The 1H-quinazoline-2,4-dione derivatives have attracted interests on their various biological activities including the selective serotonin-S2 antagonist. These compounds are structurally similar with quinazoline and quinazolinone derivatives and conventionally synthesized by the coupling of isocyanate with the amine group as nucleophile and by cyclization under the heating and basic conditions. From this main skeleton, the modified compounds had been synthesized for the desired biological activities. Of these, nonpeptide antagonists for the human gonadotropinreleasing hormone receptor were synthesized by modifying the C2 position and varying R2 derivatives. Other example is the thymidylate synthase inhibitor, ZD9331, developed by AstraZeneca. This compound was synthesized by modifying the C6 position. Recently, Ismail et al. designed and synthesized the carboxy-biphenylmethyl-quinazolin-4-one derivatives, on the basis of modeling and structure-activity studies, which could block the effects of angiotensin II by inhibiting the angiotensin-converting enzyme or rennin. According to these interesting structure-activity relationship, the development of new scaffold from 1H-quinazoline2,4-dione has been issued by our program for the new drug discovery of Ca channel blocker. For this purpose, according to our modeling team’s suggestion, it was necessary to reduce selectively the C4 carbonyl function in 1H-quinazoline-2,4-dione to methylene group as shown in structure 4 and 6 (Scheme 2). Such a work as this C4 modified structure was reported by Desikan et al. After obtaining these compounds, we can diversify this structure by modifying R1 and R2 groups, respectively. Although the various starting materials were employed to obtain this molecular scaffold, the method of direct reduction of C4 carbonyl function using synthetically well established 1H-quinazoline-2,4-dione compound will be simple and effective. These reactions have been accomplished by many research groups and more recently, target-focused selective reductions were performed using the corresponding complex compounds. But to our knowledge, no result was reported about the direct reduction of the compound 1 using reducing agent. Here we report the selective reduction of C4 carbonyl function among three carbonyl functions by the various reducing agents. Firstly, the compound 2, which was prepared as described before, was used as a substrate for reduction studies as shown in Scheme 1. It has three functional groups including ester, amide and urea. Sometimes amide bond is cleaved by the strong reducing reagent. Thus it is important to reduce C4 carbonyl group without the cleavage of amide bond. To try to find the appropriate reducing agent, the various reducing reagents were screened as shown in Table 1 and borane and aluminium hydride derivatives showed promising activities. In THF solution, these reactions were tried at the different temperatures such as –10 C and under the reflux conditions. Besides the above reducing agents, sodium cyanoborohydride, lithium 9-BBN, lithium borohydride, sodium borohydride and borane tetrahydrofuran complex were employed. But these reagents were too mild to reduce our substrate. As shown in Table 1, the compound 2 was reduced at the ester carbonyl to give alcohol 3 under the conditions of –10 C by six reducing agents. Next, it was further reduced at amide site to compound 4 under the reflux conditions. Lastly, it was fully reduced to the compound 5 by sodium bis(2-methoxyethoxy)aluminium dihydride and lithium aluminium hydride under the reflux conditions. Thus, among three active sites the urea showed the lowest reactivity according to the results of the condition of strong these reducing agents and reflux. In the case of diisobutylaluminium hydride and lithium tri-tert-buthoxyaluminium hydride, it was reduced to compound 4 even under the reflux
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Feb 3, 2024
Jillian Gamboa + 7
