Improved Methodology for the Preparation of Chiral Amines

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1.9. Conclusion Chirality plays an important role in nature and almost all biological reactions are highly affected by chirality. Pharmaceutical drugs which were sold as racemate proved to have lower therapeutic activity and more adverse effects compared to their single isomeric analogues. Catastrophic incidence of misuse of drug isomers forced drug regulatory agencies and pharmaceutical companies to focus on developing new drug entities in a single isomeric form. Despite the fact that agrochemicals and other fine chemicals are still marketed as racemate, many alerts suggest that selling these products in a single isomeric form will dramatically reduce the cost and toxicity. The significant importance of chiral agents derived chemists to develop various strategies for their preparation. Asymmetric synthesis is a powerful convenient way for developing new entities of chiral agents. Developing new chiral ligands for organometallic catalyst and new organocatalysts forms the core of organic chemistry research in the last three decades. Chiral amines synthesis is one of the ultimate goals for asymmetric synthesis. Chemoselective and bioselective methodologies have been developed for their synthesis. N-acetyl enamaide hydrogenation has been extensively investigated in the last two decades for α-chiral amine synthesis. It is four steps procedures for the final product with an overall yield not exceeding 50%. Several chiral ligands have been tested with rhodium catalyst for their hydrogenation resulting in 99% enantioselectivity. 1.10. References: [1] M. Simonyi, Med. Res. Rev. 1984, 4, 359. [2] E. J. Ariens, E. W. Wuis, Clin. Pharmacol. Ther. 1987, 42, 361. [3] K. Mislow,Topics Stereochem. 1999, 22, 1. [4] J. Gal, Enantiomer, 1998, 3, 263. [5] J. B. Biot, Bull. Soc. Philamoth. Paris 1815, 190. [6] a) L. Pasteur, C. R. Acad. Sci. 1848, 26, 535; b)Pasteur, L. Ann. Chim. Physique 1848, 24, 442. [7] a) J. H. van’t Hoff, Arch. Neerl. Sci. Extracts Nat. 1974, 8, 445; b) E. W. Meijer, Angew. Chem. Int. Ed. 2001, 40, 3783-3789. 28
[8] E. L. Eliel, S. H. Wilen, Stereochemistry of organic compounds, Wiley, New York, 1994, pp. 12. [9] M. Nógrádi, Stereoselective Synthesis, Wiley-VCH, Weinheim, Germany, 1995, pp. 1-3. [10] U. Meierhenrich, Amino Acids and the Asymmetry of Life, Springer-Verlag, Berlin Heidelberg, 2008, pp. 17-39. [11] R. A. Sheldon. Chirotechnology, Industrial synthesis of optically active compounds. Marcel Dekker, New York, 1993. [12] M. M. Islam, J. G. Mahdi, I. D. Bowen, Drug Safety 1997, 17, 149. [13] I. Wainer, Drug Stereochemistry: Analytical Methods and Pharmacology, 2nd Ed.; Marcel Dekker: New York, 1993. [14] a)D. Drayer, Clin. Pharmacol. Ther. 1986, 40, 125;b) K. M. Midha, G. McKay, M. J. Rawson, J. W. Hubbard, J. Pharm. Sci. 1998, 87, 797. [15] P. Knightley, H. Evans, E. Potter, M. Wallace, Suffer The Children: The Story of Thalidomide, The Viking Press, New York, 1979. [16] D. D. Leipold, D. Kantoci, Jr. Murray, E. D., D. D. Quiggle, W. J. Wechter, Chirality 2004, 16, 379. [17] C. D. Siebert, A. Hänsicke, T. Nagel, Chirality 2008, 20, 103. [18] S. Stinson, Chem. Eng. News 1998, 76, 83. [19] R. DiCicco, The future of S-(þ)-ibuprofen and other racemic switches, In Chiral’ 93 USA, Spring Innovations: Stockport, UK, 1993. [20] a) S. Houlton, Manufacturing Chemist 2002, 73, 28; b) A. M. Rouhi, Chem & Eng News 2003, 5, 56. [21] E. Francotte , W. Lindner, Chirality in Drug Research, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2006, pp.3-24. [22] F. Leusen, G. Engel, Pharm. Pharmacol. 1999, 51, 1. [23] a) J. Caldwell, Modern Drug Discov. 1999, 2, 51; b) I. Agranat, H. Caner, J. Caldwell, Nat. Rev. Drug Discov. 2002, 21, 753. [24] A.M. Rouhi, Chem. Eng. News 2003, 81, 45. [25] V. A. Davankov, Chirality 1997, 9, 99. [26] R. A. Sheldon, Chirotechnology: Industrial Synthesis of Optically Active Compounds, 2nd Ed., Marcel Dekker, New York, 1993. [26] L. Pasteur, C. R. Hebd. Seances Acad. Sci. 1853, 37, 162. [27] J. F. Larrow, E. N. Jacobsen, Org. Synth. 1998, 75, 1. 29
Page 1 and 2: Improved Methodology for the Prepar
Page 3 and 4: This dissertation is dedicated to a
Page 5 and 6: suppressing alcohol formation and p
Page 7 and 8: Prof. Mohamed El-Azizi, Prof. Abdel
Page 9 and 10: Et EtOH EtOAc GC h HPLC HRMS Hz J K
Page 11 and 12: Table of Contents Abstract. Acknowl
Page 13 and 14: 4.1.5. Synthesis of Emitine 85 4.1.
Page 15 and 16: Chapter 1 Introduction 1.1. Chiral
Page 17 and 18: 1. Cis-trans or geometric isomers.
Page 19 and 20: O O O * NH Thalidomide (R)-active a
Page 21 and 22: One enantiomer may be responsible f
Page 23 and 24: 1.5.1. Synthesis of Enantiomericall
Page 25 and 26: 1.5.2.2. Kinetic Resolution Kinetic
Page 27 and 28: compound by the auxiliary. The auxi
Page 29 and 30: 1.5.4. Stereoselective Conversion o
Page 31 and 32: It is estimated that 3000 tonnes (a
Page 33 and 34: k R R P 1 k rac S k S P 2 Figure 1.
Page 35 and 36: (S)-(α)-Methylbenzylamine and its
Page 37 and 38: fourth chapter showing different dr
Page 39 and 40: Burk was successful in reducing ary
Page 41: Table 1.1 Rhodium Catalyzed Reducti
Page 45 and 46: [42] a) J. Blacker, Innovations in
Page 47 and 48: [67] a) H. Qin, N. Yamagiwa, S. Mat
Page 49 and 50: of imine reduction in the past eigh
Page 51 and 52: 8 years beginning from the year 200
Page 53 and 54: 2.2.3. Nguyen Special Substrates. A
Page 55 and 56: Figure 2.4 General Catalyst structu
Page 57 and 58: 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
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Chapter 4 Drugs and Reductive Amina
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Scheme 4.2. Synthesis of Muraglitaz
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Studies showed that the active isom
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aminoacid producing the protected a
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O NH 2 1. p-TsOH/toluene 2. BH 3 -T
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O O 125 NH 2 a 93% O O 126 H Bu N T
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ethyl carbamate by acylation with e
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4.1.16. Synthesis of Ritonavir and
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4.2. Conclusion Different important
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Chapter 5 Stoichiometric Use of Ytt
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The unique feature of this methodol
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Ytterbium triflate is the most comm
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Ruthenium(III) chloride 31.7 4 4.2
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t-Butyl methyl ether 15 - - 82 Hexa
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2-octanone starting material. When
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3 Yb(OTf) 3 d 4 Ti(O i Pr) 4 e 5 B(
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If a [1,3]-proton shift of the init
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enhanced stereoselectivity. For exa
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WO2006030017, 2006; c) T. C. Nugent
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4 60 86 5 50 86 6 40 84 7 20 79 8 2
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The reactions described above all u
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e.g. compare entries 1, 5, 6, and 9
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solvent in the stoichiometric and c
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[2] Farina, V.; Grozinger, K.; Mül
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congested which should be favored.
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imine area % (GC analysis) time (mi
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Inversion at the nitrogen atom of t
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anti-6) would be expected to have m
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e.g. AcOH, suppresses alcohol by-pr
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eductive amination of a prochiral k
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Appendix Experimental Section Gener
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and the mixture was stirred for 30
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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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