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8 article(s) from Baumann, Marcus

Inline purification in continuous flow synthesis – opportunities and challenges

Jorge García-Lacuna and
Marcus Baumann

Perspective
Published 16 Dec 2022

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1. Graphical Abstract
2. Scheme 1: Automated in-line chromatography with the Advion puriFlash^® system. The rightmost part of the schem...
  
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3. Scheme 2: Purification via pH tuning and several Zaiput membranes. Redrawn from [51].
  
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4. Scheme 3: Two-phase recirculating system for purifications of an immobilized enzyme-based reaction. Redrawn f...
  
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5. Scheme 4: Countercurrent L–L purification using large Zaiput membranes in the presence of a phase transfer ca...
  
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6. Scheme 5: General scheme of a telescoped flow process using L–L separators.
  
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7. Scheme 6: Example of phase separation using a computer-vision approach. Redrawn from [68].
  
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8. Scheme 7: Example of an inline purification using heterogeneous scavenging. Redrawn from [76].
  
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9. Scheme 8: General scheme of a telescoped process using heterogenous cartridges.
  
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10. Scheme 9: Comparison of two strategies for flow-based imatinib syntheses. Redrawn from [91] and [92].
  
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11. Scheme 10: General purification scheme using the catch and release strategy.
  
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12. Scheme 11: Exemplar catch and release purification of a stereoselective oxidation. Redrawn from [105].
  
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13. Scheme 12: Catch and release-type purification using conventional SiO₂. Redrawn from [107].
  
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14. Scheme 13: Schematic representation of an industrial continuous crystallization. Redrawn from [109].
  
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15. Scheme 14: General scheme of an academic inline crystallization approach.
  
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16. Scheme 15: Simplified overview of purification options and selected criteria.
  
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Graphical Abstract

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

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Flow synthesis of oxadiazoles coupled with sequential in-line extraction and chromatography

Kian Donnelly and
Marcus Baumann

Full Research Paper
Published 25 Feb 2022

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1. Graphical Abstract
2. Scheme 1: Methods for accessing 1,3,4-oxadiazoles.
  
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3. Scheme 2: Synthesis of acyl hydrazones 1a–j.
  
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4. Scheme 3: Iodine-mediated cyclisation of hydrazones 1a–j yielding oxadiazoles 2a–j. Reaction conditions: 1a–j...
  
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5. Scheme 4: Synthesis of complex oxadiazoles.
  
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6. Scheme 5: Continuous flow scale-up reaction with in-line quench and extraction.
  
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7. Scheme 6: Continuous flow setup equipped with in-line extraction and purification.
  
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Graphical Abstract

Beilstein J. Org. Chem. 2022, 18, 232–239, doi:10.3762/bjoc.18.27

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Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

Alexander Leslie,
Thomas S. Moody,
Megan Smyth,
Scott Wharry and
Marcus Baumann

Full Research Paper
Published 04 Feb 2021

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1. Graphical Abstract
2. Scheme 1: The continuous flow set-up used.
  
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3. Figure 1: Scope of Cbz-carbamate products obtained via flow process (*t_Res = 60 min, **T = 80 °C; isolated yi...
  
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4. Scheme 2: Side reaction during formation of product 3m.
  
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5. Scheme 3: Flow set-up for the CALB-mediated impurity tagging approach.
  
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6. Scheme 4: Strategies towards accessing β-amino acid derivatives 8.
  
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7. Scheme 5: Complementary flow approaches towards the β-amino acid derivatives 8.
  
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8. Scheme 6: Batch hydrolysis of the ester group in the presence of the carbamate.
  
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Graphical Abstract

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

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A concise flow synthesis of indole-3-carboxylic ester and its derivatisation to an auxin mimic

Marcus Baumann,
Ian R. Baxendale and
Fabien Deplante

Full Research Paper
Published 29 Nov 2017

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1. Graphical Abstract
2. Figure 1: Natural indole containing molecules 1–7 of biological importance and synthetic auxin analogue 8 req...
  
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3. Scheme 1: Synthetic strategy towards desired indole product 8.
  
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4. Scheme 2: Initial flow reactor setup for the synthesis of intermediate 11.
  
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5. Scheme 3: Coflore ACR setup for the synthesis of intermediate 11.
  
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6. Scheme 4: Quenching and work-up of the reaction stream from the Coflore ACR for the synthesis intermediate 11....
  
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7. Figure 2: X-ray structure of intermediate 11, and reductive cyclisation products 12 and 14, assigned structur...
  
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8. Scheme 5: Stepwise reduction of intermediate 11 under hydrogenation conditions. * Indicates potential tautome...
  
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9. Scheme 6: Flow sequence for the construction of product 8.
  
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10. Scheme 7: Assembled process for flow synthesis of product 8 with yields and throughputs.
  
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Graphical Abstract

Beilstein J. Org. Chem. 2017, 13, 2549–2560, doi:10.3762/bjoc.13.251

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The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

Marcus Baumann and
Ian R. Baxendale

Review
Published 17 Jul 2015

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1. Graphical Abstract
2. Figure 1: Pharmaceutical structures targeted in early flow syntheses.
  
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3. Scheme 1: Flow synthesis of 6-hydroxybuspirone (9). Inserted photograph reprinted with permission from [45]. Copy...
  
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4. Figure 2: Configuration of a baffled reactor tube (left) and its schematic working principle (right).
  
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5. Scheme 2: McQuade’s flow synthesis of ibuprofen (16).
  
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6. Scheme 3: Jamison’s flow synthesis of ibuprofen sodium salt (17).
  
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7. Scheme 4: Flow synthesis of imatinib (23).
  
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8. Scheme 5: Flow synthesis of the potent 5HT1B antagonist 28.
  
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9. Scheme 6: Flow synthesis of a selective δ-opioid receptor agonist 33.
  
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10. Scheme 7: Flow synthesis of a casein kinase I inhibitor library (38).
  
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11. Scheme 8: Flow synthesis of fluoxetine (46).
  
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12. Scheme 9: Flow synthesis of artemisinin (55).
  
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13. Scheme 10: Telescoped flow synthesis of artemisinin (55) and derivatives (62–64).
  
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14. Scheme 11: Flow approach towards AZD6906 (65).
  
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15. Scheme 12: Pilot scale flow synthesis of key intermediate 73.
  
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16. Scheme 13: Semi-flow synthesis of vildagliptine (77).
  
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17. Scheme 14: Pilot scale asymmetric flow hydrogenation towards 83. Inserted photograph reprinted with permission...
  
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18. Figure 3: Schematic representation of the ‘tube-in-tube’ reactor.
  
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19. Scheme 15: Flow synthesis of fanetizole (87) via tube-in-tube system.
  
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20. Scheme 16: Flow synthesis of diphenhydramine^.HCl (92).
  
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21. Scheme 17: Flow synthesis of rufinamide (95).
  
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22. Scheme 18: Large scale flow synthesis of rufinamide precursor 102.
  
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23. Scheme 19: First stage in the flow synthesis of meclinertant (103).
  
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24. Scheme 20: Completion of the flow synthesis of meclinertant (103).
  
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25. Scheme 21: Flow synthesis of olanzapine (121) utilising inductive heating techniques.
  
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26. Scheme 22: Flow synthesis of amitriptyline·HCl (127).
  
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27. Scheme 23: Flow synthesis of E/Z-tamoxifen (132) using peristaltic pumping modules.
  
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28. Figure 4: Container sized portable mini factory (photograph credit: INVITE GmbH, Leverkusen Germany).
  
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29. Scheme 24: Flow synthesis of imidazo[1,2-a]pyridines 136 linked to frontal affinity chromatography (FAC).
  
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30. Figure 5: Structures of zolpidem (142) and alpidem (143).
  
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31. Scheme 25: Synthesis and screening loops in the discovery of new Abl kinase inhibitors.
  
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32. Figure 6: Schotten–Baumann approach towards LY573636^.Na (147).
  
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33. Scheme 26: Pilot scale flow synthesis of LY2886721 (146).
  
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34. Scheme 27: Continuous flow manufacture of alikiren hemifumarate 152.
  
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Graphical Abstract

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

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An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

Marcus Baumann and
Ian R. Baxendale

Review
Published 30 Oct 2013

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1. Graphical Abstract
2. Scheme 1: Scaled industrial processes for the synthesis of simple pyridines.
  
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3. Scheme 2: Synthesis of nicotinic acid from 2-methyl-5-ethylpyridine (1.11).
  
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4. Scheme 3: Synthesis of 3-picoline and nicotinic acid.
  
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5. Scheme 4: Synthesis of 3-picoline from 2-methylglutarodinitrile 1.19.
  
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6. Scheme 5: Picoline-based synthesis of clarinex (no yields reported).
  
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7. Scheme 6: Mode of action of proton-pump inhibitors and structures of the API’s.
  
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8. Scheme 7: Hantzsch-like route towards the pyridine rings in common proton pump inhibitors.
  
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9. Figure 1: Structures of rosiglitazone (1.40) and pioglitazone (1.41).
  
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10. Scheme 8: Synthesis of rosiglitazone.
  
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11. Scheme 9: Syntheses of 2-pyridones.
  
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12. Scheme 10: Synthesis and mechanism of 2-pyrone from malic acid.
  
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13. Scheme 11: Polymer-assisted synthesis of rosiglitazone.
  
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14. Scheme 12: Synthesis of pioglitazone.
  
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15. Scheme 13: Meerwein arylation reaction towards pioglitazone.
  
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16. Scheme 14: Route towards pioglitazone utilising tyrosine.
  
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17. Scheme 15: Route towards pioglitazone via Darzens ester formation.
  
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18. Scheme 16: Syntheses of the thiazolidinedione moiety.
  
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19. Scheme 17: Synthesis of etoricoxib utilising Negishi and Stille cross-coupling reactions.
  
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20. Scheme 18: Synthesis of etoricoxib via vinamidinium condensation.
  
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21. Figure 2: Structures of nalidixic acid, levofloxacin and moxifloxacin.
  
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22. Scheme 19: Synthesis of moxifloxacin.
  
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23. Scheme 20: Synthesis of (S,S)-2,8-diazabicyclo[4.3.0]nonane 1.105.
  
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24. Scheme 21: Synthesis of levofloxacin.
  
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25. Scheme 22: Alternative approach to the levofloxacin core 1.125.
  
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26. Figure 3: Structures of nifedipine, amlodipine and clevidipine.
  
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27. Scheme 23: Mg₃N₂-mediated synthesis of nifedipine.
  
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28. Scheme 24: Synthesis of rac-amlodipine as besylate salt.
  
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29. Scheme 25: Aza Diels–Alder approach towards amlodipine.
  
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30. Scheme 26: Routes towards clevidipine.
  
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31. Figure 4: Examples of piperidine containing drugs.
  
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32. Figure 5: Discovery of tiagabine based on early leads.
  
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33. Scheme 27: Synthetic sequences to tiagabine.
  
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34. Figure 6: Structures of solifenacin (2.57) and muscarine (2.58).
  
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35. Scheme 28: Enantioselective synthesis of solifenacin.
  
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36. Figure 7: Structures of DPP-4 inhibitors of the gliptin-type.
  
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37. Scheme 29: Formation of inactive diketopiperazines from cis-rotameric precursors.
  
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38. Figure 8: Co-crystal structure of carmegliptin bound in the human DPP-4 active site (PDB 3kwf).
  
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39. Scheme 30: Improved route to carmegliptin.
  
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40. Figure 9: Structures of lamivudine and zidovudine.
  
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41. Scheme 31: Typical routes accessing uracil, thymine and cytosine.
  
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42. Scheme 32: Coupling between pyrimidones and riboses via the Vorbrüggen nucleosidation.
  
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43. Scheme 33: Synthesis of lamivudine.
  
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44. Scheme 34: Synthesis of raltegravir.
  
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45. Scheme 35: Mechanistic studies on the formation of 3.22.
  
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46. Figure 10: Structures of selected pyrimidine containing drugs.
  
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47. Scheme 36: General preparation of pyrimidines and dihydropyrimidones.
  
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48. Scheme 37: Synthesis of imatinib.
  
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49. Scheme 38: Flow synthesis of imatinib.
  
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50. Scheme 39: Syntheses of erlotinib.
  
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51. Scheme 40: Synthesis of erlotinib proceeding via Dimroth rearrangement.
  
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52. Scheme 41: Synthesis of lapatinib.
  
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53. Scheme 42: Synthesis of rosuvastatin.
  
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54. Scheme 43: Alternative preparation of the key aldehyde towards rosuvastatin.
  
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55. Figure 11: Structure comparison between nicotinic acetylcholine receptor agonists.
  
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56. Scheme 44: Syntheses of varenicline and its key building block 4.5.
  
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57. Scheme 45: Synthetic access to eszopiclone and brimonidine via quinoxaline intermediates.
  
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58. Figure 12: Bortezomib bound in an active site of the yeast 20S proteasome ([114], pdb 2F16).
  
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59. Scheme 46: Asymmetric synthesis of bortezomib.
  
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60. Figure 13: Structures of some prominent piperazine containing drugs.
  
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61. Figure 14: Structural comparison between the core of aplaviroc (4.35) and a type-1 β-turn (4.36).
  
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62. Scheme 47: Examplary synthesis of an aplaviroc analogue via the Ugi-MCR.
  
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63. Scheme 48: Syntheses of azelastine (5.1).
  
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64. Figure 15: Structures of captopril, enalapril and cilazapril.
  
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65. Scheme 49: Synthesis of cilazapril.
  
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66. Figure 16: Structures of lamotrigine, ceftriaxone and azapropazone.
  
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67. Scheme 50: Synthesis of lamotrigine.
  
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68. Scheme 51: Alternative synthesis of lamotrigine (no yields reported).
  
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69. Figure 17: Structural comparison between imiquimod and the related adenosine nucleoside.
  
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70. Scheme 52: Conventional synthesis of imiquimod (no yields reported).
  
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71. Scheme 53: Synthesis of imiquimod.
  
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72. Scheme 54: Synthesis of imiquimod via tetrazole formation (not all yields reported).
  
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73. Figure 18: Structures of various anti HIV-medications.
  
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74. Scheme 55: Synthesis of abacavir.
  
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75. Figure 19: Structures of diazepam compared to modern replacements.
  
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76. Scheme 56: Synthesis of ocinaplon.
  
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77. Scheme 57: Access to zaleplon and indiplon.
  
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78. Scheme 58: Different routes towards the required N-methylpyrazole 6.65 of sildenafil.
  
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79. Scheme 59: Polymer-supported reagents in the synthesis of key aminopyrazole 6.72.
  
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80. Scheme 60: Early synthetic route to sildenafil.
  
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81. Scheme 61: Convergent preparations of sildenafil.
  
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82. Figure 20: Comparison of the structures of sildenafil, tadalafil and vardenafil.
  
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83. Scheme 62: Short route to imidazotriazinones.
  
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84. Scheme 63: Alternative route towards vardenafils core imidazotriazinone (6.95).
  
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85. Scheme 64: Bayer’s approach to the vardenafil core.
  
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86. Scheme 65: Large scale synthesis of vardenafil.
  
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87. Scheme 66: Mode of action of temozolomide (6.105) as methylating agent.
  
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88. Scheme 67: Different routes to temozolomide.
  
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89. Scheme 68: Safer route towards temozolomide.
  
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90. Figure 21: Some unreported heterocyclic scaffolds in top market drugs.
  
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Graphical Abstract

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

Full Text

The rapid generation of isothiocyanates in flow

Marcus Baumann and
Ian R. Baxendale

Full Research Paper
Published 08 Aug 2013

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1. Graphical Abstract
2. Scheme 1: Strategies towards isothiocyanates.
  
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3. Scheme 2: Flow approach towards isothiocyanates.
  
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Graphical Abstract

Beilstein J. Org. Chem. 2013, 9, 1613–1619, doi:10.3762/bjoc.9.184

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An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

Marcus Baumann,
Ian R. Baxendale,
Steven V. Ley and
Nikzad Nikbin

Review
Published 18 Apr 2011

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1. Graphical Abstract
2. Figure 1: Structures of atorvastatin and other commercial statins.
  
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3. Figure 2: Structure of compactin.
  
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4. Scheme 1: Synthesis of pentasubstituted pyrroles.
  
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5. Scheme 2: [3 + 2] Cycloaddition to prepare 5-isopropylpyrroles.
  
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6. Scheme 3: Regiospecific [3 + 2] cycloaddition to prepare the pyrrole scaffold.
  
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7. Scheme 4: Formation of the pyrrole core of atorvastatin via [3 + 2] cycloaddition.
  
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8. Scheme 5: Formation of pyrrole 33 via the Paal–Knorr reaction.
  
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9. Scheme 6: Convergent synthesis towards atorvastatin.
  
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10. Figure 3: Binding pocket of sunitinib in the TRK KIT.
  
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11. Scheme 7: Synthesis of sunitinib.
  
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12. Scheme 8: Alternative synthesis of sunitinib.
  
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13. Scheme 9: Key steps in the syntheses of sumatriptan and zolmitriptan.
  
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14. Scheme 10: Introduction of the N,N-dimethylaminoethyl side chain.
  
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15. Scheme 11: Japp–Klingemann reaction in the synthesis of sumatriptan.
  
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16. Scheme 12: Synthesis of the intermediate sulfonyl chlorides 62 and 63.
  
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17. Scheme 13: Alternative introduction of the sulfonamide.
  
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18. Scheme 14: Negishi-type coupling to benzylic sulfonamides.
  
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19. Scheme 15: Heck reaction used to introduce the sulfonamide side chain of naratriptan.
  
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20. Scheme 16: Synthesis of the oxazolinone appendage of zolmitriptan.
  
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21. Scheme 17: Grandberg indole synthesis used in the preparation of rizatriptan.
  
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22. Scheme 18: Improved synthesis of rizatriptan.
  
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23. Scheme 19: Larock-type synthesis of rizatriptan.
  
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24. Scheme 20: Synthesis of eletriptan.
  
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25. Scheme 21: Heck coupling for the indole system in eletriptan.
  
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26. Scheme 22: Attempted Fischer indole synthesis of elatriptan.
  
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27. Scheme 23: Successful Fischer indole synthesis for eletriptan.
  
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28. Scheme 24: Mechanistic rationale for the Bischler–Möhlau reaction.
  
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29. Scheme 25: Bischler-type indole synthesis used in the fluvastatin sodium synthesis.
  
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30. Scheme 26: Palladium-mediated synthesis of ondansetron.
  
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31. Scheme 27: Fischer indole synthesis of ondansetron.
  
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32. Scheme 28: Optimised Pictet–Spengler reaction towards tadalafil.
  
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33. Figure 4: Structures of carvedilol 136 and propranolol 137.
  
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34. Scheme 29: Synthesis of the carbazole core of carvedilol.
  
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35. Scheme 30: Alternative syntheses of 4-hydroxy-9H-carbazole.
  
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36. Scheme 31: Convergent synthesis of etodolac.
  
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37. Scheme 32: Alternative synthesis of etodolac.
  
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38. Figure 5: Structures of imidazole-containing drugs.
  
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39. Scheme 33: Synthesis of functionalised imidazoles towards losartan.
  
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40. Scheme 34: Direct synthesis of the chlorinated imidazole in losartan.
  
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41. Scheme 35: Synthesis of trisubstituted imidazoles.
  
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42. Scheme 36: Preparation of the imidazole ring in olmesartan.
  
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43. Scheme 37: Synthesis of ondansetron.
  
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44. Scheme 38: Alternative route to ondansetron and its analogues.
  
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45. Scheme 39: Proton pump inhibitors and synthesis of esomeprazole.
  
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46. Scheme 40: Synthesis of benzimidazole core pantoprazole.
  
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47. Figure 6: Structure of rabeprazole 194.
  
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48. Scheme 41: Synthesis of candesartan.
  
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49. Scheme 42: Alternative access to the candesartan key intermediate 216.
  
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50. Scheme 43: .Medicinal chemistry route to telmisartan.
  
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51. Scheme 44: Improved synthesis of telmisartan.
  
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52. Scheme 45: Synthesis of zolpidem.
  
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53. Scheme 46: Copper-catalysed 3-component coupling towards zolpidem.
  
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54. Figure 7: Structure of celecoxib.
  
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55. Scheme 47: Preparation of celecoxib.
  
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56. Scheme 48: Alternative synthesis of celecoxib.
  
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57. Scheme 49: Regioselective access to celecoxib.
  
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58. Scheme 50: Synthesis of pazopanib.
  
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59. Scheme 51: Syntheses of anastrozole, rizatriptan and letrozole.
  
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60. Scheme 52: Regioselective synthesis of anastrozole.
  
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61. Scheme 53: Triazine-mediated triazole formation towards anastrozole.
  
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62. Scheme 54: Alternative routes to 1,2,4-triazoles.
  
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63. Scheme 55: Initial synthetic route to sitagliptin.
  
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64. Figure 8: Binding of sitagliptin within DPP-IV.
  
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65. Scheme 56: The process route to sitagliptin key intermediate 280.
  
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66. Scheme 57: Synthesis of maraviroc.
  
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67. Scheme 58: Synthesis of alprazolam.
  
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68. Scheme 59: The use of N-nitrosoamidine derivatives in the preparation of fused benzodiazepines.
  
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69. Figure 9: Structures of itraconazole, ravuconazole and voriconazole.
  
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70. Scheme 60: Synthesis of itraconazole.
  
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71. Scheme 61: Synthesis of rufinamide.
  
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72. Scheme 62: Representative tetrazole formation in valsartan.
  
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73. Figure 10: Structure of tetrazole containing olmesartan, candesartan and irbesartan.
  
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74. Scheme 63: Early stage introduction of the tetrazole in losartan.
  
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75. Scheme 64: Synthesis of cilostazol.
  
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76. Figure 11: Structure of cefdinir.
  
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77. Scheme 65: Semi-synthesis of cefdinir.
  
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78. Scheme 66: Thiazole syntheses towards ritonavir.
  
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79. Scheme 67: Synthesis towards pramipexole.
  
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80. Scheme 68: Alternative route to pramipexole.
  
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81. Scheme 69: Synthesis of famotidine.
  
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82. Scheme 70: Efficient synthesis of the hyperuricemic febuxostat.
  
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83. Scheme 71: Synthesis of ziprasidone.
  
  Jump to Scheme 71
84. Figure 12: Structure of mometasone.
  
  Jump to Figure 12
85. Scheme 72: Industrial access to 2-furoic acid present in mometasone.
  
  Jump to Scheme 72
86. Scheme 73: Synthesis of ranitidine from furfuryl alcohol.
  
  Jump to Scheme 73
87. Scheme 74: Synthesis of nitrofurantoin.
  
  Jump to Scheme 74
88. Scheme 75: Synthesis of benzofuran.
  
  Jump to Scheme 75
89. Scheme 76: Synthesis of amiodarone.
  
  Jump to Scheme 76
90. Scheme 77: Synthesis of raloxifene.
  
  Jump to Scheme 77
91. Scheme 78: Alternative access to the benzo[b]thiophene core of raloxifene.
  
  Jump to Scheme 78
92. Scheme 79: Gewald reaction in the synthesis of olanzapine.
  
  Jump to Scheme 79
93. Scheme 80: Alternative synthesis of olanzapine.
  
  Jump to Scheme 80
94. Figure 13: Access to simple thiophene-containing drugs.
  
  Jump to Figure 13
95. Scheme 81: Synthesis of clopidogrel.
  
  Jump to Scheme 81
96. Scheme 82: Pictet–Spengler reaction in the preparation of tetrahydrothieno[3,2-c]pyridine (422).
  
  Jump to Scheme 82
97. Scheme 83: Alternative synthesis of key intermediate 422.
  
  Jump to Scheme 83
98. Figure 14: Co-crystal structures of timolol (left) and carazolol (right) in the β-adrenergic receptor.
  
  Jump to Figure 14
99. Scheme 84: Synthesis of timolol.
  
  Jump to Scheme 84
100. Scheme 85: Synthesis of tizanidine 440.
  
  Jump to Scheme 85
101. Scheme 86: Synthesis of leflunomide.
  
  Jump to Scheme 86
102. Scheme 87: Synthesis of sulfamethoxazole.
  
  Jump to Scheme 87
103. Scheme 88: Synthesis of risperidone.
  
  Jump to Scheme 88
104. Figure 15: Relative abundance of selected transformations.
  
  Jump to Figure 15
105. Figure 16: The abundance of heterocycles within top 200 drugs (5-membered rings).
  
  Jump to Figure 16

Graphical Abstract

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

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