Synthesis of pyrido[1,2-b][2,4]benzodiazepin-6(11H)-one and related compounds

Abstract

Pyrido [l,2-6] [2,4] benzodiazepin-6(1 IH)-one and its 1,2.3,4,4a,5-hexahydro-derivative have been prepared.Some chemical properties and reactions of these novel ring systems have been explored. DURING attempts to synthesise compounds of potential biological interest, the betaine (2) was treated with phosphoryl chloride to give a product assigned the pyrido--1,2-b] [2,4]benzodiazepinone structure (4) on the basis of analytical and spectral evidence (see Experimental section). This synthesis was further explored.I t was found more convenient to prepare compound (4) and its S-chloro-and 10-methoxycarbonyl derivatives directly from the corresponding pyridinium salts [e.g. (l)] by treatment with sodium methoxide in methanol. Prer i a Br'_ ' c 2 ' a sumably the reagent abstracts hydrogen bromide leaving an iminopyridone which cyclises by nucleophilic attack \ COzMe NH2 (3) 1 0 15)on the ester function. However, treatment of compound (1) with benzylamine gave 2-(2-pyridy1)isoindolin-l-one (5); this reaction may be rationalised in terms of an initial Dimroth rearrangement to form the benzylaminopyridine (3) which cyclises to structure (5) under the basic conditions.Catalytic hydrogenation of the pyridobenzodiazepinone (4) afforded the hexahydro-analogue (6), which under more vigorous conditions suffered ring cleavage to give the amide (7). N-Alkylation of the hexahydropyridodiazepinones proved difficult, but the methyl (9) and ethyl (10) analogues were prepared from compound (6) by use of the appropriate alkyl tosylate and sodium hydride. Lithium aluminium hydride reduction of compound (6) and its alkyl derivatives removed the carbonyl function to give the octahydropyridobenzodiazepines ( l l ) , (12), and (13), respectively, but under more vigorous conditions compound (6) gave the benzylamine (8). Nitration of compound (6) afforded the %nitro-derivative but attempted halogenation was unsuccessful. v The formation, i n situ, of an imino-chloride from compound (6) and phosphoryl chloride, and subsequent treatment with ammonia, led to decomposition. Similarly, no tractable product was obtained by treatment of the imino-ether of compound (6) with ammonia.However a 6-amino-derivative (14) was prepared from the reaction of 2-amino-l-(2-cyanobenzy1)pyridinium chloride with sodium 2-ethoxyethoxide in 2-ethoxy-HC[ qoa O R (9) R = M e (10) R = Et 1 ethanol followed by treatment with hydrogen chloride: Treatment of compound (6) with methyl iodide gave a quaternary derivative (15), which on reduction with lithium aluminium hydride suffered cleavage of the 4a,12-bond to form the diazacycloundecene (IS), possibly via an internal Hofmann elimination. fJ-0 R (11) R = H . (12) R = M e (13) R = Et -N N H3+ (14) EXPERIMENTAL KFJ*-K$J 2-Anzino-l-(2-metlzoxycavbonyZbenzyl)~y~idiniunz Bromide \ (1) .-Bromine (49 nil) in carbon tetrachloride (300 ml) was

Synthesis of Novel Pyrido[1,2-b][2,4]Benzodiazepine Derivatives

“…The characteristic property of their 1 H NMR spectra was the presence of a proton signal for a methylene group C (11) H 2 as an AB-system with 2 J = 13.5-15.0 Hz, that was correlated with the formation of a sufficiently inflexible cyclic structure in which conformational transformations are fixed. The assignment of the proton signals in 1 H NMR spectra and carbon signals in 13 C NMR spectra was completed on the base of COSY, NOESY, HMQC and HMBC experiments for compound 5a. The final confirmation of the structure of the pyrido[1,2-b] [2,4]benzodiazepine derivatives was based on X-ray data for 5a (Fig.…”

“…At present, less than 40 representatives of the above system have been described, the majority of which are partially hydrogenated derivatives. The first report of the synthesis of pyrido [1,2-b] [2,4]benzodiazepine derivatives appeared in 1971, 1 when the cyclisation of 2-amino-1-(2carboxybenzyl)pyridinium salts was described, which leads to 6-oxo-6,11-dihydro-derivatives of this heterocyclic system. A few methods for the synthesis of these compounds are known today.…”

“…2 In another example, the diazepine ring was added to a pyridine by using 2-bromomethylbenzoic acid derivatives. 1,[3][4][5] We now describe a new method for the synthesis of pyrido [1,2-b] [2,4]benzodiazepines which is based on the reaction of [2-(bromomethyl)phenyl](phenyl) methanone (о-bromomethylbenzophenone, 1) derivatives with 2-aminopyridines (2). Substances of type 1 are α-bromoacetophenone 7 viniloges, 6 which suggests the possibility of a cyclisation that is similar to the Chichibabin synthesis.…”