Quinagolide is a
racemate composed of the following two enantiomers:
Synthesis The first synthesis of quinagolide was disclosed in patents filed by
Sandoz. : A sequence of nine steps is required to transform the starting material 5-methoxy-2-tetralone (1) into the octahydrobenzo[g]quinoline ring system with the correct
stereochemistry required. This intermediate (11) is then converted in another five steps to the drug. Transformation of the
ester (13) into the
amine (15) is accomplished by a
Curtius rearrangement in which an
acyl hydrazide is treated with
nitrosyl chloride. :
Manufacture The laboratory route was not practical for the synthesis of quinagoline on a large scale. Therefore scientists at
Novartis developed an improved process. : The starting material is 1,6-dimethoxynaphthalene (1). This is selectively
lithiated at the C-7 position and reacts with (2Z)-ethyl 2-cyano-3-ethoxyacrylate (2), to give the cyanoacrylate (3).
Catalytic hydrogenation and
hydrolysis produces (5).
Birch reduction of (5) leads first to (6) which on acid work-up gives the
imine (7), which is reduced with
sodium borohydride to yield (8).
Fischer esterification with methanol gives an ester that is next
alkylated with
1-iodopropane to give (11). The required stereochemistry for quinagoline is set in the final steps. ==See also==