SYNTHESIS OF A SERIES OF ORO-4-CYCLOPROPYL-3,4-DIHYDROQUINAZOLIN-2(1H)-ONES AS NOVEL NONNUCLEOSIDE HIV-1 REVERSE-TRANSCRIPTASE INHIBITORS

As part of an ongoing effort to prepare novel non-nucleoside inhibitor s of human immunodeficiency virus type-1 (HTV-1) reverse transcriptase (RT), a series of oro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones 4aa-1 has been prepared. Target compounds 4a-e were synthesized via ad dition of various 1-lithio-2-(aryl)alkyne nucleophiles to a 1-protecte d-4-cyclopropylquinazolin-2(1H)-one (7), followed by deprotection. The 3-methyl compound 4aa was prepared in an analogous manner, with the 3 -alkylation performed prior to deprotection. Alternatively, the target compounds 4f-1 were prepared by addition of 1-lithio-2-(trimethylsily l)acetylene to 7, followed by deprotection and subsequent palladium-ca talyzed coupling with various aryl halides, By incorporating an aryl g roup onto the end of the 4-acetylene functionality, the requirement fo r a metabolically labile 3-methyl group on the dihydroquinazolinone nu cleus has been eliminated. A number of the target compounds were shown to be potent inhibitors of HTV-1 RT. Compound 4a, which had exhibited the most favorable overall biological profile, was' resolved via a fo ur-step procedure to provide the enantiomers 13a and 13b. Compound 13a having the (-)-4(S) configuration was shown to be the active enantiom er and was selected as a candidate for further investigation.