Improved Methodology for the Preparation of Chiral Amines

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eductive amination of the prochiral ketone resulting in 80% ee with 60% yield. They also tested reduction of isolated imine resulting in the same enantioselectivity and with unacceptable chemical purity. Higher ees are usually required for pharmaceutical development levels. Later they tested the chiral auxiliary approach for the synthesis of chiral amine moiety. They tested different derivatives of MBA and phenylglycinaol. They reported 86% yield with 90% de which was improved by crystallization. The instability of substituents under hydrogenolysis standard conditions was another challenge. BCl 3 and BBr 3 gave the cleanest N-debenzylation without affecting the chloro substituent and tetrahydrocarbazole moiety. Cl HCO 2 NH 4 ,MeOH,60 o C Cl N H O N NH 2 H 80% ee, yield 60% NH 3 (7N in MeOH) TsOH SO 2 N Ru N H 2 Cl Cl N H NH [RuCl 2 (benzene)] 2 Cl HCO 2 NH 4 ,MeOH,65 o C N H 81% ee NH 2 PPh 2 Cl N H O p-TsOH, or conc.HCl toluene, reflux H 2 N X Cl PPh 2 N H N Y X 1. NaBH 4 EtOH, -30 o CtoRT 2. HCl Cl N H (R) HN Y X Cl Y Cl N H HN OMe 1. BCl 3 ,DCM,0 o C 2. Scheme 4.17. Synthesis of Tetrahydrocarbazoles: N COOH,i-PrOH 80-92% Cl N H N ee 99.2% NH 2 COOH T3P (50% in EtOAc) i-Pr 2 NEt, DCM, 0 o C 60-87% Pr T3P= O O P P O Pr O O P Pr O Cl N H HN O Tetrahydrocarbazoles ee >99.5% N 96
4.2. Conclusion Different important pharmaceutical and natural products are prepared industrially utilizing reductive amination as a key step in their preparation. Reductive amination is the method of choice for incorporating amino group in the drug entity as it is a single step process which is highly preferable from the industrial point of view. Most of the developed methodologies for the reductive amination utilized boran as a reducing agent which suffers from many drawbacks as the large toxic waste production. In the last ten years scientists focused their efforts on developing an asymmetric version of reductive amination utilizing environmentally friendly hydride source as molecular hydrogen. 4.3. References: 1] D. L. Romero, R. A. Morge, C. Biles, N. Berrios-Pena, P. D. May, J. R. Palmer, P. D. Johnson, H. W.Smith, M. Busso, C. -K Tan,R. L. Voorman, F. Reusser, I.W. Althaus, K. M. Downey,A. G. So, L. Resnick, W.G. Tarpley, P. A. Aristoff, J. Med. Chem. 1994, 37, 999. [2] D. S. Johnson, J.J. Li, The Art of Drug Synthesis, Wiley & Sons, New Jersey, 2007. [3] M. Lautens and T. Rovis, J. Org. Chem. 1997, 62, 5246; [4] E. J. Corey and T. G. Gant, Tetrahedron Lett. 1994, 35, 5373. [5] S. Takano, M. Sasaki, H. Kanno, K. Shishido, K. Ogasawara, J. Org. Chem.1978, 43, 4169. [6] T. Fujii, S. Yoshifuji, Tetrahedron 1980, 36, 1539 . [7] D. Lednicer, The Organic Chemistry of Drug Synthesis, Wiley & Sons, New Jersey, 2008. [8] D. Lednicer, Strategies for Organic Drug Synthesis and Design, Wiley & Sons, New Jersy, 2009. [9] C. Loncle, C. Salmi, Y. Letourneux, J. M. Brunel, Tetrahedron 2007, 63, 12968. [10] J. Y. Jung, S. H. Jung a, H. Y. Kohb, European Journal of Medicinal Chemistry 2007, 42, 1044. [11] D. Menche, F. Arikan, J. Li, S. Rudolph, Org. Lett. 2007, 9, 267. 97
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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
Page 59 and 60: H 2 , toluene, 25 °C, 4 h an ee of
Page 61 and 62: 1). They described the role of each
Page 63 and 64: More recently, 2008, he described t
Page 65 and 66: [22] E. Guiu, M. Aghmiz, Y. Diaz, C
Page 67 and 68: Chapter 3 Reductive Amination 3.1.
Page 69 and 70: . CH 3 CO(CH 2 ) 5 CH 3 H 2 NCH 2 C
Page 71 and 72: superior in terms of conversion (89
Page 73 and 74: O NHR 3 R 4 R 4 R 3 N OTi(O i Pr) 3
Page 75 and 76: Scheme 3.9. Synthesis of (S)-Metola
Page 77 and 78: groups decreased both the enantiose
Page 79 and 80: progress of the reaction was monito
Page 81 and 82: attempts were directed for the asym
Page 83 and 84: hydrogen bonding, is chiral and its
Page 85 and 86: Later he utilized this methodology
Page 87 and 88: 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: 4.1.16. Synthesis of Ritonavir and
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 and 140: solvent in the stoichiometric and c
Page 141 and 142: [2] Farina, V.; Grozinger, K.; Mül
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
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etention time [min]: major (S,S)-2b
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time [min]: major (S,S)-2c isomer,
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obtain the hydrochloride salt (0.41
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with etheral HCl provided the hydro
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Research experience: Date Project S
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