The alkylation of 2-phenylacetic acid (I) with 2-chloroethyl(methyl)sulfide (II) by means of lithium diisopropylamide (LDA) in THF gives 4-(methylsulfanyl)-2-phenylbutyric acid (III), which is esterified with methanol/H2SO4 yielding the methyl ester (IV). The transesterification of (IV) with quinuclidin-3(R)-ol (V) by means of NaH in refluxing toluene affords the 3(R)-quinuclidinyl ester (VI), which is hydroxymethylated with paraformaldehyde and NaH in DMF giving 2(RS)-(hydroxymethyl)-4-(methylsulfanyl)-2-phenylbutyric acid 3(R)-quinuclidinyl ester (VII) as a diastereomeric mixture. Chromatographic separation of (VII) over SiO2 using CHCl3/methanol/NH4OH as a gradient elution yields the 2(S)-hydroxymethyl isomer (VIII), which is oxidized with trifluoroperacetic acid in trifluoroacetic acid affording the corresponding sulfinyl derivative (IX) as a new diastereomeric mixture. Finally, this mixture is resolved by HPLC over Kromasil C-8 SiO2 using as eluant water/acetonitrile containing 1% trifluoroacetic acid.

The alkylation of 2-phenylacetic acid (I) with 2-chloroethyl(methyl)sulfide (II) by means of lithium diisopropylamide (LDA) in THF gives 4-(methylsulfanyl)-2-phenylbutyric acid (III), which is esterified with methanol/H2SO4 yielding the methyl ester (IV). The transesterification of (IV) with quinuclidin-3(R)-ol (V) by means of NaH in refluxing toluene affords the 3(R)-quinuclidinyl ester (VI), which is hydroxymethylated with paraformaldehyde and NaH in DMF giving 2(RS)-(hydroxymethyl)-4-(methylsulfanyl)-2-phenylbutyric acid 3(R)-quinuclidinyl ester (VII) as a diastereomeric mixture. Chromatographic separation of (VII) over SiO2 using CHCl3/methanol/NH4OH as a gradient elution yields the 2(S)-hydroxymethyl isomer (VIII), which is oxidized with trifluoroperacetic acid in trifluoroacetic acid affording the corresponding sulfinyl derivative (IX) as a new diastereomeric mixture. Finally, this mixture is resolved by HPLC over Kromasil C-8 SiO2 using as eluant water/acetonitrile containing 1% trifluoroacetic acid.