1.5- Benzodiazepines hydrolysis

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

It has been shown that glyeine amides of aminobenzophenones are readily converted to the corresponding benzodiazepines in vivo. Peptides which terminate in such a moiety should thus serve as a benzodiazepine prodrug after hydrolysis by peptidases. One of the glycine residues in lorzafone (194)is presumably removed metabolicaUy in this manner to give a benzodiazepine precursor which spontaneously cyclizes. Acylation of benzophenone 190 with the trityl protected dipeptide 191, as its acid chloride 192, affords the amide 193. Removal of the trityl protecting group with acid yields lorzafone (194) [50]. 

Methyl l//-l,2-benzodiazepine-3-carboxylate (1) reacts with lead(IV) acetate to give the 5-acetoxy-5//-1,2-benzodiazepine 2, which is converted into the 1//-tautomer 3 in the presence of triethylamine in benzene. Further treatment of 3 with triethylamine in methanol results in hydrolysis to yield the benzodiazepinone 4. 25... 

Alkaline hydrolysis of 3-acetoxy-7-chloro-5-phenyl-l//-l,4-benzodiazepin-2(3//)-one (24b) gives the corresponding hydroxy compound 25.236... 

Alkaline hydrolysis of 1/7-1,4-benzodiazepin-2(3//)-one 4-oxides results in ring opening, e.g. formation of l.223-224... 

Benzodiazepines 1 are colorless, basic compounds which are highly susceptible to hydrolysis. They form stable, deeply colored salts 2 containing extensively delocalized cations. In stronger acids colorless diprotonated species 3 are produced. 

Alkaline hydrolysis gives either 3//-l,5-benzodiazepine-2,4-diamine (5) or the benzo-triazepine 6 (see Section 4.2.4.4.2.). depending on the strength of the alkali. With hot water the benzimidazole 7 (see Houben-Weyl, Vol.E8c, p 1315) is produced.254... 

Acidic hydrolysis of benzodiazepine 4 gives 2-(cyanomethyl)benzimidazole hydrochloride 8.288... 

Titanium(III) chloride (particularly in slightly alkaline medium) reduces the p-nitro groups of the thiophosphate insecticides to amino groups, which are then reacted with nitrite in acid mediiun in a second step to yield a diazonium compound as intermediate. This is then coupled to N-(l-naphthyl)-ethylenediamine dihydrochloride to yield an azo dye [3]. In the case of benzodiazepines the first reaction step includes an additional acid hydrolysis to the corresponding benzophenone derivative [2]. 

A A,A-dimethylcarboxamido group attached to other aromatic systems can be hydrolyzed enzymatically as demonstrated by the metabolism of the ring-opened 1,4-benzodiazepine derivative 4.84 in dogs and rats [53], Here also, hydrolysis was shown to proceed via the secondary and primary amide formed by A-demethylation. 

Hydrolytic cleavage of a seven-membered ring occurs in the metabolism of chlordiazepoxide (5.82, Fig. 5.22,a) and other benzodiazepines (see also Sect. 11.9). The lactam ring opened metabolite 5.83 was detected in humans and dogs and is believed to be generated by hydrolysis of the intermediate lactam [181][182], However, the diazepine ring can be split by other mech-... 

Zopiclone is a chiral cyclopyrrolone with hypnotic properties, possessing a pharmaceutical profile of high efficacy and low toxicity, similar to that of benzodiazepines. Zopiclone has been commercialized as a racemic mixture however, the (S)-enantiomer is more active and less toxic than the (R)-enantiomer [11]. Although enzymatic hydrolysis of esters or transesteriflcation processes of alcohols have been widely applied for enzymatic resolution or desymmetrization... 

Di-carboxy substituted diazepine 226 results in spiro 228 after Boc-protection, hydrolysis, CDl activation and imide formation (Scheme 48, Section 3.1.1.3 (1993JHC897)). The conjugated ester group of (+ )-anthramycin derivative 197 can be constructed by cross-metathesis of pyrrolo-benzodiazepine 196 (Scheme 40, Section 3.1.1.2 (2004T9649)). 

Chorazepate Chorazepate, 7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzo-diazepin-3-carboxylic acid (5.1.34), which is used in the form of a dipotassium salt, is synthesized by yet another interesting synthetic scheme. 2-Amino-5-chlorobenzonitrile is used as the initial compound, which upon reaction with phenyhnagnesiumbromide is transformed into 2-amino-5-chlorbenzophenone imine (5.1.32). Reacting this with amino-malonic ester gives a heterocyclization product, 7-chloro-l,3-dihydro-3-carbethoxy-5-phenyl-2H-benzodiazepin-2-one (5.1.33), which upon hydrolysis using an alcoholic solution of potassium hydroxide forms a dipotassium salt (5.1.34), chlorazepate [30-32]. 

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). 

Mild alkaline hydrolysis of (186 R = Me) gave the l,4-benzodiazepin-2-one 4-oxide. Grignard reagents react with the nitrone (152 R = R1 = H) and similar compounds to give the 4-hydroxy-5-phenyl derivative (77ACS(B)70l). 

The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Most of the barbiturates and other older sedative-hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral administration. 

Amino-ll//-pyrido[2,l-b]quinazolin-ll-one (203) was obtained as a degradation product of 5,ll-dihydro-6//-pyrido[2,3-b][l,4]benzodiazepin-6-one (327, R = H) and pirenzepine (328) by basic and acidic hydrolysis... 

Flurazepam and two of its metabolites have demonstrated reversible hydrolysis of the 4,5-azomethine [131]. In acid solution, this reaction may be monitored employing pulse polarography to measure the decrease in concentration of the 4,5-azomethine of the 1,4-benzodiazepine or increase in carbonyl concentration of the open benzophenone (see Fig. 26.10). 

Polarographic methods have been extremely useful for the determination of the urinary excretion of the 1,4-benzodiazepines. An assay that employs selective solvent extraction and acid hydrolysis of diazepam and its major metabolites, iV-desmethyldiazepam and oxazepam, to their respective benzophe-nones has been employed to measure the urinary excretion of diazepam [183]. A pulse polarographic assay has been reported that will measure the urinary excretion of bromazepam following a single 12-mg dose [184]. The assay employs selective extraction of bromazepam and the 2-amino-5-bromobenzoyl-pyridine metabolite from the deconjugated metabolites, 3-hydroxybromazepam and 2-amino-3-hydroxy-5-bromobenzoylpyridine, into separate diethyl ether fractions. The residues of the respective extracts are dissolved in phosphate buffer (pH 5.4) and analyzed by pulse polarography, which yields two distinct... 

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