合成路线1

The synthesis of 5-hydroxytiagabine, a metabolite of tiagabine in humans, has been undertaken to confirm that it is present entirely as (E)- and (Z)-isomers of the tautomeric 5-oxo form: The bromination of 3-methylthiophene (I) with N-bromosuccinimide gives 2-bromo-3-methylthiophene (II), which is chlorinated with N-chlorosuccinimide to yield 2-bromo-5-chloro-3-methylthiophene (III). The reaction of (III) with Mg affords 5-chloro-3-methylthien-2-ylmagnesium bromide (IV), which is condensed with 3-methylthiophene-2-carboxaldehyde (V) (obtained from (II) by reaction with magnesium and dimethylformamide) to give the bisthienylmethanol (VI). The oxidation of (VI) with pyridinium chlorochromate (PCC) yields the bisthienyl ketone (VII), which is treated with sodium methoxide to afford the bis(2-thienyl)ketone (VIII). The Grignard reaction of (VIII) with cyclopropylmagnesium bromide (IX) gives the trisubstituted methanol (X), which is submitted to ring opening with trimethylsilyl bromide to afford the thiophenone (XI) as a mixture of the (E)- and (Z)-isomers. The condensation of (XI) with piperidine-3(R)-carboxylic acid ethyl ester (XII) by means of K2CO3 gives 1-[4-(3-methyl-5-oxo-2,5-dihydrothien-2-ylidene)-4-(3-methyl-2-thienyl) butyl]piperidine-3(R)-carboxylic acid ethyl ester (XIII) (also as a mixture of (E)- and (Z)-isomers). Finally, this compound is hydrolyzed to the free acid in HCl medium.