The reaction of 2-chloro-5-fluoro-4-(methylsulfanyl)pyrimidine (I) with N-carbethoxypiperazine (II) yields (III), which upon treatment with Raney Nickel affords ethyl 4-(5-fluoro-2-pyrimidinyl)-1-piperazinecarboxylate (IV). Hydrolysis and decarboxylation of (IV) generates 5-fluoro-2-(1-piperazinyl)pyrimidine (V). The reaction of (V) with the alpha-chloroketal (VI) generates the butyrophenone derivative (VII). Sodium borohydride reduction of (VII) and treatment with ethanolic hydrochloric acid yields BMY-14802-1.
A new synthesis for [18F]-labeled BMY-14802 has been reported: The compound can be prepared by two related ways: 1) The fluorination of 4-(cyclopropylcarbonyl)nitrobenzene (I) with [18F]-FK and Kryptofix 2.2.2 gives 4-fluorophenyl cyclopropyl methanone (II), which is treated with HCl in methanol yielding 4-chloro-1-(4-fluorophenyl)-1-butanone (III). The condensation of (III) with 5-fluoro-2-piperazinopyrimidine (IV) affords 1-(4-fluorophenyl)-4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-1-butan one (V), which is finally reduced with NaBH4 in methanol. 2) The reduction of butanone (III) with NaBH4 in methanol gives 4-chloro-1-(4-fluorophenyl)-1-butanol (VI), which is then condensed with pyrimidine (IV) as before.
A new synthesis of [18F]-labeled BMY-14802 has been described: The fluorination of 4-(cyclopropylcarbonyl)nitrobenzene (I) with [18F]-CsF in DMSO - 5% water at 180 C gives 4-fluorophenylcyclopropylmethanone (II), which is treated with HCl in methanol, yielding 4-chloro-1-(4-fluorophenyl)-1-butanone (III). The condensation of (III) with 5-fluoro-2-piperazinopyrimidine (VI) affords 1-(4-fluorophenyl)-4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]-1-butan one (V), which is finally reduced with NaBH4 in methanol.