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Multistep Continuous-Flow Processes for the Preparation of Heterocyclic Active Pharmaceutical Ingredients

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Flow Chemistry for the Synthesis of Heterocycles

Part of the book series: Topics in Heterocyclic Chemistry ((TOPICS,volume 56))

Abstract

Flow chemistry has many fascinating facets, among which the most challenging is arguably the implementation of complex multistep processes within one uninterrupted fluidic network. This document provides a thorough overview of some of the most representative examples of multistep continuous-flow strategies in the specific context of preparing heterocyclic active pharmaceuticals. Selected examples emphasizing the implementation of multistep sequences, including various combinations of chemical transformations, purifications, or in-line analysis, are discussed.

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References

  1. Gutmann B, Elsner P, O’Kearney-McMullan A, Goundry W, Roberge DM, Kappe CO (2015) Org Process Res Dev 19:1062

    Article  CAS  Google Scholar 

  2. Shen B, Jamison TF (2012) Org Lett 14:3348

    Article  CAS  PubMed  Google Scholar 

  3. Zhu C, Tang C, Cao Z, He W, Chen Y, Chen X, Guo K, Ying H (2014) Org Process Res Dev 18:1575

    Article  CAS  Google Scholar 

  4. Lee DS, Amara Z, Poliakoff M, Harman T, Reid G, Rhodes B, Brough S, McInally T, Woodward S (2015) Org Process Res Dev 19:831

    Article  CAS  Google Scholar 

  5. Hopkin MD, Baxendale IR, Ley SV (2010) Chem Commun 46:2450

    Article  CAS  Google Scholar 

  6. Hopkin MD, Baxendale IR, Ley SV (2013) Org Biomol Chem 11:1822

    Article  CAS  PubMed  Google Scholar 

  7. Yang JC, Niu D, Karsten BP, Lima F, Buchwald SL (2016) Angew Chem Int Ed 55:2531

    Article  CAS  Google Scholar 

  8. Holmes N, Akien GR, Blacker AJ, Woodward RL, Meadows RE, Bourne RA (2016) React Chem Eng 1:366

    Article  CAS  Google Scholar 

  9. Baxendale IR, Deeley J, Griffiths-Jones CM, Ley SV, Saaby S, Tranmer GK (2006) Chem Commun 24:2566

    Article  CAS  Google Scholar 

  10. Pellegatti L, Hafner A, Sedelmeier J (2016) J Flow Chem 6:198

    Article  CAS  Google Scholar 

  11. Correia CA, Gilmore K, McQuade DT, Seeberger PH (2015) Angew Chem Int Ed 54:4945

    Article  CAS  Google Scholar 

  12. Correia CA, McQuade DT, Seeberger PH (2013) Adv Synth Catal 355:3517

    Article  CAS  Google Scholar 

  13. Britton J, Jamison TF (2017) Angew Chem Int Ed 56:8823

    Article  CAS  Google Scholar 

  14. Shen B, Bedore MW, Sniady A, Jamison TF (2012) Chem Commun 48:7444

    Article  CAS  Google Scholar 

  15. Shen B, Jamison TF (2013) Aust J Chem 66:157

    Article  CAS  Google Scholar 

  16. Fan X, Sans V, Yaseneva P, Plaza DD, Williams J, Lapkin A (2012) Org Process Res Dev 16:1039

    Article  CAS  Google Scholar 

  17. Yaseneva P, Plaza D, Fan X, Loponov K, Lapkin A (2015) Catal Today 239:90

    Article  CAS  Google Scholar 

  18. Lévesque F, Seeberger PH (2012) Angew Chem Int Ed 51:1706

    Article  CAS  Google Scholar 

  19. Kopetzki D, Lévesque F, Seeberger PH (2013) Chem Eur J 19:5450

    Article  CAS  PubMed  Google Scholar 

  20. Gilmore K, Kopetzki D, Lee JW, Horváth Z, McQuade DT, Seidel-Morgenstern A, Seeberger PH (2014) Chem Commun 50:12652

    Article  CAS  Google Scholar 

  21. Pieber B, Glasnov T, Kappe CO (2015) Chem Eur J 21:4368

    Article  CAS  PubMed  Google Scholar 

  22. Kamptmann SB, Ley SV (2015) Aust J Chem 68:693

    Article  CAS  Google Scholar 

  23. Lücke D, Dalton T, Ley SV, Wilson ZE (2016) Chem Eur J 22:4206

    Article  CAS  PubMed  Google Scholar 

  24. Lin H, Dai C, Jamison TF, Jensen KF (2017) Angew Chem Int Ed 56:8870

    Article  CAS  Google Scholar 

  25. Herath A, Dahl R, Cosford NDP (2010) Org Lett 12:412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ingham RJ, Battilocchio C, Hawkins JM, Ley SV (2014) Beilstein J Org Chem 10:641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bana P, Lakó Á, Kiss NZ, Béni Z, Szigetvári Á, Kóti J, Túrós GI, Éles J, Greiner I (2017) Org Process Res Dev 21:611

    Article  CAS  Google Scholar 

  28. Hartwig J, Kirschning A (2016) Chem Eur J 22:3044

    Article  CAS  PubMed  Google Scholar 

  29. Hartwig J, Ceylan S, Kupracz L, Coutable L, Kirschning A (2013) Angew Chem Int Ed 52:9813

    Article  CAS  Google Scholar 

  30. Guetzoyan L, Nikbin N, Baxendale IR, Ley SV (2013) Chem Sci 4:764

    Article  CAS  Google Scholar 

  31. Adamo A, Beingessner RL, Behnam M, Chen J, Jamison TF, Jensen KF, Monbaliu J-CM, Myerson AS, Revalor EM, Snead DR, Stelzer T, Weeranoppanant N, Wong SY, Zhang P (2016) Science 352:61

    Article  CAS  PubMed  Google Scholar 

  32. Bédard AC, Longstreet AR, Britton J, Wang Y, Moriguchi H, Hicklin RW, Green WH, Jamison TF (2017) Bioorg Med Chem 25:6233

    Article  CAS  PubMed  Google Scholar 

  33. Ewan HS, Iyer K, Hyun S-H, Wleklinski M, Cooks RG, Thompson DH (2017) Org Process Res Dev 21:1566

    Article  CAS  Google Scholar 

  34. Qian Z, Baxendale IR, Ley SV (2010) Synlett 505

    Google Scholar 

  35. Qian Z, Baxendale IR, Ley SV (2010) Chem Eur J 16:12342

    Article  CAS  PubMed  Google Scholar 

  36. Zhang P, Russell MG, Jamison TF (2014) Org Process Res Dev 18:1567

    Article  CAS  Google Scholar 

  37. Polster CS, Cole KP, Burcham CL, Campbell BM, Frederick AL, Hansen MM, Harding M, Heller MR, Miller MT, Phillips JL, Pollock PM, Zaborenko N (2014) Org Process Res Dev 18:1295

    Article  CAS  Google Scholar 

  38. Gérardy R, Winter M, Vizza A, Monbaliu J-CM (2017) React Chem Eng 2:149

    Article  Google Scholar 

  39. Martin AD, Siamaki AR, Belecki K, Gupton F (2015) J Flow Chem 5:145

    Article  CAS  Google Scholar 

  40. Suveges NS, de Souza ROMA, Gutmann B, Kappe CO (2017) Eur J Org Chem 24:6511

    Article  CAS  Google Scholar 

  41. Gutmann B, Cantillo D, Weigl U, Cox DP, Kappe CO (2017) Eur J Org Chem 914

    Google Scholar 

  42. Gutmann B, Weigl U, Cox DP, Kappe CO (2016) Chem Eur J 22:10393

    Article  CAS  PubMed  Google Scholar 

  43. Borukhova S, Noël T, Hessel V (2016) ChemSusChem 9:67

    Article  CAS  PubMed  Google Scholar 

  44. Pastre JC, Browne DL, O’Brien M, Ley SV (2013) Org Process Res Dev 17:1183

    Article  CAS  Google Scholar 

  45. Baxendale IR, Griffiths-Jones CM, Ley SV, Tranmer GK (2006) Synlett 3:427

    Google Scholar 

  46. Tsubogo T, Oyamada H, Kobayashi S (2015) Nature 520:329

    Article  CAS  PubMed  Google Scholar 

  47. Ghislieri D, Gilmore K, Seeberger PH (2015) Angew Chem Int Ed 54:678

    CAS  Google Scholar 

  48. Dai C, Snead DR, Zhang P, Jamison TF (2015) J Flow Chem 5:133

    Article  CAS  Google Scholar 

  49. Grongsaard P, Bulger PG, Wallace DJ, Tan L, Chen Q, Dolman SJ, Nyrop J, Hoerrner RS, Weisel M, Arredondo J, Itoh T, Xie C, Wen X, Zhao D, Muzzio DJ, Bassan EM, Shultz CS (2012) Org Process Res Dev 16:1069

    Article  CAS  Google Scholar 

  50. Chen J, Przyuski K, Roemmele R, Bakale RP (2014) Org Process Res Dev 18:1427

    Article  CAS  Google Scholar 

  51. LaPorte TL, Spangler L, Hamedi M, Lobben P, Chan SH, Muslehiddinoglu J, Wang SSY (2014) Org Process Res Dev 18:1492

    Article  CAS  Google Scholar 

  52. Fukuyama T, Chiba H, Kuroda H, Takigawa T, Kayano A, Tagami K (2016) Org Process Res Dev 20:503

    Article  CAS  Google Scholar 

  53. Amara Z, Poliakoff M, Duque R, Geier D, Franciò G, Gordon CM, Meadows RE, Woodward R, Leitner W (2016) Org Process Res Dev 20:1321

    Article  CAS  Google Scholar 

  54. Filipponi P, Ostacolo C, Novellino E, Pellicciari R, Gioiello A (2014) Org Process Res Dev 18:1345

    Article  CAS  Google Scholar 

  55. Cole KP, McClary Groh J, Johnson MD, Burcham CL, Campbell BM, Diseroad WD, Heller MR, Howell JR, Kallman NJ, Koenig TM, May SA, Miller RD, Mitchell D, Myers DP, Myers SS, Phillips JL, Polster CS, White TD, Cashman J, Hurley D, Moylan R, Sheehan P, Spencer RD, Desmond K, Desmond P, Gowran O (2017) Science 356:1144

    Article  CAS  PubMed  Google Scholar 

  56. Dalla-Vechia L, Reichart B, Glasnov T, Miranda LSM, Kappe CO, de Souza ROMA (2013) Org Biomol Chem 11:6806

    Article  CAS  PubMed  Google Scholar 

  57. Pinho VD, Gutmann B, Miranda LSM, de Souza ROMA, Kappe CO (2014) J Org Chem 79:1555

    Article  CAS  PubMed  Google Scholar 

  58. Leão RAC, de Lopes RO, de Bezerra MAM, Muniz MN, Casanova BB, Gnoatto SCB, Gosmann G, Kocsis L, de Souza ROMA, de Miranda LSM (2015) J Flow Chem 5:216

    Article  CAS  Google Scholar 

  59. Gauthier DR, Sherry BD, Cao Y, Journet M, Humphrey G, Itoh T, Mangion I, Tschaen DM (2015) Org Lett 17:1353

    Article  CAS  PubMed  Google Scholar 

  60. Chada S, Mandala D, Watts P (2017) J Flow Chem 7:37

    Article  Google Scholar 

  61. Mandala D, Chada S, Watts P (2017) Org Biomol Chem 15:3444

    Article  CAS  PubMed  Google Scholar 

  62. Longstreet AR, Opalka SM, Campbell BS, Gupton BF, McQuade DT (2013) Beilstein J Org Chem 9:2570

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Carneiro PF, Gutmann B, de Souza ROMA, Kappe CO (2015) ACS Sustain Chem Eng 3:3445

    Article  CAS  Google Scholar 

  64. Lau S-H, Galván A, Merchant RR, Battilocchio C, Souto JA, Berry MB, Ley SV (2015) Org Lett 17:3218

    Article  CAS  PubMed  Google Scholar 

  65. Glasnov TN, Kappe CO (2010) Adv Synth Catal 352:3089

    Article  CAS  Google Scholar 

  66. Cantillo D, Moghaddam MM, Kappe CO (2013) J Org Chem 78:4530

    Article  CAS  PubMed  Google Scholar 

  67. Moghaddam MM, Pieber B, Glasnov T, Kappe CO (2014) ChemSusChem 7:3122

    Article  CAS  PubMed  Google Scholar 

  68. Cantillo D, Baghbanzadeh M, Kappe CO (2012) Angew Chem Int Ed 51:10190

    Article  CAS  Google Scholar 

  69. O’Brien AG, Lévesque F, Seeberger PH (2011) Chem Commun 47:2688

    Article  Google Scholar 

  70. Müller STR, Murat A, Hellier P, Wirth T (2016) Org Process Res Dev 20:495

    Article  CAS  Google Scholar 

  71. Battilocchio C, Deadman BJ, Nikbin N, Kitching MO, Baxendale IR, Ley SV (2013) Chem Eur J 19:7917

    Article  CAS  PubMed  Google Scholar 

  72. Gross TD, Chou S, Bonneville D, Gross RS, Wang P, Campopiano O, Ouellette MA, Zook SE, Reddy JP, Moree WJ, Jovic F, Chopade S (2008) Org Process Res Dev 12:929

    Article  CAS  Google Scholar 

  73. Borukhova S, Noël T, Metten B, de Vos E, Hessel V (2013) ChemSusChem 6:2220

    Article  CAS  PubMed  Google Scholar 

  74. Borukhova S, Noël T, Metten B, de Vos E, Hessel V (2016) Green Chem 18:4947

    Article  CAS  Google Scholar 

  75. Chartoire A, Claver C, Corpet M, Krinsky J, Mayen J, Nelson D, Nolan SP, Peñafiel I, Woodward R, Meadows RE (2016) Org Process Res Dev 20:551

    Article  CAS  Google Scholar 

  76. Falß S, Tomaiuolo G, Perazzo A, Hodgson P, Yaseneva P, Zakrzewski J, Guido S, Lapkin A, Woodward R, Meadows RE (2016) Org Process Res Dev 20:558

    Article  CAS  Google Scholar 

  77. Šterk D, Jukič M, Časar Z (2013) Org Process Res Dev 17:145

    Article  CAS  Google Scholar 

  78. Pieber B, Cox DP, Kappe CO (2016) Org Process Res Dev 20:376

    Article  CAS  Google Scholar 

  79. Gutmann B, Elsner P, Cox DP, Weigl U, Roberge DM, Kappe CO (2016) ACS Sustain Chem Eng 4:6048

    Article  CAS  Google Scholar 

  80. Marsini MA, Buono FG, Lorenz JC, Yang B-S, Reeves JT, Sidhu K, Sarvestani M, Tan Z, Zhang Y, Li N, Lee H, Brazzillo J, Nummy LJ, Chung JC, Luvaga IK, Narayanan BA, Wei X, Song JJ, Roschangar F, Yee NK, Senanayake CH (2017) Green Chem 19:1454

    Article  CAS  Google Scholar 

  81. Lv Y, Yu Z, Su W (2011) Org Process Res Dev 15:471

    Article  CAS  Google Scholar 

  82. Gutmann B, Gottsponer M, Elsner P, Cantillo D, Roberge DM, Kappe CO (2013) Org Process Res Dev 17:294

    Article  CAS  Google Scholar 

  83. Cantillo D, Mateos C, Rincon JA, De Frutos O, Kappe CO (2015) Chem Eur J 21:12894

    Article  CAS  PubMed  Google Scholar 

  84. Pellegatti L, Sedelmeier J (2015) Org Process Res Dev 19:551

    Article  CAS  Google Scholar 

  85. Brasholz M, Johnson BA, Macdonald JM, Polyzos A, Tsanaktsidis J, Saubern S, Holmes AB, Ryan JH (2010) Tetrahedron 66:6445

    Article  CAS  Google Scholar 

  86. Brasholz M, MacDonald JM, Saubern S, Ryan JH, Holmes AB (2010) Chem Eur J 16:11471

    Article  CAS  PubMed  Google Scholar 

  87. Baumann M, Baxendale IR, Brasholz M, Hayward JJ, Ley SV, Nikbin N (2011) Synlett 10:1375

    Google Scholar 

  88. Riva E, Rencurosi A, Gagliardi S, Passarella D, Martinelli M (2011) Chem Eur J 17:6221

    Article  CAS  PubMed  Google Scholar 

  89. Roesner S, Buchwald SL (2016) Angew Chem Int Ed 55:10463

    Article  CAS  Google Scholar 

  90. Sniady A, Bedore MW, Jamison TF (2011) Angew Chem Int Ed 50:2155

    Article  CAS  Google Scholar 

  91. Venturoni F, Nikbin N, Ley SV, Baxendale IR (2010) Org Biomol Chem 8:1798

    Article  CAS  PubMed  Google Scholar 

  92. Filipponi P, Baxendale IR (2016) Eur J Org Chem 2000

    Google Scholar 

  93. Petersen TP, Mirsharghi S, Rummel PC, Thiele S, Rosenkilde MM, Ritzén A, Ulven T (2013) Chem Eur J 19:9343

    Article  CAS  PubMed  Google Scholar 

  94. Petersen TP, Ritzén A, Ulven T (2009) Org Lett 11:5134

    Article  CAS  PubMed  Google Scholar 

  95. Glotz G, Lebl R, Dallinger D, Kappe CO (2017) Angew Chem Int Ed. https://doi.org/10.1002/anie.201708533

  96. Pagano N, Teriete P, Mattmann ME, Yang L, Snyder BA, Cai Z, Heil ML, Cosford NDP (2017) Bioorg Med Chem. https://doi.org/10.1016/j.bmc.2017.03.061

  97. Pagano N, Herath A, Cosford NDP (2011) J Flow Chem 1:28

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Lövei K, Greiner I, Éles J, Szigetvári Á, Dékány M, Lévai S, Novák Z, Túrós GI (2015) J Flow Chem 5:74

    Article  CAS  Google Scholar 

  99. Li B, Widlicka D, Boucher S, Hayward C, Lucas J, Murray JC, O’Neil BT, Pfisterer D, Samp L, Van Alsten J, Xiang Y, Young J (2012) Org Process Res Dev 16:2031

    Article  CAS  Google Scholar 

  100. May SA, Johnson MD, Braden TM, Calvin JR, Haeberle BD, Jines AR, Miller RD, Plocharczyk EF, Rener GA, Richey RN, Schmid CR, Vaid RK, Yu H (2012) Org Process Res Dev 16:982

    Article  CAS  Google Scholar 

  101. Baumann M, Baxendale IR, Kuratli C, Ley SV, Martin RE, Schneider J (2011) ACS Comb Sci 13:405

    Article  CAS  PubMed  Google Scholar 

  102. Li X, Chen A, Zhou Y, Huang L, Fang Z, Gan H, Guo K (2015) J Flow Chem 5:82

    Article  CAS  Google Scholar 

  103. Zamani P, Khosropour AR (2016) Green Chem 18:6450

    Article  CAS  Google Scholar 

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Correspondence to Jean-Christophe M. Monbaliu .

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Gérardy, R., Monbaliu, JC.M. (2018). Multistep Continuous-Flow Processes for the Preparation of Heterocyclic Active Pharmaceutical Ingredients. In: Sharma, U., Van der Eycken, E. (eds) Flow Chemistry for the Synthesis of Heterocycles. Topics in Heterocyclic Chemistry, vol 56. Springer, Cham. https://doi.org/10.1007/7081_2018_21

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