Improved Methodology for the Preparation of Chiral Amines

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carbonyldiimidazole (CDI) to give amide (25). The nitro group is reduced under hydrogenation conditions using Pd-C. The resulting amine is then sulfonylated with methanesulfonyl chloride to provide delavirdine, which is then transformed to delavirdine H N Cl N N H 20 21 mesylate (3). NO 2 1) CH 2 Cl 2 96% 2) (Boc) 2 O96% BocN O 2 N N N 22 1) Pd/C, H 2 ,78% 2) acetone NaCNBH 3 91% O 2 N 24 N H HN COOH N HN 23 N CDI or EDC 74% S H N HN O O CH 3 SO 3 H N O H 3 N N N 1) H 2 , Pd/C, 66% 2) CH 3 SO 2 Cl, pyr, CH 2 Cl 2 3) CH 3 SO 3 H O 2 N N H HN N O 25 N N Scheme 4.1. Synthesis of Delavirdine. 4.1.2. Synthesis of Muraglitazar: Muraglitazar is developed to treat hyperglycemia and dyslipidemia through decrease triglycerides and increase HDL cholesterol with minimal effects on LDL cholesterol. [2] Several syntheses have been developed for its efficient preparation. Synthesis starts with the alkylation of 4-hydroxybenzaldehyde with phenyloxazolemesylate (23), which can be easily synthesized from commercially available alcohol (22), resulting in the aldehyde (24) synthesis. The aldehyde is then treated with glycine methyl ester under reductive amination conditions to provide secondary amine (25) in an excellent yield. Reaction of amine (25) with 4-methoxyphenyl chloroformate followed by hydrolysis of the methyl ester afforded Muraglitazar in 94% yield. 82
Scheme 4.2. Synthesis of Muraglitazar. 4.1.3. Synthesis of Amphetamine: Amphetamines synthesis is one of the well known classical examples of drugs synthesised utilising reductive amination. [2] Other methodologies were also developed for there synthesis as the direct displacement of a leaving group by an amine, nitro alkane addition followed by reduction of the nitro group and metal-promoted amination of an unsaturated carbon compound. The reductive amination of methyl benzyl ketone was one of the earliest strategies used in amphetamine synthesis. Despite being developed in the thirties of last century it continues to be one the best developed methodologies because of its simple elegance and the availability of cheap starting materials. According to the developed methodology, oxime is formed as a mixture of isomers upon exposure of the ketone to hydroxylamine hydrochloride under mildly basic conditions. 83
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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
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
Page 95: Chapter 4 Drugs and Reductive Amina
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 and 140: solvent in the stoichiometric and c
Page 141 and 142: [2] Farina, V.; Grozinger, K.; Mül
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Page 145 and 146: 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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Improved Methodology for the Preparation of Chiral Amines

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