Synthesis and asymmetric resolution of a dopaminergic compound: 2-amino-5-methoxyindane

The racemic synthesis and subsequent resolution of 2-amino-5-methoxyindane enantiomers were achieved starting from 5-bromoindan-2-ol in six steps with 38% total yield. The first step involved the substitution of the Br atom by using NaOMe in the presence of CuI to afford 5-methoxyindan-2-ol. The OH group of 5-methoxyindan-2-ol was converted into its mesylate ester, which was converted into the corresponding azide by reaction with sodium azide. The Pd–C-catalyzed hydrogenation of the azide functional group in the presence of CHCl3, followed by neutralization of the amine hydrochloride salt with NaOH, furnished the rac-2-amino-5-methoxyindane. Next, rac-2-amino-5-methoxyindane was converted into its diastereomeric amide derivatives by reaction with (R)-mandeloyl chloride. The diastereomeric amide mixture was separated by recrystallization to give the (R,S)- and (R,R)-diastereomers. The absolute configuration of the (R,S)-isomer was determined by X-ray crystallography. The hydrolysis of these diastereomers gave (R)- and (S)-2-amino-5-methoxyindane with high enantiopurity.

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(R)-2-(((S)-5-Methoxy-2,3-dihydro-1H-indan-2-yl)amino)-2-oxo-1-phenylethyl acetateC20H21NO4De: 92.4%Absolute configuration: (R,S)[α]D25 = −38 (c 1, CHCl3)Source of chirality: resolution

(R)-2-(((R)-5-Methoxy-2,3-dihydro-1H-indan-2-yl)amino)-2-oxo-1-phenylethyl acetateC20H21NO4De: 94.4%Absolute configuration: (R,R)[α]D25 = −124 (c 1, CHCl3)Source of chirality: resolution

(R)-5-Methoxy-2,3-dihydro-1H-indan-2-amineC10H13NOAbsolute configuration: (R)[α]D25 = +7 (c 1, CHCl3)Source of chirality: resolution