Tefludazine, Lu-18012

替氟达嗪Chemical Name: trans-4-[3-(4-Fluorophenyl)-2,3-dihydro-6-(trifluoromethyl)-1H-inden-1-yl]-1-piperazineethanol; trans-4-[3-(p-Fluorophenyl)-6-(trifluoromethyl)-1-indanyl]-1-piperazineethanol; trans-1-[4-(2-Hydroxyethyl)-1-piperazinyl]-3-(4-fluorophenyl)-6-(trilfuoromethyl)indan
CAS No. 80680-06-4
项目整合开发状态: Phase I
项目研究机构: Lundbeck (Originator)
合成路线:The Sandmeyer reaction of 4-trifluoromethylanthranilic acid (I) with NaNO2,HBr and Cu2Br2 gives 2-bromo-4-trifluoromethylbenzoic acid (II),which by reaction with SOCl2 is converted into 2-bromo-4-trifluoromethylbenzoyl chloride (III).The Rosemind reduction of (III) with H2 over Pd/BaSO4/S yields 2-bromo-4-trifluoromethylbenzaldehyde (IV),which is condensed with ethyl cyanacetate (V) in refluxing toluene affording ethyl 2-cyano-3-[2-bromo-4-(trifluoromethyl)phenyl]propenoate (VI).The addition of 4-fluorophenylmagnesium bromide (VII) to (VI) in toluene ether gives ethyl 2-cyano-3-[2-bromo-4-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)propanoate (VIII),which is hydrolyzed and decarboxylated partially with H2SO4 in refluxing acetic acid water to yield 3-[2-bromo-4-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)propanoic acid (IX).Cyclization of (IX) with butyllithium in ether affords 3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-one (X),which is reducted with NaBH4 in methanol giving 3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-ol (XI).The reaction of (XI) with SOCl2 in hot toluene yields 1-chloro-3-(4-fluorophenyl)-6-(trifluoromethyl)indan (XII).

合成路线:Compound (XII) is finally condensed with piperazine-ethanol (XIII) in refluxing butanone.The separation of the trans isomer is performed by precipitation of the oxalate,treatment with dimethyl-amine in water and extraction with ether.