Synthesis of Unsymmetrical Analogs Desmethyltiagabine

Reaction of 4-chloro-l-(2-thienyl)-l-butanone (20) with the Grignard reagent (21) provided the 2,2-disubstituted tetrahydrofuran (22) in good yield. The tet-rahydrofuran ring could be opened with concomitant dehydration to provide an 

Condensation of 32 with ethyl f -(-)-piperidine-3-carboxylate (16) in acetone yielded 33. Hydrolysis of the ester residue with base followed by extraction and acidic workup yielded the hydrochloride salt of desmethyltiagabine (HI). It is important to note the crystallization of the product as a methylene chloride solvate. The material revealed slow loss of methylene chloride on standing and was shown to be a 90 10 mixture of the Z and E isomers, respectively, by NMR. 

Cyclopropyl thien-2-yl ketone (34), available commercially, was subjected to a Grignard reaction with 21 to yield a carbinol (31) in excellent yield. Bromotrimeth-ylsilane-mediated opening of the cyclopropyl ring led to the 4-bromo derivative 32. Condensation with ethyl i -(-)-pipeildme-3-carboxylate (16) was conducted in isopropyl acetate as a solvent with anhydrous lithium carbonate as the base. The transformation was cleaner and did not provide any of the diene (26) arising from elimination of hydrogen bromide. The alkylation of the nipecotate residue could also be directly effected with a mixture of the tartrate salt of 16, lithium carbonate, and isopropyl acetate. Compound 33 was readily isolated as the hydrochloride isopropyl acetate was superior to all other solvents used in this reaction. Since it is not itself prone to hydrolysis, it is preferable to ethyl acetate. Moreover, it appears to crystallize hydrochlorides much better. 

Acid-catalyzed hydrolysis with aqueous hydrochloric acid was a facile process the hydrochloride salt of the product could be crystallized out of the same solution. 0.15 N hydrochloric acid was found to be optimally effective in cleaving the ester without ra-cemizing the chiral center. The methods developed here were general ones that could be adapted to the synthesis of several analogs of tiagabine. 

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