Quinazoline properties

The present review describes recent advances in quinazoline chemistry, some of which are but modem applications of earlier methods, whereas others strike out on new, and sometimes surprising, pathways. The structure of the cation of the parent substance, quinazoline, has only recently been made clear, and it has become evident that covalent hydration is a phenomenon widely distributed throughout the quinazoline series. With this fact in mind, it seems better to set forth the newly found properties of quinazolines before proceeding to an account of advances in synthesis. 

The halogen atom in benz-chloro substituted quinazolines is very stable (as in chlorobenzene), whereas the halogen atoms in positions 2 and 4 show the enhanced reactivity observed with halogen atoms on carbon atoms placed a and y to heterocyclic ring nitrogens. The chlorine atom in position 4 is more reactive than in position 2, and this property has been used to introduce two different substituents in the pyrimidine ring. ... 

These compounds show the typical reactions of heterocyclic N-oxides and their structure was proved by methylation which takes place on N-1. Quinazoline 3-oxide is soluble in water and melts at 155°C. It has basic properties and its pKa value in water is 1.47. ... 

The A -oxide reactions in quinazoline 3-oxide are, however, modified to a certain extent by the aforementioned properties. Thus, whereas it can be reduced to quinazoline with phosphorus trichloride or iron and ferrous sulfate in ethanol, reactions with alkali, acetic anhydride, and benzoyl chloride in the presence of cyanide result in ring fission (Scheme 4). 

The present review covers the literature to the end of 1967 and all original sources have been consulted. Syntheses of each of the four ring systems are summarized separately, but physical, chemical, and biological properties are considered generally. Many pjTidopyri-midines were initially synthesized for a study of biological activity or physical properties because of the close structural relationship of these systems to the quinazolines (5) and pteridines (6). Recent reviews have discussed these related compounds. 

The physical properties of the pyridopyrimidines closely resemble those of their nearest A-heteroeyclie neighbors the quinazolines and the pteridines. Thus, in common with the pteridines, the presence of groups capable of hydrogen-bonding markedly raises the melting point and lowers the solubility. - The acid dissociation constants (pif a values) and ultraviolet absorption spectra of all four parent pyridopyrimidines have been determined by Armarego in a comprehensive study of covalent hydration in these heterocyclic systems. The importance of these techniques in the study of covalent hydration, and... 

In many cases, addition or removal of water proceeds sufficiently slowly that some of the physical properties of unstable species (such as hydrated neutral quinazoline or anhydrous 2-hydroxypteridine) can be observed. In these cases, reaction kinetics can also be examined. Addition of water to pteridine is of special interest in relation to studies of the formation and hydrolysis of Schiflf bases. The reaction proceeds in two reversible stages, 3 4 5 ... 

Rutaecarpine (46) is the major alkaloid found in Evodia rutaecarpa (Juss.) Benth., and activities relevant to AD have been identified with the extract and with rutaecarpine. Dehydroevodiamine (47), another alkaloid from the same species, inhibited AChE in vitro, and reversed scopolamine-induced memory impairment in rats and increased cerebral blood flow in vivo in cats, a property which would supplement its usefulness in AD. The structures of (46) and (47) and tacrine (28) have been used as templates for the development of a series of synthetic compounds which have been evaluated for their antiChE activity. These were found to be inhibitory against both AChE and BuChE with A -(2-phenylethyl)-A -[(12Z)-7,8,9,10-tetrahydroazepino [2,l- ]quinazolin-12(6//)-ylidene] amine (48) showing higher affinity for BuChE. 

Reaction of trithioisatoic anhydride with 1,4-diaminobutane gave the title compound 681 (73ZC428). 1,3-Diazepino-quinazolines possess tran-quilizing and bronchodilating properties (73SZP532068). 

Certain types of pyrimido[l,2-Z ]isoquinolines, ll//-pyrido[2,l-Z ]quina-zolin-ll-ones, pyrimidol,2-a]quinolines, and pyrimido[2,l-a]isoquinolines have aroused much interest owing to their valuable pharmacological properties. 1 //-Pyrido[ 1,2-a]quinazolin-6-ones are used as charge-transporting agents. 

In the following sections structure, thermodynamic aspects, theoretical calculations, spectroscopic properties, reactions, syntheses, and, more briefly, the uses of these tricyclic ring systems are discussed. Within the individual subsections of reactivity, synthesis, and applications, the pyrim-ido[l,2-6]isoquinolines, pyrido[2,l-6]quinazolines, pyrimido[l,2-a]quino-lines, pyrido[l,2-a]quinazolines, and pyrimido[2,l-a]isoquinolines are considered. 

The pK of quinazoline, as commonly measured, is 3.51 this represents mainly the equilibrium between the two most stable species, namely, the hydrated cation and the anhydrous neutral species. The true anhydrous pKa (i.e., for the instantaneous equilibrium between anhydrous cation and anhydrous neutral species) was obtained25 for quinazoline, twelve substituted quinazolines, and triazanaphthalenes in the rapid-reaction apparatus just described. The true anhydrous pKa of quinazoline turned out to be 1.95. The true hydrated pKa of quinazoline has already been reported26 as 7.77, the slower rate of hydration permitting its determination in the usual rapid-reaction apparatus. Thus, in general, three pKa values exist for each hydrating base, and the equilibrium between the totally hydrated species furnishes the strongest basic properties. 

But do remember, with the harmaline and harmine content of the seeds of Peganum harmala, you are also accepting an equal weight of quinazoline alkaloids with pharmacological properties that are quite different from those of the carbolines. 

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