合成路线1

Condensation of (1S,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexyl tosylate (I) with 3(R)-benzyloxypyrrolidine (II) provides vernakalant benzyl ether (III), which is then debenzylated by catalytic hydrogenolysis over Pd/C (1). In a more direct approach, tosylate (I) is condensed with 3(R)-hydroxypyrrolidine (IV) to provide vernakalant (1, 2). An alternative strategy consists of the cyclization of (1R,2R)-2-[2-(3,4-dimethoxyphenyl)ethoxy]cyclohexylamine (V) with (R )-2-acetoxysuccinic anhydride (VI) by means of acetyl chloride or with ethyl 4-chloro-3(R )-hydroxybutyrate (VII) to give, respectively, the cyclic imide (VIIIa) or the pyrrolidinone (VIIIb), which is subsequently reduced and deprotected by means of Red-Al to yield the title hydroxypyrrolidine derivative (2). The O-benzyl precursor of vernakalant (III) can alternatively be obtained by condensation of 2(R )-[3(R )-benzyloxy-1-pyrrolidinyl]cyclohexan-1(R )-ol (IX) with 3,4-dimethoxyphenethyl trichloroacetimidate (X) (prepared from dimethoxyphenethyl alcohol [XI] and trichloroacetonitrile) in the presence of trifluoromethanesulfonic acid (2, 3). A related strategy for preparing the succinimide precursor of vernakalant (VIIIa) consists of the condensation of 2(R)-acetoxy-N-[2(R)-hydroxy-1(R)-cyclohexyl]succinimide (XII) with imidate (X) in the presence of boron trifluoride etherate (4). Scheme 1.