 1178-1184, ISSN 0039-7881
Herausgeber: Georg Thieme Verlag
DOI: 10.1055/s-0037-1610404

Biphasic Biocatalysis using a CO2-Switchable Pickering Emulsion

Autoren: Shijie Yu, Duyan Zhang, Jianzhong Jiang, Zhenggang Cui, Wenshui Xia, Bernie Binks, Hengquan Yang
Veröffentlicht in: Green Chemistry, 2019, ISSN 1463-9262
Herausgeber: Royal Society of Chemistry
DOI: 10.1039/c8gc03879a

Capsules from Pickering emulsion templates

Autoren: Ana Maria Bago Rodriguez, Bernard P. Binks
Veröffentlicht in: Current Opinion in Colloid & Interface Science, Ausgabe 44, 2019, Seite(n) 107-129, ISSN 1359-0294
Herausgeber: Pergamon Press
DOI: 10.1016/j.cocis.2019.09.006

Development of a multistep reaction cascade for the synthesis of a sacubitril precursor in continuous flow

Autoren: Katharina Hiebler, Carina Dertnig, Sebastian Soritz, Manuel C. Maier, Theresa R. Hörmann, Bianca Grabner, Heidrun Gruber-Woelfler
Veröffentlicht in: Journal of Flow Chemistry, 2019, ISSN 2062-249X
Herausgeber: Akademiai Kiado
DOI: 10.1007/s41981-019-00058-5

A tutored discourse on microcontrollers, single board computers and their applications to monitor and control chemical reactions

Autoren: Daniel E. Fitzpatrick, Matthew O'Brien, Steven V. Ley
Veröffentlicht in: Reaction Chemistry & Engineering, 2020, ISSN 2058-9883
Herausgeber: Royal Society of Chemistry
DOI: 10.1039/c9re00407f

Latest development in the synthesis of ursodeoxycholic acid (UDCA): a critical review

Autoren: Fabio Tonin, Isabel W C E Arends
Veröffentlicht in: Beilstein Journal of Organic Chemistry, Ausgabe 14, 2018, Seite(n) 470-483, ISSN 1860-5397
Herausgeber: Beilstein-Institut
DOI: 10.3762/bjoc.14.33

Multistep synthesis of a valsartan precursor in continuous flow

Autoren: Katharina Hiebler, Sebastian Soritz, Kristian Gavric, Sam Birrer, Manuel C. Maier, Bianca Grabner, Heidrun Gruber-Woelfler
Veröffentlicht in: Journal of Flow Chemistry, 2019, ISSN 2062-249X
Herausgeber: Akademiai Kiado
DOI: 10.1007/s41981-019-00044-x

Pickering emulsion-enhanced interfacial biocatalysis: tailored alginate microparticles act as particulate emulsifier and enzyme carrier

Autoren: Xin Yang, Yaolei Wang, Ruixue Bai, Hulin Ma, Weihao Wang, Hejia Sun, Yuman Dong, Fengmei Qu, Qiming Tang, Ting Guo, Bernard P. Binks, Tao Meng
Veröffentlicht in: Green Chemistry, Ausgabe 21/9, 2019, Seite(n) 2229-2233, ISSN 1463-9262
Herausgeber: Royal Society of Chemistry
DOI: 10.1039/c8gc03573c

Screening of functional solvent system for automatic aldehyde and ketone separation in aldol reaction: A combined COSMO-RS and experimental approach

Autoren: Chenyue Zhang, Zhen Song, Can Jin, Job Nijhuis, Teng Zhou, Timothy Noël, Harald Gröger, Kai Sundmacher, Jan van Hest, Volker Hessel
Veröffentlicht in: Chemical Engineering Journal, Ausgabe 385, 2020, Seite(n) 123399, ISSN 1385-8947
Herausgeber: Elsevier BV
DOI: 10.1016/j.cej.2019.123399

Life cycle assessment of vitamin D3 synthesis: from batch to photo-high p,T

Autoren: Olivia Maria Morales-Gonzalez, Marc Escribà-Gelonch, Volker Hessel
Veröffentlicht in: The International Journal of Life Cycle Assessment, Ausgabe 24/12, 2019, Seite(n) 2111-2127, ISSN 0948-3349
Herausgeber: Springer Verlag
DOI: 10.1007/s11367-019-01634-6

A Revised Modular Approach to (-)- trans -Δ 8 -THC and Derivatives Through Late-Stage Suzuki-Miyaura Cross-Coupling Reactions

Autoren: Victor R. L. J. Bloemendal, Daan Sondag, Hidde Elferink, Thomas J. Boltje, Jan. C. M. van Hest, Floris P. J. T. Rutjes
Veröffentlicht in: European Journal of Organic Chemistry, Ausgabe 2019/12, 2019, Seite(n) 2289-2296, ISSN 1434-193X
Herausgeber: John Wiley & Sons Ltd.
DOI: 10.1002/ejoc.201900059

Chemoenzymatic Synthesis of Sialic Acid Derivatives Using Immobilized N‐ Acetylneuraminate Lyase in a Continuous Flow Reactor

Autoren: Victor R. L. J. Bloemendal, Sam J. Moons, Jurriaan J. A. Heming, Mohamed Chayoua, Olaf Niesink, Jan C. M. van Hest, Thomas J. Boltje, Floris P. J. T. Rutjes
Veröffentlicht in: Advanced Synthesis & Catalysis, 2019, ISSN 1615-4150
Herausgeber: John Wiley & Sons Ltd.
DOI: 10.1002/adsc.201900146

Solvent impact assessment for the “One-Flow Functional Solvent Factory”

Autoren: O.M. Morales-Gonzalez, C. Zhang, S. Li, V. Hessel
Veröffentlicht in: Chemical Engineering Science: X, Ausgabe 3, 2019, Seite(n) 100024, ISSN 2590-1400
Herausgeber: Elsevier
DOI: 10.1016/j.cesx.2019.100024

A New World for Chemical Synthesis?

Autoren: Steven V. Ley, Yiding Chen, Daniel E. Fitzpatrick, Oliver May
Veröffentlicht in: CHIMIA International Journal for Chemistry, Ausgabe 73/10, 2019, Seite(n) 792-802, ISSN 0009-4293
Herausgeber: Schweizerische Chemische Gedellschaft
DOI: 10.2533/chimia.2019.792

NAD + ‐Dependent Enzymatic Route for the Epimerization of Hydroxysteroids

Autoren: Fabio Tonin, Linda G. Otten, Isabel W. C. E. Arends
Veröffentlicht in: ChemSusChem, Ausgabe 12/13, 2019, Seite(n) 3192-3203, ISSN 1864-5631
Herausgeber: Wiley - V C H Verlag GmbbH & Co.
DOI: 10.1002/cssc.201801862

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Catalyst Cascade Reactions in ‘One-Flow’ within a Compartmentalized, Green-Solvent ‘Digital Synthesis Machinery’ – End-to-End Green Process Design for Pharmaceuticals

Leistungen

Veröffentlichungen

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