Modified pictet-spengler reaction and products prepared therefrom

Abstract

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 - 15 . (canceled) 
     
     
         16 . A method of preparing a compound having a formula 
       
         
           
           
               
               
           
         
         wherein R 1  represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan, and pyridine, or an optionally substituted bicyclic ring 
       
       
         
           
           
               
               
           
         
         attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur, and nitrogen; and R 3  represents hydrogen or C 1-6 alkyl, comprising the steps of: 
         (a) providing a desired diastereomer of a tetrahydro-β-carboline having a formula 
       
       
         
           
           
               
               
           
         
         (1) by providing a tryptophan esterified using an alcohol having a formula R 2 OH: and 
         (2) reacting the tryptophan ester of step (1) with an aldehyde having a formula R 1 CHO to provide the desired diastereomer and an undesired diastereomer of the tetrahydro-β-carboline, wherein the reaction is performed in a solvent in which the desired diastereomer is insoluble and the undesired diastereomer is soluble; 
         (b) reacting the tetrahydro-β-carboline of (a) with chloroacetyl chloride to provide an N-substituted tetrahydro-β-carboline; and 
         (c) reacting the N-substituted tetrahydro-β-carboline with an amine having a structure R 3 NH 2 , wherein R 3  is C 1-6 alkyl or hydro, to provide the compound. 
       
     
     
         17 . The method of  claim 16  wherein the amine is selected from the group consisting of ammonia, methylamine, ethylamine, propylamine, isopropylamine, butyl amine, and sec-butyl amine. 
     
     
         18 . The method of  claim 16  wherein the amine is methylamine. 
     
     
         19 . The method of  claim 16  wherein the compound has a structure 
       
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 19  wherein R 3  is methyl. 
     
     
         21 . The method of  claim 19  wherein the compound is purified by recrystallization from glacial acetic acid. 
     
     
         22 . The method of  claim 16  wherein step (c) is performed in tetrahydrofuran, and wherein the tetrahydrofuran is removed and replaced with an alcohol for isolation and purification of the compound. 
     
     
         23 . (canceled)