Improved Methodology for the Preparation of Chiral Amines

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hormone noradrenaline. The (R)-enantiomer of the betablocker does not give serious sideeffects, but it does not add to the pharmacological effect either, so it can be considered as ‘isomeric ballast’. The most sold beta-blockers (propranolol, atenolol, metoprolol) were developed in the 1970s and are still marketed as racemate. If these substances would have been developed today, it can be expected that they would have been introduced as a single enantiomer. [17] Therefore from the points of view of safety and efficacy, the pure enantiomer is preferred over the racemate in many marketed dosage forms. In past decades the pharmacopoeia was dominated by racemates, but since the emergence of new technologies in the 1980s that allowed the preparation of pure enantiomers in significant quantities, the awareness and interest in the stereochemistry of drug action has increased. Although some ‘‘blockbuster’’ drugs, such as fluoxetine hydrochloride (Prozac) is still marketed as racemates. However, the recent trend is toward marketing a single-enantiomer drugs. [18] Previously the chiral drug is often synthesized in the racemic form, and it is frequently costly to resolve the racemic mixture into the pure enantiomers. Another approach by pharmaceutical companies is what is called racemic switch. This fashionable approach involves the development of a pure enantiomer of the drug that is already marketed as a racemate. This means if a patent on a drug that is marketed as a racemic mixture is expiring; it is sometimes possible to obtain a new patent for the active enantiomer. In this way, the pharmaceutical company retains the exclusive rights on the substance for another period, but they will have to change their manufacturing method as well. [19] Although only a minority of all racemic drugs has proved to be suitable for a racemic switch, this development has boosted the development of new manufacturing and separation methods. An example of a successful racemic switch is the local anaesthetic bupivacaine (AstraZeneca's Marcain). The (S)-isomer is now marketed under the trade name Chirocaine. This isomer was found to be substantially less cardiotoxic than the (R)-isomer, and therefore a new patent was granted. Furthermore, the (S)-isomer of omeprazole (a proton pump inhibitor by AstraZeneca, known as Losec/Prilosec) is now marketed as a single enantiomer under the trade name Nexium. [20] 6
One enantiomer may be responsible for the activity; its paired enantiomer could be inactive, possess some activity of interest, be an antagonist of the active enantiomer or have a separate activity that could be desirable or undesirable. To market drug as racemate or as the enantiomeric pure form is mainly based on pharmacology, toxicology and economics. From a pharmaceutical perspective, the physical properties of both the racemate and the enantiomer should be characterized in detail in order to develop a safe, efficacious, and reliable formulation, no matter whether the racemate or the enantiomer pure form is chosen as the marketed form. Chirality of a drug can also influence the efficiency of delivery, which has not been well investigated in the pharmaceutical field. [21] Density, solubility, dissolution behaviour, stability, and mechanical properties which are the many physical properties of a crystalline solid, are governed by the crystal structure. [22] Understanding the relationship between the crystal structure and the physical properties, and their influence on drug release, may therefore provide a clear picture of chirality–delivery relationship. This discussion supports the fact that using single enantiomeric pure form of a drug has major advantages as reducing the overall administered dose, improving drug therapeutic window, reducing any intersubject variability and finally estimating the dose response relationship accurately. [23] All previously reported reasons have led to an increasing preference for production of the single enantiomers in both industry and regulatory authorities. Regulation regarding control of chiral drugs began in the US with a publication in 1992 about the formal guidelines on the development of chiral drugs in a document entitled Policy Statement for the Development of New Stereoisomeric Drugs by FDA and European Union. The major outlines for the guidelines state that the drug applicants must recognize the occurrence of chirality in the new drugs, attempt to separate the stereoisomers, assess the contribution of the various stereoisomers to the activity of interest and make a rational selection of the stereoisomeric form that is proposed for marketing. Global sales of chiral drugs in single-enantiomeric form continue to grow. The annual sales of chiral drugs as a single enantiomeric form increased dramatically, from 27% (US $74.4 7
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: O O O * NH Thalidomide (R)-active a
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 and 42: Table 1.1 Rhodium Catalyzed Reducti
Page 43 and 44: [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
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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
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compared to the oil refinery indust
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[14] V. I. Tararov, R. Kadyrov, T.H
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[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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Improved Methodology for the Preparation of Chiral Amines

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