1.5- Benzodiazepines, ring syntheses

PHC431, 2005PHC389) discussions. The specialized review (1993H601) surveyed the synthesis of 1,5-benzodiazepines with three-, four- and five-membered rings fused to different positions of the 1,5-benzodiazepine skeleton. Synthesis of DNA-interactive pyrrole[2,l-c][l,4]benzodiazepines (1994CR433) and medicinal chemistry aspects of the novel thieno benzodiazepine antipsychotic Olanzapine (1997MI1743) have been reviewed. 

The first representative of ring system Type III was obtained by Sorrentino during the synthesis of 1,2,3,5-tetrahydro-3//-l,4-benzodiazepines. Ring expansion of 2-halomethyl-1 -methyl-4-phenyl-1,2,3,4-tetrahydroquinazo-lines to 1,4-benzodiazepines involves the formation of azirino[2, l-6]quina-zolines of type 30. This step is followed by cleavage of the C—N bond of the aziridine ring by the action of sodium borohydride. 

A new, broadly based synthesis of l,4-benzodiazepine-3,5-diones has been described by Bergman et al. <04JOC6371>. It utilises the A-substituted anthranilic acid 86, which was N-nitrosated to give 87 and then cyclized to the dione 89 via 88. Removal of the A-nitroso group then afforded 90 this represents a novel use of the A-nitroso group in 7-membered ring synthesis. The compound 91 was also used to prepare an A-ethoxycarbonyl derivative of 90. 

The solid-phase synthesis of 1,4-benzodiazepines has been conducted using a traceless silicon anchor 8g that was prepared via a preformed handle. Cleavage from the resin was effected with HF [352] because the anchoring group was inert to concentrated aqueous TFA due to the highly electron-deficient character of the benzodiazepine ring. 

Total synthesis of asperlicin C and E via condensation route by Bock et al. is well known [76-79,243]. The first total synthesis of asperlicin D via both cyclodehydration and intramolecular aza-Wittig routes has been fulfilled very recently by Al-Said et al. [244], and the iminophosphorane intermediates having secondary amide protons have been shown to provide a one-step entry to quinazolino[l,4]benzodiazepine ring system like asperlicin D (a positional isomer of asperlicin C). A facile route to N-benzylsclerotigenin has been reported also by this group [245]. On the other hand, total synthesis of circumdatin F (19) (and circumdatin C) via dehydrative cyclization (or ben-zoxazine) route has been also fulfilled by Bergman et aL [246]. 

Azete, trisdimethylamino-isolation, 7, 278 Azetes, 7, 237-284, 278-284 benzo fused, 7, 278 benzodiazepine fused applications, 7, 284 fused ring, 7, 341-362 structure, 7, 360 2,3-naphtho fusion, 7, 278 reactivity, 7, 279 structure, 7, 278 synthesis, 7, 282-283 Azetidine, acylring expansion, 7, 241 synthesis, 7, 246 Azetidine, 3-acyl-irradiation, 7, 239 synthesis, 7, 246 Azetidine, N-acyl-synthesis, 7, 245 Azetidine, alkyl-synthesis, 7, 246 Azetidine, 3-alkylthio-synthesis, 7, 246 Azetidine, 3-amino-synthesis, 7, 246 Azetidine, N-amino-oxidation, 7, 241 synthesis, 7, 246 Azetidine, aryl-synthesis, 7, 246... 

The same approach was readily adaptable to solid-phase synthesis. A small library of unnatural derivatives of 140 was prepared with variation of the configuration and nature of R1 and R4 and with substitution on the benzene ring <2000JC0186>. Three natural alkaloids, Verrucine A, B, and Anacine, were synthesized by a similar pathway and the pyrazino[2,l- ]quinazoline as opposed to the benzodiazepine structure of Anacine was proved <2001JNP1497>. Fiscalin B and other derivatives were prepared by solid-phase synthesis using polyethylene glycol (PEG) resin <2002USP6376667>. 

Cuny G, Bois-Choussy M, Zhu JP (2004) Palladium- and copper-catalyzed synthesis of medium- and large-sized ring-fused dihydroazaphenanthrenes and 1, 4-benzodiazepine-2, 5-diones. Control of reaction pathway by metal-switching. J Am Chem Soc 126 14475-14484... 

The alkaline hydrolysis of the l,4-benzodiazepin-2-one (236) and its 4-oxide resulted in ring opening via amide cleavage. Similarly treatment with methylamine gave (246) which proved to be a useful intermediate in the synthesis of the 3-carboxamide (247). 

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