(S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate → (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate
Reaction equation
[C:1]1([C@@H:7]([NH:9][C:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH3-])(=O)C.[Na+]>C(#N)C>[C:1]1([C@@H:7]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1Participants
Procedure
In an additional 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 a catalyst, ytterbium trifluoromethanesulfonate, and heptane to produce (S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8). The next step is reduction of the amine (8) with sodium acetoxyborohydride in the presence of a acetonitrile produce (1R,2S)-Ethyl 2-((S)-1-phenylethylamino)cyclohexanecarboxylate (9), as illustrated in FIG. 1. The production of the cis-cyclohexane derivative (9) is followed by epimerization of the chiral center adjacent to the ethyl ester functionality using sodium t-butoxide to afford trans-cyclohexane derivative (10) as a major diastereomer. Reduction of the ester functionality in compound (10), using lithium borohydride yields (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11) in good overall yield, which is subsequently purified by chromatography.
Sources & evidence
- ORD record
- ord-c794248b7e544bbfb5fb14f0a15c75c3
- Source dataset
- uspto-grants-2012_10
- Patent number
- US08288565B2
Reaction notes
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