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

HRID 2065923Notes

Reaction equation

HRID 2065923 reaction equation
CO.O=[C:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[C:15]1([C@@H:21]([NH2:23])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[C:15]1([C@@H:21]([NH:23][C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1

Participants

5

Reactant 3

HCID 887MethanolHCID 758181-Phenethylamine, (-)-HCID 95543Ethyl 2-oxocyclohexanecarboxylate2×

Product 1

HCID 11737390(S)-Ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

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.

Sources & evidence

ORD record
ord-d5b64cdfbfe744aeb1ee4fdfdfe609e3
Source dataset
uspto-grants-2012_10
Patent number
US08288565B2

Reaction notes

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