Methanol → (S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate

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Reaction Steps

In another embodiment, (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) is produced from a starting material comprising ethyl 2-oxocyclohexane carboxylate (6). This embodiment comprises reacting ethyl 2-oxocyclohexane carboxylate (6) with (S)-(−)-1-phenylethylamine (7) in the presence of toluene to produce (S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8). Further, reduction of the amine (8) with sodium borohydride in the presence of isobutyric acid will produce (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9), as illustrated in FIG. 4. Additionally, the conversion of the amine (8) to the cis-cyclohexane derivative (9) is further treated with hydrogen bromide and ethyl acetate in propionic acid to create the hydrobromide salt of the cis-cyclohexane derivative (9). The production of the cis-cyclohexane derivative (9) is followed by epimerization of the chiral center adjacent to the ethyl ester functionality using sodium tert-butoxide to afford the trans-cyclohexane derivative (10) as a major diastereomer. After conversion to trans-cyclohexane derivative (10), the compound is subjected to reduction of the ester functionality in compound (10), using potassium borohydride in the presence of lithium chloride, to yield (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11). Generally, the conversion from compound (10) to compound (11) may incorporate tetrahydrofuran as a co-solvent and may be refluxed to afford the desired compound (11) in good overall yield.

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