Quinazolinone nucleus

Fluproquazone (97) contains a 2-quinazolinone nucleus and is found to be an analgetic agent useful in mild to moderate pain. One of the preparations involves reaetion of 2-isopropylamino-4-methyl-4 -fluoro-benzophenone (96) with potassium cyanate in hot acetic acid [27],... 

The total synthesis of CP-465,022 is described. This former drug candidate exists as two separable rotational isomers (atropisomers). The discovery and separation of these rotational isomers is described, as well as the methodology used to prepare the pyridyl sidechain and the quinazolinone nucleus. Testing showed that the desired biological activity existed in just one of the atropisomers. 

Once we knew that CP-392,110 was the final candidate, a more efficient bond disconnection was the one across the olefin linker to provide the same quinazolinone nucleus 2 and a novel aldehyde 4 (Scheme 4). The initial starting materials for each of these were meto-fluorobenzoic acid and 2,6-dibromopyridine, which were both available in kilogram quantities at a reasonable price. This disconnection would provide a more efficient synthetic sequence and avoid the potential for "dimer" formation in the aldol addition. The major xmcertainty with this approach was finding an efficient synthesis of the aldehyde 4. 

Our plan as outlined in Scheme 5 was to treat 2,6-dibromopyridine with butyllithium, to quench the mono-anion with DMF (dimethylformamide), and then to do a reductive amination with diethylamine to provide the diethylamine 5. This would be followed by a second metal-halogen exchange and the resultant anion would be trapped with DMF to provide the desired aldehyde 4. This aldehyde would then be condensed with die quinazolinone nucleus 2 under conditions analogous to those developed by our Discovery group. 

With the synthesis of the sidechain 4 in hand, we turned our attention to the quinazolinone nucleus 2, which is a known confound. We carried out a reaction sequence which was a modification of the one in the literature (6). As shown in Scheme 12, me/a-fluorobenzoic acid was nitrated to form 24. This reaction will be discussed in more detail vide infra). The nitro group in 24 was reduced with Pd C/Ha to form 25, and the benzoxazinone 26 was formed by treatment of 25 with trimethylorthoaceate (TMOA). Treatment of con5)ound 26 with or Ao-chloroaiiiline provided the quinazolinone 2. This sequence was carried out starting with 10 kg of the we a-fluorobenzoic acid derivative to provide 3.7 kg of final product 2 with the isolation of only two intermediates (25% yield overall). Although this yield has room for considerable optimization, speed was more important than efficiency at this stage of development. 

With both coupling partners in hand, the quinazolinone nucleus 2 and aldehyde sidechain 4 were treated with ZnCl2 in THF in the presence of acetic anhydride, which facilitated elimination of the initially formed aldolates to... 

Returning to the aldol conditions to form CP-392,110 (Scheme 13), we treated the quinazolinone nucleus 2 and the aldehyde 4 with ZnCl2 in THF in the... 

Acetylation of 2-(l-hydroxyphenylmethyl)quinazolin-4-one (195) with refluxing acetic anhydride gave the expected acetate 196. Refluxing the starting compound (195) or its acetate (196) with acetic anhydride and sodium acetate gave the oxazolo[3,4-a ]quinazolinone (197). Spectral as well as chemical evidence favored the assigned structure(197) rather than the alternative oxazolo-[4,3-fc]quinazolinone structure (198) that could arise as a result of cyclization with N-3 of the quinazoline nucleus (74JOC3828). 

Benzoxazin-4-ones (39) react with amines to give quinazolinones (40) (77JOC656), but this typical reaction is replaced in 1,3-benzoxazine-2-thiones (41) by the formation of imino derivatives (42) since now the oxygen ring atom is joined directly to the aryl nucleus (76MI22700). 

The quinazoline ring of 1,2,4-triazolo[4,3-a]quinazoline 348 was formed (62TL1193) by the dehydrative cyclization of 3-benzoylamino-4,5-diphenyl-1,2,4-triazole (347). Alternatively, 1,2,4-triazolo[4,3-a]-quinazolines were prepared by assembling the fused 1,2,4-triazole ring onto the quinazoline nucleus when 2-hydrazinoquinazolines (e.g. 349) were cyclized with formic acid or acetic anhydride to give (86JHC833) angular l,2,4-triazolo[4,3-a]quinazolinones 350 in addition to linear 1,2,4-triazolo[3,4-/>]quinazolinones 351. 

Apart from early reports on the bromination of quinazolinones which gave undefined products, reports dealing with the direct introduction of a halogen into a quinazoline nucleus via the electrophilic reaction are scarce, probably because these derivatives are more easily accessible by cyclization of appropriate halogen-substituted precursors (cf. Section 6.3.1.1.1.). Quinazolin-4(3//)-one can be brominated by bromine in aqueous potassium bromide solution... 

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