Hydrochloric Acid → Benzyl chloromethyl ether

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Reaction Steps

In either instance, the resulting protected (2R,3S)-3-phenylisoserine ethyl ester compound of formula 8 may simply be converted to the N--CBZ protected C-2' O-BOM-protected (2R,3S) phenylisoserine intermediate hydroxyl by the reaction: ##STR15## Here, the protected (2R,3S)-3-phenylisoserine ethyl ester is dissolved in ethanol/water (ratio 8:1). Lithium hydroxide (or other suitable alkali hydroxide) is added to the solution and the resulting mixture stirred for approximately three hours in order to saponify the compound. The mixture is then acidified (1N HCl) and extracted with ethyl acetate. The resulting organic layer is separated, dried and reduced under vacuum. The residue acid is then isolated for use without further purification. This produces the desired side chain having the general formula: ##STR16## Benzyl itself is another example of a hydrogenatable benzyl protecting group that may be used instead of BOM. The compound of the formula: ##STR17## was therefore produced as above with the substitution of benzyl bromide for BOM-Cl in Reaction V according to the reaction ##STR18## Here, the CBZ protected (2R,3S)-3-phenylisoserine ethyl ester is dissolved in anhydrous THF under a nitrogen atmosphere and cooled to a reduced temperature such as -40° C. or -78° C., for example, in a dry ice/acetone bath followed by the dropwise addition of an alkylithium agent, such as n-butyl lithium, although it is desirable that the alkylithium agent be a straight chain alkyl. The resulting mixture was stirred for about ten minutes. Benzyl bromide (BnBr) was then added dropwise over an interval of about five minutes and the mixture stirred for approximately two to five hours at the reduced temperature. Thereafter, the solution was warmed to -0° C. and quenched with water. The resulting mixture is reduced under vacuum to residue, and this residue is thereafter taken up in ethyl acetate and washed with water and brine. The organic layer may then be dried and reduced under vacuum and the residue recrystallized from ethyl acetate:hexane or chromatographed with ethyl acetate:hexane to give the compound of Formula 10.

Provenance & Evidence