Modified Pictet-Spengler reaction and products prepared therefrom
A method of introducing a second stereogenic center into a tetrahydro-β-carboline have two stereogenic centers using a modified Pictet-Spengler reaction is disclosed. The method provides a desired cis- or trans-isomer in high yield and purity, and in short processes times.
1. A method of preparing a compound having a structural formula:
comprising the steps of:
(a) esterifying D-tryptophan in methanol and thionyl chloride to provide D-tryptophan methyl ester hydrochloride;
(b) reacting the D-tryptophan methyl ester hydrochloride with piperonal in refluxing isopropyl alcohol to provide cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester;
(c) reacting the product of step (b) with chloroacetyl chloride and triethylamine to provide (6R, 12aR)-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxyphenyl)-pyrazino-[2′,1 ′:6,1]pyrido[3,4-b]indole-1 ,4′dione
(d) reacting the product of step (c) with methylamine to provide the compound.
2. The method of claim 1 wherein step (d) is performed in tetrahydrofuran, and wherein the tetrahydrofuran is removed and replaced with an alcohol for isolation and purification of the compound.
3. The method of claim 1 wherein the compound is purified by recrystallization from glacial acetic acid.
4. The method of claim 2 wherein the compound is purified by recrystallization from glacial acetic acid.
5. The method of claim 1 wherein the cis-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester of step (b) is isolated in greater than 90% yield.