Cbz-S-phenyl-L-cysteine methyl ester

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a nitrogen atmosphere, 150 ml of methanol was added to 30.01 g of N-benzyloxycarbonyl-S-phenyl-L-cysteine and 864 mg of p-toluenesulfonic acid monohydrate, and the reaction was allowed to proceed under reflux. After 6 reaction hours, the mixture was cooled to about 50° C., and the pH was adjusted to 5.5 by adding 8 ml of a 5% (by weight) aqueous solution of sodium hydrogen carbonate. Then, the methanol was replaced with toluene at about 50° C., to give 103.87 g of a toluene-substituted reaction mixture containing 30.97 g (concentration: 29.8% by weight; yield: 99%; optical purity: 99.7%) of N-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester (Example 4). Then, 15 ml of pure water was added to this toluene-substituted reaction mixture at room temperature, and the mixture was stirred for 15 minutes and then allowed to stand, whereupon the aqueous phase formed a large number of droplets, which remained dispersed or settled in the organic phase but did not unite with one another. This procedure thus failed to form two layers, namely the upper and lower layers, separable from each other, hence to enable phase separation (Reference Example 2). under reflux After 6 reaction hours to give

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Recently, Knight and Sibley (D. W. Knight and A. W. Sibley, J. Chem. Soc., Perkin Trans. 1, 1997, 2179-2187) reported that the displacement of N-benzyloxycarbonyl-O-p-toluenesulfonyl serine methyl ester (or methyl (S)-2-benzyloxycarbonylamino-3-methylsulfonyloxypropanoate) with freshly prepared sodium thiophenylate in DMF at about 0° C. afforded the desired N-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester (or methyl (R)-2-benzyloxycarbonylamino-3-phenylthiopropanoate) in 98% yield providing a reported optical rotation of [α]20D−17.2 (c, 1.8; MeOH). No enantiomeric ratio of the product was reported. Furthermore, the use of sodium phenolate, prepared from sodium hydride, thiophenol and DMF is not amenable to large scale manufacture.