SYNTHESIS OF α,ω-BIS-(p-AMINOPHENOXY AND p-AMINO-THIOPHENOXY)-ALKANES AND THEIR POLYHYDROXY DERIVATIVES

Condensation of sodium p-acetaminophenoxide with 1,7-dibromoheptane and subsequent hydrolysis gave 1,7-bis-(p-aminophenoxy)-heptane dihydrochloride(Ⅰ).Condensation of sodium p-acetaminothiophenoxide with 1,3-dibromopropane,1,6-dibromohexane or 1,7-dibromoheptane and subsequent hydrolysis gave the dihydrochlorides of the a,ω-disubstituted alkanes(Ⅱ, Ⅲ,Ⅳ).Similar treatment of sodium p-acetaminophenoxide and its thio derivative with 3-chloro-1,2-propanediol or 1,3-dibromo-2-propanol gave the hydrochloric salts of 3-p-ami- nophenoxy-1,2-propanediol(Ⅴ)or 1,3-bis-(p-aminophenoxy)-2-propanol(Ⅶ)and their thio analogs(Ⅵ,Ⅷ). 1,6-Dichloro-2,3-4,5-bis-methylene-D-mannitol upon prolonged heating with sodium p-acetaminophenoxide in sealed tubes gave a small yield of the 1,6-diether(Ⅺ).A more convenient route to the 1,6-disubstituted mannitol was as follows.The triisopropylidene derivative of mannitol was partially hydrolyzed to gave the 3,4-isopropylidene derivative which was in turn tosylated at the 1,6-positions and acetylated at the 2,5-positions,giving Ⅻ. Treatment of Ⅻ with sodium p-acetaminophenoxide gave the 1,6-diether(ⅩⅢ),with concomittant loss of acetyl groups.Hydrolysis of ⅩⅢ gave ⅪⅤ.Similar treatment of sodium p-acetaminothiophenoxide gave the corresponding thio analog(ⅩⅤ). Condensation of sodium p-nitrophenoxide with 1,4-dibromo-2-butene gave 1,4-bis-(p- nitrophenoxy)-2-butene(ⅩⅥ).Hydroxylation of the double bond and then reduction of the nitro groups gave 1,4-bis-(p-aminophenoxy)-2,3-threo-dihydroxybutane dihydrochloride (ⅩⅧ). These p-aminophenoxy ethers and thioethers were shown to have no therapeutic value against schistosomiasis japonica when tested with experimentally infected animals.