合成路线1

Methiothepin can be prepared in several ways, two of which have been described with experimental details. The common intermediate of both is the ketone (VIII). 4-Bromothioanisol (I) is converted to the Grignard reagent, which is treated with sulfur yielding 4-(methylthio)thiophenol (II). The same compound is accessible by reduction of 4-(methylthio)benzenesulfonyl chloride (A), done best with phosphorus and iodine in acetic acid. The potassium salt of (II) is treated with a boiling solution of potassium 2-iodobenzoate (B) in the presence of copper giving 2-(4-methylthiophenylthio)benzoic acid (III). Further reduction with LiAlH4 results in 2-(4-methylthiophenylthio)benzyl alcohol (IV). This reduction proceeds very well with NaAlH2(OCH2CH2OCH3)2 in benzene. (IV) is then converted with SOCl2 in benzene to the chloride (V), which is treated with NaCN or KCN in boiling aqueous ethanol to give the nitrile (VI). Hydroysis with KOH in aqueous ethanol yields 2-(4-methylthiophenylthio)phenylacetic acid (VII), which is cyclized with polyphosphoric acid to 8-(methylthio)dibenzo[b,f]thiepin-10(11H)-one (VIII). The ketone (VIII) may be reduced with NaBH4 to the alcohol (IX), which is transformed by treatment with anhydrous HCl in benzene to the chloride (X). Substitution reaction with 1-methylpiperazine (C) at 120-130 C or more in boiling chloroform gives 80% crude metitepine base, which is transformed to the maleate. The other method consists first in transforming the ketone (VIII) into the methylpiperazine enamine (XI) by treatment with 1-methylpiperazine (C) and TiCl4 in boiling benzene. The enamine (XI) is then reduced to metitepine; the best method of reduction for this particular case seems to be the treatment with diborane generated by interaction of NaBH4 with acetic acid in tetrahydrofuran. An additional three methods of metitepine synthesis are covered by patents; howewer, they do not describe experimental details for the particular case of metitepine.