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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.

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YM-905 has been obtained by two related ways: 1) The benzoylation of 2-phenylethylamine (I) with benzoyl chloride (II) and triethylamine in chloroform, or with benzoic acid (III), DPPA and triethylamine in DMF, gives the corresponding benzamide (IV), which is cyclized by means of POCl3 and P2O5 in refluxing xylene and reduced with NaBH4 in ethanol, yielding racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V). The reaction of (V) with ethyl chloroformate by means of K2CO3 in chloroform affords racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI), which is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to provide the quinuclidinyl ester (VIII) as a diastereomeric mixture. This mixture is resolved by chiral HPLC, giving the target compound as a pure enantiomer. 2) The racemic 1-phenyl-1,2,3,4-tetrahydroisoquinoline (V) can also be submitted to optical resolution with (+)-tartaric acid to give 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline (IX), which is condensed with ethyl chloroformate by means of K2CO3 in chloroform to afford 1(S)-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid ethyl ester (VI). This compound is transesterified with quinuclidine-3(R)-ol (VII) by means of NaH in refluxing toluene to directly provide the pure enantiomer.

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