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A three step synthesis to a β-lactam antibiotic drug Author ynthesis to a β-lactam antibiotic drug Floran Hüpscher Academy of Technology for Health and Environment Avans Hogeschool, Breda Paula Contreras Carballada Abstract In this study, the β-lactam antibiotic drug 2-Azetidinecarboxylic acid, 4-oxo-1-(phenylmethyl)-, ethyl ester (structure shown in the bottom right in figure 1) is synthesized using the commercially available chemicals ethyl glyoxylate, N - benzylhydroxylamine, trimethylsilylacetylene and cesium fluoride in a three step synthesis. In th e synthesis step, requiring a source of fluorine, TBAF (Tetra-n-butylammoniumfluoride) was used in literature but resulted in a low yield (a maximum of 31% was acquired)[1]. The low yield is possibly the result of the 5% water content in commercial TBAF so lutions[2] The aim of this study is to investigate the effect of using an anhydrous source of fluorine (cesium fluoride instead of TBAF) on the yield of the respective synthesis step. It is expected that the yield will be higher than 36%. The intermediate structure needed to synthesize the desired β-lactam product is synthesized using reflux apparatuses and is purified using column chromatography. This two-step synthesis of the intermediate is depicted in figure 1. The third and final step in the synthesis is a 96-hour reflux reaction using cesium fluoride as fluorine source. The reaction will be monitored using TLC and purified using column chromatography. The intermediates and the product are analyzed using FTIR and H -NMR spectroscopy. Keywords: β-lactam, trimethylsilyl group removal, cesium fluoride. Table of content Figure 1: The three step reaction path to synthesize β-lactam structure. [1] Chuljin. A. e. al., „A New Approach to the Synthesis of Monocyclic / beta-Lactam derivatives,” Journal of Organic Chemistry, vol. 59, nr. 21, pp. 6282-6286, 1994. [2] P. C. Carballada, „Untersuchung zur Darstellung von 5 -trimethylsilyl-substitulerten Isoxazolinen und deren Spaltung zu beta-Lactamen,” unpublished results, Berlin, 2003. 58
Isoxazoline ring opening by TBAT to form a β-lactam ring Author Linsey van Kempen Academy of Technology for Health and Environment Avans Hogeschool, Breda Paula Contreras Carballada g opening by TBAT to form a β-lactam ring Abstract Because β-lactam antibiotics are a widely used medicine, bacteria will be resistent through the excessive exposure. Therefore, new molecules with improved activity have to be found. In this research a β-lactam will be synthesized in three steps (Figure 1). The focus lies within the last step. In the research of P. Contreras Carballada there was TBAF used in this step. However, this didn’t work [1] In this experiment TBAT (Figure 2) will be examined to open the isoxazoline ring of 5 and form the β-lactam ring. A big advantage of TBAT in comparison with TBAT is that it is anhydrous [2]. The first step is the condensation of N-benzylhydroxylamine 1 with ethylglyoxylate 2 in MTBE to form 3. Isoxazoline 5 will be formed by a [3+2] cycloaddition of 3 with trimethylsilylacetylen e 4 in THF [3]. In the last step, TBAT 6 will react with 5 in THF to form β- lactam 7. The intermediates and the product will be analysed with 1 H-NMR and FT-IR. Keywords: antibiotics, TBAT, β-lactam, condensation, [3+2] cycloaddition Table of content Figure 1: Overal reaction scheme. Figure 2: Tetrabutylammonium difluorotriphenylsilicate (TBAT). [1] P. Contreras Carballada, Untersuchung zur darstellung von 5 -trimethylsilyl-substituierten isoxazolinen und deren spaltung zu bèta-lactamen, 2003 [2] P. DeShong and A. S. Pilcher, Utilization of tetrabutylammonium triphenyldifluorosilicate as a fluoride source for silicon-carbon bond cleavage, J. Org. Chem, 1996, 61, 6901 -6905 [3] P. DeShong et al, J. Org. Chem. 1994, 59, 6282-6286 59
Page 1 and 2:
Book of Abstracts Poster presentati
Page 3 and 4:
Avans University of Applied Science
Page 5 and 6:
Collaborations 5
Page 7 and 8: Preface Dear reader, We present her
Page 9 and 10: Index SPOC1 13 Tutor: Nishant Sewgo
Page 11 and 12: Group index SPOC1 The inhibition of
Page 13 and 14: The inhibition of the Pseudomonas A
Page 15 and 16: Synthesis of a surface-active RAFT-
Page 17 and 18: Synthesis for a building block for
Page 19 and 20: 19
Page 21 and 22: Group index SPOC2 In situ catalysed
Page 23 and 24: Book of abstracts SPOC 2018 3,4-uns
Page 25 and 26: Determination of activation energie
Page 27 and 28: Book of abstracts SPOC 2018 Synthes
Page 29 and 30: Group index SPOC3 Decarboxylation o
Page 31 and 32: Decarboxylation of ferulic acid to
Page 37 and 38: Group index SPOC4 The kinetics of t
Page 39 and 40: The kinetics of the Knoevenagel con
Page 41 and 42: Isolation of catalytic intermediate
Page 43 and 44: Chemical recycling to Oxazolines Au
Page 45 and 46: Group index SPOC5 Molecular Imprint
Page 47 and 48: Taxus extract Molecular Imprinted P
Page 49 and 50: MIP synthesis of 4-vinylpyridine Au
Page 51 and 52: Biobased Block-Copolymers due ATRP
Page 53 and 54: 53
Page 55 and 56: Group index SPOC6 Synthesis of Beta
Page 57: Synthesis of Beta-lactam in three s
Page 61 and 62: Synthesis of a ligand for a synthet
Page 63 and 64: Group index SPOC7 Synthesis of a te
Page 67 and 68: Synthesis of a terpyridine ligand f
Page 69 and 70: Synthesis of peptides for IR foldin
Page 71 and 72: Peptide synthesis for unravelling p
Page 73 and 74: Dear reader, Acknowledgement s Afte
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