The synthesis of possible hydroxylated metabolites of 2‐chlorophenothiazine derivatives

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Abstract
The synthesis of 7‐hydroxy, 8‐hydroxy and 7,8‐dihydroxy prochlorperazines (3a) and per‐phenazines (3b) is reported. The parent ehlorophenothiazines were prepared analogously to previously reported chlorpromazine (3e) metabolite syntheses. The prochlorperazine side chain was introduced in one step using 1‐(3‐chloropropyl)‐4‐methylpiperazine and the perphenazine side chain in two steps, first reaction with 1‐bromo‐3‐chloropropane followed by reaction with 1‐piperazineethanol. The methoxymethyleneoxy O‐proteetive groups were removed under mild conditions using methanolic hydrogen chloride. The preparations of 7‐hydroxydesmethylprochlorperazine and 7‐hydroxychlorpromazine quaternary methyl iodide are also reported.