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The Synthesis of Novel Analogues of the Antitumour Antibiotic Pyrrolobenzodiazepines.

By Christopher Steven Chambers


In this thesis, the novel synthesis of tetra- and triazolo-analogues of the pyrrolobenzodiazepines,\ud pyrrolobenzothiadiazepines, benzodiazepines and benzothiadiazepines are described. These\ud compounds are of great interest as synthetic targets due to their potential medical properties. The key processes are the intramolecular 1,3-dipolar cycloaddition between the azide and the nitrile present in compound (1), the azide and the alkyne present in compound (2) the azide and the alkene present in compound (3), to form the novel final compounds of type (4). The synthesis of these precursors from readily available starting materials is discussed.\ud \ud \ud The intramolecular 1,3-dipolar cycloaddition of the alkene with the azide (3) afforded the triazoline(4, Z = CH2) which upon nitrogen extrusion formed either the methyl imine (5) or an aziridine (6) as shown in the Scheme on the next page. Reactions of other alkenes, more highly substituted than compound (3) are also described.\ud \ud \ud This thesis will also describe a general route to triazolobenzodiazepines and triazolobenzothiadiazepines (7, X = CO, SO2; Z = CH). The reactions of the corresponding nitriles\ud (7, X = CO, SO2; Z = N) will also be described, as with other approaches to the\ud pyrrolobenzodiazepines

Topics: Q1, QD
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  5. 131.6 (q), 133.6 (CH), 138.4 (q), 167.3 (q). max (thin film cm ArH),
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  16. concentrated to give the product as a pure orange oil (1.61 g, 96%). δH (400 MHz, CDCl3): 1.67-1.78 (1H, m, CHH), 1.79-1.99 (3H, m, CHH + CH2), 2.79 (1H, bs, CH2OH), 3.38 (1H, dt,
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  28. was added slowly and the whole was stirred for 18 hours. The organic layer was separated and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organics were dried

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