Process for synthesis of chiral 3-substituted tetrahydroquinoline derivatives

摘要

The present invention relates to novel and concise process for the construction of chiral 3-substituted tetrahyroquinoline derivatives based on proline catalyzed asymmetric α-functionalization of aldehyde, followed by in situ reductive cyclization of nitro group under catalytic hydrogenation condition with high optical purities. Further the invention relates to conversion of derived chiral 3-substituted tetrahydroquinoline derivatives into therapeutic agents namely (−)-sumanirole (96% ee) and 1-[(S)-3-(di-methylamino)-3,4-dihydro-6,7-dimethoxy-quinolin-1(2H)-yl]propanone[(S)-903] (92% ee).

主权项

1. A process for the synthesis of a chiral 3-substituted tetrahydroquinoline of general formula 2 from a 4,5 disubstituted o-nitrohydrocinnamaldehyde of general formula 1 with high enantioselectivity (99%) wherein, R and R1 are independently hydrogen, hydroxyl, (C1-C6) alkyl, halogen, aryl, alkylaryl, (C1-C6) alkoxy, t-Butyldiphenylsilyl ether (OTBDPS), Methoxymethyl ether (O-MOM), Tosyl, Benzyl, t-Butyl carbamate (Boc) or R and R1 together form a —O—CH2—O— linkage; and X is selected from —OH or disubstituted hydrazine-1,2-dicarboxylate of formula (—N—CO2R2—NH—CO2R2); wherein R2 is selected from the group consisting of branched or unbranched (C1-C6) alkyl, wherein said process comprises α-functionalizing of aldehyde by stirring the 4,5 disubstituted o-nitrohydrocinnamaldehyde, a polar aprotic organic solvent, and nitrosobenzene or dialkyl azodicarboxylate in presence of D or L proline at a temperature ranging between −20 to 30° C. for a period ranging between 10 min to 4 hrs, followed by in situ intramolecular reductive cyclization of α-functionalized aldehyde by stirring in presence of 10% Pd/C/H2, (1 atm) and an organic solvent at a temperature ranging between 20° to 30° C. for a period ranging between 6 to 12 h to obtain the chiral 3-substituted tetrahydroquinoline.