Chlordiazepoxide chemistry

Sternbach, LH, Randall, LO and Gustafson, SR (1964) 1,4-Benzodiazepines (chlordiazepoxide and related compounds). In Medicinal Chemistry, Volume 1, Psychopharmacological Agents (Ed. Gordon, M), Academic Press, New York London, pp. 137-224. 

In the case of xylometazoline hydrochloride, imine hydrolysis chemistry occurs to open the 4,5-dihydro-lH-imidazole ring (Fig. 55) (90). Similar degradation chemistry is observed for the following APIs flurazepam hydrochloride (91), clorazepate dipotassium (92), clonazepam (93), methaqualone (94), chlordiazepoxide, and oxazepam (18). 

Chlordiazepoxide is prepared by the reaction scheme shown in Figure 6. 6-chloro-2-chloromethyl-4-phenyl-quinazoline 3-oxide is reacted with methylamine which presumably attacks the quinazoline at the 2 position. The nucleophilic attack is followed by enlargement of the ring to yield the 7-chloro-2-(methylamino)-5-phenyl-3H-l,4-benzodiazepine 4-oxide13. A complete review of the chemistry of benzodiazepines presents alternative pathways14. 

An example of the complex chemistry occurring upon irradiation of a seven-membered heterocycle is shown below for the case of the sedative chlordiazepoxide 22 (see Equation 99.17), where both ring contraction and expansion occur. 

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