Continuous-flow technology - A tool for the safe manufacturing of active pharmaceutical ingredients

Angewandte Chemie - International Edition

Volumn 54, Issue 23, 2015, Pages 6688-6728

  Gutmann, Bernhard ^a   Cantillo, David ^a   Kappe, C Oliver ^a  

^a UNIVERSITY OF GRAZ   (Austria)

Author keywords

flash chemistry; flow chemistry; microreactors; pharmaceuticals; scale up

Indexed keywords

CHEMICAL REACTORS; DRUG PRODUCTS; HAZARDS; HEAT TRANSFER; MASS TRANSFER; MIXING; SMALL NUCLEAR REACTORS;

ACTIVE PHARMACEUTICAL INGREDIENTS; CHARACTERISTIC PROPERTIES; CONTINUOUS FLOW TECHNOLOGY; FLASH CHEMISTRIES; FLOW CHEMISTRY; MICRO REACTOR; SCALE-UP; SYNTHETIC ORGANIC CHEMISTRY;

REACTION INTERMEDIATES;

DRUG;

CHEMISTRY; MEDICINAL CHEMISTRY; MICROFLUIDIC ANALYSIS; PHARMACEUTICS;

CHEMISTRY, PHARMACEUTICAL; MICROFLUIDIC ANALYTICAL TECHNIQUES; PHARMACEUTICAL PREPARATIONS; TECHNOLOGY, PHARMACEUTICAL;

EID: 84930202202     PISSN: 14337851     EISSN: 15213773     Source Type: Journal    
DOI: 10.1002/anie.201409318     Document Type: Review

References (352)

1. L. Malet-Sanz, F. Susanne, J. Med. Chem. 2012, 55, 4062
2. P. Poechlauer, J. Colberg, E. Fisher, M. Jansen, M. D. Johnson, S. G. Koenig, M. Lawler, T. Laporte, J. Manley, B. Martin, A. O'Kearney-McMullan, Org. Process Res. Dev. 2013, 17, 1472
3. A. M. Thayer, Chem. Eng. News 2014, 92(21), 13
4. P. Poechlauer, J. Manley, R. Broxterman, B. Gregertsen, M. Ridemark, Org. Process Res. Dev. 2012, 16, 1586
5. C. Jiménez-González, P. Poechlauer, Q. B. Broxterman, B.-S. Yang, D. A. Ende, J. Baird, C. Bertsch, R. E. Hannah, P. Dell′Orco, H. Noorman, S. Yee, R. Reintjens, A. Wells, V. Massonneau, J. Manley, Org. Process Res. Dev. 2011, 15, 900.
6. For a further discussion on continuous-flow manufacturing in pharma, see, I. R. Baxendale, R. D. Braatz, B. K. Hodnett, K. F. Jensen, M. D. Johnson, P. Scharrat, J.-P. Sherlock, A. J. Florence, J. Pharm. Sci. 2015, 104, 781.
7. Flow Chemistry (Eds.:, F. Darvas, V. Hessel, G. Dorman,), DeGruyter, Berlin, 2014
8. Microreactors in Preparative Chemistry (Ed.:, W. Reschetilowski,), Wiley-VCH, Weinheim, 2013
9. Microreactors in Organic Synthesis and Catalysis, 2nded. (Ed.:, T. Wirth,), Wiley-VCH, Weinheim, 2013
10. Handbook of Micro Reactors (Eds.:, V. Hessel, J.C. Schouten, A. Renken, Y. Wang, J.-i. Yoshida,), Wiley-VCH, Weinheim, 2009
11. Chemical Reactions and Processes under Flow Conditions (Ed.:, S.V. Luis, E. Garcia-Verdugo,), RSC Green Chemistry, 2010.
12. K. F. Jensen, B. J. Reizmana, S. G. Newman, Lab Chip 2014, 14, 3206
13. R. L. Hartman, J. P. McMullen, K. F. Jensen, Angew. Chem. Int. Ed. 2011, 50, 7502
14. Angew. Chem. 2011, 123, 7642
15. N. G. Anderson, Org. Process Res. Dev. 2012, 16, 852
16. I. R. Baxendale, L. Brocken, C. J. Mallia, Green Process. Synth. 2013, 2, 211
17. I. R. Baxendale, J. Chem. Technol. Biotechnol. 2013, 88, 519
18. M. Baumann, I. R. Baxendale, S. V. Ley, Mol. Diversity 2011, 15, 613
19. R. J. Ingham, C. Battilocchio, D. E. Fitzpatrick, E. Sliwinski, J. M. Hawkins, S. V. Ley, Angew. Chem. Int. Ed. 2015, 54, 144
20. Angew. Chem. 2015, 127, 146.
21. C. Wiles, P. Watts, Green Chem. 2012, 14, 38
22. C. Wiles, P. Watts, Green Chem. 2014, 16, 55
23. S. G. Newman, K. F. Jensen, Green Chem. 2013, 15, 1456
24. J.-i. Yoshida, H. Kim, A. Nagaki, ChemSusChem 2011, 4, 331.
25. P. Plouffe, A. Macchi, D. M. Roberge, in Flow Chemistry, Fundamentals, Vol.1. (Eds.:, F. Darvas, V. Hessel, G. Dorman,), DeGruyter, Berlin, 2014, p. 139
26. I. Dencic, V. Hessel, in Microreactors in Organic Synthesis and Catalysis, 2nded. (Ed.:, T. Wirth,), Wiley-VCH, Weinheim, 2013, p. 373.
27. flow photochemistry:, Y. Su, N. J. W. Straathof, V. Hessel, T. Noel, Chem. Eur. J. 2014, 20, 10562
28. flow electrochemistry:, K. Watts, A. Baker, T. Wirth, J. Flow Chem. 2014, 4, 2
29. radiopharmaceutical synthesis:, A. M. Elizarov, Lab Chip 2009, 9, 1326
30. materials chemistry:, R. M. Myers, D. E. Fitzpatrick, R. M. Turner, S. V. Ley, Chem. Eur. J. 2014, 20, 12348
31. asymmetric synthesis:, D. B. Zhao, K. L. Ding, ACS Catal. 2013, 3, 928
32. biocatalysis:, J. M. Bolivar, B. Nidetzky, Green Process. Synth. 2013, 2, 541
33. natural products synthesis:, J. C. Pastre, D. L. Browne, S. V. Ley, Chem. Soc. Rev. 2013, 42, 8849.
34. S. Mascia, P. L. Heider, H. Zhang, R. Lakerveld, B. Benyahia, P. I. Barton, R. D. Braatz, C. L. Cooney, J. M. B. Evans, T. F. Jamison, K. F. Jensen, A. S. Myerson, B. L. Trout, Angew. Chem. Int. Ed. 2013, 52, 12359
35. Angew. Chem. 2013, 125, 12585
36. P. L. Heider, S. C. Born, S. Basak, B. Benyahia, R. Lakerveld, H. Zhang, R. Hogan, L. Buchbinder, A. Wolfe, S. Mascia, J. M. B. Evans, T. F. Jamison, K. F. Jensen, Org. Process Res. Dev. 2014, 18, 402.
37. T. Rodrigues, P. Schneider, G. Schneider, Angew. Chem. Int. Ed. 2014, 53, 5750
38. Angew. Chem. 2014, 126, 5858.
39. V. Hessel, D. Kralisch, N. Kockmann, T. Noël, Q. Wang, ChemSusChem 2013, 6, 746
40. V. Hessel, D. Kralisch, N. Kockmann, Novel Process Windows, Wiley-VCH, Weinheim, 2014.
41. T. Razzaq, C. O. Kappe, Chem. Asian J. 2010, 5, 1274.
42. D. Reay, C. Ramshaw, A. Harvey, Process Intensification-Engineering for Efficiency, Sustainability and Flexibility, Elsevier, Oxford, 2008
43. A. Gõrak, A. I. Stankiewicz, Annu. Rev. Chem. Biomol. Eng. 2011, 2, 431.
44. B. J. Reizman, K. F. Jensen, Org. Process Res. Dev. 2012, 16, 1770
45. J. S. Moore, K. F. Jensen, Angew. Chem. Int. Ed. 2014, 53, 470
46. Angew. Chem. 2014, 126, 480
47. R. A. Skilton, A. J. Parrott, M. W. George, M. Poliakoff, R. A. Bourne, Appl. Spectrosc. 2013, 67, 1127
48. M. F. Roberto, T. I. Dearing, S. Martin, B. J. Marquardt, J. Pharm. Innovation 2012, 7, 69
49. S. E. Hamilton, F. Mattrey, X. Bu, D. Murray, B. McCullough, C. J. Welch, Org. Process Res. Dev. 2014, 18, 103
50. D. L. Browne, S. Wright, B. J. Deadman, S. Dunnage, I. R. Baxendale, R. M. Turner, S. V. Ley, Rapid Commun. Mass Spectrom. 2012, 26, 1999.
51. J.-i. Yoshida, Flash Chemistry: Fast Organic Synthesis in Microsystems, Wiley, Chichester, 2008.
52. D. Webb, T. F. Jamison, Chem. Sci. 2010, 1, 675
53. D. T. McQuade, P. H. Seeberger, J. Org. Chem. 2013, 78, 6384
54. B. Ahmed-Omer, D. A. Barrow, T. Wirth, ARKIVOC 2011, 4, 26.
55. K. Jähnisch, V. Hessel, H. Löwe, M. Baerns, Angew. Chem. Int. Ed. 2004, 43, 406
56. Angew. Chem. 2004, 116, 410.
57. N. Kockmann, D. M. Roberge, Chem. Eng. Technol. 2009, 32, 1682.
58. D. A. Crowl, J. F. Louvar, Chemical Process Safety: Fundamentals with Applications, 3rded., Prentice-Hall, Upper Saddle River, 2012.
59. C. O. Kappe, A. Stadler, D. Dallinger, Microwaves in Organic and Medicinal Chemistry, 2nded., Wiley-VCH, Weinheim, 2012
60. Microwaves in Organic Synthesis (Eds.:, A. deLaHoz, A. Loupy,), Wiley-VCH, Weinheim, 2012.
61. For a recent review describing the translation of microwave batch to continuous-flow procedures ("microwave-to-flow paradigm"), see, T. N. Glasnov, C. O. Kappe, Chem. Eur. J. 2011, 17, 11956.
62. M. Damm, T. N. Glasnov, C. O. Kappe, Org. Process Res. Dev. 2010, 14, 215.
63. R. Morschhäuser, M. Krull, C. Kayser, C. Boberski, R. Bierbaum, P. A. Püschner, T. N. Glasnov, C. O. Kappe, Green Process Synth. 2012, 1, 281.
64. J. M. Sauks, D. Mallik, Y. Lawryshyn, T. Bender, M. Organ, Org. Process Res. Dev. 2014, 18, 1310
65. for related examples, see, K. Engen, J. Sävmarker, U. Rosenström, J. Wannberg, T. Lundbäck, A. Jenmalm-Jensen, M. Larhed, Org. Process Res. Dev. 2014, 18, 1582.
66. T. Razzaq, T. N. Glasnov, C. O. Kappe, Chem. Eng. Technol. 2009, 32, 1702
67. T. Razzaq, T. N. Glasnov, C. O. Kappe, Eur. J. Org. Chem. 2009, 1321
68. H. Kobayashi, B. Driessen, D. J. G. P. vanOsch, A. Talla, S. Ookawara, T. Noël, V. Hessel, Tetrahedron 2013, 69, 2885
69. U. Tilstam, T. Defrance, T. Giard, Org. Process Res. Dev. 2009, 13, 321
70. T. Iwasaki, J.-i. Yoshida, Macromolecules 2005, 38, 1159.
71. S. Borukhova, T. Noel, B. Metten, E. deVos, V. Hessel, ChemSusChem 2013, 6, 2220.
72. P. Zhang, M. G. Russell, T. F. Jamison, Org. Process Res. Dev. 2014, 18, 1567.
73. D. R. Snead, T. F. Jamison, Chem. Sci. 2013, 4, 2822.
74. S. A. May, M. D. Johnson, T. M. Braden, J. R. Calvin, B. D. Haeberle, A. R. Jines, R. D. Miller, E. F. Plocharczyk, G. A. Rener, R. N. Richey, C. R. Schmid, R. K. Vaid, H. Yu, Org. Process Res. Dev. 2012, 16, 982.
75. M. W. Bedore, N. Zaborenko, K. F. Jensen, T. F. Jamison, Org. Process Res. Dev. 2010, 14, 432.
76. N. Zaborenko, M. W. Bedore, T. F. Jamison, K. F. Jensen, Org. Process Res. Dev. 2011, 15, 131.
77. D. Cantillo, C. O. Kappe, J. Org. Chem. 2013, 78, 10567.
78. X. Han, M. Poliakoff, Chem. Soc. Rev. 2012, 41, 1428.
79. U. Hintermair, G. Franciò, W. Leitner, Chem. Eur. J. 2013, 19, 4538.
80. P. Clark, M. Poliakoff, A. Wells, Adv. Synth. Catal. 2007, 349, 2655.
81. E. Garcia-Verdugo, Z. Liu, E. Ramirez, J. Garcia-Serna, J. Fraga-Dubreuil, J. R. Hyde, P. A. Hamley, M. Poliakoff, Green Chem. 2006, 8, 359
82. C. Yan, J. Fraga-Dubeuil, E. Garcia-Verdugo, P. A. Hamley, M. Poliakoff, I. Pearson, A. S. Coote, Green Chem. 2008, 10, 98
83. J. Fraga-Dubreuil, M. Poliakoff, Pure Appl. Chem. 2006, 78, 1971
84. J. Fraga-Dubreuil, E. Garcia-Verdugo, P. A. Hamley, E. M. Vaquero, L. M. Dudd, I. Pearson, D. Housley, W. Partenheimer, W. B. Thomas, K. Whiston, M. Poliakoff, Green Chem. 2007, 9, 1238.
85. High Pressure Chemistry: Synthetic, Mechanistic, and Supercritical Applications (Eds.:, R. vanEldik, F.-G. Klärner,), Wiley-VCH, Weinheim, 2008.
86. W. Verboom, Chem. Eng. Technol. 2009, 32, 1695
87. F. Benito-Lõpez, R. J. M. Egberink, D. N. Reinhoudt, W. Verboom, Tetrahedron 2008, 64, 10023.
88. C. Wentrup, Aust. J. Chem. 2014, 67, 1150
89. H. McNab, Aldrichimica Acta 2004, 37, 19.
90. D. Cantillo, H. Sheibani, C. O. Kappe, J. Org. Chem. 2012, 77, 2463.
91. G. M. Keser, T. Soõs, C. O. Kappe, Chem. Sov. Rev. 2014, 43, 5387.
92. N. Kockmann, Transport Phenomena in Micro Process Engineering, Springer, Berlin, 2008.
93. T. D. Gross, S. Chou, D. Bonneville, R. S. Gross, P. Wang, O. Campopiano, M. A. Ouellette, S. E. Zook, J. P. Reddy, W. J. Moree, F. Jovic, S. Chopade, Org. Process Res. Dev. 2008, 12, 929.
94. D. R. Fandrick, F. Roschangar, C. Kim, B. J. Hahm, M. H. Cha, H. Y. Kim, G. Yoo, T. Kim, J. T. Reeves, J. J. Song, Z. Tan, B. Qu, N. Haddad, S. Shen, N. Grinberg, H. Lee, N. Yee, C. H. Senanayake, Org. Process Res. Dev. 2012, 16, 1131.
95. P. R. D. Murray, D. L. Browne, J. C. Pastre, C. Butters, D. Guthrie, S. V. Ley, Org. Process Res. Dev. 2013, 17, 1192.
96. L. Kupracza, A. Kirschning, Adv. Synth. Catal. 2013, 355, 3375.
97. X. Zhang, S. Stefanick, F. J. Villani, Org. Process Res. Dev. 2004, 8, 455
98. E. Riva, S. Gagliardi, M. Martinelli, D. Passarella, D. Vigo, A. Rencurosi, Tetrahedron 2010, 66, 3242
99. A. E. Cervera-Padrell, J. P. Nielsen, M. J. Pedersen, K. M. Christensen, A. R. Mortensen, T. Skovby, K. Dam-Johansen, S. Kiil, K. V. Gernaey, Org. Process Res. Dev. 2012, 16, 901
100. E. Riva, A. Rencurosi, S. Gagliardi, D. Passarella, M. Martinelli, Chem. Eur. J. 2011, 17, 6221
101. B. Pieber, T. Glasnov, C. O. Kappe, RSC Adv. 2014, 4, 13430.
102. P. Grongsaard, P. G. Bulger, D. J. Wallace, L. Tan, Q. Chen, S. J. Dolman, J. Nyrop, R. S. Hoerrner, M. Weisel, J. Arredondo, T. Itoh, C. Xie, X. Wen, D. Zhao, D. J. Muzzio, E. M. Bassan, C. S. Shultz, Org. Process Res. Dev. 2012, 16, 1069.
103. N. Kockmann, M. Gottsponer, B. Zimmermann, D. M. Roberge, Chem. Eur. J. 2008, 14, 7470.
104. P. Barthe, C. Guermeur, O. Lobet, M. Moreno, P. Woehl, D. M. Roberge, N. Bieler, B. Zimmerman, Chem. Eng. Technol. 2008, 31, 1146
105. D. M. Roberge, N. Bieler, M. Mathier, M. Eyholzer, B. Zimmermann, P. Barthe, C. Guermeur, O. Lobet, M. Moreno, P. Woehl, Chem. Eng. Technol. 2008, 31, 1155.
106. J.-i. Yoshida, A. Nagaki, T. Yamadayoshida, Chem. Eur. J. 2008, 14, 7450
107. J.-i. Yoshida, Drug Discovery Today 2013, 10, 53
108. H. Kim, A. Nagaki, J.-i. Yoshida, Nat. Commun. 2011, 2, 264
109. J.-i Yoshida, Y. Takahashi, A. Nagaki, Chem. Commun. 2013, 49, 9895.
110. T. Kawaguchi, H. Miyata, K. Ataka, K. Mae, J.-i. Yoshida, Angew. Chem. Int. Ed. 2005, 44, 2413
111. Angew. Chem. 2005, 117, 2465.
112. J. R. McConnell, J. E. Hitt, E. D. Daugs, T. A. Rey, Org. Process Res. Dev. 2008, 12, 940
113. P. J. Nieuwland, K. Koch, N. vanHarskamp, R. Wehrens, J. C. M. vanHest, F. P. J. T. Rutjes, Chem. Asian J. 2010, 5, 799.
114. J. J. M. vanderLinden, P. W. Hilberink, C. M. P. Kronenburg, G. J. Kemperman, Org. Process Res. Dev. 2008, 12, 911.
115. D. Webb, T. F. Jamison, Org. Lett. 2012, 14, 568
116. D. Webb, T. F. Jamison, Org. Lett. 2012, 14, 2465.
117. L. Ducry, D. M. Roberge, Org. Process Res. Dev. 2008, 12, 163.
118. P. N. Rylander, Hydrogenation Methods, Academic Press, New York, 1990
119. P. N. Rylander, Catalytic Hydrogenation in Organic Synthesis, Academic Press, New York, 1979
120. S. Nishimura, Handbook of Heterogeneous Catalytic Hydrogenation for Organic Synthesis, Wiley-Interscience: New York, 2001.
121. For a review on continuous-flow hydrogenations, see, M. Irfan, T. N. Glasnov, C. O. Kappe, ChemSusChem 2011, 4, 300.
122. M. Baumann, I. R. Baxendale, C. H. Hornung, S. V. Ley, M. V. Rojo, K. A. Roper, Molecules 2014, 19, 9736
123. R. J. Ingham, C. Battilocchio, J. M. Hawkins, S. V. Ley, Beilstein J. Org. Chem. 2014, 10, 641
124. M. J. Fink, M. Schön, F. Rudroff, M. Schnürch, M. D. Mihovilovic, ChemCatChem 2013, 5, 724
125. S. Lou, P. Dai, S. E. Schaus, J. Org. Chem. 2007, 72, 9998
126. M. Irfan, E. Petricci, T. Glasnov, M. Taddei, C. O. Kappe, Eur. J. Org. Chem. 2009, 1327.
127. T. N. Glasnov, C. O. Kappe, Adv. Synth. Catal. 2010, 352, 3089.
128. S. Balogh, G. Farkas, J. Madarász, A. Szöllłsy, J. Kovács, F. Darvas, L. Ürge, J. Bakos, Green Chem. 2012, 14, 1146.
129. J. Kobayashi, Y. Mori, K. Okamoto, R. Akiyama, M. Ueno, T. Kitamori, S. Kobayashi, Science 2004, 304, 1305.
130. T. Haywood, P. W. Miller, ChemCatChem 2014, 6, 1199
131. R. Lin, X. Ma, T. R. Fielitz, S. O. Obare, R. Y. Ofoli, Catal. Commun. 2012, 18, 168
132. J. J. W. Bakker, M. M. P. Zieverink, R. W. E. G. Reintjens, F. Kapteijn, J. A. Moulijn, M. T. Kreutzer, ChemCatChem 2011, 3, 1155
133. O. Trapp, S. K. Weber, S. Bauch, T. Baecker, W. Hofstadt, B. Spliethoff, Chem. Eur. J. 2008, 14, 4657
134. A. Iles, M. Habgood, A. J. deMello, R. C. R. Wootton, Catal. Lett. 2007, 114, 71.
135. M. D. Johnson, S. A. May, J. R. Calvin, J. Remacle, J. R. Stout, W. D. Diseroad, N. Zaborenko, B. D. Haeberle, W.-M. Sun, M. T. Miller, J. Brennan, Org. Process Res. Dev. 2012, 16, 1017.
136. D. I. Enache, G. J. Hutchings, S. H. Taylor, R. Natividad, S. Raymahasay, J. M. Winterbottom, E. H. Stitt, Ind. Eng. Chem. Res. 2005, 44, 6295
137. D. I. Enache, G. J. Hutchings, S. H. Taylor, E. H. Stitt, Catal. Today 2005, 105, 569
138. D. I. Enache, G. J. Hutchings, S. H. Taylor, S. Raymahasay, J. M. Winterbottom, M. D. Mantle, A. J. Sederman, L. F. Gladden, C. Chatwin, K. T. Symonds, E. H. Stitt, Catal. Today 2007, 128, 26
139. B. Buisson, S. Donegan, D. Wray, A. Parracho, J. Gamble, P. Caze, J. Jorda, C. Guermeur, Chim. Oggi-Chem. Today 2009, 27, 12
140. A.-K. Liedtke, F. Bornette, R. Philippe, C. deBellefon, Chem. Eng. J. 2013, 227, 174.
141. M. O'Brien, I. R. Baxendale, S. V. Ley, Org. Lett. 2010, 12, 1596
142. for a recent review, see, M. Brzozowski, M. O'Brien, S. V. Ley, A. Polyzos, Acc. Chem. Res. 2015, 48, 349.
143. M. O'Brien, N. Taylor, A. Polyzos, I. R. Baxendale, S. V. Ley, Chem. Sci. 2011, 2, 1250.
144. S. Newton, S. V. Ley, E. C. Arc, D. M. Grainger, Adv. Synth. Catal. 2012, 354, 1805.
145. M. A. Mercadante, C. B. Kelly, C. X. Lee, N. E. Leadbeater, Org. Process Res. Dev. 2012, 16, 1064.
146. For a theoretical modeling of the gas-transport properties of the Teflon-AF2400 device, see, L. Yang, K. F. Jensen, Org. Process Res. Dev. 2013, 17, 927.
147. R. A. Sheldon, I. W. C. E. Arends, G.-J. tenBrink, A. Dijksman, Acc. Chem. Res. 2002, 35, 774
148. S. S. Stahl, Angew. Chem. Int. Ed. 2004, 43, 3400
149. Angew. Chem. 2004, 116, 3480
150. S. S. Stahl, Science 2005, 309, 1824.
151. N. Zotova, K. Hellgardt, G. H. Kelsall, A. S. Jessimanc, K. K. (M.) Hii, Green Chem. 2010, 12, 2157.
152. D. Obermayer, A. M. Balu, A. A. Romero, W. Goessler, R. Luque, C. O. Kappe, Green Chem. 2013, 15, 1530.
153. Z. Hou, N. Theyssen, A. Brinkmann, K. V. Klementiev, W. Grünert, M. Bühl, W. Schmidt, B. Spliethoff, B. Tesche, C. Weidenthaler, W. Leitner, J. Catal. 2008, 258, 315
154. M. Caravati, J.-D. Grunwaldt, A. Baiker, Appl. Catal. A 2006, 298, 50
155. G. Jenzer, T. Mallat, A. Baiker, Catal. Lett. 2001, 73, 5.
156. B. Pieber, S. T. Martinez, D. Cantillo, C. O. Kappe, Angew. Chem. Int. Ed. 2013, 52, 10241
157. Angew. Chem. 2013, 125, 10431
158. B. Pieber, T. Glasnov, C. O. Kappe, Chem. Eur. J. 2015, 21, 4368.
159. Z. He, T. F. Jamison, Angew. Chem. Int. Ed. 2014, 53, 3353
160. Angew. Chem. 2014, 126, 3421.
161. X. Ye, M. D. Johnson, T. Diao, M. H. Yates, S. S. Stahl, Green Chem. 2010, 12, 1180.
162. T. P. Petersen, A. Polyzos, M. O'Brien, T. Ulven, I. R. Baxendale, S. V. Ley, ChemSusChem 2012, 5, 274.
163. S. L. Bourne, S. V. Ley, Adv. Synth. Catal. 2013, 355, 1905.
164. P. R. Ogilby, Chem. Soc. Rev. 2010, 39, 3181.
165. R. C. R. Wootton, R. Fortt, A. J. deMello, Org. Process Res. Dev. 2002, 6, 187.
166. K. Jähnisch, U. Dingerdissen, Chem. Eng. Technol. 2005, 28, 426.
167. R. A. Bourne, X. Han, M. Poliakoff, M. W. George, Angew. Chem. Int. Ed. 2009, 48, 5322
168. Angew. Chem. 2009, 121, 5426.
169. C. P. Park, R. A. Maurya, J. H. Lee, D.-P. Kim, Lab Chip 2011, 11, 1941
170. R. A. Maurya, C. P. Park, D.-P. Kim, Beilstein J. Org. Chem. 2011, 7, 1158.
171. F. Lévesque, P. H. Seeberger, Org. Lett. 2011, 13, 5008.
172. D. Kopetzki, F. Levesque, P. H. Seeberger, Chem. Eur. J. 2013, 19, 5450.
173. F. Lévesque, P. H. Seeberger, Angew. Chem. Int. Ed. 2012, 51, 1706
174. Angew. Chem. 2012, 124, 1738.
175. K. Gilmore, D. Kopetzki, J. W. Lee, Z. Horváth, D. T. McQuade, A. Seidel-Morgenstern, P. H. Seeberger, Chem. Commun. 2014, 50, 12652.
176. J. L. Turconi, F. Griolet, R. Guevel, G. Oddon, R. Villa, A. Geatti, M. Hvala, K. Rossen, R. Göller, A. Burgard, Org. Process Res. Dev. 2014, 18, 417.
177. Y. Wada, M. A. Schmidt, K. F. Jensen, Ind. Eng. Chem. Res. 2006, 45, 8036.
178. S. Hübner, U. Bentrup, U. Budde, K. Lovis, T. Dietrich, A. Freitag, L. Küpper, K. Jähnisch, Org. Process Res. Dev. 2009, 13, 952.
179. M. Irfan, T. N. Glasnov, C. O. Kappe, Org. Lett. 2011, 13, 984.
180. S. G. VanOrnum, R. M. Champeau, R. Pariza, Chem. Rev. 2006, 106, 2990.
181. M. Nobis, D. M. Roberge, Chim. Oggi-Chem. Today 2011, 29, 57.
182. M. Exner, H. Pluim, P. Dyer-Smith, Chim. Oggi-Chem. Today 2011, 29, 59.
183. C. W. Jones, Applications of Hydrogen Peroxide and Derivatives, Royal Society of Chemistry, Cambridge, 1999.
184. F. Ebrahimi, E. Kolehmainen, I. Turunen, Org. Process Res. Dev. 2009, 13, 965
185. F. Ebrahimia, E. Kolehmainen, P. Oinas, V. Hietapelto, I. Turunen, Chem. Eng. J. 2011, 167, 713.
186. A. Hartung, M. A. Keane, A. Kraft, J. Org. Chem. 2007, 72, 10235; see also
187. B. A. M. W. vandenBroek, R. Becker, F. Kössl, M. M. E. Delville, P. J. Nieuwland, K. Koch, F. P. J. T. Rutjes, ChemSusChem 2012, 5, 289.
188. T. Illg, V. Hessel, P. Löb, J. C. Schouten, Chem. Eng. J. 2011, 167, 504.
189. K. Mikami, Md. N. Islam, M. Yamanaka, Y. Itoh, M. Shinoda, K. Kudo, Tetrahedron Lett. 2004, 45, 3681
190. K. Mikami, M. Yamanaka, Md. N. Islam, T. Tonoi, Y. Itoh, M. Shinoda, K. Kudo, J. Fluorine Chem. 2006, 127, 592.
191. R. Noyori, M. Aoki, K. Sato, Chem. Commun. 2003, 1977
192. Y. Kon, Y. Ono, T. Matsumoto, K. Sato, Synlett 2009, 1095.
193. K. Sato, M. Aoki, R. Noyori, Science 1998, 281, 1646.
194. Y. Wen, X. Wang, H. Wei, B. Li, P. Jin, L. Li, Green Chem. 2012, 14, 2868.
195. M. Damm, B. Gutmann, C. O. Kappe, ChemSusChem 2013, 6, 978.
196. M. Shang, T. Noel, Q. Wang, V. Hessel, Chem. Eng. Technol. 2013, 36, 1001.
197. A. B. Leduc, T. F. Jamison, Org. Process Res. Dev. 2012, 16, 1082.
198. G. S. Kumar, B. Pieber, K. R. Reddy, C. O. Kappe, Chem. Eur. J. 2012, 18, 6124.
199. J. Sedelmeier, S. V. Ley, I. R. Baxendale, M. Baumann, Org. Lett. 2010, 12, 3618.
200. K. C. Basavaraju, S. Sharma, R. A. Maurya, D.-P. Kim, Angew. Chem. Int. Ed. 2013, 52, 6735
201. Angew. Chem. 2013, 125, 6867.
202. For a review on continuous-flow fluorinations, see, H. Amii, A. Nagaki, J.-i. Yoshida, Beilstein J. Org. Chem. 2013, 9, 2793.
203. N. deMas, A. Günther, M. A. Schmidt, K. F. Jensen, Ind. Eng. Chem. Res. 2003, 42, 698
204. K. Jähnisch, M. Baerns, V. Hessel, W. Ehrfeld, V. Haverkamp, H. Löwe, C. Wille, A. Guber, J. Fluorine Chem. 2000, 105, 117.
205. C. B. McPake, G. Sandford, Org. Process Res. Dev. 2012, 16, 844.
206. R. D. Chambers, R. C. H. Spink, Chem. Commun. 1999, 883.
207. R. D. Chambers, M. P. Greenhall, J. Hutchinson, Tetrahedron 1996, 52, 1.
208. J. R. Breen, G. Sandford, D. S. Yufit, J. A. K. Howard, J. Fray, B. Patel, Beilstein J. Org. Chem. 2011, 7, 1048.
209. C. B. McPake, C. B. Murray, G. Sandford, Tetrahedron Lett. 2009, 50, 1674.
210. T. Gustafsson, R. Gilmour, P. H. Seeberger, Chem. Commun. 2008, 3022
211. M. Baumann, I. R. Baxendale, S. V. Ley, Synlett 2008, 12, 2111
212. M. Baumann, I. R. Baxendale, L. J. Martin, S. V. Ley, Tetrahedron 2009, 65, 6611
213. D. Cantillo, O. deFrutos, J. A. Rincon, C. Mateos, C. O. Kappe, J. Org. Chem. 2014, 79, 8486.
214. U. Budde, Statuskolloquium Mikroverfahrenstechnik, Deutsche Bundesstiftung Umwelt, Osnabrück, 2007.
215. H. Ehrich, D. Linke, K. Morgenschweis, M. Baerns, K. Jähnisch, Chimia 2002, 56, 647
216. H. Matsubara, Y. Hino, M. Tokizane, I. Ryu, Chem. Eng. J. 2011, 167, 567.
217. P. Löb, V. Hessel, H. Klefenz, H. Löwe, K. Mazanek, Lett. Org. Chem. 2005, 2, 767
218. R. Becker, S. A. M. W. vandenBroek, P. J. Nieuwland, K. Koch, F. P. J. T. Rutjes, J. Flow Chem. 2012, 2, 87
219. T. Fukuyama, M. T. Rahman, N. Kamata, M. Tokizane, Y. Fukuda, I. Ryu, J. Flow Chem. 2013, 3, 4.
220. D. Cantillo, O. deFrutos, J. A. Rincon, C. Mateos, C. O. Kappe, J. Org. Chem. 2014, 79, 223.
221. D. Šterk, M. Jukič, Z. Časar, Org. Process Res. Dev. 2013, 17, 145.
222. K. Midorikawa, S. Suga, J.-i. Yoshida, Chem. Commun. 2006, 3794.
223. J. Barton, R. Rogers, Chemical Reaction Hazards, IChemE, Trowbridge, 1997.
224. A. M. Thayer, Chem. Eng. News 2005, 83(22), 43.
225. A. A. Kulkarni, Beilstein J. Org. Chem. 2014, 10, 405.
226. L. Ducry, D. M. Roberge, Angew. Chem. Int. Ed. 2005, 44, 7972
227. Angew. Chem. 2005, 117, 8186
228. J. Pelleter, F. Renaud, Org. Process Res. Dev. 2009, 13, 698
229. C. E. Brocklehurst, H. Lehmann, L. L. Vecchia, Org. Process Res. Dev. 2011, 15, 1447.
230. S. Braune, P. Pöchlauer, R. Reintjens, S. Steinhofer, M. Winter, O. Lobet, R. Guidat, P. Woehl, C. Guermeur, Chim. Oggi-Chem. Today 2009, 27, 26
231. A. M. Thayer, Chem. Eng. News 2009, 87(11), 17.
232. P. Knapkiewicz, K. Skowerski, D. E. Jaskõlska, M. Barbasiewicz, T. K. Olszewski, Org. Process Res. Dev. 2012, 16, 1430.
233. G. Panke, T. Schwalbe, W. Stirner, S. Taghavi-Moghadam, G. Wille, Synthesis 2003, 2827.
234. Y. Chen, Y. Zhao, M. Han, C. Ye, M. Danga, G. Chen, Green Chem. 2013, 15, 91.
235. D. Cantillo, M. Damm, D. Dallinger, M. Bauser, M. Berger, C. O. Kappe, Org. Process Res. Dev. 2014, 18, 1360.
236. B. J. Deadman, S. G. Collins, A. R. Maguire, Chem. Eur. J. 2015, 21, 2298
237. S. T. R. Mueller, T. Wirth, ChemSusChem 2015, 8, 245.
238. M. Struempel, B. Ondruschka, R. Daute, A. Stark, Green Chem. 2008, 10, 41
239. E. Rossi, P. Woehl, M. Maggini, Org. Process Res. Dev. 2012, 16, 1146.
240. T. G. Archibald, F. Oaks, J. C. Barnard, S. Springs, H. F. Reese, "Continuous process for diazomethane from an, N-methyl-N-nitrosoamine and from methylurea through N-methyl-N-nitrosourea". (Aerojet-General Corporation). US Patent 5,854,405, 1998 (CAN130:83188).
241. M. Struempel, B. Ondruschka, A. Stark, Org. Process Res. Dev. 2009, 13, 1014.
242. P. Poechlauer, Chim. Oggi-Chem. Today 2012, 30, 51.
243. L. D. Proctor, A. J. Warr, Org. Process Res. Dev. 2002, 6, 884.
244. L. Proctor, Industrialisation of Diazomethane-The Application of Flow Technology Towards Hazardous Chemistry, 2006. http://www.chemspecevents.com/europe/images/uploads/chemsource/4-1-Proctor.pdf Chemsource 2006, Elements of Success-P, Si, F & N. ChemSpec Events Homepage (accessed on September 4th of 2014).
245. R. A. Maurya, C. P. Park, J. H. Lee, D.-P. Kim, Angew. Chem. Int. Ed. 2011, 50, 5952
246. Angew. Chem. 2011, 123, 6074.
247. F. Mastronardi, B. Gutmann, C. O. Kappe, Org. Lett. 2013, 15, 5590.
248. V. D. Pinho, B. Gutmann, L. S. M. Miranda, R. O. M. A. deSouza, C. O. Kappe, J. Org. Chem. 2014, 79, 1555.
249. V. D. Pinho, B. Gutmann, C. O. Kappe, RSC Adv. 2014, 4, 37419.
250. L. J. Martin, A. L. Marzinzik, S. V. Ley, I. R. Baxendale, Org. Lett. 2011, 13, 320
251. P. Pollet, E. D. Cope, M. K. Kassner, R. Charney, S. H. Terett, K. W. Richman, W. Dubay, J. Stringer, C. A. Eckert, C. L. Liotta, Ind. Eng. Chem. Res. 2009, 48, 7032.
252. R. A. Maurya, K.-I. Min, D.-P. Kim, Green Chem. 2014, 16, 116.
253. R. C. R. Wootton, R. Fortt, A. J. deMello, Lab Chip 2002, 2, 5.
254. H. Salimi-Moosavi, T. Tang, D. J. Harrison, J. Am. Chem. Soc. 1997, 119, 8716
255. H. Hisamoto, T. Saito, M. Tokeshi, A. Hibara, T. Kitamori, Chem. Commun. 2001, 2662
256. C. Wille, H.-P. Gabski, Th. Haller, H. Kim, L. Unverdorben, R. Winter, Chem. Eng. J. 2004, 101, 179
257. H. Pennemann, S. Forster, J. Kinkel, V. Hessel, H. Löwe, L. Wu, Org. Process Res. Dev. 2005, 9, 188
258. P. M. Günther, F. Möller, T. Henkel, J. M. Köhler, G. A. Groß, Chem. Eng. Technol. 2005, 28, 52.
259. R. Fortt, R. C. R. Wootton, A. J. deMello, Org. Process Res. Dev. 2003, 7, 762.
260. L. Malet-Sanz, J. Madrzak, S. V. Ley, I. R. Baxendale, Org. Biomol. Chem. 2010, 8, 5324
261. L. Malet-Sanz, J. Madrzak, R. S. Holvey, T. Underwood, Tetrahedron Lett. 2009, 50, 7263
262. Z. Yu, Y. Lv, C. Yu, Org. Process Res. Dev. 2012, 16, 1669.
263. N. Chernyak, S. L. Buchwald, J. Am. Chem. Soc. 2012, 134, 12466.
264. B. Ahmed-Omer, D. A. Barrow, T. Wirth, Tetrahedron Lett. 2009, 50, 3352.
265. X. Wang, G. D. Cuny, T. Noël, Angew. Chem. Int. Ed. 2013, 52, 7860
266. Angew. Chem. 2013, 125, 8014.
267. B. Li, D. Widlicka, S. Boucher, C. Hayward, J. Lucas, J. C. Murray, B. T. O'Neil, D. Pfisterer, D. Samp, J. VanAlsten, Y. Xiang, J. Young, Org. Process Res. Dev. 2012, 16, 2031.
268. D. X. Hu, M. O'Brien, S. V. Ley, Org. Lett. 2012, 14, 4246.
269. D. X. Hu, M. Bielitza, P. Koos, S. V. Ley, Tetrahedron Lett. 2012, 53, 4077.
270. M. Chen, S. L. Buchwald, Angew. Chem. Int. Ed. 2013, 52, 4247
271. Angew. Chem. 2013, 125, 4341.
272. M. E. Kopach, M. M. Murray, T. M. Braden, M. E. Kobierski, O. L. Williams, Org. Process Res. Dev. 2009, 13, 152.
273. M. M. E. Delville, P. J. Nieuwland, P. Janssen, K. Koch, J. C. M. vanHest, F. P. J. T. Rutjes, Chem. Eng. J. 2011, 167, 556.
274. M. Weber, G. Yilmaz, G. Wille, Chim. Oggi-Chem. Today 2011, 29, 8.
275. C. D. Smith, I. R. Baxendale, S. Lanners, J. J. Hayward, S. C. Smith, S. V. Ley, Org. Biomol. Chem. 2007, 5, 1559
276. I. R. Baxendale, S. V. Ley, A. C. Mansfield, C. D. Smith, Angew. Chem. Int. Ed. 2009, 48, 4017
277. Angew. Chem. 2009, 121, 4077
278. S. Ceylan, T. Klande, C. Vogt, C. Friese, A. Kirschning, Synlett 2010, 2009
279. C. O. Kappe, E. VanderEycken, Chem. Soc. Rev. 2010, 39, 1280.
280. I. R. Baxendale, S. V. Ley, A. C. Mansfield, C. D. Smith, Angew. Chem. Int. Ed. 2009, 48, 4017
281. Angew. Chem. 2009, 121, 4077.
282. M. Fuchs, W. Goessler, C. Pilger, C. O. Kappe, Adv. Synth. Catal. 2010, 352, 323.
283. A. C. Varas, T. Noël, Q. Wang, V. Hessel, ChemSusChem 2012, 5, 1703.
284. A. R. Bogdan, N. W. Sach, Adv. Synth. Catal. 2009, 351, 849.
285. A. R. Bogdan, K. James, Chem. Eur. J. 2010, 16, 14506
286. A. R. Bogdan, K. James, Org. Lett. 2011, 13, 4060.
287. H. R. Sahoo, J. G. Kralj, K. F. Jensen, Angew. Chem. Int. Ed. 2007, 46, 5704
288. Angew. Chem. 2007, 119, 5806.
289. J. C. Brandt, T. Wirth, Beilstein J. Org. Chem. 2009, 5, 30.
290. B. Gutmann, J.-P. Roduit, D. Roberge, C. O. Kappe, Angew. Chem. Int. Ed. 2010, 49, 7101
291. Angew. Chem. 2010, 122, 7255
292. B. Gutmann, D. Obermayer, J.-P. Roduit, D. M. Roberge, C. O. Kappe, J. Flow Chem. 2012, 1, 8.
293. P. B. Palde, T. F. Jamison, Angew. Chem. Int. Ed. 2011, 50, 3525
294. Angew. Chem. 2011, 123, 3587.
295. B. Gutmann, J.-P. Roduit, D. Roberge, C. O. Kappe, Chem. Eur. J. 2011, 17, 13146.
296. A. G. O'Brien, F. Lévesque, P. H. Seeberger, Chem. Commun. 2011, 47, 2688.
297. F. R. Bou-Hamdan, F. Lévesque, A. G. O'Brien, P. H. Seeberger, Beilstein J. Org. Chem. 2011, 7, 1124.
298. S. G. Newman, L. Gu, C. Lesniak, G. Victor, F. Meschke, L. Abahmane, K. F. Jensen, Green Chem. 2014, 16, 176.
299. A. DeAngelis, D.-H. Wang, S. L. Buchwald, Angew. Chem. Int. Ed. 2013, 52, 3434
300. Angew. Chem. 2013, 125, 3518.
301. C. Wiles, P. Watts, S. J. Haswell, Org. Process Res. Dev. 2004, 8, 28.
302. D. Cantillo, M. Baghbanzadeh, C. O. Kappe, Angew. Chem. Int. Ed. 2012, 51, 10190
303. Angew. Chem. 2012, 124, 10337
304. D. Cantillo, M. M. Moghaddam, C. O. Kappe, J. Org. Chem. 2013, 78, 4530.
305. M. M. Moghaddam, B. Pieber, T. Glasnov, C. O. Kappe, ChemSusChem 2014, 7, 3122.
306. L. R. Odell, F. Russo, M. Larhed, Synlett 2012, 23, 685.
307. M. T. Rahman, T. Fukuyama, N. Kamata, M. Sato, I. Ryu, Chem. Commun. 2006, 2236.
308. E. R. Murphy, J. R. Martinelli, N. Zaborenko, S. L. Buchwald, K. F. Jensen, Angew. Chem. Int. Ed. 2007, 46, 1734
309. Angew. Chem. 2007, 119, 1764.
310. X. Gong, P. W. Miller, A. D. Gee, N. J. Long, A. J. deMello, R. Vilar, Chem. Eur. J. 2012, 18, 2768
311. P. W. Miller, N. J. Long, A. J. deMello, R. Vilar, J. Passchier, A. Gee, Chem. Commun. 2006, 546.
312. B. Gutmann, P. Elsner, T. Glasnov, D. M. Roberge, C. O. Kappe, Angew. Chem. Int. Ed. 2014, 53, 11557
313. Angew. Chem. 2014, 126, 11741.
314. T. Fukuyama, Md.T. Rahman, N. Kamata, I. Ryu, Beilstein J. Org. Chem. 2009, 5, DOI:.
315. P. W. Miller, N. J. Long, A. J. deMello, R. Vilar, H. Audrain, D. Bender, J. Passchier, A. J. Gee, Angew. Chem. Int. Ed. 2007, 46, 2875
316. Angew. Chem. 2007, 119, 2933.
317. C. Csajági, B. Borcsek, K. Niesz, I. Kovács, Z. Székelyhidi, Z. Bajkõ, L. Ürge, F. Darvas, Org. Lett. 2008, 10, 1589.
318. D. Cantillo, C. O. Kappe, ChemCatChem 2014, 6, 3286
319. R. Greco, W. Goessler, D. Cantillo, C. O. Kappe, ACS Catal. 2015, 5, 1303.
320. T. Noel, S. L. Buchwald, Chem. Soc. Rev. 2011, 40, 5010.
321. C. Brancour, T. Fukuyama, Y. Mukai, T. Skrydstrup, I. Ryu, Org. Lett. 2013, 15, 2794.
322. T. S. A. Heugebaert, B. I. Roman, A. DeBlieck, C. V. Stevens, Tetrahedron Lett. 2010, 51, 4189.
323. D. R. J. Acke, C. V. Stevens, Green Chem. 2007, 9, 386.
324. C. Wiles, P. Watts, Org. Process Res. Dev. 2008, 12, 1001.
325. C. Wiles, P. Watts, Eur. J. Org. Chem. 2008, 5597.
326. S. Sharma, R. A. Maurya, K.-I. Min, G.-Y. Jeong, D.-P. Kim, Angew. Chem. Int. Ed. 2013, 52, 7564
327. Angew. Chem. 2013, 125, 7712.
328. S. Fuse, Y. Mifune, T. Takahashi, Angew. Chem. Int. Ed. 2014, 53, 851
329. Angew. Chem. 2014, 126, 870
330. S. Fuse, N. Tanabe, T. Takahashi, Chem. Commun. 2011, 47, 12661.
331. B. Reichart, G. Tekautz, C. O. Kappe, Org. Process Res. Dev. 2013, 17, 152.
332. P. Tundo, P. Venturello, E. Angeletti, J. Chem. Soc. Perkin Trans. 1 1987, 2157
333. P. Tundo, M. Selva, Green Chem. 2005, 7, 464
334. P. Tundo, Pure. Appl. Chem. 2012, 84, 441.
335. J. C. Brandt, S. C. Elmore, R. I. Robinson, T. Wirth, Synlett 2010, 3099
336. L. Audiger, K. Watts, S. C. Elmore, R. I. Robinson, T. Wirth, ChemSusChem 2012, 5, 257.
337. I. Dencic, V. Hessel, in Microreactors in Organic Synthesis and Catalysis, 2ned. (Ed.:, T. Wirth,), Wiley-VCH, Weinheim, 2013, p. 435
338. I. Dencic, V. Hessel, in Microreactors in Organic Synthesis and Catalysis, 2ned. (Ed.:, T. Wirth,), Wiley-VCH, Weinheim, 2013, p. 436.
339. T. Gustafsson, F. Pontën, P. H. Seeberger, Chem. Commun. 2008, 1100.
340. D. M. Roberge, C. Noti, E. Irle, M. Eyholzer, B. Rittiner, G. Penn, G. Sedelmeier, B. Schenkel, J. Flow Chem. 2014, 4, 26.
341. D. Ghislieri, K. Gilmore, P. H. Seeberger, Angew. Chem. Int. Ed. 2015, 54, 678
342. Angew. Chem. 2015, 127, 688.
343. The US Defense Advanced Projects Agency's (DARPA) Battlefield Medicine program has announced a research project termed Pharmacy on Demand (PoD) where end-to-end continuous manufacturing of US Food and Drug Administration (FDA) approved pharmaceuticals using miniaturized devices is proposed. For further details, see, E. J. Choi, G. S. F. Ling, PDA J. Pharm. Sci. Technol. 2014, 68, 312.
344. (R)-Rolipram:, T. Tsubogo, H. Oyamada, S. Kobayashi, Nature 2015, 520, 329
345. Ibuprofen:, D. R. Snead, T. F. Jamison, Angew. Chem. Int. Ed. 2015, 54, 983
346. Angew. Chem. 2015, 127, 997
347. Vildagliptin:, L. Pellegatti, J. Sedelmeier, Org. Process Res. Dev. 2015, 19, 551
348. Doravirine:, D. R. Gauthier, Jr., B. D. Sherry, Y. Cao, M. Journet, G. Humphrey, T. Itoh, I. Mangion, D. M. Tschaen, Org. Lett. 2015, 17, 1353
349. Taxadienone:, S. G. Krasutsky, S. H. Jacobo, S. R. Tweedie, R. Krishnamoorthy, A. S. Filatov, Org. Process Res. Dev. 2015, 19, 284
350. Telmisartan: A. Martin, A. Siamaki, K. Belecki, B. Gupton, J. Flow. Chem. DOI
351. Efavirenz:, C. A. Correia, K. Gilmore, D. T. McQuade, P. H. Seeberger, Angew. Chem. Int. Ed. 2015, 54, 4945
352. Angew. Chem. 2015, 127, 5028.