Synthesis of Indole Annulated Benzazepine Derivative of Medicinal Interest

The ubiquity of benzazepines in medicinal chemistry is undoubtedly a consequence of the multifarious biological response which they elicit in combating a variety of body ailments.A benzazepine derivative-‘Fenoldopam mesylate’has emerged as avasodilator in peripheral arteries ansd as a diuretic in the kidneys. This discovery provided an optimism for the search of other novel agents from benzazepine class of compounds which could show a higher level of medicinal efficacy. The proposed synthesis (scheme-1) , in its first step was propelled forward with the formation of compound 1.3(which resulted from the reaction of succinyl chloride and p-fluoroaniline).The reaction of 1.3 with ethyl formate in the presence of a base formed 1.4 which underwent Japp-Klingemann reaction with aryl diazonium chloride followed by cyclocondensation with acid under the conditions of Fischer indolization to give indole substituted derivative 1.5.


INTRODUCTION
Benzazepine moiety occurs frequently in both natural and synthetic drugs and is of highly biological interest.The use of this class of compound is not merely confined to the management of stress related conditions and for their use as antibacterial agents 1,3 , but their additional applications are continuously emerging.Galantamine(Galanthamine), a benzazepine derived from norbelladine,has been studied in the treatment for Alzheimer disease 4 .In a quest to develop easily accessible routes to the synthesis of some novel heteroring annulated benzazepine derivatives, the present investigation aims to examine the operational feasibility of

MATERIALS AND METHOD
P-fluoroaniline and succinyl chloride were the product of Fischer Scientific.All the chemicals employed for synthesis were of analytical grade and were used as supplied without further purification.All the solvents were dried and distilled before use.Melting points were determined in open glass capillaries and are uncorrected.The purity of the compounds was checked by TLC on silica gel(G) plates .The visualization of spot was carried in an iodine chamber.IR spectra were recorded on CE(SHIMADZU)FTIR-8400S.1 H NMR spectra were recorded on model AC-300F(Brucker) using CDCl3/DMSO-d6 as solvent and TMS as an internal reference.Chemical shift are expressed in d ppm.

Friedel craft reaction
Compound above prepared(2.58g)was mixed with PPA(5g) and heated at 150-160°C for 4hr (the process of the reaction was monitored by TLC).The reaction mixture was cooled to 20°Cand concenterated salt of Na 2 CO 3 was added to make it alkaline.The product was extracted with ethyl acetate (3x10 ml).The extract was dried overNa 2 SO 4 and concenterated in vaccum.The residue was purified by column chromatography of silica gel with CHCl 3 as an eluent to give compound 1.3.yield60%,m.p.120-122 °C.

Cyclization of hydrazone
A solution of hydrazone above prepared (3.18g) in a mixture of acetic acid(19.0ml)and hydrochloric acid(4.7 ml)was refluxed on an oil-bath preheated to 125-130°C for 0.5 hours.The contents were then cooled and poured into cold water with stirring.The separated brown solidwas purified by passing through a column of silica gel using 50% benzene in petroleum ether as eluent.yield66%,m.p.133-135°C.

RESULTS AND DISCUSSION
Scheme -1 envisaged that the reaction of 1.3 with ethyl formate in presence of a base formed 1.4 which undergo Japp-Klingemann reaction with aryl diazonium chloride followed by cyclocondensation with acid under the conditions of Fischer indolization to give indole ring substituted derivative 1.5

IR spectra
Infrared spectra of compound 1.3 on KBr pellet exhibited strong absorption bands at 1660cmand 1700cm-for the carbonyl group of CONH and CO groups respectively,along with this IR spectum also exhibited bands at 3400cm
Scheme 1: 1 H NMR spectra 1H NMR spectrum of compound 1.3 in CDCl 3+ DMSO-d6 displayed signals for the presence of 8 protons.Appearence a downfield broad singlet for 1H at d8.0 was attributed to NH group.Appearence of multiplet at d 7.40-7.87wasassignedto the three protons of fluorobenzene ring.A singlet for four protons which appeared at d2.93 and d2.42 was attributed to two CH2 groups of azepanedione ring.