【药物名称】Tefludazine, Lu-18012
化学结构式(Chemical Structure):
参考文献No.65685
标题:Tefludazine
作者:Casta馿r, J.; Serradell, M.N.
来源:Drugs Fut 1984,9(5),346
合成路线图解说明:

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).

合成路线图解说明:

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.

参考文献No.75667
标题:Neuroleptic activity and dopamine-uptake inhibition in 1-piperazino-3-phenylindans
作者:Bogeso, K.P.
来源:J Med Chem 1983,26(7),935-947
合成路线图解说明:

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).

合成路线图解说明:

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.

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