The synthesis of novel indazole alkaloids with potential medicinal properties.

ELHMALYE, Elsanoussi. (2005). The synthesis of novel indazole alkaloids with potential medicinal properties. Masters, Sheffield Hallam University (United Kingdom)..

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The black seeds of Nigella sativa Lin. are universally accepted as a panacea. In particular the black seed oil extract has been shown to have bronchodilatory, antidiabetic, antibacterial, antifungal, analgesic, anti-inflammatory, and immunopotentiang activities. Four principal alkaloids Nigellicine 1, Nigellimine W- oxide 2, Nigellimine 3 and Nigellidine 4 have been isolated from Nigella sativa Linn. The isoquinoline alkaloids 2 and 3 have recently been synthesised in these laboratories. The aim of this research programme was to prepare the other two compounds, by two alternate routes I and II, so that their pharmacological properties could be elucidated subsequently. Route I represented a novel approach in which four p-monoacylated acid hydrazides 7a-d were prepared for cyclisation into indazoles 8a-d. Reaction of phenylhydrazine with benzoyl chloride, 4-benzyloxy benzoyl chloride and 4-nitrobenzoyl chloride gave hydrazides 7a-c whilst reaction of and 2-ethylphenyl hydrazine with 4-nitrobenzoyl chloride produced 7d. All the four acid hydrazides 7a- d failed to cyclise to yield indazoles 8a-d in polyphosphoric acid (PPA), polyphosphate ester and cone.sulphuric acid at a variety of reaction temperatures (60- 160°C). However, 4-nitrobenzoyl 2-ethylphenylhydrazide with tosic acid cyclised in refluxing xylene to give 7-ethyl-3-(4'-nitrophenyl)-7-indazole 8c in 37.5% yield. By route II the indazole 47 was prepared from 2,4,6-trimethoxyacetophenone and hydrazine hydrate in PPA in only 6-16% yield (lit. 65% yield). The reaction of 2,4,6-trimethoxyphenyl a-ketoester 65 and 2,4,6-trimethoxy phenyl a-ketoacid 66 with hydrazine hydrate and benzylhydrazine dihydrobromide failed to produce indazole products on heating in glacial acid, PPA, DMF and xylene. Retrosynthesis of Nigellidine required trimethoxyphenyl 4-benzyloxyphenyl ketone 53 as a starting material which failed by Friedel-Crafts acylation of 1,3,5-trimethoxybenzene with 4-benzyloxybenzoyl chloride. 2,4,6-Trimethoxy benzaldehyde and 4-benzyloxyphenyl magnesium bromide reacted in THF to give the alcohol 52 which resisted oxidation to ketone 53 by several methods. Oxidation of the alcohol with TEMPO successfully gave the ketone 53 albeit in a low yield. While it was not possible to obtain Nigellicine 1 and Nigellidine 4 the present studies have progressed understanding of the synthetic pathways. Some strategies are proposed to enable future work to be undertaken to obtain these alkaloids.

Item Type: Thesis (Masters)
Thesis advisor - Khan, Akram [0000-0002-0386-3667]
Thesis advisor - Rainsford, Kim
Additional Information: Thesis (M.Phil.)--Sheffield Hallam University (United Kingdom), 2005.
Research Institute, Centre or Group - Does NOT include content added after October 2018: Sheffield Hallam Doctoral Theses
Depositing User: EPrints Services
Date Deposited: 10 Apr 2018 17:19
Last Modified: 03 May 2023 02:05

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