Improved Methodology for the Preparation of Chiral Amines

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6.3. Conclusion: I developed the use of catalytic quantities of Lewis acids in reductive amination for the first time. The use of catalytic quantities of Yb(OAc) 3 or Y(OAc) 3 or Ce(OAc) 3 proved to be efficient in reducing the alcohol by product formation and to produce the secondary amine in good yield and normal de. No enhancement of the de resulted from the use of catalytic quantities of Lewis acids. Other Lanthanide salts were also successful in suppressing alcohol formation but with lower efficiency. Brønsted acids were used historically in reductive amination but without enough reports on their role in reductive amination. I have conducted extensive study on the use of different Brønsted and mineral acids in reductive amination. 20 mol % of acetic acid and formic acid proved to be efficient in suppressing alcohol formation in reductive amination. The use of mineral acids resulted in more alcohol formation (20-30 area % GC). Reductive amination of sterically congested ketones and also aromatic ketones are best performed using Ti(O i Pr) 4 not catalytic amount of Lewis acids nor Brønsted acids. 6.4. References: [1] For advances in the diastereoselective reduction of (R)- or (S)-α-MBA ketimines, see: (a) Nichols, D. E.; Barfknecht, C. F.; Rusterholz, D. B. J. Med. Chem. 1973, 16, 480. (b) Clifton, J. E.; Collins, I.; Hallett, P.; Hartley, D.; Lunts, L. H. C.; Wicks, P. D. J. Med. Chem. 1982, 25, 670. (c) Eleveld, M. B.; Hogeveen, H.; Schudde, E. P. J. Org. Chem. 1986, 51, 3635- 3642. (d) Bringmann, G.; Geisler, J.-P. Synthesis 1989, 608. (e) Marx, E.; El Bouz, M.; Célérier, J. P.; Lhommet, G. Tetrahedron Lett. 1992, 33, 4307. (f) Moss, N.; Gauthier, J.; Ferland, J.-M. Synlett 1995, 142. (g) Lauktien, G.; Volk, F.-J.; Frahm, A. W. Tetrahedron: Asymmetry 1997, 8, 3457. (h) Bisel, P.; Breitling, E.; Frahm, A. W. Eur. J. Org. Chem 1998, 729. (i) Gutman, A. L.; Etinger, M.; Nisnevich, G.; Polyak, F. Tetrahedron: Asymmetry 1998, 9, 4369. (j) Cimarelli, C.; Palmieri, G. Tetrahedron: Asymmetry 2000, 11, 2555. (k) Storace, L.; Anzalone, L.; Confalone, P. N.; Davis, W. P.; Fortunak, J. M.; Giangiordano, M.; Haley, J. J. Jr.; Kamholz, K.; Li, H.-Y.; Ma, P.; Nugent, W. A.; Parsons, R. L. Jr.; Sheeran, P. J.; Silverman, C. E.; Waltermire, R. E.; Wood, C. C. Org. Process Res. Dev. 2002, 6, 54. 126
[2] Farina, V.; Grozinger, K.; Müller-Bötticher, H.; Roth, G. P. Ontazolast: The Evolution of a Process. In Process Chemistry in the Pharmaceutical Industry; K. G. Gadamasetti, Ed.; Marcel Dekker, Inc.: New York, 1999, pp 107–124. [3] a) T. C. Nugent, A. K. Ghosh, V. N. Wakchaure, R. R. Mohanty, Adv. Synth. Catal. 2006, 348, 1289; b) T. C. Nugent, Chiral Amine Synthesis - Strategies, Examples, and Limitations. In Process Chemistry in the Pharmaceutical Industry, Second Edition: Challenges in an Ever-Changing Climate, T. F. Braish, K. Gadamasetti Eds.; CRC Press-Taylor and Francis Group: New York, 2008; c) T. C. Nugent, A. K. Ghosh, V. N. Wakchaure, R. R. Mohanty, WO2006030017, 2006; d) T. C. Nugent, V. N. Wakchaure, A. K. Ghosh, R. R. Mohanty, Org. lett. 2005, 7, 4967; e) T. C. Nugent, A. K. Ghosh, Eur. J. Org. Chem. 2007, 3863. 127
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Improved Methodology for the Prepar
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This dissertation is dedicated to a
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suppressing alcohol formation and p
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Prof. Mohamed El-Azizi, Prof. Abdel
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Et EtOH EtOAc GC h HPLC HRMS Hz J K
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Table of Contents Abstract. Acknowl
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4.1.5. Synthesis of Emitine 85 4.1.
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Chapter 1 Introduction 1.1. Chiral
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1. Cis-trans or geometric isomers.
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O O O * NH Thalidomide (R)-active a
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One enantiomer may be responsible f
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1.5.1. Synthesis of Enantiomericall
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1.5.2.2. Kinetic Resolution Kinetic
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compound by the auxiliary. The auxi
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1.5.4. Stereoselective Conversion o
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It is estimated that 3000 tonnes (a
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k R R P 1 k rac S k S P 2 Figure 1.
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(S)-(α)-Methylbenzylamine and its
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fourth chapter showing different dr
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Burk was successful in reducing ary
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Table 1.1 Rhodium Catalyzed Reducti
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[8] E. L. Eliel, S. H. Wilen, Stere
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[42] a) J. Blacker, Innovations in
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[67] a) H. Qin, N. Yamagiwa, S. Mat
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of imine reduction in the past eigh
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8 years beginning from the year 200
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2.2.3. Nguyen Special Substrates. A
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Figure 2.4 General Catalyst structu
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2.3.2. Different Substrates Categor
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H 2 , toluene, 25 °C, 4 h an ee of
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1). They described the role of each
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More recently, 2008, he described t
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[22] E. Guiu, M. Aghmiz, Y. Diaz, C
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Chapter 3 Reductive Amination 3.1.
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. CH 3 CO(CH 2 ) 5 CH 3 H 2 NCH 2 C
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superior in terms of conversion (89
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O NHR 3 R 4 R 4 R 3 N OTi(O i Pr) 3
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Scheme 3.9. Synthesis of (S)-Metola
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groups decreased both the enantiose
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progress of the reaction was monito
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attempts were directed for the asym
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hydrogen bonding, is chiral and its
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Later he utilized this methodology
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OMe OMe O HN HN HN O 2 N 71 % yield
Page 89 and 90: compared to the oil refinery indust
Page 91 and 92: [14] V. I. Tararov, R. Kadyrov, T.H
Page 93 and 94: [55] a) R. Kadyrov, T. H. Riermeier
Page 95 and 96: Chapter 4 Drugs and Reductive Amina
Page 97 and 98: Scheme 4.2. Synthesis of Muraglitaz
Page 99 and 100: Studies showed that the active isom
Page 101 and 102: aminoacid producing the protected a
Page 103 and 104: O NH 2 1. p-TsOH/toluene 2. BH 3 -T
Page 105 and 106: O O 125 NH 2 a 93% O O 126 H Bu N T
Page 107 and 108: ethyl carbamate by acylation with e
Page 109 and 110: 4.1.16. Synthesis of Ritonavir and
Page 111 and 112: 4.2. Conclusion Different important
Page 113 and 114: Chapter 5 Stoichiometric Use of Ytt
Page 115 and 116: The unique feature of this methodol
Page 117 and 118: Ytterbium triflate is the most comm
Page 119 and 120: Ruthenium(III) chloride 31.7 4 4.2
Page 121 and 122: t-Butyl methyl ether 15 - - 82 Hexa
Page 123 and 124: 2-octanone starting material. When
Page 125 and 126: 3 Yb(OTf) 3 d 4 Ti(O i Pr) 4 e 5 B(
Page 127 and 128: If a [1,3]-proton shift of the init
Page 129 and 130: enhanced stereoselectivity. For exa
Page 131 and 132: WO2006030017, 2006; c) T. C. Nugent
Page 133 and 134: 4 60 86 5 50 86 6 40 84 7 20 79 8 2
Page 135 and 136: The reactions described above all u
Page 137 and 138: e.g. compare entries 1, 5, 6, and 9
Page 139: solvent in the stoichiometric and c
Page 143 and 144: congested which should be favored.
Page 145 and 146: imine area % (GC analysis) time (mi
Page 147 and 148: Inversion at the nitrogen atom of t
Page 149 and 150: anti-6) would be expected to have m
Page 151 and 152: e.g. AcOH, suppresses alcohol by-pr
Page 153 and 154: eductive amination of a prochiral k
Page 155 and 156: Appendix Experimental Section Gener
Page 157 and 158: and the mixture was stirred for 30
Page 159 and 160: Reaction details: Yb(OAc) 3 (1.1 eq
Page 161 and 162: etention time [min]: major (S,S)-2b
Page 163 and 164: time [min]: major (S,S)-2c isomer,
Page 165 and 166: obtain the hydrochloride salt (0.41
Page 167 and 168: with etheral HCl provided the hydro
Page 169 and 170: Research experience: Date Project S
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