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

860 Accesses

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

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Comparative study of thermally activated delayed fluorescent properties of donor–acceptor and donor–acceptor–donor architectures based on phenoxazine and dibenzo[a,j]phenazine

Saika Izumi,
Prasannamani Govindharaj,
Anna Drewniak,
Paola Zimmermann Crocomo,
Satoshi Minakata,
Leonardo Evaristo de Sousa,
Piotr de Silva,
Przemyslaw Data and
Youhei Takeda

Full Research Paper
Published 25 Apr 2022

857 Accesses

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1. Graphical Abstract
2. Figure 1: Chemical structures of 1 and POZ-DBPHZ.
  
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3. Scheme 1: Synthesis of compound 1.
  
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4. Figure 2: Steady-state UV–vis absorption (Abs) and photoluminescence (PL) spectra of dilute solutions (c ≈ 10...
  
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5. Figure 3: Time-resolved PL decay profiles (intensity vs delay time) and spectra of 1 in a), b) Zeonex^® and c,...
  
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6. Figure 4: The characteristics of the OLED devices: a) electroluminescence spectra; b) current density-bias ch...
  
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7. Figure 5: Schematics of the TADF mechanisms along with NTOs for the relevant electronic states for a) D–A com...
  
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Beilstein J. Org. Chem. 2022, 18, 459–468, doi:10.3762/bjoc.18.48

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Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides

Md Imran Hossain,
Md Imdadul H. Khan,
Seong Jong Kim and
Hoang V. Le

Full Research Paper
Published 22 Apr 2022

488 Accesses

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1. Graphical Abstract
2. Figure 1: Routes to isoxazoles.
  
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3. Figure 2: Possible products of the reaction between nitrile oxides and 1,3-diketones. Path D (C-trapping) pro...
  
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4. Figure 3: Reactions between various arylhydroximoyl chlorides and 1,3-diketones. The reactions were performed...
  
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5. Figure 4: Reactions between various phenyl hydroximoyl chlorides and β-ketoesters or β-ketoamides. The reacti...
  
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6. Figure 5: Reactions between 4-fluorophenyl hydroximoyl chloride (1a) and diethyl malonate (2j) or dibenzyl ma...
  
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7. Figure 6: Reactions between phenyl hydroximoyl chlorides 1a,c and 4,4,4-trifluoro-1-phenyl- (2l) and 4,4,4-tr...
  
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8. Figure 7: ¹H NMR spectra of 1-phenyl-1,3-butanedione (2a) in methanol-d₄ (top) and in CDCl₃ (bottom).
  
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9. Figure 8: A plausible mechanism for the formation of the 3,4,5-trisubstituted isoxazoles 3 in the presence of...
  
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10. Figure 9: Structures of β-lactamase-resistant antibiotics oxacillin, cloxacillin, dicloxacillin, and flucloxa...
  
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Beilstein J. Org. Chem. 2022, 18, 446–458, doi:10.3762/bjoc.18.47

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Synthesis of spiro[dihydropyridine-oxindoles] via three-component reaction of arylamine, isatin and cyclopentane-1,3-dione

Yan Sun,
Jing Sun and
Chao-Guo Yan

Full Research Paper
Published 03 Jan 2013

455 Accesses

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1. Graphical Abstract
2. Scheme 1: The four-component reactions containing dimedone (a) and cyclopentane-1,3-dione (b).
  
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3. Figure 1: Molecular structure of spiro[dihydropyridine-oxindole] 1b.
  
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4. Figure 2: The two kinds of spiro compounds from reactions of isatins with arylamines and cyclic 1,3-diketones....
  
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5. Figure 3: Molecular structure of spiro[dihydropyridine-oxindole] 2f.
  
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6. Scheme 2: Condensation reactions of isatins with cyclopentane-1,3-dione.
  
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7. Figure 4: Molecular structure of compound 3d.
  
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8. Scheme 3: Proposed reaction mechanism for the three-component reaction.
  
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Beilstein J. Org. Chem. 2013, 9, 8–14, doi:10.3762/bjoc.9.2

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Tosylhydrazine-promoted self-conjugate reduction–Michael/aldol reaction of 3-phenacylideneoxindoles towards dispirocyclopentanebisoxindole derivatives

Sayan Pramanik and
Chhanda Mukhopadhyay

Full Research Paper
Published 27 Apr 2022

411 Accesses

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1. Graphical Abstract
2. Figure 1: Representative bioactive dispirooxindoles.
  
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3. Scheme 1: Reductive cyclization for the synthesis of dispirocyclopentanebisoxindole derivatives.
  
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4. Scheme 2: Substrate scope of product 3 (part 1). Reaction conditions: substrates: 1 (1 mmol) and 2 (0.5 mmol)...
  
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5. Scheme 3: Substrate scope of product 3 (part 2). Reaction conditions: substrates: 1 (1 mmol) and 2 (0.5 mmol)...
  
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6. Figure 2: ORTEP diagram of product 3g (CCDC NO. 2072521).
  
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7. Figure 3: NOESY Spectra of compound 3e.
  
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8. Scheme 4: Plausible mechanism of the reaction.
  
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9. Figure 4: HRMS spectrum of the crude reaction mixture after 1 hour of the reaction.
  
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10. Scheme 5: Control experiment.
  
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Beilstein J. Org. Chem. 2022, 18, 469–478, doi:10.3762/bjoc.18.49

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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

393 Accesses

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

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Expedient syntheses of the N-heterocyclic carbene precursor imidazolium salts IPr·HCl, IMes·HCl and IXy·HCl

Lukas Hintermann

Full Research Paper
Published 28 Aug 2007

376 Accesses

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1. Graphical Abstract
2. Figure 1: The carbenes IPr, IMes, IXy and their imidazolium salt precursors
  
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3. Scheme 1: Synthetic routes to and diazadiene precursors for imidazolium salts.
  
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4. Scheme 2: The imidazolium salt synthesis as a 1, 5-dipolar electrocyclization.
  
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5. Scheme 3: Potential side-reactions in the imidazolium salt synthesis.
  
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Beilstein J. Org. Chem. 2007, 3, No. 22, doi:10.1186/1860-5397-3-22

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Substituent effect on TADF properties of 2-modified 4,6-bis(3,6-di-tert-butyl-9-carbazolyl)-5-methylpyrimidines

Irina Fiodorova,
Tomas Serevičius,
Rokas Skaisgiris,
Saulius Juršėnas and
Sigitas Tumkevicius

Full Research Paper
Published 05 May 2022

370 Accesses

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1. Graphical Abstract
2. Figure 1: 2-Modified 4,6-bis(3,6-di-tert-butyl-9H-carbazol-9-yl)-5-methylpyrimidines.
  
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3. Scheme 1: Synthesis of 4,6-bis(3,6-di-tert-butyl-9H-carbazol-9-yl)-5-methyl-2-substituted pyrimidines 1–6. Re...
  
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4. Figure 2: HOMO and LUMO spatial distributions of carbazole–pyrimidine TADF compounds.
  
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5. Figure 3: Absorption (grey lines), fluorescence (black lines) and 10K phosphorescence (red lines) spectra of ...
  
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6. Figure 4: Fluorescence decay transients of 1 wt % PMMA films of carbazole–pyrimidine TADF compounds in oxygen...
  
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Beilstein J. Org. Chem. 2022, 18, 497–507, doi:10.3762/bjoc.18.52

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Computational methods in drug discovery

Sumudu P. Leelananda and
Steffen Lindert

Review
Published 12 Dec 2016

366 Accesses

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1. Graphical Abstract
2. Figure 1: Schematic representation of a computer-aided drug discovery (CADD) pipeline. CADD methods are broad...
  
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3. Figure 2: FDA approved drugs Saquinavir and Amprenavir for the treatment of HIV infections. (a) The structure...
  
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4. Figure 3: (a) The crystal structure showing the binding of Dorzolamide (orange) to carbonic anhydrase II (pur...
  
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5. Figure 4: The best ligand binding site identified by SiteHound in HIV-1 protease. The ligand binding pocket i...
  
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6. Figure 5: Binding mode prediction. The known inhibitor Dorzolamide is docked into Carbonic anhydrase II cryst...
  
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7. Figure 6: The molecular structure of Raltegravir. Raltegravir is an FDA approved drug used in the treatment o...
  
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8. Figure 7: An example alchemical thermodynamic cycle for a protein–ligand binding free energy calculation. The...
  
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9. Figure 8: Schematic diagram showing the steps involved in QSAR. Known drug molecule activity and descriptor d...
  
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10. Figure 9: A few drugs discovered with the help of ligand-based drug discovery tools. (a) Zolmitriptan: used a...
  
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Beilstein J. Org. Chem. 2016, 12, 2694–2718, doi:10.3762/bjoc.12.267

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Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities

Viktor A. Zapol’skii,
Isabell Berneburg,
Ursula Bilitewski,
Melissa Dillenberger,
Katja Becker,
Stefan Jungwirth,
Aditya Shekhar,
Bastian Krueger and
Dieter E. Kaufmann

Full Research Paper
Published 09 May 2022

335 Accesses

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1. Graphical Abstract
2. Figure 1: The structures of chloroquine, hydroxychloroquine, and amodiaquine.
  
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3. Scheme 1: Synthesis of 3-azolylpyrazoles 3a–c.
  
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4. Scheme 2: Assumed mechanism for the formation of 1H-pyrazoles 3a–c.
  
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5. Scheme 3: Synthesis of 3-aminopyrazoles 5b–k and 5-aminopyrazoles 5a and 5l–o.
  
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6. Scheme 4: Orientation of nucleophilic attack of 7-chloro-4-hydrazinylquinoline on nitrobutadienes 4.
  
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7. Scheme 5: Synthesis of oxazolidine 6 and pyrazole 7.
  
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8. Scheme 6: A plausible mechanism for the formation of pyrazole 7.
  
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9. Scheme 7: Synthesis of pyrazoles 9 and sulfoxide 10d.
  
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10. Scheme 8: Synthesis of pyrazole 11.
  
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Beilstein J. Org. Chem. 2022, 18, 524–532, doi:10.3762/bjoc.18.54

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

Comparative study of thermally activated delayed fluorescent properties of donor–acceptor and donor–acceptor–donor architectures based on phenoxazine and dibenzo[a,j]phenazine

Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides

Synthesis of spiro[dihydropyridine-oxindoles] via three-component reaction of arylamine, isatin and cyclopentane-1,3-dione

Tosylhydrazine-promoted self-conjugate reduction–Michael/aldol reaction of 3-phenacylideneoxindoles towards dispirocyclopentanebisoxindole derivatives

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

Expedient syntheses of the N-heterocyclic carbene precursor imidazolium salts IPr·HCl, IMes·HCl and IXy·HCl

Substituent effect on TADF properties of 2-modified 4,6-bis(3,6-di-tert-butyl-9-carbazolyl)-5-methylpyrimidines

Computational methods in drug discovery

Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities

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